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

Abstract

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 Ca 2؉ to 50 mg/liter. The MICs at which 90% of isolates tested were inhibited (MIC 90 s) for telavancin and vancomycin were as follows: Actinomyces spp. (n ‫؍‬ 45), 0.25 and 1 g/ml, respectively; Clostridium difficile (n ‫؍‬ 14), 0.25 and 1 g/ml, respectively; Clostridium ramosum (n ‫؍‬ 16), 1 and 4 g/ml, respectively; Clostridium innocuum (n ‫؍‬ 15), 4 and 16 g/ml, respectively; Clostridium clostridioforme (n ‫؍‬ 15), 8 and 1 g/ml, respectively; Eubacterium group (n ‫؍‬ 33), 0.25 and 2 g/ml, respectively; Lactobacillus spp. (n ‫؍‬ 26), 0.5 and 4 g/ml, respectively; Propionibacterium spp. (n ‫؍‬ 34), 0.125 and 0.5 g/ml, respectively; Peptostreptococcus spp. (n ‫؍‬ 52), 0.125 and 0.5 g/ml, respectively; and Corynebacterium spp. (n ‫؍‬ 31), 0.03 and 0.5 g/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 g/ml) against 14 strains of Actinomyces spp. and all C. ramosum, Eubacterium lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 g/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 g/ml. The MIC 90 of TD-6424 for all strains tested was <2 g/ml. TD-6424 has potential for use against infections with gram-positive anaerobes and deserves further clinical evaluation.The development of resistance in gram-positive organismsincluding Staphylococcus aureus resistant to oxacillin and vancomycin (10,11,13) and linezolid (12) and vancomycinresistant 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 infe...

Life-Threatening Infection Caused by Daptomycin-Resistant Corynebacterium jeikeium in a Neutropenic Patient

“…1]) might have caused a reduction of the commensal microbial flora and a concomitant growth of C. jeikeium, finally resulting in selection of the daptomycin-resistant strain. While highlevel resistance to daptomycin has not been described in corynebacteria so far (8,17), and the genetic basis for daptomycin resistance also remains to be elucidated, daptomycin's activity against C. jeikeium is known to be inferior to its activity against staphylococci, suggesting the presence of intrinsic factors contributing to lower susceptibility (20). Although we cannot exclude the possibility that the genetic determinant conferring resistance to daptomycin in C. jeikeium resides on a low-copy-number plasmid, our attempts to isolate extrachromosomal DNA failed.…”

Efficacy of Telavancin in the Treatment of Experimental Endocarditis Due to Glycopeptide-Intermediate Staphylococcus aureus

“…This multifunctional mechanism of action may help to minimize the potential for the selection of resistance (16,27). In several studies, telavancin has exhibited in vitro activity superior to that of vancomycin (12,15,20,26,33).…”

Tissue Penetration of Telavancin after Intravenous Administration in Healthy Subjects

“…Due to the concern of rising resistance rates among gram-positive pathogens, the development of new antibiotics with the ability to overcome current resistance mechanisms is essential. Telavancin displays rapid, bactericidal, concentration-dependent activity against clinically important gram-positive aerobic pathogens, such as Staphylococcus aureus (methicillin susceptible and methicillin resistant) (3,8,10). Telavancin exhibits its killing effects via multiple mechanisms of action, including inhibition of peptidoglycan synthesis and disruption of cell membrane integrity (7,10).…”