The therapeutic significance of β-lactam antibiotics at sub-MIC concentrations was studied. Phagocytosis by human PMN and adherence to human uroepithelial cells were examined on Escherichia coli, pre-treated with cefmetazole, cefpimizole, ampicillin, mecillinam, and cefoperazone at 1/4 MIC. The phagocytosis of cefmetazole-and cefpimizole-treated bacteria was increased compared with untreated bacteria, whereas the phagocytosis of ampicillin-, mecillinam-or cefoperazone-treated bacteria was decreased. The bactericidal activity of PMN, measured by chemiluminescence, was also increased when bacteria were treated with cefmetazole and decreased when treated with ampicillin, mecillinam or cefoperazone. Cefmetazole and cefpimizole treatment inhibited bacterial adherence to uroepithelial cells at an inhibition rate of 42-56%, and such inhibition was observed in bot mannose-sensitive and mannose-resistant strains. Thus, cefmetazole and cefpimizole at sub-MIC concentrations may cooperate with the host defense mechanisms against bacterial infections and inhibit the pathogenicity of bacterial adherence.

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The in vitro combined action of aminoglycosides (AGs), isepamicin (ISP) or netilmicin (NTL), with β-lactams, flomoxef (FMOX) or imipenem/cilastatin sodium (IPM/CS), was studied against Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. The following results were obtained:
1. The antibacterial activity of each antibiotic by itself against E. coli was strong.
2. Synergistic action of ISP or NTL with FMOX or IPM/CS was observed in all bacteria, especially S. marcescens. The combination of ISP with FMOX was most effective (mean minimum FIC index: 0.272).
3. With each combination bactericidal activity was observed in S. marcescens T-55 at concentrations in which the respective drugs alone showed only bacteriostatic activity.
4. Phase-contrast microscopic observation of S. marcescens T-55 demonstrated that the bacterial cells treated with FMOX showed a filament-like form, those treated with IPM/CS a spherical form and those treated with ISP or NTL almost a normal form. With each combination lysed cells were observed.

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The prevalence of multiply resistant Staphylococcus aureus (methicillin-resistant S.aureus, MRSA) in Japan was assessed in a collaboration of 18 University Hospitals and 1 Metropolitan General Hospital.
Of 902 strains of S.aureus collected during 1986 and 1988, 436 strains (48%) were MRS A. The frequency was high in pus samples (58%), followed by sputum (48%), urine (44%), throat-swab (41%), blood (37%) and otorrhea (33%).Most were isolated from in-patient specimens, but in otorrhea samples, 80% were from out-patients.
Multiple resistance in these MRSA was prominent; 67% were simultaneously resistant to more than 10 antimicrobial agents tested.
MRSA were resistant to beta-lactam antibiotics with the exception of dicloxacillin and imipenem, 75% of MRSA were still susceptible to dicloxacillin and 55% to imipenem.Among other antimicrobial agents, habekacin, minocycline, ofloxacin, rifampicin and vancomycin were active against MRSA with MIC80 of 1.56, 3.13, 1.56, <0.1, 1.56 μg/ml, respectively.

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Against 29 strains of methicillin-resistant Staphylococcus aureus (MRS A, MIC ≥12.5μg/ml) clinically isolated in three hospitals in Osaka and 6 standard strains (MSSA), the antibacterial activity of 10 antibotics, methicillin, ampicillin, cefotiam, cefuzonam, gentamicin, minocycline (MINC), doxycycline (DOXY), fosfomycin, vancomycin (VCM) and imipenem/cilastatin sodium and the bactericidal activity of 4 disinfectants, benzalkonium chloride (BAC), chlorhexidine digluconate (CHG), alkyldiaminoethylglycine (TG) and povidone iodine (PVP-I) were investigated by time-kill kinetic studies to clarify susceptibility to the drug.
MICs of 10 antibiotics against 6 MSSA strains were between 0.006-1.56μg/ml except in the case of FOM. BAC and PVP-I had strong bactericidal activity against MSSA strains, but CHG and TG did not kill MSSA strains within 10 min.
The MICs₅₀ of MINO, DOXY and VCM were 0.39, 0.78 and 0.78μg/ml, but those of the other antibiotics tested were above 25μg/ml. The MICs₈₀ of DOXY and MINO were 3 times larger than those of MICs₂₀ in a ratio of two step dilution, but The MIC₈₀ of VCM was equal to its MIC₂₀. These results indicated that DOXY, MINO and VCM showed stronger antibacterial activity than the other antibiotics tested in this study.
BAC and PVP-I killed standard strains effectively. PVP-I, mainly used in wound sites, had the strongest bactericidal activity against MRSA strains. The bactericidal activity of BAC against MRSA strains was stronger than that of CHG and TG. By addition of 10-20% ethanol or of 0.01% sodium carbonate to BAC, its bactericidal activity against the MRSA strains was notably increased as compared with 0.1% BAC alone.

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Five grams of a pepsin-treated human immunoglobulin preparation was administered by i. v. drip infusion over 60 min to 4 patients undergoing T-tube drainage of the common bile duct, and the preparation's passage into bile was studied. Its binding to clinical isolates of Pseudomonas aeruginosa and Escherichia coli was also examined in vitro. The results were as follows:(1) The biliary and serum levels of the preparation both reached the maximum 4 h after administration, with peak levels ranging from 3.6 to 23μg/ml and from 406 to 2, 586μg/ml, respectively.(2) Fluorescent microscopy showed that the preparation was able to bind to the bacteria in vitro at concentrations of down to 0.01μg/ml. The above results suggest the usefulness of the immunoglobulin preparation in biliary tract infection.

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We examined clinically the penetration of cefmetazole (CMZ) into wound exudate after radical mastectomy. CMZ was administered to 22 patients, twice d day, in three different ways:(a) bolus injection of 2 g intravenously (2g i.v., n=8), (b) bolus injection of 1g (1gi.v., n=7) and (c) drip infusion of 2 g for 60 minutes (2g d. i., n=7). Wound exudate was collected daily, and every 30 or 60 minutes on the first post-operative day. The concentration of the drug was measured by thin layer cup method.
The volume of wound exudate and the concentration of hemoglobin in wound exudate on the day of operation were 156 ml and 3.03 g/dl, and decreased significantly after the first post-operative day. On the other hand, the concentration of albumin and CMZ in wound exudate showed little change in the five days after operation.
A statistically significant correlation was observed between the volume of exudate and the concentration of CMZ in exudate, but no correlation between the concentration of hemoglobin and CMZ.
The daily concentration of CMZ in wound exudate was 13.1μg/ml (2g i.v.), 7.11μg/ml (1g i.v.) and 14.8μg/ml (2g d.i.). The maximum concentration and the area under the curve of CMZ in wound exudate were 33.5μg/ml, 130μg/ml (2g i.v.), 17.7μg/ml, 76.6μ/ml (1g i.v.) and 32.8μg/ml, 143μ/ml (2g d.i.). That is, the higher the dose, the higher the concentration of the drug in wound exudate. The results of 2g i.v. and 2g d.i. were similar to each other.
The time-concentration curve of CMZ in wound exudate was gently-sloping. So about 3 hours was needed to reach the peak. The peak time (during which the concentration of the drug is higher than half the peak level) of CMZ in wound exudate was 3.26 h (2g i.v.), 4.18 h (1g i.v.) and 4.29 h (2g d.i.). The level of CMZ in wound exudate remained higher than 12.5μg/ml (2g i.v. and 2g d.i.) or 6.25μg/ml (1g i.v.) for about 5 hours.

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Twenty-four children ranging from 1 month to 13 years old were treated with flomoxef (FMOX). Daily doses of FMOX ranged from 17.4-25.6 mg/kg every 6-8 hours for 2 to 13 days. Clinical efficacy in 17 cases of pneumonia, 2 of lymphadenitis, 2 of staphylococcal scalded skin syndrome, 1 each of sepsis, suspected sepsis, parapharyngeal abscess and phlegmon of the hand was evaluated as excellent in 15, good in 8 and poor in one (4.2%). Of the 24 patients, 11 (45.8%) had diarrhea.
The influence of FMOX on fecal flora was studied in 6 children, ranging from 10 months to 3 years old. The counts of bacteroides and Enterobacteriaceae decreased significantly, but those of enterococci increased during FMOX treatment. The isolated rates of bifidobacteria, bacteroides, clostridia, lactobacilli, Enterobacteriaceae and staphylococci also decreased significantly. Enterococci and/or yeasts were isolated exclusively during treatment in 3 patients.

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In 559 female patients with acute uncomplicated cystitis treated by oral cephems or new quinolones for 7 days we studied 1) clinical efficacy on the third and seventh days, 2) the early recurrence rate according to the criteria of the UTI Committee of Japan.
The results were as follows:
1) The overall clinical efficacy on the third day of treatment was 98.7%(552/559 patients), and on the seventh day 98.9%(553/559 patients). The excellent rate on the third day was 73%(408/559 patients). This rate was increased to 83.9% on the seventh day by additional 4 day-administration of the drug. The increase reflected an improvement in pyuria and symptoms.
2) After interruption of drug treatment for 7 days, patients showing excellent efficacy were evaluated for recurrence. This yielded an early recurrence rate of 1.1%(3/278 patients).

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The virulence of Pseudomonas aeruginosa in normal and leukopenic mice was compared with that of Escherichia coli by whole body autobacteriography (ABG), susceptibility tests, and viable bacterial counts in peritoneal lavage fluid and blood. The therapeutic effect of antibacterial drugs including ceftazidime against experimental P.aeruginosa infections in leukopenic mice was also evaluated. For the ABG, infective organisms were selected rifampicin-resistant strains. Mouse infections were induced by intraperitoneal inoculation with bacteria suspended in 6% mucin.
In the autobacteriograms of leukopenic mice which were infected with P.aeruginosa and died within 24 h, bacterial cells were distributed throughout the body. Up to 4 h post-infection, the increase of bacterial counts in the peritoneal cavity of the leukopenic mice was suppressed as in normal mice. After 4 h post-infection, the bacterial counts of leukopenic mice increased more rapidly than those of normals in all tested strains. In contrast, some strains of E.coli showed equal virulence in both normal and leukopenic mice. These findings suggest that the virulence of P.aeruginosa in the immuno-suppressed host is severer than that of E.coli.
The ED₅₀ values of antibacterial drugs including ceftazidime against P.aeruginosa infections in leukopenicmic were higher than in normals, and chemotherapy was also less effective. The therapeutic effect of these drugs in whole body ABG reflected their ED₅₀ well.

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We performed clinical and bacteriological studies on eleven cases of candidemia, developed in our wards, from May 1987 to September 1988, and obtained the following results.
1) All eleven patients underwent intravenous hyperalimentation, and all had underlying diseases, including six with cerebrovascular disorder and four chronic respiratory failure.
2) The duration of intravenous hyperalimentation was one to twenty-one months. Nine patients had received an indwelling urethral catheter, six patients had been treated with antibiotics and one given a steroid preparation.
3) Candida parapsilosis was the most frequently isolated organism from blood and was also isolated from the skin around the injection site of the intravenous hyperalimentation catheter of one patient and the table for preparing i. v. fluids in the nurses' station. So the possibility of hospitalacquired infection was also considered.
4) These cases were treated with miconazole intravenously, the efficacy rate being 72.7% and eradication rate of Candida species 100%. Replacement of the IVH catheter increased the efficacy rate and decreased the incidence of candidemia relapse. Miconazole is a safe and useful drug and empiric use for suspected fungal infections is recommended.

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