PHARMACOKINETIC AND CLINICAL EVALUATIONS OF IMIPENEM/CILASTATIN SODIUM IN NEONATES AND PREMATURE INFANTS

• Published in: Japanese journal of antibiotics Vol. 42; no. 5; pp. 1102 - 1124
• Main Authors: MOTOHIRO, TAKASHI, SAKATA, YASUTAKA, ODA, KEIKO, KAWAKAMI, AKIRA, TANAKA, KOICHI, KOGA, TATSUHIKO, SHIMADA, YASUSHI, TOMITA, SHOBUN, FUJIMOTO, TAMOTSU, TOMINAGA, KAORU, YAMASHITA, FUMIO, TAKAJO, NOBUHIKO, TASHIRO, HIROKO, MURAKAMI, TAIYU, AMAMOTO, YUSUKE, KOMORI, HIRONORI, OHBU, KEIZO, IMAI, SHOICHI, NAGAYAMA, KIYOTAKA, KANEKO, SHINYA, YAMAMURA, JUNICHI, YANO, SHOJI, ANDO, AKIKAZU, SASAKI, HIROKAZU, MIYAJIMA, ICHIRO, TAKAGI, JUNICHI, ISHIKAWA, YUTAKA, MATSUMOTO, KOJI, ARAKI, HISAAKI, HASHIMOTO, TAKEO, OKI, SHINICHIRO, YAMASHITA, YASUHIRO, TSUMURA, NAOKI, NISHIYORI, ATSUSHI, MIYAKE, TAKUMI, NAKAO, MITSUYOSHI, HONMA, SHINICHI, SATO, NOBORU, YAMASHITA, YUSHIRO, HORIKAWA, MIZUHO, URABE, DAISAKU, NISHIMI, TOSHIHIRO, FUKUDA, SEIICHI, SAYAMA, TAKESHI, HARADA, YUTAKA, ISHIMOTO, KOJI, MOROI, TOSHIHIRO, MATSUO, HIROSHI, AIDA, KATSUMA, USHIJIMA, KOSUKE, NISHI, AKINORI, MATSUKUMA, YOSHINORI, SUEYOSHI, KEIKO, FUJISAWA, TAKUJI, TANAKA, TETSURO, NISHIYAMA, TOHRU
• Format: Journal Article
• Language: Japanese
• Published: Japan Japan Antibiotics Research Association 01.05.1989
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Bacterial Infections - drug therapy; Bacterial Infections - metabolism; Cilastatin - pharmacokinetics; Cilastatin - therapeutic use; Clinical Trials as Topic; Drug Combinations - pharmacokinetics; Drug Combinations - therapeutic use; Female; Humans; Imipenem - pharmacokinetics; Imipenem - therapeutic use; Infant, Newborn; Infant, Premature, Diseases - drug therapy; Infant, Premature, Diseases - metabolism; Male; Multicenter Studies as Topic
• ISSN: 0368-2781; 2186-5477
• DOI: 10.11553/antibiotics1968b.42.1102

Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS), a β-lactam antibiotic of the carbapenem class and its renal dehydropeptidase-I inhibitor in a 1:1 ratio, were performed in neonates, premature infants and an infant. IPM/CS was administered intravenously to 4 neonates and 5 premature infants at a dose level of 10mg/kg. Plasma levels and urinary excretion of IPM and CS were determined in 2 neonates and 2 premature infants after 30-minute infusion, and in 2 neonates and 3 premature infants after 1-hour infusion. Plasma and cerebrospinal fluid (CSF) concentrations of IPM and CS were determined in 2 cases with purulent meningitis with ages of 2 and 26 days and 1 with purulent meningitis/bacteremia with an age of 4 days. The drug was administered to a total of 31 patients with ages between 0 and 30 days, consisting of neonates, premature infants and an infant (24 suffering with various bacterial infections, 5 treated for prophylaxis of infections and 2 treated for aseptic meningitis diagnosed at the completion of therapy) by intravenous drip infusion in a mean daily dose level of 50.1 mg/kg in 2 to 4 divided doses for 9 days on the average. Clinical efficacy, prophylactic effectiveness and bacteriological response of IPM/CS were evaluated in 29 cases. Adverse effects and abnormal laboratory test results were examined in 31 cases including 2 drop-out cases. The results obtained are summarized as follows. 1. Plasma concentrations of IPM and CS after 30-minute infusion of the drug reached their peaks at the end of administration, and obtained values were 22.4 to 29.0μg/ml for IPM and 26.3 to 34.6μg/ml for CS, thus peak plasma levels of CS were a little higher than IPM. Plasma half-lives of IPM were 1.05 to 2.43 hours, and those of CS were 1.24 to 4.76 hours, and the half-life of CS tended to be longer than that of IPM. Drug concentrations in plasma after 1-hour infusion of IPM/CS reached their peaks at the end of administration and the levels of CS (25.7 to 32.0μg/ml) were a little higher than those of IPM (20.8 to 23.9μg/ml). Plasma half-lives of IPM were 1.40 to 1.63 hours, whereas those of CS were 1.51 to 2.90 hours. The half-life of CS tended to be longer than IPM. 2. Urinary concentrations of IPM by 30-minute infusion of IPM/CS reached their peaks in the collecting period between 0 and 2 hours in 1 of 4 cases and between 2 and 4 hours in the remaining 3 cases with levels ranging from 183.0 to 993.7μg/ml. Peak concentrations of CS in urine were achieved in the collecting period between of 0 and 2 hours in 1 case, between 2 and 4 hours in 2 cases and between 4 and 6 hours in 1 case with levels ranging from 281.6 to 1,865.9μg/ml. Urinary recovery rates of IPM were 30.8 to 52.2% and those of CS were 63.2 to 99.4% in 8 hours after administration. The urinary recovery rates of CS were higher than those of IPM. Urinary concentrations of IPM by 1-hour infusion of the drug reached their peaks in the collecting period between 2 and 4 hours in 4 of 5 cases and between 4 and 6 hours in the other case with levels ranging from 260.4 to 618.6μg/ml. Peak concentrations of CS in urine were achieved in the collecting period between 2 and 4 hours in 3 of 5 cases and between 4 and 6 hours in the remaining 2 cases with levels ranging from 302.8 to 553.1μg/ml. No clear differences were observed between the concentrations of IPM and CS. Urinary recovery rates of IPM were 45.7 to 71.6% and those of CS were 61.6 to 66.3% in 8 hours after administration, and the recovery rates of CS tended to be higher than those of IPM. 3. The drug concentration in CSF which was obtained at 10 minutes after completion of a 45-minute infusion of 19.4 mg/kg in a case of purulent meningitis on the 13th day of illness was 0.8μg/ml for IPM. The concentration of CS was below the detection limit. IPM concentration in CSF to that in plasma was 2.3%.