1 APRIL
Correspondence
Pandrug Resistance (PDR),
Extensive Drug Resistance
(XDR), and Multidrug
Resistance (MDR) among
Gram-Negative Bacilli:
Need for International
Harmonization in
Terminology
To the Editor—In a recent commentary,
Paterson and Doi [1] addressed the need
for universal definitions for the various
degrees of antimicrobial resistance among
gram-negative bacilli. In light of the recent
evidence suggesting that polymyxins, a
“rediscovered” category of antimicrobial
agents [2], and tigecycline, a new drug [3],
constitute valuable additions to the clinician’s armamentarium against highly resistant gram-negative bacteria, these authors proposed the term “extreme drug
resistance” (XDR) to signify resistance of
pathogens that are gram negative to all
potentially effective antibiotics. They also
narrowed the meaning of the already-used
term “panresistance” to refer to pathogens
that are specifically resistant to 7 antimicrobial agents (cefepime, ceftazidime, imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and levofloxacin).
Although we welcome the authors’ endeavor to suggest terms related to bacterial
drug resistance, we would like to express
our reservations regarding the proposed
definitions and our consideration that the
attribution of improper meaning to the
aforementioned terms may increase the
relevant confusion observed in the medical literature [4], with potentially important implications for researchers, health
care professionals, or even the public.
The prefix “pan-” has its origin in the
ancient Greek language, meaning “all” or
“whole.” With this meaning, it is used in
common English [5] and other languages.
Of importance, it has been used for the
generation of numerous combined bio-
medical terms, to denote the inclusion of
all parts or aspects of an entity (table 1)
[6]. In this respect, the term “panresistance” or “pandrug resistance” (PDR) cannot be interpreted in a sense other than
signifying resistance to all antibiotics [4,
7, 8].
In regard to the term “extreme drug
resistance,” it was first used in the field of
oncology/hematology to designate tumorcell colonies that exhibit significantly decreased responsiveness in vitro to a studied
chemotherapeutic agent [9]. In the field
of infectious diseases, “XDR” has been
used to abbreviate “extensively drug resistant” Mycobacterium tuberculosis, defined by resistance to both rifampin and
isoniazid, as well as to fluoroquinolones
plus an injectable agent [10]. Presumably,
Paterson and Doi [1] introduced the term
“extreme drug resistance” for gram-negative bacteria to designate a wider resistance pattern than “extensive drug resistance.” Still, semantically, “extreme”
cannot be more inclusive than “pan-,”
meaning all.
It should also be noted that, in the proposed definitions [1], a category of highly
resistant pathogens, with resistance patterns intermediate to those described in
the authors’ commentary by the terms
“panresistance” and “extreme drug resistance,” remains unclassified. The inevitable need to characterize these pathogens
with either 1 of the 2 or other terms would
eventually generate further confusion. In
fact, apart from the term pandrug resistance, notable diversity has been observed
as well in the medical literature regarding
the use of the term “multidrug resistance”
(MDR), which has rather arbitrarily been
used to denote resistance of gram-negative
pathogens to a varying number of antimicrobial agents [4, 11].
In our view, when all these issues are
Table 1. List of common biomedical
terms in which the prefix “pan” is used to
signify involvement of all constituents.
Pancytopenia
Pandemic
Panencephalitis
Panhypopituitarism
Pancolitis
Panoramic (radiography)
Panbronchiolitis
Panretinal (photocoagulation)
Panophthalmitis
Pansinusitis
Pancarditis
Panacinar (emphysema)
considered, the terms “pandrug resistance,” “extensive drug resistance,” and
“multidrug resistance” should designate,
respectively, resistance of a pathogen to all,
resistance to all but 1 or 2, and resistance
to ⭓3 classes of antimicrobial agents,
among those that are available at the time
of use of the definition and in most parts
of the world and that are regarded as potentially effective against the respective
pathogen.
We advocate the term “extensive drug
resistance”—rather than “extreme drug
resistance”—to avoid confusion with the
different meaning of the latter term in the
context of neoplastic diseases [9]. Furthermore, the definitions of PDR and extensive drug resistance, as we herein state,
will retain their semantic properties in
time, without the need of introduction of
new terms in cases in which more therapeutic options against highly resistant
bacteria become available. In addition, because these definitions respect the etymology of the terms used, they are expected to correspond to the use of the
same terms in other fields of infectious
diseases or in medicine in general.
CORRESPONDENCE • CID 2008:46 (1 April) • 1121
Acknowledgments
Potential conflicts of interest. M.E.F. and
D.E.K.: no conflicts.
Matthew E. Falagas1,2
and Drosos E. Karageorgopoulos1
1
Alfa Institute of Biomedical Sciences (AIBS),
Athens, Greece; and 2Department of Medicine,
Tufts University School of Medicine,
Boston, Massachusetts
References
1. Paterson DL, Doi Y. A step closer to extreme
drug resistance (XDR) in gram-negative bacilli. Clin Infect Dis 2007; 45:1179–81.
2. Falagas ME, Kasiakou SK. Colistin: the revival
of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005; 40:1333–41.
3. Hoban DJ, Bouchillon SK, Dowzicky MJ. Antimicrobial susceptibility of extended-spectrum b-lactamase producers and multidrugresistant Acinetobacter baumannii throughout
the United States and comparative in vitro
activity of tigecycline, a new glycylcycline
antimicrobial. Diagn Microbiol Infect Dis
2007; 57:423–8.
4. Falagas ME, Koletsi PK, Bliziotis IA. The diversity of definitions of multidrug-resistant
(MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa. J Med Microbiol 2006; 55:1619–29.
5. Merriam-Webster Online Dictionary. 2005.
Available at: http://www.merriam-webster
.com/. Accessed 10 October 2007.
6. Dorland’s Illustrated Medical Dictionary, 30th
ed. Philadelphia: WB Saunders, 2003.
7. Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos
A. Outcome of infections due to pandrugresistant (PDR) gram-negative bacteria. BMC
Infect Dis 2005; 5:24.
8. Falagas ME, Kasiakou SK. Correct use of the
term “pan-drug-resistant” (PDR) gram-negative bacteria. Clin Microbiol Infect 2005; 11:
1049–50.
9. Kern DH, Weisenthal LM. Highly specific prediction of antineoplastic drug resistance with
an in vitro assay using suprapharmacologic
drug exposures. J Natl Cancer Inst 1990; 82:
582–8.
10. Extensively drug-resistant tuberculosis (XDRTB): recommendations for prevention and
control. Wkly Epidemiol Rec 2006; 81:430–2.
11. Paterson DL. The epidemiological profile of
infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
Clin Infect Dis 2006; 43(Suppl 2):43–8.
Reprints or correspondence: Dr. Matthew E. Falagas, Alfa
Institute of Biomedical Sciences (AIBS), 9 Neapoleos St., 151
23 Marousi, Greece ([email protected]).
Clinical Infectious Diseases 2008; 46:1121–2
2008 by the Infectious Diseases Society of America. All
rights reserved. 1058-4838/2008/4607-0025$15.00
DOI: 10.1086/528867
Table 1. Responsibilities of proposed task force on multidrug resistance among gramnegative bacilli.
Create internationally acceptable terminology for gram-negative bacilli lacking susceptibility to all
first-line antibiotic therapy.
Create internationally acceptable terminology for gram-negative bacilli lacking susceptibility to both
first-line and second-line antibiotic therapy (i.e., lacking susceptibility to all currently available
antibiotics).
Determine the most appropriate breakpoints (European Committee on Antimicrobial Susceptibility
Testing vs. Clinical and Laboratory Standards Institute) for defining resistance.
Determine the most appropriate methods for assessment of additive or synergistic effects of
antibiotic combinations against gram-negative bacilli.
Establish multinational surveillance programs for antibiotic resistance of gram-negative bacilli.
Establish priorities for randomized trials evaluating methods for control of spread of these organisms.
Reply to Falagas and
Karageorgopoulos
To the Editor—The term “extensively
drug-resistant tuberculosis” first appeared
in peer-reviewed journals in March 2006
[1]. It is believed that prior reports of resistance to multiple second-line drugs associated with a high case-fatality rate did
not reach the global public health community because the entity did not have
this new name, “extensively drug resistant” [2]. We are at a crisis point with
antibiotic resistance among gram-negative
bacilli. Patients are dying because of a lack
of antibiotic options. We believe that, just
as the extensively drug resistant terminology has reached public attention with
regard to tuberculosis, so it should with
regard to gram-negative bacilli. In our
mind, semantically correct as it may be,
“panresistance” does not adequately capture the desperate need for attention to
this problem.
Although not as familiar with the Greek
language as Drs. Falagas and Karageorgopoulos [3], we are well aware that “pan”
refers to “all.” Our definition of “panresistance” refers to decreased susceptibility
to all antibiotics recommended as empirical therapy for ventilator-associated
pneumonia in the joint guidelines of the
Infectious Diseases Society of America/
American Thoracic Society [4]. Thus,
“panresistance” refers to decreased susceptibility to cefepime, ceftazidime, imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and levofloxacin [5, 6].
(Aminoglycosides are also included in that
guideline as part of empirical therapy but
1122 • CID 2008:46 (1 April) • CORRESPONDENCE
never as monotherapy.) Thus, our definition of “pan-resistance” refers to all antibiotics that an infectious diseases physician would likely prescribe as first-line
empirical therapy for a patient suspected
to have a serious infection with a gramnegative bacillus. We believe that this is a
practical, clinically appropriate definition.
In the field of tuberculosis, strains resistant to all available first- and secondline drugs have been referred to as “extremely drug resistant” (“XXDR”) [7]. We
chose the terminology “extreme drug resistance” to mirror the complete resistance
of gram-negative strains to the first-line
antibiotics mentioned above plus the second-line drugs such as tigecycline and
polymyxins.
We agree with Drs. Falagas and Karageorgopoulos [3] that international harmonization of this terminology would be
useful. We support establishment of a task
force to assess this issue, perhaps sponsored by an organization such as the Centers for Disease Control and Prevention.
Because definitions of susceptibility and
resistance differ between the European
Committee on Antimicrobial Susceptibility Testing and the Clinical and Laboratory
Standards Institute, a task force looking at
terminology for drug resistance among
gram-negative bacilli needs to determine
which breakpoints are most appropriate
in this situation. Consideration of results
of susceptibility testing of combinations of
antibiotics is also needed. Other responsibilities of such a task force are listed in
table 1.
We conclude by emphasizing that we