Comprehensive evaluation of pharmacokinetic and clinical studies on tazobactam/piperacillin in pediatric field

To evaluate the pharmacokinetic and clinical effects of the newly developed combination antibiotic tazobactam/piperacillin (TAZ/PIPC, YP-14) on various infections in pediatric field, a study group was organized, and a joint research by 17 institutions and their related hospitals was conducted. Informed consents of subjects were obtained prior to the study. The results obtained in this study are as follows: 1. Blood concentration and urinary excretion Pharmacokinetics of TAZ/PIPC was studied in children at doses of 25 and 50 mg/kg through intravenous injection or intravenous drip infusion. With intravenous injection, maximum blood concentrations (C_max's) of TAZ and PIPC were achieved 5 minutes after the administration. C_max's of TAZ were 26.9 µg/ml with 25 mg/kg and 45.1 µg/ml with 50 mg/kg, and those of PIPC were 131.0 and 199.6 µg/ml, respectively. Values of the total area under the blood concentration curve (AUC's) of TAZ were 14.2 µg·hr/ml with 25 mg/kg and 26.1 µg·hr/ml with 50 mg/kg, and those of PIPC were 64.0 and 112.8 µg·hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC. The C_max's of desethyl piperacillin (DEt-PIPC), the active metabolite of PIPC, achieved at 60 minutes after administration, were 1.2 and 2.0 µg/ml, respectively. The AUC's of DEt-PIPC were 2.6 and 4.2 µg·hr/ml, respectively. The half-lives (T 1/2's) of TAZ were 0.60 and 0.54 hour, respectively, and those of PIPC were 0.62 and 0.65 hour, respectively. In the first 6 hours after the initiation of administration, the cumulative recovery rates of TAZ in the urine were 46.7 and 56.0% respectively, those of PIPC were 46.1 and 57.2%, respectively, and those of DEt-PIPC were 5.9 and 3.0%, respectively. With intravenous drip infusion, the C_max's of both TAZ and PIPC were achieved at the completion of drip; the C_max's of TAZ were 12.1 µg/ml with 25 mg/kg and 28.9 µg/ml with 50 mg/kg, and those of PIPC were 54.6 and 137.9 µg/ml, respectively. The AUC's of TAZ were 11.6 µg·hr/ml with 25 mg/kg and 25.6 µg·hr/ml with 50 mg/kg, and those of PIPC were 49.0 and 117.2 µg·hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC. C_max's of DEt-PIPC, achieved at 60 minutes after completion of drip, were 0.9 and 1.7 µg/ml, respectively. The AUC's of DEt-PIPC were 2.0 and 3.8 µg·hr/ml, respectively. The half-lives (T 1/2's) of TAZ were 0.59 and 0.62 hour, respectively, and those of PIPC were 0.58 and 0.57 hour, respectively. In the first 6 hours after the initiation of drip, the cumulative recovery rates of TAZ in the urine were 43.3 and 56.9%, respectively, those of PIPC were 39.9 and 56.4%, respectively, and those of DEt-PIPC were 2.1 and 2.3%, respectively. Cerebrospinal fluid concentrations of TAZ, administrated at a dose of 70 to 108 mg/kg, to patients with purulent meningitis were 0.26 to 3.88 µg/ml in 2 to 4 hours after administration, and those of PIPC were 0.29 to 3.89 µg/ml 2. Clinical results Three-hundred cases were assessable for analysis of clinical effects after 32 cases of exclusion and drop-out were deduced from a total of 332 cases; however, the cumulative number of cases assessable for analysis was considered to be 302, because two cases that had two different diseases at the same time were counted twice in each category of disease. In the cases where causative organisms were identified (group A), 177 of 178 cases were rated as good or excellent, hence the efficacy rate was 99.4%. In the cases where causative organisms were not identified (group B), 117 of 124 cases were rated as good or excellent, thus the efficacy rate was 94.4%. As for clinical effects according to different causative organisms, regarding cases from which β-lactamase producing strain were isolated, were as follows: 57 (98.3%) of 58 cases of infections with single strain were rated as “excellent” or “good”, and all of the 14 cases of infection with two or more strains were rated as “excellent” or “good”. Thus the overall efficacy rate was 98.6% (71/72). In cases of group A, most (74.7%) of daily doses of TAZ/PIPC ranged from >60 mg/kg to 150 mg/kg, and the efficacy rate was 99.2%. As for bacteriological effects, 58 (92.1%) of 63 strains of Gram-positive bacteria and 126 (96.2%) of 131 strains of Gram-negative bacteria were eradicated. The overall bacterial eradication rate was 94.9%. Regarding β-lactamase producing strains, 9 (75.0%) of 12 strains of Gram-positive bacteria and 57 (93.4%) of 61 strains of Gram-negative bacteria were eradicated. The overall bacterial eradication rate with the β-lactamase producing strains was 90.4%. The efficacy rate of this drug was 100% (46/46) in cases where more than 3 days of previous treatment resulted in “poor” efficacy. Of these cases, the efficacy rate in cases of infection with β-lactamase producing strains was 100% (22/22). As for bacteriological effects, 11 (84.6%) of 13 strains of Gram-positive bacteria and 32 (91.4%) of 35 strains of Gram-negative bacteria were eraticated. Regarding β-lactamase producing strains, 2 (66.7%) of 3 strains of Gram-positive bacteria and 17 (89.5%) of 19 strains of Gram-negative bacteria were eradicated. The overall bacterial eradication rate with the β-lactamase producing strains was 19 (86.4%) of 22 strains. 3. Adverse reactions and abnormal laboratory data The adverse reactions of the drug was evaluated in 324 cases after 8 cases were excluded. The adverse reactions were observed in 28 cases (8.6%), consisting of diarrhea, skin rash, pyrexia, diarrhea and abdominal pain, nausea and dorsal paraesthesia, and slight clouding of consciousness. The laboratory profile was assessed in 318 cases after 14 cases were excluded. Of these cases, 42 cases had abnormal laboratory test profile that mainly consisted of elevation in platelet counts, increases in eosinophils and elevations of transaminase levels. The adverse reactions and the abnormalities in laboratory data observed in this study were not particularly serious and disappeared or recovered to normal with discontinuation or completion of the treatment with this drug.