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Antimicrobial Agents and Chemotherapy, December 1998, p. 3279-3281, Vol. 42, No. 12
Area de Bioquímica y Biología
Molecular,
Received 16 March 1998/Returned for modification 28 July
1998/Accepted 16 September 1998
Ninety-four erythromycin-susceptible and 107 erythromycin-resistant
enterococcal strains (MIC of Ketolides are novel semisynthetic
14-membered-ring macrolides. They are characterized by a
3-keto function on the aglycone A instead of an
L-cladinose. The lack of L-cladinose
allows a greater stability in acidic environments (4).
Ketolides have the same spectrum of action as macrolides, but they have
better in vitro activity against gram-positive microorganisms
(1, 7, 8, 11).
The genus Enterococcus is increasingly being recognized as a
nosocomial pathogen; indeed, it is considered the third most common
cause of nosocomial infections (5). The treatment of enterococcal infections has always been of concern, due to the intrinsic resistance of the genus to several antibiotics. Moreover, this genus frequently acquires mechanisms of antibiotic resistance to
aminoglycosides, In the present study, the in vitro activity of the ketolide HMR3647 was
compared with that of macrolides and pristinamycins on 202 Enterococcus strains with different antibiotic resistance phenotypes.
Bacterial strains.
A total of 202 Enterococcus
strains of different species were studied (163 Enterococcus
faecalis strains, 32 E. faecium strains, 3 E. gallinarum strains, 2 E. durans
strains, and 2 E. hirae strains). Forty-seven of them
were selected according to their pattern of resistance to vancomycin
and penicillin, including 18 vanA-positive Enterococcus strains (13 E. faecium, 2 E. hirae, 2 E. faecalis, and 1 E. durans strain), characterized by PCR
(13), and 29 non- Susceptibility testing.
MICs were determined by agar dilution
in Mueller-Hinton agar medium according to the National Committee
for Clinical Laboratory Standards method
(10). The antibiotics included were the
ketolide HMR3647, erythromycin A, clarithromycin, azithromycin, and
roxithromycin, all of them supplied by Hoechst Marion Roussel
(Romainville, France); spiramycin (Sigma); and pristinamycin I and II
(supplied by Rhône-Poulenc Rorer).
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Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Activity of the New Ketolide HMR3647 in
Comparison with Those of Macrolides and Pristinamycins against
Enterococcus spp.
ABSTRACT
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512 µg/ml) were inhibited by the
ketolide HMR3647 at MICs of 
0.007 to 0.06 and 0.03 to 8 µg/ml,
respectively. Eighteen vanA-positive isolates and 29 high-level-penicillin-resistant isolates, all of them erythromycin resistant, were inhibited by HMR3647 at an MIC range of 0.015 to 4 µg/ml. The new ketolide has excellent activity against
Enterococcus species.
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-lactams, glycopeptides, and macrolides. Therefore,
any new therapeutic alternative for the treatment of enterococcal
infections should be urgently evaluated.
-lactamase-producing, penicillin-resistant E. faecium strains (MIC of 16
µg/ml). The other 155 strains were randomly selected. Therefore, MIC
distributions in this work are not intended to reflect the behavior of
natural enterococcal strains and are used to compare the relative
activities of the different antibiotics.
4 µg/ml, due to the clear bimodal distribution observed (Fig.
1), even though some of these strains (for which MICs were 1 to 4 µg/ml) are classified "intermediate" by the National Committee for Clinical Laboratory Standards general criteria (10).
TABLE 1.
Resistance of 202 Enterococcus strains to
HMR3647, macrolides, and pristinamycins, according to phenotype
View larger version (11K):
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FIG. 1.
MICs of HMR3647 and erythromycin A for 202 Enterococcus strains. Black bars, erythromycin A; stippled
bars, HMR3647 against erythromycin A-susceptible strains; white
bars, HMR3647 against erythromycin A-resistant strains.
512 µg/ml. The MIC50s and
MIC90s for C14, C15, and
C16 macrolides (erythromycin A, clarithromycin, roxithromycin, azithromycin, and spiramycin) were 512 and 512 µg/ml in all cases. Interestingly, the MIC50 and
MIC90 of the ketolide HMR3647 were only 2 and 4 µg/ml, respectively (MIC range of 0.03 to 8 µg/ml), significantly
lower than those of macrolide antibiotics. Similar results were
obtained with Enterococcus strains studied by other authors
(6, 9); in one study, the MICs obtained were 1 dilution
higher than those in our study (12).
Figure 1 shows the MIC distribution for erythromycin A and HMR3647
against 202 Enterococcus strains. For erythromycin, a
bimodal distribution was observed. The first distribution peak
corresponded to strains for which MICs were in the range of 0.06 to 4 µg/ml. The second peak included the erythromycin-resistant
strains for which MICs were usually 512 µg/ml. The MIC
distribution for the ketolide HMR3647 also showed a bimodal
shape. The first peak corresponded to the erythromycin-susceptible
strains, for which MICs of the ketolide were in the range of 0.007 to
0.06 µg/ml, while the second peak corresponded to the
erythromycin-resistant strains, for which MICs were 0.06 to 8 µg/ml. Thus, the erythromycin resistance mechanism slightly
influences the MIC of the ketolide. The better intrinsic activity of
the ketolide against Enterococcus, compared with that
of macrolides, does not account for the low MICs observed for
erythromycin-resistant isolates, which indicates that this compound is
less affected by the major erm-encoded
macrolide-lincosamide-streptogramin B mechanism of resistance in this
genus. Ketolides do not induce macrolide-lincosamide-streptogramin B
resistance against erythromycin A in inducibly resistant bacteria
(2, 3).
The MIC50 and MIC90 of pristinamycin I for
erythromycin-resistant and erythromycin-susceptible strains were
128 and 256 µg/ml and 2 and 4 µg/ml, respectively;
the MIC50 and MIC90 of pristinamycin II were
both 256 µg/ml, irrespective of the erythromycin A
susceptibility pattern (Table 1). Most E. faecalis
strains (162 of 163) were highly resistant to pristinamycin II (MIC of
16 µg/ml); for the only susceptible strain the MIC was 4 µg/ml. The MIC of pristinamycin I was related to the erythromycin
A susceptibility or resistance (for 86 of 89 erythromycin-susceptible
strains the MIC of pristinamycin I was 4 µg/ml, and for 73 of
74 erythromycin-resistant strains it was 8 µg/ml). Most
E. faecium strains studied were erythromycin resistant (30 of 32), and for 27 and 20 of these 30 strains the MICs of pristinamycin I and pristinamycin II were 8 µg/ml.
Table 1 shows the activities of HMR3647 and macrolides against
Enterococcus, according to their vancomycin or
penicillin pattern of susceptibility. All vancomycin-resistant
strains were resistant to macrolide-streptogramin antibiotics.
The MIC50 and MIC90 of erythromycin A,
clarithromycin, roxithromycin, azithromycin, and spiramycin were
512 and 512 µg/ml, respectively, and those of both
pristinamycin I and pristinamycin II were 128 and 256 µg/ml,
respectively. The activity of the new ketolide appeared to be better
than those of the other drugs against these strains. All
vanA strains were inhibited by HMR3647 at concentrations
of 4 µg/ml, and the MIC50 and MIC90
were 0.5 and 4 µg/ml, respectively, a range identical to
that observed with vanA-negative,
erythromycin-resistant strains. Jones and Biedenbach
(8) reported an MIC50 and MIC90 of
the ketolide HMR3647 of 1 and 8 µg/ml, respectively, for
vanA strains. Therefore, the susceptibility of
vancomycin-resistant enterococci to HMR3647 depends on the
phenotype of resistance to erythromycin A, as previously suggested
(1). The MIC50s of erythromycin A,
clarithromycin, roxithromycin, azithromycin, and
spiramycin for the penicillin-susceptible strains were 4, 2, 8, 16, and
2 µg/ml, and the MIC50 of the ketolide
HMR3647 was 0.03 µg/ml. For penicillin-resistant
strains, the MIC50s of erythromycin A,
clarithromycin, roxithromycin, azithromycin, and spiramycin were
512 µg/ml and that of the ketolide was 1 µg/ml. As in the case of vancomycin-resistant isolates, this difference was attributable not to the penicillin-resistant phenotype but to the higher
frequency of erythromycin resistance among penicillin-resistant strains.
All vanA enterococcal strains and all
high-level-penicillin-resistant strains were resistant to
erythromycin A (MIC of 512 µg/ml); nevertheless, the MIC
of the ketolide HMR3647 was always 4 µg/ml, with
MIC50s of 0.5 and 1 µg/ml in the two groups of strains, respectively. This observation may suggest that this compound may be eventually useful, alone or in combination, in some
difficult-to-treat enterococcal infections. The results in animal
models should provide some evidence to support such a possibility.
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ACKNOWLEDGMENTS |
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We thank L. de Rafael for a critical review of this paper and R. del Campo for technical assistance.
This work was supported in part by a grant from Hoechst Marion Roussel.
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FOOTNOTES |
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* Corresponding author. Mailing address: Area de Bioquímica y Biología Molecular, Universidad de La Rioja, Avenida de la Paz, 105, 26004 Logroño, Spain. Phone: 34-941-299284. Fax: 34-941-299274. E-mail: carmen.torres{at}daa.unirioja.es.
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Antimicrobial Agents and Chemotherapy, December 1998, p. 3279-3281, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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