In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

Abstract

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The E max Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log 10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentrationtime curve over 24 h (AUC 0 -24 )/MIC ratio was the PD index most closely linked to efficacy (R 2 ϭ 0.96). The mean free-drug AUC 0 -24 /MIC ratios required to achieve net bacterial stasis, a 1-log 10 kill, and a 2-log 10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae. KEYWORDS antofloxacin, PK/PD, murine lung infection, Klebsiella pneumoniaeA cute exacerbations of chronic bronchitis (AECB) represent an important health burden to patients, including increased morbidity, mortality, and health care costs worldwide (1, 2). Although viral infections have an important role in both development and progression of AECB, the pathophysiological mechanisms are not completely understood and seem to be a complex of many interrelated factors (3). Apart from exacerbations caused by viral infections and environmental irritants, approximately 40 to 50% of exacerbations are attributed to bacteria that include Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, and Staphylococcus spp. (4). It is a common practice to prescribe antibiotics for AECB patients with severe illness (5, 6). However, treatment of these bacterial infections is frequently challenging due to drug resistance and limited therapeutic options.

Fecal Microbiota, Lactic Acid and Short Chain Fatty Levels of Infants Following Rotavirus Infection Revealed by Illumina Miseq High-Throughput Sequencing and HPLC Method

“…This study was the first testing of increasing Klebsiella, which belonged to Proteobacteria in RD infants. More recent studies suggested Klebsiella may contribute to inflammation (33,34), such as bronchitis, pneumonia, and meningitis (35). Therefore, it could be supposed that RD infection, as the major cause of the viral gastroenteritis might disrupt the gut microbiota and introduce more effects from Klebsiella.…”

In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model

“…This potent activity has been observed in vitro and in vivo against both S. aureus and Mycobacterium tuberculosis (18,19). Our previous studies with antofloxacin showed a dose-dependent activity with prolonged postantibiotic effects against Klebsiella pneumoniae in a model of lung infection in neutropenic mice (20). Similar to other fluoroquinolones, the most predictive PK/PD index of antofloxacin associated with efficacy against E. coli was the free drug AUC/MIC (21,22).…”

“…Blood samples were obtained by retro-orbital puncture at the following times after dosing: 0.08, 0.25, 0.5, 0.75, 1, 2, 4, and 8 h. Plasma was isolated by centrifugation of the blood samples at 3,000 ϫ g for 10 min at 4°C. Antofloxacin concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as we have described previously (20). The assay limit of quantification (LOQ) and limit of detection (LOD) were 0.01 and 0.005 mg/liter, respectively.…”

“…Linear extrapolation was used to estimate the PK parameters for dose levels that were not directly measured in this study. Previous studies have determined that the levels of protein binding of antofloxacin in mice and humans are 20.3% and 17.5%, respectively (12,20). The free drug fractions were utilized in the PK/PD analyses.…”

“…Pharmacodynamic target associated with efficacy. The AUC/MIC ratio was chosen as the predictive PK/PD index correlating with the exposure-response relationships of antofloxacin on the basis of the findings of previous studies (18,20). In vivo treatment experiments were performed using the murine thigh infection model with each isolate of E. coli.…”