Fluconazole is a novel triazole antifungal agent with excellent activities against a broad range of medically important fungi.
The in vitro antifungal activities of fluconazole especially against Candida albicans were examined and the results summarized as follows:
1. Fluconazole was proved to exhibit the highest antifungal activity in synthetic aminoacid medium, fungal (SAAMF), well buffered in a physiologically neutral range.
2. In a exposed time-killing test performed using SAAMF (pH7.4), the growth inhibition by fluconazole was enhanced in proportion to an increase of fluconazole concentration and 99% inhibition was observed at a concentration of 1μg/ml though further increases of concentration up to 80μg/ml failed to demonstrate complete inhibition.
3. Activities of fluconazole against medically important various yeasts were determined by a broth dilution method in SAAMF using the viable counts technique. Among 9 species tested, C. albicans and Candida kefyr were the most sensitive to fluconazole with a IC₉₉ range from 0.20μg/ml to 0.39μg/ml. On the contrary, Candida glabrata, Cryptococcus neoformans and Trichosporon cutaneum were the least sensitive with a IC₉₉ range from 3.13μg/ml to 12.5μg/ml.
4. Growth inhibition activities of fluconazole against 4 species of Aspergillus were measured on the basis of mycelial protein content. IC₅₀, and IC₉₀ of fluconazole against Aspergillus fumigatus were distributed in the range of 23.9-43.5μg/ml and 50->100μg/ml, respectively.
5. The anti-Candida activity of fluconazole was little affected by serum concentrations. Fluconazole at a concentration of 0.20μg/ml inhibited significantly the mycelial-phase growth and germ tube elongation of C. albicans in a medium supplemented with serum.
6. The germ tube formation and elongation of C. albicans cells engulfed by murine peritoneal exudative cells were significantly affected in a medium containing 1μg fluconazole perml.

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Fluconazole, a novel triazole antifungal agent, was studied for its safety and pharmacokinetics following single oral or intravenous dose to 8 healthy male volunteers. Dosages employed were 25mg, 50mg and 100mg orally and 25mg and 50mg intravenously.
With oral doses, peak plasma levels were achieved in 2 hours in all subjects, with maximum plasma levels of 0.53μg/ml at a dose of 25mg, 0.92μg/ml at 50mg and 1.88μg/ml at 100mg showing a clear dose-response.
Plasma-half lives of the drug were about 31 hours in both oral and intravenous administrations. Its urinary recoveries were about 70% as given orally as well as intravenously. There was no difference between areas under plasma concentration-time curves (AUC) obtained with the 2 administration methods. No side effects nor abnormal clinical test values were reported with any subjects studied.

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Clinical evaluation of fluconazole was performed on 12 cases of mycotic infections (7 cases of Candida esophagitis; one each case of cryptococcal meningitis with AIDS, Candida tropicalis fungemia and disseminated cryptococcosis in kidney transplant patient; 2 cases of Candida pneumonia). Satisfactory responses were obtained except 1 case of Candida pneumonia in which clinical efficacy could not be evaluated. Hiccup was noted in 1 case during the fluconazole treatment. No other adverse reaction was observed. When 150mg and 200mg of fluconazole were administered orally to a patient with hemodialysis (HD) after HD on separate occasions, concentrations of the drug in serum at 20 hours after ingestion were 5.9μg/ml and 11.6μg/ml, respectively, and in cerebrospinal fluid (CSF) were 3.5μg/ml and 9.2μg/ml, respectively.
Two clinical benefits were obtained in our studies. First, it was possible to treat the AIDS-patient as an outpatient with Candida esophagitis using orally administered fluconazole. Second, it was possible to treat the case of cryptococcal meningitis, in which relapse often occurs, to complete the therapy when the cryptococcal antigen in serum and CSF diminished to an undetectable level and to maintain the therapy preventing relapse without severe adverse effects.
Ongoing and future clinical trials will define the specific roles of fluconazole more clearly in the treatment of systemic mycosis.

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Fluconazole is a novel triazole antifungal agent. Its in vitro antifungal activity against Aspergillus spp. is rather weak, but in vivo animal protection studies in mice with Aspergillus infections showed that the activity of fluconazole was about 15 times as potent as that of ketoconazole.
We have studied the clinical efficacy and the safety of fluconazole given to 6 patients with chronic intractable respiratory disease, pulmonary aspergillosis, at an oral dose of 400mg once dialy for 23 days to 110 days (70 days on the average).
Patients were selected from those who fulfilled 2 of the following 3 criteria: 1) those with chest X-ray evidence of fungus ball, 2) those from whom Aspergillus was continuously isolated through culture of their sputum, 3) those with evidence of serum precipitinogen against Aspergillus.
Clinical efficacies were good in 2 patients out of 6 with marked contraction of fungus balls, fair in 2 with slight contraction of fungus balls or improvement of clinical symptoms, and failed in 2.
Side effects and laboratory parameter abnormalities possibly considered to be related to fluconazole were not observed in any of the patients enrolled in the study, suggesting the safety in a long-term usage of the drug.

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The clinical efficacy and the safety of fluconazole as given at an intravenous dose of 100-400mg daily were assessed in 7 patients with deep mycosis associated with hematological malignancy. Enrolled in the study were 1 patient with acute lymphatic leukemia, 1 with acute myelocytic leukemia, 2 with acute myelomonocytic leukemia, 2 with malignant lymphoma and 1 with myelodysplastic syndrome. Pathogens isolated from 4 patients were all Candida species including 2 Candida albicans, 1 Candida parapsilosis and 1 Candida krusei. Diagnoses of fungal infections of the patients were Candida pneumonia in 3 patients, candidemia in 1 and fungemia suggested in 3. Assessment of the clinical efficacy was made on 4 patients from whom pathogens were isolated. The global clinical improvement was good in 2 patients and fair in 1 with Candida pneumonia and good in 1 with candidemia.
In the mycological assessment, pathogenic fungi were eradicated in 3 patients and decreased in 1 patient.
No significant adverse reactions nor abnormality in clinical laboratory tests related with the dosing of fluconazole were observed in any of the patients.

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Efficacies of fluconazole, a new triazole antifungal agent, were evaluated in 11 cases of systemic mycoses (1 case each of candiduria, pulmonary cryptococcosis, pulmonary aspergillosis, pulmonary penicilliosis and suspected fungal pulmonary infection, and 3 cases each of candidemia and Candida endophthalmitis).
The clinical efficacies were excellent or good in 8 out of 9 cases and poor in 1.
Side effects observed were mild with 1 incident each of gastrointestinal symptom and reversible leukopenia.
This drug appears to be promising in treatment of systemic mycoses.

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Fluconazole is a novel antifungal agent, available in oral and intravenous forms, which was developed by Pfizer Central Research. It is characterized by its long serum half-life (approximately 30 hours) to allow once-a-day dosing and favorable safety profile.
Fluconazole was administered orally or intravenously to 166 patients with deep-seated mycosis and it was possible to evaluate clinical efficacies in 99 patients.
Clinical cures were obtained in 41 (87.2%) out of 47 cases of candidiasis, in 10 (66.7%) out of 15 cases of cryptococcosis, in 17 (48.6%) out of 35 cases of aspergillosis and in 1 case each (100%) of mucormycosis and mycosis due to an unspecified yeast.
Side effects were observed in 10 cases (rash 2, fever 2, abdominal discomfort 1, nausea 1, edema 1, edema/pleural effusion/oliguria 1, finger stiffness 1, hiccup 1) with incidence rate of 6.06/9. Drug administrations were discontinued in 4 cases. In general, however, fluconazole was well tolerated. Abnormal changes in laboratory test values due to the drug were observed in 32 cases and incidence rate was 19.3%. These were, however, slight and temporary changes and most of them were in parameters of liver function. It is not clear if these changes were related to the fluconazole administration, because other drugs were concomitantly administered to these cases.
These results indicate that fluconazole is an agent with very good potential for the treatment of the systemic deep-seated mycoses.

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The clinical efficacy of fluconazole at doses of 100-400mg daily given intravenously in the treatment of 6 cases of deep mycosis complicated with leukemia was evaluated. Types of leukemia as underlying disease were acute lymphatic leukemia in 4 patients (included post bone marrow transplantation in 2 patients), acute myelocytic leukemia in 1 and acute myelomonocytic leukemia (AMMoL) in 1. Causative fungi were Candida in all patients. Diagnoses established were pulmonary or bronchial candidiasis in 3 patients, candiduria in 2 and suspected candidemia accompanied with stomatitis in 1. A patient with candiduria died from AMMoL thus the evaluation of efficacy was made with 5 patients.
Overall clinical efficacies were judged to be good in 3 cases of pulmonary or bronchial candidiasis and in 1 case of suspected candidemia accompanied with stomatitis and excellent in 1 case of candiduria with an efficacy rate of 100%.
No side effect, either subjective or objective, was reported with any patient. In clinical laboratory tests, elevations of serum transaminase and Al-P were observed in 2 patients and a rise of S-Cr. in 1, but all these abnormalities were judged to be related to the drugs for leukemia treatment.

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Effects on pulmonary cryptococcosis and aspergillosis and the pharmacokinetics of the new antimycotic agent, fluconazole, were examined.
1. Cases
Pulmonary cryptococcosis: Two cases, 30 and 29 year-old men who were suspected of pulmonary tuberculosis by routine health examinations.
Pulmonary aspergillosis: A 65 year-old man with collagen disease and a 62 year-old man with bacilli free cavities of tuberculosis.
2. Method
Fluconazole was administered at a dose level of 400mg/day per os for 2 to 4 weeks. One exception was the 65 year-old aspergillosis patient who was administered with fluconazole 50mg/day for 4 weeks, 100mg/day for 6 weeks then 400mg/day for 4 weeks.
Sera of the cases 1, 2 and 4 were harvested before, and 1/2, 1, 2, 4, 8 and 24 hours after administration of fluconazole on the 1st and the 7th day, and in every morning until the 9th day before administration and stored in a freezer. Serum fluconazole concentrations were determined at Pfizer Taito Laboratory. As pharmacodynamic parameters, T 1/2, T_max and C_max were calculated.
3. Result
Effects of fluconazole on 2 of the 2 cases with cryptococcosis were excellent. On the other hand, the effects on the aspergillosis were poor.
The average T_max was 2-4 hours. The average C_maxS were 10.3μg/ml on the 1st day and 30.6μg/ml on the 7th day. Serum concentrations reached the plateau on the 5th-7th day, and the average C_min (concentration before administration) was 21-23μg/ml. Average T 1/2s were 34.4 hours on the 1st day and 37.2 hours on the last (32th) day.
4. Conclusion
Fluconazole may be regarded as the promising remedy for pulmonary cryptococcosis but not for pulmonary aspergillosis.

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Fluconazole, a novel triazole antifungal agent, was given orally or intravenously to 10 patients with pulmonary mycosis (7 patients with primary pulmonary cryptococcosis and 3 with pulmonary aspergillosis). Routes of administration were changed in some patients depending on their condition. Two patients from whom foci was removed by surgical operations were excluded from the efficacy assessment. Clinical efficacies in the remaining 8 patients were good in 2 cases and fair in 3 cases of pulmonary cryptococcosis; excellent in 1 case of pneumonia due to Aspergillus; and fair in 1 case and poor in the other case of pulmonary aspergilloma. Side reactions developed in 9 patients who received intravenous drip infusion were nausea or loss of appetite in 3 patients, fever and/or feverish sensation in 3, vascular pain in 1 and diarrhea and eruption in 1. In the patient who reported fever the drug was discontinued and in the patient who complained of pain at the site of injection, dosing was changed to the oral route but was discontinued due to elevated GOT, GPT, Al-P and γ-GTP. Seven patients who received the drug orally did not report side effects except 2 patients. None of these side effects reported was serious and from the above results, fluconazole was considered to be a useful agent for the treatment of pulmonary mycosis.

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Fluconazole is a novel triazole antifungal agent developed by Pfizer Inc. and available in both oral and intravenous forms. It is characterized by a long serum half-life of 25 to 30 hours and good absorbability into tissues.
In the present study, fluconazole was given to 12 patients with deep mycosis orally, intravenously or by local infusion. The patients included 4 cases of candidemia, 1 case each of candidemia and candiduria, candiduria, esophageal candidiasis, Candida hepatic abscess, pulmonary cryptococcosis and septicemia due to unspecified yeasts and 2 cases of pulmonary aspergillosis. Clinical efficacies of fluconazole against these infections were excellent in 2 cases, good in 8 and fair in 2. None of the patients reported any side effects.
From the results of the study, fluconazole appears to be a useful and safe drug for the treatment of deep seated mycosis.

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Fluconazole, a triazole antifungal agent newly developed by Pfizer Inc., was given orally to 4 patients with deep mycosis. Fluconazole was markedly effective against septicemia due to Candida and oral candidiasis accompanied with lingual ulcer in spite of seriousness of these underlying disease. In 2 patients with aspergilloma, eradication or contraction of fungus ball was observed and the drug was judged to be effective. In vitro MICs of fluconazole against clinically isolated Aspergillus spp. were much higher than its serum levels leaving a large discrepancy between in vitro activity and clinical efficacy.
Although the dosage was 100-300mg daily for 8 days to 6 months, neither adverse reactions nor laboratory parameter abnormalities were observed.
The above results suggest that fluconazole is a useful agent in the treatment of fungal infections.

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Fluconazole is a triazole agent and possesses a potent antifungal activity against fungi such as Candida, Cryptococcus and Aspergillus.
Fluconazole is well absorbed following oral administration and shows bioavailability almost comparable to that attained in intraveneous administration.
The serum half-life is as long as about 30 hours and distributed widely into organs and tissues. Because of these it is expected to exhibit good clinical efficacy in the deep-seated mycosis.
We evaluated the efficacy of fluconazole given orally to 3 pediatric patients with deep mycosis and also with aim of evaluating its prophylactic effect, gave fluconazole to 4 patients who had high risks of mycotic infections.
Pathogenic fungi isolated from the 3 patients with mycosis were all Candida albicans and diagnoses made were Candida pneumonia, oral candidiasis and gastrointestinal candidiasis.
Clinical efficacies were judged to be good in all of the 3 patients and C. albicans were found eradicated following the treatment.
In the 4 patients to whom fluconazole was given prophylactically, no mycosis developed.
Fluconazole was well tolerated and no incidence of side effects or clinical laboratory parameter abnormalities were seen any of the patients involved in the study.

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Fluconazole, a new antifungal agent was administered to 7 patients with complicated urinary tract fungal infections.
Patients were 6 males and 1 female with ages of 29 to 83 years, with underlying conditions of bladder tumor (3 patients), neurogenic bladder (3 patients) and hydronephrosis (1 patient).
Urinary fungi identified were Candida albicans in 5 patients and Candida tropicals in 2 patients over 10⁴ CFU/ml. These fungi were isolated at least twice in intervals of 5 to 7 days before treatment.
Fluconazole was given either orally (4 patients) or intraveneously (3 patients) in a dose of 50mg per day.
Clinical efficacies were excellent in 3 patients, moderate in 3 patients and poor in 1 patient, showing an efficacy rate of 85.7%. Mycologically, 6 Candida out of the 7 were eliminated.
No side effects nor abnormal laboratory data were observed.
In conclusion, fluconazole is effective and safe in the treatment of urinary tract fungal infections.

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Fourteen patients with purulent skin diseases were treated orally with fosfomycin (FOM) 1.5-3g in the tablet form for 1 week to determine its efficacy andsafety. The results obtained are summarized as follows.
1. The clinical efficacy rate was 71.4%. A bacteriological eradication rate of 71.4% was obtained.
2. As adverse reactions 3 patients experienced diarrhea and abdominal pain. But in all of these patients, symptoms were relieved with a reduction in dosage.
3. Taking the efficacy and the safety into account, utility rate was assessed to be 71.4%.
From these results it is considered that FOM tablets are useful equally to conventional FOM capsules.

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Latamoxef (LMOX) and tobramycin (TOB) were administered to 50 patients via intravenous drip infusion to prevent postoperative infections in the field of obstetrics and gynecology. Blood levels of TOB were determined, and effects of the combined use of TOB and LMOX on renal functions were clinically studied. The results obtained are summarized as follows:
1. Determination of blood levels of TOB after intravenous drip infusion of 90mg TOB with 1g LMOX revealed a peak at the end of drip infusion, and thereafter the levels decreased rapidly. The maximum level and the level upon commencement of the next administration were within the safe range.
2. Clinical laboratory test before and after surgery using markers of renal functions (BUN, creatinine, β2-MG and NAG) revealed a tendency for slight increases in BUN and NAG, but no significant differences were shown.
3. There were no abnormalities in other clinical laboratory parameters or any appearance of subjective or objective side effects.

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Lomefloxacin (NY-198) [(±)-1-ethyl-6, 8-difluoro-1, 4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride] strongly inhibited the growths of not only Gramnegative Escherichia coli but Gram-positive Staphylococcus aureus.
In vivo and in vitro experiments showed deoxyribonucleic acid (DNA) synthesis was specifically inhibited by this drug in E. coli.

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Pharmacokinetics of arbekacin (HBK), a new aminoglycoside, was studied. Serum concentrations and urinary excretion were determined after single intravenous drip infusion of 100mg HBK for 1 hour to healthy volunteers and patients with renal insufficiency of various kinds. The drug concentration was determined with bioassay, fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). Pharmacokinetic analysis was made in accordance with the two-compartment open model, and 24-hour endogenous creatinine clearance (Ccr) was used as the renal function index.
In all cases peak serum levels were detected 1 hour after administration, and similar values were noted regardless of subjects' proficiencies of renal function. However, the serum clearance during β-phase tended to be prolonged parallel with the degree of renal insufficiency.
The excretion of HBK into urine was prolonged and cumulative recovery tended to be decreased in association with the decreased valued of Ccr.

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Cefodizime (THR-221, CDZM), a new antibiotic, was studied pharmacokinetically and clinically. The results obtained are summarized as follows:
1. Concentrations of CDZM in internal genital tissues were quite high after an intravenous infusion.
2. Clinical effects of the therapy with CDZM using intravenous infusion twice daily were evaluated in 1 patient with endometritis, 2 patients with pyometra, 1 patient with extragenital abscess and 1 patient with BARTHOLIN'S gland abscess. Clinical responses were good in all 5 patients. No side effects nor abnormal laboratory test values due to the drug were noted.

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In order to objectively evaluate the efficacy and the safety of ceftriaxone (CTRX) using once daily administration of 1g to cases of acute suppurative otitis media and acute exacerbation of chronic suppurative otitis media, a group comparison study by the envelope method was conducted using cefotiam (CTM) as the control drug (2g twice daily). The results obtained are summarized as follows.
1. Clinical efficacies evaluated by the committee were 71% in the CTRX group and 86% in the CTM group for acute suppurative otitis media, and 63% and 60%, respectively, for chronic suppurative otitis media. When all cases were considered both groups evidenced a clinical efficacy of 64%, and no significant difference was observed between the 2 groups.
2. Clinical efficacies evaluated by the physician in charge were 65% in the CTRX group and 86% in the CTM group for acute suppurative otitis media, and 72% and 60%, respectively, for chronic suppurative otitis media. When all cases were considered efficacies were, respectively, 70% and 64%, showing no significant difference between the 2 groups.
3. Bacteriological efficacies were 88% in the CTRX group and 86% in the CTM group for acute suppurative otitis media, and 74% and 62%, respectively, for chronic suppurative otitis media. With all cases bacterial eradication rates were, respectively, 76% and 67%. Bacterial eradication rates were always higher for the CTRX group than for the CTM group, but the difference was not significant between the 2 groups.
4. Against infections caused by Staphylococcus aureus alone, CTRX showed equal clinical and bacteriological efficacies to CTM.
5. As side effects, dermatitis, vomiting, and malaise were observed in 5 cases (4%) of the CTRX group and 3 cases (3%) of the CTM group. As clinical testing abnormalities, elevations of GOT, GPT, and Al-P, and thrombocytopenia were noted only in 3 cases (5%) of the CTRX group. Furthermore, all of these abnormalities were temporary and of moderate degree or mild, thus the safety of either drug was considered high.
6. Clinical utilities were 71% in the CTRX group and 86% in the CTM group for acute suppurative otitis media, and 72% and 62%, respectively, for chronic suppurative otitis media. When all cases were included, they were 72% and 66%, respectively, and there was no significant difference between the 2 groups.
It is concluded from the above results that CTRX is a highly useful drug with once daily administration of 1g in the treatment of suppurative otitis media.

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