We investigated the efficacy of ceftazidime (CAZ) plus vancomycin (VCM) combination therapy in polymicrobial infection by MRSA and Pseudomonas aeruginosa, both in vitro and in vivo. In the in vitro study, fractional inhibitory concentration indexes were determined by the checkerboard method. The combination exhibited no antagonism, but was additive in all cases. In the in vivo study, the effects of combination therapy were assessed in mice which had been infected intraperitoneally. MRSA to P. aeruginosa superinfection was observed when mice were infected polymicrobially, with a small amount of P. aeruginosa and a large amount of MRSA, and then treated with VCM monotherapy. The effect of combination therapy was assessed using this superinfection model. The 50% effective dose (ED₅₀) of CAZ in monomicrobial infection with P. aeruginosa NG 91003 strain was 0.07mg/mouse, and the ED₅₀ of CAZ in the superinfection model treated with 0.3mg/mouse VCM combination therapy was lowered to 0.02mg/mouse. In the case of the P. aeruginosa NG 91012 strain, the ED₅₀ of CAZ in both the monomicrobial infection and superinfection model were almost equal (0.04mg/mouse and 0.05mg/mouse respectively). Changes in viable cells in the blood were assessed using selective media. An increase in MRSA or P. aeruginosa was observed when the mice were treated with monotherapy using CAZ or VCM. In the case of combination therapy, both MRSA and P. aeruginosa were found to decrease or disappear. These results suggested that the CAZ plus VCM combination is one of the most effective forms of therapy for the MRSA and P. aeruginosa polymicrobial infections which is frequently observed clinically.

View full abstract

Extracellular and intracellular β-lactamase activity in culture was studied using Escherichia coli TK-3 and Klebsiella pneumoniae Y-4, which produce constitutive penicillinases, Proteus vulgaris T-178, which produces an inducible oxyiminocephalosporinase, Pseudomonas aeruginosa GN 918, which produces a constitutive cephalosporinase (CEPase), and Enterobacter cloacae H-27, which produces an inducible CEPase. In the cultures of the three strains which produce constitutive filactamases, extracellular β-lactamase activity was increased (without any drugs), and amounted to 15-26% and 30-56% of intracellular activity on days 1 and 2 of incubation, respectively. In the cultures of the two inducible β-lactamase producers, on the other hand, extracellular β-lactamase activity was low (≤1mU/ml) without an inducer, but upon the addition of cefmetazole (as an inducer) extracellular activity increased to 36-229% of intracellular activity on day 2. The in vitro stability of the β-lactamases from these five strains was studied in various human body fluids (serum, urine, bile, peritoneal fluid, and pleural fluid). All five enzymes were stable in these human body fluids, except bile, and their residual activity was greater than 60% after incubation for eight days. All of the β-lactamases used were rapidly inactivated in bile.

View full abstract

The transfer of cefodizime to breast milk was investigated in 26 subjects. The peak level of cefodizime (CDZM) in milk was 0.41μg/ml at 2.94 hours and 1.08μg/ml at 2.83 hours after intravenous administration of 1 g and 2 g of CDZM, respectively.

View full abstract

We investigated correlations between blood concentrations of new quinolones (NQLs) norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX) and lomefloxacin (LFLX), age and renal function (24-hour creatinine clearance, Ccr) in 180 patients (51-87, 70.6±7.7 years old) with benign prostatic hyperplasia undergoing transurethral resection of the prostate (TUR-P). One of 5 NQLs was administered to them orally in a dose of 200 mg t.i.d. for 3 days before TUR-P, and blood was sampled at 5.5 or about 17 hours after the final dose. The following conclusions were drawn based on the results. Blood concentrations of NQLs rise with age, because renal function diminishes with increasing age. The blood concentrations of OFLX, LFLX and ENX, which had higher urinary excretion rates, seemed more likely to rise, when elderly patients take these 3 NQLs, careful adjustment of the dosage and monitoring of blood concentrations are required to prevent adverse reactions.

View full abstract

The safety, tolerance and pharmacokinetic profile of SY 5555, an oral penem antibiotic, were examined in 24 healthy male volunteers. In the single dose study, 12 subjects were given an oral dose of 150 or 600mg in the fasting state. In the cross-over study, the effect of food on the pharmacokinetics of SY 5555, was investigated in 6 subjects treated with an oral dose of 300mg. In the multiple-dose study, 6 subjects were given 400mg of SY 5555 t.i. d. after meals for 7 days. The results obtained were as follows:
1. In the single dose study, there were no abnormal objective symptoms attributable to the agent. Neither physical abnormalities nor abnormal clinical laboratory findings were observed, except for one subject treated with a 600mg dose who showed slight elevation of GPT.
2. In the multiple-dose study, all subjects treated with a 400mg dose showed changes in stools. There was one case of slightly soft stools, 3 cases of loose stools and 2 cases of diarrhea during the period of dosing. All changes in stools recoverd after the completion of treatment. There were no abnormal objective symptoms. Neither physical abnormalities nor abnormal clinical laboratory findings were observed, except for one subject treated with 400mg who showed slight elevation of eosinophils.
3. In the single dose study, the plasma levels of SY 5555 reached C_max of 2.36, 6.24 and 7.37μg/ml at doses of 150, 300 and 600mg, respectively, about 1-1.4 hours (T_max) after administration. The AUCs of SY 5555 were 3.94, 11.73 and 19.59μg·h/ml, respectively, with an average half-life (T_1/2) of about 0.9 hours. These C_max and AUCs were proportional to the doses, and the respective urinary recoveries were 3.12, 6.78 and 5.26% of the dose.
4. At a single dosing of 300mg after meals, the average T_max was delayed about 1 hour, but C_max, AUC and urinary recovery were not different form those in the fasting state.
5. In the multiple dosing study with 400mg t.i.d., the Cmax on days 1, 4 and 7 (1st, 10th and 19th administration) were 5.51, 4.25 and 4.83μg/ml, respectively, and the respective AUCs were 12.54, 10.11 and 12.19μg·h/ml, demonstrating no cumulative effect.
6. Changes in fecal bacterial flora, especially anaerobes, due to the antibacterial activity of SY 5555 were observed during the multiple dosing. The bacterial flora, however, recovered to the normal range on the 6 th day after the completion of dosing.

View full abstract

To determine the pharmacokinetic and safety profiles of SY 5555, a new oral penem antibiotic, a multiple-dose study (200mg t. i. d. after meals for 7 days) was performed in 6 healthy male volunteers. No abnormal clinical signs or laboratory findings were observed except for one subject who developed transient loose stool. This side effect disappeared after the competion of the study. Changes in fecal bacterial flora, especially anaerobes, were observed during multiple dosing, but the bacterial flfora returned to the normal range six days after the last dosing At the 1st, 10th and 19th administrations of a multiple dose of 200mg, C_max. were 1.90, 2.02 and 1.89μg/ml, respectively. The range of curnmulative urinary excretion after 24h was from 3.81% to 4.49% of the dose. No accumulation of SY 5555 in serum was observed in this study.

View full abstract

Combinations of piperacillin and aztreonam vs. piperacillin, aztreonam and amikacin sulfate were compared in a prospective randomized trial of empiric therapy. The subjects were 42 febrile patients with hematological malignancies. Male/female ratio was 23/19; age ranged from 17 to 84 (median, 56 years). The underlying diseases were: acute myelogenous leukemia in 23, acute lymphoblastic leukemia in 3, non-Hodgkin's lymphoma in 8, myelodysplastic syndrome in 1, multiple myeloma in 3, aplastic anemia in 2 and others in 2. The overall efficacy rate was 54.8%(23/42) and breakdown by the type of infection was as follows: sepsis, 2/4; suspected sepsis, 14/26; acute bronchitis, 4/5; pneumonia, 2/4; and other infections, 1/3. The two regimens were equally effective: 55.0%(11/20) with the two-drug combination vs. 54.5%(12/22) with the three-drug combination. The efficacy rates of the two- and three-drug combinations in patients with neutropenia (less than 500/μl) were 72.7%(8/11) and 46.7%(7/15), respectively; the total efficacy was 57.7%(15/26). The side effects were minimal with no difference between the two regimens. Because piperacillin and aztreonam cover both Staphylococci and Pseudomonas aeruginosa, common isolates from bacterial infections in patients with hematological malignancies, additional use of amikacin sulfate would yield no further benefits.

View full abstract

A randomized double-blind comparative study of S-1108, a new oral cephem antibiotic, and cefteram pivoxil (CFTM-PI) was carried out in the treatment of complicated urinary tract infections. Patients were randomly assigned to receive 300 mg of S-1108 or CFTM-PI a day in 3 divided doses for 7 days. All patients were shown to have pyuria with at least 5 WBCs per high-power field, bacteriuria with at least 10⁴ CFU per ml of urine and identifiable underlying urinary tract disease. Only outpatients without indwelling catheters aged over 16 years old were enrolled in the study. Overall clinical efficacy was evaluated as “excellent”, “moderate” or “poor” on the basis of criteria proposed by the Japanese UTI Committee. Of the 222 patients evaluated for clinical efficacy, 112 patients received S-1108 and 110 received CFTM-PI. No significant differences were observed in the background characteristics of the two treatment groups. The overall efficacy rate of 77.7% obtained in the S-1108 group was slightly higher than the 67.3% in the CFTM-PI group. Bacteriological eradication rates were 83.8% of 167 strains in the S-1108 group and 79.5% of 171 strains in the CFTM-PI group, with no statistically significant difference. Eradication rates for Gram-negative bacteria in the S-1108 group, however, were significantly higher than in the CFTM-PI group, Clinical adverse reactions were experienced in 2.9% of the patients in the S-1108 group and in 3.6% of the patients in the CFTM-PI group. Laboratory adverse reactions were observed in 7.6% of the patients in the S-1108 group and in 7.4% of the patients in the CFTM-PI group. There were no significant differences between the incidences of either clinical or laboratory adverse reactions in the two treatment groups. Nor were there any significant differences in global safety or clinical value in the two treatment groups. From the results obtained in this study, we concluded that S-1108 is useful in the treatment of complicated urinary tract infections, except those due to Enterococcus species or Pseudomonas aeruginosa and those associated with indwelling catheters.

View full abstract

We experienced three patients with intraperitoneal abscess who were successfully treated with azole antifungal drugs. Case 1 was a 65-year-old man who had had total gastrectomy for advanced cancer of the residual stomach. Case 2 was a 65-year-old man under conservative therapy for perforated gastric ulcer. Case 3 was a 60-year-old man who had undergone simple closure for perforated duodenal ulcer. CT scan and measurement of serum β-D-glucan were helpful in making the diagnoses. The patients became well and afeverish soon after administration of fluconazole (cases 1 and 2) or miconazole (case 3). No side effects were experienced due to administration of azole antifungal drugs.

View full abstract