Abstract
BackgroundDaptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates. This study reports the therapeutic activity of high-dose daptomycin compared to standard regimens of oxacillin and vancomycin in a difficult-to-treat, rat tissue cage model of experimental therapy of chronic S. aureus foreign body infection.MethodsThe methicillin-susceptible S. aureus (MSSA) strain I20 is a clinical isolate from catheter-related sepsis. MICs, MBCs, and time-kill curves of each antibiotic were evaluated as recommended by NCCLS, including supplementation with physiological levels (50 mg/L) of Ca2+ for daptomycin. Two weeks after local infection of subcutaneously implanted tissue cages with MSSA I20, each animal received (i.p.) twice-daily doses of daptomycin, oxacillin, or vancomycin for 7 days, or was left untreated. The reductions of CFU counts in each treatment group were analysed by ANOVA and Newman-Keuls multiple comparisons procedures.ResultsThe MICs and MBCs of daptomycin, oxacillin, or vancomycin for MSSA strain I20 were 0.5 and 1, 0.5 and 1, or 1 and 2 mg/L, respectively. In vitro elimination of strain I20 was more rapid with 8 mg/L of daptomycin compared to oxacillin or vancomycin. Twice-daily administered daptomycin (30 mg/kg), oxacillin (200 mg/kg), or vancomycin (50 mg/kg vancomycin) yielded bactericidal antibiotic levels in infected cage fluids throughout therapy. Before therapy, mean (± SEM) viable counts of strain I20 were 6.68 ± 0.10 log10 CFU/mL of cage fluid (n = 74). After 7 days of therapy, the mean (± SEM) reduction in viable counts of MSSA I20 was 2.62 (± 0.30) log10 CFU/mL in cages (n = 18) of daptomycin-treated rats, exceeding by >2-fold (P < 0.01) the viable count reductions of 0.92 (± 0.23; n = 19) and 0.96 (± 0.24; n = 18) log10 CFU/mL in cages of oxacillin-treated and vancomycin-treated rats, respectively. Viable counts in cage fluids of untreated animals increased by 0.48 (± 0.24; n = 19) log10 CFU/mL.ConclusionThe improved efficacy of the twice-daily regimen of daptomycin (30 mg/kg) compared to oxacillin (200 mg/kg) or vancomycin (50 mg/kg) may result from optimisation of its pharmacokinetic and bactericidal properties in infected cage fluids.
Highlights
Daptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates
Infections due to Staphylococcus aureus associated with foreign implants, such as orthopaedic prostheses and intravascular devices, are very difficult to manage by antimicrobial therapy alone and frequently require the removal of infected materials [1]
The growing proportion of clinical isolates of methicillin-resistant S. aureus (MRSA) displaying multidrug resistance against all semi-synthetic penicillins and penems, and frequently against macrolides, aminoglycosides, fluoroquinolones [2,3,4], and glycopeptides [3,5,6,7] recently prompted the development of novel antimicrobial agents active against such dangerous pathogens
Summary
Daptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates. The relatively high protein binding and low volume of distribution of daptomycin recorded in humans or animal models represent a difficult challenge for defining a dosing schedule exerting optimal bactericidal activity against major categories of serious S. aureus infections [12,21,22,23,24,25,26,27,28,29] in various deep-seated compartments though minimizing skeletal muscle side-effects [30,31] Another issue is the recently shown observation that pulmonary surfactant interfered with daptomycin antimicrobial activity providing a likely explanation for treatment failures in clinical trials of community-acquired pneumonia and animal models of gram-positive pneumonia [28]
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