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Antimicrobial Agents and Chemotherapy, August 2002, p. 2716-2719, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2716-2719.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activities of ABT-773 against Microaerophilic and Fastidious Organisms

Sydney M. Finegold,1,2,3* Denise Molitoris,4 V. T. Phan,4 M.-L. Vaisanen,4 and Hannah M. Wexler2,4

Infectious Diseases Section,1 Research Service, VA Greater Los Angeles Healthcare System, West Los Angeles Division, Los Angeles, California 90073,4 Departments of Medicine,2 Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, Los Angeles, California 900243

Received 25 June 2001/ Returned for modification 29 November 2001/ Accepted 17 April 2002


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ABSTRACT
 
ABT-773 was tested against 317 fastidious isolates; it inhibited 99% of organisms at a concentration of 4.0 µg/ml. With ampicillin-sulbactam and levofloxacin, only 2 and 6% of these strains, respectively, were resistant at the breakpoint. With clindamycin, penicillin G, and metronidazole, 22, 26, and 58% of the strains, respectively, were resistant.


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TEXT
 
ABT-773 is a new ketolide antibiotic, a semisynthetic derivative of erythromycin A. Ketolides are more acid stable than macrolides or azalides (4). ABT-773 has good activity against gram-positive organisms, some gram-negative organisms, and intracellular bacteria. It is initially being developed as an agent for respiratory infections (2).

Several studies have shown good activity of this compound against several different groups of anaerobic bacteria (1, 3, 5, 7), but there is little data on the organisms reported on in this study. The present report describes the activity of ABT-773 against a variety of microaerophilic and fastidious bacteria compared to that of five other agents.

All bacteria were recent isolates, primarily from clinically significant infections in patients at the Greater Los Angeles VA Healthcare Center. Bacteria were identified according to established procedures (6). MICs were determined by the agar dilution technique using an inoculum of 105 CFU and Brucella base laked sheep blood agar for most organisms studied, Mueller-Hinton agar with 5% sheep blood for Eikenella, and Haemophilus test medium for Actinobacillus. Plates were incubated in GasPak jars (BBL, Cockeysville, Md.) or in an anaerobic chamber (Anaerobe Systems, San Jose, Calif.) for 48 h at 37°C. MICs were defined as the lowest concentrations of antimicrobial permitting no growth, one discrete colony, a barely visible haze, or any distinct change from the growth control. Antimicrobial agents were obtained as powders from their respective manufacturers: ABT-773, Abbott Laboratories (Chicago, Ill.); ampicillin-sulbactam and penicillin G, Pfizer, Inc. (New York, N.Y.); clindamycin, Pharmacia & Upjohn (Bridgewater, N.J.); levofloxacin, Ortho-McNeil (Raritan, N.J.); and metronidazole, Searle Laboratories (Chicago, Ill.).

Results of the susceptibility tests are presented in Table 1.


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  		TABLE 1. Summary of activity of ABT-773 against microaerophilic and fastidious organisms

Current susceptibility testing techniques are considered to be accurate within one twofold dilution. MICs may cluster at or near breakpoints, so excessive importance should not be placed on differences of a few percentage points at a specific (e.g., breakpoint) concentration. Therefore, the percent susceptible is reported at a range of concentrations from one twofold dilution below to one twofold dilution above the breakpoints of the drugs tested, which are as follows: ampicillin-sulbactam, 16 µg/ml; clindamycin, 4 µg/ml; levofloxacin, 4 µg/ml; metronidazole, 16 µg/ml; and penicillin G, 1 µg/ml. A breakpoint has not yet been established for ABT-773, so data were analyzed by calculating the percentage of strains susceptible at 4 µg/ml. The NCCLS has not established breakpoints for the organisms tested in this study; the breakpoints noted are those for anaerobes, which are also fastidious organisms. Also, when interpreting this data it should be kept in mind that ABT-773 has high protein binding activity (90%).

Overall, ABT-773 showed excellent activity against this group of organisms, inhibiting 99% of the organisms at 4.0 µg/ml, with only one strain each of Leptotrichia, Selenomonas, Campylobacter rectus, and Streptococcus intermedius being resistant at that level (but inhibited by 8 µg/ml). Furthermore, 100% of the strains tested from the following groups were inhibited at 2 µg/ml or less: Desulfomonas species, Mitsuokella species, Capnocytophaga ochracea and Capnocytophaga species, Campylobacter curvus and Campylobacter species (including two Campylobacter showae and one Campylobacter sputorum), Eikenella corrodens, Gardnerella vaginalis, Actinomyces species, Propionibacterium propionicus, Gemella morbillorum, Streptococcus anginosus, Streptococcus constellatus, and the Streptococcus milleri group.

Ampicillin-sulbactam and levofloxacin showed good activity, with only 2 and 6% of strains, respectively, resistant at the breakpoint. However, for clindamycin, penicillin G, and metronidazole, 22, 26, and 58% of strains, respectively, were resistant at the breakpoint.

Some of our results may be skewed because of relatively small numbers of strains studied in certain cases. On the whole, though, our results are comparable to those obtained in other studies cited in which the same organisms were studied. Principally, this was the S. milleri group studied by Andrews et al. (1) and E. corrodens studied by Goldstein et al. (5).

Clinical trials will obviously be required to define the role of ABT-773 in treating infections involving the organisms studied here.


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ACKNOWLEDGMENTS
 
This work was supported in part by VA Medical Research Funds and in part by Abbott Laboratories (Chicago, Ill.).


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FOOTNOTES
 
* Corresponding author. Mailing address: Infectious Diseases Section (111 F), Greater Los Angeles Healthcare System, W. L. A., Los Angeles, CA 90073. Phone: (310) 268-3678. Fax: (310) 472-7097. E-mail: sidfinegol{at}aol.com. Back


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REFERENCES
 
    1
  1. Andrews, J. M., T. M. A. Weller J. P. Ashby, R. M. Walker, and R. Wise. 2000. The in vitro activity of ABT773, a new ketolide antimicrobial agent. J. Antimicrob. Chemother. 46:1017-1022.[Abstract/Free Full Text]
    2. 2
  2. Barrett, J. F., and T. J. Dougherty. 2001. ABT-773: a new ketolide antibiotic. Expert Opin. Investig. Drugs 10:343-351.[CrossRef][Medline]
    3. 3
  3. Citron, D. M., and M. D. Appleman. 2001. Comparative in vitro activities of ABT-773 against 362 clinical isolates of anaerobic bacteria. Antimicrob. Agents Chemother. 45:345-348.[Abstract/Free Full Text]
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  4. Douthwaite, S., and W. S. Champney. 2001. Structures of ketolides and macrolides determine their mode of interaction with the ribosomal target site. J. Antimicrob. Chemother. 48:1-8.[Abstract/Free Full Text]
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  5. Goldstein, E. J. C., D. M. Citron, V. Merriam, Y. Warren, and K. Tyrrell. 2000. Comparative in vitro activities of ABT-773 against aerobic and anaerobic pathogens isolated from skin and soft-tissue animal and human bite wound infections. Antimicrob. Agents Chemother. 44:2525-2529.[Abstract/Free Full Text]
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  6. Murray, P. R., E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken. 1999. Manual of clinical microbiology, 7th ed. American Society for Microbiology, Washington, D.C.
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  7. Sillerström, E., E. Wahlund, and C. E. Nord. 2000. The in vitro activity of ABT-773 against anaerobic bacteria. Eur. J. Clin. Microbiol. Infect. Dis. 19:635-637.[CrossRef][Medline]

Antimicrobial Agents and Chemotherapy, August 2002, p. 2716-2719, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2716-2719.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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