The intraocular pharmacokinetics of norfloxacin (NFLX) after 2 weeks of consecutive oral administration or instillation of [¹⁴C]-NFLX in beagle dogs and pigmented rabbits were studied for 6 months. The following results were obtained.
1) The concentration of radioactivity in the choroid and pigment epithelium (choroidpigment epithelium) of dogs was 433 μg eq./g at 24 hours, 276 μg eq./g at 1 month, and 89.6 μg eq./g at 6 months after the last 30 mg/kg administration of [¹⁴C]-NFLX.
2) The concentration in choroid-pigment epithelium of rabbit was about 90.3 μg eq./g at 24 hours after the last 50 mg/kg administration of [¹⁴C]-NFLX
3) Concentrations in non-pigmented tissues were lower than the serum level.
4) In the case of instillation with 50 μl of 0.3%[¹⁴C]-NFLX at 5 times/day for 2 weeks, the concentration in the iris-ciliary body and the choroid-pigment epithelium of dogs were 6.74 and 2.03 μg eq./g, respectively, at 24 hours after the last application, and these radioactivities decreased slowly thereafter.
5) Microautoradiography showed the localization of radioactivity only in the uvea, without showing diffusion into the retina.
These results indicate that NFLX has an affinity for melanin, and results in a high accumulation and retarded residue in the melanotic ocular tissues. Fluoroquinolones are known to have a strong affinity for melanin. Lomefloxacin and levofloxacin are reported to accumulate in the uvea of beagle dogs at the level of 1, 200 μg/g. In the monkey, fluoroquinolone accumulation of 138-300 μg/g is reported. Based on these findings, long-term use of fluoroquinolones should be considered in order to avoid melanin disorder.

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The Penetration of SY 5555, a new oral penem antibiotic, into female genital tissues was examined. SY 5555 was orally administered at a dose of 100 mg, 200 mg or 300 mg to 91 patients undergoing total hysterectomy. After administration of SY 5555, cubital vein blood, uterine artery blood and female genital organs were obtained. The concentration of drug was determined by bioassay method. Serum concentration in the uterine artery was the same as that in the cubital vein. The mean maximal serum concentration was 1.1μg/ml at 60-120 minutes after administration of 200 mg. The peak levels in various tissues of genital organs were obtained at 60-120 minutes, the mean levels in the portio vaginalis, oviduct, cervix uteri, myometrium, endometrium and ovary were 0.43μg/g, 0.35μg/g, 0.33μg/g, 0.26μg/g, 0.24μg/g and 0.21μg/g, respectively, after administration of 200 mg. The ratios of these tissues to serum concentration in the cubital vein ranged from 20.9% to 44.8%. Thus, SY 5555 rapidly penetrates into the female genital tissues, and we consider SY 5555 to be one of the most useful drugs for infections in the field of obstetrics and gynecology.

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The Present authors previously reported the clinical efficacy of long-term chemotherapy with erythromycin (EM) in patients with chronic lower airway infections. Efficacy occurred in about 80% while the remaining 20% of patients failed to show improved clinical symptoms or arterial blood gas findings; furthermore, these patients did not respond to, β-lactum antibiotics or new quinolones, and their Quality of life (QOL) failed to improve. In the present study, we investigated the usefulness of long-term chemotherapy with clarithromycin (CAM) in erythromycin-ineffective patients with chronic lower airway infections. This report presents the results obtained. The subjects were 10 patients with chronic lower airway infections that were not responsive to long-term chemotherapy with erythromycin. They consisted of 2 men and 8 women, 30 to 76 years of age, with diffuse panbronchitis (5 cases), bronchiectasis (4 cases) and chronic bronchitis (one case). The causative organisms were Pseudomonas aeruginosa in 8 cases and Haemophilus influenzae in 2 cases. Each patient had received EM at daily doses of 200-1, 200mg for 24-108 months. CAM was administered at daily doses of 200-400mg for 13-23 months, and therapeutic efficacy was investigated. Our clinical results can be summarized as follows: 1) Seven of 10 patients showed improvement of PaO₂ and sputum amount, and amelioration of QOL; 2) After switchover from EM to CAM, the administration times of other antibacterial agents concomitantly used were decreased, 3) CAM at lower concentrations could not adequately inhibit elastase produced by P.aeruginosa isolated from non-responders to both EM and CAM. In summary, the above findings suggest the usefulness of long-term CAM chemotherapy in erythromycin-ineffective patients with chronic lower airway infections.

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We evaluated the clinical effect, safety, and usefulness of oral administration of vancomycin hydrochloride (VCM) in methicillin-cephem resistant Staphylococcus aureus (MRSA) enteritis. VCM at daily doses of 0.5-4.0g (mean 1.8g) was orally given to 53 patients with MRSA enteritis for 2-19 days (mean 8.0 days), and the following results were obtained:
1) Of a total 53 patients, 34 were assigned for evaluation of clinical efficacy, 27 for evaluation of bacteriological effect, 53 for evaluation of side effects, 51 for evaluation of abnormal changes in laboratory findings and 37 for evaluation of usefulness.
2) There were no patients who died of MRSA enteritis, and all patients recovered from the enteritis with oral VCM. The efficacy rate was 100%(34/34 cases). As for the bacteriological effect, the elimination of organisms in the stool was seen in 92.6% of patients (25/27 cases).
3) Although no side effects were observed, 8 patients (15.7%) showed slight abnormal changes in laboratory findings, which did not cause any disturbance in the clinical course of the patients.
4) The utility rate (satisfaction rate) for treating patients with oral VCM was 91.9%(34/37).
The results showed that oral VCM given in daily doses of 2.0 g is a useful antibiotic therapy for MRSA enteritis.

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To evaluate the efficacy, safety and usefulness of S-1108, a new ester-type oral cephem antibiotic, in bacterial pneumonia, we carried out a double-blind comparative study with cefotiam hexetil (CTM-HE) in collaborating institutions. S-1108 at a daily dose of 450 mg (divided in 3 doses) and CTM-HE at a daily dose of 600 mg (divided in 3 doses) were orally administrated for 14 days, and the following results were obtained:
1) The number of patients who were given the study drugs was 132 (S-1108 group: 64, CTM-HE group: 68). The number of evaluable patients for clinical efficacy, side effects, abnormal laboratory values and usefulness were 108 (S-1108 group: 49, CTM-HE group: 59), 126 (S-1108 group: 61, CTM-HE group: 65), 114 (S-1108 group: 61, CTM-HE group: 53) and 109 (S-1108 group: 49, CTM-HE group: 60), respectively.
2) The efficacy rates for bacterial pneumonia were 90.9% in the S-1108 group and 82.1% in the CTM-HE group, showing no significant differences between the two groups.
3) There were no significant differences between the two groups with respect to the degree of improvement in subjective and objective signs, or laboratory values except for ESR on the 7 th and 14 th day of treatment (p=0.0009 and p=0.0068, respectively), and CRP on the 3 rd day and 14th day of treatment (p=0.0160 and p=0.0440, respectively) in all of which S-1108 was superior.
4) As for the bacteriological effects, the elimination rates of causative organisms were 94.7% in the S-1108 group and 73.1% in the CTM-HE group, with no significant differences.
5) Side effects were observed in 3 patients (4.9%) in the S-1108 group and 5 patients (7.7%) in the CTM-HE group, and abnormal changes in laboratory findings in 18 patients (29.5%) in the S-1108 group and 10 patients (18.9%) in the CTM-HE group, again showing no significant differences.
6) The utility rates (satisfaction rate) for bacterial pneumonia were 90.9% in the S-1108 group and 77.2% in the CTM-HE group, with no significant differences between the two groups.
The above results indicate that S-1108 in daily doses of 450 mg is as useful as CTM-HE in daily doses of 600 mg in the treatment of bacterial pneumonia.

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We conducted a comparative double-blind study of S-1108, a new ester-type oral cephem antibiotic, and cefteram pivoxil (CFTM-PI) to evaluate the efficacy, safety and usefulness of these drugs in the treatment of chronic respiratory tract infections excluding diffuse panbroncholitis. S-1108 was given orally at a daily dose of 450 mg, and CFTM-PI at a daily dose of 600 mg three times daily for 14 days. The following results were obtained.
1) Of the total 171 patients (86 in the S-1108 group, 85 in the CFTM-PI group), 157 patients (81 in the S-1108 group, 76 in the CFTM-PI group) were evaluated for efficacy. No significant difference was noted between the two drug groups with respect to the percent excluded or background factors of patients.
2) The clinical efficacy rate were 80.2%(65/81 patients) in the S-1108 group, and 78.9%(60/76 patients) in the CFTM-PI group, showing no significant differences between the two groups.
3) Bacteriologically, the elimination rates of causative organisms were 60.5%(23/38 patients) in the S-1108 group and 65.9%(27/41 patients) in the CFTM-PI group, with no significant differences.
4) Side effects were observed in 6.9%(5/83) of patients in the S-1108 group and 6.4%(5/78) of patients in the CFTM-PI group. Abnormal changes in laboratory findings were observed in 13.9%(11/79) of patients in the S-1108 group and 13.9%(10/72) of patients in the CFTM-PI group. There were no significant differences in incidence between the two groups. None of the side effects were severe.
5) The utility rates (very satisfactory and satisfactory) were 77.1%(64/83 patients) in the S-1108 group and 77.6%(59/76 patients) in the CFTM-PI group, with no significant differences between the two groups.
The above results indicate that S-1108 at a daily dose of 450 mg is as useful as CFTM-PI at a daily dose of 600 mg in the treatment of chronic respiratory tract infections.

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Twenty-three nosocomial bacteremic episodes due to MRSA (methicillin-resistant Stapylococcus aureus) were observed in 15 aged and compromised patients. Of the 23 episodes, 21 were caused by MRSA alone and 2 by MRSA together with Bacteroides fragilis. Treatment consisted of imipenem/cilastatin (IPM/CS) combined mainly with cefotiam (CTM). Portals of entry in bacteremia were considered to be pressure wounds in 15 episodes, intravenous hyperalimentation (IVH) catheter in 3 episodes, and unknown in 3 episodes, the routes of which could have been either the urinary tract, IVH catheter or pressure wounds. Although most of the isolated MRSA strains were highly resistant to both IPM and CTM, clinical efficacy was observed in 90%(19/21) of the MRSA monobacteremic episodes. Among the total of 23 bacteremia including 2 B. fragilis strains, 4 patients (17%) died despite the subsidence of fever after antibiotic treatment. Three patients died from DIC (disseminated intravascular coagulation) and the other one from exacerbation of renal insufficiency. Two of the 3 DIC cases were associated with B. fragillis bacteremia. These results indicate IPM/SC with CTM is promising for the treatment of nosocomial MRSA bacteremia in aged and compromised patients.

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The efficacy and safety of cefodizime (CDZM) and gentamicin (GM) combination therapy in severe infections associated with hematologic disorders was studied by the Tokai Infection Study Group on Hematological Disorders. Subjects chosen for this study were 151 patients with underlying hematologic disorders, who were treated between the months of September 1991 to September 1992. These subjects were diagnosed as having severe infections which required antibiotic therapy. Basically, CDZM was administrated by drip infusion at a dose of 4 g/day for a minimum of three days, while 120 mg/day of GM was simultaneously administrated in the same manner, half the dose being given in the morning and half in the evening. Of the 151 patients initially chosen for study, 12 were deemed ineligible, leaving 139 patients for clinical evaluation. Response to the therapy was excellent in 42 patients and good in 35, indicating that therapy was effective in 55.4% of cases (77/139). Antibacteriological effectiveness was also high, with a response rate of 44.4% in gram-negative and 71.4% in gram-positive bacteria. In cases where the pathogenic bacteria could not be identified, the mean response rate was 55.9%. When neutrophil counts before treatment was <100/μl, the response rate was 54%; at 100-499/μl, the response rate was 50%, and >500/μl, 54.2%. The incidence of side effects and abnormal laboratory findings was very low: 1.3% and 0.7% respectively. From the above findings, we concluded that combination therapy with CDZM and GM is a highly useful treatment for severe infection associated with hematologic diseases.

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