Quantitative Impact of Neutrophils on Bacterial Clearance in a Murine Pneumonia Model

Abstract

The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. Currently, clinical decisions on treatment are often based on in vitro susceptibility data. The role of the immune system in combating bacterial infections is unequivocal, but it is not well captured quantitatively. In this study, the impact of neutrophils on bacterial clearance was quantitatively assessed in a murine pneumonia model. In vitro time-growth studies were performed to determine the growth rate constants of Acinetobacter baumannii ATCC BAA 747 and Pseudomonas aeruginosa PAO1. The absolute neutrophil count in mice resulting from different cyclophosphamide preparatory regimens was determined. The dynamic change of bacterial (A. baumannii BAA 747) burden in mice with graded immunosuppression over 24 h was captured by a mathematical model. The fit to the data was satisfactory (r(2) = 0.945). The best-fit maximal kill rate (K(k)) of the bacterial population by neutrophils was 1.743 h(-1), the number of neutrophils necessary for 50% maximal killing was 190.8/μl, and the maximal population size was 1.8 × 10(9) CFU/g, respectively. Using these model parameter estimates, the model predictions were subsequently validated by the bacterial burden change of P. aeruginosa PAO1 at 24 h. A simple mathematical model was proposed to quantify the contribution of neutrophils to bacterial clearance and predict the bacterial growth/suppression in animals. Our results provide a novel framework to link in vitro and in vivo information and may be used to improve clinical treatment of bacterial infections.