Efficacy of Telavancin Alone and in Combination with Ampicillin in a Rat Model of Enterococcus faecalis Endocarditis

Abstract

We first assessed telavancin (TLV) pharmacokinetics in rats after a single subcutaneous dose of 35 mg/kg of body weight. The pharmacokinetic data were used to predict a TLV dose that simulates human exposure, and the efficacy of TLV was then evaluated using a TLV dose of 21 mg/kg every 12 h against Enterococcus faecalis OG1RF (TLV MIC of 0.06 g/ml) in a rat endocarditis model with an indwelling catheter. Therapy was given for 3 days with TLV, daptomycin (DAP), or ampicillin (AMP) monotherapy and with combinations of TLV plus AMP, AMP plus gentamicin (GEN), and AMP plus ceftriaxone (CRO); rats were sacrificed 24 h after the last dose. Antibiotics were given to simulate clinically relevant concentrations or as used in other studies. TLV treatment resulted in a significant decrease in bacterial burden (CFU per gram) in vegetations from 6.0 log 10 at time 0 to 3.1 log 10 after 3 days of therapy. Bacterial burdens in vegetations were also significantly lower in the TLVtreated rats than in the AMP (P ϭ 0.0009)-and AMP-plus-GEN (P ϭ 0.035)-treated rats but were not significantly different from that of the AMP-plus-CRO-treated rats. Bacterial burdens from vegetations in TLV monotherapy and TLV-plus-AMP-and-DAP groups were similar to each other (P Ն 0.05). Our data suggest that further study of TLV as a therapeutic alternative for deep-seated infections caused by vancomycinsusceptible E. faecalis is warranted.KEYWORDS telavancin, Enterococcus faecalis, therapy, rat endocarditis E nterococci are commensals of the normal human intestinal flora and a known cause of bacterial infective endocarditis (IE). In multiple studies, enterococci have been identified as the third most frequent cause of endocarditis (1-3), with Enterococcus faecalis causing the majority of these infections. A trend toward increasing drug resistance among traditional anti-enterococcal antibiotics (i.e., penicillin, ampicillin [AMP], vancomycin [VAN], and aminoglycosides) poses significant challenges for the treatment of severe infections caused by enterococci, in particular Enterococcus faecium (4, 5). Although most E. faecalis organisms remain susceptible to penicillin and AMP, these agents are usually combined with aminoglycosides or ceftriaxone (CRO) to achieve a bactericidal effect and higher cure rates. Telavancin (TLV) is among the newer agents with in vitro activity against glycopeptide-susceptible E. faecalis. TLV has FDA approvals for complicated skin and skin structure infections (6, 7) and hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Staphylococcus aureus when alternative treatments are not suitable (8). The mechanism of bacterial killing by TLV includes inhibition of bacterial cell wall synthesis by interfering

An Experimental Infective Endocarditis Model in Rats

“…This study is important because it brings ease of application and updates to the IE rat models. Various models of experimental IE have been described to date (5)(6)(7)(8)(9)(10)(11)(12). This study has two important differences from the predefined IE animal models.…”

“…The pathophysiology of IE includes endocardial damage, hypercoagulability, and bacteremia. The experimental IE models described to date are based on this pathophysiology (5)(6)(7)(8)(9)(10)(11)(12). Animal models are widely used to investigate new diagnostic methods in IE and to evaluate the efficacy of various antimicrobial agents.…”

“…Organisms such as S. aureus, C. albicans, and Enterococcus faecalis, which have fibronectin receptors on their surface, have been reported to attach more easily to NTBE structure (13). Therefore, after the formation of NBTE, IE has been produced by injecting the microorganisms with the fibronectin receptor on the surface such as S. Aureus, C. Albicans, Enterococcus faecalis into the circulatory system in experimental animal models (5)(6)(7)(8)(9)(10)(11)(12).…”

Tedizolid as Step-Down Therapy following Daptomycin versus Continuation of Daptomycin against Enterococci and Methicillin- and Vancomycin-Resistant Staphylococcus aureus in a Rat Endocarditis Model

“…dation for rats, 70 mg/kg likely exceeds the human dose [200 mg/kg daily] [27]) via the tail vein every 24 h (Q24h) and DAP at 100 mg/kg (human equivalent, 10 mg/kg) (28,29) subcutaneously (s.c.) Q24h, and the following drugs were used for combination therapy with DAP: GEN at 3 mg/kg intramuscularly (i.m.) Q12h (25,30) and CRO at 10 mg/kg s.c. Q8h (25,31). For the no-treatment, infected, and baseline (time zero [t 0 ]) groups, numbers of CFU of bacteria per gram of aortic vegetations were determined by sacrificing 2 or 3 animals in each experiment at the time that therapy was initiated in the remaining rats (ϳ24 h after inoculation).…”

“…To assess relapse after DAP therapy, 6 to 8 animals were treated for 3 days, left untreated for 48 h, and then sacrificed in order to evaluate the effect of posttherapy residual infection; this group (referred to as the DAP Relapse group) is described as the relapse group. Animals were included in the final analysis if they survived beyond the first 24 h of therapy (24,25). Data (log 10 numbers of CFU per gram) comparisons were done between the baseline control (t 0 ) group and therapy groups and/or among therapy groups for significance.…”