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Antimicrobial Agents and Chemotherapy, October 2006, p. 3507-3513, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00499-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Comparative In Vitro Susceptibilities of 396 Unusual Anaerobic Strains to Tigecycline and Eight Other Antimicrobial Agents

Ellie J. C. Goldstein,^1,2* Diane M. Citron,¹ C. Vreni Merriam,¹ Yumi A. Warren,¹ Kerin L. Tyrrell,¹ and Helen T. Fernandez¹

R. M. Alden Research Laboratory, Santa Monica, California 90404,¹ David Geffen School of Medicine at UCLA, Los Angeles, California 90073²

Received 21 April 2006/ Returned for modification 26 July 2006/ Accepted 10 August 2006

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Tigecycline was tested against 396 strains of lesser-known anaerobic species encountered in human infections. It was active against all gram-positive strains and 228 of 232 gram-negative anaerobes at 1 µg/ml. One strain of Prevotella oralis was nonsusceptible at 8 µg/ml.

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Tigecycline, a new glycylcycline antimicrobial agent, has recently been approved by the FDA for the treatment of complicated intra-abdominal infections (IAIs) and skin and soft tissue infections (SSTIs). It has shown activity against a variety of aerobic and anaerobic bacteria (1, 2-5, 7, 8, 11, 14). While premarket testing of new antimicrobial compounds is often extensive, it focuses on typical anaerobic pathogens such as the members of the Bacteroides fragilis group, Clostridium perfringens, and Clostridium difficile (1, 2, 3, 4), yet the bacteriology of IAIs and SSTIs is complex. In IAIs, for example, B. fragilis and B. fragilis group species account for 44% of anaerobic isolates, whereas less commonly clinically identified anaerobes account for the remaining 56% (6). Clostridia account for an additional 17% of IAI isolates, with C. clostridioforme and C. innocuum comprising 30% and 23%, respectively, of Clostridium species. Complicated SSTIs, such as diabetic foot and animal and human bite wound infections are also polymicrobial, involving multiple anaerobic species, including peptostreptococci, Porphyromonas spp., and fusobacteria (6, 10, 15). These organisms are recognized pathogens yet are often not isolated or identified by routine clinical laboratories due to cost and time considerations or lack of technical expertise. Since most clinical laboratories also do not perform susceptibility testing on anaerobes, most therapy is empirical, with clinicians relying on published studies to help guide therapy choices. We therefore determined the activity of tigecycline against a large variety of these less common anaerobic species, most of which have not been tested in previously reported studies.

The strains used in this study were previously isolated from human clinical specimens from a variety of sources and were identified by standard criteria or, for atypical strains, by 16S RNA gene sequencing (9, 12). The numbers and species of isolates tested are given in Table 1. Fifty-seven of the strains were tested in a previous study of bite wound infections (5) but with different comparator antimicrobial agents.

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TABLE 1. Organisms and agents tested in this study

Frozen cultures were transferred twice onto brucella agar supplemented with hemin, vitamin K₁, and 5% sheep blood to assure purity and good growth. Susceptibility testing was performed according to CLSI standards (M11-A6) (13). Antimicrobial agents were reconstituted according to the manufacturers' instructions, and serial twofold dilutions of antimicrobial agents were prepared on the day of the test and added to the media at various concentrations. The agar plates were inoculated with a Steers replicator (Craft Machine Inc., Chester, Pa.), using an inoculum of 10⁵ CFU/spot. Control plates without antimicrobial agents were inoculated before and after each set of drug-containing plates. Plates were incubated at 37 C° for 48 h in an anaerobic chamber (Anaerobe Systems, Morgan Hills, Calif.). The control strains tested included Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741. The MIC was defined as the lowest concentration of an agent that yielded no growth or a marked change in the appearance of growth compared to that of the control plates.

Standard laboratory powders were supplied as follows: tigecycline and piperacillin-tazobactam, Wyeth Ayerst Pharmaceuticals, Pearl River, N.Y.; metronidazole, Searle Research & Development, Skokie, Ill.; imipenem, Merck & Co., West Point, Pa.; meropenem, Astra Zeneca, Wilmington, Del.; moxifloxacin, Bayer Pharmaceuticals, West Haven, Conn.; clindamycin, Voigt Global Distribution, Kansas City, Mo.; and doxycycline and penicillin G, Sigma Chemical Co., St. Louis, Mo.

The MICs are shown in Table 1. The MICs of tigecycline and their frequency of occurrence for the quality control strains were as follows: B. fragilis ATCC 25285, 0.125, once, and 0.25, 7 times; B. thetaiotaomicron ATCC 29841, 0.25, once, 0.5, 3 times; and 1, 3 times.

Against gram-positive anaerobes (Actinomyces spp., clostridia, lactobacilli, and peptostreptococci), tigecycline compared favorably to the other agents tested. In our study, it showed excellent activity against C. difficile, as was also noted in several other studies (2, 3, 14), with all isolates susceptible to 0.06 µg/ml. Tigecycline was also very active at 0.25 µg/ml against 82 of 85 strains from the eight Clostridium species tested. Only one strain each of C. bifermentans and C. butyricum required 1 µg/ml for inhibition. Tigecycline was the most active agent tested against Lactobacillus species, which included multidrug-resistant strains of L. casei. Isolates from three infrequently studied Actinomyces species, including several doxycycline-resistant strains, were all susceptible to 1 µg/ml of tigecycline.

The gram-negative anaerobes were also very susceptible to tigecycline, with MICs of 1µg/ml for 228 of 232 strains. Isolates requiring >1 µg/ml for inhibition included one strain each of Prevotella buccae (MIC, 2 µg/ml; also penicillin and clindamycin resistant), Prevotella melaninogenica (MIC, 4 µg/ml; also penicillin, moxifloxacin, and doxycycline resistant), and 1 strain each of Prevotella oralis and Prevotella disiens (MIC, 8 and 4 µg/ml, respectively; both penicillin and doxycycline resistant). Veillonella species generally required 1 µg/ml of tigecycline for inhibition.

Overall, tigecycline had excellent in vitro activity against both gram-positive and gram-negative unusual anaerobes, with 395 of 396 (99.7%) of strains susceptible at 4 µg/ml, the FDA-assigned breakpoint.

 
This study was funded in part by a grant from Wyeth-Ayerst.

We thank Judee H. Knight and Alice E. Goldstein for various forms of assistance.

 
* Corresponding author. Mailing address: R. M. Alden Research Laboratory, 2021 Santa Monica Blvd., 740 East, Santa Monica, CA 90404. Phone: (310) 315-1511. Fax: (310) 315-3662. E-mail: ejcgmd{at}aol.com.

Published ahead of print on 28 August 2006.

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Antimicrobial Agents and Chemotherapy, October 2006, p. 3507-3513, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00499-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Goldstein, E. J. C. Articles by Fernandez, H. T. Search for Related Content PubMed PubMed Citation Articles by Goldstein, E. J. C. Articles by Fernandez, H. T.