Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin.
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.
Calandra
G
G
Research Laboratories, Merck Sharp and Dohme, West Point, Pennsylvania 19486.
Lydick
E
E
Carrigan
J
J
Weiss
L
L
Guess
H
H
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001424:Bacterial Infections / Q000188:drug therapy*; D001835:Body Weight; D002493:Central Nervous System Diseases / Q000150:complications; D015377:Cilastatin; D000077728:Cilastatin, Imipenem Drug Combination; D002986:Clinical Trials as Topic; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects; D004338:Drug Combinations / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D015378:Imipenem; D007677:Kidney Function Tests; D008297:Male; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D012640:Seizures / Q000139:chemically induced*; D013845:Thienamycins / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors; D014481:United States
D000900:Anti-Bacterial Agents; D003521:Cyclopropanes; D004338:Drug Combinations; D013845:Thienamycins; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination