cilastatin--imipenem-drug-combination and Central-Nervous-System-Diseases

Observations on 1,754 patients treated with imipenem/cilastatin in phase III dose-ranging studies in the United States were reviewed to determine risk factors for seizures. The patients were moderately to severely ill with numerous background disorders known to be associated with an increased risk of seizures. Fifty-two patients (3 percent) had seizures and in 16 (0.9 percent) of them the seizures were judged by the investigators to be possibly, probably, or definitely related to imipenem/cilastatin. An incidence of seizure of 2 to 3 percent was noted among patients treated with other antibiotics (usually including a beta-lactam in the regimen) at times when imipenem/cilastatin was not being given. The average time of onset of seizures for patients receiving imipenem/cilastatin was seven days after start of therapy. As with other beta-lactam antibiotics, central nervous system lesions and disorders including seizures and renal insufficiency were found to be strong risk factors for seizures. Imipenem/cilastatin dosages in excess of those currently recommended by the manufacturer, particularly in patients with renal insufficiency, were also associated with an increased risk of seizures. There was an association with Pseudomonas aeruginosa infection that remained statistically significant even after controlling for imipenem/cilastatin dosage as well as for the other factors indicated. A high background incidence of seizures in general in a group of severely ill patients makes it both difficult to assess the etiology of a seizure and important to consider the risk factors when choosing the appropriate dose of an antibiotic. Guidelines are presented for appropriate dosing of imipenem/cilastatin in relation to renal function, body weight, and infecting pathogen.

Topics: Anti-Bacterial Agents; Bacterial Infections; Body Weight; Central Nervous System Diseases; Cilastatin; Cilastatin, Imipenem Drug Combination; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Female; Humans; Imipenem; Kidney Function Tests; Male; Regression Analysis; Retrospective Studies; Risk Factors; Seizures; Thienamycins; Time Factors; United States

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