小児科領域におけるL-627 (Biapenem) の総合的評価 [in Japanese] PHARMACOKINETIC AND CLINICAL STUDIES WITH L-627 (BIAPENEM) IN THE PEDIATRIC FIELD [in Japanese]
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新しく開発されたL-627 (Biapenem) の小り己科領域各種感染症に対する基礎的・臨床的検討を目的として研究会を組織し, 参加15施設とその関連施設による協同研究を実施し, 以下の結果を得た。治験対象小児はすべて親権者のInformed consentが得られている。<BR>1. 血中濃度・尿中排泄<BR>L-627の小児での体内動態を6mg/kg及び12mg/kgの30分点滴静注にて29例につき検討した。本剤の最高血中濃度は共に点滴静注終了時に見られ, 6mg/kg投与で平均25.1μg/ml, 12mg/kg投与で39.2μg/mlを示し, これら投与量間でC<SUB>max</SUB>, AUCにつき用最依存性を認めた。乳児 (1歳未満) では5例についての検討であったが, それ以上の小児との間に大きな差はみられなかった。<BR>尿中回収率は6mg/kg及び12mg/kgそれぞれ平均66.0%及び62.3%が回収された。<BR>2. 髄液中濃度化膿性髄膜炎9症例に対し, 1回量20～40mg/kgを投与した場合, 病日3日以内では静注後30～240分で0.76～854μg/mlの髄液中濃度を示した。<BR>3. 臨床成績<BR>総症例330例から除外・脱落例33例を除いた297例を臨床効果解析対象例として検討した。<BR>臨床効果は起炎菌の判明したA群173例中166例が有効以上となり, 有効率は96.0%であった。起炎菌不明のB群では124例中114例, 有効以上91.9%となり, 起炎菌検出例と同等の高い有効率であつた。A, B群間に有意差がないので合計して示すと, 297例について943%といずれも高い有効率であった。また, 有効例中著効例が占める率は, A群62.7%(104例/166例), B群55.3%(63例/114例) と前者が特に高かった。<BR>起炎菌別臨床効果は単独菌感染症96.7%(145例/150例), 複数菌感染症91.3%(21例/23例) と高い有効率を示した。<BR>細菌学的効果はグラム陽性菌では78株中74株 (94.9%) が消失し, グラム陰性菌では123株中115株 (93.5%) が消失した。除菌率が低いものでもMRSA 57.1%, <I>Pseudomonas aeruginosa</I>71.4%であり, 百日咳菌も3株中2株が除菌された。起炎菌全体に対する除菌率は940%であった。<BR>3日以上先行投与された他抗菌剤無効例に対する本剤の有効率は93.0%(93例/100例) と高く, かつ有効症例中の著効経過をとったものは51.6%(48例/93例) であった。本剤投与直前に証明された残存した菌に対する除菌効果はグラム陽性菌に対し96.6%(28株/29株), グラム陰性菌に対し93.9%(31株/33株) の除菌率であった。<BR>4. 副作用・臨床検査値異常<BR>安全性の検討は, 副作用316症例, 臨床検査313症例で行った。<BR>副作用は10例 (3.2%) に認められ, その内訳は発疹, 下痢が各4件及び紅斑, 腹痛, 発熱が各1件の計11件であった。臨床検査値異常は46例 (14.7%) に認あられ, 血小板増多, 好中球増多, トランスアミラーゼ上昇が艶であった。副作用, 臨床検査値異常は特に重篤なものはなく, 本剤の投与中止及び投与終了により正常に復した。
To conduct pharmacokinetic and clinical studies on newly developed L-627 (biapenem) against various infections in pediatrics, a study group was organized and a joint research by 15 institutions and their related hospitals was undertaken. Informed consents of subjects were obtained prior to the study. The obtained results are as follows.<BR>1. Plasma concentrations and urinary excretion<BR>Pharmacokinetics of L-627 in children was studied in 29 subjects using 30 minutes intravenous drip infusion of 6mg/kg and 12mg/kg. Maximum plasma levels of L-627 was observed at the completion of drip infusion and were 25.1μg/ml with administration of 6mg/kg and 39.2μg/ml with administration of 12mg/kg on average. Dose dependency was noted in C<SUB>max</SUB>. and AUC with these doses. Maximum blood levels in all of the 5 participated sucklings under the age of one year were similar to the average. As for urinary excretion, L-627 was excreted 66.0% with administration of 5mg/kg and 62.3% with 12mg/kg.<BR>2. Cerebrospinal fluid concentrations<BR>Cerebrospinal fluid concentrations ranged from 0.76 to 8.54μg/ml in 30-240 minutes after the completion of drip infusion with dose of 20-40mg/kg in 9 subjects with purulent meningitis, when they were measured within 3 days after the initiation of the treatment with L-627.<BR>3. Clinical results Thirty-three cases of exclusion and drop-out were deducted from a total of 330 cases, hence 297 cases were evaluated as the subjects in the study for analysis of clinical effects. As for clinical effects in group A where pathogenic bacteria were detected, 166 out of 173 were rated as effective or above, hence the efficacy rate of 96.0% was obtained. In group B where pathogenic bacteria were not detected, 114 out of 124 cases were rated as effective or above, thus the efficacy rate was 91.9%, which is similar to that of the group A. The overall efficacy rate was 94.3% in the entire 297 cases. The rates of “excellent” responses out of the cases rated as effective or above were 62.7%(104/166) in the group A and 55.3%(63/114) in the group B, thus the rate was markedly high in the former group.<BR>Efficacy rate for each pathogenic strain was also high, and that in subjects infected by a single pathogenic strain was 96.7%(145/150) and that in subjects infected by two or more pathogenic strains was 91.3%(21/23).<BR>As for the bacteriological effect 74 (94.9%) out of 78 strains of Gram-positive bacteria and 115 (93.5%) out of 123 strains of Gram-negative bacteria disappeared. Even among examples of poor responses, the eradication rates were high: including 57.1% for MRSA and 71.4% for <I>Pseudomonas aeruginosa</I>. Besides, 2 out of 3 strains of <I>Bordetella pertussis</I> were eradicated. The overall bacterial eradication rate was 94.0%.<BR>The efficacy rate of L-627 was 93.0%(93/100) in cases where other antibacterial drugs were administered for more than 3 days and proved to be ineffective. The rate of “excellent” response out of the 93 cases was 51.6%(48/93). The bacterial eradication rate for Gram-positive bacteria was 96.6%(28/29) and that for Gram-negative bacteria was 93.9%(31/33).<BR>4. Side effects and abnormal laboratory data<BR>A study on the safety was conducted in 316 cases to evaluate side effects and in 313 cases to evaluate abnormalities in laboratory data. Side effects were noted in 10 cases (3.2%), consisting of 11 events: skin rash in 4, diarrhea in 4, erythema in 1, abdominal pain in 1 and pyrexia in 1.<BR>Abnormalities in laboratory data were found in 46 cases (14.7%), consisting mainly of elevations in platelet count, increases in eosinophils and elevations of transaminase. Side effects and abnormalities in laboratory data were not particularly serious and disappeared or returned to normal with discontinuation or completion of the treatment with L-627.
- The Japanese Journal of Antibiotics
The Japanese Journal of Antibiotics 47(5), 530-552, 1994
Japan Antibiotics Research Association