Thirty-six clinical isolates of Staphylococcus aureus (twenty-nine fluoroquinolone-resistant strains and seven susceptible strains) were studied for the presence of point mutations of the gyrA gene by non-radioisotopic single-strand conformation polymorphism (Non-RI SSCP) analysis using silver stain. Direct DNA sequencing analysis of polymerase chain reaction (PCR)-amplified DNA fragments confirmed the results obtained by Non-RI SSCP analysis and revealed that fluoroquinolone resistance is closely associated with six types of mutations in the gyrA gene, three of which were newly identified (one point mutation and two double point mutations): Ser-84→Leu and Glu-88→Gly; Ser-84→Leu and Glu-88→Lys; and Glu-88→Gly. Furthermore, a novel ATT→ATC mutation at codon 86 (silent mutation) was seen in only one fluoroquinolonesusceptible strain. All of these seven mutational types were separated from the wild type in a single electrophoretic run within 3 h after PCR amplification. Thus we conclude that this new technique is a rapid, simple and useful screening method for the genotyping of gyrA mutations associated with fluoroquinolone resistance.

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The in vitro antifungal activity of hydroxy-itraconazole (ITZ-OH), an active metabolite of itraconazole (ITZ) was determined by a liquid microdilution assay method using four different media: Sabouraud dextrose broth (SAB), synthetic amino acid medium-fungal (SAAMF), yeast nitrogen base with 1% glucose (YNBG) and brain heart infusion broth (BHI). ITZ-OH showed almost the same antifungal activity as ITZ against all tested filamentous and yeast-like fungi. When the activities of ITZ-OH and ITZ were compared with those of 8 reference antifungals, i. e., amphotericin B, bifonazole, clotrimazole, fluconazole, flucytosine, griseofulvin, ketoconazole and miconazole, both drugs were found to have much higher activities against Aspergillus fumigatus and Candida albicans. However, the MIC values of ITZ-OH and ITZ against dermatophytes, including Trichophyton mentagrophytes and Trichophyton rubrum were similar to those of reference antifungals. The MIC values of ITZ-OH and ITZ fluctuated depending on the medium used. The lowest MIC value was observed with A. fumigatus in BHI medium. However, the MIC end point of ITZ-OH and ITZ against C. albicans was difficult to determine in the medium. SAAMF medium was considered a good choice for MIC determination in C. albicans.

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The efficacy of tosufloxacin (TFLX) for the treatment of experimental osteomyelitis was compared with that of lomefloxacin (LFLX), which is indicated for the treatment of osteomyelitis. Mice were inoculated intravenously into the tail vein with 10⁷ to 10⁸ CFU per mouse of Staphylococcus aureus strain F-1478 isolated from a clinical specimen. The number of organisms was 10⁵ CFU per femur at 1 day after inoculation. The organisms were detected in the femurs of all mice at 28 days after inoculation. Roentgenological examination showed bone destruction and periosteal reaction, and extravasation of polymorphonuclear leukocytes and new bone formation were observed by histological examination. These findings were similar to those in human osteomyelitis. Treatment of TFLX at a single oral dose of 25 mg/kg at 1 hour after inoculation significantly reduced the number of organisms in femur compared with non-treatment, at 7 days after inoculation. The same effect was observed with two oral doses of TFLX of 25 mg/kg given at 1 hour before inoculation and 3 hours after inoculation. However, the effect was not as prolonged as that following a single oral dose of TFLX at 1 hour before inoculation or a single oral dose at 3 hours after inoculation. A single oral dose of 10 mg/kg of TFLX was ineffective. In this connection, LFLX failed to reduce the number of organisms. The level of TFLX (25 mg/kg, p. o.) in femur was more than four times the MIC (MIC 0.2μg/ml) at 4 hours after administration, but the level of LFLX (25 mg/kg, p.o.) was less than two times the MIC (MIC 3.13μg/ml) at all times. These levels in femur may influence efficacy in experimental osteomyelitis.

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In vitro and in vivo effects of leukocytes on suppression of the growth of Klebsiella pneumoniae treated with gentamicin, cefodizime and ceftazidime were investigated. When bacteria pretreated with 4 MICs of each antibiotic were incubated with leukocytes, growth of the bacteria was suppressed more than in the absence of pretreatment. Bacterial growth in a mouse sepsis model was more suppressed in normal and G-CSF treated mice than in X-ray irradiated mice administered of each of the antibiotics. These results confirm that not only gentamicin but cefodizime and ceftazidime have suppressive effects on bacterial growth as a result of cooperative activity with host defense mechanisms.

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We conducted a multicenter clinical trial to find an appropriate dose of S-1108, a new oral cephalosporin, in the treatment of skin and skin structure infections. A double-blind and doubleplacebo design was employed to compare S-1108 at a dose of 75 mg t.i.d.(S 225), S-1108 at a dose of 150 mg t.i.d.(S 450), and cefaclor at a dose of 250 mg t.i.d.(cefaclor (CCL)). The efficacy rates were 92.3% in the S 225 group (13 patients), 92.9% in the S 450 group (14 patients), and 93.8% in the CCL group (16 patients). The safety rates were 92.9% in the S 225 group (14 patients), 87.5% in the S 450 group (16 patients), and 94.1% in the CCL group (17 patients). The cure rates on day 3, 5, and 7 were 7.7%, 15.4%, and 53.8% in the S 225 group, 16.7%, 28.6%, and 57.1% in the S 450 group, and 0%, 0%, and 18.8% in the CCL group. The bacteriologic response rates for Staphylococcus aureus were 2/2 in the S 225 group, 6/7 in S 450 group, and 4/7 in the CCL group. The rates for all isolates were 90% in the S 225 group (10 patients), 84.6% in the S 450 group (13 patients), and 66.7% in CCL group (12 patients). The differences were not statistically significant. These data suggest that S-1108 at dosages of 75 mg t.i. d. and 150 mg t.i.d. is as effective, safe, and useful as cefaclor at a dosage of 250 mg t. i. d. In consideration of the cure rates during the course of the treatment and a possible variation in severity of disease in clinical practice, we may conclude that S-1108 at the dosage of 150 mg t.i.d. is an appropriate clinical dosage of this drug.

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We performed a multicenter, double-placebo, double-blind trial to compare the efficacy and safety of S-1108 with those of cefaclor (CCL). Patients with hair structure infections (furuncle, furunculosis and carbuncle) and diffuse deep-seated skin infections (erysipelas, lymphangitis and cellulitis) were randomly assigned to receive two 75mg tablets of S-1108 and one CCL placebo capsule, or two placebo tablets of S-1108 and one 250 mg CCL capsule, three times a day after meals for 7 days. The overall efficacy rates were 90.5% for the S-1108 group (95 patients) and 89.8% for CCL the group (88 patients). The overall safety rates were 91.7% for the S-1108 group (96 patients) and 90.3% for the CCL group (93 patients). The bacteriologic response rates were 88.5% for the S-1108 group (52 patients) and 86.8% for the CCL group (53 patients). All of twenty-five Staphylococcus aureus strains were eradicated in the S-1108 group. Five of twenty-seven S. aureus strains persisted in the CCL group. Two patients in the S-1108 group complained of diarrhea or loose stools. One patient in the CCL group had epigastric pain. All these symptoms were minor. Abnormal laboratory findings were seen in 7.8% in the S-1108 group and in 5.3% in the CCL group. All were minor. The differences were not statistically significant. We could conclude that S-1108 at the dosage of 150 mg t.i.d. is as effective, safe and useful as CCL at the dosage of 250 mg t.i.d. in the treatment of skin and skin structure infections.

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The efficacy of granulocyte colony-stimulating factor (G-CSF) used with various regimens of chemotherapy for non-Hodgkin's lymphoma (NHL) was evaluated in 108 patients with NHL, consisting of 67 untreated cases and 41 recurrent cases, and the incidence of infections and side effects of G-CSF were also analyzed. G-CSF diminished the grade of nadirs of granulocyte counts and shortened granulopenic duration (WBC≤1, 000/μl) and also the duration of high fever (≥37.5°C). On evaluation by therapeutic regimens, patients with recurrent NHL, paticularly those having undergone ACVP-16 (Ara-C, CBDCA, VP-16) therapy, were found to have significantly lower nadirs of granulocyte counts and more prolonged granulopenic duration than those with untreated NHL. The incidence of high fever was significantly lower in patients treated with G-CSF (40%) than in those without G-CSF administration (80%). Side effects include bone pain (11%), high fever (20%), liver dysfunction (4%) and interstitial peneumonia (4%). But they were transient and were abated by discontinuation of G-CSF administration. In chemotherapy combined with G-CSF, G-CSF shortened the granulopenic duration and decreased the incidence of infections, suggesting the effectiveness of concomitant use of G-CSF. Furthermore, we think G-CSF can be safely used because of the low incidence of its side effects.

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The safety and efficacy of cefuzonam (CZON) were compared with those of cefotiam (CTM) for prophylaxis in patients undergoing elective biliary tract surgery from July 1990 to August 1992. One hundred twenty-seven patients were randomized to receive either CTM or CZON. An initial dose of 2g i.v. was given in the operating room at the beginning of surgery, followed by 1 g i.v. every 8 hours for 4 days. Sixty-four patients were given CTM and 63 were given CZON. The groups were comparable in age, sex, type of intervention and diagnosis. Ten patients (15.6%) in the CTM group and 8 (12.7%) in the CZON group developed postoperative infections. The rate of postoperative infection was not significantly different in the groups. The rates of side effects and abnormal laboratory findings were also not significantly different between the groups. We suggest that CTM and CZON are equally safe and effective prophylactic antibiotics for patients undergoing elective biliary tract surgery.

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