Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study) : protocol for a randomised controlled clinical trial

The clinical trial is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF grant awarded to THD. This work is part of THD’s PhD work at London School of Hygiene & Tropical Medicine (LSHTM). LSHTM is the sponsor of this clinical trial (sponsor address: Keppel Street, Bloomsbury, London WC1E 7HT). ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901.Introduction Over 40% of global tuberculosis case notifications are diagnosed clinically without mycobacteriological confirmation. Standard diagnostic algorithms include ‘trial-of-antibiotics’—empirical antibiotic treatment given to mycobacteriology-negative individuals to treat infectious causes of symptoms other than tuberculosis, as a ‘rule-out’ diagnostic test for tuberculosis. Potentially 26.5 million such antibiotic courses/year are prescribed globally for the 5.3 million/year mycobacteriology-negative patients, making trial-of-antibiotics the most common tuberculosis diagnostic, and a global-scale risk for antimicrobial resistance (AMR). Our systematic review found no randomised controlled trial (RCT) to support use of trial-of-antibiotic. The RCT aims to determine the diagnostic and clinical value and AMR consequences of trial-of-antibiotics. Methods and analysis A three-arm, open-label, RCT randomising (1:1:1) Malawian adults (≥18 years) seeking primary care for cough into: (a) azithromycin 500 mg one time per day for 3 days or (b) amoxicillin 1 g three times per day for 5 days or (c) standard-of-care (no immediate antibiotic). We will perform mycobacteriology tests (microscopy, Xpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) and Mycobacterium tuberculosis culture) at baseline. We will use audiocomputer-assisted self-interview to assess clinical improvement at day 8. First primary outcome will be proportion of patients reporting day 8 improvement out of those with negative mycobacteriology (specificity). Second primary outcome will be day 29 incidence of a composite endpoint of either death or hospitalisation or missed tuberculosis diagnosis. To determine AMR impact we compare proportion of resistant nasopharyngeal Streptococcus pneumoniae isolates on day 29. 400 mycobacteriology-negative participants/arm will be required to detect a ≥10% absolute difference in diagnostic specificity with 80% power. We will estimate measures of effect by comparing outcomes in antibiotic arms (combined and individually) to standard-of-care. Ethics and dissemination The study has been reviewed and approved by Malawi College of Medicine Research and Ethics Committee, London School of Hygiene & Tropical Medicine (LSHTM) Research Ethics Committee and Regional Committee for Health and Research Ethics – Norway, and Malawi Pharmacy, Medicines and Poisons Board. We will present abstracts at relevant conferences, and prepare a manuscript for publication in a peer-reviewed journal.Publisher PDFPeer reviewe

Which health care facilities do adult malawian antiretroviral therapy patients utilize during intercurrent illness? a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Antiretroviral therapy (ART) clinic populations have expanded enormously in the successful Malawi ART scale-up programme. Overcrowding, long waiting times and living far away from the clinic may affect the extent to which patients use their ART clinic for intercurrent illnesses.</p> <p>Methods</p> <p>We interviewed patients of a large urban ART clinic in Blantyre, Malawi, during routine visits about the choice of health care facility during recent illness episodes.</p> <p>Results</p> <p>Out of 346 enrolled adults, mean age 39.8 (range 18-70) years, 54.3% female, 202 (58%) reported one or more illness in the past 6 months, during which 85 (42.1%; 95%-confidence interval: 36.9-47.3%) did not utilize their own clinic. Long distance to the clinic was the main subjective reason, while low education attainment, rural residence, perceived mild illness and dissatisfaction with the ART service were associated with not using their own clinic in multivariate analyses. Of all participants, 83.6% were satisfied with the service provided; only 6.1% were aware of the full service package of the ART clinic.</p> <p>Conclusions</p> <p>ART patients often seek health care outside their own clinic, which may have detrimental effects, and has consequences for ART counseling content and reporting of ART information in health passports.</p

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

Background: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. Methods: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. Findings: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). Interpretation: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. Funding: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

BACKGROUND: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. METHODS: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. FINDINGS: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). INTERPRETATION: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. FUNDING: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development

Utilisation of laboratory services by health workers in a district hospital in Malawi

Aims: To identify priorities for improving effective use of laboratory services in a district hospital in Malawi. Methods: A prospective observational study of clinician-patient interactions to analyse laboratory test requesting practices and utilisation of laboratory results. The proportion of tests that was appropriately ordered, processed and ultimately influenced clinical management was used to assess effectiveness of utilisation. Results: 420 clinical consultations between health professionals and patients were observed. 92% of tests were ordered appropriately, 84% were processed by the laboratory and 64% of results influenced patient management. 73-79% of high-volume tests (haemoglobin, microscopy for malaria and tuberculosis) and 32% of low-volume tests influenced management. Conclusions: 25% of commonly requested laboratory tests were not utilised effectively; because of the high volume, interventions to improve their use are likely to be cost effective. Although 68% of low-volume tests were not used efficiently, the cost of providing support for these tests in a resource-poor setting needs to be balanced against their clinical usefulness. In contrast to published information, this study shows significant underrequesting of laboratory tests that were available. Measures to increase appropriate test requests will have implications for clinician education as well as laboratory space, budgets and staffing levels

What water are we really pumping? The nature and extent of surface and groundwater substitutability in Australia and implications for water management policies

Submitted 24 April 2020; editorial decision 20 August 2020Little is known about the interdependence between surface and groundwater extractions and trade. Groundwater metered extraction was modelled at the bore level (n = 1,890) in the Goulburn-Murray Irrigation District, Victoria, from 2007–08 to 2016–17 to understand its associations with hydrologic, location, climatic, and economic factors. Surface and groundwater extractions were found to be substitutes for each other, with groundwater extractions statistically significantly increasing when: (i) bores were closer to surface water watercourses, (ii) surface water allocations and rainfall were lower, and (iii) surface water temporary market prices and entitlement trade out-of-zone volumes were higher. Other key groundwater extraction influences included pumping costs and commodity prices.Sarah Ann Wheeler, Alec Zuo, and John Kandul

The impact of microcredit loans on school enrolment in Bangladesh

Received 04 Dec 2018, Accepted 26 Nov 2019, Published online: 26 Dec 2019Human capital investment, especially in education, is a well-known precursor of economic growth in developing countries. In recent years, there has been a proliferation of microfinance programmes, yet evidence on whether microfinance leads to increased educational investment is tenuous at best. We utilise a large-scale cross-sectional household dataset from Bangladesh and geospatial data to study how microcredit participation and increasing microcredit incomes – that is, the extensive and intensive margins of microcredit – affects the probability of children’s school enrolment. The causal influence of microcredit participation on enrolments was estimated by utilising the propensity score matching (PSM) technique – a quasi-experimental treatment effects model. Whilst microcredit participation, the extensive margin, did not significantly influence the likelihood of school enrolment for boys, it increased girls’ enrolment. Further, microcredit income, the intensive margin, had a stronger influence on girls’ and younger siblings’ enrolment than on boys’ and older siblings’ enrolment. Omission of spatial influences can overstate microcredit influence on enrolment; while not utilising PSM can underestimate the influence of microcredit participation on enrolment. Results suggest policies that focus solely on increasing microcredit participation, without increasing the amount of microcredit incomes accessed by households, may be less effective at improving child education outcomes.John Kandulu, Sarah Wheeler, Alec Zuo and Nicholas Si