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Antimicrobial Agents and Chemotherapy, August 1998, p. 2138-2140, Vol. 42, No. 8
The Clinical Microbiology Institute,
Wilsonville, Oregon 97070
Received 9 February 1998/Returned for modification 27 April
1998/Accepted 3 June 1998
The ketolide HMR 3647 (previously RU 66647) was evaluated against
2,563 recent clinical isolates of gram-positive pathogens and 200 Haemophilus influenzae isolates. HMR 3647 was active
against macrolide-resistant streptococci, including pneumococci, but
was not active against macrolide- or lincosamide-resistant
staphylococci. Against H. influenzae, the potency of HMR
3647 was similar to that of azithromycin.
Ketolides are new semisynthetic
14-membered ring macrolides that differ from erythromycin A in that a
3-keto group is substituted for L-cladinose on the
erythronolide A ring (1). They exhibit an antimicrobial
spectrum comparable to erythromycin A, but for gram-positive cocci,
ketolide MICs tend to be significantly lower than those of erythromycin
A (2, 4, 5, 7, 8, 10). They are active against some
anaerobic bacteria (6). Macrolide-resistant strains of
Streptococcus pneumoniae are susceptible to the ketolides (4, 5, 10). HMR 3647 (previously RU 66647) is the ketolide that was selected for further evaluation in clinical studies. In this
report, we describe the in vitro activity of HMR 3647 against 2,563 consecutive gram-positive clinical isolates collected from 10 North
American medical centers and 200 stock cultures of Haemophilus
influenzae.
The 10 North American medical centers that contributed consecutive
clinical isolates for this study are listed in the Appendix. A total of
2,563 recent gram-positive clinical isolates, each from a different
patient, was collected during the first quarter of 1997. The species or
major groups of microorganisms are described in Table
1. In addition, 200 stock
cultures of H. influenzae (84 ampicillin-susceptible
cultures, 27 ampicillin-resistant and
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Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Activities of the Ketolide HMR 3647 against Recent Gram-Positive Clinical Isolates and
Haemophilus influenzae
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-lactamase-negative cultures,
and 89 -lactamase-positive cultures) were also tested.
TABLE 1.
Comparative susceptibility of recent gram-positive
clinical isolates and H. influenzae stock cultures to
HMR 3647, erythromycin A, and clindamycina
All isolates were subjected to in vitro antimicrobial susceptibility tests by the broth microdilution procedure as recommended by the National Committee for Clinical Laboratory Standards (9). All test trays were incubated at 35°C without added CO2. For testing streptococci, the cation-adjusted Mueller-Hinton broth was supplemented with 2 to 3% lysed horse blood. For testing H. influenzae isolates, freshly prepared Haemophilus Test Medium (HTM) broth was used. HMR 3647 was provided by Hoechst Marion Roussel. The other drugs, used for comparison, were procured from their respective U.S. manufacturers or purchased from Sigma Chemical Company, St. Louis, Mo. Only breakpoint concentrations of penicillin or oxacillin and vancomycin were tested. Concentrations of HMR 3647, erythromycin A, and clindamycin ranged from 0.12 to 16 µg/ml. Azithromycin and clarithromycin were tested only against H. influenzae, at concentrations ranging from 0.12 to 32 µg/ml.
When the broth microdilution trays were first prepared, they were validated by testing standard quality control organisms in triplicate. Those control strains were again tested on each day that a set of tests was initiated. Controls included Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, and Streptococcus pneumoniae ATCC 49619. The MICs of erythromycin and clindamycin were all within accepted control limits (9). The MICs of azithromycin and clarithromycin (diluted in HTM broth) were also within control limits when tested against H. influenzae ATCC 49247 (9).
Table 1 summarizes the MIC data of HMR 3647, erythromycin A, and clindamycin (and of azithromycin and clarithromycin for H. influenzae). By comparing geometric mean MICs, we defined the relative potency of drugs tested against H. influenzae to be as follows: azithromycin > HMR 3647 > clarithromycin. The difference between azithromycin and HMR 3647 was marginal. HMR 3647, erythromycin A, and clindamycin showed little useful activity against oxacillin-resistant staphylococci and vancomycin-resistant enterococci. Against most species, the ketolide was substantially more potent than erythromycin A. The frequency of off-scale MICs at either end of the range of concentrations tested precludes accurate assessment of the magnitude of differences between MICs. For different species, median MICs of HMR 3647 and erythromycin A differed by a magnitude of 0- to 64-fold.
The MICs of HMR 3647 for erythromycin-resistant staphylococci and
enterococci were greater than those for erythromycin-susceptible strains (Table 2). In the case of
streptococci, over 90% of the HMR 3647 MICs were 
0.25 µg/ml
regardless of erythromycin A or clindamycin resistance patterns. Two of
175 (1%) Streptococcus pyogenes isolates were resistant to
erythromycin (MICs, 2.0 and 4.0 µg/ml), but both strains were
susceptible to clindamycin and to HMR 3647. Over 95% of the
erythromycin-resistant or clindamycin-resistant pneumococci and other
streptococci were susceptible to 1.0 µg of HMR 3647 per ml. However,
for E. faecalis, 1 µg of HMR 3647 per ml inhibited only
74% of the erythromycin-resistant strains and 87% of the
clindamycin-resistant strains. The majority of erythromycin-resistant
staphylococci and Enterococcus faecium isolates were also
resistant to HMR 3647 (Table 2).
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All clindamycin-resistant isolates were also resistant to erythromycin A, but the reverse was not true. The clindamycin-resistant strains were not as susceptible to HMR 3647 as the clindamycin-susceptible strains were (Table 2). This was particularly true of staphylococci and enterococci. Only 26% of the 185 clindamycin-resistant S. aureus strains were susceptible to 1 µg of HMR 3647 per ml, and only 3% of 138 clindamycin-resistant coagulase-negative staphylococci were susceptible to the same concentration of HMR 3647. On the other hand, clindamycin-resistant pneumococci were uniformly susceptible to HMR 3647, as were 96% of the clindamycin-resistant nonpneumococcal streptococci. That is particularly noteworthy because the majority of clindamycin-resistant pneumococci are also resistant to penicillin G and are often resistant to many other unrelated drugs (3).
In summary, for a sample of 2,563 recent gram-positive clinical isolates, HMR 3647 demonstrated significantly greater activity than erythromycin A or clindamycin, particularly against erythromycin- and penicillin-resistant S. pneumoniae and other streptococci. Additional studies with 200 H. influenzae isolates demonstrated that azithromycin and HMR 3647 were similar in potency and that clarithromycin was substantially less potent. Such differences in the in vitro potency of these drugs do not necessarily predict differences in their clinical efficacy, but HMR 3647 is likely to be a valuable addition to the macrolide-lincosamide-streptogramin B class of drugs.
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APPENDIX |
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We thank the following individuals for providing the clinical isolates included in this report: Timothy Cleary, University of Florida, Miami; Dwight Hardy, University of Rochester Medical Center, Rochester, N.Y.; Janet Hindler, University of California at Los Angeles, Los Angeles; Steven Jenkins, Carolinas Medical Center, Charlotte, N.C.; James McLaughlin, University of New Mexico Medical Center, Albuquerque; Michael Pfaller, University of Iowa College of Medicine, Iowa City; Robert Rennie, University of Alberta Hospital, Edmonton, Alberta, Canada; Daniel Sahm, Barnes Jewish Hospital, St. Louis, Mo.; Kenneth Waites, University of Alabama at Birmingham, Birmingham; John Washington, The Cleveland Clinic Foundation, Cleveland, Ohio.
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ACKNOWLEDGMENTS |
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This survey was made possible by a grant from Hoechst Marion Roussel R & D, Romainville, France.
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FOOTNOTES |
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* Corresponding author. Mailing address: The Clinical Microbiology Institute, 9725 SW Commerce Circle, Suite A1, Wilsonville, OR 97070. Phone: (503) 682-3232. Fax: (503) 682-2065. E-mail: cmi{at}hevanet.com.
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REFERENCES |
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| 1. | Agouridas, C., A. Bonnefoy, and J. F. Chantot. 1994. Ketolides, a new semi-synthetic class of macrolides: in-vitro and in-vivo antibacterial activities, abstr. F168, p. 227. In Program and Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. |
| 2. | Agouridas, C., A. Bonnefoy, and J. F. Chantot. 1997. Antibacterial activity of RU 64004 (HMR 3004), a novel ketolide derivative active against respiratory pathogens. Antimicrob. Agents Chemother. 41:2149-2158[Abstract]. |
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Barry, A. L.,
P. C. Fuchs, and S. D. Brown.
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Macrolide resistance among Streptococcus pneumoniae and Streptococcus pyogenes isolates from outpatients in the USA.
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| 4. | Barry, A. L., P. C. Fuchs, and S. D. Brown. 1997. In vitro activity of the new ketolide HMR3004 compared to an azalide and macrolides against Streptococcus pneumoniae and Haemophilus influenzae. Eur. J. Clin. Microbiol. Infect. Dis. 16:767-769[Medline]. |
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Barry, A. L.,
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Antimicrob. Agents Chemother.
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| 6. | Ednie, L. M., M. R. Jacobs, and P. C. Appelbaum. 1997. Comparative antianaerobic activities of the ketolides HMR 3647 (RU 66647) and HMR 3004 (RU 64004). Antimicrob. Agents Chemother. 41:2019-2022[Abstract]. |
| 7. | Jamjian, C., D. J. Biedenbach, and R. N. Jones. 1997. In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004. Antimicrob. Agents Chemother. 41:454-459[Abstract]. |
| 8. | Jones, R. N., and D. J. Biedenbach. 1997. Antimicrobial activity of RU-66647, a new ketolide. Diagn. Microbiol. Infect. Dis. 27:7-12[Medline]. |
| 9. | National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa. |
| 10. | Schülin, T., C. B. Wennersten, R. C. Moellering, Jr., and G. M. Eliopoulos. 1997. In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria. Antimicrob. Agents Chemother. 41:1196-1202[Abstract]. |
Antimicrobial Agents and Chemotherapy, August 1998, p. 2138-2140, Vol. 42, No. 8
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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