Results
death, allergy, tuberculosis, cough, tuberculosis-negative
SECONDARY, ALLERGY, RECRUITMENT, TUBERCULOSIS
Between Feb 25, 2019, and March 14, 2020, we screened 5825 adults presenting with cough to Limbe and Ndirande Health Centres, Malawi, of whom 2659 (45·6%)expressed interest after a brief description of the study. 1076 participants were ineligible, with most common reasons being recent antibiotic treatment (503 [46·7%] of 1076), recent or current tuberculosis preventive treatment (198 [18·4%]), and being aged younger than 18 years (95 [8·8%]). 43 (4%) of 1076 adults were eligible but did not give consent. 1583 (27·2%) of 5825 met the eligibility criteria, gave written consent to participate, and were randomly assigned (530 to standard of care, 527 to azithromycin, and 526 to amoxicillin (Trial profile*Unable to return for follow-up visits (42 [4%]), lives outside the study catchment areas (25 [2%]), unable to walk independently (13 [1%]), took tuberculosis treatment in the past 6 months (12 [1%]), and reported an allergy to study medication (1 [<1%]). †Denominator for diagnostic accuracy primary outcome. ‡Experiencing either death, hospitalisation, or missed tuberculosis diagnosis by day 29. §Nasopharyngeal swab with Baseline characteristics of the randomised populationData are n (%), median (IQR), or mean (SD). ART=antiretroviral therapy.HIV status unknown in 55 participants (25 in the standard of care group, 14 in the azithromycin group, and 16 in the amoxicillin group), and HIV was newly diagnosed for 17 of 122 participants tested (six of 43 participants in the standard of care group, four of 37 participants in the azithromycin group, and seven of 42 participants in the amoxicillin group).97·7% (214 of 219 participants) of the previously diagnosed HIV-positive participants were already on ART.Out of the randomised 1583 participants 1171 (74·0%) provided a sputum sample for day 1 Xpert MTB/RIF, 1181 (51·7%) for day 1 smear microscopy and culture, 818 for day 8 smear microscopy and culture, and 65 (4·1%) for unscheduled day 29 smear microscopy and culture based on clinical need (More participants missed the day 8 visit (35 [3%] of 1583) than day 29 visit (24 [1·5%]; 1162 participants with negative mycobacteriology and known day 8 symptom status contributed to the diagnostic accuracy primary outcome (392 [34%] of 1162 in the standard of care group, 383 [33%] in the azithromycin group, and 387 [33%] in the amoxicillin group). This sample size achieved the required number of tuberculosis-negative participants per group (around 388 participants) without needing the planned full recruitment of 625 per group (or 1875 total) because tuberculosis prevalence had declined from the anticipated 20% to 6%.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; Diagnostic effect of trial-of-antibiotics (primary, secondary, and pre-specified outcomes)Data are n/N (%), unless otherwise stated. n=number of participants with outcome for the index test (day 8 self-reported symptom status) defined as positive (improvement) or negative (no improvement, no change, or worsened).Mycobacteriology based on day 1 and day 8 smear microscopy, Xpert/MTB/Rif, and tuberculosis culture, in which positive was defined as sputum positive on at least one test, and negative if none of the tests is positive and at least one is known to be negative. All risk differences are adjusted for study site.Specificity by HIV status among participants with sputum results.When participants who could not produce sputum were included in the denominator for the diagnostic effect outcome (diagnostic accuracy secondary outcome), trial-of-antibiotics with either azithromycin (439 [90·5%] of 485) or amoxicillin (441 [91·1%] of 484) still showed improvement in specificity compared with standard of care (398 [82·6%] of 482), although the effect was smaller than in the primary outcome analysis (The sensitivity of the three arms against the primary reference mycobacteriology was 25·6% (10 of 39 patients; 95% CI 13·0–42·1) for standard of care, 10·7% (3 of 28 patients; 2·3–28·2) for azithromycin, and 23·3% (7 of 30 patients; 9·9–42·3) for amoxicillin (Compared with standard of care (7 [1·3%] of 530), the percentage of participants who experienced the day 29 composite clinical outcome (at least one of death, hospitalisation, or missed tuberculosis diagnosis) did not differ by group (azithromycin –0·2%, 95% CI –1·5 to 1·1; and amoxicillin 1·0%, –0·6 to 2·6; The effect of trial-of-antibiotics on the clinical coprimary outcome and secondary outcome of antimicrobial resistanceData are n/N (%), unless otherwise stated. All risk differences and ratios are adjusted for study site.Number randomised.It was possible for an individual participant to have more than one of the three components of the composite clinical outcomes.Number of participants who provided nasopharyngeal swab samples for 1529 of 1583 participants (96·6% of the total randomised) provided day 29 nasopharyngeal swab samples, of which 10·9% (167 of 1529) grew Compared with standard of care, the proportions of participants whose day 29 nasopharyngeal swabs grew The percentage of day 29 resistant isolates in the amoxicillin group was similar (risk difference –0·2%, 95% CI –2·9 to 2·5; p=0·90) to that of standard of care. In a post-hoc analysis excluding 139 participants who had resistant isolates at baseline, the percentages of antimicrobial resistance positive at day 29 were 21 of 485 in the standard of care group, 36 of 485 in the azithromycin group, and 18 of 474 in the amoxicillin group. Risk differences, adjusted for study site, were 3·1% (95% CI 0·1 to 6·1; p=0·04) for the azithromycin group and –0·6 (95% CI –3·1 to 1·9; p=0·66) for the amoxicillin group versus the standard of care group.More participants (118 [23·1%] of 511) in the amoxicillin group (dosage was 12 tablets per day over 5 days) remained with at least one unused study medication tablet by day 8, compared with the azithromycin group (11 [2·2%] of 511; dosage was two tablets per day over 3 days; Diagnostic and antimicrobial resistance effect among participants who adheredData are n/N (%), unless otherwise stated.The question was: out of all the study medication tablets we gave you, are there any remaining?Denominator is the number of participants who completed the study medication adherence questionnaire in audio computer assisted self-interview at day 8.Adherence to treatment defined as not missing any single study drug and not taking any non-study antibiotic before or on day 8.Adherence to treatment defined as not missing any single study drug and not taking any non-study antibiotic by day 29.