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

Abstract

Antimicrobial resistance among uropathogens has increased the rates of infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli, such as This study monitored the efficacy of antofloxacin using bioluminescent imaging and determined pharmacokinetic (PK)/pharmacodynamic (PD) targets against isolates in a neutropenic murine thigh infection model. The PK properties were determined after subcutaneous administration of antofloxacin at 2.5, 10, 40, and 160 mg/kg of body weight. Following thigh infection, the mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 h. Efficacy was assessed by quantitative determination of the bacterial burdens in thigh homogenates and was compared with the bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index area under the concentration-time curve (AUC)/MIC correlated well with efficacy ( = 0.92), and the dose-response relationship was relatively steep, as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce net bacterial stasis and 1-log and 2-log kill for each isolate were 38.7, 66.1, and 147.0 h, respectively. bioluminescent imaging showed a rapid decrease in the bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with the results of PK studies with humans will be useful in setting optimal dosing regimens for the treatment of urinary tract infections due to.

Concentration-Dependent Activity of Pazufloxacin against Pseudomonas aeruginosa: An In Vivo Pharmacokinetic/Pharmacodynamic Study

“…aeruginosa isolate when the pazufloxacin dosage exceeded the MIC, similar to that of aminoglycosides; this finding verifies the concentration-dependent efficacy of this antimicrobial agent [ 16 ]. The most suitable PK/PD parameter for fluoroquinolones in animal models is the AUC 24 /MIC or C max /MIC ratio [ 8 , 9 , 10 ]. In our study, the f AUC 24 /MIC and f C max /MIC ratio required for a static effect and maximum killing of the P .…”

“…Andes et al reported that the target value of gatifloxacin AUC24/MIC for stasis was 41.2, for 1 log 10 it was 72.2, and for 2 log 10 it was 126 [ 9 ]. Zhou et al reported that the target value of antofloxacin fAUC 24 /MIC for stasis was 38.7, for 1 log 10 it was 66.1, and for 2 log 10 it was 147 [ 10 ]. The target value may vary among fluoroquinolones.…”

Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1- and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study

“…Our correlation data indicated that the coix seed extract enhanced anti-cancer efficacy of gemcitabine in pancreatic cancer cells was strong associated with the downregulation ABC transport mediated drug efflux, which may lead to increased gemcitabine accumulation in cells. Previous studies have already indicated that pharmacokinetic indexes could reflect the process of tumorigenesis and cancer development when monitoring of therapeutic efficacy using bioluminescent imaging [18,30,47]. Although there are several pathways for regulating gemcitabine efflux and influx, ABC transporters may be essential and critical for inducing gemcitabine resistance [3].…”

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

“…However, as compared with viable counting methods, the sensitivity of bioluminescence is generally lower. Consequently, they are not useful to evaluate compounds with mild antibacterial effect [40].…”