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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
dc.contributor.author | Steed, Molly E. | |
dc.contributor.author | Werth, Brian J. | |
dc.contributor.author | Ireland, Cortney E. | |
dc.contributor.author | Rybak, Michael J. | |
dc.date.accessioned | 2015-05-05T21:49:59Z | |
dc.date.available | 2015-05-05T21:49:59Z | |
dc.date.issued | 2012-11 | |
dc.identifier.citation | Steed et al. "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." Antimicrob. Agents Chemother. November 2012 vol. 56 no. 11 5709-5714 http://dx.doi.org/10.1128/AAC.01185-12 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/17617 | |
dc.description.abstract | 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. | en_US |
dc.description.sponsorship | We are grateful to St. Joseph’s Hospital Center, Syracuse, NY, for SA H9749-1 and to Albany Medical Center for R5599. This work was funded by an investigator-initiated grant from Cubist Pharmaceuticals. M.J.R. has received grant support, consulted for, or provided lectures for Astellas, Cubist, Forest, Clinical Therapeutics, and Rib-X and is supported in part by grant R21AI092055 for the NIAID. | en_US |
dc.publisher | American Society for Microbiology | en_US |
dc.title | 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 | en_US |
dc.type | Article | |
kusw.kuauthor | Steed, Molly E. | |
kusw.kudepartment | Department of Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1128/AAC.01185-12 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |