cilastatin--imipenem-drug-combination and Kidney-Diseases

Topics: Adult; Aged; Cilastatin, Imipenem Drug Combination; Drug Therapy, Combination; Female; Humans; Kidney Diseases; Male; Meropenem; Middle Aged; Propensity Score; Retrospective Studies; Vancomycin

Imipenem/cilastatin is a broad-spectrum β-lactam antibiotic used to treat several bacterial infections. The present study was designed to validate the nephrotoxic effect of this drug in rats and to explore its potentional urolithiatic effect. Thirty two Wistar rats were randomly divided into four groups: three experimental groups treated with different imipenem/cilastatin dosages (30, 50 and 80 mg/kg/day) and a control group.The experimental groups were given intraperitoneal imipenem/cilastatin injections twice daily for 7 days, and the control group was given intraperitoneal vehicle NaCl 0.9% solution. Nephrotoxic effect of this antibiotic was assessed based on urine and plasma biochemistry, oxidative stress parameters, histopathological examination and infrared spectroscopy characterization. Imipenem/cilastatin administration resulted in alkaline urine, polyuria, crystalluria, raised plasma levels of urea, creatinine and uric acid, decreased contents of plasma gamma glutamyltranspeptidase and alkaline phosphatase, oxidative stress status, malpighian metaplasia as well as crystal deposition in kidneys and urinary tracts of Wistar rats. In addition, the precise nature of the calculi was identified, being formed by imipenem/cilastatin, thus confirming their iatrogenic origin. In conclusion, this study demonstrated through rat model that subacute exposure to imipenem/cilastatin may induce nephrotoxicity and increase the risk for developing kidney stones even at therapeutic dose levels in a dose-dependent manner.

Topics: Animals; Anti-Bacterial Agents; Cilastatin, Imipenem Drug Combination; Dose-Response Relationship, Drug; Kidney Diseases; Male; Rats; Rats, Wistar; Urolithiasis

A deep-seated Pseudomonas aeruginosa mouse kidney abscess model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of clinically relevant standard drugs. Following 50 mg/kg oral doses, twice daily for five consecutive days, clinafloxacin produced a 4 log decrease in mean bacterial count, the greatest decrease of all drugs tested. The same dosage regimen resulted in complete bacterial eradication in 88% of the kidneys. No other compound produced total bacterial clearance in 50% of the kidneys at the highest dose tested.

Topics: Abscess; Animals; Anti-Infective Agents; Area Under Curve; Ceftazidime; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Fluoroquinolones; Half-Life; Imipenem; Kidney; Kidney Diseases; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Treatment Outcome

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.

Topics: Aged; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Half-Life; Humans; Imipenem; Injections, Intramuscular; Kidney Diseases

This article describes an imipenem/cilastatin (I/C) target drug program. The program, developed following completion of a drug usage evaluation study, was designed to improve I/C dosing, reduce central nervous system (CNS) adverse effects, and reduce antibiotic costs. Following completion of an inservice education program for the medical and pharmacy professional staffs, ongoing monitoring of I/C usage was accomplished through the pharmacy-based drug-dosing service. Pharmacists evaluated I/C dosage based upon culture/sensitivity results and indicators of renal function. If deemed inappropriate, the pharmacist contacted the prescribing physician with a dosage recommendation. Two hundred ten courses of I/C therapy were prescribed in the nine-month period following implementation of the target drug program; 26 cases (12 percent) required dosage adjustment. The incidence of CNS adverse effects including seizures decreased from 15 to 1 percent (p = 0.0015). A $6033 drug cost avoidance also resulted from pharmacist intervention.

Topics: Adult; Anti-Bacterial Agents; Bacteria, Anaerobic; Bacterial Infections; Central Nervous System Diseases; Cilastatin; Cilastatin, Imipenem Drug Combination; Cost Savings; Drug Combinations; Drug Costs; Drug Monitoring; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Imipenem; Kidney Diseases; Pharmacy Service, Hospital