Nemonoxacin exhibited a linear PK profile in the 250-750 mg dose range with moderate food effects. There was no accumulation following consecutive administration for 10 days. The PK and safety profiles of nemonoxacin in Chinese subjects support evaluation of once-daily dosing in the future development of this agent.
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/l, 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.The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. To prevent further spread of multidrug resistance and returning to the preantibiotic era, it is imperative that the current approach to treatment be improved. Presently, clinical decisions on treatment are often based on in vitro susceptibility data (MICs), which only provide information about antibacterial activity at a single time point and potentially miss information on the changes in bacterial population dynamics over time. Drug selections solely based on MIC values may not always correlate to patient outcomes (11). One major reason for the discrepancy may be due to in vitro investigations neglecting the presence of the immune system in patients, which is well known to be significant.The immune system (especially neutrophils) plays an important role in combating bacterial infections. This is best exemplified by patients with neutropenia or after transplantation, who have significantly higher mortality than patients without neutropenia (8, 10, 13). However, the effect of the immune system is not well accounted for when data obtained from in vitro investigations are used to provide guidance for treatment. The overall antimicrobial effect in a patient is the sum of the antibacterial activity from drug therapy and the effect ...
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