Evaluation of high-dose daptomycin for therapy of experimental Staphylococcus aureus foreign body infection.
BACKGROUND
Daptomycin 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.


METHODS
The 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.


RESULTS
The 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.


CONCLUSIONS
The 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.
Schaad
Heinz J
HJ
Service of Infectious Diseases, Geneva University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. heinz.schaad@spitalfmi.ch
Bento
Manuela
M
Lew
Daniel P
DP
Vaudaux
Pierre
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D017576:Daptomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005547:Foreign Bodies / Q000188:drug therapy* / Q000382:microbiology*; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000627:therapeutic use; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy*; D014640:Vancomycin / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin; D010068:Oxacillin