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Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

ABSTRACT: SETTING:Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure. OBJECTIVES AND DESIGN:We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0-12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings. RESULTS:Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0-12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69-89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97-111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients. CONCLUSION:Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.

SUBMITTER: Court R

PROVIDER: S-EPMC5905389 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

Court R R Chirehwa M T MT Wiesner L L Wright B B Smythe W W Kramer N N McIlleron H H

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 20180501 5

<h4>Setting</h4>Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure.<h4>Objectives and design</h4>We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FD ...[more]

PMID: 29663959

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Project description:ObjectiveThis is the first large-scale assessment of the implementation of HIV Rapid Test Quality Improvement Initiative in South Africa.MethodsWe used a quasi-experimental one group post-test only design. The intervention implemented starting April 2014 comprised health-care worker training on quality assurance (QA) of HIV rapid testing and enrolment of the facilities in proficiency testing (PT), targeting 2,077 healthcare facilities in 32 high HIV burden districts. Following the intervention, two consecutive rounds of site assessments were undertaken. The first, conducted after a median of 7.5 months following the training, included 1,915 facilities that participated in the QA training, while the second, conducted after a median of one-year following the first-round assessment included 517 (27.0%) of the 1,915 facilities. In both assessments, the Stepwise-Process-for-Improving-the-quality-of-HIV-Rapid-Testing (SPI-RT) checklist was used to score facilities' performance in 7 domains: training, physical facility, safety, pre-testing, testing, post-testing and external quality assessment. Facilities' level of readiness for national certification was assessed.ResultBetween 2016 and 2017, there were four PT cycles. PT participation increased from 32.4% (620/1,915) in 2016 to 91.5% (1,753/1,915) in 2017. In each PT cycle, PT results were returned by 76%-87% of facilities and a satisfactory result (>80%) was achieved by ≥95% of facilities. In the SPI-RT assessment, in round-one, 22.3% of facilities were close to or eligible for national certification-this significantly increased to 38.8% in round-two (P-value<0.001). The median SPI-RT score for the domains HIV pre-testing (83.3%) and post-testing (72.2%) remained the same between the two rounds. The median score for the testing domain increased by 5.6% (to 77.8%).ConclusionFacilities performance on the domains that are critical for accuracy of diagnosis (i.e. pre-testing, testing and post-testing) remained largely unchanged. This study provided several recommendations to improve QA implementation in South Africa, including the need to improve routine use of internal quality control for corrective actions.

Project description:Although elevated surface ozone (O3) concentrations are observed in many areas within southern Africa, few studies have investigated the regional atmospheric chemistry and dominant atmospheric processes driving surface O3 formation in this region. Therefore, an assessment of comprehensive continuous surface O3 measurements performed at four sites in continental South Africa was conducted. The regional O3 problem was evident, with O3 concentrations regularly exceeding the South African air quality standard limit, while O3 levels were higher compared to other background sites in the Southern Hemisphere. The temporal O3 patterns observed at the four sites resembled typical trends for O3 in continental South Africa, with O3 concentrations peaking in late winter and early spring. Increased O3 concentrations in winter were indicative of increased emissions of O3 precursors from household combustion and other low-level sources, while a spring maximum observed at all the sites was attributed to increased regional biomass burning. Source area maps of O3 and CO indicated significantly higher O3 and CO concentrations associated with air masses passing over a region with increased seasonal open biomass burning, which indicated CO associated with open biomass burning as a major source of O3 in continental South Africa. A strong correlation between O3 on CO was observed, while O3 levels remained relatively constant or decreased with increasing NO x , which supports a VOC-limited regime. The instantaneous production rate of O3 calculated at Welgegund indicated that ~ 40 % of O3 production occurred in the VOC-limited regime. The relationship between O3 and precursor species suggests that continental South Africa can be considered VOC limited, which can be attributed to high anthropogenic emissions of NO x in the interior of South Africa. The study indicated that the most effective emission control strategy to reduce O3 levels in continental South Africa should be CO and VOC reduction, mainly associated with household combustion and regional open biomass burning.

Project description:BackgroundTuberculosis (TB) is amongst the top five causes of death in women of childbearing age (15-≤44 years). Little is known about treatment of pregnant women with drug-resistant TB (DR-TB). Treatment for pregnant women remains challenging and more complex in DR-TB/HIV co-infection, where an evidence-based guide to clinical practice is limited. The study reviewed treatment and pregnancy outcomes and birth outcomes of their new-born in a cohort of pregnant women with DR-TB from three MDR-TB hospitals during 2010 and 2018.Design/methodsData were extracted from: TB register and patient clinic notes using a standardized case record form. Information on DR-TB treatment, pregnancy and Adverse Drug Events (ADEs) of twenty-six pregnant women treated with individualized second-line TB medications were captured. The frequency of favourable and adverse outcomes regarding disease and pregnancy were evaluated.ResultsThe mean age was 29 years (SD ±5.1), with the minimum and maximum age of 21 and 40 years, respectively. Eleven (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 women, 15 (57.7%) had at least one ADE, but most had more than one ADE. Seventeen women were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively.ConclusionDR-TB treatment should be delayed until after the first trimester. Routine pharmacovigilance surveillance integrated antenatal and delivery services with an integrated record of DR-TB treatment during pregnancy is recommended. Prospective studies using standardised case record forms for DR-TB treatment for pregnant women could provide more insight on the effect of DR-TB treatment on the birth outcome.

Dataset Information

Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

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Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

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