Author ORCID Identifier

https://orcid.org/0000-0001-8047-5978

Date Available

11-8-2021

Year of Publication

2021

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Clinical and Translational Science

Advisor

Dr. Peter Morris

Co-Director of Graduate Studies

Dr. Alison Woodworth de Salvo

Abstract

Sepsis is a devastating diagnosis affecting over 750,000 patients a year, accounting for approximately 10% of all hospital admissions, costs more than $50,000 per patient, and exceeds $17 billion annual spending. The mortality rate for sepsis remains unacceptably high: one out of every three patients diagnosed with sepsis dies. Sepsis physiology induces physiologic changes to drug pharmacokinetic (PK) parameters that alter the ability to achieve the goal pharmacodynamic (PD) target for beta-lactams of >4-fold unbound concentration above the minimum inhibitory concentration for 100% of the dosing interval (100% fT >4x MIC). Sepsis treatment such as volume resuscitation and vasopressor agents increase cardiac output and circulating blood flow, resulting in increased glomerular filtration and enhanced elimination of antibiotics. The PK alterations observed in critically ill septic patients are strongly associated with sub-optimal beta-lactam concentrations. Sub-optimal beta-lactam dosing has resulted in higher rates of therapeutic failure and increased mortality in critically ill patients with sepsis. In addition to the risk of under-exposure, growing data suggest certain beta-lactam combinations are associated with increased nephrotoxicity. Therapeutic drug monitoring of beta-lactam antibiotics is a strategy to improve the outcomes of critically ill septic patients by maximizing efficacy and minimizing toxicity.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.075

Funding Information

This study was supported by the American Society of Health-system Pharmacists Foundation 2018-2021.

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