Laboratory and clinical studies o tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin (PIPC) with the new β-lactamase inhibitor tazobactam (TAZ), were carried out in the field of pediatrics.
1. After intravenous administration of TAZ/PIPC at a dose of 25 mg/kg to one child, the peak plasma levels of TAZ and PIPC were 24.4μg/ml and 119μg/ml respectively after 5 min. The half-lives of TAZ and PIPC were 0.48 and 0.60 hours respectively. Same as 50 mg/kg to two children, the peak plasma levels of TAZ and PIPC were 17.5, 32.2μg/ml and 92.8, 163μg/ml after 5 min. The half-lives of TAZ and PIPC were 0.37, 0.50 hours and 0.51, 0.59 hours. A ratio of TAZ to PIPC was about 1 to 4 in plasma levels.
The cumulative urinary recovery rates of TAZ and PIPC in the first 6 hours after intravenous administration were 15.8, 64.9% and 39.8, 53.4%.
2. The antibacterial activity of TAZ/PIPC against clinically isolated organisms was determined. The MICsof TAZ/PIPC were≤0.05μg/ml against Haemophilus influenzae and Streptococcus pneumoniae and ≥1.56μg/ml against Escherichia coli, Staphylococcus aureus and Haemophilus parainfluenzae.
3. The clinical efficacy of TAZ/PIPC could be evaluated in 14 patients with various bacterial infections, and was evaluated as “excellent” in 9 patients and as “good” in 5.
The overall clinical efficacy rate in 14 cases was 100% and excellent was 64.3%. Bacteriological efficacy rate was 91.7% (10/11).
4. As a side effect, loose stool was observed in one case, no abnormal laboratory test values were observed.
It has been concluded that TAZ/PIPC was a useful drug in the field of pediatrics.

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Pharmacokinetics, efficacy and safety of tazobactam/piperacillin (TAZ/PIPC), a new β-lactamase inhibitor combined with a penicillin antibiotic, were studied in pediatrics and the following results were obtained.
1) Serum concentration and urinary excretion of TAZ/PIPC after intravenous administration at a dose of 46 mg/kg to one child were investigated.
Serum half-lives were 0.5 hours for TAZ and 0.6 hours for PIPC, while the urinary recovery rates in the first 6 hours after administration, were 61.6% and 56.3% respectively.
2) TAZ/PIPC was administered at a dose of 46.0-73.5 mg/kg t.i.d. for 3-13 days to 10 patients, 6 with respiratory infection, 1 with pharyngotonsillitis, 1 with pertussis and 2 with soft tissue infection of skin.
Clinical response were excellent in 5 cases and good in 5 cases, and the efficacy rate was 100%.
Bacteriologically, 2 strains (Staphylococcus aureus and Streptococcus pyogenes) isolated from 2 patients were eradicated after the treatment.
As for adverse reaction, mild skin rash was observed in 1 case but disappeared within 2 days after withdrawal of the drug.
As for abnormal laboratory test results decrease in neutrophiles and increase in eosinophiles in each 1 case were obserbed, which were, however, normalized after administration.
From the above results, tazobactam/piperacillin was considerd to be a useful antibiotic in the pediatric field.

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A drug susceptibility test of the combination drug TAZ/PIPC, which consists of a newly developed β-lactamase inhibitor, tazobactam (TAZ), and one of penicillin antibiotics, piperacillin (PIPC), with combination ratio of 1: 4 in potency, was conducted with stock strains and clinical isolates. The clinical efficacy and safety of its injection was also evaluated in children with a variety of infectious diseases. The results were as follows:
1. In susceptibility test, 114 strains from 4 species of stock strains were treated with 8 drugs, that is, TAZ/PIPC, PIPC, penicillin G (PCG), ampicillin (ABPC), cefotiam (CTM), cefotaxime (CTX), ceftazidime (CAZ), and sulbactam/cefoperazone (SBT/CPZ). Of three clinically isolated species from patients, Staphylococcus aureus (S. aureus) was treated with TAZ/PIPC, PIPC, methicillin (DMPPC), CTM, CTX, and SBT/CPZ, and theothers were treated with the same drugs except for DMPPC. The MICs were measured for these bacterial strains inoculated at the concentration of 106 CFU/ml.
The MIC₉₀ values of TAZ/PIPC against 45 strains of Streptococcus pyogenes (S. pyogenes), one of the stock cultures of Gram-positive cocci, were 0.05μg/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. The MICs of TAZ/PIPC for 28 strains of Streptococcus agalactiae (S. agalactiae) were 0.39μg/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. As for Gram-negative bacilli, the MIC₉₀ of TAZ/PIPC against 10 strains of Bordetella pertussis (B. pertussis) were 0.10μg/ml and similar to those of PIPC. The MIC₉₀ of TAZ/PIPC against 31 strains of Haemophilus influenzae (H. influenzae) were 0.05μg/ml and similar to those of PIPC, CTX, and SBT/CPZ. Regarding Gram-positive cocci isolated from patients received this combination drug, the MIC90 of TAZ/PIPC against 2 strains of S. aureus, a non β-lactamase producing strain and a low-β-lactamaseproducing strain, were 0.78μg/ml and 3.1μg/ml, respectively; the former value was similar to those of PIPC, DMPPC, CTM, and CTX, and the latter was similar to those of PIPC, DMPPC, CTX, and SBT/CPZ. Of 4 strains of Streptococcus pneumoniae, 2 strains were inhibited at 0.05μg/ml, and the others at 1.56μg/ml; both values were similar to those of PIPC, SBT/CPZ. As for Gram-negative bacilli, 6 of 7 strains of H. influenzae did not produce β-lactamase and 1 strain was a high producer. The MICs of TAZ/PIPC against β-lactamase nonproducing strains were≤0.025μg/ml in 5 strains and 0.39μg/ml in 1 strain, and the values were similar to those of PIPC and SBT/CPZ. While the MIC of TAZ/PIPC against the high β-lactamase producing strain was 0.78μg/ml; similar to that of SBT/CPZ and smaller than that of PIPC.
2. The results of clinical effects on 7 diseases in 33 cases were as follows:
TAZ/PIPC was clinically judged “gexcellent” in 17 (51.5%); good in 14 (42.4%); fair in 2 (6.1%). No case with no response was seen in this study, and the total efficacy rate of “excellent” and “good” was 93.9%.
3. Bacteriological effects were evaluated in 17 strains of 4 species, and all of them were eradicated.
4. Adverse reactions were judged in 35, which consisted of 33 in which the clinical effects were evaluated and 2 dropped from this study. Of these cases, diarrhea was observed in 4 (11.4%).
5. Laboratory tests revealed an increase in platelets in 1 of 32 cases (3.1%), and eosinophilia in 2 of 29 cases (6.9%). Biochemical profile showed an increase in GPT alone and abnormal increases in both GOT and GPT in 1 each out of 21 cases.

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The transferability of tazobactam/piperacillin (TAZ/PIPC) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus.
125 or 250 mg/kg of TAZ/PIPC was intravenously administered to rabbits with experimental meningitis then concentrations of TAZ and PIPC in CSF and serum were mesured.
In the group to which 125 mg/kg of TAZ/ PIPC was administered, mean concentration of TAZ in CSF was 7.3 and 2.4μg/ml at 30 and 60 min after administration, respectively, and concerning PIPC, it was 10.1 and 3.5μg/ml, respectively.
CSF/serum ratio of TAZ was 29.4% and 31.4%, respectively, and that of PIPC was 24.3 and 35.6%, respectively.
In the group to which 250 mg/kg of TAZ/PIPC was administered, mean concentration of TAZ in CSF was 16.5 and 12.6μg/ml, respectively, and concerning PIPC, it was 25.6 and 18.2μg/ml, respectively.
CSF/serum ratio of TAZ was 22.1 and 56.1%, respectively, and that of PIPC was 12.2 and 51.9%, respectively.
Addition of TAZ did not make significant change of transferability of PIPC to CSF.
Considering the antibacterial effect of TAZ/PIPC against main causative organism of meningitis, this agent was thought to be effective for the treatment of purulent meningitis.

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