We investigated biapenem (BIPM, L-627) a newly carbapenem antibiotic, for its antibacterial activity, tissue penetration, clinical efficacyand bacteriological effect in obstetric and gynecological infections, and obtained the following results.
1. Antibacterial activity
MICs of L-627 against 149 strains isolated from80 patients in this clinical trial were examined and compared with those of imipenem (IPM) and ceftazidime (CAZ). The MICK₅₀, and MICK₉₀, of L-627 against the isolates were 0.2and 12.5 μg/ml, respectively. Those of IPM were 0.2and 6.25μg/ml, respectively.
The antibacterial activity of L-627 was quite similar to that of IPM, and was superior to that of CAZ.
2. Tissue and retroperitoneal fluid penetration
The peak levels in venous and uterine arterial sera were 24.0 and 26.2μg/ml, respectively, after 300mg drip infusion. The peak levels in the uterine or adnexal tissues were 2.39-9.60μg/g, and 0.2μg/g of L-627 was detected at 275 minutes after administration.
Peak levels in retroperitoneal fluid were 8.7±1.7 ktg/ml at 1 hour after the completion of 30 minutes drip infusion (300 mg) and 7.9±0.2, ug/ml at 30 minutes after 300 mg 60 minutes drip infusion (300 mg). These levels expected the MICs against main pathogenic organisms.
3. Clinical results
L-627 was given to the following 144 patients (No.of analytical subjects) at a daily dose of0.3-1.2 g for 2-13 days: intrauterine infections (54), adnexitis (36), parametritis (17), pelvic peritonitis (27), bartholins abscess (6) and other infections (4). The clinical efficacy was93.1% (134/144) and the eradication rate against isolated organisms was 88.7% (110/124). Side effects were observed in 2 patients: eruption (1) and vomiting with numbness of the tongue (1). Abnormal change in laboratory test results included increase in eosinophiles in 1, increase in GOT, GPT and γ-GTP in 1 and increase in GPT and Al-P in 1, but all of these abnormalities were very mild and withdrawal of the drug was not required.
Our results suggest that this drug is useful inthe treatment of gynecological infections.

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Biapenem (L-627), a novel injectable carbapenem antibiotic, was studied with regard to its effect on mice inoculated with four types of bacteria and on the intestinal flora of pediatric patients. L-627 was given i. m., 40mg/kg once daily for 5consecutive days, to mice inoculated enterically with four types of bacteria (Escherichia coli, Enterococcus faecalis, Bacteroides fragilis, and Bifidobacterium breve). Except for a mild decrease in E. coli, there were no major fluctuations in viable bacterial counts in the feces during the treatment.
Five children with bacterial infections (3 boys and 2 girls; ages: 1 month to 7 years and 7 months; body weights 4.62-21.8kg) were given L-627 at 6.0 to 11.7mg/kg 3 times daily for 7 to 11 days. Among aerobes, although Enterobacteriaceae such as E. coli tended to decrease remarkably in all patients, there was no major change in Enterococcus. Consequently, total aerobe counts did not change significantly in any patient. Among anaerobes, Bifidobacterium, Bacteroides, and Eubacterium, which are the predominant organisms in infants, decreased remarkably in some patients. One of the patients showed a marked decrease in total anaerobe count associated with a change in fecal characteristics (diarrhea). Glucose nonfermenting Gram-negative bacilli or fungi did not become predominant organisms in any patient. Recovery from these changes in the intestinal flora was noted promptly after terminating L-627 treatment. L-627 was detected in the feces of 4 patients during treatment. The fecal concentration ranged from 0.24 to 2.22μg/g. Clostridium difficile was not detected in any patient. Although C. difficile D-1 antigen was observed in 2 patients, it bore no relationship to fecal properties.
The results indicated that L-627 had relatively few effects on the intestinal flora compared to other new β-lactam antibiotics.

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Antibiotic susceptibilities were evaluated for 48 strains of Streptococcus pneumoniae collected in 1992-1993 at Ichihara City of Chiba Prefecture. Twenty two (46%) of the 48 strains were benzylpenicillin (PCG) insensitive or resistant (PRSP) judged from the MICs of PCG to higher than 0.1μg/ml. MICs of piperacillin and cefotaxime increased as the MICs of PCG increased. However, elevations of MICs of imipenem and biapenem (L-627) were small in spite of the increases of MICs of PCG.
L-627 was effective in a case of purulent meningitis due to PC-insensitive S. pneumoniae. Thus, L-627 is a candidate to be used in treatment of PRSP infections including purulent meningitis.

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Pharmacokinetic and clinical studies on biapenem (L-627), a newly developed carbapenem, were performed and the following results were obtained.
1. Absorption/excretion
Pharmacokinetics of biapenem was studied in 14 children at doses of 6 mg/kg and 12 mg/kg administered through 30 minuts-drip infusion.
Peak plasma levels and plasma half-lives of the 2 doses were 22.5, 29.9 μg/ml, and 0.84, 0.85 hours, respectively.
Their urinary recovery rates were 54.5 to 76.1% and 37.3 to 59.5%, respectively.
Cerebrospinal fluid levels of biapenem in two patients with purulent meningitis were 0.88 and 2.72 μg/ml, and the penetration rates were 3.7 to 8.3%.
2. Clinical study
Forty-nine patients were treated with biapenem at doses exceeding 90 to 100 mg/kg/day for purulent meningitis and at does between 15.0 and 36.0 mg/kg/day for other infections.
Biapenem gave ‘Excellent’ or ‘Good’ responces in 48 cases, hence an efficacy rate of 98.0% was obtained. Only one patient with pneumonia showed a fair response.
No adverse reactions were observed. Abnormal laboratory test results were noted in 7 patients including elevation of GOT, GPT, and eosinophils. In no cases the treatment had to be discontinued.

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Pharmacokinetic, bacteriological and clinical studies on biapenem (L-627), a newly developedcarbapenem antibiotic, were performed in the field of pediatrics.
1. Antibacterial activities of biapenem against 54 strains of Streptococcus pneumoniae isolated in 1993 were compared with those of 13 other antibiotics, consisting primarily of β-lactam compounds. Minimal inhibitory concentrations (MICs) of biapenem were≤0.78 aug/ml against all strains, and excellent values were obtained even against benzylpenicillin (PCG)-resistant strains. Based on MIC₈₀ values, biapenem, imipenem, and cefuzonam showed highest antibacterial activities, followed by cefotaxime.
2. Blood concentrations and urinary excretion were studied after intravenous drip infusion of 6.0 mg/kg and 6.1 mg/kg of biapenem, given over 30 min., to two children (ages: 4 years and 11 years).
Blood drug concentrations were 14.7 and 37.6 μg/ml, respectively (mean: 26.2 μg/ml), at 30min. after starting infusion (at completion of infusion). Blood concentrations then declined gradually with half-lives of 0.66 and 1.16 hrs., respectively (mean: 0.91 hrs.). After 5.5 hrs., blood concentrations were no longer measurable in the former and 0.46μg/ml in the latter. Urinary recovery rates of drug in the first 6 hrs. after starting administration were 65.8% and 60.9%, respectively (mean 63.4%).
3. Penetration of the drug to the cerebrospinal fluid (CSF) was studied in 2 patients with purulent meningitis. Biapenem, 31.6 mg/kg, was administered four times daily by 30-min. intravenous drip infusion. CSF concentration 1 hr. after administration was 8.54 μg/ml on the day of the start of treatment (day 0), and 3.00, 2.04, 16.1, 4.16, 3.24, and 1.60μg/ml on days 1,-7 of treatment, respectively. In a patient similarly administered with the drug at 33.7 mg/kg four times daily, the CSF concentration at 1.5 hrs. after administration was 2.62μg/ml on the next day of the start of treatment. On days 2-7 of treatment, CSF concentrations at 0.5-1 hr. after administration were 4.60, 12.9, 20.6, and 1.32μg/ml, respectively.
4. Clinical efficacy was evaluated in 27 patients with pediatric infections. The dose administered per dosage was 5.2-33.7mg/kg. Three or four dosages were given daily. The duration of therapy ranged from 3 1/3 to 11 days. Total administered doses were between 0.675 and 20.475 g.
Clinical efficacy was evaluated in a total of 24 patients (purulent meningitis 1, acute otitis media 1, acute bronchitis 2, acute pneumonia 19, acute urinary tract infection 1). Responses to treatment were excellent in 14 patients and good in 10 patients. The efficacy rate, based on excellent and good responders, was 100.0%. Bacteriological efficacy was determined against the following presumptive pathogens: Staphylococcus aureus 4 strains (MSSA 1 strain, MRSA 3 strains), Streptococcus pneumoniae 2 strains, Escherichia coli 1 strain, Haemophilus influenzae 4 strains, Moraxella (Branhamella) catarrhalis 1 strain, and Pseudomonas aeruginosa 3 strains. All strains were eradicated except 2 strains (MRSA) of S. aureus (decreased), and 2 strains of P. aeruginosa (decreased 1, persisted 1). The overall eradication rate was 73.3%. Bacterial replacement occurred only in 1 patient in whom E. coli was replaced by Enterococcus faecalis.
Adverse reactions were noted in a total of 4 patients (fever and skin rash 1, skin rash 2, diarrhea 1). All adverse reactions disappeared promptly after completing or terminating drug administration. Laboratory abnormalities were found in a total of 10 patients (elevation of GOT/ GPT 3, elevation of GPT 4, eosinophilia 2, thrombocytosis 1). All cases were mild and normalization was confirmed during follow-up observation in 5 patients.
The results indicate that biapenem may be highly efficacious and safe when used in the treatment of pediatric infections.

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The efficacy and the safty of biapenem (L-627), a new carbapenem antibiotic, against infections in pediatrics were studied. The obtained results are summarized as follows. 1. L-627 at dose levels of 5.4 mg/kg to 12.4 mg/kg (daily doses of 16.2 mg/kg to 37.2 mg/kg) was administered by intravenous drip infusion 3 times daily for 5 to 7 days to 2 cases of pneumonia, 3 cases of skin and soft-tissue infections and 1 case of urinary tract infection for a total of 6 cases. As results, all the cases showed good or better responses including 4 excellent and 2 good results. Bacteriological efficacies in all of the 3 eligible cases were assessed as “eradicated”.
2. As for the safety, a decrease in the WBC count and slight elevation of GOT and GPT were observed in 1 case as abnormal changes in the laboratory test results, only incidence of side effect observed was the eruption in 1 case.
3. The results above indicate that L-627 is useful for the treatment of general infections in pediatrics.

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Antibacterial activities were determined and pharmacokinetics and a clinical studies were performed on biapenem (L-627), a novel parenteral carbapenem antibiotic, in infections in children. The following results were obtained:
1. MICs of L-627 against clinical isolates were as follows: Among Gram-positive bacteria, MICs were 0.78 μg/ml to >100μg/ml against 3 strains of methicillin-resistant Staphylococcus aureus (MRSA), and 0.10μg/ml to 0.39μg/ml against 8 strains of methicillin-sensitive S. aureus(MSSA), MICs against 5 of them were similar to those of imipenem (IPM), and MICs against 3 of them were slightly higher than those of IPM. MICs were ≤0.025μg/ml to 0.39μg/ml against 7 strains of Streptococcus pneumoniae, and were similar to those of IPM, and lower than those of ceftazidime (CAZ) and piperacillin (PIPC). Among Gram-negative bacteria, MICs were 0.78μg/ml and 3.13 g/ml against 2 strains of Haemophilus influenzae, and were similar to those of IPM.
2. Maximum plasma concentrations determined by the bioassay method after intravenous infusion of L-627 over 30 minutes at doses of 6.0 and 12.0 mg/kg, respectively, in 2 different pairs of 2 children each (total 4 cases) were observed upon completion of the treatment. Maximum concentrations at a dose of 6.0 mg/kg were 28.8μg/ml and 24.6μg/ml, and at a dose of 12.0mg/kg were 65.4μg/ml and 39.6μg/ml, exhibiting a dose response. Plasma half lives in the beta phase were 0.97 and 1.20 hours at 6.0 mg/kg, and 0.72 and 0.94 hour at 12.0 mg/kg. Plasma concentrations determined by the HPLC method were lower than those determined by the bioassay.
3. Urinary excretion rates in the first 5.5 hours after the 6.0 mg/kg dose were 81.4 and 75.3%, and after the 12.0 mg/kg dose were 91.0 and 73.8%, and these values were higher than those obtained using HPLC.
4. Concentrations of L-627 in cerebrospinal fluid were determined in 2 cases of purulent meningitis. In one case, 30.3 mg/kg of L-627 was infused intravenously over 30 minutes and concentrations on days 1, 3, 7 and 14 observed at 60, 60, 45 and 45 minutes after respective dosages were 7.60, 1.30, 1.42 and 0.38μ. Cerebrospinal fluid-plasma concentration ratio was determined on days 7 and 14 to be 5.5 and 1.2% respectively. In another case, in which 25.6 mg/kg of L-627 was infused intravenously over 30 minutes, concentrations on days 2, 3, 4, 5, and 9 observed at 60 minutes, and days 19 at 120 minutes after respective dosage were 1.08, 0.62, 0.54, 1.52, 1.50 and 0.80μg/ml. Cerebrospinal fluid-plasma concentration ratios were determined on days 2, 4, 9 and 19, and the ratios were, respectively, 13.3, 4.5, 8.4 and 9.6%.
5. Clinical efficacies were evaluated in 50 cases (14 illness). Poor effects were obtained in 2 out of 20 cases with pneumonia, fair response in one case with acute sinusitis, and fair and poor responses in 2 cases out of 3 with subcutaneous abscess. All other cases showed excellent or good responses. Thus an efficacy rate of 90.0% was obtained.
6. Bacteriological efficacy was examined for 31 strains (9 species). 2 out of 12 strains of S. aureus remained unchanged, but in all the other 29 strains, bacteria were eradicated. Thus the eradication rate was 93.5%.
7. A side effect of diarrhea was observed in one patient (2.0%).
8. Abnormal laboratory test results included eosinophilia in 4 cases (9.5%), increased platelets in 3 cases (6.8%), simultaneous increases in GOT and GPT in 2 cases (4.4%), one of which also showed increased β-GTP.

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Antibacterial activities of cefetamet (CEMT) against clinically isolated strains from patients with community acquired respiratory tract infections were compared to those of other oral β-lactam antibiotics in the period from January to March 1994.
The following results were obtained.
1. CEMT showed strong antibacterial activities against three major pathogens causing community acquired respiratory tract infections, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. However, antibacterial activities of CEMT against benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) and PCG-resistant S. pneumoniae (PRSP) were sligthly weaker than of those of some the reference antibiotics.
2. No MIC value changes of CEMT were observed from year to year against Moraxella subgenus Branhamella catarrhalis and Klebsiella pneumoniae.

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Effects of imipenem/cilastatin (IPM/CS) therapy, flomoxef (FMOX) therapy and combined ceftazidime+aspoxicillin (CAZ/ASPC) therapy as initial therapies for chorioamnionitis were assessed clinically.
1. The subjects were 49 women with threatened abortion and 29 with premature rupture of membranes (PROM), complicated in all cases by chorioamnionitis. The inflammation was treated with IPM/CS in 19 patients, FMOX in 39, CAZ in 11, and CAZ/ASPC in 9.
2. The response rate to therapy for chorioamnionitis was 95.9% (47/49) in the threatened abortion group. Of the 49 patients in this group, 16 (32.7%) underwent premature labor. Of the therapies administered, IPM/CS tended to prevent premature labor more frequently than did any other therapy. The latent period (from rupture of membranes to delivery) was equal to or longer than 7 days in the PROM group. The percent prolongation of the latent period in these patients (55.5%) was significantly greater than that previously obtained with penicillin therapy.
3. The bacterial elimination rate was 50.9% (29/57). Of the 36 bacterial isolates, 66.7% were Gram-positive bacteria. The bacteriological efficacy rate was 89.7% (26/29).
These results suggest that antibacterial agents effective against Gram-positive bacteria should be selected for treatment of chorioamnionitis, and that IPM/CS therapy is particularly useful considering the drug's good transfer into amniotic fluid and its antibacterial spectrum.

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