| 1. |
- Rao, Komal Umashankar, et al.
(författare)
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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.
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| 2. |
- Forsman, L. Davies, et al.
(författare)
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Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis
- 2014
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 58:12, s. 7557-7559
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC(0-24)/MIC) using >= 25 as a potential target, the cumulative fraction response was >= 90% at doses of >= 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.
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| 3. |
- Balcha, Taye, et al.
(författare)
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Detection of lipoarabinomannan in urine for identification of active tuberculosis among HIV-positive adults in Ethiopian health centres
- 2014
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Ingår i: Tropical medicine & international health. - : Wiley. - 1360-2276 .- 1365-3156. ; 19:6, s. 734-742
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo assess the diagnostic performance of urine lipoarabinomannan (LAM) detection for TB screening in HIV-positive adults in Ethiopia. MethodsTesting for LAM was performed using the Determine TB-LAM lateral flow assay on urine samples from participants in a prospective cohort with baseline bacteriological categorisation for active TB in sputum. Characteristics of TB patients with regard to LAM status were determined. Participants were followed for 6months to evaluate survival, retention in care and incident TB. ResultsPositive LAM results were found in 78/757 participants. Among 128 subjects with definite (confirmed by culture and/or Xpert MTB/RIF) TB, 33 were LAM-positive (25.8%); the respective figure for clinically diagnosed cases was 2/20 (10%). Five of the remaining 43 LAM-positive individuals had died during the 6-month follow-up period, whereas 38 remained in care without clinical signs of TB. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 25.8%, 92.9%, 42.3% and 86.0%, respectively. Among TB patients, LAM positivity was associated with higher WHO clinical stage, lower body mass index (BMI), CD4 cell and haemoglobin levels, and with increased mortality. A combination algorithm of urine LAM testing and sputum smear microscopy detected 49 (38.2%) of definite TB cases; among those with CD4 count 100cells/mm(3), this proportion was 66.7%. ConclusionsThe performance of urine LAM testing for TB detection was poor in this population. However, this was improved among subjects with CD4 count 100cells/mm(3). In combination with sputum microscopy urine, LAM could be considered for targeted TB screening in this subgroup.
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| 4. |
- Balcha, Taye, et al.
(författare)
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Intensified Tuberculosis Case-Finding in HIV-Positive Adults Managed at Ethiopian Health Centers: Diagnostic Yield of Xpert MTB/RIF Compared with Smear Microscopy and Liquid Culture
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:1, s. 85478-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia. Methods: Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture. Results: TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert-positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts greater than200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts less than= 100 cells/mm(3). Compared with Xpert-positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics. Conclusions: Previously undiagnosed TB is common among HIV-positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study.
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| 5. |
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| 6. |
- Juréen, P., et al.
(författare)
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Wild-type MIC distributions for aminoglycoside and cyclic polypeptide antibiotics used for treatment of Mycobacterium tuberculosis infections
- 2010
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Ingår i: Journal of Clinical Microbiology. - : American Society for Microbiology. - 0095-1137 .- 1098-660X. ; 48:5, s. 1853-1858
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Tidskriftsartikel (refereegranskat)abstract
- The aminoglycosides and cyclic polypeptides are essential drugs in the treatment of multidrug-resistant tuberculosis, underscoring the need for accurate and reproducible drug susceptibility testing (DST). The epidemiological cutoff value (ECOFF) separating wild-type susceptible strains from non-wild-type strains is an important but rarely used tool for indicating susceptibility breakpoints against Mycobacterium tuberculosis. In this study, we established wild-type MIC distributions on Middlebrook 7H10 medium for amikacin, kanamycin, streptomycin, capreomycin, and viomycin using 90 consecutive clinical isolates and 21 resistant strains. Overall, the MIC variation between and within runs did not exceed +/-1 MIC dilution step, and validation of MIC values in Bactec 960 MGIT demonstrated good agreement. Tentative ECOFFs defining the wild type were established for all investigated drugs, including amikacin and viomycin, which currently lack susceptibility breakpoints for 7H10. Five out of seven amikacin- and kanamycin-resistant isolates were classified as susceptible to capreomycin according to the current critical concentration (10 mg/liter) but were non-wild type according to the ECOFF (4 mg/liter), suggesting that the critical concentration may be too high. All amikacin- and kanamycin-resistant isolates were clearly below the ECOFF for viomycin, and two of them were below the ECOFF for streptomycin, indicating that these two drugs may be considered for treatment of amikacin-resistant strains. Pharmacodynamic indices (peak serum concentration [Cmax]/MIC) were more favorable for amikacin and viomycin compared to kanamycin and capreomycin. In conclusion, our data emphasize the importance of establishing wild-type MIC distributions for improving the quality of drug susceptibility testing against Mycobacterium tuberculosis.
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| 7. |
- Nilsson, Ingrid, et al.
(författare)
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Helicobacter ganmani infection associated with a spontaneous outbreak of inflammatory bowel-like disease in an IL-10-deficient mouse colony
- 2008
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Ingår i: Scandinavian Journal of Laboratory Animal Science. - 0901-3393. ; 35:1, s. 13-24
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Tidskriftsartikel (refereegranskat)abstract
- Background: A breeding colony of IL-10 deficient B6.129P2-Il10(tmICgn/J) mice, kept under conventional conditions, developed an inflammatory bowel-like disease (IBD) with rectal prolapse and blood tinged diarrhoea. No clinical signs of disease were observed at the time of arrival to our animal house. These animals were originally planned to serve as a negative control group in an experimental infection study with Helicobacter species to investigate colonization of the murine gut. Results: A spiral-shaped, Gram-negative bacterium was isolated from the breeding mice colony. In a first group of six animals, tissue specimens from the liver, small and large intestines, faeces and blood, were analysed by culture, PCR-denaturing gradient gel electrophoresis (PCR-DGGE), species-specific PCR assays and DNA-sequencing, histology and serology. Helicobacter ganmani, but no other Helicobacter species, was isolated from the liver, small bowel, caecum, colon and faeces. We found inflammation in caeca, colon and livers, most pronounced in the caecal areas of culture positive mice with a severe typhlitis with cystic dilatation of glandular structures and irregular crypt architecture. Some animals showed a pronounced colitis with mucosal and sub-mucosal inflammatory infiltrates. Other animals displayed large lymphoid infiltrates in the livers and hepatitis. Tissue samples and sera from 18 additional animals from the same breeding colony were analysed by the same methods, except for culture. H. ganmani was identified by PCR in most tissue samples of the 18 additional animals as well. Sero-conversion to H. ganmani correlated well with histopathological changes. Conclusions: Our findings emphasize the importance of using Helicobacter-free animals to develop murine models of chronic hepatitis and colitis.
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| 8. |
- Sjunnesson, Håkan, et al.
(författare)
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High intake of selenium, beta-carotene, and vitamins A, C, and E reduces growth of Helicobacter pylori in the guinea pig
- 2001
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Ingår i: Comparative Medicine. - 1532-0820. ; 51:5, s. 418-423
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Helicobacter pylori is a human gastroduodenal pathogen associated with type-B gastritis and gastric cancer. Low gastric tissue antioxidant levels are believed to increase the risk of developing gastric cancer. We investigated whether dietary antioxidant levels protect against infection and type-B gastritis in H. pylori-infected guinea pigs. METHODS: Dunkin-Hartley guinea pigs infected for 6 weeks with H. pylori were fed diets with various antioxidant levels. Stomach specimens were cultured, and gastritis was graded from 0 to 3. RESULTS: Supplementation with vitamins A, C, and E and with selenium yielded H. pylori recovery from 17% of challenged animals, compared with 43% of those fed a control diet. Gastritis was scored at 0.33 and 0.93, respectively. Supplementation with only vitamin C or astaxanthin had less effect on gastritis and recovery rate. In a second experiment, gastritis score in a group given vitamins A, C, E, and selenium and beta-carotene was 2.25 and in a control group, it was 2.57. The H. pylori recovery rate was 75 and 100%, respectively, with fewer colonies from animals given antioxidant supplementation (P < 0.05). CONCLUSIONS: A combination of antioxidants can protect against H. pylori infection in guinea pigs. In animal studies, antioxidant intake should be low to optimize development of H. pylori-associated disease. Furthermore we established that H. pylori causes severe gastritis in guinea pigs.
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| 9. |
- Sturegård, Erik
(författare)
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Gastric and enteric Helicobacter species in animal models and in the human colon
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Gram-negative genus of Helicobacter consists of many bacterial species that colonize a wide range of animal hosts. The genus can be divided into gastric species that colonize the stomach, and enteric species that preferentially colonize the colon and biliary tree of various animal hosts. Helicobacter pylori cause gastritis, gastro-duodenal ulcer disease and gastric adenocarcinoma and lymphoma in infected individuals. Enteric Helicobacter species cause typhlocolitis, hepatitis and neoplasia of the colon and liver in various rodent models of disease. A novel guinea pig model of H. pylori infection was developed and the infection was found to cause severe inflammatory changes in the stomach and an H. pylori-specific antibody response in infected animals after 3 and 7 weeks of infection. Different strains of H. pylori, with regards to the cagA gene and VacA protein expression, could infect mice. The infection was found to cause an H. pylori specific antibody response in mice infected with strains expressing the VacA protein. Simultaneous co-infection of mice with seven different strains of H. pylori showed evidence of colonization with two different strains. Gastritis was not apparent in mice infected with H. pylori for up to 17 weeks. H. pylori infection was found to lead to substantially more gastritis and serologic antibody response in guinea pigs than in mice. In guinea pigs, the infection was found to cause an elevation of acute-phase protein C3 and cholesterol, which could constitute a possibility to study an H. pylori trigger of extra-alimentary diseases. Helicobacter ganmani was isolated from interleukin-10 deficient mice with typhlocolitis and hepatitis. Analysis of serum antibodies demonstrated an immune response against H. ganmani in animals with disease. This recently described species of Helicobacter was implicated as the possible source of the disease found among the animals but this link needs to be evaluated in a controlled, experimental set-up. The importance of using Helicobacter-free animals for a wide range of experiments, especially when using immune deficient animals, needs to be stressed. Human colon biopsies from 20 patients with inflammatory bowel disease and other ailments were investigated for Helicobacter colonization. DNA resembling H. pylori was detected in two, Helicobacter cholecystus in one and Helicobacter muridarum in one patient. The latter two species have previously not been described in human tissue. No apparent link was found between the detection of Helicobacter species and human inflammatory bowel disease. In summary, this thesis deals with development and optimization of two animal models for H. pylori infection and also explores the role of enteric Helicobacter species in human and animal disease.
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| 10. |
- Wang, Xin, et al.
(författare)
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Dietary factors influence the recovery rates of Helicobacter pylori in a BALB/cA mouse model
- 1998
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Ingår i: Zentralblatt für Bakteriologie: Ternational Journal of Medical Microbiology: Medical Microbiology, Virology, Parasitology, Infectious Diseases. - 0934-8840. ; 288:2, s. 195-205
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to assess the ability of different mouse diets to sustain an H. pylori infection in BALB/cA mice. Four commercially available mouse diets were compared. Experiment 1: Mice were fed the four diets for seven days before infection, infected three times at two-day intervals with 0.1 ml of 10(9) colony-forming units/ml H. pylori cells. H. pylori strains (n = 4) were cultured on GAB-Camp agar for 2 days, harvested and suspended in PBS. All animals were sacrificed at 2 and 4 weeks post inoculation. Experiment 2: Mice infected for 8 weeks were fed RM2, changed to the different diets for 10 days and sacrificed. Stomachs were collected, cultured on GAB-Camp agar to estimate H. pylori growth and stomach biopsies were analyzed by PCR. There were significant differences between diets in their ability to sustain growth of H. pylori. The range was from a few hundred colonies to no growth at all on the GAB-Camp agar. PCR signals showed good correlation with the culture results. All H. pylori-infected mice gave a significantly higher inflammation score compared to non-infected mice. The diet RM2, having the highest number of culturable H. pylori in the mouse stomach, also showed the highest inflammation. These results suggest that the dietary factors affect the amounts of H. pylori in an infection of BALB/cA mice.
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