Comparison of Ampicillin-Sulbactam and Ticarcillin-Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Study Objectives . To evaluate the pharmacodynamic antibacterial activity of ticarcillin-clavulanic acid (T-C) and ampicillin-sulbactam (A-S) combinations against reference bacterial strains in patients with end-stage renal disease maintained on long-term hemodialysis. Design . Randomized, crossover, controlled study. Setting . National Institutes of Health-funded general clinical research unit in a Veterans Administration Medical Center. Patients . Nine adult men with end-stage renal disease maintained on long-term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons. Interventions . On a nondialysis day, each subject was randomly administered either T-C 3.1 g or A-S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination. Measurements and Main Results . The mean observed apparent β-half-life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A-S and T-C against non-β-lactamase-producing (Nβ-LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against β-lactamase-producing (β-LP) S. aureus, the geometric mean SBTs for A-S were at least 1:25 throughout the study period, while the geometric mean SBTs for T-C decreased over 24 hours from 1:29 to 1:6. Against β-LP E. coli, the bactericidal activities for both A-S and T-C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T-C against this E. coli strain had declined to 1:1 at 6 hrs. Conclusion . Increasing the dosing interval for T-C in patients with end-stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from β-lactamase degradation.     

Disposition of 14C-dapoxetine in rats: Complementary experiments with whole-body autoradiographic and tissue dissection techniques

Tissue distribution studies, utilizing whole-body autoradiography and organ dissection techniques, were conducted in male Fischer 344 rats following the oral administration of ¹⁴C-dapoxetine HCl, a potent serotonin reuptake inhibitor. The preliminary study using whole-body autoradiography proved invaluable in locating radioactivity in an organ not usually harvested in a tissue distribution study, namely the preputial gland. Selected organs, based on whole-body autoradiography findings, were dissected from rats and analyzed for radiocarbon content by liquid scintillation counting and for parent drug and N-dealkylated metabolites by extraction and HPLC analysis. Highest concentrations of radiocarbon were observed in the organs of absorption and elimination (ileum, cecum, stomach, duodenum, liver, colon, and kidney) but notable quantities were observed in the lung and preputial and Harderian glands. Most tissues had returned to background radioactive levels 72 h after dosing but persistent concentrations of radiocarbon were present in the preputial gland and liver one week after the single dose of ¹⁴C-dapoxetine. Analysis by HPLC demonstrated the presence of parent drug and N-desmethyl metabolite (nor-dapoxetine) in those organs examined; however, the majority of the radioactivity remained unidentified.     

Desmoplastic malignant melanoma presenting with orbital involvement

Desmoplastic malignant melanoma (DMM) is a rare variant of spindle cell melanoma. We report a case of DMM of the forehead secondarily involving the orbit. The diagnosis was based on light microscopic features, including prominent peripheral cell nest formation and spindle cell fascicles in densely collagenous stroma. Immunohistochemical studies showed strong uniform staining for S100 antigen throughout the tumour. It was negative for HMB 45, smooth muscle actin, desmin, cytokeratins and Type IV collagen. Electron microscopy showed neither melanosomes nor myelin figures. The clinical and histological characteristics of desmoplastic malignant melanoma, and its differential diagnosis of malignant schwannoma, are discussed. DMM has a poor prognosis, since it tends to invade deeply, recur locally and metastasise readily.     

Organ hypertrophy and responses of colon microbial populations of growing swine to high dietary protein

Thirty-two castrated male crossbred growing pigs (average initial wt 26.9 kg) were used to determine the effect of a high level of dietary protein (37%) compared with a normal level of protein (15%) on enterobacteria and Campylobacter sp. inhabitation in the large intestine and on visceral organ hypertrophy and the interrelationships between these two factors. Pigs were kept in pairs (eight pens of two pigs/diet) and fed their respective diets and libitum. Eight pigs (two pens of two pigs fed each diet) were killed at wk 4, 8, 12 and 16 without fasting. Fecal samples were obtained every 2 wk from animals scheduled for necropsy at 16 wk, and colon contents were obtained from all pigs at necropsy; samples were enumerated individually for enterobacteria and Campylobacter sp. Weights of heart, lungs, liver, kidneys, perirenal fat and empty stomach, small intestine and large intestine were recorded at necropsy. Stomach, cecum and proximal colon were sectioned for histopathologic examination. Daily body weight gain was depressed by high dietary protein, but liver and kidneys were heavier in the high protein group than in controls at each time interval. Mild lymphoid hyperplasia of Peyer's patches in the small intestine in some pigs in both groups was indicative of antigenic stimulation but not of pathologic significance. There was no effect of diet on counts of enterobacteria or Campylobacter sp. in feces or colon contents during the 16-wk experiment. We conclude that the hypertrophic response of the tissues of growing pigs to high dietary protein is not the result of the presence of Campylobacter sp. or enterobacteria in the colon contents.     

Spinal epidural abscess: a ten-year perspective

A retrospective study of spinal epidural abscess spanning 10 years and encompassing 40 patients was done. Epidemiology, clinical features, laboratory findings, radiographic imaging, therapy, and outcome were examined and compared with previous series. An increasing incidence of the disease (up to 1.96 patients per 10,000 admissions per year) and an older, more debilitated population (67% having factors predisposing them to infection) were discovered. Over half of the population was studied with magnetic resonance imaging, which was found to be equally as sensitive (91%) as myelography with computed tomography (92%). Magnetic resonance imaging offers the advantages of being noninvasive and able to delineate other entities, which makes it the imaging modality of choice. Preoperative paralysis and neurological deterioration from normal were identified as poor prognostic features. Of 7 patients with preoperative paralysis, 5 died, and the rest failed to recover neurological function. Eleven patients with initially normal neurological exams deteriorated in the hospital before surgical intervention. Eight of these patients were being treated with appropriate antibiotics; 2 became paralyzed despite more than 3 weeks of antibiotic therapy. Only 3 of these 11 patients recovered fully. Immediate surgical decompression combined with antibiotics remains the treatment of choice.     

Critical appraisal of neuroprotection trials in head injury: What have we learned?

To date, despite very encouraging preclinical results, almost all phase II/III clinical neuroprotection trials in traumatic brain injury (TBI) have failed to show any consistent improvement in outcome for TBI patients. To understand the reasons behind such developments we need to review and evaluate the evolution of trial design as a result of our changing understanding of the pathophysiology of brain cell death and progress of translational research from the laboratory bench to the bedside. This paper attempts to critically appraise these neuroprotection trials, rationalize the paucity of effectiveness, review any recent developments in the field, and try to draw some conclusions on how to move forward.