Susceptibilities of 289 strains of 34 bacterial species to cefodizime (CDZM) were determined using the 2-fold agar dilution method in parallel with the measurement of inhibition zone diameters in the single-disc method under the experimental conditions established by KANAZAWA.
The experiments demonstrated a significant correlation between MIC by the dilution method and diameter of inhibition zone in each of the conventional, overnight assay (about 16 hours incubation), thus the applicability of the single-disc assay for CDZM was established.
Analysis of the data obtained using discs containing 30μg of CDZM/disc revealed that the primary regression equation was in the form: D (Diameter, mm)= 2.3-13.5log MIC (μg/ml) in the conventional assay for staphylococci, Enterococcus group and glucose-non-fermentative Gramnegative rods.
For other bacteria, the primary regression equation was in the form: D (diameter, mm)=24.1-8.4 log MIC (μg/ml) in the conventional assay.
The range of variations in MICs estimated from diameters of inhibition zones in the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution test to estimate experimental errors which may be involved in the determination of MICS of CDZM using the single-disc assay.

View full abstract

An in vitro investigation was done on antimicrobial activities of cefodizime (CDZM) in combination with gentamicin (GM) against clinically isolated Gram-negative rods. The results are summarized as follows.
1. Combined antimicrobial activities were dependent on antimicrobial activities of GM, similar to the CDZM+sisomicin (SISO) combination. The combined activities were concentration dependent, and they were more strongly dependent on GM concentrations than on CDZM concentrations. The obtained results suggested that synergistic or cooperative antimicrobial activities of the combination would be expected when GM concentrations in blood are at or somewhat lower than 1 MIC, and clinical activities would be exerted regardless of the presence of CDZM resistant organisms, similarly to CDZM+SISO combination.
2. It seems possible that, with regard to combinations of β-lactam antibiotics and aminoglycoside antibiotics, there exist universal rules that combined activities are dependent on activities of aminoglycoside antibiotics, and that stronger concentration dependencies on aminoglycosides would be observed than those on β-lactams.

View full abstract

Antimicrobial activities of cefodizime (CDZM) in combination with dibekacin (DKB) were studied in vitro against clinically isolated Gram-negative rods. The results obtained are summarized as follows.
1. Similarly to combinations of CDZM+sisomicin (SISO) and CDZM+gentamicin (GM), combined activities of CDZM and DKB were dependent on antimicrobial activities of DKB, and the combined activities were more strongly dependent on DKB concentrations than on CDZM concentrations. The obtained results suggested that synergistic or cooperative antimicrobial activities of the combination would be expected when DKB concentrations in blood are at or somewhat lower than 1 MIC, and that clinical activities would be exerted regardless of the presence of CDZM resistant organisms, similarly to CDZM+GM combination.
2. As we have suggested previously, it seems possible that, with regard to combinations of β-lactam antibiotics and aminoglycoside antibiotics, there exist universal rules that combined activities are dependent on activities of aminoglycoside antibiotics, and that stronger concentration dependencies on aminoglycosides would be observed than those on β-lactams.

View full abstract

Antimicrobial activities of amikacin (AMK) against 269 strains of various clinical isolates obtained in 1989 were determined and the reliability of the AMK disc susceptibility test in estimating approximate values of MICs was studied. In addition, clinical significance of various systems for the interpretation of the disc tests was evaluated to determine more useful method in theevaluation of clinical efficacy of AMK. Included in the study were a 3 category system of NCCLS, a 4 category system used in Japan, and the system proposed by the British Society for Antimicrobial chemotherapy.
In this study, MICs were determined using the MUELLER-HINTON agar containing 50mg/L of Ca and 25mg/L of Mg at an inoculum level of 103-4 CFU/ml. MIC 80 values of AMK against Staphylococcus aureus and Staphylococcus epidermidis were 6.25 and 25μg/ml, respectively. Those against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Enterobactor aerogenes, and Citrobacter spp. were<3.13μg/ml. MIC values against Pseudomonas aeruginosa and Serratia marcescens were both≤12.5, μg/ml.
The disc susceptibility test was carried out according to the instruction in the Showa disc manual. Inhibition zones obtained with the disc method were compared with MIC values. The results of AMK disc susceptibility test obtained either with 30 μg discs or 10μg discs were well correlated with MICs, indicating that the disc method was reliable in estimating approximate values of MICs (r=-0.807 to-0.897, P<0.01 in both instances).
In the 4 category classification system currently used in Japan, the break points in MIC values of AMK proposed are (Off) MIC≤3μg/ml,(++) MIC>3-15μg/ml, and (+) MIC>15-60μg/ml. The results obtained with Showa 30μg discs and 30μg discs prepared in this laboratory showed false positive results in 13% and 10.8% of the samples, and false negative results in 1.5% and 3.3%, respectively.
In the 3 category classification system of NCCLS, the MIC break points proposed are defined sensitive (S) for MIC 16μ/ml and resistant (R) for MIC 32μg/ml. In this study, the 30μg disc tests using the above-mentioned 2 different types of discs resulted in false positive responses in 6.3% and 5.2% of the samples tested and false negative results in 1.1% and 1.9% of the samples, respectively. With 10μg discs, false positive and false negative results observed were obtained with 1.9% and 5.6%, respectively.
In the 2 break point classification system of British Society for Antimicrobial Chemotherapy, the MIC break points proposed are MIC 4μg/ml and 16μg/ml. The results obtained with Showa 30μg discs and 30μg discs prepared in this laboratory showed false positive results in 13.4% and 10.8% of the samples tested and false negative results in 0.4% and 2.2% of the samples, respectively. With 10μg4 discs, however, false positive and false negative results were obtained with 2.2% and 5.6% of the samples, respectively.
A pharmacokinetic examination with the recommended dose schedule for AMK (100 mg or 200 mg i. m. or i. v.) in Japan showed that plasma levels of AMK reached 6-19 μg/ml. Based on the pharmacokinetic data and recommended dose schedule for AMK, MIC break points presently used in the 4 category system and proposed by British Society for Antimicrobial Chemotherapy are reasonable and appear to be better than those in the 3 category system by NCCLS. This suggestion is further supported by the clinical findings of MOORE et al.(J. Inf. Dis. 155: 93-99, 1987). An increase in the number of positive responses to AMK therapy was demonstrated in increasing rations of peak concentration in plasma/in vitro MIC, and the maximum responses are obtained when the ratio reaches about 8.

View full abstract

Norfloxacin (NFLX), a new quinolone antibiotic agent, was evaluated for its efficacy in experimental osteomyelitis in rabbits.
Osteomyelitis was induced in male rabbits by the inoculation of 107 CFU/ml (0.1ml) of Staphylococcus aureus (MIC for NFLX: 0.78 μg/ml) with 0.4 ml of 3% sodium tetradecyl sulphate into the medullary cavity of the proximal tibia.
The rabbits were divided into 3 different groups of 4 animals each. The animals in 2 groups were orally administered with NFLX; 100 mg/kg once-daily (group 2) and 50 mg/kg twice-daily (group 3) for 7 days from the 6th hour after inoculation. Group 1 was established as a control without administration of NFLX. All animals were sacrificed on the 7th day after inoculation.
Acute osteomyelitic changes were found microscopically in all animals in group 1. In each of the 2 therapeutic groups, incidence of microscopic changes was 50% associated with remission of S-sialic acid value.
Thus, NFLX may be considered a useful antimicrobial agent for the treatment of suppurative osteomyelitis.

View full abstract

Pharmacokinetics and clinical efficacy of ciprofloxacin (CPFX) were investigated in aged patients with chronic respiratory diseases.
Serum and sputum concentrations of CPFX were determined upon oral administration of 200mg CPFX in 6 aged patients with chronic respiratory diseases (mean age=78.8 ±3.2 years, 2 cases diagnosed chronic obstructive pulmonary disease with penumonia, 3 cases were diagnosed bronchiectasis with acute exacerbation, and 1 case diagnosed chronic lung abscess). Maximal serum concentrations in these patients were 0.88-1.29 μg/ml (mean =1.084μg/ml). Thus, maximal serum concentrations of CPFX after oral administration in these aged patients were slightly lower than those in young subjects. However, peak sputum levels of CPFX following oral administration of 200 mg CPFX ranged from 0.53 to 1.47 μg/ml at 1-4 hours. These sputum concentrations of the 6 patients were sufficiently high for the inhibition of most infecting organisms in vitro.
Clinical responses to CPFX in these 6 patients were good in 5, fair in 1, with an efficacy rate of 100%. Upon administration of CPFX, these 6 patients did not show any adverse reactions.
These results suggest that oral administration of CPFX may keep effective levels in serum and sputum over 3 hours in aged patients with chronic respiratory diseases, and good clinical responses should be obtained without side effects in such patients.

View full abstract

One hundred thirty-eight patients with severe infections associated with hematopoietic disorders were treated with cefclidin (CFCL), and the efficacy and the safety of the drug were evaluated.
The results obtained are summarized below.
1. Of the 126 patients in whom the efficacies were evaluable, 22 (17.5%) responsed markedly well and 48 (38.1%) moderately, and the overall efficacy rate was 55.6%.
2. Efficacy rates for different infections were: 20.0% in septicemia, 61.2% in suspected septicemia, 46.7% in respiratory tract infection and 25.0% in others.
3. Significantly different efficacy ratings were observed between a group of patients with neutrophil counts of less than 100/mm3 and that with neutrophil counts of higher than 501/mm3.
4. Out of 138 patients in whom the safety was evaluable, side effects were observed in 5 patients (3.6%) and abnormal laboratory test values in 9 (6.5%). None was serious, however.

View full abstract

Fifty patiens with infections associated with hematological disorders were treated with ceftazidime (CAZ). Among them 44 cases were evaluable, including 21 with acute leukemia, 17 with malignant lymphoma, and 6 with other hematological disorders. Excellent responses were obserbed in 15 patients (34.1%) and good responses in 15 (34.1%), with an overall efficacy rate of 68.2%. The efficacy rate among sepsis and suspected sepsis cases was 67.6%. This treatment was also effective in 7 of 10 cases in which neutrophil counts were less than 500/mm3 through the course of administration. Laboratory abnormalities included mild eosinophilia in 1 case, slight elevation of GOT in 1 case and slight elevation of GPT in 1 case. These results suggest that CAZ is an effective and safe antibiotics for the treatment of infections in patients with hematological disorders.

View full abstract

We studied a newly developed oral quinolone antimicrobial agent, levofloxacin (LVFX, DR-3355), and obtained the following results.
1. Serum and urine levels of LVFX were determined after oral administration of LVFX 100mg to 11 elderly patients with various degrees of renal function insufficiencies. The patients were classified according to creatinine clearance (Ccr) values into. Group I (n=1, Ccr≥70 ml/min), Group II (n=4, 40≤Ccr<70 ml/min), and Group III (n=6, Ccr<40ml/min). The peak levels of LVFX did not differ greatly among the 3 groups, but in patients with severely impaired renal functions, serum concentrations decreased more slowly than in those with slightly and moderately impaired renal functions, and high serum levels were maintained over a long period. Urinary excretion of LVFX diminished in relation to degrees of renal failure.
2. LVFX was administered to treat 13 elderly patients with respiratory tract infections. Clinical responses were good in all patients with a high efficacy rate of 100%. Laboratory tests revealed eosinophilia in 1 case. The symptom was mild, however, and no severe side effects due to the drug were observed.

View full abstract

Sputum penetration of levofloxacin (LVFX) was evaluated after a single oral dose of 100 mg or 200 mg to 4 patients with copious purulent sputa. The sputum concentration of LVFX reached maximum levels of 1.27 and 4.36μ/ml at 4 hours, and still remained at concentrations of 0.32 and 1.68μ/ml at 8 hours after administration of 100mg and 200mg, respectively. The AUC ratio of sputum/serum was 0.9-1.0, indicating good sputum penetration of LVFX in these patients.
The clinical efficacy and the safety of LVFX were also evaluated in a total of 13 patients with respiratory tract infections associated with bronchiectasis, diffuse panbronchiolitis, etc. LVFX was administered orally at a daily dose of 200 mg once a day, 100 mg t.i.d. or 200 mg t.i.d. for 7-28 days (mean 14.7 days). The clinical response to the drug was rated as excellent in 1 case, good in 5, fair in 3, and poor in 2 cases in 11 evaluable cases, thus the efficacy rate was 54.5%. All the 3 strains of Haemophilus influenzae were eradicated. Of the 3 strains of Pseudomonas aeruginosa, eradication, decrease, and unchange was observed for 1 strain each.
One strain of Streptococcus pneumoniaeremained unchanged. No adverse reaction was observed except for 1 case with slight and temporary increase of eosinophils. The above results suggested that LVFX would be clinically useful in the treatment of chronic lower respiratory tract infections.

View full abstract

A newly developed broad-spectrum fluoroquinolone, levofloxacin (LVFX, DR-3355), was evaluated in vitro and in vivo in comparison with ciprofloxacin (CPFX), ofloxacin (OFLX) and norfloxacin (NFLX). The results were as follows.
1. Antimicrobial activity
Minimal inhibitory concentrations (MICs) against 480 clinical isolates including 16 different spesies were determined using the microbroth dilution method. LVFX showed excellent antimicrobial activities against Gram-positive and-negative bacteria. The MIC values of LVFX for Gram-positive bacteria were superior to those of the other quinolones tested. The MIC values of LVFX for Gram-negative bacteria were comparable to those of CPFX and superior to those of OFLX and NFLX. 2. LVFX concentrations in serum and sputum LVFX was orally administered in a single dose of 200 mg to 2 patients with chronic lower respiratory tract infections, and its concentrations in serum and sputum were measured at intervals using bioassay. The peak concentrations of LVFX in serum were 1. 52 and 1. 24μg/ml, and 84-95% of serum level were detected in sputum. From these data, it appeared that LVFX penetrate well into the lung.
3. Clinical efficacy and adverse reactions
Fifteen patiens with respiratory tract infections were treated with LVFX, and the overall efficacy rate was 78. 6% (exellent in 3 cases, good in 8, fair in 3, poor in 0). As adverse reactions, anorexia was observed in 2 cases, diarrhea in 1 case and tremor of finger in 1 case. Although an elevation of total bilirubin in serum was observed in a case as an abnormal laboratory finding, it was mild, transient and improved rapidly after the completion of LVFX treatment.

View full abstract

Evaluations were made on biliary excretion and penetration into the gallbladder tissue of levofloxacin (LVFX, DR-3355), a new quinolone antibacterial agent, and its clinical efficacy in biliary tract infections.
1.Gallbladder tissue concentrations and biliary concentrations of LVFX at 2-6 hours after oral administration of 100 mg were 0.58-1.99μg/g and 0. 49-5. 63μg/ml, respectively. These tissue and biliary levels are almost equal or somewhat higher than the serum levels (0. 55-1. 63μg/ml) of the compound.
2. The concentrations of LVFX and optical isomer DR-3354 in the serum, gallbladder tissue, and bile were determined after a single or a concomitant administration of LVFX 100 mg and/or ofloxacin (OFLX) 100 to 200 mg. The concentration ratio of LVFX to DR-3354 paralleled with the ratio of the 2 compounds administrated.
3. At a dose of 100 mg, the glucuronide of LVFX in the commom duct bile was detected at proportions between 0. 9 and 36. 0%.
4. A total of 11 patients with biliary tract infections, including 6 cholecystitis 3 cholangitis, and 1 each of cholecystocholangitis and liver abscess was treated with LVFX at 100-200 mg t. i. d. for 3-14 days. Clinical results were excellent or good in 8 cases and fair in 3 cases, resulting in an efficacy rate of 72. 7%.
5. A side effect and an abnormal change in laboratory findings were observed in both 1 case each and they were both mild. It was concluded that LVFX showed good penetration to the biliary tract as does OFLX, and that it would be a useful oral agent for the treatment of biliary tract infections.

View full abstract

he penetration into bile of a new pyridonecarboxylic acid derivative, levofloxacin (LVFX), was studied in a closs-over method with ofloxacin (OFLX) as the control drug in 6 post-operative patients. The lengths of time to the maximum concentrations in bile and the total areas under the curves were both almost the same for these 2 compounds, although the maximum bile concentration of LVFX was slightly lower than that of OFLX. A stability test for LVFX in human bile revealed that over 95.4% of the initial amount was recovered up to 24 hours after commencement of incubation at a room temperature, thus the stability in bile was similar to that in water. The penetration of LVFX which possesses twice as strong antibacterial activities as OFLX was similar to that of OFLX, suggesting that LVFX is useful against bile duct infections.

View full abstract

1. Minimum inhibitory concentrations (MICs) of levofloxacin (LVFX, DR-3355), ofloxacin (OFLX), tosufloxacin (TFLX), norfloxacin (NFLX) were determined, with an inoculum size of 106 cfu/ml, against 122 strains of Staphylococcus aureus isolated from lesions of skin infections. LVFX showed most frequent MIC values of 0.20μg/ml. OFLX, TFLX, and NFLX showed most frequent MIC values of 0.39μg/ml, ≤0.05μg/ml and 0.78μg/ml, respectively.
2. Serum and skin levels of LVFX after oral administration (10mg/kg, fasting) were determined in rats. Serum levels were 1.79, 1.29, 0.60, 0.43 and 0.18μg/ml, and corresponding skin levels were 1.63, 1.77, 1.04, 0.87 and 0.64μg/g (wet weight) at 0.5, 1, 2, 4 and 8 hours after administration (n=5), respectively.
3. LVFX was used clinically in 43 cases at doses of 200-300 mg divided into 2 or 3 doses, and evaluated for final overall clinical efficacy in 41 cases. Cure was observed in 21 cases, remarkable improvement in 13 cases, improvement in 4 cases, unchanged in 1 case, aggravation in 1 case, and remarkable aggravation in 1 case. Diarrhea was obseved in 2 cases, diffuse erythema with feverishness in 1 case and slight dyspnea in 1 case. Transient slight eosinophilia, elevation of Al-P, anemia and leukopenia were observed.

View full abstract

We investigated the clinical efficacy and the safety of levofloxacin (LVFX, DR-3355) in obstetrical and gynecological infections and the following results were obtained.
1. Clinical efficacies were evaluated as excellent in 2 and good in 9 cases, hence the efficacy rate was 100%.
2. Bacteriologically, the eradication rate was 16/17 (94.1%).
3.
No Side effects nor abnormal changes in laboratory test results were observed. These results indicated that LVFX was highly useful in the treatment of obstetrical and gynecological infections.

View full abstract