Date of Award

1-1-2013

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Epidemiology and Biostatistics

Program

Epidemiology

Content Description

1 online resource (ix, 304 pages) : illustrations (some color)

Dissertation/Thesis Chair

Louise-Anne McNutt

Committee Members

George Drusano, Victoria Lazariu, leon Cosler

Keywords

epidemiology, infectious diseases, MRSA, outcomes, Methicillin resistance, Staphylococcus aureus infections, Drug resistance in microorganisms, Antibiotics

Subject Categories

Epidemiology

Abstract

This dissertation advances our understanding of antimicrobial exposure-response relationships among patients with serious infections due to Staphylococcus aureus. The need is pressing as treatment of this invasive pathogen has been complicated by the development of antibiotic resistance. One antibiotic resistant phenotype of particular concern is methicillin-resistant S. aureus (MRSA). Due to the multi-drug resistant nature of most MRSA strains, vancomycin emerged as the cornerstone of therapy. Although widely used for serious MRSA infections, many clinicians now question its continued utility due to the emergence of MRSA strains with reduced vancomycin susceptibility phenotypes (rVSPs). The literature is developing rapidly, but characterization of the outcomes associated with these rVSPs remains largely incomplete. The paucity of clinical exposure-response evaluations also makes it difficult to determine whether outcomes can be improved by optimizing the vancomycin concentration-time profile. The emerging concerns with vancomycin have prompted clinicians to consider alternate agents. Linezolid is one the more promising antibiotics with MRSA activity. However, concerns over its potential to cause serotonin toxicity have tempered its use despite limited clinical data to substantiate an increased risk. To address these voids in the literature, the first specific aim was to critically evaluate the relationships between rVSPs and assess their individual and combined effects on outcomes among patients who received vancomycin for a MRSA bloodstream infection. The second specific aim was to quantitatively evaluate the relationship between vancomycin exposure and outcomes among patients with MRSA bloodstream infections. The third specific aim was to delineate the risk of serotonin toxicity associated with linezolid relative to vancomycin among hospitalized patients. There were several notable findings across the studies. The first study strongly suggested that rVSPs contribute to deleterious treatment outcomes in concert. The second study highlighted the critical importance of daily area under the curve (AUC) profiles during the first two days of vancomycin therapy. The collective findings from the third study failed to establish an increased risk of serotonin toxicity with linezolid relative to vancomycin. The investigations presented here have important implications for clinical practice and provide clear directions for future research.

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