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.
Method: Streptozotocin induced diabetic female BALB/c mice were infected trans-urethrally 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 (for PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, 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). The magnitude of plasma AUC/MIC of 412 was associated with maximum PD effect Imax=3.7 Log10CFU/bladder and Imax =1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80).
Conclusion: The PK/PD of CIP in the mouse of model of cUTI was comparable to clinical data.