In vitro pharmacodynamic modelling of nafcillin alone and in combination with daptomycin against Staphylococcus aureus
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Issue Date
2013
Authors
Mall, Kiran J. '13
Degree
MS in Biotechnology
Advisor
Nicasio, Anthony
Committee Members
Malik, Meenakshi
Stein, Markus
Stein, Markus
Journal Title
Journal ISSN
Volume Title
Abstract
Methicillin resistant staphylococcus aureus (MRSA) is global healthcare concern due to increased rates of death associated with this infection. Recently, studies have reported increasing rates of vancomycin and daptomycin non-susceptibility and therapeutic failure with both drugs. This recent development has led researchers to look for therapeutic replacements to circumvent this potentially growing problem. Fortunately, through clinical and in vitro experimental studies, researchers have been able to demonstrate that the combination of daptomycin and an anti-staphylococcal beta-lactam antibiotic enhances the bactericidal efficacy of daptomycin against daptomycin non-susceptible S. aureus (DNSA). The rationale for the increased efficacy of daptomycin plus an anti-staphylococcal beta-lactam is a phenomenon called the "see-saw effect". This effect takes place when an organism's susceptibility to an anti-staphylococcal beta-lactam increases as the susceptibility to daptomycin decreases. In an attempt to further characterize the relationship between daptomycin and an anti-staphylococcal beta-lactam, this study has explored this combination treatment (nafcillin and daptomycin) using a time kill assay and mutation frequency study against four phenotypically diverse MRSA isolates. The purpose of the study is to observe the utility of nafcillin with daptomycin against DNSA and daptomycin susceptible S. aureus (DSSA) isolates. The following objectives were tested in the study: 1) evaluate the efficacy of daptomycin plus nafcillin against DNSA by comparing the changes in bacterial density over 24 and 48 hours; 2) determine if the combination of daptomycin plus nafcillin will suppress the development of resistant subpopulations; 3) determine if an inoculum effect exists with this combination regimen. As demonstrated by the time kill assay, nafcillin plus daptomycin not only demonstrated synergistic effects at a lower multiple of their respective MIC as compared to either agent alone, but also provided resistance suppression at 1.5xMIC and 3xMIC of daptomycin. Interestingly, an inoculum effect was present with daptomycin alone and in combination as observed by the increased bactericidal activity with lower concentrations against an inoculum of 10^6 CFU/ml. The combination of daptomycin and nafcillin appears to be a potent, bactericidal option for the treatment of DNSA infection.
Citation
Mall, Kiran J. "In Vitro Pharmacodynamic Modelling of Nafcillin Alone and in Combination with Daptomycin against Staphylococcus Aureus." Albany College of Pharmacy and Health Sciences, New York, Proquest/UMI, 2013.
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