Multi-center bacteriological and clinical studies on fosfomycin (FOM) nasal solution were performed in subjects with paranasal sinusitis from January, 1988 to May, 1990. In these studies, we were exclusively responsible for bacterial isolation from clinical sources, bacterial identification and the determination of drug susceptibility.
Before local administration of FOM nasal solution, many strains of various bacterial species were isolated from sources totalling 396 cases involved in phase II clinical studies, dose-finding and open clinical studies.
From antibacterial activities of FOM against those isolates, we obtained the following conclusions.
1. Among the 447 isolates, Streptococcus spp. occupied 25.7%, Staphylococcus spp. 21.7% and anaerobic Gram-postivie cocci (GPC) 13.6%, showing high detection frequency of aerobic and anaerobic GPC. Next to these, Haemophilus influenzae, Pseudomonas aeruginosa, Klebsiella spp. and Branhamella catarrhalis also were often obtained.
2. After exclusion of possibly contaminating strains which might have entered into cultures at samplings or transfers, the MIC50 and the MIC80 of FOM against the remaining 354 isolates were determined to be 12.5 and 25μg/ml, respectively, indicating that local use of FOM would be fully effective to eradicate most of the bacteria.
3. FOM nasal solution showed sufficient eradication efficacy against most clinical isolates of possible causative organisms of paranasal sinusitis, and appeared to be useful as a topical preparation for the treatment of this disease.

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In the subjects of 835 strains of 37 clinically isolated microbial strains, which were separated and identified among materials collected from patients with various infections and which were sent from medical therapeutic institutions throughout Japan in 1990, for the purpose of examining the antimicrobial activity of cefpiramide (CPM), its minimum inhibitory concentration (MIC), together with those of other cephem antibiotics, was determined, and the following conclusions were obtained.
1. Microbial strains in which no CPM-resistant strains emerged were Streptococcus pyogenes, Streptococcus pneumoniae and Anaerobic Gram-positive cocci.
2. In comparison with reports by many researchers at the former half of the 1980s, microbial strains suggesting an increase in resistance to CPM were Staphylococcus aureus, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas putida, Acinetobacter calcoaceticus, and Haemophilus influenzae, but also in other microbial strains the resistance to CPM was observed in high ratios.
3. Among strains used in the test, methicillin-resistant S. aureus, cephamycin and oxime type cephalosporin-resistant Gram-negative bacilli of Enterobacteriaceae, and new quinolone-resistant microbes were observed in high ratios; therefore, it was considered that CPM could not exert sufficient antimicrobial activities to these strains because of many resistant strains being complicated among these “CPM-resistant strains”.
4. It was discussed that “the resistance mechanism observed throughout β-lactam drugs as a while and the study themes in the dimension including social circumstances where resistant strains emerged”, as pointed out by the authors in 1989, increased the significance of these days in the evaluation of timecourse changes in microbes resistant to specific drugs including CPM.
5. There are many unfavorable conditions in the antimicrobial activities of CPM to clinically isolated strains in recent years. However, it was jointly confirmed that CPM maintained effective antimicrobial activities to the majority of clinically isolated strains. Furthermore, when it was additionally considered that CPM was one of not many cephem drugs having persistent blood levels, a conclusion was drawn that CPM was one of clinically useful cephem drugs even at present.

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The clinical efficacy of ciprofioxacin (CPFX) was investigated in pulmonary infections in patients with chronic respiratory diseases.
Out of 58 cases collected, 54 were evaluable for utility of CPFX includin g20 with pneumonia, 34 with chronic bronchial infection.
CPFX was given orally at 200 mg 3 times per day.
In 20 cases of pneumonia, the mean age was 62.O years underlying diseases were chronic bronchitis 9, bronchiectasis 6, inactive pulmonary tuberculosis 4, and diffuse panbronchiolitis 1.The efficacy rate of CPFX in this group was 90.0%. In 34 cases of chronic bronchial infection, the mean age was 59.8 years, underlying diseases included bronchiectasis 10, chronic bronchitis 8, inactive pulmonary tuberculosis 7, diffuse panbronchiolitis 5, and pulmonary emphysema 4.The efficacy rate of CPFX in this group was 70.6%.
The overall efficacy rate in the entire cases was 77.8%, and we consider CPFX to beeffective in the treatment of patients with chronic respiratory diseases.

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The pharmacokinetics of netilmicin (NTL) was examined in normal volunteers and patientsafter abdominal surgery who received a single administration of 100 mg, intramuscularly (i. m.) or intravenously (d.i. v.) over 30 or 60 minutes. In postoperative patients, the serum half life after i. m. or d.i. v. was increased, and absorption after i. m. was delayed compared to those in normal volunteers.
No large differences between normal volunteers and postoperative patients were found in peak serum levels. The clearance of NTL from circulation was so rapid that the serum level decreased to below 1.0μg/ml at 8 hours after administration.
Renal functions were monitered after abdominal surgery in 116 patients who received NTL at a dose of 200 mg daily for 3-13 days by i.m. or d.i. v. Slight increases in serum creatinine were observed in only 2 patients after i. m., but not after d. i. v.
From these results, intravenous infusion over 30 or 60 minutes of NTL seemed safe and effective for the prevention of postoperative infections after abdominal surgery.

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Although it has been reported that the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections is extremely low in the obstetrics/gynecology setting, we recently had 5 patients with MRSA infections in the obstetrics/gynecology departments of 4 clinics in Yamagata Prefecturefrom September 1990 to February 1991.
1) Classified by disease, 4 of the patients had intrauterine infections (3 puerperal intrauterine infections and 1 intrauterine infection) and 1 had a postoperative wound infection.
2) Classified by treatment after the MRSA isolates had been determind, 2 of the patients were given imipenem/cilastatin alone (which turned out to be effective), 2 were given concomitant IPM/CS + quinolone agents (ofloxacin, tosufloxacin; effective) and 1 was given minocycline and OFLX.
The principal lessons we learned from these cases are that attention should be paid to the occurrence of MRSA infection even in the obstetrics/gynecology field and that the method of selecting and administering antibiotics to prevent and treat such infections should be reconsidered.

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The safety and pharmacokinetics of imipenem/cilastatin soduium (IPM/CS) were evaluated in comparative studies using single intramuscular injection, intravenous infusion or multiple intramuscular administration. The studies were done employing 30 healthy volunteers.
Adverse effects were observed in 5 of 18 volunteers in the single intramuscular dose study. One of them complained of mild itching and mild pain at the injection site, and the other 4 volunteers had mild pain at the injection sites. With the other methods of administration, no adverse effects were observed. No other abnormal physical findings nor abnormal laboratory test values were observed in any of the studies.
Imipenem (IPM) was absorbed rather slowly through the muscles, resulting in a low maximum plasma concentration (C_max) and a prolonged half life (T 1/2) upon intramuscular injection compared to the results obtained upon intravenous infusion. The total areas under the curves obtained with these 2 methods were similar, however. Cilastatin (CS) was absorbed rapidly after intramuscular injection, and the C_max obtained was higher than that obtained for IPM. The T 1/2 and the AUC of CS obtained with intramuscular injection were similar to those obtained with intravenous infusion. Cumulative urinary recovery rates obtained with these 2 different routes of administration were not different. Detectable urinary levels of IPM were maintained much longer upon intramuscular injection than upon intravenous infusion.
In the multiple dose study, neither IPM nor CS showed tendency to accumulate.

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Fifty-two patients with moderate or severe infections associated with internal medicine were treated with imipenem/cilastatin sodium (IPM/CS) and the efficacy and the safety of this drug were evaluated.
There were 20 patients with pneumonia, 10 with acute exacerbation of chronic respiratory tract infections, 9 with sepsis, 2 with pyothorax, 3 with intraabdominal infection, 2 with urinary tract infection, 1 with pulmonary abscess, 1 with infective endocarditis, 4 with fever of unknown origin. Forty-four patients were evaluable for the efficacy. Clinical efficacies were exellent in 12 patients, good in 26, fair in 3 and poor in 3. The overall clinical efficacy was 86.4%.The efficacy rate was 63.6% in patients previously treated and 93.9% in patients previously untreated with other antibiotics.
Bacteriologically, Staphylococcus aureus (8 strains), Streptococcus pneumoniae (5), Streptococcus pyogenes (1), other Gram-positive coccus (1), Klebsiella pneumoniae (8), Haemophilus influenzae (4), Pseudomonas aeruginosa (3), Serratia marcescens (3), Escherichia coli (3), Branhamella catarrhalis (1), Citrobacter freundii (1), Klebsiella oxytoca (1), Enterobacter sp.(1), and Peptostreptococcus sp.(1) were eradicated. P. aeruginosa (3) and Acinetobacter sp.(1) decreased. S. aureus (1), S. epidermidis (1), P. aeruginosa (5), and S. marcescens (1) persisted or appeared. The eradication rate was 83.7%. Six patients showed advers reactions including general fatigue 1, epigastralgia 1, eruption 1, eosinophilia 1 and elevation of S-GOT 2. But all of the advers reactions were mild or slight, and trasient.
These findings indicate that IPM/CS is a useful and safe drug against bacterial infections in internal medicine.

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Imipenem/cilastatin sodium (IPM/CS), which has abroad spectrum of activity against both Gram-positive and-negative bacteria including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, was used as the second choice for severe infections associated with hematological disorders.
Sixty-five patients were treated with IPM/CS. Amongthem, 53 patients were evaluable for the clinical efficacy. Twelve patients were not evaluable due to the following reasons: 5 patients were treated with combinations of other regimens such as cefzonam, cefmenoxime, ciprofloxacin or γ-globulin, 5 were patients to whom IPM/CS was administered as the first choice, and the remaining 2 patients were thought to be suffering not from febrile infections but from febrile tumor.
Excellent responses were observed in 10 (18.9%) patients and good responses in 23 (43.4%) patients, with anoverall rate of emcacy of 62.3%. The efficacy in septic patients was 75% (3/4), and that in patients whose peripheral granulocytes were continuously below 100/μl was also 75% (6/8).
Two patients who suffered from tumor fever and 5 patients who had received no chemotherapy before IPM/CS administration were included in the final evaluation of side effects.
Side effects were observed in 16 patients (16/60, 26.7%). In a 61 years, female patient, askin eruption was fbund 4 days after IPM/CS therapy was started. In 15 patients, mild gastrointestinal symptoms such as nausea and vomiting were identified within a few days after IPM/CS treatment was started. Abnormal laboratory data such as eosinophilia, liver dysfunction or renal dysfunction were also identified in 4 patients (4/60, 6.7%). Degrees of these abnormalities were very slight, however, and the continuation of treatment was not disturbed.
These results indicated that IPM/CS was an effective second line regimen of chemotherapy for the treatment of severe infections in patients with hematological disorders.

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Imipenem/cilastatin sodium (IPM/CS) was administered to a total of 67 patients with severe infections complicating hematological disorders and solid tumors. Fifty patients are included in the present analysis of efficacy and 64 in that of safety.
1. Out of 31 patients with hematological disorders, responses were excellent in 10 patients, good in 10 patients, and the efficacy rate was 64.5%. Out of 19 patients with solid tumors, responses were excellent in 8 patients, good in 8 patients and the efficacy rate was 84.2%.
2. For patients whose responses to other antibiotics had been poor, the efficacy rate was 59.3% in the group with hematological disorders and 62.5% in the group with solid tumors.
3. The relationship between the neutrophil count and efficacy was studied in the patients with hematological disorders. The efficacy rate for 8 patients whose neutrophil counts were 500/mm³ or less was 75.0%.
4. For the patients with hematological disorders, the efficacy rate for patients from whom causative organisms were isolated was 70.0% and that for patients for whom they were unknown was 61.9%.
5. Adverse reactions were observed in 3 patients and abnormal laboratory test results in 2 patients. However, they were mild and disappeared after discontinuation of this drug.
From these results, IPM/CS is considered to be a useful antibiotic for the treatment of severe infections complicating hematological disorders and solid tumors.

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