Discussion
tuberculosis
ACTIVE TUBERCULOSIS, TUBERCULOSIS, ACUTE RESPIRATORY INFECTIONS
The main findings of this individually randomised trial to investigate the diagnostic, clinical, and antimicrobial resistance effect of trial-of-antibiotics during tuberculosis investigations were that, compared with standard of care, trial-of-antibiotics with either azithromycin or amoxicillin improved diagnostic specificity for mycobacteriologically confirmed tuberculosis. However, routine prescription of antibiotics did not improve day 29 clinical outcomes (all-cause mortality, hospitalisation, and missed diagnosis of tuberculosis), and might have generated antimicrobial resistance in the azithromycin group.The improvement in diagnostic specificity shown by trial-of-antibiotics using either azithromycin or amoxicillin confirms the long-established clinical rationale for national and global guidelines for addressing the suboptimal nature of tuberculosis diagnosis. Our randomised trial further adds to the body of evidence by quantifying the magnitude of the diagnostic benefit allowing for a comparison against the WHO criteria (target product profiles) for tuberculosis diagnostic test performance.In this study, the limited nature of the diagnostic benefit is further underscored by the extremely low sensitivity for both azithromycin (three [10·7%] of 28 participants) and amoxicillin (seven [23·3%] of 30 participants; appendix p 3). We did not include sensitivity as a trial outcome, due to the anticipation of much lower numbers of sputum-confirmed patients than sputum-negative patients but did anticipate sufficient power to provide reasonable precision around the point estimate of sensitivity per group for which at least 30 confirmed patients per group is required. These estimates fall well below target, even when only the upper 95% CIs are considered (28·2% for azithromycin, and 42·3% for amoxicillin) against the minimum acceptable target of 90% for triage test, and more than 80% for smear microscopy-replacement tests.Apart from diagnostic performance, safety is the other key consideration for national programmes and clinicians before routine prescription of trial-of-antibiotics to outpatients without danger signs can be discontinued. Withholding a course of effective antibiotic treatment could affect patient safety because bacterial causes of illness in patients with respiratory symptoms are common,Our safety data results are consistent with those from a 2017 systematic review update comparing immediate prescription with antibiotic-sparing strategies for outpatients with uncomplicated acute respiratory infections.We additionally found results consistent with previous reports of rapid acquisition of resistance following brief exposure to azithromycin,Antibiotic prescription for patients presenting with respiratory symptoms was common practice at the study sites, with 46·7% (503 of 1076) of the potential participants excluded due to having taken antibiotics within 14 days, and self-reported use of non-study antibiotics by day 29 reported by 15·1% (80 of 530) of standard of care group participants. The most common non-study antibiotic was amoxicillin, consistent with previous reports of wide availability and easy access in Malawi.Our main study limitations include no blinding and consequential room for misclassifying exposure status for participants who could have accessed antibiotics outside the study beyond that reported, and possible underdiagnosis of active tuberculosis status. However, exploratory analysis of different tuberculosis diagnostic criteria and exclusion of patients known to have taken antibiotics outside of the study prescriptions do not support a major impact on our key conclusions. Another potential source of misclassification of exposure status is the self-administration of study drugs, but this reflects clinical practice for oral treatment in ambulatory adults. Provision of daily dosing oral antibiotics under directly observed treatment approach is not routinely practised for outpatients as it might not be practical. We recruited participants from a single city, limiting generalisation to other settings. We did not power the study on sensitivity, limiting our ability to compare differences between groups to specificity. However, the upper 95% CI for our point estimates of sensitivity fell well below the WHO target ranges for both antibiotic groups, suggesting that trial-of-antibiotics is unlikely to meet diagnostic acceptability criteria in this respect.In conclusion, our results do not support routine prescription of trial-of-antibiotics for the purposes of establishing a diagnosis of tuberculosis in ambulatory adult outpatients. Antibiotic prescriptions can be reduced for adult outpatients with symptoms suggestive of tuberculosis without affecting patient clinical outcomes. Policy and research should urgently establish antibiotic-sparing diagnostic approaches for primary care management of respiratory symptoms.