Quantifying trade-offs between therapeutic efficacy and resistance dissemination for enrofloxacin dose regimens in cattle.

The use of antimicrobial drugs in food-producing animals increases the selection pressure on pathogenic and commensal bacteria to become resistant. This study aims to evaluate the existence of trade-offs between treatment effectiveness, cost, and the dissemination of resistance in gut commensal bacteria. We developed a within-host ordinary differential equation model to track the dynamics of antimicrobial drug concentrations and bacterial populations in the site of infection (lung) and the gut. The model was parameterized to represent enrofloxacin treatment for bovine respiratory disease (BRD) caused by Pastereulla multocida in cattle. Three approved enrofloxacin dosing regimens were compared for their effects on resistance on P. multocida and commensal E. coli: 12.5 mg/kg and 7.5 mg/kg as a single dose, and 5 mg/kg as three doses. Additionally, we explored non-approved regimes. Our results indicated that both 12.5 mg/kg and 7.5 mg/kg as a single dose scenario increased the most the treatment costs and prevalence of P. multocida resistance in the lungs, while 5 mg/kg as three doses increased resistance in commensal E. coli bacteria in the gut the most out of the approved scenarios. A proposed scenario (7.5 mg/kg, two doses 24 hours apart) showed low economic costs, minimal P. multocida, and moderate effects on resistant E. coli. Overall, the scenarios that decrease P. multocida, including resistant P. multocida did not coincide with the scenarios that decrease resistant E. coli the most, suggesting a trade-off between both outcomes. The sensitivity analysis indicates that bacterial populations were the most sensitive to drug conversion factors into plasma (ß), elimination of the drug from the colon (υ), fifty percent sensitive bacteria (P. multocida) killing effect (Ls50), fifty percent of bacteria (E. coli) above ECOFF killing effect (Cr50), and net drug transfer rate in the lung (γ) parameters.

Modeling county level COVID-19 transmission in the greater St. Louis area: Challenges of uncertainty and identifiability when fitting mechanistic models to time-varying processes.

We use a compartmental model with a time-varying transmission parameter to describe county level COVID-19 transmission in the greater St. Louis area of Missouri and investigate the challenges in fitting such a model to time-varying processes. We fit this model to synthetic and real confirmed case and hospital discharge data from May to December 2020 and calculate uncertainties in the resulting parameter estimates. We also explore non-identifiability within the estimated parameter set. We find that the death rate of infectious non-hospitalized individuals, the testing parameter and the initial number of exposed individuals are not identifiable based on an investigation of correlation coefficients between pairs of parameter estimates. We also explore how this non-identifiability ties back into uncertainties in the estimated parameters and find that it inflates uncertainty in the estimates of our time-varying transmission parameter. However, we do find that R0 is not highly affected by non-identifiability of its constituent components and the uncertainties associated with the quantity are smaller than those of the estimated parameters. Parameter values estimated from data will always be associated with some uncertainty and our work highlights the importance of conducting these analyses when fitting such models to real data. Exploring identifiability and uncertainty is crucial in revealing how much we can trust the parameter estimates.

Parameter identifiability and optimal control of an SARS-CoV-2 model early in the pandemic.

We fit an SARS-CoV-2 model to US data of COVID-19 cases and deaths. We conclude that the model is not structurally identifiable. We make the model identifiable by prefixing some of the parameters from external information. Practical identifiability of the model through Monte Carlo simulations reveals that two of the parameters may not be practically identifiable. With thus identified parameters, we set up an optimal control problem with social distancing and isolation as control variables. We investigate two scenarios: the controls are applied for the entire duration and the controls are applied only for the period of time. Our results show that if the controls are applied early in the epidemic, the reduction in the infected classes is at least an order of magnitude higher compared to when controls are applied with 2-week delay. Further, removing the controls before the pandemic ends leads to rebound of the infected classes.