Neutropenic Rat Thigh Infection Model for Evaluation of the Pharmacokinetics/Pharmacodynamics of Anti-Infectives.

The neutropenic mouse infection model is extensively used to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of anti-infective agents. However, it is difficult to evaluate agents following intravenous (i.v.) infusions using this model. Furthermore, in many drug discovery programs, lead identification and optimization is performed in rats, and pharmacology is performed in mice. Alternative models of infection are needed for robust predictions of PK/PD in humans. The rat is an alternative model of infection which can overcome the shortcomings of the mouse model. However, the rat neutropenic thigh infection (NTI) model has not been adequately characterized for evaluation of the PK/PD of anti-infectives. The aim of this study was to characterize the PK/PD of ciprofloxacin against bacterial pathogens in a rat NTI model. We studied the PK/PD relationships of ciprofloxacin against wild-type Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae in neutropenic Wistar rats following administration of 10, 30, and 100 mg/kg as single intravenous boluses and 30- and 60-min infusions. The PK/PD of ciprofloxacin against all four pathogens was AUC/MIC dependent and independent of the duration of administration at 10, 30, and 100 mg/kg. At human-equivalent rat doses, the PK/PD targets of ciprofloxacin achieved in rats for microbiological cure were similar to those reported in human patients. The neutropenic rat thigh infection model can be used to evaluate anti-infective agents intended to be administered as infusions in the clinic, and it complements the mouse model, increasing the robustness of PK/PD predictions in humans. IMPORTANCE Many antibiotics are administered as intravenous infusions in the clinic, especially in intensive care units. Anti-infective drug discovery companies develop clinical candidates that are intended to be administered as i.v. infusions in the clinic. However, there are no well-characterized models with which they can evaluate the PK/PD of the candidates following i.v. infusions. The neutropenic rat thigh infection model reported in this study helps in evaluating anti-infective agents that are intended to be administered as i.v. infusions in the clinic. The rat model is useful for simulating the clinical conditions for i.v. infusions for treatment of infections, such as acute bacterial skin and skin structure, lung, and urinary tract infections. This model is predictive of efficacy in humans and can serve as an additional confirmatory model, along with the mouse model, for determining the proof of concept and for making robust predictions of efficacy in humans.

Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice.

BACKGROUND: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). OBJECTIVE: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients. METHODS: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment. RESULTS: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68). CONCLUSION: Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.