Role of antibiotics and fungal microbiota in driving pulmonary allergic responses.
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Over the past four decades, there has been a significant increase in allergy and asthma in westernized countries, which correlates with alterations in fecal microbiota (microflora) and widespread use of antibiotics (the "hygiene hypothesis"). Antibiotics also lead to overgrowth of the yeast Candida albicans, which can secrete potent prostaglandin-like immune response modulators. We have developed a mouse model of antibiotic-induced microbiota disruption that includes stable increases in gastrointestinal (GI) enteric bacteria and GI Candida levels with no introduction of microbes into the lungs. Mice are treated for 5 days with cefoperazone in the drinking water, followed by a single oral gavage of C. albicans. This results in alterations of GI bacterial populations and increased yeast numbers in the GI microbiota for at least 2 to 3 weeks and can drive the development of a CD4 T-cell-mediated allergic airway response to subsequent mold spore (Aspergillus fumigatus) exposure in immunocompetent mice without previous systemic antigen priming. The allergic response in the lungs is characterized by increased levels of eosinophils, mast cells, interleukin-5 (IL-5), IL-13, gamma interferon, immunoglobulin E, and mucus-secreting cells. In the absence of antibiotics, mice exposed to Aspergillus spores do not develop an allergic response in the airways. This study provides the first experimental evidence to support a role for antibiotics and fungal microbiota in promoting the development of allergic airway disease. In addition, these studies also highlight the concept that events in distal mucosal sites such as the GI tract can play an important role in regulating immune responses in the lungs. (+info)
In vitro bactericidal activity of antimicrobial agents against enterohaemorrhagic Escherichia coli.
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OBJECTIVES: In vitro bactericidal activity of four antimicrobial agents was determined against nine strains of enterohaemorrhagic Escherichia coli. METHODS: Pulsed-field gel electrophoresis was carried out with the Bio-Rad Gene Path system. Each antimicrobial agent was added to logarithmic phase of enterohaemorrhagic E. coli (four strains of E. coli O157:H7, two of E. coli O26, two of E. coli O111, and one of E. coli O165) in broth to obtain a concentration of 10 or 50 mg/L, and viable cells were counted after 1, 2, 6 and 24 h. RESULTS: All nine strains were confirmed to differ in their DNA pattern by pulsed-field gel electrophoresis. Norfloxacin at concentrations of 10 and 50 mg/L had bactericidal effects on all nine strains of enterohaemorrhagic E. coli. However, cefoperazone, kanamycin and fosfomycin had no bactericidal effects on some strains. In particular, after addition of 10 mg/L fosfomycin or kanamycin, four of the nine strains showed proliferation. CONCLUSIONS: Norfloxacin had marked bactericidal effects on enterohaemorrhagic E. coli. This information could be of value in planning randomized clinical trials of antimicrobial agents as treatment for enterohaemorrhagic E. coli infection. (+info)
Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13.
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Lending support to the hygiene hypothesis, epidemiological studies have demonstrated that allergic disease correlates with widespread use of antibiotics and alterations in fecal microbiota ("microflora"). Antibiotics also lead to overgrowth of the yeast Candida albicans, which can secrete potent prostaglandin-like immune response modulators, from the microbiota. We have recently developed a mouse model of antibiotic-induced gastrointestinal microbiota disruption that is characterized by stable increases in levels of gastrointestinal enteric bacteria and Candida. Using this model, we have previously demonstrated that microbiota disruption can drive the development of a CD4 T-cell-mediated airway allergic response to mold spore challenge in immunocompetent C57BL/6 mice without previous systemic antigen priming. The studies presented here address important questions concerning the universality of the model. To investigate the role of host genetics, we tested BALB/c mice. As with C57BL/6 mice, microbiota disruption promoted the development of an allergic response in the lungs of BALB/c mice upon subsequent challenge with mold spores. In addition, this allergic response required interleukin-13 (IL-13) (the response was absent in IL-13(-/-) mice). To investigate the role of antigen, we subjected mice with disrupted microbiota to intranasal challenge with ovalbumin (OVA). In the absence of systemic priming, only mice with altered microbiota developed airway allergic responses to OVA. The studies presented here demonstrate that the effects of microbiota disruption are largely independent of host genetics and the nature of the antigen and that IL-13 is required for the airway allergic response that follows microbiota disruption. (+info)
A model of cefoperazone tissue penetration: diffusion coefficient and protein binding.
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The apparent diffusion coefficient of a bound drug, cefoperazone, was studied. The protein binding of cefoperazone was studied by voltammetry, a technique which permitted instant measurements. The apparent diffusion coefficients were similar in agar and fibrin and lower in rat brain tissue. The influence of protein on the value of the apparent diffusion coefficient was negligible. The hypothesis that only the free drug diffuses was supported. The percentage of binding determined by voltammetry corresponded to the true concentration of drug which diffuses and is much lower than the percentage of binding determined by the ultrafiltration centrifugation method. This discrepancy could be explained by the rate of dissociation of the protein-drug complex. (+info)
Use of a predictor panel for development of a new disk for diffusion tests with cefoperazone-sulbactam.
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The proper disk mass for diffusion susceptibility tests with cefoperazone-sulbactam was determined by using a predictor panel of clinical isolates that included staphylococci and gram-negative bacteria intrinsically susceptible, intrinsically resistant, and of various susceptibilities because of the production of different types and amounts of beta-lactamase. A primary panel of 24 isolates was used to screen various disk masses of cefoperazone and sulbactam in disk diffusion susceptibility tests. Regression analyses were performed for each combination by comparing MICs to zone diameters. Analysis of each component demonstrated that decreasing the disk mass of cefoperazone shifted the regression line to the left while decreasing the disk mass of sulbactam diminished the slope of the line. Ten candidate disks that adequately separated susceptible and resistant strains among the primary panel were identified, and these 10 disks, along with the previously proposed 75/30-micrograms disk, were then tested against an expanded panel of 265 isolates. Results indicated that a 30/20-micrograms cefoperazone-sulbactam disk provided the best separation between susceptible and resistant strains when interpretive criteria of less than or equal to 15 mm for resistance, 16 to 19 mm for moderate susceptibility, and greater than or equal to 20 mm for susceptibility were used. They also identified discrepancies between agar and broth microdilution MICs of sufficient size to warrant separate interpretive criteria for the two methods. Overall, the use of a predictor panel to develop interpretive criteria for susceptibility tests appeared to be a very useful approach, especially when antibiotics designed to be used against drug-resistant organisms are involved. (+info)
Pharmacokinetic disposition and bactericidal activities of cefepime, ceftazidime, and cefoperazone in serum and blister fluid.
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Cefepime is a new broad-spectrum cephalosporin with excellent gram-positive and gram-negative activity including activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter cloacae. The pharmacokinetic disposition of cefepime is similar to that of ceftazidime. We compared the pharmacokinetic characteristics and the extent and duration of bactericidal activity in serum and suction-induced blister fluid after single 2-g intravenous doses of cefepime, ceftazidime, and cefoperazone given to healthy subjects. One clinical isolate each of E. cloacae, P. aeruginosa, and S. aureus was used to assess bactericidal activity. Results of the pharmacokinetic analysis were similar to previously reported data for these drugs. The high serum protein binding of cefoperazone (approximately 90%) contributed to poor blister fluid penetration. The other drugs penetrated well into this fluid compartment. Cefepime showed significantly greater bactericidal activity in serum and blister fluid against E. cloacae than the other study drugs, ceftazidime was significantly better in serum and blister fluid against P. aeruginosa, and cefoperazone was significantly better against S. aureus only in serum. None of the study drugs had significant bactericidal activity in blister fluid against S. aureus. Cefepime is a promising antimicrobial agent for the treatment of infections due to E. cloacae. (+info)
Syndrome of inappropriate secretion of antidiuretic hormone associated with multiple sclerosis.
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A 63-year-old man who developed episodes of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) twice in the course of multiple sclerosis (MS) is reported. SIADH in this patient occurred only during the administration of antibiotics (sulbactam/cefoperazone, SBT/CPZ). At autopsy, demyelinating lesions in the optic nerves, cervical and thoracic spinal cord, and areas adjacent to the lateral ventricles were observed. Destruction and loss of neuronal cells were found in the supraoptic nuclei. Lymphocytic infiltration was observed in the area adjacent to the supraoptic nuclei. Destruction and swelling of axons and reactive astrocytic gliosis were observed in the hypothalamus. SIADH associated with MS is rare and the histological findings in such a case have not yet been reported. It is suggested that the development of SIADH in MS may be related to the damage in the supraoptic nuclei of the hypothalamus. (+info)
Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia.
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Multiple antibiotic resistance threatens successful treatment of Acinetobacter baumannii infections worldwide. Increasing interest in the well-known activity of sulbactam against the genus Acinetobacter has been aroused. The purpose of this study was to compare the outcomes for patients with Acinetobacter bacteremia treated with cefoperazone/sulbactam versus imipenem/cilastatin. Forty-seven patients with Acinetobacter baumannii bacteremia were analyzed through a retrospective review of their medical records for antibiotic therapy and clinical outcome. Thirty-five patients were treated with cefoperazone/sulbactam, and twelve patients with imipenem/cilastatin. The percentage of favorable response after 72 hours was not statistically different between cefoperazone/sulbactam group and imipenem/cilastatin group. The mortality rate was not statistically different, too. Cefoperazone/sulbactam was found to be as useful as imipenem/cilastatin for treating patients with Acinetobacter bacteremia. (+info)