Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Abstract

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 micro g/ml), vancomycin (MIC = 0.5 micro g/ml), and rifampin (MIC = 0.5 micro g/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 micro g/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log(10) number of CFU per gram +/- the standard deviation) in untreated controls reached 10.6 +/- 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 +/- 2.5; daptomycin at 25 mg/kg, 5.5 +/- 1.7; daptomycin at 40 mg/kg, 4.2 +/- 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 +/- 1.6; rifampin, 3.6 +/- 1.3; vancomycin plus rifampin, 3.3 +/- 1.1; daptomycin plus rifampin, 2.9 +/- 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.

FIG. 1.

Vegetation (veg.) bacterial densities after monotherapy for 5 days with vancomycin (VAN; n = 14), daptomycin at 25 mg/kg (DAP-25; n = 15), or daptomycin at 40 mg/kg (DAP-40; n = 14) and in control animals sacrificed at 5 days (n = 12). Each datum point represents one rat. The mean log₁₀ number of CFU per gram ± the SD for each group is noted at the bottom of each column. P < 0.05 for controls versus all treatment groups and for vancomycin versus daptomycin at 40 mg/kg. Surviving animals at 5 days are shown as solid circles, while animals that were sacrificed or that died before 5 days are shown as open circles.

FIG. 2.

Vegetation (veg.) bacterial densities after therapy with vancomycin (VAN) plus rifampin (RIF) (n = 9), daptomycin at 40 mg/kg plus rifampin (n = 14), daptomycin at 40 mg/kg (DAP-40; n = 10), or rifampin (n = 13) for 5 days and in control animals (n = 5) that received no therapy. The far left set of data (controls at 6 h, n = 8) demonstrates the vegetation bacterial density at the start of therapy. The mean log₁₀ number of CFU per gram ± the SD for each group is noted at the bottom of each column. P < 0.05 for controls at 5 days versus all treatment groups and for monotherapy with daptomycin at 40 mg/kg versus daptomycin at 40 mg/kg plus rifampin. Surviving animals at 5 days are shown as solid circles, while animals that were sacrificed or that died before 5 days are shown as open circles.

FIG. 3.

Population analysis of surviving colonies from daptomycin-treated animals. Individual colonies were isolated and analyzed as described in Materials and Methods. Shown in the graph are three representative clones isolated from three individual animals treated with daptomycin at 25 mg/kg (DAP-25), two colonies from two individual animals treated with daptomycin at 40 mg/kg (DAP-40), and one colony from an untreated animal (CONTROL).