ESF Networking program DRUGS
Preprint No. 1
Papers presented, 16th – 18th June 2009
At the conference
Circulation of Antibiotics:
Journeys of Drug Standards, 1930-1970
Centro de Ciencias Humanas y Sociales
Consejo Superior de Investigaciones Científicas (CSIC)
Madrid, SPAIN
Edited by
Ana Romero
Christoph Gradmann
Maria Santemases
Madrid and Oslo, 2nd ed., June 2011
Contents
Christoph Gradmann
Exploring the „Therapeutic Biology of the Parasite‟ Antibiotic Resistance and Experimental
Pharmacology 1900 – 1940 ............................................................................................................ 5
Robert Bud
Innovators, deep fermentation and antibiotics: Promoting applied science before and after WW2
........................................................................................................................................................ 7
Marlene Burns
Wartime Research to Post-War Production: Bacinol, Dutch Penicillin, 1940-1950 ...................... 9
Mauro Capocci
A Chain is Gonna Come Building a penicillin production plant in post-war Italy ....................... 33
Ulrike Thoms
Travelling back and forth. Antibiotics in the clinic, stable and food industry in Germany in the
1950s and 60s ............................................................................................................................... 35
María Jesús Santesmases
An antibiotic screening programme: In search of antagonism in the 1950s ................................. 76
María-Isabel Porras-Gallo
The place of serums and antibiotics in the influenza pandemic of 1918-1919 and 1957-58
respectively................................................................................................................................... 77
Viviane Quirke
„From antibiotics to cancer chemotherapy (1950s-1980s): the transformation of Rhône-Poulenc
in the era of biomedicine‟ ............................................................................................................. 97
Scott H. Podolsky
From Antiserum to Antibiotics: Antimicrobials, Controlled Trials and Limits to the
Standardization of Therapeutic Practice in America, 1930-1970” ............................................. 111
Robert Kirk; Flurin Condrau
Negotiating Hospital Infections: The Debate between Ecological Balance and Eradication
Strategies in British Hospitals, 1947-1969 ................................................................................. 147
Ana Romero de Pablos
Penicillin patents in Spain .......................................................................................................... 149
Sébastien Janiki; Marina Sellal
Standardization in antibiotherapy: how and why? The case of aminoglycoside dosages. .......... 151
Exploring the „Therapeutic Biology of the Parasite‟
Antibiotic Resistance and Experimental Pharmacology 1900 –
1940
Christoph Gradmann
Universitetet i Oslo
Seksjon for medisinsk antropologi og medisinsk historie
[email protected]
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
Innovators, deep fermentation and antibiotics: Promoting applied
science before and after WW2
Robert Bud
Science Museum
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
Wartime Research to Post-War Production: Bacinol, Dutch Penicillin,
1940-1950
Marlene Burns, PhD.
By the end of 1946, the Dutch Company, Nederlandsche Gist- en Spiritusfabriek (Netherlands
Yeast- and Spirits Factory; NG&SF) was supplying all the penicillin needed by Dutch
hospitals. By 1948, NG&SF was able to supply all the penicillin requirements for the whole
of the Netherlands and, in 1949, NG&SF started exporting penicillin. Fifty years after the end
of the Second World War, Gist Brocades, as NG&SF had become 1, was one of the world‟s
largest producers of bulk penicillin.
Considering that for most of the Second World War, from 10 May 1940 until 5 May 1945, the
Netherlands had been occupied by Nazi Germany and, in effect, cut off from the outside
world for almost exactly five years, how was this possible? How could a yeast fermentation
plant in Delft meet the standard set by the USA and the UK for the production of penicillin so
soon after the end of the war?
That this was so, is seen from a meeting in November 1946 between Alexander Fleming and
the Dutch Professor Albert Jan Kluyver. At the time Kluyver was Professor of Microbiology
at Delft‟s Technische Hoogeschool (Technical Highschool, TH).2 Both were in Paris for the
50th anniversary of the death of Louis Pasteur. Giving Fleming a sample of NG&SF‟s
penicillin, Kluyver asked Fleming if he would have it analysed. Fleming took the sample to
Glaxo Laboratories. In December 1946, Fleming reported back to Kluyver that both chemical
and microbiological analysis had shown that “this penicillin is at least as good as most
penicillin either here (UK) or in America”.3 How was this possible?
1
2
3
In 1968 the Nederlandsche Gist- en Spiritusfabriek merged with Brocades, Stheeman & Pharmacia to
become Gist Brocades.
Now Technical University Delft, TUD.
Kluyver Archive (KA), Catalogue 1990091, Folder 2, Letters D-H.
10
It is known that many groups in many countries had a wartime interest in the development of
penicillin. However, at the end of the war, for most, penicillin was either imported or made
under British/American licence. In the post-war market, NG&SF achieved independent
success with their own penicillin brand, a brand that met both British and American penicillin
standards. What accounts for the difference between the failure of others and the success of
those in Delft? How, in the face of incredible post-war hardship, could those in Delft consider
financing the research, development and production of a Dutch penicillin?
In order to answer these questions, I will focus firstly on the experiences of NG&SF under
Occupation during World War II. I will then introduce the wartime research of the „Delft
Team‟ and, before my concluding remarks, I will detail steps taken to take NG&SF‟s
penicillin, Bacinol, from wartime research to post-war production.
Pre-War Position.
To begin with, some information on the pre-war status of NG&SF is necessary. In contrast to
the general depression of the 1930s, NG&SF was buoyant. For them, 1920-1940 had been a
period of expansion with subsidiary companies established in Bruges, Belgium, Monheim,
Germany, Lisbon in Portugal and London, UK. They were the market leader with their
baker‟s yeasts, Koningsgist and Engedura, Other products included butanol, acetone, and
ether. During these years too, NG&SF‟s Research Department was expanded and
strengthened with a well-trained staff of biochemists and microbiologists most of whom were
recruited directly from Prof. Kluyver‟s Microbiology Department in Delft‟s TH.4 In short,
NG&SF and its employees were the accepted authority in the fermentation field.
Wartime Experience.
Under the occupation NG&SF‟s reputation allowed them to stay open. They were required in
the production of yeast, and yeast was necessary for a staple food – bread. Workers were
given „essential worker‟ status, and, as fermentation was a round the clock process, workers
4
M. Burns, „The Development of Penicillin in The Netherlands 1940-1950: The Pivotal Role of NV
Nederlandsche Gist- en Spiritusfabriek, Delft‟, PhD (History) Thesis, University of Sheffield, Sheffield,
11
came and went even during curfew. Although it must be said that most lived in the „Agneta
Park‟, a company-owned area specifically for workers‟ homes, bordering the company
grounds.
As the war progressed, however, production was reduced. The Delft headquarters was cut off
from its daughter companies, which restricted sales. Raw materials also became severely
rationed and were obtainable only through Dutch Government agencies, Rijksbureaus. As a
result, NG&SF‟s market stagnated.
Ultimately, though, this lack of materials stimulated new research and development. In a joint
project with Shell and Chemische Fabriek Naarden, NG&SF worked on the production of
vitamin C to supplement the increasingly poor Dutch diet. Vitamin shortages also drove
research with yeast-derived vitamin B and into the development of food enhancers, Gistex and
Aromex.5 With this „new‟ research came new technical skills and processes which the Deputy
Director in charge of the Delft plant, F.G. Waller, Jnr., said: “Would stand us in good stead in
the production of penicillin”.6
5
6
England, UK, September 2005, 109-112. This thesis forms the base of all the research contained in this
publication.
Ibid.
F.G. Waller Jnr., De Fabrieksbode (Factory Newsletter),15 October 1960, 269.
12
F.G.Waller Jnr
Penicillin at Delft.
“When we first started looking, in 1943, only one publication was available, that of Fleming
1929. It was on that basis we started our research”.7
Which raises the question: What happened in 1943 to stimulate the interest of Waller and his
colleagues in penicillin?
To this day, this question remains debatable. Did it have to do with news of Allied success in
North Africa during which penicillin, the „wonder‟ drug, had made such an impact on the
recovery and survival of the Allied war wounded? Did those at Delft hear of penicillin
through clandestine radio programmes, Allied propaganda material or the Dutch press? My
research in the BBC archive has shown no radio broadcast about penicillin that could be
picked up in the Netherlands at that time. Although it must be noted that the BBC did not
archive BBC news items. Neither does the Dutch Radio Oranje service based in London make
any mention of penicillin. In the case of Allied propaganda material dropped over the
13
Netherlands, the first reports on penicillin found are contained in the magazine De
Wervelwind (The Whirlwind) dated April 1944. In Dutch newspapers, too, it is well into
1944, August, before penicillin is mentioned. All dates well outside Waller‟s statement and,
as will be shown, well outside NG&SF‟s first research with penicillin moulds.
A.J. Kluyver
Kluyver Archive, (KA).
If, however, we turn to the archive of Albert Jan Kluyver a different strand appears. Albert
Jan Kluyver was Professor of Microbiology at TH Delft from 1921. Under his leadership
comparisons between various yeast cultures had led to one of the subjects for which he is
most famous, namely comparative biochemistry. In the wider academic world Kluyver‟s
knowledge and ability in the field of microbiology had earned him an esteemed reputation
both in and outside the Netherlands. For example, at the Second International Congress for
Microbiology in London in July 1936 Kluyver took his place beside Alexander Fleming,
Harold Raistrick and Selman Waksman. He also actively emphasised the industrial usefulness
of his Department‟s research within the Netherlands and was advisor to many Dutch
companies. His relationship as advisor to NG&SF had started in 1933. F.G. Waller was one of
his former pupils.
7
Ibid.
14
Kluyver‟s archive introduces a key to the „knowledge base‟ of antibacterial substances held in
Delft before and during the war years in correspondence with a former pupil, Johannes
Hoogerheide, who in 1940 was employed in biochemical research at the Franklin Institute,
Newark, Delaware. In a letter dated 15 April 1940, Hoogerheide told Kluyver that he had
cultivated a substance that inhibited capsule forming similar to Dubos, a close associate of
Waksman. There was great excitement about it in the press as it was seen as a potent antibacterial substance. Almost a year later, on 24 March 1941, Hoogerheide wrote about his
substance, which he had called H1, and said that it had been used in various hospitals for the
treatment of badly infected wounds and the results were „more than pleasing‟. Kluyver replied
on 17July 1941 saying he was very interested in Hoogerheide‟s work, lamenting that because
of the war and the occupation he did not have access to any American journals and had to
make do with reprints. Hoogerheide‟s reply on 14 October 1941 told Kluyver of his move to
the Squibb Institute in New Brunswick, New Jersey where he would be close to Waksman‟s
laboratory. His task at Squibb was to produce larger quantities of H1. He also had to obtain
other bacterial extracts of fungi and for this research he quoted „Fleming, 1929‟.8
The correspondence between Hoogerheide and Kluyver stops at this point. In December 1941,
following the Japanese attack on Pearl Harbor, the United States entered the war. Germany in
turn declared war on the US. It would be October 1945 before Hoogerheide and Kluyver
could correspond again. What these few letters illustrate, however, is that up to October 1941,
Kluyver, through a former pupil, had an active and informed interest in the antibacterial
properties of both soil and fungal cultures. If he did, so too would his associates at Delft and
his former pupils at NG&SF. The „knowledge-base‟ and expertise for the development of
penicillin at NG&SF, therefore, is evident.
Starting Position.
Bearing in mind the severe restrictions of the occupation and ensuing lack of availability of
academic publications, the NG&SF R&D Reports about the first research into penicillin allow
us to see the scientific publications available to NG&SF researchers. The first is Report 412,
8
KA, Catalogue 1990083, Folder 3, Letters H to Z.
15
dated March-June 1944. The author is A.P. Struyk, one of NG&SF‟s 1930s academic intake
and a graduate of Kluyver‟s Microbiology Department.
A.P. Struyk
Struyk‟s original report refers only to journals and page numbers; research in Chemical
Abstracts has produced specific article titles. These are:
Fleming, A., „On the Antibacterial Action of Cultures of a Penicillium with Special Reference
to Their Use in the Isolation of B. influenzae’, British Journal of Experimental Pathology, 10,
(1929), 226─36.
Clutterbuck, P. W., Lovell, R. and Raistrick, H., „The Formation from Glucose by Members
of the Penicillium chrysogenum Series of a Pigment, an Alkali-Soluble Protein and Penicillin
─ the Antibacterial Substance of Fleming, Biochemical Journal, 26, (1932), 1907─18.
Waksman, S. A., „Antagonistic Interrelationships among Microorganisms‟, Chronica
Botanica, 6, (30 December 1940), pp.145─8.9
9
M. Burns, „Scientific Research in the Second World War; The case for Bacinol, Dutch penicillin‟, Chapter 3
in A. Maas and H. Hooijmaijers, eds., Scientific Research in World War II. What scientists did in the war,
(Abingdon, Oxon, and New York: Routledge, 2009), pp44-61.
16
The above publications make up only half of Struyk‟s sources, and it is from the others on
Struyk‟s list that we can begin to glean the existence of dissemination of information
concerning penicillin during the war years. The three other sources are:
Vonkennel, J., Kimmig, J. und Lembke, A., „Die Mycoine, eine Neue Gruppe Therapeutisch
Wirksamer Substanzen aus Pilzen‟, (The Mycoins, a New Group of Therapeutically Active
Substances from Fungi), Klinische Wochenschrift, 22, 16─17, (17 April, 1943), 321.
Kiese, M., „Chemotherapie mit Antibakteriellen Stoffen aus Niederen Pilzen und Bakterien‟,
(Chemotherapy with Antibacterial Substances from Moulds and Bacteria), Klinische
Wochenschrift, 22, 32─33, (7 August 1943), 505─11.
Penau, H., Levaditi, C., et G. Hagemann, G., „Essais d‟Extraction d‟une Substance
Bactéricide d‟Origine Fungique‟, (Attempts to Extract a Bacterial Substance of Fungal
Origin), Bulletin de la Société de Chimie Biologique, 25, (1943), 406-410.10
All of the above articles were published in 1943. All illustrate a widening, albeit small, circle
of research into mould-based, penicillin-like, antibacterial substances in Germany and
occupied France. In particular, Kiese listed in his publication a very impressive 61 references
on penicillin and antibacterial substances that had been published between 1923 and 1943.
His publication also covered the research by Florey‟s unit at Oxford in detail.
But Struyk‟s sources raise yet another question: How did Struyk, a microbiologist at a yeast
factory in occupied Delft, obtain these foreign academic publications? Struyk‟s report does
not list the source of his material. However, the Kluyver Archive contains photocopies of all
of Struyk‟s source material. All bear the stamp of Bibliotheek D.B.M. (Library D.B.M.).
Research has shown this to be the stamp of NG&SF‟s Library Service in Delft with its
subsidiary companies in Bruges and Monheim.11 It would appear, therefore, that the basis for
Struyk‟s research came innocently enough through NG&SF‟s own inter-library loan system.
Strain Selection.
10
11
Ibid.
Personal Communication, February 2003, Dr. Jan de Vlines, Director R&D Gist Brocades, retired.
17
R&D Report 412, March–June 1944, lets us see Struyk‟s strain selection. According to
Struyk, he received twenty-one fungal strains from the Centraalbureau voor Schimmelcultures
(CBS: National Collection of Fungal Cultures) in Baarn, near Utrecht. These consisted of
eighteen Penicillium strains and three Aspergillus. To this Struyk added two fungal strains
that had been found on old cacao powder.
Research in the archive of the CBS has shown that the then director of CBS, Professor
Johanna Westerdijk, did not supply Struyk‟s twenty-one strains en bloc. She did so over a
period of five months. Also, Westerdijk‟s contact with NG&SF was through the Yeast
Division staff member, Johannes Rombouts. Correspondence between Westerdijk and
Rombouts began on 19 January 1944 with the delivery from CBS to NG&SF of twelve
moulds. On 24 February 1944, Rombouts thanked Westerdijk and said that if she heard of
other moulds producing a „good bacteriostatic substance‟ he would be pleased to receive
them. More strains followed on 15, 16 and 21 March; 1 April; and 15 and 24 May 1944.12
Struyk‟s research, therefore, was not limited to one experiment; from Rombouts‟s contact
with Westerdijk it appears that Struyk‟s research was an ongoing process.
Strain Evaluation.
Report 412 goes on to illustrate the methodology Struyk followed to evaluate the strength of
any antibacterial substance produced by his twenty-one Penicillium strains. Using an agar
block test and Micrococcus aureus (Rosenbach), an old name for Staphylococcus aureus,
which he had obtained from Kluyver‟s laboratory, he developed a „zone of inhibition‟. From
this „zone‟ the activity of the strains could be compared. To monitor differences he created a
„Delft Unit‟ with which to define any antibacterial activity. By so doing, Struyk‟s followed
Fleming‟s initial work.
Seven of Struyk‟s experimental strains produced an antibacterial substance. The mould
culture with the highest yield and the one chosen for further study was sixth on Struyk‟s list,
P6: Penicillium baculatum Westling. Struyk named this substance Bacinol.
12
CBS Archive, 1944, Correspondence File, Nos. 516, 511, 513, 514, 515.
18
Further research with Bacinol is noted in Struyk‟s following reports, numbered 413 and 414.
These R&D reports reflect research with Bacinol during the period March─June 1944. For
example, Report 413 illustrates that if Penicillium baculatum was allowed to grow on
NG&SF‟s own Liquitex base for five days at a constant temperature of 26°C and shaken once
a day, the results appeared to be identical to those reported by Fleming using a bouillon mash
and Penicillium notatum. Also, the substance produced by P6 was soluble in acetone and
alcohol, which facilitated extraction from the growth mash, and, when mixed with water, its
properties were resistant to boiling. Bacinol, therefore, had the same antibacterial and physical
properties as Fleming‟s penicillin. He could not be sure, however, whether or not Bacinol,
from Penicillium baculatum, was the same as the „wonder drug‟ Penicillin from Penicillium
notatum.
In all, Struyk‟s R&D Reports 412, 413 and 414 total twenty-eight pages. They are bundled
together as one report. It is not marked „secret‟. The office stamp shows that it was ready for
circulation on 29 July 1944. The recipients are noted as F. G. Waller Jnr, A. A. Stheeman and
J. R. Rombouts.
A. Querido
‘Chance’.
The influence of „chance‟ in the development of Dutch penicillin is seen through the
experience of Andries Querido. In 1939 Querido returned to Amsterdam from his postgraduate research at the Pasteur Institute in Paris. On the recommendation of Kluyver he was
employed by NG&SF as a part-time advisor. In January 1943, however, his Jewish
background meant his internment in Barneveld Camp. In September 1943 he was moved to
19
Westerbork Camp and, in September 1944, transported to Theresienstadt in Czechoslovakia.
Before this, however, as an employee of NG&SF he had „Required Worker‟ status and was
allowed to visit the Delft factory, albeit on an irregular basis. On what was to be his last visit
to Delft, Querido met a fellow Jewish doctor, S. van Creveld, in Amsterdam‟s Central Station.
Van Creveld was Professor of Paediatrics in Amsterdam and he told Querido that he had just
had a visit from a colleague from neutral Portugal. That colleague had brought with him a
copy of the latest Schweizerische Medizinische Wochenschrift (Swiss Medical Journal) and
that the whole publication was given over to the subject of penicillin. Querido asked if he
could borrow it and took it to Delft.13
Critically for those at Delft this issue of the Swiss Medical Journal, dated June 1944,
contained an article by A. Wettstein. Simply entitled „Penicillin‟, it clearly showed the results
the Allies had achieved in the development and production of penicillin. For example,
Wettstein gave details of penicillin growth on a maize extract; of the scale-up of penicillin
production in bottles and porcelain containers; the measurement of strength by the Oxford
unit; a dilution method; physical and chemical properties; human studies; animal studies; and
it named bacteria known to be sensitive or insensitive to penicillin. At NG&SF this
information proved invaluable. The entire Journal was photocopied and circulated at least
thirteen times. The Kluyver Archive holds „Photocopie nr. 13 (Photocopy number 13), there
may have been more. On the protective cover is stamped „Bibliotheek D.B.M.‟, which shows
us that the copies were made and distributed through NG&SF‟s library service.
This issue of the Swiss Medical Journal also serves to illustrate the ongoing dissemination of
information about penicillin during the war years. Written only a year after Kiese‟s German
publication, which had been based on 61 sources of reference, Wettstein, in neutral
Switzerland, could cite 159 sources. At a time of embargo, the jump is enormous.
Increasing Production.
From July 1944 Rombouts, with his assistant Ans Addison, tested Bacinol for toxicity in
Staphylococcus aureus-infected rabbits and mice. Struyk also continued his research. To
13
Personal Communication, Prof. Andries Querido, December 1999.
20
enhance the growth of Bacinol, he tried various types of flat glass and enamel containers. In
the end, he chose milk bottles.
Klaas Scheurkogel described the scene. The milk bottles were kept for 10─12 days at a
temperature of 25°C. After processing the fluid produced, the result was fairly crude
penicillin. Sometimes the surface culture became contaminated, which made the content of
the bottle unusable. This had to be disposed of and the process started again. From time to
time such „calamities‟ seemed insurmountable but the Delft researchers kept going. By
August 1944 they had a small amount of a gold-brown substance, which, according to
Scheurkogel, had „all the desired properties‟.14
Waller confirms this:
By around Dolle Dinsdag we had a small amount of a substance, which we hoped, and later to
our joy proved to be penicillin.15
Dolle Dinsdag refers to Tuesday, 5 September 1944, when the BBC erroneously reported the
Allies had broken through in the South of the Netherlands. The Dutch in euphoria lined the
streets to welcome their liberators. In fact, the Battle for Arnhem failed. The south of the
country was liberated but the northern and western provinces remained firmly under Nazi
control. Ultimately, those caught in the west were to face the devastation of the hongerwinter,
Hunger Winter.
The „Hunger Winter‟ did not mean that there was no food. Little though it was, some food
was available. In retaliation for the Dutch workers‟ railway strike, an attempt to help the
Allied cause at Arnhem, the occupier refused to permit the transport of food supplies to the
west. In the face of one of the coldest and bitterest of winters, the Dutch population was left to
flounder. A situation that Kluyver describes as: „a well organised famine‟.
Continuing Research.
14
15
K. Scheurkogel, „Technische Bereiding van Penicilline‟, Chemische Weekblad, 45, 29 January 1949, 69-72.
F.G. Waller, 269.
21
However, during those dark days of the winter of 1944─45 work continued with Bacinol.
Between July 1944 and March 1945 Reports 847─904 show that A.A. Stheeman, with his
assistants J. Knotnerus and G.T. Mathu, continued to improve penicillin extraction methods
from the broth culture. Also, in Report 243 of April─May 1945, Stheeman signalled the
differing levels of success in the search for an improved „mash‟ with which to „feed‟ Bacinol
by growing Penicillium baculatum on sugars, beet pulps and grain mixes. His conclusion was
that the most successful was quite simply „grain mash‟.
Penicillin and Liberation.
Officially, it was to be 5 May 1945 before liberation came to the west of the Netherlands.
Before this, however, an agreement was reached between the occupier and the Allies, which
allowed food to be dropped by British and American bombers to the beleaguered Dutch. The
British started these drops on 28 April 1945 at the airfields of Ypenburg (Delft), Duindigt
(The Hague), Valkenburg (Leiden) and Waalhaven (Rotterdam). Wider drops came with
American help and the contents dropped were distributed by the Dutch themselves.
Until now, most sources relating the history of NG&SF penicillin claim that American
penicillin was included in the food dropped at Ypenburg, Delft. Some say that a Delft doctor,
Evert Verschuyl, took „dropped‟ penicillin to NG&SF against which they compared their own
antibacterial substance. Others simply report that American penicillin was part of the food
drop.
It is difficult to see why the Allies would have dropped penicillin. At the time, penicillin was
restricted to military use only. There was no surplus. Added to that, Dutch doctors had no
experience with penicillin as a medical treatment. They did not know its properties or how to
use it. At the time, penicillin could only be administered by intramuscular or intravenous
injection. In powdered form it had to be mixed with sterile water before an injection could be
given. Injections had to be sustained on a twenty-four-hour basis. Finally, many of the
containers crashed open on landing, the contents spilling out over the drop area. How could it
have been possible for the new „wonder drug‟ to be part of any food drops, let alone only at
Delft?
22
Bacinol: Dutch Penicillin.
Nevertheless, at the end of the war American penicillin did reach Delft. In Reports 244─246
for June─July 1945, Stheeman gives the result of an analysis with a sample of American
penicillin made by Chas Pfizer & Co and supplied by Upjohn of Kalamazoo. His source is not
noted but his conclusion is that Bacinol and „this‟ penicillin are the same. In July 1945,
therefore, barely two months after liberation, the Delft Team knew they were in possession of
an antibacterial substance similar to the penicillin being mass-produced in the United States.
First Clinical Application.
In November 1945, the recovery of Maria Geene, a patient of Dr. Evert Verschuyl in Delft‟s
Bethel Hospital, signalled the successful development of NG&SF‟s penicillin. Aged twentyone, Maria had been admitted to the Bethel hospital on 26 October 1945. She was critically ill
with a staphylococcal infection. She was treated with sulphonamide to no effect and her
temperature remained high at 39─40°C. On 15 November 1945 she received an intravenous
injection of 50,000 units of Bacinol. Her temperature returned to normal and she was
discharged on 29 November 1945. Her complete recovery had taken only fourteen days.16
However, she was not the only patient to receive treatment with NG&SF penicillin at that
time. Another young woman, who, like Maria Geene was dying of septicaemia, was treated
with Bacinol. While her identity remains unknown, it is known that she was eighteen years
old and was admitted to the Bethel on 26 November 1945. Her temperature was 40─41°C. On
that day she received 50,000 units of NG&SF penicillin. Intravenous injections continued on
27 and 28 November with 100,000 and 150,000 units, respectively. Her infection cleared and
her temperature returned to normal. She was discharged on 14 December 1945. Her recovery
had taken just nineteen days.17
16
17
Personal Communication, Dr. Bob Griffieon, Delft; Temperature Charts, November 1945 contained in H.L.
Houtzager and M.A. Verschuyl, „Delfts pionierswerk: de fabricage en klinische toepassing van penicilline‟,
Medisch journal Delft, 4, (December 1995), p.194.
Ibid.
Dutch Penicillin 1945-46.
In 1945, the US and the UK, as stated earlier, were producing as much penicillin as possible
but it was not enough to meet the demand. In war-torn Europe, when penicillin arrived it was
either as an import or made under licence.
At the end of the war the Dutch Health Care system had a shortage of everything.
Nonetheless, in October 1945 a Dutch Government committee was established to look into
research on „Penicillin and other antibiotic medicines‟. The points under consideration were:
should penicillin be imported; should the Dutch Government take on the responsibility of
making penicillin; or, should it be produced by private enterprise? In the end there was no
clear proposal apart from the decision that any penicillin produced in the Netherlands should
be under the control of the National Institute for Public Health.1
The Commission for Antibiotic Medicines was established in January 1946. A report on
penicillin production in America and Canada led the Commission to the view that while there
should be State involvement in the production of penicillin in the Netherlands, because of
costs, the better option was a compact of State, academics and private enterprise. However,
should such a compact take place, the development of Dutch penicillin should be overseen by
the State but not funded by the State. The emphasis was on „Big Science‟ and „Teamwork‟.2
As we have seen, at the end of the war, those at NG&SF knew they could produce penicillin
equal in quality to that of the American and British companies. There was no need to wait.
They had their own penicillin strain, Penicillium baculatum, their own research and
development team, and they had developed their own production techniques. Waller and his
team may have had a passion for research but they also had „a will to succeed‟ in the post-war
production of penicillin.
1
2
Personal Communication, Dr. A.J. de Neeling, Bilthoven, November 2003; Rijks Instituut voor de
Volksgezondheid (RIV) Report U.317/45, October 1945.
RIV Report, Commissie inzake antibiotische geneesmiddelen (Commission for Antibiotic Medicines), Report
10 January 1946.
Scale-up.
In August 1946, NG&SF penicillin produced on an industrial scale arrived on the Dutch
market. Before this could happen, though, more immediate developments in the large-scale
production of Bacinol had to be addressed.
For this, the Delft Team went back to their advisor and mentor, Kluyver. The influence of
Kluyver in the scaling-up of Penicillin/Bacinol from a laboratory bench to an industrial level
is plain to see. During the 1930s Kluyver had published on a new concept, deep fermentation
technology. Just as the concept of deep fermentation technology had increased the production
of penicillin during the war at NRRL in the US, in the early post-war years it also influenced
his former students at NG&SF.
Large-scale production of penicillin at NG&SF was successfully started on 15 May 1946
when the first industrial fermentation took place in a 1.5 hectolitre Ensinkketel (Ensink tank).
Upscaling to 15, 60 and 300-hectolitre fermentation tanks soon followed, an incredible rate of
expansion. 1
In order to achieve this, a new group of workers was established expressly for the large-scale
fermentation of penicillin. A group of young men, they quickly acquired the title „Penicillin
Experts‟. H. de Horn, another of the first NG&SF employees to be included in the scale-up of
NG&SF‟s penicillin, paints the scene: „We had to think on our feet. We had to solve problems
as we went along‟.2
But the team had more to learn. For example, they learned how to deal with the sensitivity of
penicillin to impurities. A method was developed called „double steam sealing‟ whereby the
contents of the tanks had to go through not just one but two steam-filled „dips‟ in the
extraction pipe. The theory behind this was that impurities might be able to filter through one
steam „dip‟ but not a second. The breakthrough freeze-drying techniques came from the
Blood Transfusion Service in Amsterdam. Finally, at a time when the whole of the
1
2
Personal Communication, Jan van den Berg, 20 April 2005.
Personal Communication, H. de Horn, November/December 1999; De Fabrieksbode, 29 September 1978 and
2 May 1995.
25
Netherlands was in need of reconstruction, in 1947 Waller purchased the Leidse Machine
Fabriek which he renamed Leidsche Apparaten Fabriek (LAF). Critically for NG&SF, the
LAF had a fifty-man workforce expert in the production of metal tanks. In its first year of
production the LAF met 75% of NG&SF‟s new apparatus requirements.3
In contrast to the Dutch State idea of the production of Dutch penicillin resulting from
„Teamwork‟ and „Big Science‟, overseen by the State but not funded by the State, what in fact
happened was Waller‟s drive to produce penicillin. NG&SF brought Dutch penicillin onto the
market as a completely private enterprise.
Running parallel with the advances on the technical side of penicillin production, in January
1946, NG&SF established an Antibiotics Department. The first coordinator was Klaas
Scheurkogel. Shortly afterwards, R. A. Jellema was appointed head of the first NG&SF
Penicillin Department. Together, their duty was to establish contact with the Dutch medical
world and to promote the use of NG&SF penicillin.
In 1946, as has been shown, penicillin in the Netherlands was rationed as the Government
grappled with the cost of importing it. A voucher system for the distribution of penicillin was
introduced and, in August 1946, NG&SF penicillin received the remit to supply seven
hospitals. These were the Academic Hospitals of Leiden, Utrecht and Groningen; Johannes de
Deo, The Hague; Wilhelmina Gasthuis, Amsterdam; St Jacobus Stichting, Wassenaar; and De
Gemeente Apotheek, The Hague.4 Further, it was agreed that as the production of NG&SF
penicillin increased, so the allocation system would increase to meet NG&SF‟s capacity.
Information Base.
On the medical side, the Medical Brains Trust was formed. This Trust, chaired by Kluyver,
consisted of Querido, Jacob Mulder and Willem Goslings from Leiden‟s Academic hospital,
3
4
Over en Weer, July 1968, 1, pp18-19; Personal Communication P. Fritz., February 2000.
GB Archive, NG&SF Monthly Reports November 1946-January 1947.
26
L. E. den Dooren de Jong, a bacteriologist from Delft‟s TH, and, as and when necessary,
Waller and his staff.5
The Medical Brains Trust published Digesta Antibiotica, an academic publication given over
completely to the „wonder drug‟ penicillin. Using the most up-to-date material now available
from both Britain and the US they wrote articles explaining the manner in which the by now
various forms of penicillin could and should be administered. The editorial team ─ Querido,
Mulder and Goslings ─ also answered questions about penicillin and its use.6
However, in the standardisation of the use of penicillin, where did this information come
from?
Standardisation.
The Kluyver Archive lets us see the effect of Kluyver‟s academic network in helping to
bridge the gap caused by intellectual „isolation‟ during the occupation. At the end of the war a
virtual avalanche of information arrived at Delft from the United States. While space does not
allow extensive detail to be given here, the Kluyver Archive shows, for example, that H.A.
Barker at Berkeley had set up a „Delft Library Fund‟ during the war to purchase reprints for
Kluyver. He had them ready to send immediately the war ended. He also arranged for
academics to send reprints of material they had published during the war directly to Delft.
Similarly, from the commercial field, Merck sent their brochures for 1942, 1943, 1944 and
1945.
At the same time, as early as October 1945, NG&SF sent one of their Chemical Engineers,
C.W. Spiers, to the United States. The intention was that Spiers should gain firsthand
experience in penicillin production. He took with him a blanket letter of introduction from
Kluyver.
5
6
A. Querido, Andries Quesirdo de binnenkant van de geneeskunde, (Amsterdam: Meulenhoff, 1990), p117;
B. Elema, Opkomst, evolutie en betekenis van research gedurende honderd jarren Gistfabriek, (Delft:
Koninklijke Nederlandsche Gist- en Spiritusfabriek, 1970), p40.
Digesta Antibiotica, 1, 1947. Source: Kluyver Archive.
27
Dutch Penicillin: Standard Confirmation.
Kluyver also re-established contact with his British associates when, at the invitation of
Marjorie Stephenson, he attended the British Society for General Microbiology on 19 and 20
December 1945. This brought with it re-connection with, among others, R. St John Brookes
of the National Collection of Type Cultures.
On 1 March 1946, Kluyver wrote to St. John Bookes asking for „cultures of Staphylococcus
aureus used in the standardisation tests for Penicillin‟. On 8 March 1946 St. John Brookes‟
reply listed the strains sent as „Number 6571A (Heatley) ... the Oxford strain used for testing
penicillin‟ and „Number 6718… FDA number 219‟, which reputedly had a special advantage
in „penicillin assay work‟.7 This information would undoubtedly have been shared with
NG&SF.
Like Kluyver, Querido was quick to assist NG&SF in Waller‟s quest for up-to-date
information on penicillin and their check on penicillin standards when he went to London in
September 1945. He picked up the wartime publications that had been kept for NG&SF by
their London agent and re-established subscriptions for academic journals. Also, Querido‟s
report to Waller of 30 October 1945 indicates that he had a copy of the „British standard‟ in
his refrigerator in Leiden.8
There is no doubt, therefore, that as NG&SF increased their production of Bacinol they
continued to check and re-check their antibacterial substance against the standard being set by
their British and American counterparts. As stated earlier, in December 1946 Fleming himself
had organised an analysis of NG&SF‟s penicillin with Glaxo Laboratories at Kluyver‟s
request. The finding was that „this penicillin is at least as good as most penicillin either here
(UK) or America‟.9
By the end of 1946, NG&SF was supplying all the penicillin needed by Dutch hospitals. By
1948 Dutch penicillin met all penicillin requirements for the whole of The Netherlands. In
7
8
9
KA, Catalogue 1990090, Folder 2, Letters M-Z.
Gist Brocades Archive, F.G. Waller Jnr Archive, Correspondance Waller – Querido, 30 October 1945.
KA, Catalogue 1990091, Folder 2, Letters D-H.
28
1949, NG&SF started exporting penicillin. Fifty years from the end of the Second World War,
Gist Brocades, as NG&SF had become, was one of the world‟s largest producers of bulk
penicillin.
However, in March 2005, DSM, as Gist Brocades had become, closed down most penicillin
fermentation tanks at Delft. Almost exactly sixty years from the first large-scale production of
penicillin in Delft, „market forces‟ took the large-scale production of Dutch penicillin to India
and China.
Conclusion
Codenamed Bacinol, the secret production of penicillin at NG&SF, Delft, whilst under the
extreme conditions of Nazi occupation, did happen. It ran alongside legitimate wartime
research, the food enhancers Gistex and Aromex and a new joint venture for the development
of vitamin C with Chemische Fabriek Naarden and Shell.
The true identity of NG&SF‟s antibacterial substance remained secret because of its name.
The name Bacinol was derived from the mould strain sixth on Struyk‟s list, Penicillium
baculatum. Wartime experiments with Bacinol were adapted to suit conditions with the
growth of Bacinol on what was available, namely NG&SF‟s own fermentation mash,
Liquitex. Milk bottles were used as the container.
Yet, as in all experimental procedures, reports had to be written and, as we have seen, these
were clear and concise in methodology and observation. Consequently, while these reports
highlight the fact that some contemporary scientific journals were reaching those working at
NG&SF they also reflect a confidence when addressing the recent microbiological research
and an ability to put that research into practice. To this ability the Delft Team added their own
expertise.
In the end, the development of Dutch penicillin was a technical problem that required in-depth
knowledge of microbiology, fermentation and recovery. The Delft Team had all of that.
29
Waller was a determined, inspirational, leader. The Team was small and cohesive, with no
bureaucracy and short lines of communication.
At the same time, NG&SF had unique access to Kluyver, a world authority in the
microbiological field. All of those involved in the development of Bacinol had come through
Kluyver‟s laboratory. Querido‟s experience, though, brings the influence of „chance‟. Cut off
from the outside world by the occupation, Querido‟s delivery of the Swiss Medical Journal of
June 1944 offered the „chance‟ to compare NG&SF‟s research with what had been achieved
elsewhere.
At the end of the war, NG&SF took the massive step of adding a pharmaceutical product to its
fermentation skills. At a time when the whole of the Netherlands required reconstruction this
was a step that demanded considerable investment. Here, again, Waller‟s determination
showed through. He invested not only in plant and machinery but also expanded NG&SF
personnel and advisors.
Yet, uncertainty seemed to remain. It was with Kluyver‟s help that, at the end of the war,
Waller‟s group was introduced to the wider academic and commercial penicillin-producing
world. A world that was able to affirm and re-affirm the standard of NG&SF‟s penicillin.
Given the pre-war expertise of Waller and his NG&SF researchers there was no doubt a „local
edge‟ to the first orienteering experiments. An expertise that added to their „knowledge base‟
from Kluyver‟s laboratory at the TH. There is no doubt that, at the end of the war, this „local
edge‟ remained in place albeit supported by imported British and American know-how. At the
end of the war, after five years of occupation and isolation, the Delft Team continued the
large-scale production of their own penicillin, Bacinol, a penicillin at least as good as that
produced in Britain or United States.
The Delft Team:
Leader: F.G. Waller Jnr, NG&SF Deputy Director, Delft
Researchers: A.P. Struyk, A.A. Stheeman, J.R. Rombouts.
30
Research Assistants: Lagendijk, Knotnerus, Mathu, Spiers, Addeson
Fermentation: W.A. Verkennis, J.M. Klokgieters
Clinical Application: E. Verschuyl
Upscaling: W. Berends, H.M. de Horn, L.M. Rientsma.
Upscaling Assistants: Jongbloed, van den Berg, Elzenga, ter Horst, Kamps, Mensinga,
Mostert, Saltet, van der Zijde
Antibiotics Department: K. Scheurkogel, R.A. Jellema
Advisors: W.H. van Leeuwen, NG&SF President; H.F. Waller, NG&SF Deputy Director,
brother of F.G. Waller Jnr; Professors A.J. Kluyver, TH, Delft, and J. Westerdijk, CBS,
Baarn. Physicians: A. Querido, J. Mulder and W.R.O. Goslings of Leiden University Hospital
Marlene Burns, PhD.
Kluyver Archive, Delft University of Technology;
Descartes Centre, University Utrecht.
References:
Thesis.
Burns, M., „The Development of Penicillin in The Netherlands 1940-1950: The Pivotal Role
of NV Nederlandsche Gist- en Spiritusfabriek, Delft‟, PhD (History) Thesis, University of
Sheffield, Sheffield, England, UK, September 2005.
Books.
Burns, M., „Scientific Research in the Second World War; The case for Bacinol, Dutch
penicillin‟, Chapter 3 in A. Maas and H. Hooijmaijers, eds., Scientific Research in World
War II. What scientists did in the war, (Abingdon, Oxon, and New York: Routledge,
2009).
Elema, B., Opkomst, evolutie en betekenis van research gedurende honderd jarren
Gistfabriek, (Delft: Koninklijke Nederlandsche Gist- en Spiritusfabriek, 1970).
Querido, A., Andries Quesirdo de binnenkant van de geneeskunde, (Amsterdam: Meulenhoff,
1990).
31
Journals/Magazines.
Digesta Antibiotica, 1, 1947.
Fabrieksbode, 15 October 1960.
Houtzager,H.L. and Verschuyl, M.A., „Delfts pionierswerk: de fabricage en klinische
toepassing van penicilline‟, Medisch journal Delft, 4, (December 1995).
Over en Weer, July 1968.
Scheurkogel, K.,„Technische Bereiding van Penicilline‟, Chemische Weekblad, 45, 29 January
1949.
Reports.
Rijks Instituut voor de Volksgezondheid (RIV) Report U.317/45, October 1945.
RIV Report, Commissie inzake antibiotische geneesmiddelen, Report 10 January 1946.
Archives.
Centraal Bureau voor Schimmelcultures Archive, Baarn/Utrecht, the Netherlands.
Gist Brocades Archive, Gemeente Archief, Delft, the Netherlands.
Kluyver Archive, Department of Biotechnology, Delft University of Technology, Delft, the
Netherlands.
Nederlandsche Gist- en Spiritusfabriek Archive, Gemeente Archief, Delft, the Netherlands.
Personal Communications.
J. van den Berg, B. Griffieon, H. de Hoorn, A.J. de Neeling, A. Querido, J. de Vlines.
A Chain is Gonna Come
Building a penicillin production plant in post-war Italy
Mauro Capocci
(Section of History of Medicine, La Sapienza – Università di Roma, Italy)
[email protected]
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
Travelling back and forth. Antibiotics in the clinic, stable and food
industry in Germany in the 1950s and 60s
Ulrike Thoms
Institute for the History of Medicine, Klingsorstr. 119, 12203 Berlin, Germany
Email: [email protected]
According to the widely accepted account, the first antibiotic Penicillin was the result of the
specific and targeted work of several researchers. In their search for a new and rewarding
project, the Englishmen Ernest Boris Chain (1906-1976) and Howard Florey (1898-1968)
read an article published by Alexander Fleming (1891-1955) in 1928, in which he had already
described the effects of a certain substance on bacteria. Neither Fleming nor the scientific
community recognized the importance of this discovery, but Chain and Florey were
convinced of the substance‟s potential. They managed to interest the Rockefeller Foundation
in developing a drug and financing their work for five years (Wolf 1993, 20f.).
Chain and Florey demonstrated the healing effects of Penicillin on bacterial infection in mice
in 1938. Thereafter they developed purification procedures and carried out the first successful
trial on a woman with terminal cancer. The crucial experiment took place on February 17,
1942 on a young policeman who was suffering from an infection with staphs and streps. He
was treated with the new substance and recovered, but Florey and Chain did not have enough
Penicillin, so he finally relapsed and died (Pieroth 1992, 31).1 This demonstrated that
everything depended on developing a more efficient method of production. Because of the
substance‟s potential and its importance for military medicine and the war, Florey and Chain
succeeded in getting the American Government and Army interested and in obtaining more
subsidies for the research, which was then undertaken in an American-English project. All the
participants were strictly forbidden to publish their findings during war, but physicians in the
English and American military campaigns used Penicillin as early as 1943. In order to
increase production, research concentrated on identifying new, more productive strains and
perfecting the production process, namely by introducing deep fermentation in tanks instead
of mould fermentation. As production increased, penicillin was also given to civilians,
1
For the history of penicillin in general see Bud 2007.
36
initially on the basis of a detailed rationing plan, but this became unnecessary when larger
quantities became available (Adams 1991).
Research was also taking place in Germany, but it started later and did not achieve reliable
results because coordination of the research was lacking. Therefore it had more or less ended
by 1945 (Pieroth 1992, 107-109). Large-scale production began after 1945, based on
American licenses, so in the 1950s West Germany was able to sustain its own production,
(Pieroth 1992, 107-109) but in East Germany output only met demand from 1970 onwards.
Based on the number of relevant publications the ongoing research activities peaked in the
1950s and 1960s. The main goal was to find new and promising strains of bacteria. By 1957,
350 antibiotics had been isolated (Vogel 1954, 44).2 Apart from some attempts to synthesize
antibiotics, pharmaceutical firms were mainly restricted to biotechnological production,
which had some advantages (Bud 1994; Wolf 1992, 29; Marschall 2000). Antibiotics soon
became the wonder drug that physicians and patients believed in and everyone could afford,
because the price dropped enormously.3 Due to the close cooperation of researchers and
pharmaceutical companies the industrial production of Penicillin increased from a few mg in
1940 to 200 tons in 1953, while the monetary value of Penicillin production rose from 268.5
million to 385 million dollars during this time period. American production amounted to 110
tons in 1948, 1,399 in 1956 and 13,925 tons in 1962 with a value of 301 million dollars in
1956 and 370 million dollars in 1962. These figures show that the prices were already going
down as production was industrialized and standardized. This was particularly true for those
antibiotics that were used for non-medical purposes. In the USA this kind of use was
approved in 1949 and expanded quickly although the prices obtained were lower. In 1951
236,000 pounds of antibiotics at a price of 72 dollars per pound had been used as feed
supplement. Only ten years later this figure had risen to 1,800,000 pounds and the price had
dropped to 45.4 dollars. In 1956, 27-28 % of all American antibiotics produced had been used
in agriculture; by 1961 it had climbed to 46 %.4
So far, this is the usual success story, as told over and over again, and in recent years
numerous works on the research undertaken by different laboratories, scientific networks and
2
3
4
Just to name the most important discoveries of the first years: 1928 Penicillin, 1939 Tyrothricin, 1940
Gramicidin D, 1943 Streptomycin, 1944 Gramicin S, 1945 Bacitracin, 1947 Polymyxin, Chloramphenicol
and Streptomyces lavendulae; 1947 Neomycin; 1948 Aureomycine; 1948 Cephalosporin, Chlortetracycline
and Xanthocillin, 1949 Oxytetraclin, 1950 Colimycin, Terramycin/OxyTetracycline, 1951 Carbomycin, 1952
Erythromycin, see Remane 1986; Raper 1952. Remane, Horst, Rüdiger Stolz and Irene Strube: Geschichte
der Chemie, Berlin 1986; Tab. 7, 13 and Raper, Kenneth B.: A Decade of Antibiotics in America, in:
Mykologia 44(1952), 1-85, both cited according to Pieroth 1992, 137; Patsch 1965.
See the graph in Elsässer 1955, 93.
The figures are taken from: Ippen 1960, 119; Seidlen 1963, 760-76 and Smart and Marstrand 1971/72, 363385.
37
experimental systems have been published demonstrating the specific character of national
research. Though hardly controversial, they almost exclusively considered antibiotics for use
in human medicine. However, other sides of the story have until now been mostly overlooked.
First there is the aspect of increasing competition: The first grams of antibiotics had been
awaited and there were seldom scarcities, but lower prices very quickly made them a standard
medical treatment. Parallel with increased production, competition in the market for
antibiotics rose. Initially the first penicillin sold easily, but from the mid-1950s onwards there
was an overproduction. A steadily increasing variety of antibiotics was heavily advertised and
the number of different preparations of one antibiotic increased. Many of these were only
slight variations or new combinations of existing drugs which were marketed under different
names. This led to high expenditure on the promotion of new medicines: when Cyanamid
introduced Achromycin, which is basically Tetracycline, in the 1950s the firm invested 2.5
mill. dollars in advertising and Pfizer spent 2 million dollars alone on Aureomycine samples
during its introduction. Moreover the number of employees in its marketing division was
increased from 8 to 300 persons (Ippen 1960, 119).
Secondly: Increasing competition in the pharmaceutical industry made the enterprises look for
alternative markets in the food industry and agronomy. Even though more recent works have
underlined the close links between agriculture, medicine and biotechnology in breeding
science and reproductive technologies, the role of the veterinarian in the history of drugs as
well as his role in food production and food control has not yet been fully acknowledged,
although communicable diseases such as tuberculosis and brucellosis play an important role
in humans as well as in animals and can be transmitted by milk and meat. 5 It is only in the
history of breeding science that the role of the farm in experimentation and as a place to
exploit the scientific findings for the capitalist production of food has been fully recognized.6
This is due primarily to the fact that until today the history of consumption has not been an
important field of research among people who were and are interested in the history of drugs.
Instead, until now experimental systems, the process of scientific investigation which results
in new and sensational scientific findings have dominated historical research, although there
is important work from business historians on individual pharmaceutical enterprises.
Accordingly even the history of marketing has been neglected, although this allows
5
6
Stanziani 2002, 209-237; Atkins 2004, 161-182; Atkins 2000a, 83-95; Atkins 2000b, 37-51. On food risks in
general see: Scholliers 2008, 3-6 and the literature given there.
For a general outline of the relations between the farm and the clinic with regard to reproduction techniques
see: Gaudillière 2007, 521-529. Among the papers in the special number of this journal see in particular
Woods 2007, 462-487.
38
interesting insights into the creation and construction of medical markets and also medical
routines and beliefs.
In companies it was a consideration of marketing opportunities that determined research
strategies, as Bernd Gausemeier and Jean-Paul Gaudillière have pointed out in the case of
German penicillin research by Merck. Merck, being one of the three pharmaceutical firms
which were involved in the research on penicillin, frankly declared that it was not very
interested in penicillin. As the firm thought that it was more “likely to achieve a practically
applicable result here” it concentrated its research on an antibiotic substance suitable for
treating Bang-Infections which occur in cows.7 In doing so it considered the prospects of a
marketable veterinary drug to be higher than the pharmaceutical relief of severe infections of
humans, which killed large numbers of people. But this approach had several advantages:
legal regulations in the veterinarian drug market were not as strict as in the market for human
medicines, even though veterinarians and physicians were subject to the same drug law.
German regulation allowed veterinarians to sell pharmaceuticals and medical feeds and some
German regions did not restrict the free sale of antibiotics to farmers at all as long as the
medicines were not injected. In some German regions a prescription from a veterinarian
could be used repeatedly – as often as the farmer desired (Barke 1954, 55-57). This opened
marketing opportunities. From the viewpoint of transaction cost marketing drugs to
veterinarians and farmers was much more profitable, as admission was easier. Thus to what
extent pharmaceutical companies preferred to market antibiotics to the veterinarian market is
an interesting question, which I cannot yet answer, especially as hard data on items sold,
prices and so on are hard to obtain.
It was mainly the drop of prices from 1947 onwards that paved the way for non-medical use.8
From the 1950s onwards large amounts of all antibiotics were used in agriculture, where they
were used to treat bacterial and fungal infections in animals and plants, as disinfectants, and
as food preservatives for meat and fish as well as a means of increasing weight gain in
breeding livestock. In 1956 27-27 % of all antibiotics were sold for non-medical uses and this
percentage rose even further until it reached 37 % in 1962 (Seidlen 1963, 761). This clearly
demonstrates that companies were successful in developing this market in the USA. Using
antibiotics in these alternative ways meant a crossing many boundaries: Antibiotics first
crossed the boundary from human to veterinary medicine, then from veterinary medicine to
7 Schering to RWA, 29. Sept.194, III. Abt. Rep. 84, Rostock correspondence, MPGA, cited according to
Gaudillière and Gausemeier 2005, 196.
8
The case of milk research as a factor in the industrialization of farming and the peculiar role of the Federal
Institute for Milk Rresearch is discussed in Thoms 2009.
39
agriculture and finally from agriculture to the food industry. By using them in different
spheres, antibiotics were to become unreliable: firstly it was noticed with surprise that some
people had severe allergic reactions and reacted shocks to antibiotics with anaphylactic shock.
Secondly it seemed as if bacteria had a life of their own as they developed resistance to
antibiotic substances by becoming desensitized, thus becoming ineffective. This meant that
they endangered the stock of bacteria and fungi which were traditional production factors in
the dairy industry, that is, for making yoghurt and cheese. Researchers, the pharmaceutical
industry and the food industry had to recognise that the application of the new wonder drugs
endangered the therapeutic regime and the economic basis they had established.
This seemed to become a serious problem for the disciplines involved, mainly for toxicology,
especially as the conventional means, methods and principles of “classical” toxicology were
simply inadequate for understanding, explaining and avoiding these effects. In contrast to
basic toxicological principles such as overdosage, the basic problem proved to be dosages that
were too small and periods of treatment that were too short. Then there was the problem of
detecting the substances: tests to show the presence of antibiotics in meat and milk had to be
developed, and food chemistry had to change its basic beliefs from considering foods as
mixtures of chemical substances to a more systemic view, which had been part of life reform
movement and the concepts of microbiologists like Elie Metchnikoff from the 19th century
onwards.9 All these aspects presented real challenges for the sciences involved and helped
them advance.
In the following chapters I will analyse proceedings and articles from different scientific
journals from the 1950s and 1960s in order to record and analyse the way in which the
problematic issue of antibiotics in foods has been perceived, how this problem has been
discussed and which measures have been taken to deal with the danger that the 'wondrous
weapon' might ultimately become ineffective.
1. The use of antibiotics in agriculture and the food industry
Farmers used antibiotics for different purposes. They used them to treat animals that were ill,
to prevent disease and finally to promote growth, especially in chicken. Moreover they were –
and still are – generously used in commercial gardening and farming for mycosis in plants,
especially to combat fire blight, which is a dangerous, rapidly spreading plant disease and can
easily destroy entire orchards of fruit trees. However, I shall not explore all these uses, but
concentrate instead on their use in human and veterinary medicine.
9
On Metchnikoff see: Tauber and Chernyak 1991; Metchnikoff 1907.
40
1.1. Antibiotics as pharmaceuticals in veterinary medicine
The use of Penicillin and other antibiotics in veterinary medicine basically followed the same
principles as in human medicine and was aimed at treating infections, particularly in cows and
chicken. In the case of intensive farming, infections spread very rapidly in the overcrowded
conditions stables of modern intensive husbandry, which served the increasing demand for
meat. The Allies had found German agriculture to be out of date, backward and highly
unproductive in 1945. Therefore agricultural modernisation and industrialization formed part
of allied policies, which were initially aimed at reducing hunger. The Marshall Plan and the
Technical Assistance Program encouraged the transfer of American economic models to
West-Germany.10 This process included the structural change from small to large farms and
increased their productivity and efficiency. It was accompanied by the implementation of the
American way of life and eating; this strategy worked, as the recovery of West German
economy and the rise of agricultural production demonstrates.11 Consumption of meat rose
considerably, from 36 kg in 1950 to 102 kg in 1990 in West Germany and from 22.1 kg to
100 kg in East Germany. Poultry in particular went from being a scarce luxury item to a daily
food, as consumption rose from 1.2 to 8.8 kg in West Germany and from 1.2 to 10.4 kg in
East Germany respectively between 1950 and 1974/75.12 This increase was due to improved
methods of animal feeding as well as to the use of antibiotics to treat, control and prevent
infections.
As Robert Bud has nicely described, the situation was precarious when this practice began. In
1939/40 the World Fair took place in New York, where a milk company displayed the socalled “Rotolactor” to the public. This was a modern, automated milking parlour, which was
advertised under the heading: “The Dairy World of tomorrow”. It was designed to produce
hygienic milk, completely untouched by human hands. Unfortunately, 16 of the 116 cows
exhibited on this stand caught mastitis, a painful infection of the udder. Mastitis regularly
caused enormous loss of cattle. According to estimates the financial value of these losses was
500 million dollars in the USA, 100 million dollars in France and 19 million pounds a year in
England (1877-1967. 90 Jahre Milchforschung in Kiel, 71).
The company was concerned, and called in René Dubos (1901-1981), who treated the cows
with Gramicidin which he had recently discovered, but which was found to be toxic when
10
11
12
There is a vast body of literature on this topic, which includes: Krige 2006; Zeitlin and Gary Herrigel 2000;
Nolan 1994; Bjarnar and Kipping 1998. From a more cultural perspective: Linke and Tanner 2006; Becker
and Reinhardt-Becker (Eds) 2003; Rutschky 2004; Döring-Manteuffel 1999.
On the development of German agricultural politics, production and consumption see: Kluge 1989.
Figures according to: Teuteberg 1986, 225-279, here 237; Poutrus 2002, 214; Kaminsky, 1999, 48.
41
taken internally by humans (Dubos and Hotchkiss 1940a, 791-792; Dubos and Hotchkiss
1940b, 793-794). Three quarters of the infected cows were saved (Bud 2007, 166-167). This
demonstrated the healing power of the new drug very effectively, and saved the reputation of
the company and also apparently confirmed the soundness of its utopian dream of the “Dairy
World of Tomorrow”.
Mastitis was not the only reason why milk researchers were interested and involved in the
research into antibiotics. From the early days fungi and bacteria played an important role in
processing milk, particularly in the case of cheese making. The collection and identification
of strains of bacteria played an important role in the work of the agricultural research
institutions concerned with fermentation, like the Institute for Brewing in Berlin and the
German Institute for Milk Research in Kiel. The first was involved in the production of
protein rich feeds using yeast and fungi, the latter in the research on Penicillin. Both projects
were strongly supported by the Nazi regime (Forth, Gericke and Schenck 1995, 32-40;
Heinecke 2001). This clearly demonstrates that research and researchers in veterinary and
human medicine and especially in antibiotics were identical. It is telling that among the
researchers and research teams from Hoechst, around Adolf Windaus in Göttingen and Adolf
Butenandt in Berlin and Bernhauer from the Institute for Enzymology in Prague, the people
from Kiel formed part of the research group which was sponsored by the National Socialist
Regime. Their interdisciplinary work crossed the boundaries of classical scientific disciplines.
Andreas Lembke in particular was a very modern biochemist: having studied veterinary
medicine in Kiel, he then turned to bacteriological and biomedical questions, for example the
metabolism of bacteria (Lembke 1939, H.2). Although worked in the laboratory, he always
kept in touch with basic agricultural problems such as the role of single bacteria and fungi in
cheese production.13 As his Institute in Kiel had begun to collect strains of bacteria since its
earliest days, he had a large number of them to hand that he could use in his own research.
Nevertheless, he freely distributed them to the other work groups and companies that were
active in this field (Shama 2002, 355). Funded by the Reich‟s Working Community of
Agricultural Industry (Reichsarbeitsgemeinschaft landwirtschaftliche Gewerbeforschung) for
basic research, such as his work on the serological differential diagnosis of Streptococci and
microbiological examination of yeast and mould fungi in 1941 and 1942,14 although the
institution in which he worked was regarded as conducting inferior, that is, applied science.
13
14
See for example: Lembke 1940, 82-84, 93-95; Lembke 1943.
In 1941/42 he obtained 5000, in 1942/43 was granted 5280 Reichsmark, see Reichsarbeitsgemeinschaft V
Landwirtschaftliche Gewerbeforschung, Arbeitsbericht für das Haushaltsjahr 1942/43, in: BA Koblenz, B
316/13, 1-2.
42
Nevertheless Lembke was extremely interested in human medicine and graduated in 1943
from the Medical Faculty in Kiel. At the same time he took up extensive work on
sulphonamides, penicillin and other antibiotics as well as on the application of electron
microscopy in bacteriology, a brand-new field of research, in which he cooperated with H.
Ruska, the constructor of the electron microscope (Lembke et al. 1940, 217-220). In 1943 he
published articles on the impact of sulfonalimids [sic] and the mycoins respectively together
with Josef Vonkennel (1897-1963) und Joseph Kimmig (1906-1976) (Vonkennel et al. 1943a,
129-130; Vonkennel et al. 1943b, 321). Together with Adolf Windaus, Adolf Butenandt and
Konrad Bernhauser from the Institute for Enzymatic Chemistry in Prague the scientists from
Kiel were involved in a nationwide research project that was launched by the
Reichswirtschaftsamt and formed part of the German policy of autarchy. 15 They succeeded in
producing Penicillin, even if they were not able to develop its production on a large industrial
scale before 1945 (Forth/Gericke/Schenck 1995, 32-40; Pieroth 1992, 105ff). Recognizing
that his technical supplies were insufficient to yield any practical results, Butenandt withdrew
from the field of antibiotic research. He had searched for a method of synthesizing antibiotics,
but researchers in the field of applied microbiology were familiar with the methods of
biological production that they used to make beer and cheese. Andreas Lembke continued his
research on antibiotics after the war and founded his own Bacteriological Institute for Virus
Research and Experimental Medicine in Eutin-Sielbeck near Kiel (100 Jahre 1990, 58). It was
here that he developed Patulin from 1947-49 for which he obtained a patent. Patulin was used
against Bang-Infections (Brucellose).16 It was quite promising, as miscarriages in pregnant
cows led to overall losses of about 250 million Marks per year. Moreover he researched the
potencies of different substances against tuberculosis of humans and animals (Lembke and
Krüger-Thieme 1952, 7-222; Lembke et al. 1952, 717-718; Lembke and Menninger 1952, 4184) and proved the efficacy of neoteben, which is still used against tuberculosis today (100
Jahre 1990, 73). 17
On one hand milk researchers helped to develop modern hygienic methods of milk production
and processing, so that spoiled milk was no longer a serious problem for the 20th century
consumer. This was very clear for the physicians too, but during the 1950s, antibiotics
became a major problem for the hygienic and microbiological use of milk in the dairy
industry. Antibiotics destroy not only the “bad” bacteria, but even the fungi and lactobacilli,
15
On this group see Gaudillière and Gausemeier 2005, 194-195.
Patulin is regarded as an effective antibiotic, but is not used in therapy because of its toxicity; see
http://de.wikipedia.org/wiki/Patulin, last access 8.7.2008.
17
Today Neoteben is marketed under the name "Isoniazid".
16
43
which are indispensable for making cheese and yoghurt.18 First reports on disturbances in
milk processing were published as early as 1948 (Kästli 1948, 685-695). Experimental assays
on the effects of antibiotic treatment on milk showed that penicillin residues were to be found
in the milk of cows that had developed mastitis and had been treated with penicillin. Such
milk would result in the early fermentation (Frühblähung) of cheese made from it, which
could not be sold at all, although in fact it was forbidden to sell milk with drug residues
(Milchfehler 1953). Thus the beneficial drug also proved to be a real danger for dairies, 19 and
measures where needed to prevent harm. On the other hand, it was clearly shown that waiting
would be a simple, but efficient method of preventing this happening, as the penicillin would
quickly leave the animal‟s body within two days. Seen from this point of view the rapid
elimination of penicillin was an obvious advantage. However, it meant that injections had to
be given every three hours and this was a problem in clinical treatment, and even more so on
farms, because the animals would not cooperate with multiple injections. Moreover multiple
injections were hard work and expensive. Therefore scientific discussions began on how the
excretion of penicillin could be slowed down by administering it in other ways, using
different solvents or by adding certain substances. The trials led to the discovery that using
Procain in wax oil as a solvent would secure a stable antibiotic level in the blood for up to 28
hours (Schermer 1949, 250-253).
Moreover, antibiotics could cause mutations of bacteria – maybe within the dairy itself –
which could have unknown virtues, but might endanger the existence of whole starter cultures
and thus the basis for production.
Initial inquiries in this field took place as early as in 1949/50,20 others followed in subsequent
years (Meewes and Pawlawski 1951, 543-549; Meewes et al. 1955, 225-236). It proved to be
extremely difficult to discover the reason why milk spoiled, to obtain evidence on antibiotics
and to discover how long it would take for cows' milk treated with antibiotics to become free
of residues of antibiotics (Meewes and Milosivic 1951, 59-74; Milosivic 1953).
1.2. Antibiotics as food preservatives
The use of antibiotics as a preservative is not unusual in Germany today. It goes back to the
plausible idea that a substance which kills harmful germs prolongs the shelf life of foods as
18
19
20
The Federal Institute for Milk Research (Bundesanstalt für Milchforschung) in Kiel had a large collection of
fungi, which included beneficial as well as harmful specimens. Every year, some thousand cultures were
send out by mail, see 100 Jahre 1990, 45; Lembke 1952.
See Kieler milchwirtschaftliche Forschungsberichte 29(1977), 370f.
See Bundesversuchs- und Forschungsanstalt für Milchwirtschaft, Kiel, Wissenschaftlicher Jahresbericht
1949/50.
44
well. As early as 1949 articles were published in Germany that reported that penicillin had
been used to preserve women‟s milk in a paediatric clinic (Linneweh 1949, 666-670). In the
USA, Canada and Great Britain the food industry used antibiotics (mainly Aureomycine) in
all kinds of food, in vegetables, cream fillings, and particularly with fish, crabs and meat in
order to prolong the shelf life of foods for 7-10 additional days (Eichholtz 1956, 125,
Partmann 1954, 505-512, Partmann 1957, 210-227). Preserving food in this way was regarded
as a “revolution in the field of food” (Streiflichter 1956). There were different methods of
applying the antibiotics: antibiotics were added to the water to make the ice used for storing
fish; they were injected in beef cattle shortly before slaughtering to extend the storage life of
the meat; pieces of beef, poultry and fish were dipped into a solution containing antibiotics in
order to kill germs on the surface (White-Stevens 1956.).
Tab. Dipping Poultry in a solution of Aureomycine
Source: White-Stevens (1956), 114.
Developed at the end of the 1940s, this method was tried out during the 1950s with the food
conservation boom. It was the American Cynamid Company that organised conferences to
advertise the use of its Aureomycine in fresh food. In 1956 it presented its so-called Akronize
method at a conference in Vienna. Lectures by Cynamid employees were distributed amongst
lectures by renowned German food scientists and nutritionists and were presented in the
format of “normal” scientific papers. They demonstrated the thorough investigation into the
effectiveness of the various Tetracycline antibiotics, in which Aureomycine was found to be
the most effective drug for protecting food against bacteria (Streiflichter 1956) In fact, this
45
practice was of great economic and medical importance, especially as deep freezing was still
in its infancy. Moreover one should not forget the experience of hunger and food shortages
suffered by the Germans and the Allies, who had to finance enormous food imports to
Germany. This had been the most pressing reason for abandoning the Morgenthau plan and
modernizing German agriculture with the financial aid provided by the Marshall plan. Food,
especially fish and meat, was still expensive. This was precisely the point made by the
Cyanamid representatives. They argued that fish and meat “were expensive commodities, in
which losses play an important economic role, so that it is worth the price of a safety
measure” such as using Aureomycine (White-Stevens 1956, 106). The economic relevance
was obvious, as approximately a quarter of all fish deteriorated in the USA and Canada before
it even reached the consumer (Tagesnotizen 1959, 35). And as the use of Aureomycine
facilitated the transport, storage and sale of food it was welcomed enthusiastically
(Streiflichter 1956).
Compared with other
preservatives,
Acronize works best
Table 2: Left: Results of trials with different antibiotics on cultures of poultry. The Petri dish
in the middle is the one with Aureomycine and shows almost no bacterial affection.
Right: The development of germ numbers in fish treated with different preservatives during storage for seven
days (Acronize = Aureomycine)
Source: White-Stevens (1956), 109.
On the other hand, antibiotics were used to shorten cooking time during the conservation
process and lower the cooking temperature respectively. Again Aureomycine was advertised
for this purpose by Cyanamid, but Nisin was even more commonly used. Nisin is a
polypeptide obtained from cultures of streptococcus lactis and inhibits the germination of
46
gram-positive bacteria and clostridia. It was mainly added to soft cheese and tinned food in
order to allow the temperature to and the duration of the sterilisation process to be reduced
(Vas, Kiss and Kiss 1967, 141-144; Vonderbank 1956, 82-89; White-Stevens (1953), Nisin
2002). This helped not only improve the taste and consistency of the product obtained, but
saved precious time and energy. From this point of view it was part of the rationalization of
food production, and facilitated transport and sale. Nevertheless, in contrast to the USA and
Canada where the possibility of keeping meat and fish for an extra 7-10 days was welcomed,
this method of conservation was rather short-lived in Germany, where food chemists hesitated
to allow any additives.21 Moreover some of the new substances had proved to be toxic when
ingested orally and toxicity was the major concern in discussions on food safety (Mossel
1955, 254-268). And last but not least it was found that antibiotics are able to mask
pathogenic bacteria in meat (Sinell 1957, special no., 30-32). Research into this topic
continued, but already the first West German food law of 1964 prohibited the use of
antibiotics as food preservatives. It was simply argued that a sufficient number of permitted
preservatives such as benzoic and ascorbic acid existed that had been found to be harmless, so
there was no need for other, possibly harmful substances.22
1.3. Antibiotics as growth promoters
The history of antibiotics as growth promoters began with the search for cheap protein, which
is once again bound up with the history of brewing science. Protein was scarce during and
after the Second World War, and even in times of peace proteins were – and still are – the
most expensive nutrients in animal feed. At the same time they are the factor that limits
growth. If there is insufficient protein, an animal will simply stop growing and will eventually
show deficiencies. Recognized for its high protein content, yeast had already been used in
animal feed since WW I (Lüers 1949, 64-68.). During the 1940s the mycelium from which
Streptomycin was extracted was given to chicken, especially as it was rich in Vitamin B12,
which had been proven to stimulate growth. Surprisingly enough, the chicken grew much
faster than they would have done normally, as a group of researchers discovered in 1946. In
the search for an explanation, the residues of streptomycin were identified as the cause of
accelerated growth (Moore et al. 1946, 437; Stokstad 1953, 434-441).23 But because of the
limited amounts of mycelium it made no sense at that time to encourage feeding it to animals.
21
22
23
See the explanations in Nüse 1963, 266f.
Ibid.
The large-scale production of antibiotics in West-Germany started later and East-Germany lagged even
further behind. Here trials with residues from the production of antibiotics were still conducted during the
mid-1950s, see the reports from the University of Halle-Wittenberg: Columbus/Gebhardt 1956.
47
Nevertheless the idea of speeding up the growth and fattening process, which was based on
these new scientific insights, fascinated the agrarian economists, so they followed it up. In
April 1949 the American researchers Stokstad and Jukes reported on their feeding
experiments with Aureomycine in chicken (Stokstad and Jukes 1949). In September 1949
their findings were confirmed by experiments with pigs and in April 1950 Stokstad and Jukes
substantiated this effect even for crystalline Aureomycine (Jukes et al.1950, 452). The
outcome of these experiments was rather exciting for veterinary doctors, as it offered the
possibility of rationalizing the farm to an extent that had previously been unthinkable by
speeding up meat production and lowering production cost at the same time. From this time
onwards, numerous experiments repeatedly confirmed the influence of antibiotics on the
health and the physical condition of animals, their development and growth rate as well as the
utilization rate of the feeds given. They even confirmed the effects of antibiotics on the
growth of plants (Nickel 1953, 449-459).
Tab. 3: Effects of terramycin on the growth of maize
Source: Nickel 1953.
New journals were founded and the literature proliferated: during the 1960s alone there were
more than 100,000 relevant research papers on the effects of antibiotics on animals.
Initially, researchers focused on the role of Vitamin B12 and a miraculous factor, called APFFactor (animal-protein-factor), as Vitamin B12 apparently improved growth, particularly in
combination with antibiotics. The effect was most obvious with a low animal protein
proportion in the feed (Behma and Jäger 1955, 288-328) and in animals living in poor
hygienic conditions (such as high stress levels for the animal with poor, insufficient animal
feed. Antibiotics reduced the amount of protein of animal origin needed in the feed, the
number of cases of diarrhoea decreased, the outer appearance of the animals improved,
whereas the number of undersized animals decreased and growth accelerated by 10-200 %.
48
This effect was particularly marked during the phase of while the animal was young and
growing. Finally it was found that not all, but only some antibiotics produced these effects
(e.g. Neomycin, Subtilin, Rimocidin, Polymyxin, and Chloromycetin) and that combinations
seem to increase the observed effects (Tangl 1959, 274).
The advantages were calculated carefully. In 1957 H. Hegener from the Federal Milk
Research Institute in Kiel demonstrated that the application of Dihydrostreptomycin and
Procain-Penicillin raised the cost of feed by 17.50 and 27.50 Deutsche Marks respectively in
1957, whereas the additional meat brought in an additional 25.00 and 42.50 Deutsche Marks
respectively. Ultimately this resulted in an increase of 17.50 and 27.50 Deutsche Mark
respectively. Moreover 25 days of feeding were saved, as the pigs reached their slaughtering
weight faster, so the farmer could begin to raise the next generation earlier (Hegener 1953,
47-48). These arguments were convincing, even though the reasons for these empirical
findings were unclear and were disputed at least until the 1960s. Some researchers thought
increased appetite was the factor responsible; others attributed it to the reduction of latent
infections or the higher permeability of the intestinal mucosa to antibiotics. But although the
scientific discussions on the effects of antibiotics were still going on, antibiotics were widely
used in animal husbandry, as they served to reduce production costs and increase output.
Obviously the danger was not entirely recognized and was outweighed by the economic
advantages. J. Brüggemann argued that “an agronomy such as the German cannot afford to
neglect such an economic advantage, which stands in opposition to only vague conclusions
based on analogy and assumptions.”24
Virtually the same products were used in animal husbandry and in human medicine, targeting
infection in children‟s diseases, but at the same time, they were advertised on the grounds of
safety for raising chicks, that is as growth promoters as well as for enhancing performance
and increasing the number of eggs laid by hens.
24
This was Brüggemann‟s argument at the first meeting of Society for the Nutritional Physiology of husbandry
which was founded on 11.12.1953 in Giessen, see Brüggemann 1954/55, 71-75.
49
Tab. 4: Advertising Terramycin for different purposes
Sources: Antibiotics and Chemotherapy 3(1953), no. 6; Deutsches Tierärzteblatt 8(1960).
50
The animal feed industry advertised the use of antibiotics in its own journals, 25 at conferences
they organized such as the one in Wien in 1956 mentioned above (Die Bedeutung 1956), and
in books, which were written by scientific experts contracted by industrial companies. The
authors even included experts from State Committees such as Johannes Brüggemann (Vogel
1959; Brüggemann and Niesar 1957). The experts from the variety of commissions do not
appear to have been very critical, but confirmed the findings of industrial research. 26 Overall
Antibiotics were not only promising substances for their producers, but even for the
manufacturers of pre-mixed animal feed, because the farmer could not blend the
pharmaceutical ingredients himself. To mix the relatively small amount of 5 kg Aureomycine
with 1 tn of feed was only possible with the help of large mixing machines, which the small
farmer did not possess (Zunker 1961, 352). This situation resulted in new dependencies
developing, in which antibiotics stood for a modern, economical way of farming, which was
strongly orientated towards the farming methods used in the USA, if not identified with it. It
is important to note that US-American farming methods entered German farming not only in
this way, but also through the study trips that German representatives of agriculture, food
chemistry and food industry took to the USA on invitation and which were funded by the
European Recovery Program.27 So it comes as no surprise that the relevant publications relied
heavily on American articles and books. But although production developed along American
lines, evaluation of the arguments for and against the use of antibiotics in animal medicine did
not. Moreover, the structure of German agriculture was very different from American
farming, with its large, highly rationalized and mechanized farms. At least during the 1950s
and 1960s German farms and herds were much smaller, which meant production conditions
were different. And finally animal protection played an important role in Germany: the first
Animal Protection Association was founded as early as 1837, there was a lively debate on
vivisection in the 19th century, the life reform movement developed, espousing
vegetarianism, and the first animal Protection Law was enacted in 1933.28 When the reasons
for the increased growth of animals on medicated feeds were researched it was found that
antibiotics would only speed up growth in poor living conditions, with animals living in old,
dirty and infected stables, because it reduced the amount of bacteria in the guts (Haenel 1959,
25
26
27
28
Mitteilungen für Tierhaltung 1(1954)-28(1958) was published by Lederle and from 1958 onwards until 1972
by the Cynamid GmbH.
Uekötter stresses this point in the case of fertilizers and pesticides, see Uekötter 2004, 24-45.
See the numerous travel reports in the “Ergebnisse des Programms für technische Hilfeleistung“, later
published under the title: Berichte über Studienreisen im Rahmen der Auslandshilfe der USA, Frankfurt a.M.
1954-59.
See Tröhler and Maehle 1987, 149-187; Arluke and Sax 1981, 6-31; Heintz 2008, Eberstein 1993; Martin
1989.
51
500-513). To encourage breeding practices that went hand in hand with bad living conditions
for animals by opening opportunities to compensate for them by using antibiotics seemed
entirely undesirable from the point of animal protection. Some microbiologists simply
declared that such living conditions were only common in the USA, but not in Germany
(Freerksen 1956, 158). On the other hand, lowering the amounts of animal protein in the feed
by adding antibiotics (Degener 1952/53, 313-323; Brehm/Jäger 1955) was not a point of
discussion during the 1950s, partly because this substitution had had been pursued by the
science of animal nutrition since the 19th century for economic reasons and secondly because
of the bad nutritional situation in Germany. In 1950 per capita meat consumption was still
only 36 kg per year, whereas it was 65 kg in the USA.29
2. Discussions on advantages and disadvantages
Researchers were not only interested in the risks but also fascinated by the opportunities for
improving ways of producing and selling foods, especially as they were deeply influenced by
the food shortages of WWII and the post-war period and throughout their scientific careers
had looked for ways of increasing the available amounts of food. Their outlook was shared by
the World Health Organisation. Its report No. 241 of 1962 stressed “that the world scarcity of
protein makes it necessary to conserve and utilize meat supplies to the fullest possible
extent.”30 Nevertheless the use of antibiotics in food was much discussed from the time they
were first developed. Researchers said: “The success justifies the measures (i.e. the use of
medicated feeds) and as long as no disadvantages of any kind can be proved we can make use
of the agents (Wirkstoffe), as another means of keeping our animals healthy and improving
their performance.” (Brüggemann 1957, 14-16)
Overall, there seemed to be more advantages, as long as the research considered the classical
questions of toxicity and residues. Would antibiotics harm cattle, swine, and poultry? Would
residues in their tissues and especially in milk harm humans who consumed them? Would it
alter the quality of the meat?
Investigations proved that the organs of treated and slaughtered animals showed almost no
changes. Moreover, the meat was not altered in any negative way, as had been observed in the
case of feeding with hormones. Instead the quality of meat seemed to be better and the
29
The figures for the USA are cited according to:
http://www.hsus.org/farm/resources/pubs/stats_meat_consumption.html (last request on
18.10.2009), figures for Germany according to Teuteberg 1986.
52
amount of fat was apparently lower in animals which had been fed antibiotics (Ibid., 15). But
over time the focus shifted. This was mainly due to the work of the milk researchers and
veterinarians who observed the development of resistance in the bacteria that cause mastitis.
At first the extent of this resistance was not fully recognized: studies concentrated on
resistance in humans (Knothe 1967, 28f) and disregarded the so-called low nutritive doses all
together. According to the old toxicological saying that the dose makes the poison, it seemed
unimaginable that the low prophylactic doses of 10-20 mg antibiotics in feed could do any
harm, as therapeutic doses were two or three times higher and had no negative consequences
at all. During the 1950s, influential scientists still said that the resistance found would not
occur in animals.31 At the beginning of the 1960s it was impossible to maintain this belief, as
the evidence was clear (Bisping 1962, 498). Research between 1962 and 1967 clearly showed
that the resistance of Staphylococci to Penicillin had risen to 48 % in the case of penicillin
and to 28 % in the case of Tetracycline, whereas it had reached 70 % in case of Streptococci
to penicillin and 70 % in the case of Tetracycline. There was no doubt that this was due to
nonspecific treatment of mastitis (Weight and Kramer 1968, 167-622). These findings were
irrefutable, but the connection with the impact of medicated feeds was not commonly
believed. Overall the discussion centred on the effects of antibiotics on human health,
whereas animals were only regarded only as a production factor. The death of animals was
accepted as long as the overall calculation of these costs remained reasonable. That they
might pass on the resistance was simply denied.
Criticism came mainly from the life reform movement and the nascent environmental and
consumer movement. Their representatives pointed at the potential of antibiotics for causing
severe allergies, as anaphylactic shock had been observed to occur in some patients.
Moreover, they stressed the need for ingested food to be unadulterated and thus asked that all
additives should be abandoned, as they might endanger the body's inner equilibrium (Zinzius
1954). For a long time, they had accepted the idea of dysbacteria as the cause of diseases and
promoted the consumption of yoghurt and kefir by referring to the works and findings of Elie
Metchnikoff. According to Metchnikoff and his followers, many diseases resulted from
imbalances within the bacterial flora of the intestines, and the destruction of bacteria by
antibiotics was regarded as medical malpractice, doing severe harm to patients. One of the
most active critics of the increasing use of antibiotics was the newly founded Gesellschaft für
30
31
WHO Technical report Series No. 241, Joint FAO/WHO Expert Committee on Meat Hygiene, Second
Report, Geneva/London 1962, cited according to Pearson 1962.
Brüggemann argued, that the doses of antibiotics would be too small to do so, Freeksen thought that no
resistance would not occur at all, see Brügemann 1957, Freerksen 1956, 158.
53
Vitalstoff-Lehre, which was a staging area for former Nazis as well as an important arena for
people who thought differently about food. The society held yearly assemblies, called
“Konvente”, in which resolutions on different topics were passed. It is no accident that the
first of these resolutions in 1955 was on antibiotics and asked for more research (Vitalstoffe
1956, H. 1, 3.). Again, resolution No. 18 asked for the administration of antibiotics to be
restricted, as they would destroy the body‟s natural immune system, weaken resistance to
infections and thus make the body receptive to possible future diseases. In addition, they
demanded that medical students be taught not only about the antibiotic treatment of diseases,
but also classical pro-biotic treatment (Vitalstoffe 1956, H. 1, 20). On the whole, history has
proved their claims to be correct, but at that time their claims and their methods of
formulating them were considered odd, over-sceptical and backward. The reason may be that
articles in the society‟s journal and elsewhere often exaggerated and painted horror stories of
the consequences of taking antibiotics (Bazala 1957, 132-134, 139). The experience of
patients and doctors contrasted strongly with such images, as antibiotics brought quick relief.
However the public had not yet recognised the long-term effects.
Orthodox natural scientists heavily criticized the fact that critiques emotionalized the
discussion and information on antibiotics. They referred to tales of atrocities and claimed that
problems in the natural sciences and toxicology could not be solved in an emotional way, but
only on the basis of research and scientific experiments. Above all they criticized the artificial
opposition of what was considered “natural” and “synthetic”, which had brought elements of
a philosophical nature into the discussion.32 In their discussions about the dangers and risks
caused by pharmaceutical substances they therefore stressed the 'naturalness' of some of the
most toxic substances such as Coumarin in order to make clear that the differentiation
between natural/synthetic was obsolete (Lang 1957, 140-141).
Nevertheless, orthodox scientists had to accept that these heterogeneous groups were
reinforced by the environmental movement from the late 1960s onwards (Bud 2007, 174). In
1964 the book “Animal Machines” by Ruth Harrison was published and became a bestseller.
Its effect on public debate was comparable to that of “Silent Spring” by Rachel Carson, which
discusses the dangers of pesticides, and it is no accident that Rachel Carson wrote a foreword
for Harrison‟s book. “Animal machines” was published in Germany in 1965; it perfectly
reflected the general unease in social and political organisations, the critics of the capitalist
market and its orientation towards the maximization of profits (Harrison 1964).33
32
33
Such were the arguments against Werner Kollath‟s systemic view, see: Spiekermann 2001, 247-274.
In German under the title: Tiermaschinen. Die neuen landwirtschaftlichen Fabrikbetriebe, München 1965. A
second German edition followed as early as 1968.
54
The advocates of antibiotics pursued different lines of argument and strategies in stressing the
advantages of antibiotics. Ironically they took up the argument of 'naturalness' and stressed
the point that antibiotics are natural substances that could be found in many plants and foods,
for example onions, mustard and garlic (Haenel 1962, 680-692; Partmann 1952, 246-264). By
doing so they declared them to be a natural part of the world and underlined their
acknowledged harmlessness. Microbiologist Enno Freerksens (1910-2001) went so far to
argue that “antibiotic substances are part of every fully-fledged food; feeds with antibiotics
are not more unnatural but on the contrary even more natural than antibiotic-free food. Even
plants and animals produce antibiotic substances.”34 Moreover it was stressed that they would
leave the body unchanged and would not be absorbed by the tissue (Trautmann and Hill 1952,
207; Degener 1952/53, 315.). Advertisements of that time took up this argument and
pinpointed the natural offspring of antibiotics, such as Terramycin, on which a journal
advertisement stated that the substance “comes from mother earth” and that “100,000 samples
of soil were analyzed, before this precious agent could be extracted from mushroomfermentation” (Kraftfutter 1953, 18).
Tab. 5: Advertisement for Terramycin, arguing that it was a natural substance
Source: Kraftfutter 1953, p. 13.
34
Antibiotika-Fütterung 1956, a more detailled and sophisticated discussion in Freerksen 1956.
55
In the case of Nisin, a natural polypeptide, its natural character was stressed over and over
again. In fact this was the only one that was allowed to be used as a food preservative, that is,
in cheese and preserves.35
It has already been mentioned that researchers instilled memories of food shortages in WWI
and WWII in order to underline the possibilities of ensuring plenty of food. From the late
1950s they broadened this view and extended it to the so-called Third World by arguing for
the need to maximize food production in the face of the population explosion in these
countries. We should not forget that the international dimension of this problem became a
matter of public interest and action during these years. In 1964 that the FAO started its
“Freedom from Hunger”-Campaign, in which numerous well-known German nutritional
scientists were involved, namely Heinrich Kraut and Hans-Diedrich Cremer.36 Only a few
years later the report by the Club of Rome described the extent of the environmental and
social catastrophe to come (Meadows 1972).
Finally they stressed the economic need from the farmer's point of view to increase
production while lowering the production cost for the sake of their survival and economic
performance. This was backed by official agricultural policy, although it soon proved to be
counter-productive. Boosting production “justifies these measures provided it has not been
possible to show any disadvantages, if we can make use of active agents (Wirkstoffe) as
another means of maintaining the health and increasing the performance of our livestock”
(Brüggemann 1957, 14-16). In this respect the feed industry became a central actor in the
game, as feed accounted for 37 % of the production cost of meat, so was the most important
production factor (Futtermittelrecht wird reformiert 1974). But the same is true for the
veterinarian, who alone was able to prescribe antibiotics as medicines. Sales figures for feed
additives in the USA had risen from 55-60 million dollars in 1950 to 142 million dollars in
1965. Accordingly productivity rose by 77 % in the case of cattle, 15 % in the case of swine
and 300 % in the case of broilers. In Germany the industrialisation of agriculture began later,
but the use of ready-to-use, industrially mixed feeds also increased, from 500,000 tn in 1949
to 7.7 million tn in 1967 (Entel 1970).
This large and still expanding market was regulated by old, contradictory laws. In fact three
laws were involved, as medicated feed concerned problems of animal feeding, human food
and drug legislation. All three relevant laws in question were outdated in the 1950s: the feed
35
36
Later on other antibiotic substances were introduced, such as Natamycin which was and is allowed for the
disinfection of the outer skin of hard cheese. Natamycin was developed by Andreas Lembke, mentioned
above, see 125 Jahre Milchforschung am Standort Kiel, ed. by the Bundesanstalt für Milchforschung, Kiel
2002.
See: Cremer 1962 and for the background: Staples 2003.
56
law dated back to 1926, the food law to 1927 and the drug law to 1941, when antibiotics were
unknown. Moreover, there was regulatory chaos as the regions (Bundesländer) were
responsible for the organisation of food control. In order to fulfil their duty, they had enacted
decrees, which regulated different aspects and were partly contradictory. In fact, effective
control was completely impossible (Barke 1954).37
Violation was the usual practice,
especially as breaking the laws was punished with ridiculously low fines that were totally
disproportionate to the profits made from the illegal sale of forbidden substances.38
Accordingly a black market with a turnover of about 40-50 million Marks per year had
developed, in which veterinarians played an important role.39
The basic problem for regulation was the ambiguous status of medicated feeds, which
contained antibiotics as growth promoters: were they feeds or drugs? If one regarded them as
feeds, as the feed industry postulated, they would fall under the feed law. Then the regulations
of the German agricultural society (Deutsche Landwirtschaftschaftsgesellschaft/DLG) would
be important. This society had developed standards for feeds and awarded producers quality
labels for their feeds if they successfully passed the quality control procedures of the DLG.40
The Feed regulation (“Futtermittelanordnung”) of 24 October 1951 followed this practice. It
stipulated that all feed had to be registered with the Federal Ministry of Food, Agriculture and
Forestry (BMELF) and had to fulfil certain quality requirements, which were to be declared
on the packaging and would be tested (Entel 1970). These regulations were thought to protect
the buyers against overreaching and economic disadvantages on one hand and to protect the
health of the animals on the other. 41
The practice with medicated feeds did not comply with the drug law of 1941, in which the
term “Heilmittel” (healing agent) was used and thus connected with healing illnesses. The
feed industry argued that this was not the case for the antibiotic additives, as these were used
in lower, non-therapeutic doses and only in order to improve the animal‟s diet and the growth
process. It took the view that the purpose made the drug, and for a long time the federal
agencies took the same view. The feed law of 1961 proved to be unsatisfactory and long
37
38
39
40
41
Barke 1954.
The production cost of feeds with Thyreostatics i.e. was 4 Marks per feed ration, but these feeds were sold
for 44 marks in 1968, see Deutsches Tierärzte-Blatt 1968, 404. In 1968 a seller of these illegal growth
promoters was sentenced to pay 3000 Marks, see Wolff 1968, 404-409.
Brühann 1971, 167-170, the numbers from p. 168.
This quality label was introduced after the war and is based on neutral scientific advice in order to improve
the quality of feeds, see Münzberg 1954; Behm/Jäger (1955), 288-328. The quality label is awarded to firms,
which follow trade customs, have the requested production plants and experienced personnel. They have to
conduct quality controls and their products have to be proved in practice, see
http://ps4.rkwsued.de/filestore/27/93/916a30a5-501e-4512-9820-5f323d2e72d7-web.pdf. For the feed codex
of the DLG of today see: http://www.dlg.org/kodex_mischfutter.html (last access 11.05.2009.).
Bundesanzeiger Nr. 213, 2. November 1951.
57
debates between veterinarians, representatives of the federal government and the regions of
Hesse and Lower Saxony, from the Feed Industry‟s Trade Association (Fachverband für
Futtermittelindustrie)
and
the
Working
Group
for
Agents
in
Animal
Feeding
(Arbeitgemeinschaft für Wirkstoffe in der Tierernährung) followed during a series of the socalled “Talks in Wiesbaden” (Wiesbadener Gespräche) in the early 1960s in order to
exchange information and viewpoints. It was aimed at finding a solution that harmonized the
different interests of science, law, practice, of the veterinarian, the farmer and industry. 42 The
Federal Health Counsel (Bundesgesundheitsrat) set up a special committee on “Drug
Residues in Food” (Arzneimittelrückstände in Lebensmitteln), in which leading scientists
were involved.43 In order to answer the unanswered questions, research projects were
conducted, partly within the Federal Institute of Milk Research in Kiel, partly at the
Veterinarian Hochschule München. Moreover the German Research Association, which had
its own commission on preservatives in food financed several research projects on the role of
agents in feeds.44 This policy was clearly directed at reaching a compromise between the
different parties involved. That meant that lobbying played an important role.
One would expect that the new drug law of 16 May 1961 (Gesetz über den Verkehr mit
Arzneimitteln”) would have clarified the situation, but this did not happen. The new drug law
of 1961 had not
foreseen the vast changes brought about by the industrialization of
agriculture, as intensive husbandry was just beginning in Germany (Brühann 1970). The law
created new uncertainties instead of resolving the old situation by replacing the old term
“Heilmittel/healing agents” with the term “Arzneimittel”/drug. The latter had a much broader
meaning, as § 1 defined drugs (i.e. Arzneimittel) as substances and preparations from agents
that are designed to influence or reveal the constitution, the state and functions of the body or
soul, or which secondly replaced agents or bodily fluids which are produced by the human or
animal body or thirdly are designed to eliminate pathogenic germs, parasites or agents which
are foreign to the body or to render them ineffective (Gesetz 1961). In fact, feed antibiotics
were agents within the meaning of the law when used as disinfectants or when used as
prophylactics since they obviously influenced the constitution of the animals. But critics –
including the feed industry – argued that the purpose of using them would be decisive: only if
an agent was used as a medication and at a medical dosage would it be a “real” medical drug,
but otherwise feeds with antibiotic supplements in low, so-called nutritive, not curative doses
42
43
44
Such was the conclusion in Jahn 1964.
Among its members were Prof. Marquardt, Freiburg, Prof. Kaemmerer, Hannover, Prof. Kiedrowski, Berlin,
Prof. Klimmer, Bonn and Dr. Schulz, see: Deutsches Tierärzteblatt 13(1969), 240.
Several of these were conducted by the above mentioned Johannes Brüggemann and Reploh; see the yearly
reports from the German Research Association 1949 ff.
58
would not be a drug, but remain a feed.45 An antibiotic that was used for plant protection
would never become a drug, but its different use would simply follow from changes of the
agrarian structure (Kaemmerer 1967, 9). This opened opportunities for lobbying. Already the
report that had been commissioned from the nutritionist Pannhorst by the federal Health
Counsel in 1961 adopted this argument. Pannhorst argued that antibiotics would be drugs only
when they were used to cure a disease. This was not the case if antibiotics where given at
lower doses to act as food additives. In this view the dose made the drug, as nutritive doses
were accepted as being part of feed (Entel 1970, 44-47). Obviously the law allowed
arbitrariness and different interpretations, and in addition special permits could be issued by
the Ministry of Food, Agriculture and Forestry. This shows why the farmers‟ lobby welcomed
the new law warmly with the words “Our new drug law contains something very wonderful,
which is a democratic-liberal view, as it reflects the principles of our economic ideas. We
should take care not to dilute this thought in its proper contents as we tend to regulate
everything.” (Kaemmerer 1967, 9)
This situation was found to be unsatisfactory, so two amendments to the feed law of 1961
were introduced in 1966. They were based on the concept of the veterinarian as a gatekeeper
and strengthened his role in this game even further. Basically veterinarians were obliged to
follow the same Drug law as the physician and in fact both used the same tests to determine
diseases and used similar substances to cure their patients and both were obliged to do them
no harm (nil nocere). However, the veterinarian‟s responsibility was not limited to the health
of the animals, but followed the food chain one step further, in that he was responsible for
human health as well and held a strong position in the food inspection system, in which he
decided on the quality of meat and milk and all their by-products. State bodies simply
expected that veterinarians – like doctors – would carry out their duties. They expected food
inspection to detect misuse and especially residues of antibiotics in feed.
However, unlike the physician, the veterinarian was part of the economic system of feed
production. He was not only allowed to prescribe special mixes of registered antibiotics with
feeds. Although the drug law stipulated that only pharmacies were allowed to sell drugs,
veterinarians had the right to dispense them for practical reasons, including the distance to a
pharmacy in rural areas. Farmers were not obliged to ask for a new prescription on every
occasion, but got repeat prescriptions, which they could use as often as they wanted. It was
accepted that the farmer would not be able to mix the relatively small amounts of drugs with
the large amounts of feed or to stock the amounts of prefabricated, mixed feeds that were
45
This was the position of Johannes Brüggemann, see Bronsch 1967, 24-26
59
necessary to feed large herds. In fact, large machines were needed to distribute the medicine
equally with the feed (Die Rolle des Tierarztes in der Tierernährung 1967). In principle, the
veterinarian was allowed to mix the medicated feed himself but he could hand over
responsibility for this task to persons or firms he trusted. In fact the differences between
veterinarians and physicians were underestimated, especially the economic impact, which is
of the utmost importance on the farm: the veterinary doctor had to follow economic
principles, he was partly seen as an entrepreneur and was allowed to do so, whereas his
colleague in human medicine was not, and was bound by the Hippocratic oath and ethical
guidelines.
It was widely accepted that the veterinarian had to seek and secure his share of the market, for
example by cooperating with the feed industry or by setting up his own production firm
(Brühann 1975). Therefore practical solutions were accepted in veterinary medicine. By and
large the law of 1961 obviously did not fit the still developing industrial production regime of
the industrialized farm, in which the veterinarian‟s role was not only to cure sick animals, but
to maximize output and to administer substances which were also used as drugs. As such he
was part of the production system he had to supervise. In the long run the Ministry of Food,
Agriculture and Forestry realized that this in-between-agreement was not sustainable at all
(Theorie und Praxis 1964) as drugs got into lay people‟s hands and the farmer would use them
all too often (Schultz 1967).
Nevertheless, the advocates of antibiotics pursued the argument of successful risk control
proved by extensive experiments on animals. As long as methods of testing were inadequate
and residues could barely be detected it was possible to argue that antibiotics would not be
passed into meat and internal organs and would thus not, like hormones, influence
metabolism (Antibiotika-Fütterung 1956, 158). But when refined test methods were
developed it was impossible to continue using this argument. Now proponents argued that
residues would only exist in the case of over-dosage, whereas normal doses would be
excreted quickly. If – which would almost never happen – some antibiotics were ever left on
or in the food, the cooking process would surely destroy them as they were basically strains of
protein (Broquist 1953, 9). However, it turned out that milk was indeed contaminated with
antibiotics. In 1962 it was reported that about 12 % of all milk in the USA contained
antibiotics (Bisping 1962, 496). This percentage was considerably lower in West Germany,
where it was only 2 % in 1967, and (Großklaus 1967, 462-465). But meanwhile it was shown,
firstly, that penicillin survived pasteurisation and, secondly, the introduction of depot
antibiotics meant that the excretion process would be extended from one or two to five days
60
(Ibid). Government reacted to this development by prolonging the waiting time between the
administration of drugs to animals and their slaughter to five days. Proposals to colour the
antibiotics used in order to make their use visible and easily detectable, as was usual in other
countries, were not implemented at all (Sellin 1967, 31). On the whole it was found that
concerted action in relation to drug, food and feed law and even in relation to the advertising
of veterinarian drugs, was needed. New advisory bodies were set up, such as a permanent
commission at the German Research Association and a separate commission on drug agents
in feed at the Federal Board of Health, and the Ministry of Agriculture, Food and Forests
observed the developments in science carefully. Astonishingly the British Swann Report from
1969 was known, but it did not play an important role in the discussion, although its findings
had also been approved in Germany as well, where the relevant journals published only very
small reports.46 Instead, the government bodies were strongly inclined towards the actions of
the Food and Drug Administration of the USA (Entel 1970, 46). Although strong differences
persisted, Americanization took precedence even in German agriculture, aiming at cheap mass
production. This view was even accepted by the consumers‟ associations, as long as control
was in force. During the 1960s the American model of progressive modern farming was in
general welcomed, but there were contradictions. As an official stated in 1967, it would make
sense to make use of the wonders of chemistry to increase animal production, but “It does not
seem very convincing to underline applications for approval with hints of the example of the
USA, when most simple measures that are adopted by farmers there would allegedly not be
possible with us for technical reasons.” (Großklaus 1967). Instead of picking elements from
here and there it seemed necessary to find an applicable national solution, one which fitted the
respective local situation but did not neglect international development. In relation to the
European Union, which released the first drafts of regulations as early as 1967, this seemed
inevitable,47 so that even the WHO and the FAO took measures. One element of such a
national policy was to generally suspect and deny the use of chemical substances in food
against the historical background of the idea of “natural” foodstuffs. Consequently giving
antibiotics to slaughter cattle in order to prolong their shelf life was forbidden as was using
antibiotics as preservatives in food, because other preservatives where available and
considered to be sufficient.48
46
47
48
See for example: Antibiotika in Futtermitteln 1970.
See the discussion in: Pharmazeutische Industrie 285(1967), 336, on European Regulation see: Zusatzstoffe
in der Tierernährung 1971.
Already the governmental justification for the food law of 1958 had argued that antibiotics were forbidden as
additives by § 4a., 2 of the food law itself. See: Nüse and Frank 1963, Brühann 1956, 414.
61
The main problem was to tackle the illegal market through a concerted reform of drug, food
and feed law. These efforts resulted in the new feed law of 1975, but did not aim to abolish
antibiotics in animal feed or even reduce them. Instead, it was targeted against illegal imports,
a black market, supplying antibiotics to lay people, technicians, advisers and other people. Its
aim was to establish supervisory bodies, and to give them the organisational, scientific and
financial means to exert effective supervision and to prosecute offenders (Brühann 1975, 367372; Kaemmerer 1967, 51). The new food and feed law distinguished clearly between food
and drug advertising of medicated feed to farmers and other lay people, which was forbidden
and possibility of buying medicated feeds directly was abolished. First and foremost it was
established that a drug is and remains a drug in any preparation, that it has to pass the usual
approval procedures and has to be prescribed by a veterinarian in any case, who then has to
supervise its application (Heuner 1974, 590-596). These measures were designed to protect
human health, whereas the industrial system of meat production was – although criticized by
the nascent environmental movement – left untouched. The environmentalists succeeded in
being heard in the Bundestag, but their claims were ignored. The interests of the agricultural
industry dominated practical politics and health, and politicians simply addressed the
possibilities of risk control. Moreover, the problem of the veterinarian‟s involvement in the
feed industry was not resolved at all. In the end, the new Feed Law of 2 July 1975 stated that
its purpose was “to enhance the performance of productive livestock.”49 However, in the long
run most of these arguments turned out to be less important, if not to say irrelevant, in relation
to the massive problem of resistance (Haenel 1964, 169-189).
Resistant bacteria had already been discovered shortly after antibiotics were synthesized in
the 1940s, but it took a relatively long time to recognise the full extent of the problem. The
usual term for depicting this phenomenon was “hospitalism”. This indicates the area which
was recognised as the place where the problem occurred and was located. At first it seemed as
if this process could be handled and managed. As long as the number of newly discovered,
identified or synthesized substances grew, the doctor could easily switch to another antibiotic
if the bacterium living in the patient showed resistance to the substance administered.
But during the 1960s long-term studies found increasing numbers of resistant bacteria in
hospitals, so the federal health service became alarmed. From 1970 onwards the
Bundesgesundheitsamt (Federal Health Office) began to monitor resistance (Dierk 1977;
Diefenhardt 1984).50 This shows that in the meantime health policy had been paying attention
to the problem. When plasmids where found in 1970 and an international conference
49
Futtermittelgesetz vom 2. Juli 1975, in: Bundesgesetzblatt 1975, Teil I, 1747-1753.
62
acknowledged their role in the development of the so-called cross-resistance of bacteria that
had never been in contact with this or that antibiotic, the ongoing development was clear
(Krcméry, Rosival and Watanabe 1972) on one hand there was a growing number of resistant
bacteria, a growth in consumption of antibiotics for medical therapy and food additives in
agriculture, and on the other hand a slowing down in the invention and subsequently the
manufacture of new antibiotics.
German food scientists and health officers followed a somewhat purist position. As early as
the late 1950s they had argued in favour of the consumer‟s expectation that fresh food should
not contain any additives, thus rejecting the use of antibiotics for the preservation of fresh
food such as meat and fish. Based on the work of an expert committee, the new food law of
1958 prohibited any use of antibiotics as a food additive. The report justified the regulation by
stating that the use of antibiotics raised serious medical concerns, and that antibiotics might
cause allergies, possibly harming the microbiological flora of the gut and might lead to the
development of resistant strains, which would ultimately resist any treatment (Höfer,
Juckenack and Nüse 1961, 84).
However, neither the food chemists nor the members of the commission took part in the
public debate. Instead, they claimed there was an uneducated longing for sensational reports –
but never cited a single one, although they said that a large number of such reports existed. In
fact, they considered the public to be of negligible importance and since 1949 expert
commissions had worked on the question of food additives very quietly. The findings of the
commissions of the German Research Association (DFG) published only “Mitteilungen”, that
is announcements. These announcements contained strict statements on certain topics
(Mergenthaler 1955, 185f). Reports on the discussions within the commission were not
published at all and the members themselves were rather reluctant to publish on the issue, so
it would seem that they simply avoided any
public discussion. Representing a rather
paternalistic position, the experts presented themselves more or less as benefactors of
mankind.
In Germany, it was the food chemists and microbiologists who opposed the use of antibiotics
in food. Doctors seem to have been almost uninterested in food questions and especially in
food additives. In 1958 a publication spoke of the doctor‟s absolute lethargy towards this
problem. It stressed that it was the female members of parliament who had asked for
legislation and implicitly assumed that these women were speaking on behalf of housewives,
who were still regarded as being responsible for the physical well-being of their families
50
See Dierk 1977; Diefenhardt 1984.
63
(Eichholtz 1958). Medical boards asserted the harmless nature of antibiotics in animals, which
are important as a source of food for humans (Bär 1963, 94). It was only during the 1960s that
the work of several English committees and the ongoing American discussion on this question
was acknowledged and that the discussion at least began.
In fact, the use of antibiotics in food or as growth promoters was not banned at all until 1972,
when the use of Tetracycline for this purpose was forbidden. This measure proved to be
successful since the number of resistances declined. Nevertheless, it took a long time to take
action at a European level, although the importance of the approaching European market was
becoming clear and Sweden‟s ban of all antibiotics as growth promoters had obviously had no
negative economic effects on farmers (Wrede, 2004; Castonon 2007, 2471).
The main problem was that solid evidence was lacking. This clearly indicates the
government‟s lack of interest in this issue as well as the pharmaceutical industry‟s interest in
avoiding public discussion. Even in 2001 the European Union had still to ask its member
states to collect statistical data on the amounts of antibiotics consumed (de With et al.
2004,1987). It took until 2003 before the relevant data were made available, at least at the
national German level, by a veterinary panel of the Society for Consumer Research. 51 These
efforts were then taken up at the European level as well.52
Remarkably, the amount of antibiotics in veterinary medicine and agriculture has already
declined in the run-up to legislation. Food industry and agribusiness acted before antibiotics
were banned in animal food, and it is an open question whether they anticipated the possible
negative effects of discussion in the public arena that would have been disadvantageous for
their sales figures. In contrast to this, there was no reduction of their use in human medicine.
Instead the consumption of antibiotics went up from 4.5 to 5.2 doses per person from 1998 to
2005, a rise of 16.6 per cent. Most remarkably, this figure is even higher for children. The
number of doses per child climbed from 6.7 to 8.1 doses per child and year, i.e. they rose by
20.8 per cent.53 That means that those who are endangered most by life-long exposure to
dangerous resistant bacteria are being given increasing numbers of doses. In this respect, the
amount of energy that was and is spent on discussions about the use of antibiotics in
veterinary medicine, agriculture and the food industry is as remarkable as the amount of
pressure exerted on the whole food producing sector. It seems as if antibiotics have had the
51
52
53
But even these figures were only based on estimations, see Schaeren 2006, 234-239.
Stellungnahme des Wirtschafts- und Sozialausschusses zum Thema Antibiotikaresistenz 1999; Eine
Strategie 1999; Mitteilung der Kommission gegen die mikrobiologische Bedrohung 1999; Wrede 2004.
Arzneimittelmarkt-News des Wissenschaftlichen Institutes der AOK, Februar 2007, see
http://wido.de/fileadmin/ wido/ downloads/pdf_arzneimittel/wido_arz_gamsi_ammnews_0207.pdf, Abfrage
vom 21.02.2007.
64
function of a proxy and that the discussion ended when this deputy was thrown out of the
game.
Antibiotics are unreliable substances, which not only kill harmful bacteria, but also all the
useful bacteria in the gut. As such, they certainly do harm the body and can have long-lasting
negative effects. Eventually a whole series of infections follows, when the “natural”
microbiological flora of the intestines have been destroyed and the body no longer has the
means to fight harmful bacteria.
How do we explain that people take this risk without thinking? First we may think of the
importance of efficiency and speed, which followed the general trend of a faster pace of life
(Borscheid 2004). But maybe it is the unreliable nature of antibiotics themselves which can at
least partly explain this finding, as the perception of dangerous substances also contains an
emotional component. In the case of antibiotics this perception is based on the fear that
bacteria themselves threaten the most powerful and seemingly wondrous weapon mankind
has found for fighting infectious diseases. For a long time it has been observed that patients
long for powerful medicines and are willing to accept even very severe and unpleasant side
effects as a kind of guarantee of the medicine‟s strength and healing power (Lachmund and
Stollberg 1995, 95). In everyday life the issue of whether someone needs to take antibiotics or
not, for example in the case of a cold or bronchitis, has become a crucial question concerning
the severity of the disease. From this point of view the increasing fear of jeopardizing the only
means left to mankind for fighting dangerous bacteria would be an emotional side effect of
taking antibiotics. This would be the accepted price society as well as every single individual
has to pay for the promise of quick and effective relief.
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AN ANTIBIOTIC SCREENING PROGRAMME:
IN SEARCH OF ANTAGONISM IN THE 1950s
María Jesús Santesmases
Consejo Superior de Investigaciones Científicas
Departamento de Ciencia, Tecnología y Sociedad, IF-CCHS, Madrid
[email protected]
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
THE PLACE OF SERUMS AND ANTIBIOTICS IN THE
INFLUENZA PANDEMICS OF 1918-1919 AND 1957-58
RESPECTIVELY1
María-Isabel Porras-Gallo
Unit of History of Science
Medical Sciences Department
Faculty of Medicine
C/ Almansa, 14
02006 Albacete (Spain)
INTRODUCTION
The 21st century is providing us with a rich historiography of influenza and the
major pandemics of this illness, particularly that of 1918-19192. Although these studies
attempt to fill the gaps in existing research, there are some aspects that still remain
insufficiently explored. This is the case of the treatments used to fight the flu in each of
its pandemic manifestations3 and, in particular, with reference to the development of the
treatment of influenza throughout its “bacteriological” and virological history4. This
explains why there have been few approaches from the point of view of the history of
medication, and why until now the study and evaluation of the role played by the first
flu pandemics of the 20th century in the process of standardizing the use of antibiotics
1
2
3
4
Some of the ideas put forward in this paper have been published in Spanish in Porras 2008.
Evidence of this great output can easily be found by making a bibliographical search in Pubmed. Of
the more than 800 bibliographical references thrown up by this search, if we limit ourselves to works
of medical history, some 200 relate to the 1918 flu pandemic (search made on 28 December 2009,
starting from 1 January 2000).
To date, we have had practically exclusively information on the treatments used to fight the pandemic
of 1918–1919, although the majority of this information forms a part of studies devoted to the analysis
of the consequences of and responses to this health crisis. Only recently have there appeared
monographic works analysing some of the treatments used and their principal consequences. See, for
example, the contributions of Starko 2009, Porras 2008 or that of Hobday and Cason 2009. The latter
calls for an in-depth study of therapeutic measures adopted during the 1918 pandemic.
An example of this type of work may be found in the book edited by Paul F. Torrence 2007. The
study limits itself to the virological history of influenza, and only deals with the discovery and
progressive use of antiviral drugs to fight against the pandemics of influenza.
78
has been ignored. This is the general aim of this paper, a preliminary version of which
was presented at the workshop entitled The circulation of Antibiotics: Journeys of Drug
Standards5. With this in mind, and for this initial approach to the subject, we have
turned to case studies, and have chosen two: that of the flu pandemic of 1918-19 –
which has once again become topical in view of the epidemics of avian flu and, more
recently, swine flu in Mexico, later known as the type A flu pandemic – and that of
1957-1958. The extent of the former, and the importance of its associated pulmonary
complications, the fact that it was the first great influenza pandemic of the
bacteriological age, and that serums were available as the new “specific” therapeutic
resources which science made available to doctors to combat the disease, have been the
main criteria for our choice. In addition, the high mortality, especially among young
adults, the minimal or non-existent response offered by serums for preventing mortality
and the consequent feelings of failure felt by medical science and by doctors, to a
considerable extent determined the type of reaction and the response to the later flu
pandemics of the 20th century, and even to the first of the 21st century. The 1957-1958
pandemic occurred under different political, economic and social circumstances, when
antibiotics were available and were theoretically the equivalent resources to the 19181919 serums.
My specific aims during the pages that follow are first of all to show, using the
example of the Spanish case, how Medical Science responded to the flu epidemic of
1918-19, and to evaluate to what extent the recommended treatment was adapted to the
theoretical background of Bacteriological Doctrine; and, secondly, to establish the role
played by serums in the fight against the disease. Later we shall look at what theoretical
part antibiotics, had they existed, would have played in the pandemic of 1918-1919 in
order to reduce mortality. Then there will be a brief analysis of what action was taken
during the 1957-1958 pandemic of Asian flu, and the position held by the antibiotics
existing at that time. We shall then try to make an assessment of the value that the
experience of this pandemic may have had in contributing to the standardization of the
use of antibiotics in the treatment of infectious diseases.
THE 1918-1919 INFLUENZA PANDEMIC AND ITS SPANISH CONTEXT
5
This international meeting was held from 16 to 18 June 2009, hosted by the Centro de Ciencias
Humanas y Sociales (CCHS) of the Consejo Superior de Investigaciones Científicas (CSIC) in
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First of all, we should recall that the 1918-1919 pandemic was called “Spanish
Influenza” because of the military censorship in the countries that were taking part in
the Great War. Thus, when the epidemic broke out in some of these countries, the
information was suppressed. On the other hand, the lack of military censorship in Spain,
due to our neutrality, meant that the outbreak of the epidemic in Madrid in the middle of
May 1918 was widely covered by the local, national and international press.
As we know, the pandemic had three outbreaks: the first, during the spring of
1918; the second, in the autumn of the same year, and the third in the spring of 1919.
Although it developed differently in each country, it is clear that this pandemic caused a
great increase of influenza and general mortality rates, as well as of influenza morbidity.
In fact, according to various different authors, the total number of victims of this
pandemic seems to have been 21 (Jordan 1927, 214-218), 30 (Patterson and Pyle 1991,
5 & 21), 50 or even 100 (Patterson 1986; Johnson and Mueller 2002) million deaths.
Spain‟s contribution to this figure was around 270,000 victims (Echeverri 1993, 120). In
most of Spain the second wave was the worst (Echeverri 1993, 122), except in the city
of Madrid, where the first wave was the most serious (Porras 1997, 54-55). It is
important to stress that the gravity of this pandemic depended to a great extent on the
deaths caused by pulmonary complications6. We should also remember that the 19181919 influenza produced its greatest morbidity and mortality rates in people aged
between 20 and 40 years, and not in children under one year old or older people, as was
normally the case. Because of these enormous repercussions on the active population,
the economic consequences and social upheaval were tremendous in every country and
the whole world over. Some idea of this social disquiet may be seen in the self portraits
Edvard Munch painted in 1919, showing a man much older than he really was,
convalescing from the disease.
The seriousness of the flu pandemic of 1918-1919 seems to indicate that the
medical profession of the time which, under the influence of the bacteriological doctrine
felt itself to be powerful, and capable of successfully fighting infectious diseases, did
not yet have effective resources to fight it. Indeed, as we shall show later, the great
expectations that the world of medicine and the medical profession harboured when the
epidemic broke out were not met. Experience provided by the 1918-1919 influenza
6
Madrid.
There is a perfect parallel between the mortality rates from influenza, pneumonia and other respiratory
diseases in the city of Madrid during the three outbreaks of the 1918-19 pandemic (Porras 1997, 61).
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called into question the term “avoidable diseases” (Porras 1994) that doctors used to
describe infectious diseases as the development of the doctrine of bacteriology
advanced and effective vaccines and serums became available.
At that time Spain, with a parliamentary political system in crisis, was in the
midst of a desperate social, political and economic situation, with increasing awareness
on the part of doctors (especially hygienists) of the backwardness of the country in
health terms, and of the need to carry out a complete reform and modernization of the
health system. As for the medical and pharmaceutical professions, we should point out
that both of them were in the midst of a process of professional reorganization that had
begun in the final decades of the 19th century, and that acquired a prominent position
during the “Spanish Influenza” pandemic (Porras 1997, 103-114). They – especially the
doctors – wanted to assume an important role in Spanish society, due to their status as
scientific experts on all subjects related to health and disease. A similar position was
maintained by some of the pharmacists who, following the example of the doctors,
wanted to modernize their profession and to become specialists on certain areas instead
of the doctors.
THE TREATMENT OF THE 1918-1919 INFLUENZA PANDEMIC: THE
LEADING ROLE OF SERUMS
According to the doctrine of bacteriology, it seemed feasible to deal with the
influenza pandemic, but it was necessary to do so in a specific way because it was an
infectious disease. This meant that doctors had to establish what illness was responsible
for it, not only by examining symptoms, but by undertaking bacteriological research. So
when, in May 1918, the epidemic began in Madrid, apart from the clinical diagnosis of
influenza, it was necessary to isolate Pfeiffer‟s bacillus, at that time officially
considered to be the specific agent causing influenza (Théodoridès 1974, 188) 7. The
isolation of this bacillus or the germ considered responsible for influenza would enable
the preparation of a specific serum against the 1918-1919 influenza pandemic.
However, the laboratory was unable to corroborate the role of the Pfeiffer
bacillus as the aetiological agent of influenza, nor to attribute this role to any other
bacterium. Throughout the three outbreaks of the epidemic research was carried out into
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all the aetiological theories developed since the pandemic of 1889-1890. Some
scientists continued to defend the role of the Pfeiffer bacillus, but others proposed a
single bacillus different from that of Pfeiffer, or a still-unknown germ. In view of
laboratory results it was once again felt that a bacterial connection (streptococcus,
pneumococcus, meningococcus...) could be the aetiological agent of influenza or
perhaps of the associated pulmonary complications. As happened in other countries, it
was thought possible that a “filter-passing virus” could be the long sought-after specific
agent of influenza (Porras 2002, 311-327.
In view of the foregoing, it is clear that, as some doctors and the Royal Academy
of Medicine declared, there could be no medicine which was really specific to fight
influenza8. However, the gravity of the situation called for the recommendation and use
of some kind of treatment. Society demanded it, and the doctors wanted to respond to
that demand, even if it meant not offering a specific treatment but simply general
indications “to activate organic defences and to maintain vital energies”9, or medicines
to fight the symptoms of flu and its major complications.
The Royal Academy of Medicine and the doctors proposed a broad and varied
range of resources10. Each doctor produced his own therapeutic combination. They used
antipyretics, sudorifics, tonics, stimulants, baths, purges, disinfectants, fresh air, healthy
diets and even bleeding, but also serums, the new therapeutic resource. Not all doctors,
however, saw the value of serums in the fight against influenza from the same point of
view. While for some they were the most effective and specific remedy for treating
illnesses caused by germs, for others they merely activated the body‟s general defences.
This divergence of opinion, justified by the still shaky state of knowledge of immunity,
7
8
9
10
We should remember that there was no real consensus among scientists on the role of the Pfeiffer
Bacillus.
Information on this point may be found, for example in Cañizo 1918, 10 and in the sessions of the
Royal Academy of Medicine of 26 October and the 23 November 1918 (session of 26 October 1918.
Anales de la Real Academia de Medicina 38:403-424, p. 414 and session of 23 November 1918.
Anales de la Real Academia de Medicina 38:511-528, p. 527).
Session of 23 November 1918. Anales de la Real Academia de Medicina 38:511-528, p. 516.
Proof of this therapeutic variety was the reply that the Royal Academy of Medicine gave to the
Minister of the Interior on 29 October 1918 concerning the treatments considered by that institution as
effective against the flu outbreak of 1918-1919. This reply included different medicines, disinfectants
and serums. Archive of the Royal National Academy of Medicine, Folder 289 (Miscellaneous Papers,
1918-1919). “Carta fechada el 29 de octubre de 1918 y dirigida a la Real Academia Nacional de
Medicina por la Inspección General de Sanidad, Ministerio de la Gobernación” [letter dated 29
October 1918 addressed to the Royal National Academy of Medicine by the Inspectorate-General of
Health of the Interior Ministry], enquiring about “the most indispensable medicines for the treatment
of influenza, with the intention of remedying their shortage in the market and avoiding hoarding and
excessive prices”, together with the Academy‟s reply to the question.
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explains not only the heated debate arising in different forums about the value of
serums, but also the different positions and recommendations of doctors during the
1918-19 influenza epidemic11, most particularly at the peak of its second outbreak.
The classic example is perhaps that of the anti-diphtheria serum, which was
widely recommended to fight against the influenza of 1918-19 and at the same time
provoked considerable controversy. In fact, the doctor and academic Espina y Capo
(1850-1930) considered that the anti-diphtheria serum was only one of many treatments
for flu, and that it was not specific to that illness12. The Royal Academy of Medicine13
and the majority of academicians as well as doctors shared this view and, from the point
of view of immunity theory, maintained that anti-diphtheria serum was specifically
effective only against diphtheria14. However, Tomás Maestre (1857-1936), a leading
professor in the Medical Faculty of the Complutense University of Madrid, disagreed
and declared that “the anti-diphtheria serum was the most efficient remedy against
influenza in all its forms”15. In the opinion of the academic Antonio Simonena (18611941), positions such as that of Maestre were due to the eagerness of doctors to calm
public disquiet, and to answer the call for the “urgent availability of remedies against
the advance of the disease”
16
. Certainly, the reasons put forward by Simonena may
explain the defence Maestre made of the efficiency of anti-diphtheria serum. However,
the results of its administration were contradictory. While the Professor of Medicine
from Zaragoza, Ricardo Royo Villanova (1868-1943), and Tomás Maestre claimed that
they had only had four deaths among the six thousand patients they had treated (Maestre
11
12
13
14
15
16
A wide debate was generated not only in the Academy of Medicine, but also in many other forums
such as the Congress, the Senate, the Royal Health Council, the leading scientific or medical journals
or the press in general.
Session of 25 October 1918. Libro de Actas de las Sesiones de las Cortes. Senado 83 (legislature of
1918-1919), p. 1475.
After heated debate, the Royal Academy of Medicine concluded that the anti-diphtheria serum was “a
useful remedy for influenza, but not specific” (Session of 26 October 1918. Anales de la Real
Academia de Medicina 38:404 and 424).
In this sense Manuel Martín Salazar (1854-1936), at the time Inspector General of Health, was very
clear in his declarations (Session of 26 October 1918. Anales de la Real Academia de Medicina
38:403-424).
Session of 25 October 1918. Libro de Actas de las Sesiones de las Cortes. Senado 83 (legislature of
1918-1919):1471-1475, pp. 1471-1472. Maestre expressed the same opinion in the general press at the
most serious point of the first outbreak of the pandemic (Maestre 1918a).
Session of 26 October 1918. Anales de la Real Academia de Medicina 38:403-424, p. 420.
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1918b, 4-5; Royo 1918, 8), other doctors credited it with only limited effectiveness17 or
none at all against influenza18.
The foregoing shows how the initial expectations of having a specific serum
available to treat the 1918-1919 flu could not be met within the theoretical framework
of bacteriological doctrine, since the problem of the aetiology of influenza had not been
resolved. The theoretical situation had its practical counterpart in the contradictory
results obtained from the administration of anti-diphtheria serum by doctors19.
However, it did seem possible to have specific serums to fight the pulmonary
complications of the influenza of 1918-1919. This idea was supported by laboratory
results, which showed the presence of streptococcus and/or pneumococcus in
complicated cases of influenza, and was further backed by the report issued by the
Commission appointed by the Spanish government to study the development of the
epidemic and the measures adopted in France (Marañón, Pitalluga & Ruiz 1918a &
1918b). This Commission, which included the famous Doctor Gregorio Marañón (18871960), the important hygienist Gustavo Pittaluga (1876-1956) and Doctor Ruiz Falcó,
reported that anti-pneumococcal and anti-streptococcal serums were used by some
French clinicians20 for the treatment of the pneumococcal and streptococcal
complications of influenza respectively21.
Following the example of these French clinicians, some Spanish doctors also
used anti-pneumococcal and anti-streptococcal serums, either separately or together, to
treat complications due to pneumococcus and/or streptococcus22. They used serums
from foreign companies – Institut Pasteur, Institut de Berne, Burroughs-Wellcome of
London, etc. (Mas 1918, 10-11; Salvat 1918, 8), and administered them subcutaneously
and/or intravenously. However, we must also point out the initiative of Pablo Colvée
17
18
19
20
21
22
This was the opinion of Martínez Vargas (1861-1948), Chair of Medicine in Barcelona (Vargas,
1918:9-10).
This was the opinion of the Cartagena doctor Manuel Mas Gilabert (Mas 1918, 10-11) and of the
hygienist Darío Álvarez (Álvarez 1918, 6).
Besides, its administration was not standardized. It was mainly administered by mouth, but some
clinics also gave hypodermic injections, and doses varied between 10 cc every eight hours to 40 cc
(Porras 2008, 275).
H. Violle (1918) was one of these French clinicians.
This Commission also reported that anti-diphtheria serum was never, or hardly ever, used in France
(Marañón, Pitalluga & Ruiz 1918a & 1918b).
After heated debate, the Royal Academy of Medicine acknowledged the value of anti-pneumococcal
or anti-streptococcal serums for the treatment of the pneumococcal and streptococcal complications of
influenza respectively. Session of 23 November 1918. Anales de la Real Academia de Medicina
38:511-528, p. 527.
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Reig, director of the Municipal Bacteriological Laboratory of Valencia (Barona,
2006:114-136), who prepared and used an anti-pneumococcal serum. With the object of
complying with scientific requirements, Colvée tested it on animals before proceeding
to its use in humans (Colvée 1920). This procedure delayed its administration in the
1918-1919 pandemic, in which the anti-pneumococcal serum was used on a limited
scale (Colvée 1920). However, this important research allowed Colvée not only to use
the serum more widely during the flu epidemic of 1919-1920 (Colvée 1920), but also to
become the “National Academic Correspondent” of the Royal Academy of Medicine 23.
Nevertheless, the effectiveness of the serum prepared by Colvée was questioned by the
academic and hygienist Francisco Murillo (1865-1944). In Murillo‟s opinion, the
effectiveness of the anti-pneumococcal serum, like that of all the others, could only be
evaluated if it was applied to infected persons24. Murillo‟s objection to Pablo Colvée‟s
procedure for establishing the efficiency of his serum reveals that, as Eyler (2009) has
pointed out in the case of vaccines, the medical profession still could not agree on what
constituted a proper serum trial, and how such a trial ought to be conducted. This
occurred even among those who asserted that clinical impression was not enough. It
was therefore necessary to establish standards for the profession.
The experience gained from the influenza pandemic of 1918-1919 revealed the
need to standardize the preparation and application of serums and vaccines, those new
resources which had raised so many hopes which had failed to materialize during the
pandemic. In fact, International Serological and Biological standardization was an
important aim of the newly created League of Nations Health Organization (LNHO)
from its creation in 192125. As Borowy has pointed out, such international
standardization work was due to the coincidence that the renowned Danish serologist
Thorvald Madsen became President of the Health Committee of the LNHO (Borowy
2009a, 208).
WHAT THEORETICAL PART MIGHT ANTIBIOTICS HAVE PLAYED IN
THE PANDEMIC OF 1918-1919?
23
24
25
Archive of the Royal National Academy of Medicine, Folder 292 [Miscellaneous Papers, 1920 (II)].
«Expediente nº 24. Pablo Colvé y Reig».
Archive of the Royal National Academy of Medicine, Folder 292 [Miscellaneous Papers, 1920 (II)].
«Expediente nº 24. Pablo Colvé y Reig».
An interesting recent work about the role of this institution has been published by Borowy 2009b. On
Spanish participation in the LNHO, see: Barona & Bernabeu-Mestre 2008, 143-229.
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In view of the importance given to pulmonary complications in the seriousness
of the influenza pandemic of 1918-1919 and thus in its high mortality, we may ask what
part antibiotics, if they had existed, might theoretically have played in this pandemic. A
very obvious answer seems to be that antibiotics could have been the perfect treatment
for the respiratory complications of influenza caused by various bacteria
(pneumococcus, streptococcus, staphylococcus, etc.). So we may conclude that the
majority of deaths caused by the pandemic of 1918-19 would have been avoided.
It is true that, as some authors have pointed out, the downward trend of deaths
from influenza and pneumonia began in about 1937 with the advent of the sulpha drugs,
and became more pronounced a few years later with the introduction of penicillin and
Aureomycin (Collins & Leihmann 1957, 779). However, we also know that bacterial
resistance to antimicrobial substances had been recognized from the start, and that by
the 1930s, bacterial resistance to sulphonamides was well established; and by the 1940s
there was also evidence of the resistance of some bacteria to penicillin26. Indeed, the
resistance of Staphylococcus aureus to penicillin soon became clear, and became an
increasingly worrying problem from the late 1940s onward, despite the appearance of
new antibiotics.
Bearing in mind what has just been said above, it may be interesting to
undertake a brief review of what happened during the 1957-1958 pandemic, in order to
evaluate the role played by antibiotics in it, and to establish to what extent their use
might have contributed to reducing mortality in this pandemic. The examination of what
happened during that health crisis will also be of interest to prove whether there was any
protocol for the administration of antibiotics to treat the pulmonary complications of flu.
Before doing so, I shall give a little basic information on the main characteristics of the
pandemic of 1957-1958, the so-called Asian flu.
A FEW REMARKS ABOUT THE INFLUENZA PANDEMIC OF 1957-1958, OR
ASIAN FLU, AND ITS MEDICAL-SCIENTIFIC CONTEXT
The influenza pandemic of 1957-1958 had some temporal similarities with the
1918-1919 pandemic. It started in Peking in the spring of 1957, reached Hong Kong
about the beginning of April 1957, and the United States and Europe late in the spring
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(by the third week of May) of this same year (Dauer 1958, 803). A new and more
virulent outbreak occurred after the summer in the majority of countries, followed by
another outbreak in early 1958. However, the Asian flu differed from that of 1918-1919
in that its mortality was lower - according to different authors, between one and four
million deaths - and also in that death was relatively more common in older age groups,
in contrast with the high mortality, principally from influenza and pneumonia, among
young adults in the 1918-1919 pandemic. Most of the excess deaths of 1957-1958 were
attributed to pneumonia and cardiovascular disease (Dauer 1958, 809).
What new knowledge did Medicine have about flu in 1957-1958? One of the
fundamental differences was that the subject of its aetiology had been resolved in 1933
with the discovery of the virus by Andrewes, Smith and Laidlaw. From then on, the
viral aetiology of influenza was accepted, both in humans and animals. Research carried
out in the almost 25 intervening years had enabled scientists to prove the immunity
caused by the flu virus, but also the complexity of this phenomenon in practice. This
complexity arose from the existence of various types of human flu virus, and from their
capacity to vary from one year to another, as well as to incorporate elements of any of
the porcine or avian flu viruses.
The scientific research carried out had shown that the flu virus was frequently
associated with various bacteria (streptococcus, pneumococcus, staphylococcus,
Pfeiffer‟s Bacillus, etc.). It was thought that these bacteria were those responsible for
the complications (particularly respiratory) of flu and thus of the seriousness of some
epidemics and pandemics. However, such an important role played by bacterial
association in the mortality provoked by the flu had begun to be questioned in the
1950s. Consideration was also given to the responsibility that the flu virus itself might
have in the matter. As we shall see shortly, the “Asian” flu was considered to be a good
opportunity to clarify this point once and for all.
Although we have already mentioned that sulphonamides and antibiotics were
incorporated quite early into the treatment of flu, it is worth remembering that their
initial use was also to treat flu. A similar procedure was followed in the case of other
viral diseases. However, the ineffectiveness of these antimicrobial resources in fighting
flu led to them being relegated to the treatment of the bacterial complications of the flu:
26
For more information on this matter, see Condrau 2009, 349-354 and the bibliography given in that
work.
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bronchopneumonia, otitis, etc. When the “Asian” flu broke out, this debate was still
open, and there were different opinions between clinicians and laboratory specialists.
The knowledge that the latter had acquired about antibiotics led them to be more
restrictive and selective in their use, and to defend the role of specialists in this matter,
the need for their existence and their incorporation into hospitals to achieve greater
control of infectious diseases. An important endorsement for these demands was the
phenomenon of resistance, which the appearance of the new antibiotics was not able to
eliminate, and which they attempted to fight using combinations of antibiotics. Before
the flu pandemic of 1957-1958 this formula had been tried out with some degree of
success for tuberculosis (Condrau 2009, 347-349).
THE
TREATMENT
OF
PULMONARY
COMPLICATIONS
IN
THE
INFLUENZA PANDEMIC OF 1957-1958. SEARCHING FOR A SPECIFIC
ANTIBIOTICS PROTOCOL
Against a scientific background such as that described, during the Asian
influenza pandemic some research concentrated on the in-depth study of pulmonary
complications, with the aim of answering the perennial question: was bacterial
pneumonia the major cause of fatalities in an influenza pandemic? And, if so, might
fatalities be prevented by modern antimicrobial drugs? (Louria, Blumenfeld, Ellis;
Kilbourne & Rogers 1958, 213). The new studies revealed that the influenza virus could
cause many deaths on its own account, but also showed the important role played by
bacteria – especially staphylococcus (Langmur 1958, 491; Dauer 1958, 810),
streptococcus, pneumococcus and Haemophilus influenza – which were associated with
the influenza virus. According to these new studies, several authors recommended
keeping a constant watch as well as undertaking post-mortem examinations, in order to
enable the nature of the secondary infecting organisms to be rapidly discovered
(Pulmonary... 1957, 873). This information should be passed as quickly as possible to
the medical profession, who could then choose the specific antibiotic. The theory was
clear, but specific antibiotic therapy, to forestall or combat pulmonary complications,
was still by no means standardized. However, efforts were made to establish it during
this influenza pandemic, in order to control secondary bacterial infections with the use
of antibiotics, and subsequently to reduce the number of deaths during influenza
pandemics and epidemics.
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A review of the main specialized literature shows that the tetracyclines were
considered the most fashionable drugs for treating the pulmonary complications of
influenza; but at the same time it was acknowledged that they had “the disadvantage
that an effective blood concentration cannot be achieved in under twenty-four hours,
and with the common occurrence of gastro-intestinal symptoms in the Asian epidemic
their uncertain action upon the bowels may cause confusion. For these reasons the
quicker-acting penicillin was preferable for routine use” (Pulmonary... 1957, 873).
However, this treatment was not effective in combating all bacterial pneumonia.
As had been observed in previous epidemics, staphylococcal infections were
particularly troublesome in most countries because of resistance to new antimicrobial
drugs. Indeed, some studies showed that “the proportion of strains resistant to
antibiotics was relatively high in fatal cases, compared with those isolated from cases of
pneumonia that recovered” (Payne 1958, 1013). As Payne (1958, 1013) pointed out: “in
these strains resistance was common to penicillin and streptomycin, less common but
quite frequent to Aureomycin and Terramycin, and least common to erythromycin”.
Hence, as already mentioned, the importance of identifying the bacteria that provoked
the pneumonia as soon as possible, in order to choose the specific antibiotic; but also
the need to establish a protocol for combating secondary infections due to
Staphylococcus aureus, the most resistant bacteria. According to these results, for some
authors, the treatment should consist of penicillin in large doses combined with 1 g. of
erythromycin four-hourly (the first doses being given intravenously), 25 mg. of
hydrocortisone six-hourly (either by intravenous drip or intramuscularly), and
continuous oxygen (Pulmonary complications... 1957, 873). Chloramphenicol and
novobiocin were other antibiotics used to fight staphylococcus (Lowbury 1963, 585; A
combined study group 1958, 912). Furthermore, according to some doctors,
staphylococcal antitoxin or gamma globulin should also be given, if available
(Pulmonary complications... 1957, 873). The final aim of such treatment was to prevent
sudden deaths following pulmonary bacterial infections.
It was also recognized that chronic bronchitic patients constituted a serious
problem in an influenza epidemic. Consequently, they should be among those given
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priority in any scheme of vaccine prophylaxis27, and specific antimicrobial remedies
should be administered earlier and in larger doses than for the rest of the population.
In view of the above we may say that the flu pandemic of 1957-1958 served to
highlight more clearly the need to establish a protocol for using antibiotics to treat
respiratory complications of flu and, above all, to combat secondary infections due to
Staphylococcus aureus, which was responsible for a large proportion of the cases with a
fatal outcome (Lowbury 1963, 585; Darke, Watkins & Whitehead 1957; Deaths from...
1958).
To what extent did Spanish doctors follow the international standards we have
just mentioned during the pandemic of 1957-1958? It is difficult to give a complete
answer to this question, due to the historical circumstances in which the health crisis
occurred. Spain was governed by a dictatorship that, after having been excluded from
the principal international political and health organizations, was beginning to come out
of its isolation after signing agreements with the United States and being admitted to
some of these international agencies. However, the shortage of economic resources was
still a major problem. Let us remember, too, that the degree of scientific and health
modernization which had been achieved during the Second Republic had been lost after
the Civil War as a result of the widespread exile of leading Spanish scientists and
doctors. We should therefore not be surprised by the lack of scientific works devoted to
the flu pandemic of 1957-1958. Some of them (Hannoun 1957; Mouy 1957) are simply
translations of those published in foreign journals. Among the original articles we may
distinguish different types of author, and different types of information provided. We
find some contributions from figures of the scientific stature of the epidemiologist and
virologist L. Albaladejo28 (1958) on the virus of the pandemic. But the most frequent
are those by doctors wishing to relate what had happened in the place where they
practised (Tello 1957; Bravo 1958; Sarragúa & Gómez 1958). In addition, as was to be
expected, there are clear discrepancies between the information provided by these
doctors and that given by the health authorities. While the former stressed the shortage
of drugs for treating the flu (Bravo, 1958), the Inspector General of Health took pains to
27
28
There were many problems with the allocation and distribution of influenza vaccine (Preparation...
1957).
L. Albaladejo, García-Berenguer, trained in the Virchow-Krankenhaus in Berlin, who worked at Johns
Hopkins University, played a leading part in the modernisation of epidemiological studies of
poliomyelitis in 1929 (Albaladejo 1930). His dedication continued in the fifties (Albaladejo 1958)
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emphasize that the “Asian” flu had not presented such a serious problem in Spain as in
other countries (García 1958).
After an examination of the scant Spanish medical literature concerning the
pandemic of 1957-1958, we may say that Spanish doctors also used antibiotics during
the pandemic of 1957-1958. Nevertheless, their use was conditioned by the political,
social and economic circumstances surrounding Franco‟s dictatorship, and it is very
difficult to evaluate the real role played by antibiotics in the treatment of influenza
complications during that pandemic. Judging by the considerable number of articles
devoted to antibiotics, and the issues analyzed in them and their quality, there appears to
have been a good degree of knowledge about antibiotics, and the problems they
presented – such as the resistance to staphylococcus – and the guidelines given in
international forums (Martínez & Lizaur 1954; Lorenzo 1958; Sánchez 1958).
Similarly, we have evidence of the interest shown by some hygienists in providing
doctors with up-to-date knowledge on the different aspects of influenza prior to the
pandemic of 1957-1958. Indeed, one of these initiatives (Dominguez 1954) included
abundant information on the treatment of flu and its complications, and gave some
guidelines for the selection of the most appropriate antibiotic or antibiotics, depending
on the bacterial flora predominant in the complications. For bronchitis and
bronchopneumonia it recommended sulphonamides for normal cases, but in serious
cases it proposed the use of a combination of antibiotics. Specifically, it recommended
“penicillin (4 million units per day for five to ten days) in combination with 2 grams a
day of streptomycin, Terramycin or Chloromycetin” (Domínguez 1954, 47).
All this leads us to think that Spanish doctors (at least some of them) had
sufficient theoretical knowledge about antibiotics and their use in the bacterial
complications of flu to have been able to deal with the pandemic of 1957-1958 in a
similar way to that adopted outside Spain. However, the shortage of resources – health
infrastructure and medicines – would have made standard use of antibiotics difficult.
This statement – perhaps a little rash and to be taken as provisional29 – is supported by
the testimony of the doctor Gabriel Bravo (1958). This doctor denounced the shortage
of antipyretics and painkillers in Spanish pharmacies during the pandemic, and
during the epidemic presence of polio in Spain. For more information on his work, see Ballester &
Porras 2009, 67-68.
90
91
demanded that “the broad-spectrum antibiotic medication which is not manufactured in
our country should be imported in the necessary quantities” in order to put it “within the
reach of all those who need it and not just of the financially well-off” (Bravo 1958, 76).
Similarly, he declared that “the hospitalization of influenza patients” in Spain was “a
utopia”, and pointed out the difficulties in following the recommendations of the
specialized literature to rapidly identify the specific bacterium responsible for
respiratory complications. Hence the need not to delay “treatment until the germ
causing it has been identified” (Bravo 1958, 77). The therapeutic guidelines that he had
used for pulmonary complications of flu consisted in the combination of a penicillinstreptomycin mix in a dose of one gram every 24 hours in adults with intramuscular
Terramycin – 100 milligrams every 12 hours (Bravo 1958, 77). To these he added a
steroid (prednisone or prednisolone) in extremely serious cases.
BY WAY OF AN EPILOGUE
As we have shown, the expectations placed by health professionals in the
Science of serums at the beginning of the influenza pandemic of 1918-1919 were not
entirely met. The experience of this pandemic showed that what was missing was,
above all, the necessary scientific consensus to approach the aetiology, treatment and
prophylaxis of “Spanish flu” properly, within the bacteriological paradigm. It also
highlighted the need to standardize the preparation and application of serums and
vaccines, the new resources that science offered in 1918-1919.
When the Asian influenza pandemic occurred, science was confident of its
ability to confirm whether the pneumonia bacteria were the major cause of fatalities in
pandemic influenza, and to demonstrate the important role that antibiotics could play in
preventing deaths due to pulmonary complications.
Although worldwide there was a generalized use of antibiotics which made it
possible to successfully combat some of the pulmonary infections of the 1957-1958
influenza pandemic and reduce the mortality rate – lower than in the 1918-1919
pandemic – it was unable to prevent a considerable number of deaths provoked by
certain bacteria (such as staphylococcus) which were resistant to these new drugs
29
We are well aware of the lack of sources we have to back up this statement. It should thus be taken as
provisional, since it may be qualified or rejected if future research has access to other sources
containing more information on this subject.
91
92
(Lowbury 1963). Nor were antibiotics effective in preventing other major fatalities: the
deaths caused by the influenza virus itself.
In other words, and to conclude, the pandemic of 1957-58 revealed the important
role played by antibiotics, but also their limitations in combating the infectious
pulmonary complications of influenza pandemics. In order to reduce these limitations
and avoid deaths caused by germs resistant to the new anti-microbial drugs, some
doctors thought it would be necessary to establish a protocol for the use of antibiotics.
Although this statement may appear rather hasty, and is strictly provisional, we
may say that the standardized use of antibiotics by Spanish doctors (at least, one sector
of them) during the pandemic was hampered by the shortage of resources (health
infrastructures and medicaments) rather than by a lack of sufficient theoretical
knowledge about antibiotics and their use in the bacterial complications of flu.
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96
„From antibiotics to cancer chemotherapy (1950s-1980s):
the transformation of Rhône-Poulenc in the era of biomedicine‟
Viviane Quirke
Introduction
This paper presents the preliminary results of a Wellcome-Trust funded project to
compare the cancer chemotherapy programmes of two companies: the British group
Imperial Chemical Industries (which in 1999 spun off its pharmaceutical division,
now part of AtraZeneca), and its French counterpart, Rhône-Poulenc (now part of
Sanofi-Aventis). A major difference between the two firms is the fact that, whereas
ICI‟s cancer programme began with the study of nitrogen mustards and synthetic
hormones during World War Two, Rhône-Poulenc‟s grew out of an antibiotherapy
programme in the 1950s. This was based on the knowledge and know-how acquired
under license from the American drug company Merck, was originally directed
towards the treatment of infectious diseases, and led to Rhône-Poulenc‟s first major
anti-cancer drug, daunorubicin (Cérubidine, discovered almost simultaneously by
Farmitalia, Rhône-Poulenc‟s partly-owned Italian subsidiary), followed by the semisynthetic anthracyclin, rubidazon, still used today in combination therapy for
leukaemia and other cancers. Rhône-Poulenc‟s cancer chemotherapy programme
therefore involved numerous and complex contacts, which will be touched upon in
this paper: 1) between different firms; 2) between different countries; 3) between
different areas of scientific and technical expertise; 4) between different therapeutic
fields; 5) and last but not least between firms, research institutions, and hospitals, as
part of France‟s burgeoning post-war biomedical complex. I argue that in the process
of developing antibiotic substances, and applying them to the field of cancer, the
French chemical group not only underwent a profound transformation, but also played
an active part in the creation of French biomedicine. To begin, I present an overview
of the history of Rhône-Poulenc and its involvement in the field of antibiotics, before
describing in greater detail the French group‟s cancer chemotherapy programme.
98
Origins and development of Rhône-Poulenc
Rhône-Poulenc was formed in 1928 from the merger between the pharmaceutical firm
Poulenc-Frères and the chemical company la Société des Usines Chimiques du Rhône
(SUCR). At the same time, a selling company was founded, named Spécia (derived
from the word „spécialités‟, i.e. ethical preparations), with the purpose of bringing
together the pharmaceutical activities of the new group, (Chauveau 1999, 577; Cayez
1988, 121) and the British company May & Baker became its wholly-owned
subsidiary. (Ibid., 126; Slinn 1984)
From its creation, Poulenc-Frères had been one of the most innovative pharmaceutical
companies in France, building one of the first industrial research laboratories in the
country, and embarking on the development of synthetic remedies inspired by the
products of the German dyestuffs industry. Many of these remedies were developed
by the pharmacist Ernest Fourneau, who continued to collaborate with the firm after
he left in 1911 to direct the new Therapeutic Chemistry Laboratory at the Pasteur
Institute in Paris, and again after the merger between Poulenc and SCUR in 1928
(Liebenau and Robson 1991, 52-61; Quirke 2008). The special relationship forged
between the Therapeutic Chemistry Laboratory and Rhône-Poulenc around the
personality of Fourneau was to play an important role in the development of a modern
French pharmaceutical industry, culminating in the discovery of the broad-spectrum
antibacterial drug sulphanilamide in 1936, and later in the development of synthetic
anti-histamines, analogues of curare, and the psychotropic drug chlorpromazine
(Robson 1990, 107-22; Blondel-Mégrelis 1994, 283-96). Until World War Two,
Rhône-Poulenc‟s expertise in pharmaceuticals therefore lay essentially in the field of
synthetic organic chemistry. However, during the war, the group became involved in
the development of penicillin, a development that marked its entry into the antibiotics
industry. I will say a few words about it here, as this was to have a major impact on
Rhône-Poulenc‟s R&D activities, which grew along two principal axes after the war:
1) synthetic drugs, 2) antibiotics.
98
99
Developing French penicillin during World War Two
In 1942, Rhône-Poulenc obtained English technical reports describing the preparation
and dosage of penicillin. My evidence suggests that these were the 1940-1 Lancet
articles written by Howard Florey and his team at Oxford, and received via RhônePoulenc‟s Spanish subsidiary.1 However, at first, Rhône-Poulenc ignored these
reports. The group‟s penicillin project was spurred on by the realisation in April 1943
that the Germans had become aware of progress made with the antibiotic. An article
on penicillin had appeared in the German journal Klinische Wochenschrift on 17 April
1943, encouraging Rhône-Poulenc‟s director of research, Raymond Paul, to contact
Federico Nitti, one of their collaborators at the Pasteur Institute,
2
in the hope that
Nitti would study the question, and in order not to fall behind in what he referred to as
„the penicillin race‟.3
Nitti was a bacteriologist, who worked on the production of vaccines and sera at the
Pasteur Institute. At first, Nitti worked by himself. In the Pasteur Institute‟s
mycological collection, he found a sample of Penicillium notatum mould that had
been donated by Alexander Fleming during one of his visits to Paris. From this, Nitti
succeeded in growing the mould, and sent two batches of penicillin juice for
extraction to the group‟s main research and production centre in Vitry, the first on 1 st,
and the second on 6th October 1943. However, Nitti‟s subsequent attempts to step up
production failed, and Vitry took over the task in the second half of the month,
obtaining enough solid penicillin for tests to be undertaken in mice.4 The results of
these tests were announced by Nitti at a meeting of the Association de Microbiologie
de Langue Française, on 25 October. The first clinical trials took place at the Pasteur
Hospital at the beginning of 1944, followed by more extensive trials at the Broussais
Hospital.5
1
2
3
4
5
Rhône-Poulenc Santé (RPS) 186, Pénicilline 1: R-P au Ministre de la Santé Publique (7 Aug. 1945).
(RPS) 186 Ibid., 5 May 1943.
(RPS) 186 Ibid., 30 Aug. 1943. For more on Rhône-Poulenc‟s involvement in this „penicillin race‟,
see Quirke 2008 Ch. 4.
RPS 186, 1; Dr Cosar: „Débuts de la pénicilline à Vitry‟ (15 May 1944).
(RPS) 186 Ibid., 20 Jan. 1944.
99
100
The firm‟s commitment to the project, which would become associated with the
Liberation of Europe, increased in the second half of 1944.6 Later in the year, RhônePoulenc was requested by the French Provisional Government to build a special
factory in Vitry for the extraction, drying, and conditioning of penicillin destined for
the Leclerc Division. Until it could be obtained from mould juice produced locally,
the penicillin, or „pipiline‟ as it became known, (Broch et al. 1945, 9) was at first
extracted from the urine of American soldiers (see table 1). In order to meet the
growing demand for the drug, a government penicillin plant for the production of
mould juice by surface culture was also being constructed in the rue Cabanel, in the
centre of Paris. For this, the Provisional Government sought advice from British and
American academic laboratories and manufacturers within the framework of the
Mission de la Pénicilline, set up around September 1944, as well as from the two
largest French pharmaceutical firms, Rhône-Poulenc and Roussel-Uclaf (Quirke 2008,
158-162).
Table 1
Million units of penicillin received
(either as urine or mould juice)7
Units received
Month
Unit
received
Feb. „45
March
April
May
June
July
August
8.7
31.8
urine
Units
produced
Bottles
delivered
juice
27.7
354.3
428.4
251.6
279.5
2.5
42.6
74.9
204
280.5
140.9
200
0
80
454
749
1,842
2,648
902
However, in anticipation of supplies of American penicillin, mass-produced by
submerged culture, being made available more widely to the French public in October
1945, Rhône-Poulenc asked to be released from its obligations to the French Ministry
of Health, the Ministère de la Santé Publique, and be allowed to enter into a private
6
(RPS) 186 Ibid., May 1944.
100
101
contract with Merck to import their deep-fermentation technology.8 Penicillin
symbolized France‟s reintegration into the Allied Camp, and Rhône-Poulenc had been
an instrument of this reintegration. This helps to explain why, although biological
drugs and fermentation technology were alien to them, Rhône-Poulenc retained its
penicillin plant, a legacy of its wartime role as one of the foremost pharmaceutical
companies in France, and went on to develop new antibiotics of its own.9
Rhône-Poulenc’s cancer chemotherapy programme
Although Rhône-Poulenc had gained a foothold in the antibiotics field independently
thanks to their early involvement with penicillin, their cancer chemotherapy
programme originated in the expertise the French group acquired, to a large extent,
under license from the American company Merck. This soon brought them into
contact with the knowledge and know-how required for the production of
streptomycin, as well as penicillin. Building on this knowledge and know-how,
Rhône-Poulenc was able to develop spiramycin, pristinamycin, and the semi-synthetic
antibiotic metronidazole (still used today for the treatment of parasitic infections,
including trichomonas). Rhône-Poulenc‟s cancer research programme, which had
started in 1956 and led to the discovery of the cytotoxic properties of its antibiotic
rufochromomycin, was further strengthened by the acquisition of the Laboratoires
Roger Bellon, in 1963. It produced the group‟s first major anticancer drug,
daunorubicin (Cérubidine), which like its predecessors, spiramycin, pristinamycin,
and rufochromomycin, had been isolated from a strain of streptomyces, in 1962, and
is still part of the medical armamentarium against cancer today. Daunorubicin was
found to be active against leukaemia in the firm‟s pharmacological cancer screens,
and was tested in the clinic by the physicians Jean Bernard and Claude Jacquillat at
the Hospital Saint Louis in Paris, in 1964. It was followed soon after by rubidazon, a
semi-synthetic
derivative
which
was
obtained
by
chemical
reaction
of
7
RPS 186, 2: 12 Sept. 1945.
RPS 186, 1: lettre au Ministre de la Santé Publique (7 Aug. 1945).
9
For more on the pivotal role played by war in the history of Rhône-Poulenc, see Quirke 2004, 6483.
8
101
102
benzoylhydrazine on daunorubicin in 1968, and was also tested in leukaemia, in 1971.
The expertise in the part-synthesis and pharmacological testing of antibiotics with
anti-cancer properties, which Rhône-Poulenc developed in the course of building up
its cancer programme effectively combined its two principal areas of scientific and
technical expertise (synthetic organic chemistry and fermentation technology), were
later extended to plant extracts and other natural substances. This expertise was to
play an important part in the group‟s contribution to the anti-cancer drug Taxotère,
developed in collaboration with Pierre Potier of the Institut de Chimie des Substances
Naturelles in the 1980s, and a major anti-cancer drug today (Walsh and Le Roux
2004, 1307-27). Rhône-Poulenc‟s trajectory in relation to cancer therefore involved
the exchange not only of knowledge, practices, and artefacts (from soil samples and
microorganisms or fungi, to cell lines, tumour systems, laboratory animals, and
scientific instruments), but also of standards, norms and protocols, which circulated
across institutional, national, and disciplinary boundaries, and which I describe briefly
in what follows.
Circulation between different firms
As already suggested above, Rhône-Poulenc‟s most significant interaction was with
the American drug company Merck, with whom they entered into a contract in August
1945 to manufacture penicillin by deep fermentation methods. By 1947, this had
become a two-way contract, through which Merck gained access to Rhône-Poulenc‟s
knowledge and know-how on synthetic anti-histamines and Flaxedil, a curare-like
muscle relaxant, in exchange for which the French group also obtained a licence for
the production of streptomycin by submerged culture, as well as information about
some of Merck‟s other drugs, in particular cortisone and vitamin B12.10 The history of
Rhône-Poulenc‟s cancer chemotherapy programme is therefore one of internalisation
of Merck‟s knowledge and know-how of antibiotics, and of hybridisation of this
knowledge and know-how with its own expertise in synthetic organic chemistry.
10
RPS 10285, „Visite des Drs Major et Molitor‟ (20 mai 1948) ; Ibid., „Entretien avec Mr Georges de
Merck‟ (13 mai 1949).
102
103
It is also one of assimilation of the research networks of other firms, mainly through
mergers and acquisitions. In relation to cancer, the merger with Roger Bellon in 1963
played an especially important role. Not only did the group obtain rights to
bleomycin, which had been isolated by Japanese researchers in 1962, was developed
under license by Roger Bellon, and like Rhône-Poulenc‟s own anticancer drugs was
an anthracyclin antibiotic, but it also gained valuable additional contacts in the
oncology community. As to May & Baker, Rhône-Poulenc‟s fully-owned British
subsidiary since 1928, it played a significant role as go-between between the French
group and academic scientists and clinical researchers in Britain and in
Commonwealth countries.11
Circulation between different countries
Contacts with the US were most important for Rhône-Poulenc, because of the
prominent part played by American companies in the development of antibiotics, and
because of the impetus given to cancer research by the National Institutes of Health‟s
massive post-war cancer programme.12 Although they continued to send their
anticancer drugs to the National Cancer Institute for screening, Rhône-Poulenc soon
developed its own considerable expertise in pharmacological screening, and by the
1980s they were receiving numerous requests from doctors, scientists and other firms,
at home and abroad, wishing to have their drugs tested in the firm‟s anticancer
screens. By the 1980s, the sizeable place they had gained in the market for anticancer
drugs, especially of natural origin, also made Rhône-Poulenc a valuable ally for
Japanese drug companies, which offered them their antibiotics for manufacture and
commercialisation under license.
However, at the root of this successful anticancer programme were more traditional
ties, with France‟s former colonies, which gave the firm access to a variety of natural
11
12
For more on the relationship between Rhône-Poulenc and their British subsidiary, see Quirke
YEAR, 317-38.
Bud 1978, 425-59; Goodman and Walsh 2001. See also various contributions in Cantor 2007.
More specifically on the history of cancer chemotherapy: McGregor 1966, 374-85; Zubrod et al,
1966, 349-540; Zubrod 1979, 490-505.
103
104
products and microorganisms, in the case of daunorubicin, from a soil sample
accidentally taken from a flower pot in Algeria! (Gambrelle 1995, 34-5).
Circulation between different areas of scientific and technical expertise
The role of antibiotics is an aspect of the history of cancer chemotherapy that has
largely been neglected by historians, and requires further research. Penicillin had been
tested in cancer but found to be inactive by M.R. Lewis in 1944 (Lewis 1944, 314-5).
In the 1950s, antibiotics were among the substances screened by the American
National Cancer Institute (NCI)‟s Cancer Chemotherapy National Service Centre
(CCNSC) (Endicott 1957, 257-93). One of the first antibiotics to show activity against
cancer in these screens was Merck‟s anthracyclin antibiotic, actinomycin D, which
belonged to the streptomyces family of antibiotics (Weatherall 1990, Ch. 11; Sneader
2005, 311-13). They were later shown to work against tumour cells as alkylating
agents, by an intercalative mechanism that enables them to bind strongly to DNA,
thus preventing complete separation of the two DNA strands during cell division
(Lerman 1961, 18-32).
The discovery of the cytotoxic properties of actinomycin D, marketed by Merck as
Dactinomycin, prompted Rhône-Poulenc to initiate its own cancer research
programme in 1956. This led to the identification of the cytotoxic properties of its
own anthracyclin antibiotic, rufochromomycin, which had been isolated earlier, in
1952. The Rhône-Poulenc laboratories involved in this cancer programme included
newly established laboratories, such as cancerology, as well as older ones:
biochemistry and fermentation, and organic chemistry (for the discovery of new
compounds); pharmacology and toxicology, and analytical chemistry (for further
investigation of new compounds).
By the early 1960s, the group had adopted a two-pronged approach to the search for
anticancer drugs among antibiotics and their derivatives, synthetic compounds, and
104
105
later also plant alkaloids and other natural substances.13 As well as chemotherapy, this
approach included immunology and virology labs (numbering 25 out of a total 100
researchers working on cancer). It involved acquiring expertise from outside, but also
the exchange of expertise between departments within the firm. In cancerology, Dr
René Maral, MD, was hired to develop anti-cancer screens in vitro (in various murine
cell lines) and in vivo (in both inbred and outbred mice, either bred in-house or by
commercial breeding laboratories). In biochemistry and fermentation, L. Ninet, with
an MSc in Pharmacy, was in charge of three departments: 1) bacteriology, where
microorganisms producing antibiotics with antitumour activity were isolated; 2)
fermentation, consisting of a laboratory and a „shop‟ where 36 fermentation tanks
with a 20-800 litre capacity enabled the culture of the microorganisms isolated in the
bacteriology department; and 3) extraction and purification, working in cooperation
with a technological laboratory for the formulation of biological drugs. In organic
chemistry, a chemical engineer, M Messer, was responsible for the synthesis and
semi-synthesis of new compounds from natural substances or fungi, with the aim of
attaining a greater spectrum of activity or improving the chemotherapeutic index. The
toxicology and pharmacology laboratories, under L. Julou (a veterinary doctor), dealt
with the problem of toxicity of anthracyclins (especially their cardiotoxicity) and with
their pharmacological properties, and the analytical chemistry laboratories (under J
Robert, chemical engineer) provided information about their physicochemical
characteristics and their structure, mainly in order to satisfy the requirements of the
regulatory authorities and in preparation for marketing applications.
Circulation between different therapeutic fields
In many ways, the shift from antibiotherapy to cancer chemotherapy in RhônePoulenc‟s research programme reflected what was going on elsewhere. One of their
first and foremost clinical collaborators, the paediatrician Jean Bernard, had earlier
experienced a similar shift in his own research programme: whereas before and during
13
Much of the information that follows is based on a document produced in 1976, describing RhônePoulenc‟s approach to cancer chemotherapy. Sanofi-Aventis (SA) 894402B24: M.M. Dubosc et al,
„Cancer Research at the Rhône-Poulenc company‟ (22 Oct. 1976).
105
106
World War Two he had studied infectious diseases, with the advent of the
sulphonamides and penicillin his interests switched towards the diseases from which
the terminally ill children remaining on his wards were suffering, in particular
leukaemia and cancer.14
However, as seen above, Rhône-Poulenc‟s research programme was inspired and
influenced mainly by developments taking place in the US, and within a firm like
Rhône-Poulenc the disease entity „cancer‟ was defined as much by the substances
themselves, which crossed disciplinary boundaries with ease, as by the knowledge
gained about malignant cells in the laboratory or the symptoms observed in cancer
patients in the clinic, which was transmitted by their growing network of
collaborators.
Circulation between firms, research institutions, and hospitals, at home and abroad
In the process of building its cancer research programme, Rhône-Poulenc developed
links with scientists and clinical researchers at home and abroad. These were
developed through consultancies or more informal links, through correspondence,
publications, membership of expert networks, attendance at conferences, and
sustained by the rapid internationalisation of cancer research in the decades following
World War Two.
These links read like a „Who‟s Who‟ of cancer research, beginning especially in
France, and from the 1970s onwards becoming an increasingly international network
of collaborators. In no particular order, and to name but a few, these included:
Professor Enselme (Medical Faculty, Lyon, 1940s)
Pierre Jollès (brother of George Jollès – chemical engineer at Rhône-Poulenc –
researcher in the Biological Chemistry laboratory of the Science Faculty in Paris,
from 1966 at the Institute of Cancerology and Immunogenetics (ICIG) of the Hôpital
Paul Brousse)
14
See for example Rigal 2008, 511-34.
106
107
Professor Mathé (ICIG, 1950s-60s)
Hospital Saint Louis (Paris, Professors Jean Bernard, and Claude Jacquillat – later of
the Institut de Recherches sur les Maladies du Sang, Université de Paris, Faculté de
Médecine, Unité de Chimiothérapie, 1950s-60s)
Dr Beck (Hôpital d‟Ivry)
Professeur Lemaire (Hôpital St-Antoine, Paris)
Professor Brouet (Hôpital Cochin, Paris)
Fondation Bergonié (Bordeaux)
Institut Gustave Roussy (with which the collaboration became closer in the 1980s)
Centre International de la Recherche sur le Cancer (Lyon – opened in 1972)
Institut de Chimie des Susbtances Naturelles (Gif-sur-Yvette, near Paris, Pierre Potier,
1970s)
Robert S Benjamin (Assistant Professor of Medicine and Pharmacology, University of
Texas System Cancer Centre, MD Anderson Hospital and Tumor Institute, Houston,
1970s)
Dr FJC Roe (Royal Marsden Hospital, UK, 1970s)
Dr Trouet, in Professor Duve‟s department (Laboratory of Physiological Chemistry,
Catholic University of Louvain, Belgium, 1970s)
Laboratory of Molecular Biophysics (CNRS, Orléans, Dr C Aubel-Sadron, 1980s)
These connections came in a variety forms, and evolved over time: from paying the
salaries of technicians working in hospital laboratories; to honorariums given to
consultants for work on specific projects or for more general advice; and participation
in cooperative groups for the development of cancer therapies. In this way, RhônePoulenc was not only part and parcel of, but helped to shape the French biomedical
complex in the decades following the Second World War.
Conclusion
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108
The roles of antibiotics on the one hand, and of cancer on the other, in the invention
of biomedicine and the construction of biomedical complexes after World War Two
have been noted many times. In this paper, I have shown how the two met and
combined in the laboratories of Rhône-Poulenc. In the process, the French group not
only underwent a profound transformation, from a firm focused on synthetic organic
chemistry, to one oriented towards biochemistry and fermentation technologies,
immunology and virology, and later molecular biology, but also, through its contacts
with the community of oncologists at home and abroad, it played an active part in the
creation of French biomedicine.
Acknowledgements
This paper presents the preliminary results of a research project funded by the
Wellcome Trust. I thank Marie-Thérese Bombon, Olivier de Boisboissel for their
assistance, and John Alexander for his helpful comments on an earlier version of this
paper.
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“From Antiserum to Antibiotics: Antimicrobials, Controlled
Trials and Limits to the Standardization of Therapeutic Practice
in America, 1930-1970”1
Scott H. Podolsky [for Circulation of Antibiotics: Journeys of Drug Standards, 19301970, [Madrid, 17 June 2009]
Introduction
This presentation has its origins at the intersection of two important papers.
Nearly three decades ago, at a former “History of Antibiotics” symposium held in
Honolulu, James Whorten had first drawn attention to the “Antibiotic Abandon” and
parallel emergence of “therapeutic rationalists” in the 1950s, without noting the
parallel intention of such reformers to rationalize behavior via the controlled clinical
trial (Whorton 1980). Harry Marks, who has of course demonstrated the waves of
reform groups which have dotted the American therapeutic landscape over the past
century (Marks 1997), in his “Trust and Mistrust in the Marketplace” drew particular
attention to “the social history of mistrust … [as] key to understanding both the
rationalist project and its reception in a given time, place and context.” (Marks 2000,
344).
In this presentation, and drawing upon Harry Marks‟ suggestion “to focus not on the
epistemological means for producing trust but instead on the social objects of
mistrust,” I will argue that the histories of antimicrobials, controlled clinical trials,
and attempts by academics to inculcate a rational, standardized therapeutics among
clinicians in the United States were tightly linked during a formative period from
1930-1970. Understanding such a trajectory allows us to better appreciate not only
the social history of the controlled clinical trial and the priorities of leaders in
1
This paper is an early version of an article published as "Antibiotics and the Social History of the
Controlled Clinical Trial, 1950-1970," Journal of the History of Medicine 65 (2010): 327-367.
Please see http://jhmas.oxfordjournals.org .
112
infectious disease in the United States during this time, but the consequences of their
efforts as well.
In the pre-antibiotic era, the treatment of pneumonia with antiserum was articulated as
a rational therapeutics, “proved” by 1930 via controlled clinical trials. Eventually
promulgated via centralized “pneumonia control programs” with potential public
health oversight, antipneumococcal serotherapy and the short-lived attempts to
promote its rational usage nevertheless illustrated the limits of “regulative” versus
“educational” enforcement accepted by the medical profession. Yet such veterans of
the antiserum era as Maxwell Finland and Harry Dowling would subsequently serve
at the epicenter of attempts to inculcate an explicitly rational therapeutics in the
context of first the broad-spectrum antibiotics, and still more critically, fixed-dose
combination antibiotics. With their initial attention focused less upon individual
clinicians than upon pharmaceutical marketers, Finland and his supporters would
wield the “controlled clinical trial” against the pharmaceutical “testimonial” as a
means of ensuring a rational therapeutics. In so doing, they would play a critical role
in the direction the subsequent Kefauver hearings (1959-1962) would take toward
mandating proof of drug efficacy via controlled clinical trials.
The Kefauver-Harris Amendments would set the stage for the DESI process, during
which hundreds of pre-1962 medications which did not pass this standard would be
removed from the market. The process would be epitomized by Supreme Court
hearings in 1969 regarding Panalba, Upjohn‟s fixed-dose combination antibiotic,
asserting the government‟s authority to remove the medication from the market
despite clinicians‟ insistence upon its utility in individual hands. Yet DESI would
represent the limits of the government‟s attempts to regulate antibiotics; and during
the same time that Panalba was taken off the market, both indiscriminate usage of
approved antibiotics and antibiotic resistance would proceed apace, as academic
leaders would turn their subsequent attention to educating individual providers, with
limited degrees of success.
Prelude: Antipneumococcal Antiserum
In 1892, William Osler had written of pneumonia, "It is a self-limited disease, and has
its course uninfluenced in any way by medicine" (Osler 1982, 529). Yet a year
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113
earlier, in Berlin, the brothers Georg and Felix Klemperer had attempted the first
treatment of pneumonia with antiserum.
Caught up in the advances of applied
humoral immunology which followed the countering of diphtheria and tetanus toxins
with antitoxin, they derived their serum through the inoculation of rabbits with
pneumococci (which had themselves been identified as the chief causal agent of
pneumonia by the end of the 1880s); and over the ensuing twenty years, such
treatment would become still more sophisticated through the sub-classification of
pneumococci into serological subtypes. By 1913, at the Hospital of the Rockefeller
Institute in New York, Rufus Cole and such colleagues as Oswald Avery were
successfully treating the most prevalent "type” of pneumococcal pneumonia with
type-specific horse serum, lowering the mortality rate from 25% to 7.5% (Avery et al.
1917). And by 1930, type-specific antipneumococcal serotherapy had been proved
efficacious on the wards of such large city hospitals as Boston City Hospital,
Bellevue, and Harlem Hospital (Russell and Sutliff 1928, Park et al. 1928, Finland
1930).
Nevertheless, a conundrum emerged: the treatment appeared to work best when
administered in the first days of the illness, yet patients often arrived in large urban
hospitals only when already gravely ill. Moreover, the treatment was laborious involving obtaining and incubating a sputum sample, the "typing" of the sample to
determine the serological subtype of the pneumococcus, and the testing of the patient
for anaphylactic reactions - and expensive. In response to such a quandary, the
Massachusetts Department of Public Health initiated a "Pneumonia Study and
Service" in 1931, in which antiserum was generated and "typing" centers and serum
depot stations were set up across the state. If a clinician called upon a pneumonia
patient, they could obtain a sputum sample in the home, send it by courier to a local
center for typing, have serum given to them, and administer the serum in the patient's
home (at first, with assistance from state-provided "collaborators") or a local hospital.
By 1935, nearly 1000 patients had been treated in 98 towns, with an 11.1% mortality
rate obtained when the patient was treated within the first four days of illness (Heffron
1937).
In the wake of the Massachusetts "experiment," and in the aftermath of
increased New Deal funding for public health activities, the federal government
funded what would come to be termed "pneumonia control programs" in nearly two
114
thirds of the nation's states (Dowling 1973). In the process, the United States Public
Health Service publicly reconfigured pneumonia as an "emergency," mandating the
cooperation of individual practitioners and state public health departments (U.S.
Government Printing Office 1940). By the end of World War II, however, pneumonia
collapsed as a public health concern. The more easily affordable and administered
sulfa drugs - first available for streptococcal infections by the mid-1930s, and for
pneumonia by 1939 - had already begun to displace antipneumococcal antiserum at
the peak of the pneumonia control programs' operations. And with the advent of
United States involvement in World War II, the pneumonia control programs
themselves collapsed, as physicians were called off to war and pneumonia
increasingly reverted to a private disease, treated without oversight with such magic
bullets as the sulfa drugs and then penicillin (and by the late 1940s and early
1950s, the first generation of "broad-spectrum" antibiotics) (Maclachlan 1943).
The antipneumococcal antiserum narrative provides the foreground for the
remainder of this presentation in three important respects.
First, the series of
“alternate control” trials used to “prove” the efficacy of antiserum in the 1920s and
1930s, as well as the debates over such controlled trials (concerning such issues as
internal and external validity) in the comparison of combination serochemotherapy
(serum plus sulfa drug) versus sulfa drug monotherapy in the treatment of pneumonia,
demonstrate the public attention focused upon the perceived strengths and limitations
of controlled clinical trials well before streptomycin and formal attention to
randomization itself (Podolsky 2006, 35-51, 91-131). Second, the experience of the
“pneumonia control programs” had demonstrated, even under such circumstances, the
difficulties in regulating physician prescribing behavior; instead, it had become
increasingly evident to centralized program administrators that educational measures,
rather than regulative means, would have to suffice. And with the collapse of the
pneumonia control programs, any sense of centralized oversight or monitoring of
physician prescribing behavior gave way to individualized notions of the correct
application of antimicrobial agents in respiratory disease (Podolsky2006, 53-87, 132141). As one practitioner remarked in 1941, in both an attack upon centralized
oversight and a foreshadowing of broad antibiotic “indications”:
And now I am starting in 1941 to use sulfathiazole and sulfapyridine prophylactically.
And why not? It has not been proven to work that way! Not scientific, you say!
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115
Remember we are front line soldiers; when we see the enemy we do not have to wait
for orders from headquarters through a long line of red tape. We must go for him,
without waiting for the attack! Again, it seems to me, that is common sense medicine.
What do we fear in grippe or a bad cold? Pneumonia. What do we fear in whooping
cough and other contagious diseases, or post-operative? Pneumonia. If pneumonia
develops, we have a remedy of proven value.
Why wait?
Can you tell when
pneumonia is going to develop? If it does develop, you would use sulfathiazole or
sulfapyridine with confidence. Then why not get the jump on those tough, little
bacteria? Kill them before they get a foothold. Why wait for the attack? Bomb their
channel ports! Wipe out their bases of supply! Prevent their starting out in the blood
stream; meet force with force!” (McIlwaine 1941, 410-411).
Finally, however, the antipneumococcal antiserum era – and especially, ongoing
debate over the rational utility of particular antimicrobial agents – had served as a
training ground for such emerging infectious disease experts as Boston City
Hospital‟s Maxwell Finland, as well as his first fellow, Harry Dowling. Finland, in
particular, would go on to become the nation‟s leading infectious disease expert, with
generations of trainees fanning out across the country.
And by the 1950s, as
“rational” application of first broad-spectrum and then fixed-dose-combination
antibiotics came to the fore, Finland and Dowling would focus and shape such debate
so as to apply to the wonder-drug era writ large.
The Broad-Spectrum Transformation in America
The era between 1948 and 1952 – epitomized by the advent of such “broadspectrum”
antibiotics
as
Aureomycin
(chlortetracycline),
Chloromycetin
(chloramphenicol), and Terramycin (oxytetracycline) – represents a watershed era not
only in the history of antibiotic usage, but in the history of wonder-drug marketing
and sales themselves (Kirby 1950, 235).2 As of 1948, two forms of antibiotics –
2
The term “broad-spectrum” itself appears to have entered the literature with Pfizer‟s initial
advertisement for Terramycin by name in July of 1950. Previously, the University of Washington‟s
William Kirby, at the General Scientific Meetings of the AMA in June of 1950, had spoken of the
“broad spectrum of activity of the newer antibiotics.” By February of 1951, Parke-Davis was itself
describing Chloromycetin as the “broad-spectrum antibiotic of choice,” yet Lederle does not seem
to have publicly used the term until January of 1952. See Terramycin advertisement, Journal of the
116
penicillin and streptomycin – accounted for 99.7% of United States antibiotic output
(Federal Trade Commission 1958, 67).3
Not only did they exhibit apparent
limitations to their scope of therapeutic application, but given that neither was
exclusively patented by a single company, they exhibited obvious limitations to their
profitability in the setting of multiple producers of each. 4 For such pharmaceutical
companies stimulated by the World War II efforts to produce penicillin as Lederle,
Parke- Davis, and Pfizer,5 worldwide searches were on for novel – and hence,
patentable – alternatives, ideally of wider therapeutic application.6
Lederle struck first, offering Aureomycin for interstate sale in December of
1948. Offered as “the most versatile antibiotic yet discovered, with a wider range of
activity than any other known remedy,”7 its sales would epitomize the change in scale
ushered in by the broad-spectrum antibiotics. Indeed, a presentation delivered by
American Cyanamid‟s president a decade later and intended to illustrate that
“Lederle‟s Antibacterial Drugs have a High Rate of Obsolescence” (and hence
justified their sales prices), instead, in portraying six graphs of consecutively
introduced antimicrobials, demonstrated the literal transformation in economic scale
from the era of antiserum through those of the sulfa drugs, penicillin, and then the
broad-spectrum agents.8 Parke-Davis would follow suit in March of 1949 with its own
broad-spectrum antibiotic, Chloromycetin (Maeder 1994).
However, no company would be so transformed by the broad-spectrum
antibiotics as would Chas. Pfizer and Company. The fermentation techniques used in
3
4
5
6
7
8
American Medical Association advertising section 143 (July 1, 1950): 10-11; Chloromycetin
advertisement, Therapeutic Notes (February 1951): back cover; “Why is Aureomycin the Low-Cost
Antibiotic in the Broad-Spectrum Field?” Aureomycin Digest 3 (January 1952): front cover.
Multiple formulations of such antibiotics, however, were available.
“Health for Patients, Gamble for Makers,” Business Week (March 25, 1950): 26. Federal Trade
Commission 1958, pp. 228-230.
Of the more than twenty companies producing penicillin during the wartime effort, Pfizer was by
far the single largest producer; Lederle, despite its early involvement in the penicillin efforts (along
with Pfizer, Merck, and Squibb), played a far smaller role, while Parke-Davis played a very minor
role. See Federal Trade Commission 1958, p. 331; Hobby 1985, 104-105.
For the postwar fortunes and misfortunes regarding penicillin and its derivatives, see Bud 2007.
A Review of the Clinical Uses of Aureomycin (Lederle Laboratories, 1951), 9. By the fourth issue
of its Aureomycin Digest, Lederle could report on the usage of Aureomycin for 27 types of
infection (some as narrow as Boutonneuse fever, others as broad as Gram-positive infections) with
the notation that “this list of infections is rapidly expanding and its ultimate extent cannot be
predicted.” In “The New Crystalline Aureomycin,” Aureomycin Digest 1 (July 1950): title page.
“Statement of Dr. W.G. Malcolm, President, American Cyanamid Co.,” United States Congress.
Senate Committee on the Judiciary. Subcommittee on Antitrust and Monopoly, Administered
Prices, Part 24: Administered Prices in the Drug Industry (Antibiotics), 86th Congress, 2nd session,
116
117
the production of citric acid would render Pfizer a leader in the American World War
II efforts to mass-produce penicillin, and Pfizer soon followed as one of the largest
producers of the equally nonexclusive streptomycin and dihidrostreptomycin (selling
to other companies to distribute) (Federal Trade Comision 1958, 95). Yet as prices
for such wonder drugs began to plummet, Pfizer‟s president, John McKeen, uttered to
the New York Society of Security Analysts the well-cited warning: “If you want to
lose your shirt in a hurry, start making penicillin and streptomycin.”9 Instead, he
proposed that “from a profit point of view, the only realistic solution to this
(antibiotic) problem lies in the development of new and exclusive antibiotic
specialties.”10
Five months previously, Pfizer had applied for a patent on the
production of Terramycin, (Mahoney 1980, 242) while only one month previously
Pfizer‟s board of directors had “voted to change its traditional marketing policy, and
commence selling directly to retailers, wholesalers, and hospitals, notwithstanding the
fact that Pfizer had had no experience in selling to these groups and had no sales force
adequate to undertake the promotion of ethical drug products.” (Federal Trade
Commission 1958, 140-1).
Terramycin may have ostensibly been named for the Terre Haute, Indiana site
of its origin in a clod of soil; but conveniently, as depicted in contemporary accounts
of Pfizer‟s efforts, “terra” encapsulated the entire post-streptomycin soil-sifting model
of antibiotic discovery, linking globally dispersed soil-gatherers with literally
antiseptically enshrouded mycologists, bacteriologists, and engineers involved in the
scanning, screening, testing, and production of novel antibiotic agents (Roueché 1951,
Kane et al. 1950, Pfizer 1952). And such emphasis upon production hid other stillmore radical marketing efforts behind Terramycin‟s emergence. Within eighteen
months, it had increased its sales force to three hundred detailmen; 11 by 1957, it
would boast two thousand (Mahoney 1980, 237).
More broadly, Pfizer and its
Terramycin directly changed the nature of journal advertising, especially as
exemplified by advertising in JAMA.
As later tabulated by the Federal Trade
Commission, antibiotic advertising in JAMA prior to 1950 was modest in extent and
typified by a lack of attention to trademarks or brand names (Federal Trade
9
10
11
1960, pp. 13635-13637. For the transforming influence of Aueromycin upon Lederle, see Mahoney
1959, 178.
“Health for Patients, Gamble for Makers,” 26.
“Pfizer and Antibiotics,” Drug and Cosmetic Industry 66 (1950): 393.
Pfizer Put an Old Name on a New Drug Label,” Business Week (October 13, 1951): 131.
118
Commission 1958, 132-133). Over the ensuing six years, however, the brand-name
advertising of the broad-spectrum antibiotics would both benefit from and catalyze
changing AMA journal policy to become the leading advertising presence in JAMA.12
Already the leading broad-spectrum JAMA advertiser between 1950 and 1952
(accounting for 68% of the total pages),13 Pfizer would be permitted to place its
appropriately named house organ, Spectrum, as a Terramycin-touting insert into
nearly every issue of JAMA between June of 1952 and 1956 (Federal Trade
Commission 1958, 134-135).14
The impact of such branded broad-spectrum antibiotics on antibiotic output
and prescribing as a whole was monumental. In 1948, total United States antibiotic
output totaled 240,332 pounds; by 1956, it had increased to 3.081 million pounds
(Federal Trade Commission 1958, 67).15 United States consumption, between 1950
and 1956, likewise increased from 139.8 to 645.2 metric tons (Federal Trade
Commission 1958, 269.),16 as antibiotics “ranked as the leading ingredient of
prescriptions in virtually every fortnightly survey made by the American Druggist
magazine since 1952.” (Federal Trade Commission 1958, 272)17 Moreover, despite
the decidedly non-zero-sum situation in which penicillin production generally
continued to rise, (Federal Trade Commission 1958, 73)18 it was soon surpassed by
broad-spectrum production and sales. In terms of production, in 1948, penicillin had
represented 64.9% of United States output (with streptomycin accounting for 34.8%);
by 1956, the broad-spectrum antibiotics comprised 38.6% of such output, and
penicillin only 34.4% (Federal Trade Commission 1958, 67). In terms of sales, as net
operating profit margins for broad-spectrum agents ranged from a remarkable 35.1%
12
13
14
15
16
17
18
Indeed, by 1957, 358 pages of JAMA advertising space were devoted to the broad spectrum
antibiotics, more than that devoted to all drug products in 1949. Compare Federal Trade
Commission 1958, 132 - 135.
Calculated from Federal Trade Commission 1958, 133-134; cf. with actual JAMA data.
Advertising in Spectrum was essentially Terramycin advertising for much of its existence.
Terramycin ads appeared in every issue of Spectrum from the house organ‟s inception until April of
1955.
Contributing to this, with the advent of the Korean War, was further government interest in
antibiotics and the stimulation of a dramatic private expansion of antibiotic production facilities.
Federal Trade Commission 1958, pp. 57-60.
The largest yearly percentage increase in antibiotic consumption occurred between 1950 and 1951
(with the advent of all three original broad-spectrum agents), representing a 109.7% increase; the
second-largest occurred the following year, a 43.1% increase (followed respectively by 24.9, 2.9,
16.3, and 2.9% increases).
“In the few instances when antibiotics have dropped to second place among the eight categories of
drugs prescribed, they have been outranked only briefly by barbiturates.”
A brief dip did occur between 1954 and 1955.
118
119
to 52.1% each year, (Federal Trade Commission 1958, 211-212)19 the gap was even
wider, as the broad-spectrum agents accounted for 165 million dollars in sales in
1956, as compared to 67 million dollars for penicillin (Federal Trade Commission
1958, 78).20
No single company was as transformed by the broad-spectrum revolution as
was Pfizer, the self-described “world‟s largest maker of antibiotics.”21 Indeed, by
1956, Pfizer accounted for 26% of the United States antibiotic output, rivaled only by
Lederle‟s 23.1% (Federal Trade Commission 1958, 83).22 By the same year, an
industry-leading 39.4% of Pfizer‟s sales were still accounted for by antibiotics
(compared to an industry average of 13.9% among antibiotic producers), and
Terramycin continued to account for over half of such Pfizer antibiotic sales (Federal
Trade Commission 1958, 199, 95). Such numbers reflected an expansive Pfizer
vision of the role of antibiotics in the growth of industry and the care of patients
(Winn 1950a, 467; 1950b, 984; Urdang 195, 404). As antibiotics continued to drive
the ethical drug trade itself, and as pharmaceutical sales continued to dramatically
outpace the national growth of disposable income, Pfizer‟s Thomas Winn, sales
manager of its antibiotics division, would feel free to cite Morris Fishbein‟s prophecy
that “a few years hence, with the wider spread of healthcare and the increased
productivity in new research medicines, the drug industry may easily be the number
one industry in dollars, in the United States.” (Winn 1950a, 563).
With respect to medical practice, however, Pfizer expected to have a still
greater impact. Its Terramycin campaign, it should be noted, was explicitly and
understandably geared towards demonstrating the wide range of applicability of its
wonder drug. Along such lines, and again in 1950, Pfizer president John McKeen
“roughly estimated that antibiotics can be used with fair to excellent results in 30 to
50 per cent of the cases requiring the attention of the physician.” (McKeen 1950, 652;
Winn 1950a, 472). Moreover, after enumerating a list of disease categories in which
antibiotics were of therapeutic utility (including such “general respiratory infections”
19
20
21
22
The profit margins, it should be noted, did tend to decline over the period as prices were cut and
marketing efforts were expanded.
Must footnote percentage of sales as feed supplement.
Letter-head in Finland papers; pamphlet 9445 at Library of Physicians; “Wonder Drugs‟ Wonder,”
Time (October 1, 1951), 91.
In terms of sales dollars, however, owing to Pfizer‟s heavy sales of antibiotics as feed supplements,
Lederle continued to hold 28.1% of the market, compared to Pfizer‟s 23.4%. In Federal Trade
Commission 1958, p. 96.
120
as the common cold, for the sake of
“preventing respiratory complications”),
McKeen reported that looking to the future, “if the gaps in antibiotic effectiveness
were filled in, antibiotic usage could easily double or even triple.” (McKeen 1950,
758-764)23 It was a wide - and largely home- or office-based (Winn 1950a, 473,
561)24 - “vista,” culminating in the prediction that “it is not impossible that the present
broad [sic] and energetic search for new antibiotics will lead within the next few years
to the discovery of microbial antagonists capable of hobbling all infectious disease.”
(Roueché 1951, 29-30)25
The Regulatory Vacuum
By the 1950s, the agencies traditionally relied upon to examine, if not curtail,
such exuberance were uniquely configured instead to promote its expansion. The
U.S. Public Health System, as described earlier, played no further role in monitoring
physician prescribing habits. The AMA‟s efforts in drug regulation, as detailed by
Harry Marks, had initially emerged during the Progressive era, as a self-consciously
reforming group of clinicians and pharmacologists sought to promote a “rational
therapeutics” free from commercial influence.26 Not only had the AMA advocated
the passage of the 1906 federal Food and Drug Act, but the year before it had formed
a Council on Pharmacy and Chemistry, intending, through the pages of JAMA, to
educate clinicians regarding the therapeutics emerging from an expanding
pharmaceutical industry. By 1929, the AMA granted teeth to the Council in the form
23
24
25
26
See also Terramycin‟s stated indication in “mild or severe infections associated with the upper
respiratory tract,” in Terramycin advertisement, Spectrum 10/31/53 Perhaps in response, Lederle,
after producing a somewhat cautious 1951 Review of the Clinical Uses of Aureomycin arguing
against “the indiscriminate use of antibiotics,” produced a more aggressive 1952 manuscript. In the
latter edition, Aureomycin was endorsed as “the best cold remedy which we have at present,” on the
basis of a study in which it was found “from two to two and a half times as effective as
antihistamines”; nevertheless, the original study authors themselves concluded from their study that
“neither antihistamines nor aureomycin can be regarded as satisfactory treatment for the common
cold”! Cf. Review of the Clinical Uses of Aureomycin, 10; Fifth Year of Aureomycin (Lederle
Laboratories, 1952), 39; Chen and Diens 1951.
Pfizer‟s Thomas Winn ascribed a general trend towards the home-based use of antibiotics to the
broad-spectrum antibiotics. In Win 1950a, 473, 561.
Roueché was able to render such a proclamation based on impressions “gathered on my tour of the
Pfizer laboratories.” Business Week, the previous year, declared that “antibiotics alone have made
it almost certain that infectious diseases will soon become a medical curiosity.” In “Health For
Patients, Gamble for Makers,” 34.
Ibid, 17-41.
120
121
of a Seal of Acceptance program, according to which only Council-approved products
could appear in JAMA and its affiliated specialty organs27.
By the late 1940s and early 1950s, however, the AMA itself was adjusting to the era
of the wonder drug, entering an era of close association with the pharmaceutical
industry (Greene and Podolsky, 2009). While it continued to maintain its Council on
Pharmacy (to be transformed into a Council on Drugs in 1955), in 1946 a formal
JAMA Business Division was created. Advertising revenue increased 48.3% between
1949 and 1953,28 epitomized by the inclusion of Pfizer‟s house organ, Spectrum, with
JAMA, as noted previously. By 1955, it would drop the Seal of Acceptance program
for a confluent combination of financial, logistical, and legal forces. And tellingly, by
1956, after “a member of its House of Delegates introduced a resolution that the
AMA officially go on record as condemning certain of the promotional practices of
the pharmaceutical industry as being unethical,” not only did the motion fail to carry,
but the AMA instead appointed a joint medicine-industry liaison committee to
enhance still “better understanding between the medical profession and the drug
manufacturers.”29 In the spring of 1958, “A Study of Drug Sampling” was convened
by the AMA “as a service to the pharmaceutical industry, followed a year later by a
Gaffin study concerning “Attitudes of U.S. Physicians toward the American
Pharmaceutical Industry.”30
Aside from the AMA, the remaining central agency capable of overseeing
pharmaceutical utilization and marketing was the federal government. The 1950s,
however, were notable as a uniquely industry-friendly time at the FDA generally
(Hilts 2003, 117-121) and the agency‟s Division of Antibiotics, headed by Henry
Welch, would come to exemplify such an image. Welch, born in 1902, had acquired
his Ph.D. in bacteriology before coming to the FDA in 1938. By 1945, he had been
placed in charge of the Division of Penicillin Control and Immunology (to ensure the
27
28
29
30
“The Council on Pharmacy and Chemistry: A Twenty-fifth Anniversary,” Journal of the American
Medical Association, 1930, 94: 414. Smith 1947, 883.
Subcommittee on Antitrust and Monopoly, Drug Industry Antitrust Act, July 5, 1961, p. 129.
“Attitudes of U.S. Physicians toward the American Pharmaceutical Industry,” p. iv, 1959, CD 1056,
AMA Archives.
The former, conducted through Taylor, Hawkins, and Lea, Inc. “as a service to the pharmaceutical
industry,” was presented to the industry as “a kind of „pure research‟ which can serve as a firm
foundation of strategic long term value, possibly on the policy level, in using drug samples in
pharmaceutical marketing.” In “A Study of Drug Sampling – Spring 1958,” BD 1465, 33-14, AMA
Archives; for the latter, see “Attitudes of U.S.Physicians toward the American Pharmaceutical
122
adequacy of each batch of penicillin produced in the country), and by 1951, the
Division itself had been changed to the Division of Antibiotics, with Welch as
Chief.31
In 1950, Welch had agreed to helm “an authoritative journal dealing with the
subject of antibiotics and chemotherapy,”32 as well as to co-author a textbook on
antibiotics, obtaining permission to do so from his superiors in the federal
government.33 When, by 1952, the publisher of the two ventures (Antibiotics and
Chemotherapy, and Antibiotic Therapy, respectively) had fallen into “financial
difficulties,” Welch joined with Felix Marti-Ibanez – psychiatrist, historian, and
entrepreneur, among other roles – to form two parent organizations (M.D.
Publications, and Medical Encyclopedia, Inc.) to take over the respective journal and
manuscript publishing duties.34 Ibanez was in possession of a truly remarkable CV by
1952.35 Born in Cartagena, Spain in 1911 and trained as a psychiatrist, he had served
as Under-Secretary of Public Health and Social Service in Spain before Franco came
to power in 1939. Wounded during the Spanish Civil War, Ibanez emigrated to the
United States in 1939. Originally serving as a medical adviser on overseas sales to
Hoffman-LaRoche, he would subsequently serve as “medical director” in charge of
Latin American sales at Winthrop (1942-1946) and then Squibb (1946-1950),36
garnering intimate knowledge of the ways of medical marketing as it began its own
post-war revolution.37 Once he left Squibb in 1950, the multi-tasking Ibanez would
31
32
33
34
35
36
37
Industry.” Between 1950 and 1958, the AMA had thus commissioned Gaffin to conduct 7 separate
studies; in ibid, Appendix D-1.
Subcommittee on Antitrust and Monopoly, Administered Prices, Part 22, 1960, p. 11927;
Subcommittee on Antitrust and Monopoly, Administered Prices, Part 23, 1960, pp. 12634-5,
12801-2, 12983-5.
Ibid, p. 12634.
Ibid, pp. 12218-25.
Ibid, pp. 12949-50, 12804-5.
“Dr. Felix Marti-Ibanez Presented with the Order of Carlos J. Finlay,” Antibiotics and
Chemotherapy 5 (1955): 105-6.
In the midst of this, Ibanez would also be offered the editorship of a proposed Spanish version of
JAMA, an offer he would eventually decline. See Felix Marti-Ibanez to Morris Fishbein, 8/24/45;
Ibanez to Fishbein 10/3/45; Ibanez to Fishbein, 11/2/45; Ibanez to Charles Grotherer [sp?],
12/21/45, all in “Personal, August 10, 1945 – December 1945,” Box 2, Felix Marti-Ibanez papers,
Yale University Archives (hereafter FMIP).
“CV,” Box 3, FMIP. Wrote Ibanez in 1943: “Among my duties as Medical Director, are the
preparation and handling of Medical Propaganda, direct supervision of our house organ …, the
preparation of colored mailing pieces, and all medical literature sent to physicians in Spanish
America.” In Felix Marti-Ibanez to O.F. Ball, 10/21/43, “Personal, January 1943 – October 1943,”
Box 2, FMIP. For a three-page exposition of Ibanez‟s recommended techniques for “export
marketing,” see Ibanez to Arthur M. Sackler, 8/19/52, “William Douglass McAdams,” Box 5,
FMIP.
122
123
soon be seeing patients in private practice, writing medical history (by 1956, he would
become director of the history of medicine department at New York Medical College,
Flower and Fifth Avenue Hospitals) … and working closely with fellow psychiatrist
and dear friend, Arthur Sackler at McAdams, the emerging marketing powerhouse
behind Terramycin‟s release.38
By 1952, however, Ibanez had also founded M.D. Publications,39 and with Welch, he
would soon form a remarkable partnership, responsible for a parade of journals and
manuscripts throughout the decade.
In late 1953, Welch proposed to the
Commissioner of HEW the convening of an international symposium on antibiotics,
the proceedings of which were to be published by M.D. Encyclopedia under the title,
Antibiotics Annual.40 Held each year for the ensuing seven years and attended by
more than 600 scientists and clinicians by 1954, the Symposia could be described by
President Eisenhower as “an occasion for honoring all those who, through their work
in antibiotics, have made profound changes in the practice of medicine.”41
But even by 1956, while such information-disseminating ventures had been justified
as “reflect[ing] credit on both the Food and Drug Administration and the Federal
Security Agency,” certain easily foreseen conflicts of interest had become manifest.42
The Symposia, originally requested by pharmaceutical industry members themselves,
maintained an appearance of heavy industry involvement, and AMCT, with its
similarly industry-supporting appearance, maintained a 90% article acceptance rate.43
And the antibiotic ethos put forth by Welch – and especially by Ibanez – was as
38
39
40
41
42
43
“McAdams International,” Box 3, FMIP; “William Douglass McAdams,” Box 5, FMIP; Felix
Marti-Ibanez to Miriam Perry, 5/9/56, “P,” Box 7, FMIP; The Advertiser, 3/55; Advertising Age,
2/1/60. Wrote Ibanez to Henry Welch in late 1954: “This has been the most hectic month in what
will be the most hectic year of my life. Between the work at the Agency which has again suddenly
expanded so that it is now demanding a great deal of time from me, the journals with a million
problems each, the promotional campaigns for Antibiotic Medicine, the forthcoming Annual which
keeps us in the office nights and weekends, my columns for the Latin-American papers and the
television and movie projects, I have begun to have headaches and insomnia again.” Ibanez to
Welch, 12/10/54, Box 1089, “Welch, Dr. Henry, FDA Materials Correspondence (10 of 10), RG 46,
National Archives.
Reported as 1950 in “CV,” Box 3, FMIP; reported as 1952 in Administered Prices, Part 23, p.
12949.
Ibid, pp. 12805-6, 12950-1.
“Symposia Registration,” Box 1089, “Miscellaneous (2 of 6),” RG 46; Dwight Eisenhower to
Henry Welch, 10/28/54, in preface to Antibiotics Annual (1954-1955).
Administered Prices, Part 23, p. 12223. This section will only note the conflicts obvious to outside
observers at the time.
Ibid, pp. 12310, 12563, 13155. At the initial 1953 symposium, 43 out of 102 papers were presented
by industry; by 1958, this proportion had fallen to 23 out of 181. In “Symposia Manuscripts,” Box
1089, “Miscellaneous (2 of 6),” RG 46.
124
antibiotic-promoting as if it had been written by Pfizer itself (which, as it turned out,
some of it had been.
Ibanez, in his self-appointed role as official historian-philosopher of the “Era of
Antibiotics,” (Marti-Ibanez 1953-1954, 3) would lead off each annual symposium
with a grandiose view of the state of antibiotic therapy. Ibanez promoted an ethos
with two interlocking themes. The first was that “in the history of medicine there is
perhaps no other event as revolutionary as the discovery of antibiotics,” resulting in
radical, beneficial changes in “our way of thinking in medicine.” (Marti-Ibanez 19531954, 3) It is ironic that Ibanez has been mis-cited as one who first called attention to
the potential issue of antibiotic resistance,44 as Ibanez instead consistently called for
an ever-escalating race between germs and science.45 As he stated before the second
annual symposium:
“The physician is beginning to understand that in his struggle against infection two
factors are involved: his own science, aided by chemotherapeutic resources, and the
microbe itself, and that between the two a fascinating game of chess is being played in
which the human body is the chessboard and the life of the patient at stake. As in a
ballet pas de deux, it is necessary for each participant to anticipate the reactions of the
other if the dance is to reach a successful end. The microbe defends itself by resisting
the drugs and developing new forms of attack. Hence the aphorism: “Be quick to use
a remedy while it is still effective.” (Marti-Ibanez 1954-1955, 19).
He could point forward – in the very presentation (before the third symposium) from
which he was later cited to have warned against the emergence of resistance – to still
44
45
Stephen Harbarth and Matthew H. Samore, 2005, 794. Quote Harbarth and Samore from Ibanez:
“Antibiotic therapy, if indiscriminately used, may turn out to be a medicinal flood that temporarily
cleans and heals, but ultimately destroys life.” But Ibanez‟ quote ended with “by carrying off germs
indispensable to that very life” and was instead focused upon the incidental destruction of
commensal organisms. Indeed, he continued by portraying a future in which “antibiotics that will
attack pathogenic germs and respect saprophytics will be developed.” From Marti-Ibanez 19551956, 11.
Indeed, even Ibanez‟s lone public “deplor[ing of the] abuses of this as well as of any other therapy”
occurred in the midst of an intense defense of antibiotics: “Antibiotics are constantly being accused
of encouraging the development of bacteria-resistant [sic] strains, of causing superimposed
infections activated by alterations in bacterial ecology, and of arousing secondary reactions. They
also stand accused of changing the typical course of disease, thereby increasing diagnostic
difficulties and creating new clinical pictures. … But the syndromes caused by antibiotics are only
one more chapter in the picture of diseases caused by man. … The critics of antibiotics should not
forget that antibiotics have won a place for themselves, which they will never lose, in the antiinfectious arsenal.” In Ibid, p. 12.
124
125
“more prophylactic and less therapeutic ends,” ( Marti- Ibanez 1955-1956, 13) and
still further off to predict that “by the year 2000 the diseases caused by bacteria,
protozoa, and perhaps viruses will be considered by the medical student as exotic
curiosities of mere historical interest.” (Marti-Ibanez 1954-1955, 22).
To facilitate such a revolution, however, a second, parallel revolution would
be required: that concerning medical communication. And in defining such ideal
communication, Ibanez hoped for “the widest diffusion of the maximum amount of
practical knowledge on antibiotic medicine to the greatest number of physicians in the
shortest time possible.” (Marti – Ibanez 1955-566, 41). Speed of dissemination,
rather than quality control, informed such an approach. But who, in such a model,
was to finance such an institution and to foster such communication? The answer was
the pharmaceutical industry. Paradigmatically, and with no sense of irony, Ibanez
summarized his overall ethos by transferring Herman Biggs‟ public health dictum into
a wonder-drug promoting paean to industry:
“ ‘Public health is purchasable; within natural limitations any community can
determine its own death rate.’ So also might we say that medical communication can
be financed, and within certain limits each medical community can determine the
degree of knowledge its members may attain. Who better than the pharmaceutical
industry could organize, coordinate, and integrate on an international scale the vast
and increasing knowledge on antibiotics?”46
The irony, however, would not be lost upon an emerging group of infectious disease
specialists who begged to differ, concerned that the voice of the federal government
itself had at last been transformed into the clarion call of industry.
The Emergence of the Therapeutic Rationalists
Harry Marks has related how twentieth-century clinical reform has
consistently depended upon self-appointed groups of academically based therapeutic
rationalists. And such forces at last provided the milieu in which the nation‟s leading
infectious disease specialists, in particular, would coalesce into a reforming group of
therapeutic rationalists who would have a long-standing impact. Immediately prior,
126
the nation‟s infectious disease experts had seemed almost a group in search of a
mission. In 1948, Hobart Reimann had reported in his 14th Annual Review of
infectious diseases in the Archives of Internal Medicine on the “decline of importance
of infectious disease, … [as] nothing at present … threatens to stem the downward
trend to … an irreducible minimum [of mortality].” (Reimann 1948, 468). The only
problem engendered by such a seemingly cheerful state – exacerbated, as it were, by
the advent and proliferation of the broad-spectrum antibiotics and ever more
formulations of each antibiotic – would be deciding which agent to choose in each
therapeutic instance. Enter the “new specialist, the antibioticist,” happy to help the
general practitioner – or, at the hospital level, proposed committees on
chemotherapeutics – render such decisions. (For “antibioticist,” see Reimann, 1950,
157; Long et al. 1949, 315; Kirby 1950, 233; Long, 1950, 308; Jawetz, et al. 1951,
966, 966; Rhoads 1952, 67; Chandler 1953, 369. For “committees,” see Spink 1953,
590).
Yet the placidity of such happy days would initially be shaken by a grim
reminder of the pre-antibiotic era: antibiotic-resistant staphylococcus aureus. By the
early 1950s, in fact, Maxwell Finland would consider staphylococcal resistance the
foremost issue before him.47 And it is in this clinical context that the altered attention
of the would-be “antibioticists” – towards a collective attempt to inculcate a “rational”
application of the antimicrobials – must be understood. (For such an invocation of
rationality, see Jawetz and Marshall 1950, 545, 553; Jawetz 1952, 308; Jawetz 19531954, 41; Kilbourne 1953, 35-40; Jawetz 1957-1958, 295. As can be seen, Ernest
Jawetz was most responsible for directly bringing the notion of therapeutic
“rationality” into the debate over antibiotic usage).
Finland himself offered the opening proclamation of defense at the New York
Academy of Medicine in December of 1950. While only cautiously linking the
worsening staphylococcal situation to increasing antibiotic usage, he nevertheless
leveled a strong blow at the many apparently inappropriate (or, at least, unproven)
“prophylactic” uses of antibiotics – from those to forestall the conversion of upper
respiratory tract infections to pneumonias, to those to forestall surgical complications.
46
47
Ibanez, “Antibiotics and the Problem of Medical Communication,” p. 14.
Maxwell Finland to Herbert R. Morgan, 12/11/50 [Box 3, Folder 57, Maxwell Finland Papers;
hereafter MFP]; Finland to Elmer M. Purcell, 11/6/51 [Box 4, Folder 36, MFP]; Finland to Wesley
Spink, 1/12/53 [Box 5, Folder 9, MFP].
126
127
Yet by the mid-1950s, the reforming infectious disease vanguard turned their attention
away from individual clinicians, to the perceived larger danger in the process
pharmaceutical over-promotion (Finland 1953-1954, 11; Spink 1953, 586). Whether
owing to their recognition of their limited ability to assess – let alone alter –
individual clinical encounters, or to the increasing brazenness of industrial promotion
itself, their notion of “rationality” shifted from a focus upon nosological and
therapeutic specificity to a concern with the sources of clinicians‟ therapeutic
knowledge.48
Thus, despite the first “Proposed Crusade for the Rational Use of
Antibiotics” having been declared at the 1954 Antibiotic Symposium in the context of
a speech heavily critical of nonspecific telephone prescribing, patient demands, and
self-medication with stocked prescriptions, (Hussar 1954-1955, 379-382) the
“Crusade” itself would be co-opted by those turning their attention to the apparently
more recalcitrant pharmaceutical companies. And there, for better or worse, it would
remain for over a decade.
The Advent of Fixed-Dose Combination Antimicrobials
It would be reasonable for historians to expect that Parke-Davis and its
chloramphenicol – promoted throughout the decade despite a known, if rare tendency
to induce aplastic anemia – would serve to catalyze the attack (Whorton 1980, 131132). Yet the tolerant, even supportive, approach of the rationalists towards
chloramphenicol throughout the era serves to further highlight the conception of
“rationality” that they would emphasize.
For the rationalists of the 1950s, the sin of the effective chloramphenicol rested with
nonspecifically prescribing clinicians, rather than with Parke-Davis. Instead, their
attention was focused upon Pfizer and its marketing of its fixed-dose combination
antibiotic, Sigmamycin.
The combination rationale dated back to chemotherapy‟s origins.
Paul Ehrlich
himself, speaking before the 17th International Congress of Medicine in 1913,
declared that through combination therapy against infectious microbes, “a
48
Of course, as would ultimately be enunciated at the Nelson hearings, such notions intersected at the
moment when pharmaceutical companies, in promoting drug usage, encouraged the use of
“shotgun” preparations or diagnosis by therapeutic response. See Console 1969, Part 11, 1969,
4484-4485; Maeder 1994, 191-192.
128
simultaneous and varied attack is directed at the parasites, in accordance with the
military maxim, march in detachments, fight as a unit.” (Ehrlich 1960, 514). And
upon the advent of penicillin, investigators were quick to demonstrate the synergistic
effects of combinations of sulfa drugs and penicillin (Ungar 1953; Bigger 1944; SooHoo and Schnitzer 1944), 49 with clinicians apparently quick to take note.50
The introduction of the broad-spectrum antibiotics offered geometrically
(indeed, combinatorially) enhanced opportunities for testing for such synergy, (Price
et al. 1949, 240-344) while other theoretical justifications for combination
antimicrobial therapy – from increasing the range of the antimicrobial onslaught in
mixed infections, through decreasing side effects through lessening the dosages of
each agent, to delaying the onset of resistance to one agent or another – could be
proffered in tandem (see, e.g., Dowling 1951, 195). And by the early 1950s, the
combination treatment of tuberculosis, subacute bacterial endocarditis, and brucellosis
seemed to epitomize the application of such an approach (see Finland 1951, 213).
But in parallel with such an emerging combination ethos appeared concerns
regarding its potential dangers. As early as at the annual meeting of the AMA in 1949,
a North Carolina clinician warned of potential subsequent threats to specific
diagnosis: “This type of therapy demands a painstaking search for the specific
offending organism and in no way justifies “shotgun” treatment without an etiologic
diagnosis.” (Lawson et al. 1949, 317).
Moreover, concerns were soon voiced
regarding the potential for antibiotics in combination to be antagonistic to one
another, and to be, in the best case, bacterial strain-dependent, and hence not
amenable to fixed-dose preparations.
Nonetheless, the pharmaceutical industry soon jumped at the opportunity to market
“fixed-dose combination antibiotics”; and by 1957, Dowling could report on the
marketing of sixty-one such preparations, with “twenty-nine preparations containing
two antibiotics, twenty containing three, eight containing four, and four preparations
that contained five antibiotics apiece.” (Dowling 1957, 658)51 It is perhaps fitting,
49
50
51
For the antecedent description of the “synergistic” serochemotherapeutic treatment of
(experimental) pneumonia, see Macleod 1939, 1407; Podolsky 2006, 104, 216.
See, with respect to pneumonia, Charles H. Rammelkamp to Maxwell Finland, 4/3/47 [MFP, Box 4,
Folder 39].
Actually, while Dowling attempted in his famous address to buttress his argument by including
ointments and powders, he actually undershot the actual mark, as Welch‟s list included only those
“combinations of antibiotics approved since publication of [Welch‟s] Manual of Antibiotics [in
128
129
moreover, that this information came to Dowling by way of Henry Welch; for by
1957, Welch‟s approach to antibiotic prescribing and promotion – especially as
highlighted by his advocacy of fixed-dose combination antimicrobials and as
formulated in the conferences and journals run by him and Felix Marti-Ibanez – came
to epitomize, for the rationalists, the sorry state to which antibiotic development and
therapeutics in America had fallen.
Sides had begun to take shape in early 1956, when Welch informed such
erstwhile editorial board members as Finland and Dowling that he and Ibanez were
transforming Antibiotic Medicine into a free-circulation journal (i.e., supported solely
by pharmaceutical advertising) under the title, Antibiotic Medicine and Clinical
Therapy.52 But Welch‟s final transgression came upon his delivering before the
participants of the Fourth Annual Symposium on Antibiotics in October of 1956 the
direct counter to Finland‟s restraint-centered warnings before the New York Academy
of Medicine nearly six years before. Praising, rather than condemning, the “cradle to
grave” application of antibiotics, Welch pointed out that “the worldwide interest
demonstrated in this field can only be appreciated when consideration is given to the
tremendous dollar expansion of this young industry during the past 13 years.” (Welch
1956-1957,1).
He next acknowledged the subsequent emergence of antibiotic
resistance; but rather than hold up such a process as an inducement to restraint, he
held it up as a justification for the “trend to rational combined therapy, particularly
with synergistic combinations.” (Welch 1956-1957, 1.)
Having co-opted the
rationalists‟ very vocabulary, he remarked of the expected industry-supported papers
on fixed-dose combination antibiotics:
“These presentations and others indicate a distinct trend toward combined therapy, not
an old fashioned “shotgun” approach, but a calculated rational method of attacking
52
1954]. Welch‟s manual, for instance, had already demonstrated that sixteen separate companies
were marketing combinations of penicillin with dihydrostreptomycin, while twenty-six were
marketing combinations of penicillin with “triple sulfonamides.” See Henry Welch to Harry
Dowling, 11/26/56, Box 3, “W-Z,” Harry Dowling Papers [hereafter HDP]; Henry Welch, The
Manual of Antibiotics 1954-1955 (New York: Medical Encyclopedia, 1954), pp. 33, 55-57.
Henry Welch to Maxwell Finland, 5/7/56 [Box 5, Folder 42, MFP]. In 1955, Welch and Ibanez had
first published and presented Antibiotic Medicine as a pragmatic outgrowth of Antibiotics and
Chemotherapy (which could hence be devoted to laboratory issues), hearkening a “journey towards
the luminous shores, already outlined on the present horizon, of a future Medical Science radically
transformed by the impact of antibiotics.” By 1956, the transformation in journal title and scope
was to “open up many other new windows, enabling the practicing physician to view the full
therapeutic panorama of our age.” The widened scope of expected pharmaceutical advertising
130
the problem of resistant organisms. It is quite possible that we are now in a third era
of antibiotic therapy; the first being the era of the narrow-spectrum antibiotics,
penicillin and streptomycin; the second, the era of broad-spectrum therapy; the third
being an era of combined therapy where combinations of chemotherapeutic agents,
particularly synergistic ones, will be customarily used.” (Welch 1956-1957, 2.)
The obvious beneficiary of Welch‟s invocation was Pfizer, whose Sigmamycin – a
fixed-dose combination of tetracycline with oleandomycin – was to be released in
November with the obvious imprimatur of the nation‟s reigning antibiotic tsar. In the
same November issue of Antibiotic Medicine and Clinical Therapy in which Welch
noted that “it is in [general practice] that combined therapy using synergistic
combinations of antibiotics will find its greatest usefulness” and that “the combination
of oleandomycin and tetracycline [i.e., Sigmamycin] stands out in contrast to the other
combinations referred to, because of the synergism demonstrated by this
combination,” Pfizer indeed included a four-page advertisement extolling the virtues
of its apparent wonder drug (Welch 1956, 377).53 In the wake of the symposium,
Finland and Dowling met and communicated with their network of colleagues,
concluding that “the time [was] ripe for a concerted movement,” and that “a lobby
would have to be formed and that this would have to compete with the large lobby of
the pharmaceutical manufacturers.”54 With the AMA and FDA apparently having
failed to provide appropriate leadership,55 the informal meetings of the infectious
disease experts became a nexus for the construction of manifestoes and the plan to
self-consciously flood medical journals with counters to the promiscuous promotion
and usage of fixed-dose combination antimicrobials. 56
53
54
55
56
wasn‟t a dim prospect, either. See Welch and Marti-Ibanez 1955, 2 and Welch and Ibanez 1956,
24.
“Sigmamycin,” in ibid, 363-66.
Harry Dowling to Maxwell Finland, 11/6/56 [Box 2, Folder 8, MFP]
Maxwell Finland to Harry Dowling, 11/14/56 [Box 2, Folder 8, MFP] Indeed, it would be in this
setting that Dowling would research and then deliver before the AMA his famous address
concerning the debatable output of the American pharmaceutical industry, “Twixt the Cup and the
Lip.” In Box 4, “Twixt the Cup and the Lip,” HDP.
Harry Dowling to Maxwell Finland, 11/16/56 [Box 2, Folder 8, MFP]. Indeed, when James
Whorten notes that “the medical literature of the 1950‟s and early 60‟s positively teems with such
phrases as „appalling ignorance,‟ „truly monumental abuse,‟ and „orgy of antibiotic dosing‟,” he is
reflecting the output of this purposeful and fairly coordinated flooding of the literature. See
Whorton 1980, 130.
130
131
In the initial manifesto co-authored by nine leading infectious disease
specialists (including Dowling, Finland, and Jawetz) and appearing in the Archives of
Internal Medicine, the fixed-dose combination antibiotics were first attacked with the
usual concerns: the failure to ensure adequate therapy (through failure to ensure
adequate dosing of any single component), the possibility of increased and confusing
toxicity, and the potential for engendering resistance. But the final concern of the
authors embodied their underlying rationale: “If this trend is not checked now, the
practicing physician will soon be confronted with such a bewildering array of
antibiotic combinations supported by multicolored promotional material piling up
daily upon his desk that rational chemotherapy will give way to chaos.” (Dowling et
al. 1957, 537).
Such a monologue was only a prelude to a still-more contentious dialogue
between Finland and Welch appearing, to Welch and Ibanez‟s credit, in the pages of
Antibiotic Medicine and Chemotherapy itself in January of 1957. Finland, as far back
as in 1939, when the less-specific sulfa drugs had threatened to supplant the
necessarily specific antipneumococcal antisera on the strength of seemingly meager
studies, had written:
“Similar reports have been made recently at various medical meetings and even
greater publicity has been given this drug in the lay press and in radio reports in this
country. Unfortunately no published reports have yet appeared with any data from
which the value of this drug can be assessed. … If evaluation in experimental
animals under standard and controlled conditions is difficult, it is all the more reason
for extreme caution in reporting results in human beings.” (Bullowa 1939, 570).
Nearly two decades later, he now spoke of the studies supporting the apparently
imminent expansion of fixed-dose combination antimicrobial usage:
“Much of the clinical information presented [at the symposium] had the sound of
testimonials rather than carefully collected and adequately documented scientific data.
To be sure, properly conducted clinical studies may, in the future, support the claims
and justify the enthusiasm for these or other combinations of antimicrobial agents, but
it is incumbent upon those of us who are intimately concerned with the welfare of our
patients to wait until such data are presented before we accept and acclaim any new
132
agents or special formulations and recommend them for general use, particularly in
view of their great potential for harm when they are used extensively and
indiscriminately” (Finland 1957, 18).57
“Testimonials,” reeking of clinical investigative lassitude (to be charitable) and
commercial imperative, would in this context come to epitomize the nexus of profitminded pharmaceutical companies, shoddy investigators, and a complacent (if not
complicit) FDA. In this view, while the FDA still held the legal responsibility to
certify novel agents, “clinical investigators and authors of medical and scientific
publications [had] the duty to protect the medical profession and the public against the
abuse of preliminary scientific information and against the improper and premature
exploitation of conclusions based on inadequate data.” (Finland 1957, 20).
The Invocation of the Controlled Clinical Trial
An examination of Finland‟s evolution from perhaps the foremost critic,
among infectious disease specialists, of the application of the controlled clinical trial
in the 1940s to one of its foremost proponents by the end of the 1950s provides
critical contextualization required to understand its gain in prominence in American
medicine. The post-World War II rise of the controlled clinical trial in America, in
this reading, represented not epistemological, but rather social, evolution; and its foil
was thus not the case study or series, but rather the “testimonial.”
By the early 1940s, and on the eve of the MRC‟s streptomycin study, Finland had
served as a prominent critic of such an emerging methodology.
Specifically
concerned with comparisons between the chemotherapeutic and combined
serochemotherapeutic approach to pneumonia, Finland had generalized to concerns
57
In parallel fashion, in 1939, Finland had written: “A number of … workers are now engaged in an
earnest effort to evaluate [sulfapyridine], with its benefits, limitations and dangers. They are
attempting to learn the proper methods of using the drug in order to obtain the optimum of benefit
with the minimum of harm. While such investigations are in progress and until the results of these
studies are carefully analyzed and assessed, it is well to retain and to use the proved remedies. It
would be unfortunate if the appearance of a new therapy, no matter how promising, were to cause
the abandonment of agents whose curative efficacy and life-saving qualities have become
established.” In 1957, he wrote: “We would be remiss in our duties as physicians, teachers, and
investigators were we to encourage, adopt, and recommend the use of new agents that we cannot
consider to be as good as, or no better than, those previously shown to be good, even if they are
legally certified.”
132
133
that the controlled clinical trial largely remained a heuristic ideal, impeached in
practice by the vagaries of chance, the influence of unconscious selection bias, and
the shallowness of the clinical and laboratory underpinnings of most such studies
(Plummer et al. 1941, 2366-71; Finland 1941; Podolsky 2006, 119-124.). Over the
ensuing 15 years, he continued to debate with colleagues and fellows regarding the
epistemological tenability of the controlled clinical trial to adjudicate clinical
efficacy.58
But by 1957, the commercial proliferation of apparently worthless antimicrobial (and
especially fixed-dose combination) remedies buttressed by “testimonials” would lead
Finland to become, along with such leaders of the nascent field of clinical
pharmacology as Louis Lasagna, (Lasagna 1955, 353) perhaps the foremost proponent
of the controlled clinical trial in the country. Finland unleashed a series of caustic
editorials, lamenting in the New England Journal of Medicine:
“The admonition to defer acceptance of the claims of the manufacturers until they are
confirmed by reliable and unbiased reports from other laboratories and supported by
controlled clinical trials rather than by mere testimonials may have been completely
submerged in the deluge of advertising matter that followed.
The nearly daily
mailings to physicians and the repetitive advertisements in medical journals that were
willing to carry them, by reiterating the same claims, may have had the intended
effect of dulling the senses and perception of the great majority of physicians
regarding the underlying truths that they were obscuring. These advertisements have
undoubtedly reached more physicians and have been seen and perhaps even read by
many more than have read the editorial columns of this journal.” (Lasagna 1957, 289).
As a counter to such commercial education, he offered “careful scientific work done
under controlled conditions [and which] usually requires much more time and effort
than the writing of advertising copy, which at best exaggerates the truth and all too
often only distorts it and renders it meaningless when inferior wares are being
peddled”.59
58
59
See, e.g., John H. Dingle to Arthur M. Walker, 10/28/52, Box 5, ff 34; Maxwell Finland to D.H.
Garrow, 2/27/57, Box 5, ff 45, MFP.
Lasagna 1957, 289.
134
At stake were the very principles of therapeutic rationalism. The nonspecific
therapeutics advocated by Welch and Pfizer, “far from being a rational approach to
antibiotic therapy … represent[ed] a recognition of the old authoritarianism and its
attendant nostrums as the guiding force in medicine” (Lasagna 1957, 290). Publicly
advocating methods over men, Finland concluded by countering: “This type of
medical practice has gradually been giving way to the modern scientific medicine that
was ushered in with the changes in medical education taking place during the last half
century. Therapeutics should not return to the ancient, barbaric, and irrational era of
the shotgun.”60
Scientific medicine, publicly articulated against the backdrop of
commercial quackery and clinical lassitude, was hence to be predicated upon the
defense of the controlled clinical trial.
The Public Stage – The Kefauver Hearings
Senator Estes Kefauver‟s hearings into the pharmaceutical industry –
commencing in late 1959, and resulting in the Kefauver-Harris amendments of 1962 –
represent a watershed event in twentieth-century therapeutics. Kefauver, the liberal
Tennessee Senator who had taken on the mob in the early 1950s and run
unsuccessfully as Adlai Stevenson‟s vice presidential candidate in 1956, initially
sought to tackle apparently monopolistic tendencies in the pharmaceutical industry, in
which drug prices appeared unresponsive to changing times and conditions.
Yet as
his investigation and then proceedings developed, he and his staff (including John
Blair and Paul Rand Dixon) increasingly turned their attention to pharmaceutical
marketing, which in turn shone a powerful light upon the Food and Drug
Administration‟s inability to explicitly rule on drug efficacy prior to new drug
approval. And the debate over antibiotics and their marketing would play a crucial
role in such a transformation (McFadyen 1973 and 1979).
Indeed, by the late 1950s, as the federal government had begun to turn its
attention to pharmaceutical marketing and pricing, antibiotics had helped to focus
such attention. Already in 1958 the FTC had published its Economic Report on
Antibiotics Manufacture (Federal Trade Commission 1958). And by early 1959, John
60
Ibid. For a similar harangue, exposing the “treacherous foundations” of the therapeutic approach
expressed by Welch, see “Erythromycin, Oleandomycin and Spiramycin – and their Combinations
with Tetracycline,” New England Journal of Medicine 257 (1957): 526.
134
135
Lear, of the Saturday Review, published his “Taking the Miracle out of the Miracle
Drugs,” railing against antibiotic marketing and misuse, and focusing in particular
upon Pfizer‟s Sigmamycin advertising, in which they had provided the calling cards
of a wide range of specialists who had justified the claim that “Every day …
everywhere … more and more physicians find Sigmamycin the antibiotic therapy of
choice.” (Lear 1959). As it turned out, none of the physicians actually existed, and as
Richard Harris recounts:
“One evening, Lear had dinner with an eminent research physician, and afterward the
two men visited a laboratory in the hospital where the doctor worked. „He pulled open
several drawers that were full of drug samples and advertisements,‟ Lear said later.
„Just take a look at that stuff!‟ he told me, and then went on to say that a good part of
the advertising was misleading – in fact, that some of it was downright fraudulent.
Finally, he said, „Look, you‟re walking around a big story. Why don‟t you step into
it?‟ I said I might if I had enough information. Among other things, he showed me a
small folder advertising Sigmamycin, an antibiotic put out by Chas. Pfizer, Inc.
Across the top of the folder was a banner of bold type that said, „Every day,
everywhere, more and more physicians find Sigmamycin the antibiotic therapy of
choice.‟ Below that were reproductions of what appeared to be the professional cards
of eight doctors around the country, with addresses, telephone numbers, and office
hours.
The doctor said he had himself conducted some experiments with
Sigmamycin, and at one point he had written to the eight doctors to ask the outcome
of their use of the drug in clinical tests. As he told me this, he reached into one of the
drawers and brought out eight envelopes, all stamped „Return to Writer – Unclaimed.‟
I asked him if I might report his experience, and he said that he couldn‟t get involved
in any kind of expose. He pointed out, however, that there was nothing to prevent me
from writing to the doctors myself. Lear did write to them, and all eight letters came
back. Then he sent telegrams to the doctors, and was informed that there were no
such addresses. Finally, he attempted to telephone them, and learned that there were
no such telephone numbers.” (Harris 1964, 18-19).
136
While evidence remains circumstantial, it seems almost certain that Maxwell Finland
was the “eminent research physician in question.”61 And as Harris concluded: “Lear
thereupon wrote an article entitled „Taking the Miracle Out of the Miracle Drugs,‟
dealing with the general misuse of antibiotics and describing the incident of the
professional cards. The piece appeared in the Saturday Evening Review for January 3,
1959, and Kefauver later said that it helped, as much as anything else, to spur on the
investigation and to broaden its range.” (Harris 1964, 19-20).
The investigative hearings would provide a forum for Finland, Dowling, Lasagna, and
such colleagues as William Bean to voice their concerns regarding pharmaceutical
marketing and the need for the FDA to explicitly adjudicate regarding drug efficacy.
Yet perhaps the most shocking moments of the investigative hearings were devoted to
the FDA itself and Henry Welch in particular, in May of 1960. Welch, it appeared,
had essentially rendered the FDA and his and Ibanez‟s publications a component of
industry‟s marketing apparatus. Welch received 7.5% of all advertising revenue in his
publications, along with 50% of all reprint sales (including those from Antibiotics
Annual, the report of the yearly antibiotics symposia he chaired), to the point of
earning $287,142.40 throughout the 1950s from such activities. His announcement of
Sigmamycin as ushering in a “third era” had been written by a Pfizer employee, with
Pfizer thereafter purchasing 238,000 copies of Welch‟s remarks.62
In response to Welch‟s public disgrace (he was thereafter forced to resign from the
FDA), Kefauver called on Barbara Moulton, former member of the FDA‟s Bureau of
Medicine. Moulton lambasted the FDA‟s division of antibiotics and its handling of
Sigmamycin, concluding that:
“No physician, no one who has ever been responsible for the welfare of individual
patients, will accept the idea that safety can be judged in the absence of a decision
about efficacy. … To attempt to separate the two concepts is completely irrational. …
For a drug firm to object too strongly to such a change in the law should render it
highly suspect. In general, the drug manufacturers claim that they never market a
drug … until they themselves think they have reasonable proof of its value. If they
61
62
E.g., Lear cited Finland in “Taking the Miracle out of the Miracle Drugs” as the “world dean of
antibiotic therapists” and quoted Finland as stating that “any and every combination that comes …
in a package may be a vicious distortion of the best use of medicine.”
See United States Congress Senate Committee on the Judiciary, Subcommittee on Antitrust and
Monopoly, Administered Prices in the Pharmaceutical Industry, Part 22.
136
137
have such proof, they should not fear its review by the Food and Drug
Administration.”63
The following day, Arthur Flemming, Secretary of HEW, announced at the hearings
that in view of the “serious charges” leveled at the FDA, he had arranged with the
president of the National Academy of Sciences “an outstanding committee of
scientists to review the policies, procedures, and decisions of the Division of which
Dr. Welch was formerly the chief, as well as those of the New Drug Division of the
Bureau of Medicine of the Food and Drug Administration.”64
Flemming would be
followed by George Larrick, the industry-leaning head of the FDA, who found
himself forced to conclude that “the new drug applications are not adequate to insure
[sic] the efficacy of drugs which are essentially innocuous. We would endorse a
proposal that the new drug section of the Food, Drug, and Cosmetic Act require a
showing of efficacy as well as a showing of safety.”65 Twelve days later, when
Senator Kefauver produced the first version of a bill to amend the Food, Drug, and
Cosmetic Act of 1938, the first provision was for the empowering of the FDA to rule
on drug efficacy. And over the ensuing two years of negotiations, while Kefauver‟s
initial hope to change the pricing and patent structure of the pharmaceutical industry
would be rebutted, the rule that new drugs would need to be proven efficacious via
“adequate and well-controlled investigations, by experts qualified by scientific
training and experience to evaluate the effectiveness of the drug involved” would be
written and signed into law, representing the ultimate instantiation of the controlled
clinical trial as the arbiter of therapeutic efficacy in the United States.
Epilogue: DESI, Panalba, and the Limits to Therapeutic Standardization
A key outcome of the Kefauver-Harris Amendments would be the Drug
Efficacy Study and Implementation, which allowed for the review and removal from
the market of inefficacious pre-1962 medications – including the fixed-dose
combination antibiotics. By the end of the 1960s, all such fixed-dose combination
antibiotics save one (trimethoprim-sulfamethoxazole) would be purged from the
63
64
65
Ibid, p. 12040.
Ibid, p. 12080.
Ibid, p. 12128.
138
American market; but opposition would emerge at this point not with respect to
Pfizer‟s Sigmamycin, but with respect to Upjohn‟s Panalba, a fixed-dose combination
of tetracycline and novobiocin (Hilts 2003, 169-177; Tobbell 2008). Upjohn and its
supporters brought forth traditional arguments articulated at the Kefauver hearings
(and soon at the Gaylord Nelson-led hearings on “Competitive Problems in the Drug
Industry”) regarding the “right” of autonomous physicians to apply their knowledge
and judgment to individual patients (Mintz 1969, 875).66 But in this battle over the
FDA‟s authority to withhold particular pharmaceuticals from the medical profession
and its patients, which would extend all the way to the U.S. Supreme Court, the Court
would find in favor of the FDA, representing the apotheosis of a generation of
therapeutic reform and pharmaceutical industry “mistrust.”
Yet Panalba and DESI would represent not only the end of a particular era of
therapeutic reform, but also the limits to the centralized restriction of antibiotic
prescribing in America. It had been an era focused less upon individual prescribers
than upon pharmaceutical marketers; and by the 1970s, when a second generation of
antibiotic reformers – more focused upon individual prescribers - began to emerge, it
appeared that the proverbial horse was out of the barn with respect to the prescribing
of authorized antibiotics. In 1974, Henry Simmons (at the Department of Health,
Education, and Welfare) and Paul Stolley (at Johns Hopkins) could lament in the
pages of JAMA that between 1967 and 1971, while the U.S. population had increased
5%, antibiotic use had increased 30%, with the most rapid increase among the broadspectrum antibiotics. As they ominously concluded: “Have we reached the point
where the enormous use of antibiotics is producing as much harm as good? Are the
risks beginning to outweigh the benefits?” (Simmons and Stolley 1974).
Despite local movements to restrict or cycle antibiotics in particular (often
hospital-based) formularies, the chief means of recourse was to be educational in
nature, whether in the form of utilization review or guidelines. The limits to the
governmental regulation of antibiotics in America had been reached with DESI and its
focus upon pharmaceutical companies. Indeed, the government would only begin to
play an active role in pneumococcal surveillance, e.g., in the 1990s, at a time when
(via the CDC) increasing attention would be brought to bear upon an apparent crisis
66
See also United States Senate Select Committee on Small Business, Monopoly Subcommittee,
Competitive Prices in the Drug Industry, Part 12.
138
139
of antibiotic prescribing and resistance; (Podolsky 2006, 136-141; Bud 2007, 192212) yet no more centralized or comprehensive approaches to antibiotic stewardship
have been put forth to this point. Understanding the successes and failures of the
linked trajectory of controlled clinical trials and antibiotic reformers in 20th-century
America not only offers perspective upon the “rationalist project” in medicine at a key
moment of its evolution, but reveals key components of the structural foundation of
the antibiotic resistance “crisis” as it would itself evolve from the 1970s onward.
140
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Welch, Henry. 1956. A Rational Approach to Combined Antibiotic Therapy.
Antibiotic Medicine and Clinical Therapy 3 (1956): 377 “Sigmamycin,” in Welch,
Henry. 1956-7. “Opening Remarks,” Antibiotics Annual (1956-1957): 363-66.
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Medicine: Journal of Clinical Studies and Practice of Antibiotic Therapy 1: 2
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Journal. Antibiotic Medicine and Clinical Therapy 3: 24
Whorton, James. 1980. „Antibiotic Abandon‟: The Resurgence of Therapeutic
Rationalism. In The History of Antibiotics: A Symposium, ed John Parascandola,
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Winn, Thomas J. 1950b. Increased Prescription Business Due to Antibiotics.
American Professional Pharmacist 16: 984
Negotiating Hospital Infections: The Debate between Ecological
Balance and Eradication Strategies in British Hospitals, 1947-1969#
Flurin Condrau, University of Manchester, UK
Robert Kirk, University of Manchester, UK
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
#
The research for this article was supported by the Wellcome Trust Strategic Award in the History of
Medicine, Centre for the History of Science, Technology and Medicine, University of Manchester,
Manchester M13 9PL. We thank participants of conference sessions in Glasgow and Madrid for helpful
comments.
Penicillin patents in Spain
Ana Romero de Pablos
Consejo Superior de Investigaciones Científicas
Departamento de Ciencia, Tecnología y Sociedad, IFS-CCHS, Madrid
[email protected]
A revised version of this paper has been published as a part of the dossier
"Circulation of antibiotics. Historical reconstructions"
Dynamis, 2011, 31(2), available at
http://www.revistadynamis.es.
Standardization in antibiotherapy: how and why?
The case of aminoglycoside dosages.
Sébastien JANICKI, Université de Lyon, Université Lyon 1, LEPS-LIRDHIST (EA 4148)
Laboratoire d'Études du Phénomène Scientifique - Laboratoire Interdisciplinaire de
Recherches en Didactique et Histoire des Sciences et des Techniques
Marina SELLAL, Université de Lyon, Université Lyon, Hôpitaux de Lyon
Aminoglycosides are a family of antibiotics active against certain types of bacteria and
include
amikacin,
gentamicin,
kanamycin,
neltimicin,
neomycin,
tobramycin
and
streptomycin. From their initial introduction, aminoglycosides became irreplaceable –
particularly in hospitals – initially for treating tuberculosis using streptomycin discovered in
1944 by Waksman, then in the treatment of other major infections. But the manipulation of
this class of antibiotics is particularly complex, notably because of their very narrow
therapeutic index: indeed, the concentrations of aminoglycosides in the blood necessary for a
cure are very close to toxic concentrations. Moreover therapeutic response and the evolution
of the drug in the body (pharmacokinetics) following their use is subject to broad variation
inter and intra patient.
Variation can be observed, for example, in the different responses between patients treated
with the same doses of the drug. We can distinguish kinetic variation relating to the
differences concerning the transformation of the drug in the body and clinical variation
relating to the differences in the body‟s response to the drug.
These antibiotics are eliminated exclusively by the kidneys via urine, so for a long time
kinetic variation was attributed exclusively to renal function. In fact, this factor explains only
40 to 50% of the total variation so dosage calculations based only on measuring creatinine
clearance (a parameter that relates to renal function) do not take into account very significant
inter-individual variation. Aminoglycosides are administered by parenteral intravenous
injection, which means that the variation of concentrations in the blood is a result of
distributive processes and metabolism as well as elimination.
152
The posology of an antibiotic is generally determined on the basis of its pharmacokinetics, its
toxicity, and its efficacy. Determining the optimal posology of aminoglycosides remains a
major problem due to the high level of kinetic and clinical variation to which they are subject.
A central topic of this article is, therefore, the evolution of treatment protocols using
aminoglycosides in France from 1970 to 2000.
Since 1950, Eagle has defined its criteria of effectiveness according to the Minimal Inhibiting
Concentration (MIC): this is the smallest concentration of antibiotic sufficient to inhibit the
growth of a stock of bacteria (bacterial colony) in the laboratory (in vitro). In this context, the
aim was to maintain the blood concentration of the penicillin as high and as long as possible
to maximize the MIC time of the antibiotic for the bacteria responsible for the infection. By
adopting this approach, based on determining the MIC, and taking into account the small
number of molecules available, prescribers increased the managed total amount of the drug
and the number of administrations. In some cases this attitude resulted in increased toxicity,
without any improvement in effectiveness.
Aminoglycosides were widely used in empirical therapy throughout the 1970s and the 1980s.
They belonged to the majority of the combined treatments prescribed in hospital in serious
infectious (Drusano et al. 2007, 753-60). Indeed, as there was little relevant evidence from in
vitro studies, the clinical studies enabled some doctors to defend the administration of
aminoglycosides in bolus (fast, short injection) three times a day while others believed
administration should be by continuous perfusion (a continuous slow injection). During this
period, an empirical adaptation of the dose might be proposed, but only in the event of
significant renal failure.
In 1975 Bodey‟s team (Bodey et al. 1975, 328-333) explored the possibility of giving the
aminoglycosides as a continuous perfusion. The idea was that plasmatic concentrations should
never fall to the lower end of the MIC. This concept is widely applied today to timedependent antibiotics (antibiotics for which the best predictor of effectiveness is the time that
the concentration is maintained above the MIC for the targeted germ).
Unfortunately, aminoglycoside use generates a number of toxicities, mostly oto- and
nephrotoxicity. It was noted that patients in intensive care units who developed altered renal
function had a significant risk of death. A number of articles based on data from both clinics
and clinical trials have clarified this risk of nephrotoxicity associated with the use of
aminoglycosides (Mingeot-Leclerq and Tulkens 1999, 1003-12). Because of the known
toxicities of aminoglycoside antibiotics, clinicians have avoided using them unless there were
no other alternatives. Furthermore, there has been a general feeling among clinicians that
aminoglycosides are not overly effective for treating many types of infection. Traditionally,
aminoglycosides were administered in multiple daily doses (once every 8 or 12 hrs). Indeed,
in the 1970s and the 1980s, the standard dosage of both gentamicin and tobramycin was also
too low, at 80 mg every 8 h (3.0-3.4 mg/kg for a person weighing 70-80 kg). This low dose
reduced the rate of nephrotoxicity but did not provide a high probability of a good clinical
outcome if the MIC was elevated.
Consequently, with the arrival of broad-spectrum beta-lactams (third-and fourth generation
cephalosporins, beta lactamase inhibitors such as piperacillin and tazobactam; and
carbamapenem, such as imipenem plus cilastatin and meropenem) and fluoroquinolones, the
use of aminoglycosides decreased because clinicians felt that they could obtain a good
resolution of serious infections without using drugs that would generate serious toxicities
(Drusano 2007, 753-60).
However, during the 1980s the introduction of Therapeutic Drug Monitoring (TDM) of
aminoglycosides provided proof that a rigorous adaptation of posology could effectively
prevent associated toxicity. TDM has been used extensively to guide dosage adjustments to
maximize efficacy and minimize toxicity. Moore and Craig (Moore et al. 1987, 1025-7)
showed a link between the amount given and therapeutic effectiveness, and elevated maximal
and mean peak aminoglycoside concentration/MIC ratios were shown to be strongly
associated with clinical response. These results demonstrate that a high peak concentration
relative to the MIC for the infecting organism is a major determinant for the clinical response
to aminoglycoside therapy. So an approximate characterization of aminoglycosides suggests
an acceleration of bactericidal activity when their concentration increases.
Later, Kashuba et al. (Kashuba et al. 1993, 1025-7) were able to establish a relationship
between exposure to aminoglycosides and the probability of a patient becoming afebrile or
experiencing normalization of temperature within a specific timeframe.
TDM has been proposed and extensively used to guide dose adjustments (Triggs and Charles
1999, 331-41) and has proven to be beneficial for maximizing efficacy and minimizing
toxicity. In fact, the realization of plasmatic dosage in routine practice and the intervention of
154
a specialist for the formal adaptation of the dosage were shown to be profitable both clinically
and financially in terms of the duration of hospitalization and the avoidance of iatrogenic
attacks. Thus, TDM could reduce the variation of therapeutic response to aminoglycosides.
The knowledge of co-variables responsible for this variation (morphometric variables,
biological variables, variables associated with pathology or therapeutic variables,…) and their
respective weight in the group of patients to be treated (e.g. patients in emergency wards,
hematology, AIDS, polytraumatized, geriatric patients) have allowed clinicians to propose a
reliable calculation of dosage from the start of the therapy by using an adapted Bayesian
program (mathematic program). The co-variables, and their respective importance, depend on
the population studied. For this reason, software has been proposed to assist in adapting the
posology for a group of patients.
In addition, in contrast to penicillin, the antibacterial spectrum of the aminoglycosides has not
narrowed in recent decades. This class of antibiotic remains a standard treatment for
Pseudomonas aeruginosa (bacterium responsible for many nosocomial infections acquired in
hospital). Their use has proved very satisfactory with patients receiving treatment with an
adapted posology determined by modeling. Their use moved further and further away from a
standardized use because clinicians worldwide were becoming increasingly aware that the
standard "80 mg every 8 hrs" regime was no longer an acceptable practice.
However, the expiration of patents (for example gentalline®, the generic version of which
started to be marketed in 1984) and the interest of pharmaceutical companies in developing
long-term treatments such as treatments for high blood pressure or diabetes, and preventive
treatments, contributed to a renewed interest in the concept of standardization for these
antibiotics. The general idea was to administer the daily amount in single perfusions once a
day instead of two or three perfusions per day. Indeed, the administration of the daily amounts
of aminoglycosides once a day, with higher doses but at longer intervals than in traditional
posology made it possible to increase effectiveness (higher rates with a higher peak of
maximal concentration) and improve clinical tolerance (lower residual rates which represent
the minimal concentration). This approach was first used by Labovitz (Labowitz et al 1974, 4
65-470) in 1974 and then rediscovered by several groups during the 1980s.
In 1980, gentamicin 160 mg was marketed as a single dose, but only for the treatment of
urinary infections. Note here that gentamicin is eliminated in an active form by the urinary
tract, meaning that with a dose of 160 mg it was possible to maintain an effective bactericidal
antibiotic concentration in the urine. Indeed, the clinical trials - in the case of urinary
infections - confirmed that a single dose of 160 mg was as effective as two of 80 mg each.
Nevertheless, for other doses (10, 40 and 80 mg.) this standardized, once-a-day administration
instead of the two or three initially recommended appeared only in 1993 with the
“Recommendations and Characteristics of the Product”1. It also applied to only a few types of
indications and a few categories of patients: subjects under 65 years of age with normal renal
function, for treatments shorter than one week and when the infection was not by Enterococus
faecalis or Pseudmonas aeruginosa.
This concept of a single dose was not widely adopted due to fears about its lack of efficacy
(for many, the half life of 2 to 3 hours meant a risk of secondary growth) and its toxicity
affecting the kidneys and hearing. The idea of a tight correlation between this toxicity and the
value of plasmatic peak concentrations prevailed until the 1980s. A peak of 12 mg/l for
gentamicin or tobramycin and 32 mg/l in the case of amikacin constituted values that were not
to be exceeded. At the same time some practitioners insisted on the need to respect residual
levels lower than 2 mg/l for gentamicin and tobramycin and lower than 10 mg/l for amikacin
without knowing precisely which of the two criteria, peak or residual, was the best predictor
of toxic risk.
The animal model provided an initial answer to these questions. Animal model data from
Giuliano et al (Giuliano et al. 1986, 470-5) and human data from De Broe et al (De Broe et al.
199) revealed that more fractionated administration (e.g. administration of a dose every 8 h or
12 h, rather than every 24 h) always resulted in a higher concentration of the drug in the
proximal renal tubular epithelial cells. These preclinical and clinical studies established the
hypothesis that less frequent aminoglycoside administration would result in less
aminoglycoside uptake and, ultimately, a lower rate of nephrotoxicity occurring during
reasonably short courses of therapy. Thus, Braak et al (Ter Braak et al. 1990, 58-66) were
able to demonstrate a significant difference between once-daily and more frequent
administration of aminoglycoside therapy with respect to the occurrence of nephrotoxicity.
Rybak et al (Rybak et al.1993, 173-9) performed the only randomized, double-blind trial
1
Vidal dictionary, The French PDR, 1993
156
examining this issue and were able to demonstrate that once-daily administration of the drug
was significantly less likely to result in nephrotoxicity than administration of the drug every
12h. These discoveries were immediately supplemented by some major biological data that
seemed to open the door to the use of the once-a-day doses. These were the rediscovery of the
post-antibiotic effect and the development of dynamic bactericidal models simulating contact
between bacteria and antibiotics with concentrations similar to those observed in man. The
conclusion was that a high peak concentration could very significantly retard secondary
growth to the point of making once-a-day therapy a viable option. Indeed, the
aminoglycosides are characterized by a prolonged post antibiotic effect. The post-antibiotic
effect refers to the continued suppression of bacterial growth despite the decline of the
antimicrobial concentration to zero.
Moreover, in the two or three hours following their exposure to an aminoglycoside, the gram
negative bacilli are less sensitive to the bactericidal effect generated by a new exposure to the
same class. In vitro studies indicated that more frequent administration of aminoglycosides
tended to reduce their uptake by the bacterial cells of aerobic gram negative bacilli, a
phenomenon known as adaptive post-exposure resistance. This effect disappeared in a few
hours in the absence of aminoglycosides. This result justifies the use of aminoglycosides with
an interval of 24 hours even though their apparent half life of elimination (duration necessary
to eliminate fifty per cent of the drug) is only 2 to 3 hours. From a toxicological point of view,
the penetration of the aminoglycosides into the target cells responsible for their toxicity (inner
ear and cortical renal cells) is saturable. Thus, there is dissociation between the peak
concentration of the aminoglycosides and the appearance of renal toxicity. Indeed, with equal
amounts, there is less accumulation with a single administration than with repeated
administrations or continuous perfusions. At the level of effectiveness, the aminosglycosides
are bactericidal antibiotics, so their bactericidal effect depends on the concentration as shown
both in vivo and in vitro. Any increase in the concentration is accompanied by an increase in
the intensity and speed of this bactericidal effect.
Except in the case of urinary infections, this concept was tested for the first time in humans by
Powell et al. (Powell et al. 1983, 918-32) in 1983. At that time, there were an increasing
number of animal and in vitro studies that within a few years made it possible to offer
clinicians solid arguments in favour of the once a day therapy. Prins et al (Prins et al. 1993,
335-9) showed the superiority of the single dose in terms of renal tolerance. This work
complemented the toxicity studies by Tulkens et al from 1991 (Tulkens 1991, 49-61) more
specifically focused on tolerance of hearing toxicity.
Looking at clinical research, we can find about thirty exploratory studies that tried to highlight
the potential clinical benefit of once a day administration in terms of effectiveness, reduced
toxicity, lower cost and facility of administration. These efforts were not very successful,
primarily because each study taken separately was insufficiently reliable. Meta-analysis has
since been applied in order to increase statistical reliability by increasing the number of
patients under consideration, and nine meta-analyses concerning immune-competent adults
were published (Galloe et al. 1995, 39-43). The overall trend seems to point towards the
greater clinical activity of daily administration, with a significant difference in four metaanalyses testifying to a reduction of about 3 % in the rate of clinical failure.
Five of the nine meta-analyses showed significantly greater effectiveness using the once a day
therapy. With regard to toxicity, there is a tendency towards lower nephrotoxicity with a
significant reduction of the risk documented in two meta-analyses (the studies of Barza and
Ferriols-Lisart 1996, 1141-50).
This strategy seems to be preferable from an economic point of view, since it involves lower
costs, requires less material (syringe and needles) and less working time for administration
and determining blood concentrations, and reduced toxicity also represents a saving in
accessory care. There appears to be a general consensus that „pulsed‟ dosing of
aminoglycosides offers the following advantages:
Relatively easy, straightforward initial dosing.
Enhanced efficacy due to higher peak levels (avoids sub-therapeutic dosing).
Enhanced safety due to shorter effective exposure time.
Convenience for both patients and nurses.
More probable on-time administration (observance).
Reduced demand for measuring serum aminoglycoside levels (reduced cost).
Facilitation of drug administration by home care services (reduced cost).
In light of the fact that pharmaceutical companies have only undertaken very limited studies
since 1993, these conclusions apply only to the populations studied: urinary, abdominal and
158
respiratory infections. Reservations and limitations concerning the use of once a day
aminoglycosides apply to the subject (not recommended in case of neutropenia, cystic
fibrosis, or impaired renal function, or in young or old patients), to the targeted germ and to
site of the infection. But, why are there no studies of these cases?
It is notable that the majority of the data in the literature concerning the pharmacodynamics
and the influence of the mode of administration of the aminoglycosides on their action in vivo
relate to the treatment of infections with Gram-negative bacilli. So the data on the treatment
of infections with Gram-positive Cocci are very limited, and the potential benefit should be
quantified by additional studies. Despite the potential, pharmaceutical laboratories no longer
invest in drugs of this type because they are not very profitable as they are now in the public
domain. Thus, while other studies would be desirable to establish the value of this concept of
once a day therapy, these studies are expensive for the laboratories, which prefer to invest in
more profitable innovative treatments. This seems regrettable in the light of the potential
therapeutic benefit of this class of drugs, particularly in view of their efficacy in the cases in
which it is used.
Since their introduction into clinical use 50 years ago and despite the arrival of newer agents
(carbapenems, monobactams, and fluoroquinolones), aminoglycoside antibiotics continue to
play an important role in the treatment of severe infections, particularly those due to aerobic,
Gram-negative bacilli. Several factors account for their durability and continued clinical
usefulness: therapeutic efficacy, synergy with the ß-lactam antibiotics, a low rate of
development of true resistance, and low drug cost. Indeed, Gram-negative organisms have
become increasingly resistant to both beta-lactamine and fluoroquinolones. Consequently,
aminoglycoside antibiotics have experienced a resurgence in use. Over the past 2 decades, we
have learned much about the relationship between aminoglycoside exposure and the
likelihood of a good clinical outcome or the occurrence of nephrotoxicity. The less frequent
administration of doses (an intervals of 24 hours, with longer intervals for patients with
compromised renal function) plays a central role in rendering the therapy effective and nontoxic. Furthermore, nosocomial infections caused by Gram-negative bacilli have become
increasingly difficult to treat over the past five years because of the advent of a number of
resistance mechanisms that limit the use of some of the best drugs in our arsenal.
Unfortunately, very few new drugs that are active against multidrug-resistant nosocomial
gram-negative organisms are expected to be available in the next 5 to 10 years. Consequently,
many clinicians are starting to consider the use of aminoglycoside antibiotics.
From an epistemological perspective, the possibility of standardizing this class of antibiotics
raises two issues, not only concerning the concept of variability but also concerning the
problem of individual response. In the context of the clinic, the patient treated is not only a
case but an individual with his own characteristics – or specific parameters – which have to be
taken into account. The question remains whether it is possible to define and determine all the
individual parameters relevant to antibiotherapy.
It seems as though the single dose eludes the concept of temporality, as the time of the
therapy is not the same as the time of organization, which remains individual. While
pharmacokinetic modeling is based on algorithms that make it possible to determine not only
the beneficial effects but also the risks inherent in this therapy while taking into account the
individual variations of each patient, it also necessary to set its limits. In this sense, the
individual is simultaneously the same (reproducibility of the therapeutic strategy) and not the
same (intrinsically different and capable of escaping categorization).
Thus, treatment is characterized by variation, by differences around a common center based
on common parameters or what might be called a standard. Is there a place for a single
approach to a once-a-day therapy with an invariable dose? Or on the contrary, do we have to
“play” with aminoglycosides in therapy around small inter-patient differences, small
variations? Beyond the history of pharmacy, the problem is one that relates to health policies
and concerns the relationship of the pharmaceutical laboratories to the clinic.
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