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

[ Vol. 21 , Issue. 2 ]

Author(s):

Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa , Somashekharayya Hiremath, Avinash Pawar, Mahesh Nanjundappa and Ramesh Jayaraman *   Pages 132 - 139 ( 8 )

Abstract:


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 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.

Keywords:

Pharmacokinetics, pharmacodynamics, pharmacokinetics/pharmacodynamics, ciprofloxacin, cUTI, mouse, diabetes

Affiliation:

TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore, TheraIndx Lifesciences Pvt Ltd, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, Bangalore



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