Efficacy of ticarcillin-clavulanic acid for treatment of experimental Staphylococcus aureus endocarditis in rats

Abstract

The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log1o CFU/g), or delayed until 24 h after infection, when the vegetations usually contained >9 loglo CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by ,I-lactamase-producing strains of S. aureus, illustrating the P-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal ,-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.Staphylococcus aureus remains a major pathogen, and 80% to greater than 90% of clinical isolates of S. aureus are 3-lactamase producers (10, 17). Clavulanic acid is a potent inhibitor of a wide range of bacterial 3-lactamases, including those produced by S. aureus (22). The combination of ticarcillin and clavulanic acid has been shown to extend the spectrum of ticarcillin to include P-lactamase-producing strains both in vitro (29) and in vivo (2, 21, 29), and successful treatment of clinical staphylococcal infections with ticarcillin-clavulanic acid has been reported (9, 15).Experimental Staphylococcus endocarditis represents one of the more severe of the available animal models of staphylococcal infections. It is considered to be a discriminative model closely resembling the human infection in pathology and mortality (10,25) and is a stringent test of antibiotic efficacy, especially when therapy is delayed until the endocarditis is particularly well established.The combination of clavulanic acid with amoxicillin has been shown to be effective in rats against early endocarditis in which the vegetations contained approximately 6 to 8 log1o CFU of S. aureus per g (3, 5) and against late S. aureus endocarditis in which bacterial counts were 9 to 10 log1o CFU/g (5). The activity of a combination of clavulanic acid with ticarcillin against S. aureus endocarditis in rabbits has been reported elsewhere (7,24). Accordingly, the efficacy of ticarcillin-clavulanic acid in rats against early and late endocarditis caused by four ,-lactamase-producing, methicillin-susceptible strains of S. aureus has been assessed. The activity of the combination was compared with that of ticarcillin alone and with the activities of agents commonly employed in the treatment of staphylococcal infections...

Antibiotic treatment of experimental endocarditis due to methicillin-resistant Staphylococcus epidermidis

“…Thus, the present experiments clearly illustrate the phenomenon of phenotypic tolerance in vivo. The results also provide a plausible explanation for previously reported treatment failures associated with high bacterial densities in the vegetations [33,34]. Such treatment failure (sometimes attributed to an ill-defined inoculum effect) may largely result from slow growth (i.e., a state of phenotypic tolerance) of bacteria in situ rather than from high bacterial densities per se.…”

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis

“…We utilized doses of NAF and CFZ that, although shown to be effective in previous experimental IE models, were chosen without guidance from PK evaluation or serum concentrations (21,44,45). However, the efficacy of these agents (NAF and CFZ) was confirmed in our experiments despite the limitation.…”

“…(45), and (iii) NAF at 400 mg/kg q8h subcutaneously (s.c.) (44). The animals were sacrificed ϳ15 h after the last antibiotic dose, and vegetations formed on the aortic valve and surrounding tissues were aseptically removed, weighed, and homogenized in 1 ml of 0.9% saline solution.…”

“…The CPT dose was selected to achieve an fT ϾMIC that has been shown to have efficacy against S. aureus in murine thigh and lung infection and rabbit endocarditis models (24,58,59). Doses of NAF and CFZ were selected based on previously published studies demonstrating in vivo efficacy in experimental endocarditis (21,44,45). Antibiotic treatment was initiated ϳ36 h after the bacterial challenge.…”

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

“…The TLV dose scheme was derived from the PK study. Other antibiotics were given to simulate clinically relevant concentrations in humans and/or have been used previously to evaluate efficacy in experimental endocarditis (21,41,42,(44)(45)(46)(47). The CFU of bacteria per gram of vegetation of untreated baseline controls were determined 24 h after bacterial inoculation (t ϭ 0), which was the time of therapy initiation in the treatment groups, by sacrificing 2 to 3 animals per experiment and plating homogenized aortic valves containing vegetations onto EA plus RIF (100 g/ml).…”