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Contains fulltext : 88335.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 70639.pdf (Publisher’s version ) (Closed access) Voriconazole is a triazole antifungal developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi, and opportunistic molds. Voriconazole has a nonlinear pharmacokinetic profile with a wide inter- and intraindividual variety. This variability is caused by many factors such as gender, age, genotypic variation, liver dysfunction, the presence of food, and so on. Another important factor influencing voriconazole's pharmacokinetic profile is drug-drug interactions with CYP450 inhibitors as well as inducers. Variability in plasma concentrations, as a result of the previously mentioned aspects, may lead to variability in efficacy or toxicity. Determination of plasma concentrations is indicated in situations to guide dosing and to individualize and improve the treatment options resulting in better therapeutic outcome or fewer side effects. In this article, we review factors influencing voriconazole pharmacokinetic profile, the data supporting exposure-effect and exposure-toxicity relationships, review the gaps in current knowledge, which make broad recommendations for therapeutic drug monitoring difficult for voriconazole, provide the indications in which therapeutic drug monitoring is reasonable based on currently available data (eg, children), and outline the ways in which this problem could be solved. We provide a summary of the problem so that further research can be conducted to address this are of clinical need.

Contains fulltext : 51950.pdf (Publisher’s version ) (Closed access)

The early bactericidal activity of antituberculosis agents is usually determined by measuring the reduction of the sputum mycobacterial load over time on solid agar medium or in liquid culture. This study investigated the value of a quantitative PCR assay for early bactericidal activity determination. Groups of 15 patients were treated with 6 different antituberculosis agents or regimens. Patients collected sputum for 16 h overnight at baseline and at days 7 and 14 after treatment initiation. We determined the sputum bacterial load by CFU counting (log CFU/ml sputum, reported as mean ± standard deviation [SD]), time to culture positivity (TTP, in hours [mean ± SD]) in liquid culture, and Xpert MTB/RIF cycle thresholds ( C T , n [mean ± SD]). The ability to discriminate treatment effects between groups was analyzed with one-way analysis of variance (ANOVA). All measurements showed a decrease in bacterial load from mean baseline (log CFU, 5.72 ± 1.00; TTP, 116.0 ± 47.6; C T , 19.3 ± 3.88) to day 7 (log CFU, −0.26 ± 1.23, P = 0.2112; TTP, 35.5 ± 59.3, P = 0.0002; C T , 0.55 ± 3.07, P = 0.6030) and day 14 (log CFU, −0.55 ± 1.24, P = 0.0006; TTP, 54.8 ± 86.8, P < 0.0001; C T , 2.06 ± 4.37, P = 0.0020). The best discrimination between group effects was found with TTP at day 7 and day 14 ( F = 9.012, P < 0.0001, and F = 11.580, P < 0.0001), followed by log CFU ( F = 4.135, P = 0.0024, and F = 7.277, P < 0.0001). C T was not significantly discriminative ( F = 1.995, P = 0.091, and F = 1.203, P = 0.316, respectively). Culture-based methods are superior to PCR for the quantification of early antituberculosis treatment effects in sputum.

Item does not contain fulltext In an outbreak of multidrug-resistant tuberculosis, the outbreak strain had an Asp516Tyr rpoB gene mutation. Phenotypically, low-level rifampicin (RMP) resistance (minimum inhibitory concentration [MIC] 1-2 mg/l) was observed. Based on drug susceptibility test results, three patients were treated with 12-15 month rifabutin-based regimens and one with a 12-month RMP-based regimen. We retrospectively performed pharmacokinetic calculations to assess the potential for RMP treatment, from which we conclude that MICs for RMP up to 1 mug/ml may be safely overcome by applying 20 mg/kg RMP doses in treatment regimens.

Item does not contain fulltext Non-adherence to tuberculosis (TB) treatment is a major challenge to global TB control because it increases the risk of treatment failure, relapse and the emergence of drug-resistant TB. Although the problem is widely acknowledged, there is still no clarity about the exact impact of different levels and patterns of non-adherence on treatment outcome. This hampers the provision of adequate advice to patients and clinicians, and it challenges the development and evaluation of adherence-promoting interventions. In this article, we explain why we are still in the dark with respect to predicting how different types of non-adherence to TB treatment affect treatment outcome. We show that we lack uniformity in how we define and measure non-adherence, that we have no easily accessible treatment success indicators, and that the relationship between treatment adherence and outcome is influenced by a number of pathogenic, immunological and pharmacological factors that are only partly understood. We conclude that an integral 'bench and bedside approach' that incorporates experimental studies with in vitro models and animals, as well as observational studies in patients with TB, is needed to help us get out of the dark regarding the adherence-response relationship in TB treatment.

Contains fulltext : 88141.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care. METHODS: Systematic literature review. RESULTS: Using public databases, it can be estimated that 12.6% (95% CI 9.2-17.3%) of new TB cases in the 10 countries with the highest TB burden will be attributable to TB in 2030, a relative increase of 25.5% compared to 2010. Diabetes is associated with a higher age and body weight among patients with TB, but probably not with a specific clinical presentation of TB. Rifampicin hampers glycemic control by increasing the metabolism of most oral antidiabetic drugs, while diabetes patients may have lower concentrations of anti-TB drugs. This might be one factor contributing to higher TB treatment failure rates. CONCLUSIONS: The global epidemic of diabetes has implications for control and treatment of TB. Prospective studies are needed to improve prevention, early detection and treatment of concomitant diabetes and TB, especially in developing countries. 01 november 2010

Contains fulltext : 81627.pdf (Publisher’s version ) (Closed access) SETTING: Kilimanjaro Region, northern Tanzania. OBJECTIVE: To assess the effect of the introduction of the patient-centred tuberculosis treatment (PCT) approach-which allows tuberculosis (TB) patients to choose between community and facility-based directly observed treatment (DOT)-on treatment outcomes, and to analyse factors that contribute to opting for community DOT. DESIGN: Retrospective analysis of treatment outcomes of TB patients registered in the Kilimanjaro Region in 2007, differentiating between patients under community vs. facility-based DOT and taking into account demographic factors, disease classification, TB diagnosis and human immunodeficiency virus (HIV) status. RESULTS: Data from 2769 TB patients were analysed. Treatment success rates were respectively 81% and 70% in patients under community vs. facility-based DOT (P < 0.001). Cure rates were respectively 73% and 72% in smear-positive pulmonary TB patients under community vs. facility-based DOT (P = 0.62). Women, children, patients residing in districts other than Hai, patients with newly diagnosed TB and patients with smear-negative pulmonary TB were most likely to be under community DOT. CONCLUSION: The PCT approach was shown to be effective in terms of treatment outcomes. Treatment success rates were higher in patients who opted for community DOT than in patients who chose facility-based DOT (all cases), and were similar in smear-positive pulmonary TB patients under community or facility-based DOT.

Contains fulltext : 69082.pdf (Publisher’s version ) (Closed access) A step-wise approach to identify valid and feasible methods to detect non-adherence to tuberculosis drugs was evaluated in a prospective study among pulmonary tuberculosis patients in an outpatient clinic in Indonesia. First, adherence was measured by self-reporting with the standardized Morisky questionnaire, physician assessment, pill-count, visit attendance, diary and an electronic medication event monitoring system (MEMS). Next, validity of single methods was assessed against MEMS as gold standard. Feasibility of methods was then judged by physicians in the field. Finally, when valid and feasible methods were combined, it appeared that self-reporting by a questionnaire plus physician assessment could identify all non-adherent patients. It is recommended to use a systematic approach to develop a valid and locally feasible combination of methods to detect non-adherence to TB drugs.

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Contains fulltext : 48799.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 51203.pdf (Publisher’s version ) (Closed access)

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Contains fulltext : 112906.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 19 september 2013 Promotor : Dekhuijzen, P.N.R. Co-promotores : Boeree, M.J., Aarnoutse, R.E.

Contains fulltext : 74429.pdf (Publisher’s version ) (Open Access) RU Radboud Universiteit Nijmegen, 21 augustus 2009 Promotor : Hekster, Y.A. Co-promotores : Aarnoutse, R.E., Crevel, R. van 195 p.

Contains fulltext : 80115.pdf (Publisher’s version ) (Open Access) RU Radboud Universiteit Nijmegen, 16 december 2009 Promotor : Dekhuijzen, P.N.R. Co-promotores : Boeree, M.J., Aarnoutse, R.E. 162 p.