We measured in vitro the effect of combined therapy against methicillin-resistant Staphylococcus aureus (MRSA) using the modified checkerboard method with serial 1.25-fold dilutions (1.25-fold method) and a conventional method using serial twofold dilutions (twofold method) to compare the results. Vancomycin and minocyclin, which have a low MIC value, and cefotiam, which has a high MIC value, were used. In the determination of MIC value, discrepancies were found between the twofold and 1.25-fold methods even in the same strain. Discrepancies between these two methods were also observed in the combination effect in some cases. In the twofold method, decreased intensity of the MIC value in combination could be detected only in the form of (1/2) ⁿ. Therefore, in this method results with a 1/2 decrease were outwardly obtained even with a decrease of less than 1/2. On the other hand, in the 1.25-fold method it could be detected in the form of (4/5) ⁿ, and no discrepancies were found between the results of this method and the expected decrease. Thus more exact FIC indexes and MIC values in combination were obtained. In addition, the present method could detect weak antagonism that could not be detected by the twofold method. We concluded that 1.25-fold serial dilution was better than twofold dilution in the assesment of combinations of an antibiotic with a low MIC value and one with a high MIC value.

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These studies were designed to determine age-related variations in renal gluconeogenesis inhibition by beta-lactam antibiotics. The subjects were 2 groups consisting of 344 male young adult (2-3 months) and adult (8-10 months) Fischer rats. No significant inhibition in renal glucose production from 10 mM pyruvate was observed in either the group of young adult or adult rats. However, the degree of inhibition of gluconeogenesis with beta-lactam antibiotics was 18.7% with cephaloridine (CER) and 15.5% with penicillin G (PCG) in young adult rats, compared with the control, and 27.5% with CER and 29.9% with PCG, in adult rats, showing more potent inhibitory activity with age. In conclusion, the inhibition of gluconeogenesis with beta-lactam antibiotics in renal cortical slices of rat kidney was intensified by aging.

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In vivo, multidrug resistance (MDR) is characterized by overexpression of P-glycoprotein (PGp). This 170 kd plasma membrane protein acts as an ATP-dependent drug efflux pump. A correlation between the level of this protein and chemotherapeutic effect has been reported in breast cancer, lymphoma, sarcoma in child, neuroblastoma and others. To determine whether PGp can be a marker for chemotherapeutic effect, we immunohistologically measured PGp in autopsy samples from 50 patients with advanced lung cancer (SCLC 7 cases, NSCLC 43 cases).
Results: We used the polyclonal antibody mdrAb-1 and monoclonal antibody MRK-16 in the ABC method, and recognized a correlation between the two antibodies. PGp was detected in 57.8% with mdrAb-1 and 39.5% with MRK-16. Of 39 patients who had received chemotherapy and could be evaluated, the three responders at final chemotherapy were all negative for mdrAb-1. Twenty-six of the 33 non-responders were weak and strong for mdrAb-1 (0% vs 72.2%, p<0.05). We found a similar correlation between PGp expression and final chemotherapeutic effect with MRK-16, or a combination of the two antibodies. Of 29 patients who had received chemotherapy and could be evaluated for survival, the PGp positive group had a tendency to die sooner than the PGp negative group (mdrAb-1 and MRK-16 combination study).
Conclusion: The immunohistochemical detection of PGp in advanced lung cancer may be a marker of chemotherapeutic effect.
In the future, a chemosensitizer or an antibody which reverses MDR, may be used with anticancer drug therapy.

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Among the few antimicrobial agents approved for the treatment of infections caused by methicillin-cephem resistant Staphylococcus aureus (MRSA), vancomycin hydrochloride (VCM), in particular, has been shown to be safe and effective against MRSA infections when given in appropriate and recommended doses. Although its usefulness in adults has been certified, no adequate studies have yet been conducted to establish the usefulness of VCM in pediatric patients in Japan. We performed a prospective study to examine the usefulness of VCM treatment against pediatric MRSA infections. A total of twenty-one patients were enrolled in the study, each receiving a dose of 10 mg/kg three or four times daily. Both the clinical and bacteriological effects of the drug were evaluated, along with its pharmacokinetic results, and these results were compared with those obtained in adult patients. Clinical effects were evaluated in the fourteen evaluable patients, and results of “excellent” in 5 (35.7%), “good” in 7 (50.0%), and “poor” in 2 (14.3%) were obtained: Bacteriological results were “eliminated” in 10 (71.4%) and “unchanged” in 4 cases (28.6%), in good agreement with the clinical results of preceding studies. Pharmacokinetic analysis showed that almost all the pediatric parameters obtained in this study were nearly identical to those obtained in a preceding adult study where a dose of 0.5 g twice daily was used. The highest serum level attained was 49.1mcg/ml (mean±SD=27.4±10.9), which was within recommended levels. No adverse reaction attributable to VCM administration was observed, Slight abnormal changes in laboratory data were observed in three cases: eosinophilia, thrombocytopenia, decrease in serum sodium, urinary protein and hematuria. These results suggest that VCM is both effective and safe in treating pediatric patients with MRSA, when given at a dose of 10 mg/kg three or four times daily.

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We examined the relationship between antibiotic prophylaxis and contaminating organisms in peritoneal fluid at surgery. Cefuzonam (CZON) was administered at a dose of 1 g every 8 hours until the seventh postoperative day (POD). The concentration of CZON in peritoneal fluid and the organisms isolated from peritoneal fluid after surgery were studied in 5 patients with gastric cancer and 5 patients with cob-rectal cancer. The concentration of CZON in peritoneal fluid was 4.6±4.5 μg/ml in the gastric cancer group and 6.5±2.0 μg/ml in the colo-rectal cancer group just after surgery. The mean concentrations of CZON in peritoneal fluid at 8 hours after administration on each postoperative day ranged from 2.0-4.9μg/ml in the gastric cancer group and 3.6-6.2 μg/ml in the cob-rectal cancer group. Just after surgery contaminating organisms were detected in peritoneal fluid in all patients with cob-rectal cancer, but not in those with gastric cancer. Subsequently, these organisms disappeared on POD 3. In the study of penetration into peritoneal fluid after intravenous injection of 1g of CZON on POD 1 in the gastric cancer group and the cob-rectal cancer group, the peak CZON concentrations in peritoneal at 1 hour were mean 43.3 μg/ml and 45.0μg/ml, respectively. Eight-hour values in the two groups were 5.7±3.6μg/ml and 7.5±2.9μg/ml, respectively. The concentration of CZON in postoperative peritoneal fluid at 8 hours after administration correlated with the volume of peritoneal fluid drained per day (P<0.05). The concentration of CZON in postoperative peritoneal fluid decreased rapidly in accord with the decrease in peritoneal fluid. As CZON penetrated into the peritoneal fluid at a high concentration, it seems to be valuable as a prophylactic agent against abdominal infection.

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We studied the in vitro and in vivo activities of roxithromycin (RXM) against three species of Chlamydia, Chlamydia psittaci, Chlamydia trachomatis and Chlamydia pneumoniae, and compared its therapeutic efficacy against C. psittaci-induced pneumonia in mice with erythromycin, clarythromycin and minocycline. In addition, we studied the clinical efficacy of RXM in patients with chlamydial respiratory infection. The results were as follows:
1. Antibacterial activity: In vitro and in vivo activities of RXM against Chlamydiae were investigated. MICs of RXM against the strains of C. pneumoniae (TW-183, AR-39, AR-388 and our own isolate KKpn-1), C. psittaci (Budgerigar, California 10) and C. trachomatis (serobar D/UW-3/Cx) were 0.063 to 0.25 μg/ml, superior to those of erythromycin and ofloxacin, but inferior to those of minocycline and clarythromycin. In the therapeutic efficacy of RXM against experimental C. psittaci pneumonia, the survival rates of mice treated with RXM at 10 and 20 mg/kg twice daily for 7 days were 100% at 2 weeks after infection, while 0-70% of the animals treated with EM survived.
2. Clinical efficacy and safety: RXM was administered orally to 19 patients with chlamydial respiratory infection at a dosage of 300 mg daily for 3 to 21 days, and clinical efficacy was evaluated in 14 cases. The Clinical efficacy was excellent in 2, good in 11 and fair in 1; the efficacy rate was 92.9%(13/14). As to side effects, abdominal pain and melena were observed in one case. As abnormal laboratory findings, the elevation of GOT and γ-GTP and the elevation of γ-GTP and total bilirubin were observed in one case each. These abnormalities were all mild and transient.
From these results, we conclude that RXM is one of the most useful macrolide agents for chlamydial respiratory infections.

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