The neurotoxic potencies are considerably different among various beta-lactam antibiotics. Some carbapenem antibiotics, a new class beta-lactam antibiotic, also induce convulsion in human and laboratory animals. This article reviews the structure activity relationship for the neurotoxicity of beta-lactam antibiotics, especially carbapenems.
As for the neurotoxicity of carbapenem antibiotics, the presence of amino group in the C-2 side chain is an important factor in inducing convulsion and the strength of basicity of the amino group is correlated with the convulsant activity. The beta-lactam ring of carbapenem is not necessary to evoke convulsions. The neurotoxicity of carbapenem antibiotics is related to only a part of the structure, including the C-2 side chain, but not to the carbapenem skeleton itself. In comparison with other beta-lactam antibiotics, it has been found that the structure responsible for the convulsive action of carbapenems is significantly different from penicillins and cephalosporins in which the beta-lactam ring is essential to evoke convulsion.
The induction of convulsions by carbapenem antibiotics is predominantly caused through the inhibition of gamma aminobutyric acid receptor in a similar manner as with penicillins and cephalosporins. However, the detail mechanism may be different not only among carbapenems, cephalosporins, and penicillins but among carbapenem compounds themselves.
It is important to know the neurotoxic potential of a compound by investigating the effect of direct administration into the central nervous system such as intraventricular administration, since the penetration through blood-brain barrier or the pharmacokinetic property is varied in seriously ill patients. Possible drug interactions regarding neurotoxicity are also discussed. We hope these findings described here will be helpful in developing more efficient and safer beta-lactam antibiotics of a new generation.

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An investigation was made into pharmacokinetics and clinical effects of the newly-developed cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), in pediatric patients.
In 26 patients in whom pharmacokinetics were investigated, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by i. v. injection were 21.3±10.0 (mean±standard deviation), 51.0±9.9 and 68.3±0.7 μg/ml, respectively. Serum concentrations at 6 hours after administration were 2.9±1.7, 2.3±0.9 and 4.6±2.6μg/ml, with the levels roughly above MIC90s for dominating pathogenic bacteria being maintained until 6 hours after treatment.
Urine concentrations were in the range between 200 and 560μg/ml at 4 to 6 hours after dosing. Cumulative urine excretion accounted for 70 to 80% of dose.
In 11 patients in whom pharmacokinetic investigations were performed, peak serum concentra tions of CZOP administered at doses of 10, 20 and 40 mg/kg by 30-min. i. v. drip infusion were 37.1, 66.3±25.5 and 95.7±8.9μg/ml, respectively. Serum concentrations at 6 hours after dosing were 1.6, 2.3±0.8 and 3.0±10.4μg/ml, respectively, with the levels above MIC₉₀s for dominating pathogenic bacteria also being maintained until 6 hours after administration.
Urine concentrations were 190μg/ml or more until 8 hours after dosing and the cumulative urinary excretion accounted for 50 to 70% of dose.
In 9 patients with meningitis in whom CZOP penetration into cerebrospinal fluid was investigated, concentrations in the fluid of the compound i. v. injected at doses from 40 to 53 mg/kg were in the range between 1.6 and 43.4μg/ml exceeding MICs for pathogenic bacteria at 1 to 1.5 hours after dosing.
In all of the 38 patients in whom pharmacokinetic investigations and clinical evaluations were performed, CZOP was good to excellent (excellent in 22 patients and good in 16 patients). Also in bacteriological evaluations, all of the 31 strains of investigated pathogenic bacteria were eradicated.
The clinical efficacy rates for the 335 subjects for clinical evaluations were 97.0% (195/201) for patients in whom pathogenic bacteria were detected (group A), and 95.5% (128/134) for patients in whom no pathogenic bacteria were detected (group B).
In bacteriological evaluations, the eradication rates of Gram-positive and Gram-negative bacteria were 96.3% (77/80) and 94.5% (155/164), respectively, with the eradication rate in total being 95.1% (232/244).
Safety investigations were performed in 364 patients. Adverse reactions were reported in 11 patients (3.0%), including diarrhea (aqueous stool and soft stool) in 7 patients (1.9%) and drug rash (rash, eruption and wheal) in 4 patients (1.1%). Abnormal laboratory test values were noted in 54 patients, including eosinophilia in 20 patients (6.3%) and elevated GPT in 20 patients (6.3%). The adverse reactions and abnormal laboratory test values were not serious, disappearing or improving during the continued treatment period or as a result of discontinuation of the treatment.
Serum and urine concentrations of CZOP, when administered by i.v. injection and 30-min. i. v. drip infusion at doses of 10, 20 and 40 mg/kg, were higher than the MICs for pathogenic bacteria until 6 hours after dosing. The drug also showed favorable penetration into cerebrospinal fluid. It was therefore considered that CZOP was a highly useful drug for the treatment of pediatric infections with sufficient bacteriological and clinical efficacy when administered at a dose of 40 to 80 mg/kg three to four times daily.

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Bacteria isolated from lower respiratory tract infections were collected in cooperation with institutions located throughout Japan since 1981, and IKEMOTO et al. have been investigating susceptibilities of the isolates to various antibacterial agents and antibiotics, and the relationships between the isolates and characteristics of the patients and so forth each year. We discuss the results in detail.
In 20 institutions around the entire Japan from October 1992 to September 1993, 690 strains of bacteria were isolated mainly from sputa of 549 patients with lower respiratory tract infections and presumed to be the etiological bacteria. MICs of various antibacterial agents and antibiotics were determined against 101 Strains of Staphylococcus aureus, 121 strains of Streptococcus pneumoniae, 122 strains of Haemophilus influenzae, 92 strains of Pseudomonas aeruginosa (non-mucoid), 32 strains ofPseudomonas aeruginosa(mucoid), 52 strains of Moraxella subgenus Branhamella catarrhalis, 28 strains of Klebsiella pneumoniae etc., and the drug susceptibilities of these strains were measured except the strains which died during transportation.
1. S. aureus
S. aureus strains for which MICs of methicillin were higher than 4μg/ml (methicillin-resistant S. aureus) accounted for 61.4% and the frequency of the drug resistant bacteria was higher than the previous year's 58.3%. MICs values indicated that arbekacin was as active as vancomycin against all the strains on S. aureus.
2. S. pneumoniae
Benzylpenicillin among the penicillins showed potent activities against S. pneumoniae. Cefuzonam, cefazolin, cefotaxime and cefmenoxime among the cephems showed excellent antimicrobial activities against S. pneumoniae. Imipenem; carbapenems, showed the most potent activity, and MIC₈₀ was 0.015μg/ml.
3. H. influenzae
All the drugs tested were potent against H. influenzae. Ampicillin among the penicillins showed MIC₈₀ 1 μg/ml against H. influenzae. Cefotaxime, cefmenoxime, cefuzonam and cefixime showed the most potent activities, and MIC₈₀s were 0.063μg/ml. The antimicrobial activity of ofloxacin was equivalent to those of cephems.
4. P. aeruginosa (mucoid)
Ciprofloxacin showed the most potent activity against P. aeruginosa (mucoid), and MIC₈₀ was 1μg/ml. Cefsulodin, aztreonam, carumonam and tobramycin showed the next most potent activities with an MIC₈₀s of 2μg/ml.
5. P. aeruginosa (non-mucoid)
Tobramycin and ciprofloxacin showed the highest activities against P. aeruginosa (non-mucoid) with an MIC₈₀s of 2μg/ml. Norfloxacin also showed some activity, and MIC80 was 4μg/ml. Comparing to activities against P. aeruginosa (mucoid), all the drugs tested showed lower activities against P. aeruginosa (non-mucoid).
6. K. pneumoniae
The activities of all drugs except penicillins were high activities against K. pneumoniae.
Carumonam showed the most potent activity with an MIC₈₀ of 0.063μg/ml, followed by flomoxef, cefixime and cefozopran with their MIC₈₀s of 0.125 μg/ml.
7. M.(B.) catarrhalis
Imipenem; carbapenems, showed the most potent activity against M.(B.) catarrhalis with an MIC₈₀ 0.063μg/ml. Minocycline and ofloxacin showed MIC₈₀s 0.125μg/ml, respectively.
We also investigated year to year changes in the background of patients, as well as types of respiratory infectious diseases, and the etiological bacteria.
As for patients backgrounds, there were many infectious diseases found among patients in a high age bracket, and the patients over age 60 accounted for 60.8% of the diseases.

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In order to evaluate antibacterial activities of combination uses of cefpirome (CPR) and various antibiotics in vitro, minimum inhibitory concentrations (MICs) of CPR alone and combinations of CPR+other drugs against freshly isolated clinical strains of Pseudomonas aeruginosa.
The results are summarized as follows;
1. Combined effects of CPR+β-lactams, piperacillin (PIPC), aztreonam (AZT), imipenem (IPM) showed wider antibacterial spectra and stronger antibacterial activities than CPR alone with drugs concentrations of CPR and other drugs at sub-MIC levels. At concentrations of sub-MIC levels, antibacterial effects of CPR + PIPC and CPR + AZT combination were strong but CPR+IPM was weaker than those of the former two combinations. It appeared that stronger effects were demonstrated by some combinations against strains that were susceptible to both drugs of combination, but little additive effects were shown against strains that were resistant to both drugs. Antibacterial effect of CPR + fosfomycin combination was the same as those of CPR + PIPC and CPR + AZT combinations.
2. Combined effects of CPR + aminoglycosides (AGs), gentamicin, tobramycin, amikacin showed wider antibacterial spectra and stronger antibacterial activities at sub-MIC levels of CPR or AGs. The effect against CPR-resistant strains was same. But the combined effect was weak against AGs-resistant strains.
3. Effectiveness of combinations of CPR + β-lactams and CPR + AGs depended on drug susceptibilities of strains tested. We cannot estimate effects of those combinations without investigating drug susceptibility of bacteria being tested.
4. In none of the combinations tested, antagonism was observed.

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In order to evaluate antimicrobial activity of ceftriaxone (CTRX), minimum inhibitory concentrations (MICs) of CTRX and control drugs were determined against clinically isolated strains including those from purulent meningitis and liver and biliary tract infections in 1995.
The results are summarized as follows;
1. MIC90 of CTRX was 0.05μg/ml against benzylpenicillin (PCG)-insensitive Streptococcus pneumoniae or PCG-resistant S. pneumoniae and it was ≤0.025μg/ml against β-lactamase producing strains of Haemophilus influenzae. Antimicrobial activities of CTRX against these strains were stronger than control drugs.
2. MIC distribution of CTRX was in a lower concentration range than those of ceftazidime and flomoxef against extend broad-spectrum β-lactamase (EBLA)-producing Escherichia coli and Klebsiella pneumoniae subsp. pneumoniae.
3. These results suggested that CTRX will be effective against community-acquired pneumonia, purulent meningitis and liver & biliary tract infections.

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The effectiveness of fluconazole on deep seated fungal infections associated with hematologicaldisorders was evaluated in a multicenter clinical study.
The underlying diseases included acute myeloblastic leukemia, acute lymphocytic malignant lymphoma, adult T cell leukemia, multiple myeloma and others.
Fluconazole (FLCZ) was administrated 100-400 mg/day intravenously or orally to 79 patients with systemic fungal infections complicated with hematological disorders and it was possible to evaluate clinical efficacies in 60 patients.
27 patients were diagnosed as having determinate systemic fungal infections and 33 patients suspected fungal infections.
The clinical efficacies were 81.5% (22/27) in patients with diagnosed fungal infections and 57.6% (19/33) in patients with suspected fungal infections. The overall clinical efficacy was 68.3 % (41/60).
No side effects such as gastrointestinal symptoms, vascular pain and renal dysfunction were observed in this study. As for abnormal laboratory test, transient increases in GOT, GPT, Al-P, LDH, serum Na, Cl and decrease in serum K were observed in 9 patients (11.4% ). These results indicated that FLCZ has a high therapeutic efficacy on deep seated fungal infections in patients with hematological disorders.

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