Abstract
The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p < 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.
Highlights
The appropriate management of methicillin-resistant Staphylococcus aureus (MRSA) infections has become increasingly complex due to the limited efficacy of glycopeptides in bacterial eradication, commonly attributed to the emergence of drug-resistant strains [1,2,3]
Daptomycin (DAP), a bactericidal lipopeptide, has been shown to be a viable alternative amid vancomycin (VAN) resistance; increased VAN minimum inhibitory concentrations (MICs) against S. aureus have been shown to parallel with increased DAP minimum inhibitory concentration testing (MIC) [4,5,6]
The reduction in MIC values seen in the combination therapies was significantly greater when compared to the monotherapy values (p < 0.05)
Summary
The appropriate management of methicillin-resistant Staphylococcus aureus (MRSA) infections has become increasingly complex due to the limited efficacy of glycopeptides in bacterial eradication, commonly attributed to the emergence of drug-resistant strains [1,2,3]. VAN and DAP MICs are minimal due to the associated undesirable side effects, bacteriostatic activity, and the achievement of suboptimal antimicrobial concentrations [7,8]. Dalbavancin (DAL) is a long-acting lipoglycopeptide that has demonstrated enhanced activity eliminating highly resistant S. aureus [9]. This antibiotic is approved by the FDA for the management of acute bacterial skin and skin structure infections (ABSSSIs). DAL has been shown to be more potent, in vitro, than glycopeptides such as VAN and teicoplanin in the eradication of multidrug-resistant (MDR)
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