The effects and optimal dosing regimens of the aminoglycoside isepamicin (ISP) in combination with the β-lactam imipenem/cilastatin (IPM/CS) against Pseudomonas aeruginosa were studied. The following results were obtained.
1. Strong antibacterial activity of each antibiotic alone was obtained against P. aeruginosa ATCC 27853 and 10 clinical isolates.
2. A synergistic or additive effect of ISP with IPM/CS was demonstrated with 6 strains (54%) and no antagonism was observed with any strain. The mean minimum fractional inhibitory concentration (FIC) index was 0.897.
3. Bactericidal activity of the combination of ISP and IPM/CS against P. aeruginosa ATCC 27853 was observed on in vitro killing curves at concentrations in which each drug alone showed only bacteriostatic activity. However, the three dosing regimens yielded similar regrowth inhibitory effects regardless of which drug was administered first.
4. Regrowth inhibitory effects were observed in an in vitro simulating model of plasma concentration with treatment with ISP followed by IPM/CS, treatment with ISP and IPM/CS at the same time, and treatment with IPM/CS followed by ISP, in descending order.
5. A postantibiotic effect (PAE) of each antibiotic alone against P. aeruginosa ATCC 27853 was observed, and the effect was extended by combining the two drugs. An extended PAE was obtained by treatment with ISP followed by IPM/CS, treatment with ISP and IPM/CS at the same time, and treatment with IPM/CS followed by ISP, in descending order.
These results suggest that the optimal regimen is treatment with ISP followed by IPM/CS. Controlled clinical trials are needed to determine the clinical efficacy of this regimen.

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The E Test, a recently developed technique, is a plastic test strip gradient-coated with an antimicrobial drug which allows MIC determination on agar media. The E Test is perfomed in a manner similar to the agar disk diffusion procedure. The MICs of eight different antimicrobial drugs for some standard strains were determined by the E Test and compared with those obtained by the agar dilution method, a standard reference method. In general, the E Test MICs of the drugs for the test strains were within a 2-fold dilution of the agar dilution MICs. In a few cases, the E Test MICs tended to be higher than those determined by the reference method. High accuracy and excellent reproducibility in the MICs determined by the E Test were confirmed by the results from ffive experiments repeated on different days and also by the results obtained by skilled or unskilled persons for MIC determinations. Therefore, the E Test represents a useful method for rapid MIC determination. From the results, the E Test was applies to MIC determination of nine kinds of antimicrobial drugs for methicillin-resistant (MRSA) and -susceptible (MSSA) strains of Staphylococcus aureus. The E Test MICs were compared with those determined by the agar dilution method. The MIC values of those drugs for MRSA and MSSA obtained by both the methods agreed each other.

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The E Test was applied to the MIC determination of different antimicrobial drugs for Streptococcus pneumoniae and Haemophilus influenzae strains isolated from pediatric infections. The E Test MICs were compared with those determined by the agar dilution method. The MIC values obtained by both methods were in agreement, regardless of the penicillin-susceptibility of the test strains or their β-lactamase producibility. However, the E Test MICs of imipenem, azithromycin and vancomycin for penicillin-insensitive strains of S. pneumoniae were one dilution higher than those determined by the agar dilution method. The E Test MICs were not affected by the addition of blood components. The E Test appears to be a reliable method for the determination of fastidious bacteria such as S. pneumoniae and H. influenzae.

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The in vitro resistance of Candida albicans, Candida krusei, Candida parapsilosis, Candida glabrata, Cryptococcus neoformans, Aspergillus fumigatus and Trichophyton mentagrophytes to amphotericin B (AMPH-B), flucytosine (5-FC), miconazole (MCZ), fluconazole (FLCZ) and itraconazole (ITCZ) was studied. None of the tested fungi became resistant to AMPH-B. However, all tested fungi developed resistance to 5-FC after one or three serial transfers onto yeast morphology agar. After serial subculturing of yeast-like fungi on brain heart infusion agar containing gradiently increasing concentrations of three azole drugs, some resistant colonies appeared, and interestingly, the development of resistant strains was limited to some yeast-like fungi such as C. krusei, C. glabrata and C. parapsilosis. No resistant strains against the azoles were observed with C. albicans, C. neoformans and A. fumigatus.

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An in vitro study was conducted on the effects of clindamycin (CLDM), erythromycin (EM), tobramycin (TOB), piperacillin (PIPC), ceftazidime (CAZ) and ofloxacin (OFLX) on biofilm formation, which is considered to be a contributing factor to the intractability of chronic respiratory infections caused by Pseudomonas aeryginosa. Alginic acid and extracellular polysaccharides produced by P.aeruginosa were determined as indices reflecting the level of biofilm formation. Alginic acid production by P. aeruginosa mucoid strains was investigated by determining alginic acid produced in standard agar culture medium using high performance liquid chromatography. Extracellular polysaccharide (glycocalyx) produced by non-mucoid strains was quantified by determining polysaccharides contained in biofilms formed on silicon strips using the tryptophan method. The effects of the antibiotics on these indices at concentrations below the minimum inhibitory concentration (sub-MIC) were investigated. The production of alginic acid was significantly inhibited at CLDM ≥ 1/16 MIC, EM ≥ 1/128 MIC and TOB ≥1/4 MIC (p<0.02), and that of glycocalyx at CLDM ≥ 1/16 MIC and EM ≥ 1/16 MIC (p<0.05). The indices were not affected by other drugs at sub-MIC concentrations. Observations under a scanning electron microscope showed inhibition of biofilm formation by CLDM at sub-MIC concentrations. These results suggested that CLDM as well as EM inhibit P. aeruginosa biofilm formation at sub-MIC concentrations.

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We compared the pharmacokinetics of 8 newly developed antimicrobial quinolones with those of ciprofloxacin (CPFX), ofloxacin (OFLX) and sparfloxacin (SPFX) in healthy human. Based on the average time course of serum concentrations after a single oral dose of each drug (normalized to 200 mg), grepafloxacin (GPFX) and NM 441 were similar to SPFX with low C_max and long t_1/2; temafloxacin (TMFX), balofloxacin (BLFX), AM-1155 and DU-6859 a were similar to OFLX with high C.ax and large AUC; Y-26611 was similar to CPFX with low C_max, and short t_1/2 and small AUC; pazufloxacin (PZFX) was a new type with high Cm. and short tin. However, in the cumulative urinary recovery of the unchanged drug, TMFX, BLFX, PZFX, AM-1155 and DU-6859 a as well as OFLX; had high values Y-26611 and NM 441 had lower values than CPFX; and GPFX and SPFX had the lowest values. We also tried design an optimum dosing regimen on the basis of the serum AUC/MIC, a possibly important factor in the therapeutic efficacy of this type of drug. GPFX and NM 441 as well as SPFX might require less frequent but NM 441 might require a higher dose than SPFX. TMFX, BLFX and AM-1155 might have stronger effects than OFLX especially against Streptococcus pneumoniae. It is suggested that DU-6859 a does not need as high a dose but Y-26611 requires a higher dose than OFLX and CPFX. The therapeutic effect of PZFX might be similar to that of CPFX, but an advantage of its high C_max in the therapeutic effect remains to be shown. The pharmacokinetic relationships of 16 antimicrobial quinolones including 9 previously reported derivatives in healthy humans and in five laboratory animal species were investigated according to Boxembaum's approach. All the parameters of apparent plasma clearance, renal clearance and apparent steady state volume of distribution in humans had the best correlation with those in rabbits among mice, rats, rabbits, dogs and monkeys. However, the t_1/2 in humans was significantly correlated with that only in dogs, though the correlation coefficiency was low (r=0.617). These results support the idea that the overall pharmacokinetic behavior of an antimicrobial quinolone in humans can be estimated with sufficient accuracy from that obtained in preclinical studies.

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TMA-230, a new oral penem antibiotic, was administered for infections in various departments at a dose of 300 mg t. i. d. mainly, and the clinical efficacy and safety were assessed. In respiratory tract infections 600 mg t. i. d. from 200 mg b. i. d. was administered. Although the efficacy rate was 100% for acute bronchitis and nearly 90% for bacterial pneumonia, it was 56.7% for chronic respiratory tract infection. The bacteriological effect was above 80% in Staphylococcus aureus and Streptococcus pneumoniae, but it was 9.1%(1/11) in Haemophilus influenzae. In urinary tract infection, infections in the fields of dermatology, obstetrics and gynecology, ophthalmology and otorhinolaryngology, the clinical and bacteriological effects could be obtained at a dose of 300 mg t. i. d. The revelation rate of side effects was 13.2%(28/212), and these were mainly digestive symptoms of diarrhea, loose stool, nausea and vomiting, and headache. Abnormal changes in laboratory findings were observed in 8.0%(17/212), and were mainly liver dysfunction of elevations of GOT, GPT and AL-P. These abnormalities were all transient.

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