From October 1988 to January 1992, 9 strains of Pseudomonas aeruginosa carrying a transferable plasmid encoding imipenem-hydrolyzing β-lactamase (pI-approx. 9.5) were isolated from 9 different patients hospitalized in the neurosurgical ward of Toyama City Hospital. Six strains were isolated in 1991, and the amount of antipseudomonal agents (especially imipenem) used in the neurosurgical ward increased considerably during the same year. All strains were resistant to imipenem, carbenicillin and antipseudomonal cephems such as ceftazidime, cefsulodin, cefpirome, etc.; 4 strains of were susceptible to piperacillin and 5 to aztreonam. The imipenem-hydrolyzing β-lactamase appeared to be zinc-dependent class B β-lactamase with a molecular weigh of 28, 000, pI of 9.5 and broad substrate specificities similar to those of the metallo-β-lactamase from P. aeruginosa (Watanabe et al., 1991) and Serratia marcescens TN 9106 (Osano et al., 1994). The gene encoding imipenem-hydrolyzing β-lactamase was located on the transferable plasmid of each isolate. The manner of production of these enzymes was constitutive. Both low-level imipenem-and high-level cephem-resistance were cotransferred to P. aeruginosa with the production of metallo-β-lactamase, but piperacillin-, aztreonam-, and high-level imipenem-resistance were not. Esherichia coli harboring recombinant plasmid encoding imipenem-hydrolyzing β-lactamase exhibited a pattern of resistance similar to that of transconjugants of P. aeruginosa. Production of chromosomal cephalosporinase in piperacillin-resistant strains was derepressed, and production of outer membrain protein of D2 was diminished in highly imipenem resistant strains. The serotype of all 9 strains was type B, but only 3 strains of them had the same serotype, pyocin-type and phage type. Above results suggest that the continuous isolation of imipenem-and cephem-resistant P. aeruginosa producing metallo-β-lactamase was related to the use of the antipseudomonal β-lactam agents such as imipenem.

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To predict the clinical efficacy of combination therapy with vancomycin (VCM) and cefoselis (CFSL) against methicillin-resistant Staphylococcus aureus (MRSA) infection, the human plasma concentrations of CFSL and VCM after intravenous drip infusion were simulated for eight hours in neutropenic mice by hourly subcutaneous injections of the drugs in an in vivo pharmacokinetic model. The combination of lg of CFSL and 250 mg of VCM augmented the therapeutic effect of each drug when compared with monotherapy with the same doses, and higher efficacy was obtained when VCM was given 4 hours after CFSL. The therapeutic effect of simultaneous administration of 1g of CFSL and 125 mg of VCM was almost equal to that of monotherapy with 500mg of VCM, and that of a combination of 250 mg of VCM and 1 g of CFSL was significantly higher than the effect of 500 mg of VCM alone. CFSL-VCM was more effective than flomoxef-VCM both when given at the same time and when VCM followed either CFSL or flomoxef. These results suggest that the combination of CFSL and VCM is more effective than monotherapy with VCM against MRSA infections.

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Experimental mixed respiratory tract infection with Staphylococcus aureus TY5312 and Pseudomonas aeruginosa P9 was induced in neutropenic mice by intranasal instillation of a bacterial suspension containing 10⁴ CFU and 10 CFU of S. aureus TY5312 and P. aeruginosa P9. Both infecting organisms grew logarithmically in the lungs, and the bacterial counts reached 10⁷ CFU per lung by 20 h after inoculation. Electron microscopic examination of the lungs of the infected mice revealed that S. aureus TY5312 and P. aeruginosa P9 lived apart, in separate alveoli, and even in the same alveolar space. The bactericidal effect of cefozopran (CZOP) on S. aureus TY5312 and P. aeruginosa P9 in the lungs was then assessed. Administration of CZOP clearly reduced the bacterial counts of S. aureus TY5312 and P. aeruginosa P9 in the lungs when compared with untreated mice. Morphological examination with an electron microscope revealed swelling of S. aureus TY5312, elongation of P. aeruginosa P9, and lysis of both organisms after treatment with CZOP. The therapeutic effect of CZOP was compared with that of cefepime (CFPM), cefpirome (CPR), and ceftazidime (CAZ) on the basis of survival rate on day 3 after infection. The 50% survival dose of CZOP was 3.11 mg/kg body weight, and lower than that of CFPM, CPR, and CAZ (15-22mg/kg). These findings suggest that CZOP is useful in treating mixed respiratory tract infection caused by S. aureus and P. aeruginosa in a cornpromised host.

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Pneumocystis carinii pneumonia (PCP) is one of the most common opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS). Pentamidine is one of the drugs used to prevent and treat this type of pneumonia. When administered by injection, this drug is likely to induce adverse systemic reactions. For this reason, pentamidine inhalation has been attempted and its usefulness has been reported. To date, however, few reports have been published concerning the effects of pentamidine inhalation on the respiratory functions. The present study was undertaken to examine changes in the respiratory functions of HIV-infected patients following pentamidine inhalation therapy, by means of a spirometer before and after pentamidine inhalation and a pulseoximeter during inhalation therapy. The subjects were 12 patients with established HIV infection (mean age: 33.2±8.4 years). Hemophilia was the underlying disease in all subjects. Each patient inhaled 80μg of procaterol hydrochloride during approximately the first 5 minutes, using an ultrasonic nebulizer. The patient then inhaled 300mg of pentamidine isothianate dissolved in 10 ml of distilled water. The vital capacity (VC) was 4, 226.7±577.5 ml before inhalation and 4, 171.7±608.0 ml after inhalation. The forced expiratory volume in one second (FEV1.0) was 3, 233.3±699.1 ml and 3, 253.3±741.8 ml before and after inhalation, respectively. The V₂₅/Ht was 0.80±0.32 l/secim and 0.79±0.35 1/sechn before and after inhalation, respectively. None of these parameters differed significantly between pre-and post-inhalation periods. The oxygen saturation (SpO₂) decreased in 2 cases during inhalation therapy, but it did not change in any other case. Pulse rate tended to increase during inhalation, although this change was not statistically significant. The most frequent adverse reaction was pharyngeal discomfort caused by the bitter taste of the solution inhaled. No severe adverse reactions were seen. These results indicate that pentamidine inhalation dosen't seriously affect the respiratory functions of HIV-infected patients and that it is relatively safe. It is, however, desirable to monitor the oxygen saturation level of individual patients during this therapy.

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A comparative clinical study on pazufloxacin (PZFX), a new quinolone antibacterial agent, was conducted to determine the optimal dose of PZFX using tosufloxacin (TFLX) as the active control for treatment of chronic respiratory tract infections. Patients with chronic bronchitis or bronchiectasis received orally either a dose of 300mg of PZFX (PZFX-300 group), 600mg of PZFX (PZFX-600 group) or 450mg of TFLX (TFLX group) for 14 days as a rule. All dosages were divided into three administrations per day.
1) Of a total number of 104 patients (36 in PZFX-300 group, 34 in PZFX-600 group and 34 in TFLX group), 94 patients (33, 32 and 29, respectively) were evaluated for clinical efficacy, 100 patients (34, 33 and 33, respectively) for side effects, 89 patients (31, 29 and 29, respectively) for abnormal changes in laboratory parameters, and 95 patients (33, 32 and 30, respectively) for utility. There were no significant differences between the three groups with respect to the numbers of patients for those evaluation and in the distribution of background factors.
2) The clinical efficacy rates were 76% in PZFX-300 group, 91% in PZFX-600 group and 83% in TFLX group with no significant difference among the three groups. In the presence of underlying diseases and/or complications, the efficacy rates were determined to be 95%(20/21) in the PZFX-600 group, 79%(15/19) in the TFLX group, 74%(17/23) in the PZFX-300 group, with a significant difference between the two groups of PZFX (p=0.035).
3) As for the bacteriological effects, the elimination rates were 53%(10/19) in the PZFX-300 group, 81%(13/16) in the PZFX-600 group and 78%(14/18) in the TFLX group, with no significant difference between the three groups.
4) The incidence of side effects was 6% in the PZFX-300 group, 3% for the PZFX-600 group and 6% in the TFLX group. There was no serious adverse reaction. The incidence of abnormal changes in laboratory parameters was 6% in the PZFX-300 group, 7% in the PZFX-600 group and 7% in the TFLX group. All changes were mild in degree. The safety rates were 88%(30/34) in the PZFX-300 group, 91%(30/33) in the PZFX-600 group, 88%(28/32) in the TFLX group with no significant difference between the three groups.
5) The usefulness rates were 70%(23/33) in the PZFX-300 group, 88%(28/32) in the PZFX-600 group and 79%(23/29) in the TFLX group, with no significant difference between the three groups.
The results suggest that a daily dose of 600mg (t. i. d.) is the optimal dose of PZFX of the treatment for the patients with chronic respiratory tract infections.

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We have already reported the protective effect of piperacillin against the nephrotoxicity of vancomycin and arbekacin in rats. However, Takahashi and Kanno have recently reported that piperacillin exacerbated the nephrotoxicity associated with vancomycin and arbekacin in rats. Based on our investigation of the reason for these conflicting results, it is speculated that under their experimental conditions, crystals composed mainly of vancomycin and piperacillin were formed in the rat's blood and subsequently induced acute renal damage. Therefore, it appears that their experimental conditions are inappropriate for estimating the effect of piperacillin against the nephrotoxicity associated with vancomycin arbekacin.

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