PHARMACOKINETIC AND CLINICAL STUDIES WITH IMIPENEM/CILASTATIN SODIUM IN THE PEDIATRIC FIELD

Pediatric study group for imipenem/cilastatin sodium

Abstract

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in a joint study in the pediatric field by a study group consisting of investigators at 16 institutions.
The results were summarized below.
1. Pharmacokinetic studies
Peak plasma concentrations of MK-0787/MK-0791 were 27.7-190.0/28.3-216.4 μg/ml at doses of 10/10-50/50 mg/kg administered by a 30 or 60-minute drip infusion. The above findings proved that dose response was clearly observed.
Over a period of 6 or 7 hours, the urinary excretion of MK-0787 and MK-0791 totaled 54.2-88.0% and 53.6-89.0% of the dose administered, respectively.
Plasma half-lives of MK-0787 and MK-0791 in the β-phase were 0.87-1.05 hours and 0.59-0.95 hour, respectively.
The cerebrospinal fluid (CSF) levels of MK-0787 in patients with purulent meningitis were 2.0-14.4 μg/ml; however, the penetration rate of the drug into the CSF was relatively poor in patients with normal meninges.
2. Clinical study
Clinical efficacy was evaluated in 283 patients. In 112 patients the daily dosage ranged from 30/30mg/kg to 59/59mg/kg, and in 138 patients it ranged from 60/60mg/kg to 99/99 mg/kg. The maximum dose administered was 222/222mg/kg. The drug was administered either 3 or 4 times per day.
The clinical efficacy rate was 92.5% among 187 patients with identified etiologic pathogens. The drug was effective in 3 out of 4 patients with purulent meningitis and in 7 out of 10 patients with septicemia. The clinical efficacy rate was 96.7% in 90 patients with respiratory tract infection (pneumonia, lung abscess, etc.), 96.5% in 57 patients with urinary tract infection, 90.9% in 11 patients with SSTI. The clinical efficacy rate in those with no identified etiologic pathogen was 97.0% among 101 patients.
Bacteriologically, the eradication rate for S. aureus was 87.9% of 33 isolates. Comprehensively, the eradication rate for Gram-positive bacteria was 94.7% of 75 isolates. The eradication rate for P. aeruginosa was 87.5% of 8 isolates. Including these strains, the eradication rate for Gram-negative bacteria was 90.3% of 134 isolates. The MK-0787/MK-0791 exhibited an eradication rate of 91.9% among a total of 211 Gram-positive and Gram-negative bacteria including anaerobes.
There were 51 patients who had failed to respond to treatments with other antibiotics (the duration of treatment was more than 3 days). Among these patients the efficacy rate and eradication rate in the treat-ment with MK-0787/MK-0791 were 94.1% and 88.6%, respectively.
3. Side effects and abnormal laboratory results
Among 300 patients, side effects seen in 18 patients were considered to be drug related; diarrhea and loose stools in 9, anorexia in 3, rash in 4, convulsion in 2, headache, nausea and vomiting in 1.
Abnormal laboratory results observed among a total of 298 patients included eosinophilia in 8 patients, abnormal liver function in 29 patients and increase in direct bilirubin 3 patients.
4. Conclusion
The MK-0787/MK-0791 has a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Hence, it is useful for the treatment of polymicrobial infections. It is concluded that MK-0787/MK-0791 has established its usefulness for chemotherapy in the pediatric field.
However, it will be necessary to investigate its CSF penetration in more patients.