In vitro antibacterial activities against Pseudomonas aeruginosa producing various levels of chromosomal class C β-lactamase were studied with dipolar ionic cephalosporins of cefepime (CFPM), cefpirome (CPR) and cefozopran (CZOP) in comparison with ceftazidime (CAZ). The activities of CZOP and CAZ against non-or low-class C β-lactamase-producing P. aeruginosa were superior to those of the other two agents. The MIC values against P. aeruginosa of high level production of class C β-lactamase increased with CPR, CZOP and CAZ, however, CFPM was relatively less affected with increased β-lactamase production. The effects of these antibacterials on the potentiation of class C β-lactamase production were tested, and the activities of induction of these agents were found to be lower than of imipenem. Furthermore the affinity of CFPM to the purified class C β-lactamase was the lowest of all the agents tested. CFPM also showed no selection of drug-resistant mutants at ×8 MIC, whereas, the drug-resistant mutants could be isolated at ×8 MIC of CPR, CZOP or CAZ.

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The biological properties of 130 strains of Staphylococcus aureus (S. aureus) isolated from blood samples at our hospital were investigated, and the in vitro effects of vancomycin (VCM) combined with imipenem (IPM) or meropenem (MEPM) on Methicillin-resistant S. aureus (MRSA) were evaluated. We also investigated the effects of using arbekacin (ABK), an aminoglycoside, combined with IPM. When 102 strains of MRSA were classified by the type of coagulase, 95 strains (93.1%) had type II coagulase, which was the most common, followed by 3 (2.9%) with type VII. Of 28 strains of methicillin-sensitive S. aureus (MSSA), 7 (25%) were categorized as type III and 7 (25%) as type VII. Forty percent of MRSA were of the SE C type, and strains with coagulase type II, SE C type, ad TSST-1 toxin showed a tendency to increase in prevalence. VCM and IPM showed excellent synergistic effects against 56% of the MRSA strains, and additive effects against 43%. The combination VCM and MEPM was synergistic against 30%, which was inferior to the effects of VCM and IPM. The combination IPM and ABK was not synergistic, and showed additive effects against 33% of the strains. Thus, since most MRSA strains are isolated from patients with polymicrobial infections, the combination of VCM, with IPM or MEPM is expected to be effective clinically as well as the combination of either ABK and IPM or ABK and MEPM.

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Vancomycin hydrochloride (VCM) has the highest antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The clinical usefulness of the dosage regimens based on a two compartment model and the Bayesian method were evaluated to establish a safe and effective VCM treatment for infections caused by MRSA. The subjects were 23 patients (24 courses) treated with VCM from September 1993 to September 1997. VCM (500-1, 000mg/dose) was administered by intravenous infusion over 1.0 to 1.5 hours and dosing intervals were from 12 to 48 hours. Serum VCM concentrations at the trough and 1 hour after the end of infusion (peak) were measured until 96 hours from the onset of therapy. Pharmacokinetic parameters were calculated for VCM dosage regimens based on a two compartment model and the Bayesian method by Rodvold's population pharmacokinetic parameters. The prediction of serum VCM concentrations and the dosage regimens were analyzed. The dosage and the predicted serum VCM concentration were calculated by the programs using two points of serum VCM concentrations. Although predicted values were slightly lower than measured values at the trough, the predictability of serum VCM concentrations was good. In the initial dosage setting, VCM doses of 9.09-27.03 (16.03±5.46, mean±SD) mg/kg/dose were administered and serum VCM concentrations at the trough and peak were achieved within a therapeutic range in 9 courses (37.5%) and 8 courses (33.3%), respectively. After the dosage regimens, VCM doses became 9.13-31.58 (21.28±6.49, mean±SD) mg/kg/dose and serum VCM concentrations achieved within a therapeutic range at the trough and peak were similar in 18 courses (75%), respectively. The rate of bacterial eradication (MRSA) was 60% (18/30). Although other antibiotics or β-lactam antibiotics were used in 17 courses concomitantly, the efficacy rate was 58.3%. No case developed into renal failure due to VCM treatment. These data indicate that the Bayesian method is useful for interpreting patient pharmacokinetics and conducting a safe and effective treatment with VCM.

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“General guidelines for the evaluation of the new antimicrobial agents for the treatment of respiratory tract infections” was reported by our committee in the Japanese Journal of Chemotherapy (“General Guidelines” Vol.45: 762-778, 1997). The aim of the present paper is to discuss the validity of the above “General Guidelines”, when applied for the study of the cases with acute upper respiratory tract infections (AURTI), and, if necessary, to set up a new guideline of the therapeutics of AURTI. For this purpose, a total of 2, 257 cases with acute pharyngitis, acute tonsillitis or with acute bronchitis, which had been enlisted for the phase II and phase III clinical studies of new antimicrobials in Japan, were enrolled in the present study.Most of them were selected and enrolled on the basis of the judgement by investigators, and 1, 518 cases (67%) were found to fulfil the criteria of “General Guidelines”. All of the 5 different measurements recommended by the ad hoc committee (microbial study, WBC counts, stab count, CRP level and body temperature) were done only in 1, 172 enrolled cases, and 947 cases (81%) were found to fulfil the new diagnostic criteria. The degree of the severity of the disease judged by investigators differed somewhat each other between the per os medication cases and the parenteral medication cases, and the number of moderate cases was the largest.However, the number of mild cases was the largest according to the “General Guidelines”. Of 1, 518 cases which fulfilled the new criteria, the ratio of mild/moderate/severe cases by the judgement of investigators was 41/50/9 and that by the new criteria was 50/39/11. The ad hoc committee stated that laboratory examinations at the 7 th day after initiation of chemotherapy were “a must” for the correct evaluation of the effectiveness of antimicrobials administered. However, laboratory examinations at the 7 th day were done only in 234 cases, the judgemnt by investigators was comparable to that by the committee in 203 of 234 cases (87%). As a conclusion, the new guideline set up by the ad hoc committee is appropriate for the diagnosis, evaluation of severity of diseases, and for the evaluation of the effectiveness of antimicrobial agents used for the treatment of AURTI.

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