We investigated the correlation between β-lactamase activity determined by the nitrocefin-method for clinical pathogens isolated from sputum and that of sputum per se, and discuss the possible indirect pathogenecity of non-causative organisms. Forty-six microbes, including 10 strains of Pseudomonas aeruginosa, 6 each of Staphylococcus aureus, Serratia marcescens and Enterobacter cloacae, 4 of Xanthomonas maltophilia, 3 of Acinetobacter calcoaceticus, 2 of Haemophilus influenzae and one strain each of Enterococcus faecalis, Branhamella catarrhalis, Klebsiella pneumoniae, Proteus mirabilis, Hafnia alvei, Providencia stuartii, Pseudomonas sp., Flavobacterium meningosepticum and Flavobacterium indologenes were recovered from the sputum of 39 patients with respiratory infections. The β-lactamase activity was negative in 9 of 46 strains. Of the remainder, 13 strains responded slowly and 24 rapidly in their production of β-lactamase.β-Lactamase-positive strains were recovered from 35 of 39 patients. The β-lactamase activity of sputum from 35 cases whose isolates were positive for β-lactamase, was negative in 12, weakly positive in 17 and strongly positive in 6 cases. The β-lactamase activity of sputum from cases whose isolates were negative for β-lactamase, was negative in all four cases. Both β-lactamase producing and non-producing strains were recovered from the same sputum in five of six cases in whom multi-organisms were recovered. The β-lactamase activity of sputum from cases with prior chemotherapy was stroger than that without prior chemotherapy, and the difference was statistically significant (P<0.025). We suggest from the above results that non-causative organisms which are positive for β-lactamase enhance the pathogenecity of causative organisms which are negative for β-lactamase since β-lactamase is produced by non-causative organisms in the sputum.

View full abstract

We examined clinically the excretin of 7 cephems (cefaolin, cefmetazole, cefotiam. cefoperazone, latamoxef, cefmenoxime, ceftazidime) into bile, and studied the correlation between biliary excretion and the drugs' properties.
Bile was collected every 30 or 60 minutes form patients with an indwelling T-tube. Each drug was administered in 3 different ways: bolus injection of 1g intravenously (1g i. v.), bolus injection of 2g (2g i.v.) and drip infusion of 2g for 60 minutes (2g d.i.). The concentration of the drugs was measured by bioassay.
Statistically significant correlation was observed between the peak concentration of the seven cephems in bile and the molecular weight of the drugs, the coefficients being O. 859 (1 g i. v.), 0.845 (2g 1.v.) and 0.864 (2g d.i.).
Also, the area under the curve of the drugs in bile showed statistically significant correlation with their molecular weight, the coefficients being 0.866 (1g i.v.), 0.862 (2g i.v.) and 0.865 (2g d.i.).
The peak time (during which concentration of the drug is higher than half the peak level) of the cephems in bile ranged from 1.58-8.21h, and correlated positively with the molecular weight (1g i.v. and 2g i.v.) and serum half-life (1g i.v.) of the drugs (r=0.865, 0.853, 0.755, respectively).
Dose ratio (of the results of 2 g i. v. to those of 1 g i. v.) for the peak concentration of the drugs on bile ranged from I. 28-4. 14, and correlated positively with their protein binding (r=0.819, P<0.05).
The ratio of 2g i.v. to 2g d.i. for the peak concentration of the cephems in bile ranged from 0.03-2.51, and correlated negatively with their molecular weight (r=-0.789, P<0.05)
From the above results, we concluded that the molecular wiht of cephems may play an important ole in their excretion into bile.

View full abstract

We investigated the effects of various antibiotics on the blood coagulation system in patients who had received surgical treatment for urological disease. Latamoxef (LMOX)(group A, 91 cases), cefbuperazone (CBPZ)(group B, 48 cases), cefamandole (CMD)(group C, 29 cases) or cefoxitin (CFX)(group D, 33 cases) was administered intravenously at a dose of 4g/day for 7 consecutive days after surgery. Each group was subdivided into a vitamin K₂ (K₂) treatment group and a nontreatment group; the patients in the K₂ group received K₂ in travenously at a dose of 100mg/day for 7 consecutive days after surgery. The blood coagulation parameters determined were: prothrombin time (PT), hepaplastin test (HPT), activated partial thromboplastin time (APTT), thrombotest (TT), fibrinogen, and thrombocyte count. All these parameters were measured before and 2, 4, and 8 days after surgery.
In all groups (A, B, C, D), a slight change occurred in PT, HPT, APTT, TT, fibrinogen, and thrombocyte count 2 or 4 days after surgery. At this time, there was no difference between the K₂ treatment and nontreatment groups. These changes were attributed mainly to the effects of surgery rather than to the antibiotics themselves.
The effect of aging, a potential risk factor of the blood coagulation system, was also investigated in group A; there was no difference between the elderly patient group (≥70 years) and the counterpart group (<70 years). All patients were further divided into 2 groups: the nonlaparotomy group (ingestion possible even on the day of surgery), and the laparotomy group (ingestion not possible on the day of surgery). No difference was observed between the K₂ treatment and nontreatment groups.

View full abstract

A prospective study was carried out by the Tokai Reseach Group for Infections in Hematological Disorders to evaluate the efficacy and safety of aztreonam (AZT) in infections associated with hema. tological disorders.
1. AZT was administered alone or in combination with other antibacterial agents except aminogly. cosides. The dose given was 4 g/day in 63.6% of all cases, the others being given 6 g/day, for a mean duration of 9.0 days.
2. One hundred and forty-three patients entered this study, and of these 15 patients could not be evaluated for efficacy. Eighty-three out of 128 patients had neutrophil counts of 500/cmm or lessat the beginning of treatment, and 53 patients (41.5%) had 100/cmm or less.
3. The efficacy rate (marked+moderate response) for 128 patients was 64.8% in whom the ratesfor septicemia, suspected septicemia and pneumonia were 72.7%, 61.8% and 67.9% respectively.
4. Of the patients with less than 500/cmm neutrophils, those whose neutrophil counts increased during treatment showed better response than those with decreasing or unchanged neutrophil counts (82.9% of 41 compared with 50% of 42).
5. The efficacy rate of 99 patients treated with two antibiotics including AZT was 70.7% and combinations with piperacillin or imipenem/cilastatin had higher efficacy rates (76.2%, 76.2%) than any other combinations.
6. Abnormal clinical and laboratory findings appeared in only 5 cases of each group (3.6%).
7. Aztreonam has low toxicity and is effective for the treatment of infections associated with hematological disorders.

View full abstract

In order to elucidate the mechanism of interaction of enoxacin (ENX) with theophylline (TP), we investigated the effect of ENX on the plasma and urine levels of TP in rats. The results were as follows.
1. Three concomitant oral doses of ENX at 50, 100 and 300 mg/kg with TP (15 mg/kg once orally) prolonged the plasma elimination half-life of TP from the control value of 3. 8 h to 4. 7, 6. 0 and 7. 4 h. However, treatment with ENX did not affect the maximum plasma level of TP.
2. After 3-day pretreatment with ENX (300 mg/kg three times daily), the TP alf-life on the fourth day (3.7 h) was similar to the control value (3.8 h) described above, showing only a shortlasting effect of ENX on the TP half-life.
3. In the 3-day repeated concomitant dose test of ENX (300 mg/kg three times daily) with TP (15 mg/kg twice daily), the maximum plasma TP level on the third day (in steady state) rose 1.4-fold over that on the first day.
4. In rats treated with ENX (300 mg/kg three times), 24-h urinary excretion of unchanged TP after a single TP dose (15 mg/kg) increased from the control level of 25.6%(of the dose) to 45.0%, while those of 1-methyluric acid and 1, 3-dimethyluric acid (TP metabolites) comparably decreased from 16.7% and 27.4% to 8.2% and 13.5%, respectively. Pharmacokinetic analysis demonstrated that treatment with ENX remarkably decreased total body clearance of TP from the control value of 103 ml/kg/h to 62 ml/kg/h and metabolic clearance from 78 ml/kg/h to 35 ml/kg/h, but did not change renal clearance (27 ml/kg/h) from the control value (25 ml/kg/h).
5. Consequently, an increase in the plasma TP level after repeated doses of ENX and TP is probably attributable to prolongation of the TP half-life based on the reduced metabolic clearance of TP by ENX.
Since these interactions of ENX with TP observed in rats are similar to those reported in humans, the magnitude of interactions of other pyridonecarboxylic acids with TP are possibly predictable by the methods described.

View full abstract

Using the paper disc method, we studied the concentration of TE-031, a newly developed macrolide ntibiotic for oral use, in the tissues of rabbits.
After oral administration of TE-031 100mg/kg in rabbits, serum and most tissues reached eak oncentration in 1 hour, but gingiva in 2 hours, and mandibular bone marrow in 4 hours.
The order of peak tissue concentrations was liver (42.5μg/g), lung (29.7μg/g), kidney (22.4μg/g), ub mandibular gland (11.7μg/g), spleen (9.3μg/g), submandibular lymph node (6.98μg/g), gingiva (5.78μg/g), dental pulp (5.00μg/g), tongue (4.13μg/g), masseter (2.58μg/g), mandibular bone narrow (2.32μg/g) and palatal mucosa (1.91μg/g).
We found that all the tissue concentrations examined were higher than that of serum.

View full abstract

We compared the clinical efficacy, safety and utility of T-3262 (tosufloxacin tosilate), a new derivative pyridonecarboxylic acid, with those of ofloxacin (OFLX) in patients with respiratory tract infection (RTI) by double-blind study. RTI included in the protocol were bacterial pneumonia and chronic respiratory tract infection. The drug was given orally for a fixed period of 14 days and the daily dosage was fixed at 450mg for T-3262 or 600mg for OFLX.
The following results were obtained.
1. On the basis of committee judgement, the clinical efficacy rate in all cases was 82.9% for T-3262 and 82.5% for OFLX. No significant difference was observed between the two groups, not even in clinical efficacy when classified by type of disease.
2. The clinical efficacy rate judged by the doctors in charge was similar to that judged by the committee.
3. The bacteriological eradication rate of causative organisms judged by the committee was 78.6%for T-3262 and 85.1% for OFLX, without statistically significant difference.
4. With respect to the rate of improvement of clinical signs, symptoms and laboratory findings, T-3262 was superior to OFLX as to body temperature.
5. The incidence rate of side effects was 7.8% for T-3262 and 6.7% for OFLX, and there were no significant differences between the two groups. Abnormalities in laboratory findings, mainly slightly elevated serum transaminase and eosinophils, were not significantly different between the two groups.
6. The utility rate in all cases judged by the committee was 79.6% for T-3262 and 79.8% for OFLX. No significant difference between the two groups was noted. Even when classified by typeof disease, there was no significant difference in utility between the two groups.
7. Neither was there any significant difference between the two groups in the utility rate when judged by the doctors in charge.
8. From our results, we consider both T-3262 (at a daily dose of 450mg) and OFLX (at a daily dose of 600mg) to be highly useful antibacterial agents for the treatment of respiratory tract infections.

View full abstract

We studied the effect of combined therapy with anti-cancer and immunotherapeutic agents on transplantable tumor in rats. After treatment with polysaccharide-K (PSK)(300/mg/day for 4 days) and cyclophosphamide (CPA)(20mg/mg/day for 1 day), macrophages from the bone marrow and spleen of Donryu rats were incubated in a liquid culture medium. The number of colonies and macrophage clusters was then counted. The number was greatest in the group given PSK followed by CPA. Treatment with CPA followed by PSK caused no increase in number.
Survivals were observed in the groups inoculated with Yoshida sarcoma cells in the intra-abdominal cavity and given CPA and/or PSK.
In the groups given CPA before the transplantation of tumor cells, survival time was shorter than in the untreated group.
Treatment with CPA followed by PSK induced the longest survival time as compared to single treatment with CPA or combined treatment with PSK followed by CPA.

View full abstract