In vitro activity of telithromycin (HMR 3647) and seven other antimicrobial agents against anaerobic bacteria
G. Ackermann*,
R. Schaumann,
B. Pless,
M. C. Claros and
A. C. Rodloff
Institute for Medical Microbiology and Epidemiology of Infectious Diseases, Liebigstrasse 24, University of Leipzig, D-04103 Leipzig, Germany
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Abstract
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We assessed the in vitro activity of telithromycin (HMR 3647) and seven other antimicrobials against 292 strains of obligately anaerobic bacteria. MICs were determined with the microdilution technique and WilkinsChalgren broth according to DIN 58940-83. MIC50/MIC90s (mg/L) for telithromycin were 4/4 for Bacteroides fragilis, Bacteroides ovatus and Bacteroides thetaiotaomicron, 2/4 for Fusobacterium spp. and Bilophila wadsworthia, 2/2 for Bacteroides caccae, 1/4 for Bacteroides vulgatus, 0.25/4 for Prevotella spp.,
0.03/0.5 for Clostridium spp. and 0.125/4 for Peptostreptococcus spp.
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Introduction
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Telithromycin is a semi-synthetic erythromycin A derivative and belongs to a novel class of macrolide-lincosamide-streptogramin B antibiotics, the ketolides. An outstanding antimicrobial activity of telithromycin against multiresistant pneumococci, enterococci and Haemophilus influenzae strains was documented in previous studies.1,2 Ednie et al. tested the in vitro activity of telithromycin against a broad spectrum of anaerobes and demonstrated high activity, particularly against Gram-positive anaerobes (except some strains of Clostridium difficile).3 Credito et al. compared the anti-anaerobic activity of telithromycin with that of four macrolides and found the lowest MICs for telithromycin and clarithromycin.4 In the present study, we investigated the activity of telithromycin and seven other antimicrobial agents against 292 clinical isolates of obligately anaerobic bacteria.
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Materials and methods
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The 292 strains of obligately anaerobic bacteria were isolated from clinical specimens in the R. M. Alden Research Laboratory, Santa Monica, CA, USA; the Institute for Infectious Diseases, Free University of Berlin, Germany; and the Institute for Medical Microbiology and Epidemiology of Infectious Diseases, University of Leipzig, Germany. All strains were identified as detailed earlier by Claros et al.5 The species and numbers of strains tested are shown in Table I
. Bacteroides fragilis ATCC 25285, B. fragilis ATCC 23745, Bacteroides ovatus ATCC 8483, Bacteroides vulgatus ATCC 8482, Bacteroides thetaiotaomicron ATCC 29148, Bacteroides caccae ATCC 43185, Fusobacterium mortiferum ATCC 9817, Fusobacterium varium ATCC 8501 and Peptostreptococcus magnus ATCC 14955 were used as reference strains.
Antimicrobial agents were obtained as drug substances of known potency from the manufacturers: telithromycin and erythromycin A from Hoechst Marion Roussel (Romainville, France), metronidazole from Bayer AG (Leverkusen, Germany), clindamycin from Pharmacia & Upjohn (Kalamazoo, MI, USA), imipenem from Merck & Co., Inc. (West Point, NY, USA), doxycycline and chloramphenicol from Sigma Chemical Co. (St Louis, MO, USA) and penicillin G from Serva (Heidelberg, Germany).
Broth microdilution assays were performed in accordance with the recommendations of the Deutsches Institut für Normung (DIN) standard DIN 58940-83 as described earlier by Schaumann et al. employing 96-well microdilution plates (Greiner GmbH, Frickenhausen, Germany) and WilkinsChalgren broth (Oxoid Unipath Ltd, Basingstoke, UK).6,7 The lowest antibiotic concentration that inhibited visible growth was recorded as the MIC.
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Results
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The distribution of MICs and the MIC50 and MIC90 values of telithromycin and the seven other antimicrobials for the clinical isolates tested here are summarized in Table I
. Table II
shows the results as the cumulative percentage of strains inhibited at various MICs. The MICs of the reference strains showed conformity with the published ranges of the NCCLS8 and the DIN.6
For the Bacteroides spp. tested here, similar MIC50/90 values (mg/L) were found: i.e. B. caccae (2/2), B. vulgatus (1/4), B. fragilis, B. ovatus, B. thetaiotaomicron and Bacteroides distasonis (4/4) (Table I
). The lowest MICs of telithromycin were demonstrated for Clostridium spp. (MIC50/90
0.03/0.5 mg/L). Our strains of Clostridium spp. other than Clostridium difficile (n = 23) were all inhibited at 4 mg/L telithromycin and at 8 mg/L erythromycin A (MIC50/90
0.03/0.5 mg/L and 1/4 mg/L, respectively). The six isolates of C. difficile tested showed MIC ranges of <0.032 mg/L for telithromycin and 0.58 mg/L for erythromycin A. All 292 strains were inhibited by 4 mg/L telithromycin, but only 63% by the same concentration of erythromycin A (MIC90s 4 and
32 mg/L, respectively).
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Discussion
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Results of susceptibility tests are influenced by both the strains tested and the methodology used. In general, our in vitro results correlate with previous reports on the anti-anaerobic activity of telithromycin.3,4,9,10 Differences may be more a reflection of different methods than actual epidemiological differences. Medium, additives, inoculum, type and duration of incubation as well as difficulties in reading endpoints with certain types of tests and certain drugs may lead to different results in different studies. However, broth dilution and agar dilution both yield reproducible results and in this study the in vitro activity of telithromycin was evaluated using the microbroth dilution method with almost 300 well-characterized anaerobic strains. The studies by Ednie et al.,3 Edlund et al.9 and Dubreuil et al.10 were carried out with different modifications of the agar dilution methods. In general, our MICs of telithromycin and erythromycin A with respect to Bacteroides species were one to two dilution steps lower than those described by Ednie et al.3 The most striking differences were seen with B. ovatus strains and telithromycin, for which Ednie et al.3 found MIC50/90 values of 32/>64 mg/L whereas our MIC50/90 values were 4/4 mg/L. For B. fragilis, B. vulgatus and B. thetaiotaomicron MIC50 values of telithromycin and erythromycin A reported by Dubreuil et al.10 were similar to those obtained in our study. However, they reported MIC90s for these three Bacteroides spp. of >64 mg/L whereas 90% of our strains were inhibited at 4 mg/L. Again, significant differences were seen for B. ovatus strains for which Dubreuil et al.10 established MIC50/90 values of telithromycin and erythromycin A of >64/>64 mg/L. However, the results published by Edlund et al. for telithromycin, erythromycin A, clindamycin, metronidazole and imipenem for B. fragilis were very similar to ours.9 With Fusobacterium spp. we found lower MICs of telithromycin (MIC50/90 values 2/4 mg/L) than Ednie et al.3 (MIC50/90 values 16/>64 mg/L) and Dubreuil et al.10 (MIC50/90 values 4/32 mg/L). Moreover, in the study by Dubreuil et al.10 50% of the Fusobacterium spp. were inhibited by 0.25 mg/L erythromycin A, which was more active than the ketolide (MIC50 4 mg/L). However, our results and those published by Ednie et al. show erythromycin A MIC50/90 values of
32 mg/L for Fusobacterium species.3 In our study telithromycin was more active than erythromycin A against Clostridium species. A high susceptibility of C. perfringens and C. difficile to telithromycin was also described by Edlund et al.10 In our study telithromycin displayed a higher in vitro activity against C. difficile than erythromycin A. In contrast, Ednie et al. found higher MIC50/90 values of telithromycin for C. difficile.3 Again, for C. difficile, Dubreuil et al. found MIC90s of telithromycin and erythromycin A of
64 mg/L.10
Altogether, the results of the studies discussed here indicate that there might be sufficient activity of telithromycin for therapeutic purposes against certain but possibly not all anaerobic bacteria.
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Acknowledgments
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We thank Dr A. Bryskier for his support. We gratefully acknowledge that strains for this study were given to us by Dr E. J. C. Goldstein, R. M. Alden Research Laboratory, Santa Monica, CA, USA. This study was supported by a grant from Hoechst Marion Roussel, Paris, France.
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Notes
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* Corresponding author. Tel: +49-341-9715200; Fax: +49-341-9715209; E-mail: ackermg{at}medizin.uni-leipzig.de 
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References
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Dubreuil, L., Singer, E., Odou, M. F. & Bryskier, A. (1998). Antianaerobic activity of the ketolide HMR 3647 compared to 4 macrolides, clindamycin, metronidazole and 5 ß-lactams. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract E142, p. 210. American Society for Microbiology, Washington, DC.
Received 19 August 1999;
returned 17 January 2000; revised 15 February 2000;
accepted 28 February 2000