Evaluation of the Novel Combination of High-Dose Daptomycin plus Trimethoprim-Sulfamethoxazole against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations

摘要

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10⁹ CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log10 CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P < 0.05) and trimethoprim-sulfamethoxazole monotherapy (P < 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections.