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Antimicrobial Agents and Chemotherapy, June 2004, p. 2149-2152, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2149-2152.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of the New Semisynthetic Glycopeptide Telavancin (TD-6424), Vancomycin, Daptomycin, Linezolid, and Four Comparator Agents against Anaerobic Gram-Positive Species and Corynebacterium spp.

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

Received 16 October 2003/ Returned for modification 21 January 2004/ Accepted 9 February 2004

	ABSTRACT

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Telavancin is a new semisynthetic glycopeptide anti-infective with multiple mechanisms of action, including inhibition of bacterial membrane phospholipid synthesis and inhibition of bacterial cell wall synthesis. We determined the in vitro activities of telavancin, vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, imipenem, piperacillin-tazobactam, and ampicillin against 268 clinical isolates of anaerobic gram-positive organisms and 31 Corynebacterium strains using agar dilution methods according to National Committee for Clinical Laboratory Standards procedures. Plates with daptomycin were supplemented with Ca²⁺ to 50 mg/liter. The MICs at which 90% of isolates tested were inhibited (MIC₉₀s) for telavancin and vancomycin were as follows: Actinomyces spp. (n = 45), 0.25 and 1 µg/ml, respectively; Clostridium difficile (n = 14), 0.25 and 1 µg/ml, respectively; Clostridium ramosum (n = 16), 1 and 4 µg/ml, respectively; Clostridium innocuum (n = 15), 4 and 16 µg/ml, respectively; Clostridium clostridioforme (n = 15), 8 and 1 µg/ml, respectively; Eubacterium group (n = 33), 0.25 and 2 µg/ml, respectively; Lactobacillus spp. (n = 26), 0.5 and 4 µg/ml, respectively; Propionibacterium spp. (n = 34), 0.125 and 0.5 µg/ml, respectively; Peptostreptococcus spp. (n = 52), 0.125 and 0.5 µg/ml, respectively; and Corynebacterium spp. (n = 31), 0.03 and 0.5 µg/ml, respectively. The activity of TD-6424 was similar to that of quinupristin-dalfopristin for most strains except C. clostridioforme and Lactobacillus casei, where quinupristin-dalfopristin was three- to fivefold more active. Daptomycin had decreased activity (MIC > 4 µg/ml) against 14 strains of Actinomyces spp. and all C. ramosum, Eubacterium lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 µg/ml) against C. ramosum, two strains of C. difficile, and 15 strains of Lactobacillus spp. Imipenem and piperacillin-tazobactam were active against >98% of strains. The MICs of ampicillin for eight Clostridium spp. and three strains of L. casei were >1 µg/ml. The MIC₉₀ of TD-6424 for all strains tested was 2 µg/ml. TD-6424 has potential for use against infections with gram-positive anaerobes and deserves further clinical evaluation.

	INTRODUCTION

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The development of resistance in gram-positive organisms—including Staphylococcus aureus resistant to oxacillin and vancomycin (10, 11, 13) and linezolid (12) and vancomycin-resistant enterococci also resistant to linezolid (4)—has accentuated the need for new antimicrobial agents. Telavancin is a novel glycopeptide that is bactericidal and shows concentration-dependent killing against gram-positive aerobes, including vancomycin-resistant strains (9). Unlike vancomycin, TD-6424 has multiple synergistic mechanisms of action resulting in TD-6424's enhanced activity against aerobic gram-positive species (5a, 9). At the MIC, it has exhibited postantibiotic effects of up to 6 h against S. aureus, compared to 2 h for vancomycin (9). TD-6424 is currently in phase 2 trials for serious gram-positive infections.

Little has been published regarding the activity of telavancin against either unusual aerobic bacteria or anaerobes. In order to evaluate the potential efficacy of TD-6424 against a broad spectrum of aerobic and anaerobic gram-positive species, we determined its in vitro activities against 299 recent aerobic and anaerobic clinical isolates.

	MATERIALS AND METHODS

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Strains were isolated from clinical specimens obtained from adult patients between 1996 and 2002 and identified by standard criteria (5, 6). Strains were consecutive isolates, except when needed to make at least 10 isolates per species. Staphylococcus aureus ATCC 29213 and Eubacterium lentum ATCC 43055 were tested simultaneously with the appropriate plates and environments. The numbers and species of clinical isolates tested are given in Table 1.

Susceptibility testing was performed according to the standards established by the National Committee for Clinical Laboratory Standards (7, 8), using an agar dilution method with Mueller-Hinton agar and an inoculum of 10⁴ CFU per spot for corynebacteria and brucella agar supplemented with hemin, vitamin K₁, and 5% laked sheep blood and an inoculum of 10⁵ CFU per spot for anaerobic species. Daptomycin was supplemented with Ca²⁺ (50 mg/liter) as suggested by the manufacturer.

	RESULTS AND DISCUSSION

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The results of the study are shown in Table 1. Overall, 240 of 268 (90%) of anaerobic isolates and 31 of 31 (100%) of the corynebacterium isolates tested were inhibited by telavancin at concentrations of 1 µg/ml. Telavancin was typically at least two- to fourfold more active than vancomycin against most strains, with the exception of Clostridium clostridioforme and Lactobacillus casei isolates. The activity of telavancin was similar to that of quinupristin-dalfopristin for most strains except against C. clostridioforme and L. casei, where quinupristin-dalfopristin was three- to fivefold more active. Daptomycin had decreased activity (MIC > 4 µg/ml) against 14 strains of Actinomyces spp. and all Clostridium ramosum, E. lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 µg/ml) against C. ramosum, two strains of Clostridium difficile, and 15 strains of Lactobacillus spp. Imipenem and piperacillin-tazobactam were active against >98% of strains, while the MICs of ampicillin for eight Clostridium spp. and three strains of L. casei were >1µg/ml.

All Actinomyces and Eubacterium isolates, including Actinomyces israelii, Actinomyces meyeri, Actinomyces turicensis, Actinomyces odontolyticus, Actinomyces viscosus, E. lentum, and Eubacterium limosum strains, were susceptible to telavancin at concentrations of 0.25 µg/ml. Its activity against clostridia was variable by species, with excellent in vitro activity against Clostridium perfringens (MIC at which 90% of isolates tested were inhibited [MIC₉₀], 0.125 µg/ml), C. difficile (MIC₉₀, 0.25 µg/ml), and C. ramosum (MIC₉₀, 1 µg/ml). telavancin had limited activity against C. clostridioforme (MIC ₉₀, 8 µg/ml), a gram-negative appearing species, and C. innocuum (MIC₉₀, 4 µg/ml) but had MICs similar to those of daptomycin and linezolid. All other gram-positive strains tested with the exception of two Lactobacillus species (one of eightLactobacillus catenaforme strains and one Lactobacillus leichmannii strain) were susceptible to telavancin at concentrations of 0.25 µg/ml.

The classification of the genus Peptostreptococcus has recently undergone taxonomic changes in nomenclature (2). New species names include Peptoniphilus asaccharolyticus, Finegoldia magna, Micromonas micros, and Anaerococcus prevotii. telavancin at concentrations of <0.5 µg/ml inhibited all "peptostreptococci." Corynebacterium species, Corynebacterium amycolatum, and Corynebacterium jeikeium were inhibited by telavancin, the most active agent tested, at concentrations of <0.06 µg/ml. Daptomycin had similar activities against corynebacteria. A. israelii, A. meyerii, A. turicensis, A. ondontolyticus, and A. viscosus strains that were resistant to daptomycin were very susceptible to telavancin, which was two- to fourfold more active than vancomycin.

Some Lactobacillus spp. have been associated with bacteremia and endocarditis for which therapy may be problematic; others have been associated with vaginal health, while depletion has been associated with an increased risk of urinary tract infections and bacterial vaginosis (1, 12, 14). In our study, many Lactobacillus species that were resistant to vancomycin, linezolid, and daptomycin were generally susceptible to telavancin at concentrations of 0.25 µg/ml. L. casei isolates were resistant to telavancin and vancomycin (MIC₅₀, 32 µg/ml) but were generally susceptible to daptomycin at concentrations of 2 µg/ml, quinupristin-dalfopristin at concentrations of 1 µg/ml, and linezolid at concentrations of 4 µg/ml. Limited activity against Lactobacillus acidophilus and L. casei could be viewed as a positive health factor, allowing maintenance of the normal vaginal flora.

Telavancin demonstrated potent activity (<1 µg/ml) against a broad spectrum of gram-positive anaerobes and unusual aerobes, including Actinomyces species, Propionibacterium species, the Peptostreptococcus group, and Clostridium species such as C. perfringens and C. difficile (but excluding C. clostridioforme). telavancin was typically two- to fourfold more active than vancomycin against most strains. Telavancin was less active than vancomycin against C. clostridioforme, a gram-negative species, but the MICs of telavancin were similar to those of daptomycin and linezolid. Its overall activity compared favorably with that of the other agents tested.

Telavancin was described as "one of the most promising molecules" (3) on the basis of its aerobic gram-positive activity. We found that telavancin also exhibited excellent in vitro activities against most of the anaerobic gram-positive and Corynebacterium strains tested, with 271 of 299 (91%) of all strains inhibited by telavancin at concentrations of 1 µg/ml. Telavancin warrants clinical evaluation against infections caused by anaerobic gram-positive bacteria and corynebacteria.

	ACKNOWLEDGMENTS

 
We thank Judee H. K. Knight, Alice E. Goldstein, Kone Koniga, and Stephen Barriere for various forms of assistance.

This study was supported, in part, by a grant from Theravance Inc., South San Francisco, Calif.

	FOOTNOTES

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

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