[in Japanese]

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The susceptibility of twenty-eight strains of imipenem-resistant Pseudomonas aeruginosa to ten antimicrobial agents was investigated.As a rule the criteria of resistance to each drug used in this study followed those of NCCLS except for fosfomycin.The resistance rate (28.6%) of ceftazidime was the lowest among β-lactams: ceftazidime, piperacillin, cefoperazone and cefsulodin.On the other hand, the resistance rate (39.3%) of tobramycin was the lowest among aminoglycosides: tobramycin, amikacin and isepamicin.The resistance rate of fosfomycin was 100%.The simultaneous, combined effect and prolonged combined effect of ceftazidime and tobramycin against colonies in cotton suture of imipenem-resistant P. aeruginosa strain No.23 were investigated.The simultaneous exposure of ceftazidime and tobramycin showed marked bactericidal activity.The bactericidal activity of concomitant exposure to ceftazidime and tobramycin after pre-exposure to ceftazidime were greater than that of concomitant exposure to tobramycin and ceftazidime after pre-exposure to tobramycin. Four imipenem-resistant P.aeruginosa used in this study did not produce a β-lactamase that hydrolyzed imipenem.

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Specific pathogen-free mice were divided into two groups according to whether intestinal colonization with methicillin-sensitive Staphylococcus aureus (MSSA) was confirmed (group A) or not (group B). Mice in each group were treated orally with ampicillin (ABPC) for a period of 3 days. On the next day, the treated mice and untreated control mice were challenged orally with approximately 10⁸ viable methicillin-resistant Staphylococcus aureus (MRSA). The normal intestinal flora was changed by the treatment with ABPC. The incidence of intestinal colonization with MRSA differed in groups A and B, in treatment with ABPC and without treatment. Intestinal colonization with MRSA was confirmed in group B treated with ABPC, but not other cases. The same distribution of MSSA and MRSA colonization was seen in intestine, and they competed with each other for areas to colonize.Therefore, two factors, the effects in changeing the normal flora and competition with MSSA in intestine, affected intestinal colonization by MRSA.

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The pharmacokinetics in the oral tissues of cefcamate pivoxil (CCMT-PI) following an oral dose of 20mg/kg were studied in rabbits with and without jaw bone infection by Streptococcus milleri and Bacteroides fragilis.
1.In normal rabbits, the peak level of CCMT-PI in the serum was 2.75μg/ml, While those in the mandible, maxilla, tongue, submandiblar gland were 2.47, 3.02, 3.39μg/g, respectively.
2.Autoradiograms of [¹⁴C] CCMT-PI showed that the tissue-to-blood concentration ratios of those tissues were almost the same in infected and normal rabbits.
3.Autoradiograms of [¹⁴C] CCMT-PI showed that the radioactivity was well distributed to inflammed sites in the infected rabbits about 0.77 as high as blood level, and it was about 1.6 as much as in the non-inflammed region in those rabbits.

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The influence of SY 5555, a new oral penem antibiotic, on the intestinal flora was studied in tetra-contaminated mice and pediatric patients. SY 5555 dry syrup was administered at a dose of 30mg/kg once a day for 5 consecutive days to mice contaminated with 4 different species of organism, including Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve. MICs of SY 5555 to the test strains were 0.39μg/ml (E. coli), 0.78μg/ml (E. faecalis), ≤0.025μg/ml (B. fragilis) and 0.39μg/ml (B. breve), respectively. No remarkable change was observed in fecal viable cell counts after the administration of SY 5555. The subjects in the pediatric study were 5 children with infections, 2 boys and 3 girls, aged from 1 month to 6 years 10 months. Their body weight ranged from 4.9 to 16.0kg. SY 5555 dry syrup was orally administered at a does of 6. 3-10.4mg/kg, 3 times a day for 10 to 15 days. Main aerobes in feces, including E. faecalis, Enterococcus avium, and Enterobacteriaceae, and main anaerobes in feces, including Bacteroides, Bifzdobacterium, and Eubacterium, were markedly decreased during the administration in almost all cases. 2 cases out of the 5 showed a remarkable decrease of total anaerobes, and loose stool were observed in these cases. The other 2 cases showed slight decrease of total anaerobes with/without slight decrease of total aerobes. During the administration, glucose non-fermenting Gramnegative rods increased in one case, and fungi increased in 2 cases to become the predominant species. These changes in fecal bacterial flora tended to return to predosing status after the cessation of the administration. Unchanged metabolite of SY 5555 was detected in fecal samples from 3 cases during administration and its concentration in the feces was approximately 0.10-5.4μg/g.β-Lactamase activity in feces were positive in 4 cases. The above results suggest that SY 5555 is a drug with greater influence on anaerobes of the intestinal bacterial flora than new oral cephem antibiotics, and a particular attention is required for the occurrence of diarrhea and superinfection in the continuous, long-term use of SY 5555.

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Aminoglycosides and β-lactams are frequently used in combination to enhance and widen the antibacterial spectrum. Typical side effects of aminoglycosides include ototoxicity and nephrotoxicity. Cefbuperazone (CBPZ) or amikacin (AMK), as representatives of β-lactams and aminoglycosides, respectively, were employed in this study. We administered either 4g of CBPZ per day, 4g of CBPZ and 200 mg of AMK (once a day), or 4g of CBPZ and 200 mg of AMK (twice a day), and investigated the effects on creatinine (CRE), leucine aminopeptidase (LAP), N-acetyl-β-D-glucosaminidase (NAG) and β₂-microglobulin (BMG) levels in urine. A tendency was found for the CRE, LAP/CRE, NAG/CRE and BMG/CRE levels to increase, especially with CBPZ-AMK combination therapy. The increase was more remarkable in twice-a-day therapy with AMK than in once-a-day therapy with AMK (p<0.05). Based on these results, caution should be used when giving CBPZ and AMK together. And once-a-day therapy with AMK is safer than twice-a-day therapy from the point of nephrotoxicity. It is suggested that β-lactam alone should be used against prophylaxis for post-operative infections, and combination therapy with β-lactams and aminoglycosides should be limited against the obstetric and gynecologic infections.

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We performed a clinical evaluation of vancomycin (VCM) used alone or in combination with other drugs for MRSA infection occurring in 10 infants treated at the NICU of our department. VCM was evaluated as having excellent or good efficacy in 7 of the 10 infants. However, 2 of them died due to superinfection after the discontinuation of VCM administration. These 2 patients suffered severe underlying disease and required a tracheal cathether and V-P shunt tube. A fair-efficacy case was cured after the initiation of comcomitant administration of cefmetazole (CMZ) and netilmicin (NTL). Two patients showed no response. One of them was cured after changing to minocycline. The other was a very low birth weight infant whose life could not be saved, despite the comcomitant use of VCM after his condition became critical during treatment with imipenem (IPM). Other than a slightly abnormal liver function test in one patient, there were no adverse reactions. MIC values of VCM against 13 strains of clinically-isolated MRSA were as low as 0.78-1.56μg/ml. Blood concentration of VCM were measured in 6 mature and 6 premature infants at the age of 4-50 days. VCM was administered at a dose of 14-16 mg/kg over a period of 1 hour 1-3 times a day through intravenous drip infusion. A half life was 3.0-7.4 hours (mean 5.4±1.6 hours) and 3.9-7.9 hours (mean 5.5±1.7 hours) respectively. From these results, VCM was thought to be a useful therapeutic drug in the treatment of MRSA infection in the NICU. However, special care should be taken against superinfection at the time of VCM administration in infants having an underlying disease and an indwelling catheter. Because the use of antibiotics alone, including VCM, could not be expected to provide sufficient therapeutic effects against severe MRSA infection occuring in infants with markedly impaired immunity, such as very low birth weight infants, immunotherapy should actively be used in combination with antibiotics in such cases. The dosage and abministration of VCM recommended by Schaad et al. are thought to be adequate based on the measurement of blood and CSF concentrations in our study, if used for common infection or meningitis caused by MRSA in mature infants. However, further studies are necessary to establish adequate dosage and administration of VCM for premature infants.

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The usefulness of fluconazole (FLCZ) administration was investigated in 25 patients with gastrointestinal disease with deep-seated mycosis treated in our clinic during the 1 1/2 year period from October 1991 to March 1993. Twenty-one of the 25 patients treated with FLCZ had malignant tumors such as carcinoma of the stomach or the large intestine, and the other 4 had benign diseases. Ten of 21 malignant tumor patients were terminally ill. The diagnosis of deep-seated mycosis was carried out by clinical observation, mycological and serological methods. When CAND-TEC was positive beyond twofold dilution of the serum and the β-D-glucan value was above 10pg/ml, the tests were considered positive for deep-seated mycosis. The definite diagnosis of deep-seated mycosis was established by detection of fungi on culture in 11 cases, and indefinite diagnosis based on serological examination alone was made in 14, cases. FLCZ was administered at 200-400mg/day for 4-152 days, with an average administration period of 27.5 days.The total administered dosage was 0.8-31.6g, with an average total dosage of 6.9g. Of the 23 cases where the efficacy of FLCZ could be evaluated, FLCZ was found to be clinically efficacious in 16 cases (70%). However, FLCZ was not effective in 7 cases, all of which were malignant tumors and 5 of which were at the terminal stage of cancer. The rate of efficacy for the drug was 82% in patients with the definite diagnosis and 58% in those with the indefinite diagnosis, suggesting that difference in their condition (the group with the indefinite diagnosis included nine of the ten patients with end-stage cancers) has a great effect on the results. No side effect of FLCZ was seen among these cases. The effect of FLCZ on fungi was investigated;it was found that 8 of the 11 cases where fungi were isolated became fungi negative, and that FLCZ was clinically efficacious in these cases. However, the remaining 3 cases did not become fungi negative. These werethe cases of terminal cancer or cases of serious postoperative complications. No clinical effect was seen in two of these cases. When the effect of FLCZ on serological test results was examined, it was found that 11 cases became negative or decreased in CAND-TEC; clinical efficacy was observed in these cases. Of the 7 cases where no change in CAND-TEC was observed, clinical efficacy was observed in 5 cases. No clinical efficacy was observed among the 4 cases where CAND-TEC values increased. Of the 18 cases where β-D-glucan values were negative or decreased, clinical efficacy was observed in 14 cases, while no clinical efficacy was observed in 2 of the 4 cases where β-D-glucan values increased.Since FLCZ was demonstrated to be efficacious in 70% of the cases of deep-seated mycosis in gastrointestinal disease and since no serious side effect was caused by the administration of the drug, it was concluded that FLCZ was useful. However, the efficacy of FLCZ in terminal cancer cases was not apparent. This is probably due to the lowered immune response in the body and to the advanced stage of the cancer. The CAND-TEC and β-D-glucan values generally reflected the therapeutic effect of FLCZ. In contrast to the bacterial culture tests that provided only a low detection rate, these values were useful not only for diagnosis but also for evaluating the efficacy of FLCZ treatment.

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From 1985 to 1991, MRSA sepsis was identified in 18 patients with hematological malignancies. The mortality rate was 55.6%(10/18), and the presence of DIC was significantly associated with high mortality (p=0.02). In addition to the use of standard empiric therapy, vancomycin was intravenously administered to 10 patients. The daily dose of 1.5g was divided into 3 times, and was administered in 60-minute infusions. Patients 60 years of age or older received a daily dose of 1.0g. The prognosis of 6 patients who received vancomycin within 4 days of the onset of sepsis was significantly better than that of 4 patients who received it 4 or more days after the onset of sepsis and that of 8 patients who did not receive it (mortality was 1/6 vs. 9/12;p=0.04). As for the side effects, liver dysfunction was observed in 5 patients and renal dysfunction was observed in 3 patients. The administration of VCM was discontinued in one of the former and was continued at a reduced dose in one of the latter. Because of the severity of the illness and the lack of effective drugs, we concluded that vancomycin is a highly useful drug for the treatment of MRSA sepsis in patients with hematological malignancies.

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