Infections with resistant bacteria or resistance evolving during the course of treatment are major reasons antibiotic treatment fails. But this inherited resistance is not only reason treatment fails;patients remain ill for extensive periods or die due to infections with bacteria that are and remain fully susceptible to the antibiotics used for treatment. The goals of the proposed studies are to develop and evaluate antibiotic treatment protocols that are effective in rapidly clearing bacterial infections and, at the same time, minimize the likelihood of resistance evolving during the course of treatment. To achieve these goals, we will construct and analyze the properties of mathematical and computer simulation models that combine the pharmacodynamics of antibiotics and bacteria and the pharmacokinetics of the antibiotic treatment, with the population and evolutionary dynamics of bacteria in infected hosts. Using methicillin sensitive and resistant Staphylococcus aureus (MSSA and MSRA) and E. coli in invitro culture, we will estimate the parameters of these models and evaluate the validity of the assumptions behind their construction and test the predictions (hypotheses) generated from our analysis of their properties. Based on the results of these experiments, we will modify these models to make them more accurate and proposed the single and multi- drug treatment protocols to increase their efficacy in clearing bacterial infections and preventing the evolution of resistance. Of particular concern in these investigations are bacteria- and host-mediated processes that make genetically susceptible bacteria refractory to antibiotics. Included among these mechanisms of non-inherited resistance are subpopulations of non-growing bacteria (persistence) the physical structure of the infecting population (biofilms), the density of the infection, and physiological state of the bacteria (latent stages).

Public Health Relevance

A theoretical and experimental study will be performed to improve the efficacy of antibiotic treatment and prevent the evolution of resistance. To achieve this end, we will use mathematical models, computer simulations and experiments with Staphylococcus aureus and E.coli. Particular consideration will be given to methicillin resistant S. aureus infections (MRSA).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Eckstrand, Irene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Arts and Sciences
United States
Zip Code
Levin, Bruce R; McCall, Ingrid C; Perrot, Véronique et al. (2017) A Numbers Game: Ribosome Densities, Bacterial Growth, and Antibiotic-Mediated Stasis and Death. MBio 8:
Agashe, Vikas M; Patil, Hitendra; Gundavda, Manit K (2015) Multiple Skin Abscesses and Myofibrosis of Bilateral Lower Limbs Following Repeated Intramuscular Injection of Pentazocine with Concomitant Tuberculous Infection. J Orthop Case Rep 5:15-8
Levin, Bruce R; Baquero, Fernando; Johnsen, Pål J (2014) A model-guided analysis and perspective on the evolution and epidemiology of antibiotic resistance and its future. Curr Opin Microbiol 19:83-89
Bull, James J; Vegge, Christina Skovgaard; Schmerer, Matthew et al. (2014) Phenotypic resistance and the dynamics of bacterial escape from phage control. PLoS One 9:e94690
Levin, Bruce R; Concepción-Acevedo, Jeniffer; Udekwu, Klas I (2014) Persistence: a copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics. Curr Opin Microbiol 21:18-21
Jiang, Wenyan; Maniv, Inbal; Arain, Fawaz et al. (2013) Dealing with the evolutionary downside of CRISPR immunity: bacteria and beneficial plasmids. PLoS Genet 9:e1003844
Turrientes, Maria-Carmen; Baquero, Fernando; Levin, Bruce R et al. (2013) Normal mutation rate variants arise in a Mutator (Mut S) Escherichia coli population. PLoS One 8:e72963
Levin, Bruce R; Moineau, Sylvain; Bushman, Mary et al. (2013) The population and evolutionary dynamics of phage and bacteria with CRISPR-mediated immunity. PLoS Genet 9:e1003312
Johnson, Paul J T; Levin, Bruce R (2013) Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genet 9:e1003123
Kirby, Amy E (2012) Synergistic action of gentamicin and bacteriophage in a continuous culture population of Staphylococcus aureus. PLoS One 7:e51017

Showing the most recent 10 out of 27 publications