JAC
Journal of Antimicrobial Chemotherapy (1999) 44, 445–453
In-vitro activity of HMR 3647 against Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis and
-haemolytic streptococci
M. Wootton, K. E. Bowker, A. Janowska, H. A. Holt and A. P. MacGowan*
Bristol Centre for Antimicrobial Research and Evaluation, Southmead Health Services NHS Trust and
University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym,
Bristol BS10 5NB, UK
The in-vitro activity of HMR 3647 and seven comparators (azithromycin, clarithromycin,
erythromycin A, roxithromycin, penicillin G, ciprofloxacin and levofloxacin) were tested
against 207 Streptococcus pneumoniae and 200 -haemolytic streptococci. Ten comparators
(azithromycin, clarithromycin, erythromycin A, roxithromycin, ampicillin, co-amoxiclav,
cefuroxime, cefotaxime, ciprofloxacin and levofloxacin) were tested against 143 Haemophilus
influenzae and 58 Moraxella catarrhalis. The MIC50 of HMR 3647 for S. pneumoniae was 0.008
mg/L, less than that for the macrolides or quinolones tested. Pneumococci with an erythromycin A MIC of 0.06 mg/L (n 23) had an MIC50 of HMR 3647 0.008 mg/L, whereas isolates with
an erythromycin A MIC 1 mg/L (n 34) had an MIC50 of HMR 3647 of 0.03 mg/L, a four-fold
increase. In contrast, the difference in macrolide MIC 50s for the two groups was 64-fold. The
MIC50s for -haemolytic streptococci, classified by Lancefield group, were in the range 0.015
to 0.06 mg/L for HMR 3647. H. influenzae were categorized into three groups according to
cefuroxime MIC: <1 mg/L (n 72); 2–4 mg/L (n 29); and >4 mg/L (n 42). The MIC50 of HMR
3647 increased two-fold with increasing cefuroxime MICs; -lactam MICs increased much more
markedly. The MIC50 of HMR 3647 for M. catarrhalis was 0.03 mg/L. HMR 3647 has good activity
against respiratory tract pathogens but in-vitro susceptibility is affected by erythromycin A
susceptibility in S. pneumoniae and -haemolytic streptococci.
Introduction
Respiratory tract infections, a major cause of morbidity
and mortality in the community and hospitals, are caused
by a variety of pathogens. Causes of lower respiratory tract
infections (LRTI), outside the atypical group of bacteria,
are Streptococcus pneumoniae, Haemophilus influenzae
and Moraxella catarrhalis. -Haemolytic streptococci are
often implicated in upper respiratory tract infections.
Increasing incidence of resistance in these organisms has
resulted in calls for changes in antimicrobial treatment. In
the last decade macrolides such as clarithromycin and
azithromycin have assumed an increasing role in the
management of LRTI. Azithromycin displays increased
antimicrobial activity against Gram-negative respiratory
pathogens compared with erythromycin A, with the former
*Corresponding author. Tel:
being four times more active against H. influenzae and
twice as active against M. catarrhalis. Clarithromycin has
an MIC90 of 0.25 mg/L for most erythromycin A-susceptible pathogens except H. influenzae.1–4 Ketolides, such as
HMR 3647, display the same antibacterial spectrum as the
macrolides but, in addition, show good activity against
erythromycin A-resistant isolates among Gram-positive
cocci such as S. pneumoniae and -haemolytic streptococci
of Lancefield Group A.5 Compared with clarithromycin
and azithromycin, ketolides are very stable in acidic media.
In this study we tested HMR 3647, a range of macrolides
including azithromycin, clarithromycin, erythromycin A
and roxithromycin, and other relevant comparators against
608 respiratory isolates including erythromycin A-resistant
S. pneumoniae and cefuroxime-resistant H. influenzae
strains.
44-117-9595652; Fax:
445
© 1999 The British Society for Antimicrobial Chemotherapy
44-117-9593154.
M. Wootton et al.
Materials and methods
Results
The isolates used in this study, 207 S. pneumoniae, 200
-haemolytic streptococci, 58 M. catarrhalis and 143 H,
influenzae, were from the collection held at Southmead
Hospital. They were isolated from clinical specimens
between 1990 and 1998 and grouped according to species
and erythromycin A or cefuroxime sensitivity. The groups
were: -haemolytic streptococci, divided into Lancefield
groups A (59), B (41), C (19), F (35), G (46), of which five
were erythromycin A resistant; S pneumoniae (207), of
which 173 were erythromycin A sensitive and 34 resistant
(four isolates were also clindamycin resistant); H. influ enzae (143), of which 42 were cefuroxime resistant and 101
sensitive. The control strains used were H. influenzae
NCTC 11931, Straphylococcus aureus NCTC 9144 and
Escherichia coli NCTC 10536. The antimicrobials used were
all obtained from Hoechst Marion Roussel (Romainvillecedex, France). Agar dilution MICs were performed
according to the BSAC method for sensitivity testing6 on
DST agar (Unipath, Basingstoke, UK) with 5% lysed horse
blood and, for H. influenzae, 10 mg/L of both nicotinamide
adenine dinucleotide and L-histidine.7 The antimicrobials
were incorporated into the medium in a log 2 dilution series
from 0.008 to 128 mg/L. Inocula were prepared by diluting
bacterial suspensions equivalent in turbidity to a McFarland 0.5 standard, resulting in approximately 104 cfu/spot
when applied by multipoint inoculator (Denley Instruments, Billingshurst, UK). Plates were incubated in an
atmosphere of 6% CO2 for 18 h. The MIC was defined as
the lowest concentration of drug to inhibit macroscopically
visible colonies. The breakpoints used to define resistance
to HMR 3647 were those of the manufacturer. For other
agents, those of the BSAC6 were used, and where none
were available those of the Comité de l’ Antibiogramme de
la Société Francaise de Microbiologie were used.8 Breakpoints were: for streptococci HMR 3647 1 mg/L, azithromycin 1 mg/L, clarithromycin 0.5 mg/L, erythromycin
0.5 mg/L and roxithromycin 0.5 mg/L; for H. influenzae
HMR 3647
2 mg/L, low and high breakpoints of
azithromycin 0.25 mg/L and 4 mg/L, clarithromycin
0.5 mg/L and 16 mg/L, erythromycin 0.5 mg/L and 8
mg/L, roxithromycin 0.5 mg/L and 4 mg/L. For H.
influenzae and M. catarrhalis, a cefotaxime breakpoint of
1 mg/L was used. For S. pneumoniae, penicillin breakpoints were 0.06 mg/L for sensitive, 0.12–1 mg/L for
moderate and 2 mg/L for resistant; and for cefotaxime
0.5 mg/L for sensitive, 1–2 mg/L for moderate and 4
mg/L for resistant were used. for -haemolytic streptococci, the breakpoint for penicillin was 0.12 mg/L. For all
other species the breakpoints were ciprofloxacin 0.5
mg/L, levofloxacin 2 mg/L, ampicillin 1 mg/L and coamoxiclav 1 mg/L.
The in-vitro activity of HMR 3647 against -haemolytic
streptococci is shown in Table I. HMR 3647 inhibited all
-haemolytic streptococci at 0.25 mg/L. HMR 3647 had
greater activity than clarithromycin, azithromycin, roxithromycin and erythromycin A against -haemolytic streptococci group A, with an HMR 3647 MIC90 of 0.03 mg/L
compared with 0.12 of 0.5 mg/L for the other agents. With
-haemolytic streptococci group B, HMR 3647 exhibited
similar activity to clarithromycin and with group C streptococci it was more active than all macrolides, having an
MIC90 of 0.06 mg/L compared with MIC90s in the range
1–8 mg/L for the other agents. For group F streptococci, the
HMR 3647 MIC 90 was four-fold lower than the next most
active macrolide. When tested against erythromycin Aresistant -haemolytic streptococci, HMR 3647 had an
MIC50 eight-fold lower than clarithromycin, the next most
active macrolide. With S. pneumoniae, HMR 3647 was
eight-fold more active than clarithromycin. HMR 3647 had
an MIC90 of 0.12 mg/L compared with clarithromycin 8
mg/L for erythromycin A-resistant pneumococci and a
HMR 3647 MIC90 of 0.03 mg/L compared with clarithromycin 0.12 mg/L for erythromycin A-sensitive isolates. For
those strains exhibiting the MLSB resistance, i.e. clindamycin- and erythromycin A-resistant, MR 3647 was 32fold more active than clarithromycin (Table I).
For H. influenzae, HMR 3647, with an MIC90 of 4 mg/L,
was more active than all the macrolides and cefuroxime,
but not cefotaxime which had an MIC90 of 0.5 mg/L
(Table I). Against cefuroxime-resistant H. influenzae,
HMR 3647 had an MIC90 four times higher than axithromycin, while against cefuroxime-sensitive strains it was
twice as active. HMR 3647 had a similar MIC90 to clarithromycin for M. catarrhalis (Table I).
S. pneumoniae were categorized into four groups on the
basis of their erythromycin MIC (Table II). Strains with
erythromycin A MICs 0.12 mg/L had an HMR 3647
MIC50 of 0.08 mg/L, while those with erythromycin A
MICs 0.25 mg/L had an HMR 3647 MIC50 of 0.03 mg/L.
It was notable that strains with an erythromycin MIC
1 mg/L had very markedly higher MIC50s of azithromycin
(32 mg/L), clarithromycin (4 mg/L) and roxithromycin
(32 mg/L) but not of HMR 3647 (0.03 mg/L).
H. influenzae isolates were categorized according to
cefuroxime susceptibility. The MIC90 values of ampicillin
and co-amoxiclav increased 16-fold as the cefuroxime
MIC increased from 1 mg/L to 4 mg/L. The effect on
the MIC90 of cefotaxime was less clear, although the MIC50
increased from 0.015 to 0.12 mg/L. In addition, the MIC90 of
HMR 3647 and macrolides increased four-fold as the
cefuroxime MIC increased (Table III).
446
In-vitro activity of HMR 3647 against respiratory pathogens
Table I. In-vitro activity of HMR 3647 and comparators against a range of respiratory tract
pathogens
MIC (mg/L)
range
MIC50
MIC90
% susceptible
-haemolytic streptococci Lancefield Group A (n 59)
HMR 3647
0.015–0.06
0.03
azithromycin
0.12–32
0.25
clarithromycin
0.008–2
0.03
erythromycin A
0.03–0.5
0.06
roxithromycin
0.06–16
0.25
penicillin G
0.008–0.06
0.008
ciprofloxacin
0.5–8
1
levofloxacin
1–8
2
0.03
0.5
0.12
0.12
0.5
0.008
2
4
100
98
97
100
95
100
12
83
-haemolytic streptococci Lancefield Group B (n 41)
HMR 3647
0.03–0.12
0.06
azithromycin
0.12–1
0.5
clarithromycin
0.02–0.12
0.03
erythromycin A
0.03–0.25
0.12
roxithromycin
0.25–1
0.25
penicillin G
–
0.008
ciprofloxacin
0.5–4
2
levofloxacin
2–4
2
0.06
1
0.06
0.12
0.25
0.008
4
4
100
100
100
100
98
100
7
56
-haemolytic streptococci Lancefield Group C (n 19)
HMR 3647
0.008–0.25
0.03
azithromycin
0.008–32
0.5
clarithromycin
0.008–2
0.06
erythromycin A
0.008–8
0.12
roxithromycin
0.015–16
0.25
penicillin G
0.008–0.06
0.008
ciprofloxacin
0.5–8
1
levofloxacin
1–4
2
0.06
4
1
2
8
0.008
2
4
100
84
84
84
84
100
5
68
-haemolytic streptococci Lancefield Group F (n 35)
HMR 3647
0.008–0.03
0.015
azithromycin
0.12–8
0.25
clarithromycin
0.008–1
0.06
erythromycin A
0.03–2
0.12
roxithromycin
0.03–8
0.12
penicillin G
0.008–0.015
0.008
ciprofloxacin
0.5–4
1
levofloxacin
1–8
4
0.03
0.5
0.12
0.25
0.5
0.008
2
4
100
94
97
97
97
100
3
37
-haemolytic streptococci Lancefield Group G (n 46)
HMR 3647
0.15–0.06
0.03
azithromycin
0.25–8
0.5
clarithromycin
0.03–1
0.06
erythromycin A
0.03–2
0.12
roxithromycin
0.12–0.5
0.25
penicillin G
–
0.008
ciprofloxacin
0.5–2
1
levofloxacin
1–8
2
0.06
1
0.12
0.25
0.5
0.008
2
4
100
98
98
98
100
100
4
46
447
M. Wootton et al.
Table I. (Continued)
MIC (mg/L)
range
MIC50
-haemolytic streptococci (erythromycin A-resistant) (n
HMR 3647
0.03–0.12
0.12
azithromycin
4–32
8
clarithromycin
1G2
1
erythromycin A
2–8
2
roxithromycin
0.25–16
16
penicillin G
–
0.008
ciprofloxacin
1–8
2
levofloxacin
2–4
4
S. pneumoniae (n
HMR 3647
azithromycin
clarithromycin
erthromycin A
roxithromycin
penicillin G
cefotaxime
ciprofloxacin
levofloxacin
MIC90
% susceptible
–
–
–
–
–
–
–
–
100
0
0
0
20
100
0
20
5)a
207)
0.008–0.25
0.12– 128
0.03–8
0.06–128
0.06– 128
0.008–0.25
0.008–1
0.25–64
0.015–32
0.008
0.5
0.06
0.06
0.03
0.008
0.008
2
1
0.25
32
4
128
128
0.008
0.06
4
2
100
83
86
83
83
99.5b 100c
99.5b 100c
1.5
99.5
S. pneumoniae (erythromycin A-resistant) (n
HMR 3647
0.008–0.12
azithromycin
4– 128
clarithromycin
0.03–8
roxithromycin
0.25– 128
penicillin G
0.008–0.06
cefotaxime
0.008–1
ciprofloxacin
0.25–64
levofloxacin
0.015–32
34)
0.03
32
4
32
0.008
0.015
2
0.5
0.12
128
8
64
0.06
0.06
4
1
100
0
23
3
100b 100c
97b 100c
3
97
S. pneumoniae (erythromycin A-sensitive) (n
HMR 3647
0.008–0.06
azithromycin
0.12–64
clarithromycin
0.03–1
roxithromycin
0.03–1
penicillin G
0.008–0.25
cefotaxime
0.008–0.12
ciprofloxacin
0.5–8
levofloxacin
0.015–2
173)
0.008
0.5
0.06
0.12
0.008
0.008
2
1
0.03
0.5
0.12
0.25
0.008
0.06
4
2
100
99
99
99
99b 100c
100b 100c
1.1
100
S. pneumoniae (erythromycin-resistant; clindamycin-resistant) (n 4)
HMR 3647
0.008–0.12
0.12
–
azithromycin
–
128
–
clarithromycin
0.5– 128
8
–
roxithromycin
64– 128
128
–
penicillin G
0.008–0.06
0.008
–
ceftaxime
0.03–0.25
0.03
–
ciprofloxacin
1–16
4
–
levofloxacin
0.5–8
4
–
100
0
25
0
100b 100c
100
0
25
448
In-vitro activity of HMR 3647 against respiratory pathogens
Table I. (Continued)
MIC (mg/L)
range
MIC50
MIC90
% susceptible
0.12–8
0.5–8
2–128
1–64
2–128
0.12– 128
0.008–16
0.008–32
0.008–8
0.008–1
0.015–2
2
2
16
8
16
4
0.5
2
0.03
0.015
0.06
4
4
32
16
32
64
4
16
0.5
0.03
0.06
83
0b 99c
0b 99c
0b 77c
0b 2c
45
71
71
93
99
100
H. influenzae (cefuroxime-resistant) (n 42)
HMR 3647
1–8
azithromycin
0.5–8
clarithromycin
8–128
erthromycin A
4–64
roxithromycin
8–28
ampicillin
0.25– 128
co-amoxiclav
0.5–16
cefuroxime
8–32
cefotaxime
0.03–2
ciprofloxacin
0.008–0.03
levofloxacin
0.03–0.06
2
2
16
8
32
32
2
8
0.12
0.015
0.06
16
4
32
32
64
128
4
16
0.5
0.03
0.06
55
0b 97c
0b 74c
0b 67c
0b 0c
0
0
0
95
100
100
H. influenzae (cefuroxime-susceptible) (n
HMR 3647
0.125–4
azithromycin
0.5–4
clarithromycin
2.32–
erthromycin A
1–32
roxithromycin
2–64
ampicillin
0.12– 128
co-amoxiclav
0.08–16
cefuroxime
0.08–4
cefotaxime
0.08–8
ciprofloxacin
0.008–1
levofloxacin
0.015–2
2
2
16
8
16
0.5
0.25
1
0.015
0.015
0.03
2
4
16
16
32
16
8
4
0.25
0.03
0.06
94
0b 100c
0b 97c
0b 82c
0b 3c
68
85
100
92
99
100
0.03
0.06
0.03
0.12
0.12
0.25
0.06
0.5
0.12
0.03
0.06
0.06
0.12
0.06
0.25
0.25
1
0.5
1
0.25
0.03
0.06
H. influenzae (n 143)
HMR 3647
azithromycin
clarithromycin
erthromycin A
roxithromycin
ampicillin
co-amoxiclav
cefuroxime
cefotaxime
ciprofloxacin
levofloxacin
M. catarrhalis (n
HMR 3647
azithromycin
clarithromycin
erthromycin A
roxithromycin
ampicillin
co-amoxiclav
cefuroxime
cefotaxime
ciprofloxacin
levofloxacin
101)
58)
0.015–4
0.06–8
0.03–8
0.06–8
0.06–16
0.008–4
0.008–1
0.12–8
0.015–1
0.015–0.25
0.015–0.25
a
Group C (three); Group F and G (one each).
% susceptible using low breakpoint.
c
% susceptible using high breakpoint.
b
449
98
98
97
95
93
24
100
98
100
100
100
M. Wootton et al.
450
In-vitro activity of HMR 3647 against respiratory pathogens
451
M. Wootton et al.
Discussion
Resistance in streptococci to macrolides is usually due to
modification in the ribosomal target of the macrolides.
However, resistance due to an active efflux of erythromycin A (phenotypically defined as erythromycin A
resistant, clindamycin sensitive) was recently reported in
Streptomyces pyogenes and S. pneumoniae, and is increas ing in incidence.9–11 The macrolides clarithromycin,
axithromycin and roxithromycin all seem to have greater
antibacterial activity than erythromycin A against S. pneu moniae, but do not overcome MLSB resistance (phenotypically defined as erythromycin A and clindamycin
resistant).12 In this study, MR 3647 demonstrated an eightfold increase in MIC90 compared with clarithromycin, the
most active macrolide against MLSB-resistant S. pneumo niae. HMR 3647 is a semi-synthetic 14-membered ring
macrolide.13 It differs from erythromycin A in that it
has a 3-keto group on the erythronolide ring instead of 9cladinose, a sugar with supposed antibacterial activity.14,15
It has been noted that the L-cladinose sugar moiety is
responsible for inducing MLS B resistance in staphylococci
causing cross resistance among macrolides.7 HMR 3647
lacks this moiety and the results seen in this study confirm
this view in streptococci. Increased activity of MR 3647
against erythromycin A-resistant, clindamycin-sensitive
streptococci shows that even if the efflux mechanism of
resistance is present, HMR 3647 is not greatly affected.
Some cross resistance does seem to exist, however, between
HMR 3647 and erythromycin A, but to a lesser degree. This
data is consistent with other ketolide studies16,17 which
suggests that the ketolides are not inducers of MLSB
resistance. HMR 3647 is more active than all the comparator macrolides against -haemolytic streptococci.
Against H. influenzae that are cefuroxime susceptible,
HMR 3647 had a lower MIC90 than the macrolides tested.
These strains are more likely to represent the wild-type
population than the cefuroxime-resistant strains, which
occur at an incidence of 2%.18 As expected, cefuroxime
susceptibility affects susceptibility to other -lactams19 but
surprisingly also seems to be associated with effects on
macrolide, ketolide and quinolone susceptibility. Cefuroxime resistance in H. influenzae is thought to be caused by an
alteration in penicillin-binding proteins (PBPs) and, therefore, should have no effect on the activity of other agents,
perhaps suggesting another mechanism of resistance in
these strains. Some cefuroxime-resistant H. influenzae are
ampicillin sensitive by MIC testing. Whether these strains
would respond to ampicillin therapy is as yet unknown.
In conclusion, HMR 3647 has activity against a wide
range of -haemolytic streptococci and S. pneumoniae, but
has less activity against S. pneumoniae which are resistant
to macrolides due to efflux or MLSB mechanisms. However, all these strains remain susceptible as MIC values
are still well below the breakpoint. HMR 3647 is also
equipotent or has superior potency to macrolides against
cefuroxime-susceptible H. influenzae and M. catarrhalis.
Surprisingly, ketolide, macrolide and quinolone activity
declined with increasing cefuroxime MICs in H. influenzae,
possibly suggesting a further mechanism of resistance in
addition to PBP changes. It is likely that HMR 3647 will
have useful clinical activity against S. pneumoniae and
-haemolytic streptococci, irrespective of their macrolide
susceptibility.
Acknowledgement
We wish to thank Dr A. Bryskier of Hoechst Marion
Roussel for his advice and financial support.
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Received 26 October 1998; returned 23 February 1999; revised
12 March 1999; accepted 28 May 1999
453