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

Divala, Titus Henry, Fielding, Katherine L, Sloan, Derek J, French, Neil, Nliwasa, Marriott, MacPherson, Peter ORCID: https://orcid.org/0000-0002-0329-9613, Kandulu, Chikondi Charity, Chiume, Lingstone, Chilanga, Sanderson, Ndaferankhande, Masiye John and Corbett, Elizabeth L (2020) 'Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study): protocol for a randomised controlled clinical trial'. BMJ Open, Vol 10, Issue 3, e033999.

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Abstract

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.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268 Antitubercular agents. Antitubercular antibiotics QV Pharmacology > Anti-Bacterial Agents. Tissue Extracts > QV 350 Anti-bacterial agents (General or not elsewhere classified) QW Microbiology and Immunology > Bacteria > QW 125 Actinibacteria, Actinomycetales. WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department:	Clinical Sciences & International Health > Malawi-Liverpool-Wellcome Programme (MLW)
Digital Object Identifer (DOI):	https://doi.org/10.1136/bmjopen-2019-033999
Depositing User:	Stacy Murtagh
Date Deposited:	21 Apr 2020 14:35
Last Modified:	28 May 2020 14:07
URI:	https://archive.lstmed.ac.uk/id/eprint/14285

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