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

被引：28

作者：

Steed, Molly E. ^{[1
,3
]}

Werth, Brian J. ^{[1
]}

Ireland, Cortney E. ^{[1
]}

Rybak, Michael J. ^{[1
,2
]}

机构：

[1] Wayne State Univ, Eugene Applebaum Coll Pharm & Hlth Sci, Antiinfect Res Lab, Detroit, MI 48202 USA

[2] Wayne State Univ, Sch Med, Detroit, MI USA

[3] Univ Kansas, Sch Pharm, Lawrence, KS 66045 USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2012年 / 56卷 / 11期

关键词：

BACTERICIDAL ACTIVITIES; PHARMACODYNAMIC MODEL; VANCOMYCIN; SUSCEPTIBILITY; INFECTION; MECHANISMS; REGIMENS; STRAINS; DRUGS;

D O I：

10.1128/AAC.01185-12

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

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 mu g/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 mu g/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were <= 0.06/1.19 mu g/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 log(10) 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.

引用

页码：5709 / 5714

页数：6