Antibiotics: Efficacy 'measures' and physiological state effects

Mathematical Biology Seminar
Wednesday, October 21, 2009 - 11:00am for 1 hour (actually 50 minutes)
Skiles 269
Klas Udekwu – Biology, Emory University –
Howie Weiss
Treatment of bacterial infections with antibiotics is universally accepted as one of (if not THE) most significant contributions of medical intervention to reducing mortality and morbidity during last century. Surprisingly, basic knowledge about how antibiotics kill or prevent the growth of bacteria is only just beginning to emerge and the dose and term of antibiotic treatment has long been determined by clinicians empirically and intuitively. There is a recent drive to theoretically and experimentally rationalize antibiotic treatment protocols with the aim to them and to design protocols which maximize antibiotics’ efficacy while preventing resistance emergence. Central to these endeavors are the pharmacodynamics of the antibiotic(s) and bacteria, PD (the relationship between the concentration of the antibiotic and the rate of growth/death of bacteria), and the pharmacokinetics of the antibiotic, PK (the distribution and change in concentration of the antibiotics in a treated host) of each bacteria. The procedures for estimating of PD and PK parameters are well established and standardized worldwide. Although different PK parameters are commonly employed for the design of antibiotic treatment protocols most of these considerations, a single PD parameter is usually used, the minimum inhibitory concentration (MIC). The Clinical and Laboratory Standards Institute (CLSI) approved method for estimating MICs defines testing conditions that are optimal for the antibiotic, like low densities and exponential growth, rarely obtain outside of the laboratory and virtually never in the bacteria infecting mammalian hosts. Real infections with clinical symptoms commonly involve very high densities of bacteria, most of which are not replicating, and these bacteria are rarely planktonic, rather residing as colonies or within matrices called biofilms which sometimes include other species of bacteria. Refractoriness (non-inherited resistance) is the term used to describe an observed inefficacy of antibiotics on otherwise antibiotic-susceptible bacterial populations. This talk will focus on our efforts to describe the pharmacodynamic relationship between Staphylococcus aureus and antibiotics of six classes in the light of antibiotic refractoriness. I will begin by addressing the effects of cell density on the MIC index, after which I intend to present unpublished data descriptive of physiology-related effects on antibiotic efficacy. Additionally, we will explore the potential contribution of such in vitro results, to observed/predicted clinical outcomes using standard mathematical models of antibiotic treatment which also serve to generate testable hypotheses.