During an infection or inflammation, several drug-metabolizing enzymes in the liver are down-regulated, including cytochrome P450 iso-enzymes. Since voriconazole is extensively metabolized by ...cytochrome P450 iso-enzymes, the metabolism of voriconazole can be influenced during inflammation via reduced clearance of the drug, resulting in higher voriconazole trough concentrations.
To investigate prospectively the influence of inflammation on voriconazole metabolism and voriconazole trough concentrations.
A prospective observational study was performed at the University Medical Center Groningen. Patients were eligible for inclusion if they were ≥18 years old and treated with voriconazole. Voriconazole and voriconazole-N-oxide concentrations were determined in discarded blood samples. To determine the degree of inflammation, C-reactive protein (CRP) concentrations were used. Subsequently, a longitudinal data analysis was performed to assess the effect of inflammation on the metabolic ratio and voriconazole trough concentration.
Thirty-four patients were included. In total 489 voriconazole trough concentrations were included in the longitudinal data analysis. This analysis showed that inflammation, reflected by CRP concentrations, significantly influenced the metabolic ratio, voriconazole trough concentration and voriconazole-N-oxide concentration (all P < 0.001), when corrected for other factors that could influence voriconazole metabolism. The metabolic ratio was decreased by 0.99229
and the voriconazole-N-oxide concentration by 0.99775
, while the voriconazole trough concentration was increased by 1.005321
, where N is the difference in CRP units (in mg/L).
This study shows that voriconazole metabolism is decreased during inflammation, resulting in higher voriconazole trough concentrations. Therefore, frequent monitoring of voriconazole serum concentrations is recommended during and following severe inflammation.
...mutations can be used to predict different treatment outcomes. ...by also considering phylogenetic benign mutations that do not confer resistance, a comprehensive molecular drug susceptibility ...profile could be inferred for a pathogen-tailored individualized treatment regimen in the future. cgMLST,core genome multilocus sequencing type; TB, tuberculosis. https://doi.org/10.1371/journal.ppat.1007297.g001 These examples of how genomic data inform treatment choice illustrate the concept of precision medicine in infectious diseases, in which prevention and treatment strategies take information from systems biology and individual variability into account 5. First clinical data are accumulating, demonstrating how pathogen-based genetic information provides insights on potential treatment course and outcome. ...therapeutic drug monitoring using dried blood-spots provides information on the drug level at a certain time point. ...insights on the phylogenetic lineage of the individual and infecting MTBC strain, coupled with their virulence and transmission properties, may inform and further individualize the treatment course.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • We identified 5 potential therapeutic TB vaccines—Mycobacterium vaccae, RUTI, Mycobacterium smegmatis, Mycobacterium indicus pranii and V5. • M. vaccae and RUTI appeared most advanced, ...with most safety data in humans for M. vaccae. • Addition of therapeutic vaccine candidates in MDR-TB treatment should be tested for safety and efficacy in clinical trials. • Testing TB vaccine candidate products in TB patients provides a novel platform for TB vaccine development. • New clinical trial research platforms need to be developed to further test current and future TB vaccine product candidates.
Buruli ulcer is a neglected tropical disease caused by Myocobacterium ulcerans; it manifests as a skin lesion, nodule, or ulcer that can be extensive and disabling. To assess the global burden and ...the progress on disease control, we analyzed epidemiologic data reported by countries to the World Health Organization during 2010-2017. During this period, 23,206 cases of Buruli ulcer were reported. Globally, cases declined to 2,217 in 2017, but local epidemics seem to arise, such as in Australia and Liberia. In 2013, the World Health Organization formulated 4 programmatic targets for Buruli ulcer that addressed PCR confirmation, occurrence of category III (extensive) lesions and ulcerative lesions, and movement limitation caused by the disease. In 2014, only the movement limitation goal was met, and in 2019, none are met, on a global average. Our findings support discussion on future Buruli ulcer policy and post-2020 programmatic targets.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies portend a rising global spread and adaptation of human- or healthcare-associated pathogens. Here, we analyse an international collection of the emerging, multidrug-resistant, ...opportunistic pathogen Stenotrophomonas maltophilia from 22 countries to infer population structure and clonality at a global level. We show that the S. maltophilia complex is divided into 23 monophyletic lineages, most of which harbour strains of all degrees of human virulence. Lineage Sm6 comprises the highest rate of human-associated strains, linked to key virulence and resistance genes. Transmission analysis identifies potential outbreak events of genetically closely related strains isolated within days or weeks in the same hospitals.
Establishing a correct diagnosis is challenging. We aimed to investigate the sensitivity and specificity of routine tuberculosis (TB) diagnostic work-up in lung clinics in Indonesia, a country with ...the third highest TB burden and the second highest gap between notifications of TB cases and the best estimate of incident cases in the world.
In the lung clinics of the Province of Yogyakarta, Indonesia, we recruited all consecutive patients with symptoms suggesting TB, aged ≥18 years. Routine TB examination consisted of clinical evaluation, sputum smear microscopy, and chest radiography. For research purposes, we added sputum culture, Human Immunodeficiency Virus (HIV) testing, and follow-up for 1.5 years or 2.5 years if culture results disagreed with the initial clinical diagnosis. The initial diagnosis was considered incorrect if patients did not respond to treatment. We calculated sensitivity and specificity of the TB routine examination using culture and a composite reference standard (CRS - a combination of routine examination, culture, and follow-up) as the reference standards. All analyses were conducted with IBM SPSS Statistics 25 (IBM Corp., Armonk, NY, USA).
Between 2013 and 2015, we included 360 participants, and 21 were excluded due to incomplete data. Among those analyzed, 115 were initially diagnosed with smear-positive TB, 12 with smear-negative TB, and 212 non-TB. In 15 study participants, the diagnosis was changed after median 45 (range: 14-870) days; 14 participants initially not diagnosed with TB were later diagnosed with TB, while one subject initially diagnosed with TB actually did not have TB. Compared with culture and CRS, TB routine examination had sensitivity of 85% (95%CI: 77-91) and 90% (95%CI: 84-94), and specificity of 86.3% (95%CI: 81-91) and 99.5% (95%CI: 97-100), respectively.
A combination of clinical evaluation with sputum microscopy and chest radiography provided high sensitivity and specificity in diagnosing TB in lung clinics; in only 4.4% the diagnosis was incorrect. There is a need to improve routine TB diagnostic work by using clinical evaluation, sputum smear microscopy, and chest radiography all together in other settings, such as in primary health centers.
NCT02219945 , clinicaltrials.gov . Registered 19 August 2014 (retrospectively registered).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment ...with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. Methods In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7·5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT00321178. Findings Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2·49, 95% CI 0·66 to infinity; p=0·16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). Interpretation Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. Funding European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.
IMPORTANCE Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis. OBJECTIVE To ...determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis. DESIGN, SETTING, AND PARTICIPANTS The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in the Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. INTERVENTIONS Azithromycin (250 mg daily) or placebo for 12 months. MAIN OUTCOME MEASURES Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life. RESULTS Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range IQR, 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 95% CI, 0.16-0.51). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 95% CI, 0.97-56.88 for abdominal pain and 8.36 95% CI, 1.10-63.15 for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group. CONCLUSIONS AND RELEVANCE Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00415350
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