Stereoselective disposition of sulbenicillin in humans.

Stereoselective disposition of sulbenicillin (SBPC) epimers in healthy human volunteers was studied in order to clarify the differences in pharmacokinetic behavior between the epimers. Stereospecific high-performance liquid chromatography was used for the determination of SBPC epimers. Plasma protein binding was measured in vitro with an ultrafiltration method. The binding was stereoselective, with the unbound fraction (fu) of the R-epimer being approximately 1.3-fold greater than that of the S-epimer. SBPC was administered intravenously to human volunteers, and concentrations of SBPC in plasma and urinary excretion rates were measured. Renal clearance (CLR) for the unbound drug (approximately 400 ml/min) was greater than the glomerular filtration rate (GFR) (approximately 109 ml/min) for both epimers, suggesting that both epimers are secreted at the renal tubules. Renal tubular secretion appeared to be greater for the S-epimer. When probenecid was coadministered, the CLR values of both epimers were significantly reduced and were approximately equal to the GFR values. CLR was greater for the S-epimer (37.5 and 49.8 ml/min for R-SBPC and S-SBPC, respectively), which was simply due to the greater fu of the S-epimer in plasma. In contrast, total body clearance was greater for the R-epimer (67.8 and 56.3 ml/min for R-SBPC and S-SBPC, respectively) because of the stereoselective degradation of the R-epimer in plasma. It was revealed that stereoselective degradation in the body had significant influence on the disposition of SBPC epimers.

[Infective endocarditis associated with vertebral osteomyelitis: report of two cases].

A 42-year-old man and a 65-year-old woman with infective endocarditis suffered onset of severe back pain. Magnetic resonance imaging and technetium-99 m bone scanning demonstrated osteomyelitis in the lumbar spine which is an unusual complication of infective endocarditis. The man was treated by antibiotics and finally aortic valve replacement and laminectomy with bone grafting. The woman had small patent ductus arteriosus and developed aortic regurgitation, but was treated by antibiotics and corset application with good result. The possibility of osteomyelitis in the lumbar spine should be considered in a patient with endocarditis complaining of severe back pain. The appropriate antibiotic therapy over a prolonged period is recommended.

Application of topical lomefloxacin against experimental Pseudomonas endophthalmitis in rabbits.

Lomefloxacin is a new quinolone compound with a broad antibacterial spectrum and excellent penetration into the aqueous humor by topical application. Therefore, an experimental study was done to evaluate the efficacy of topical lomefloxacin against experimental endophthalmitis with Pseudomonas aeruginosa. Lomefloxacin eye drops were instilled six times a day onto infected rabbit eyes and gentamicin, sulbenicillin and saline were also tested comparatively in the same manner as lomefloxacin. Clinical observation for 1 week and counting viable pseudomonas cell numbers in the anterior chamber were done. Among all topical eye drops tested, lomefloxacin was shown to be most effective in lowering clinical scores and viable cell numbers in the anterior chamber. In conclusion, lomefloxacin is expected to be a useful ophthalmic solution in the treatment of pseudomonal endophthalmitis.

Retinal toxicity of antibiotics: evaluation by electroretinogram.

Toxicity of an intravitreal injection of gentamicin sulfate, disodium sulbenicillin and cefazolin sodium on the retina was investigated by electroretinogram in albino and pigmented rabbits. Recordings were made before injection and 2 hours and 3, 7, 14, and 21 days after injection. Significant differences were found in the susceptibility of the electroretinogram components to various antibiotics as follows. Gentamicin 0.24 mg/0.1 ml irreversibly abolished all the components examined. Sulbenicillin 4.0, 8.0, or 12 mg/0.1 ml transiently suppressed the b-wave and the oscillatory potentials incrementally with increasing dose. Cefazolin 0.5, 2.0, or 5.0 mg/0.1 ml selectively reduced the oscillatory potentials, leaving the a- and b-waves almost unattenuated. The cefazolin-suppressed oscillatory potentials recovered within 14 days after injection. Judging from the most susceptible electroretinogram components to each antibiotic, we recommend intravitreal doses of these antibiotics for clinical use as follows: gentamicin 0.1 mg/0.1 ml, sulbenicillin 2 mg/0.1 ml, and cefazolin 0.25 mg/0.1 ml.

Electron microscopy of Pseudomonas aeruginosa treated with sulbenicillin and dibekacin.

A possible mechanism responsible for the combined effects of sulbenicillin and dibekacin on Pseudomonas aeruginosa IAM 1007 was investigated. The bactericidal activity of the above two drugs in combination was very strong. The regrowth of test strains after removal of the drugs was suppressed markedly, even when they were exposed to sulbenicillin plus dibekacin at a subinhibitory concentration of individual drugs. Sulbenicillin caused elongation of the bacterial cells. At the early stage of elongation, no demonstrable changes of ultrastructure of the cell wall were observed. At the late stage, lysis of the peptidoglycan layer occurred and spheroplast was formed. However, most of the outer membrane of the cell wall remained intact. Sulbenicillin acts upon the peptidoglycan layer, but not on the outer membrane. Thus it is difficult for sulbenicillin alone to cause cell lysis. On the other hand, dibekacin caused destruction of ribosomes and lysis of the outer membrane of the cell wall. Both sulbenicillin and dibekacin act on the cell wall, the former on the peptidoglycan layer (the inner membrane) and the latter on the outer membrane. The combined use of sulbenicillin and dibekacin caused elongation of bacilli and severe destruction of the inner and outer membranes of the cell wall. These morphological changes occurred even when the concentration of the individual drug was lower than its minimum inhibitory concentration (MIC). Furthermore, the cells elongated by sulbenicillin were ruptured easily when treated with dibekacin subsequently. The bacilli treated with dibekacin at a concentration lower than MIC and then treated with sulbenicillin at a concentration lower than MIC showed a marked elongation of the cells, which indicated that the effects of sulbenicillin was enhanced by dibekacin. These findings suggested strongly that sulbenicillin and dibekacin act on cell wall constituents and that their effects were complementary and synergistic.

Multicentre clinical and bacteriological study of sulbenicillin in patients with bronchopulmonary infection.

In view of the pharmacodynamic and therapeutic properties of a broad-spectrum semisynthetic penicillin recently introduced in Italy, namely sulbenicillin, the authors conducted a multicentre clinical and bacteriological trial of the drug administered by intramuscular or intravenous injection in daily doses of 4, 6 or 8 g given in two or three administrations daily to a group of 66 patients with acute bronchopulmonary infection, mainly exacerbation of chronic infection, hospitalized in four Pneumology Centres of Sardinia. The authors assessed clinical, radiological, microbiological, and biohumoral parameters before and after treatment to provide a basis for assessing test product effectiveness and tolerability. On the strength of their findings, the authors concluded that the clinical and bacteriological activity of sulbenicillin was satisfactory and its local and general tolerability was excellent. The assembled findings indicate that the new antibiotic molecule can be used to advantage in the treatment of nontubercular bronchopulmonary infections, including severe or otherwise "difficult" cases, providing that the drug is administered at adequate dosages and for sufficiently long treatment periods.

Clinical assessment of sulbenicillin in acute respiratory tract infection.

The effectiveness of sulbenicillin was assessed in the treatment of 15 adults, 12 suffering from bronchopneumonia and three from lobar pneumonia. Six patients had concomitant complications. At a parenteral dose of 2 g twice or thrice daily for at least seven days, all patients became afebrile by the sixth day, and chest X-rays became normal in nine patients and improved in five. It is concluded that sulbenicillin, which was well tolerated, is clinically effective in the treatment of severe respiratory tract infections, also in patients with major impairment of their immune response systems.

Results of treatment with sodium sulbenicillin in thirty elderly patients with acute bronchopulmonary infection.

Thirty elderly patients with acute bronchopulmonary infections were treated with intravenous sodium sulbenicillin for up to 20 days at a dose of 4-6 g/day. Clinical results were excellent in 19 cases and good in 10 cases. In one case treatment had to be discontinued due to a dermal side-effect. It is concluded that sulbenicillin is a useful therapy for acute bronchopulmonary infections in the elderly.

[Sulbenicillin and amikacin for febrile patients with cancer--with special reference to granulocytopenia].

Between March 1978 and March 1983 ninety-four episodes of fever in 56 mainly granulocytopenic patients with cancer were treated empirically with a combination of sulbenicillin (5.0 g, every 6 hours) and amikacin (200 mg, every 6 hours) in Saitama Cancer Center. Profound granulocytopenia at the beginning of treatment (less than 100/mm3 of granulocytes) was present in 66% of the patients. Oral absorbable or nonabsorbable antibiotics were used in 59 febrile episodes. WBC transfusion was not given. The response rate for all documented infections was 75%, including 10 of 13 (77%) of bacteremias. The majority of infections with identified organisms were caused by aerobic gram-negative bacilli: the major gram-negative pathogens being Ps. aeruginosa (11 cases), Klebsiella spp. (7 cases), E. coli (7 cases) and Enterobacter spp. (7 cases). The response rate of gram-negative bacilliary infections was 74%. Pneumonia responded less satisfactorily than all other types of infection with the response rate of 20%. The response rate of 69% for profound persistent granulocytopenia (less than 100/mm3 of granulocytes without a rise during therapy) is higher than that of any other reports. The most common adverse effect was hepatotoxicity (19%), whereas oliguria or anuria occurred in two patients, by which they eventually expired.

[Antibiotic therapy of infections in cancer patients with leukopenia].

Cancer patients with leukopenia developing infections were treated with a combination antibiotic therapy consisting of sulbenicillin and amikacin with (B) or without (A) S-sulfonated gamma-globulin. Fifty patients were randomized to either A or B, respectively. Fourty-two patients in group A and 43 in group B were evaluable for responses. Twenty-eight of 42 patients (67%) in group A and 30 of 43 (70%) in group B showed a response. These results did not demonstrate that S-sulfonated gamma-globulin enhanced the effects of the combination with sulbenicillin and amikacin, although the background factors in both groups were not completely identical. Further efforts for detecting infection were required because causes of fever were thought to be fevers of unknown origin in more than three-fourths of the patients. Few patients died of infection within 2 weeks after initiation of these therapies in both groups, indicating that these therapies presumably contributed to prolongation of life span even in patients with no response.

[Clinical investigation of combined therapy (cefotiam, sulbenicillin and cefsulodin) against infections complicated by acute leukemia].

Prophylaxis effect and clinical therapy of combination use of cefotiam (CTM), sulbenicillin (SBPC) and cefsulodin (CFS) have been investigated, and the results were as follows. 1. Prophylaxis effect of CTM-SBPC combination therapy was very useful. CTM-SBPC combination therapy was performed to patients who are at high risk for infectious complications. Prophylaxis effect of CTM-SBPC was judged by fever over 38 degrees C, and was better than usual antibiotic treatment. 2. CTM-SPBC-CFS combination therapy was performed against severe infections during early remission, and the overall effectiveness rate was 83.3% (5/6). 3. No remarkable side effect was observed in this investigation.

[Concentration of sulbenicillin in human serum and myocardial tissue].

The concentration of sulbenicillin in the serum and myocardial tissue of 13 patients were determined at cardiac surgery. About 100 mg/kg of sulbenicillin were administered intravenously for 60 minutes. Right auricle resected at the vena caval cannuration was examined for myocardial tissue. The serum concentration was also examined every 30 minutes after injection, 30 minutes, 60 minutes, 90 minutes, 120 minutes and 150 minutes. Mean values of serum concentration were 213.6 micrograms/ml, 432.5 micrograms/ml, 181.6 micrograms/ml, 236.3 micrograms/ml and 101 micrograms/ml, respectively. The values determined in myocardial tissue were 146.5 micrograms/g (60 minutes), 39.2 micrograms/g (90 minutes), 66.0 micrograms/g (120 minutes) and 23.5 micrograms/g (150 minutes). The mean value of concentration ratio of sulbenicillin in myocardial tissue was 0.23 of serum concentration. The high myocardial tissue levels of sulbenicillin suggests that its use at cardiovascular surgery would protect the myocardial tissue from the bacterial infections.

[A study on penetration of antibiotics into the cerebrospinal fluid after the ventriculo-peritoneal shunt (author's transl)].

Neurological surgeon must select the effective antibiotics to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier. In this study, we measured the concentration of cefotiam (CTM), cephalothin (CET), cephacetrile (CEC) and sulbenicillin (SBPC) into the cerebrospinal fluid in the non inflammatory cases with V-P shunt. 1. Antibiotic concentrations in CSF and CSF/serum ratio (%) were evaluated at 2 hours after an intravenous administration of antibiotics. CTM; 0.543 microgram/ml (3.66%), CET; 1.84 micrograms/ml (7.45%), CEC; 1.77 micrograms/ml (7.5%), SBPC, 6.15 micrograms/ml (5.58%). 2. The peak of antibiotic concentration in CSF appeared from 2 hours after administration and gradually decreased. In cellular tumor cases, the penetration of antibiotics into CSF showed similar levels as the cerebrovascular disease cases. 3. Concentration of CTM in CSF was higher than MIC of CTM to S. pyogenes and E. coli.