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The mutant-prevention concentration concept and its application to Staphylococcus aureus

dc.contributor.advisorBlondeau, Josephen_US
dc.contributor.committeeMemberZiola, Barryen_US
dc.contributor.committeeMemberTan, Benen_US
dc.contributor.committeeMemberSanche, Steveen_US
dc.contributor.committeeMemberDeneer, Harryen_US
dc.creatorMetzler, Kelli Leighen_US 2004en_US
dc.description.abstractStaphylococcus aureus is a ubiquitous organism causing world-wide morbidity and mortality. This species readily develops resistance to antimicrobial agents. Current dosing strategies are based, in part, on minimum inhibitory concentrations (MICs). This susceptibility test fails to detect the presence of first-step resistant mutants often present in large heterogeneous populations of infecting bacteria. Dosing strategies based on MIC results may, in fact, allow for the selective proliferation of resistant subpopulations. The mutant-prevention concentration (MPC) is the drug concentration at which all first-step resistant mutants will be eradicated along with the susceptible cells. Determination of the mutant-selection window (MSW) is possible using MIC and MPC data. When considered together with achievable drug concentrations in human bodily sites, the MSW helps determine which antimicrobials are likely to select for resistance. MIC and MPC testing on clinical isolates of methicillin-susceptible (MSSA) and -resistant (MRSA) S. aureus was performed. Characterization via the polymerase chain reaction, sequencing, and electron microscopy (EM) was done on selected organisms recovered from MPC studies (MPC-recovered). MIC and MPC testing was performed on organisms isolated sequentially from patients with recurring S. aureus infections. Pulsed field gel electrophoresis was performed on these sequential isolates. Based on the MIC and the MPC values, the most potent agents for systemic MSSA and MRSA infections are gemifloxacin and vancomycin, respectively. Re-testing MPC-recovered populations by the MIC showed increased MIC results compared to the parent populations. Macrolide-resistance genes were discovered in S. aureus MPC-recovered populations; in contrast, parental isolates lacked these resistance determinants. EM revealed an increase in cell wall thickness of a vancomycin MPC-recovered population compared to its parental population. Moxifloxacin and vancomycin had the lowest and narrowest MSWs for systemic MSSA and MRSA infections, respectively, compared to the other agents tested. Sequential isolates showed no change in MIC and MPC values. The data presented provides evidence for the application of the MPC test to S. aureus organisms. The MPC data is significant when determining appropriate dosing strategies aimed at preventing resistance.en_US
dc.subjectspontaneous mutation frequencyen_US
dc.subjectlarge bacterial populationsen_US
dc.subjectminimum inhibitory concentrationen_US
dc.subjectmutant-selection windowen_US
dc.subjectpharmacokinetic curvesen_US
dc.subjectantimicrobial agentsen_US
dc.titleThe mutant-prevention concentration concept and its application to Staphylococcus aureusen_US
dc.type.materialtexten_US and Immunologyen_US and Immunologyen_US of Saskatchewanen_US of Science (M.Sc.)en_US


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