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.