| 1. |
- Litjens, Carlijn H. C., et al.
(författare)
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Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
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Tidskriftsartikel (refereegranskat)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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| 2. |
- Msoka, Elizabeth F., et al.
(författare)
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Qualitative assessment of the impact of socioeconomic and cultural barriers on uptake and utilisation of tuberculosis diagnostic and treatment tools in East Africa : A cross-sectional study
- 2021
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Early diagnosis and timely treatment are key elements of a successful healthcare system. We assessed the role of socioeconomic and cultural norms in accelerating or decelerating uptake and utilisation of health technologies into policy and practice. Setting Secondary and tertiary level healthcare facilities (HCFs) in three East African countries. Level of HCF was selected based on the WHO recommendation for implantation of tuberculosis (TB) molecular diagnostics. Participants Using implementation of TB diagnostics as a model, we purposively selected participants (TB patients, carers, survivors, healthcare practitioners, community members, opinion leaders and policy-makers) based on their role as stakeholders. In-depth interviews, key informant interviews and focus group discussions were held to collect the data between 2016 and 2018. The data were transcribed, translated, coded and analysed by thematic-content analysis. Results A total of 712 individuals participated in the study. Socioeconomic and cultural factors such as poverty, stigma and inadequate knowledge about causes of disease and available remedies, cultural beliefs were associated with low access and utilisation of diagnostic and treatment tools for TB. Poverty made people hesitate to seek formal healthcare resulting in delayed diagnosis and resorting to self-medication and cheap herbal alternatives. Fear of stigma made people hide their sickness and avoid reporting for follow-up treatment visits. Inadequate knowledge and beliefs were fertile ground for aggravated stigma and believing that diseases like TB are caused by spirits and thus cured by spiritual rituals or religious prayers. Cultural norms were also the basis of gender-based imbalance in accessing care, 'I could not go to hospital without my husband's permission', TB survivor. Conclusion Our findings show that socioeconomic and cultural factors are substantial 'roadblocks' to accelerating the uptake and utilisation of diagnostic and treatment tools. Resolving these barriers should be given equal attention as is to health system barriers.
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| 3. |
- Ntinginya, Nyanda Elias, et al.
(författare)
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Unlocking the health system barriers to maximise the uptake and utilisation of molecular diagnostics in low-income and middle-income country setting
- 2021
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Ingår i: BMJ Global Health. - : BMJ. - 2059-7908. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Background Early access to diagnosis is crucial for effective management of any disease including tuberculosis (TB). We investigated the barriers and opportunities to maximise uptake and utilisation of molecular diagnostics in routine healthcare settings. Methods Using the implementation of WHO approved TB diagnostics, Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) and Line Probe Assay (LPA) as a benchmark, we evaluated the barriers and how they could be unlocked to maximise uptake and utilisation of molecular diagnostics. Results Health officers representing 190 districts/counties participated in the survey across Kenya, Tanzania and Uganda. The survey findings were corroborated by 145 healthcare facility (HCF) audits and 11 policy-maker engagement workshops. Xpert MTB/RIF coverage was 66%, falling behind microscopy and clinical diagnosis by 33% and 1%, respectively. Stratified by HCF type, Xpert MTB/RIF implementation was 56%, 96% and 95% at district, regional and national referral hospital levels. LPA coverage was 4%, 3% below culture across the three countries. Out of 111 HCFs with Xpert MTB/RIF, 37 (33%) used it to full capacity, performing ≥8 tests per day of which 51% of these were level five (zonal consultant and national referral) HCFs. Likewise, 75% of LPA was available at level five HCFs. Underutilisation of Xpert MTB/RIF and LPA was mainly attributed to inadequate - utilities, 26% and human resource, 22%. Underfinancing was the main reason underlying failure to acquire molecular diagnostics. Second to underfinancing was lack of awareness with 33% healthcare administrators and 49% practitioners were unaware of LPA as TB diagnostic. Creation of a national health tax and decentralising its management was proposed by policy-makers as a booster of domestic financing needed to increase access to diagnostics. Conclusion Our findings suggest higher uptake and utilisation of molecular diagnostics at tertiary level HCFs contrary to the WHO recommendation. Country-led solutions are crucial for unlocking barriers to increase access to diagnostics.
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| 4. |
- Svensson, Robin J., et al.
(författare)
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Model-Based Relationship between the Molecular Bacterial Load Assay and Time to Positivity in Liquid Culture
- 2019
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 63:10
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Tidskriftsartikel (refereegranskat)abstract
- The molecular bacterial load (MBL) assay is a new tuberculosis biomarker which provides results in ∼4 hours. The relationship between MBL and time-to-positivity (TTP) has not been thoroughly studied, and predictive models do not exist. We aimed to develop a model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients from Malawi, Mozambique, and Tanzania with joint MBL and TTP observations quantified from patient sputum collected for 12 weeks. MBL was quantified using PCR of mycobacterial RNA and TTP using the mycobacterial growth indicator tube (MGIT) 960 system. Treatment consisted of isoniazid, pyrazinamide, and ethambutol in standard doses together with rifampin 10 or 35 mg/kg of body weight. The developed MBL-TTP model included several linked submodels, a component describing decline of bacterial load in sputum, another component describing growth in liquid culture, and a hazard model translating bacterial growth into a TTP signal. Additional components for contaminated and negative TTP samples were included. Visual predictive checks performed using the developed model gave good description of the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampin (P = 0.002). In conclusion, a combined model for MBL and TTP was developed that described the MBL-TTP relationship. The full MBL-TTP model or each submodel was used separately. Second, the model can be used to predict biomarker response for MBL given TTP data or vice versa in historical or future trials.
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