Rapid detection of non-rifampicin resistant drug-resistant tuberculosis using Xpert MTB/XDR testing: Findings from a multisite drug-resistant tuberculosis case detection surge in Zambia.

Zambia continues to face a high-Tuberculosis burden with rising drug resistance, yet diagnosis of non-rifampicin resistant drug-resistance remains limited due to reliance on rifampicin as a proxy for multidrug-resistant tuberculosis. The Xpert MTB/XDR assay offers a rapid detection of resistance to isoniazid, fluoroquinolone, Ethionamide and aminoglycosides, addressing a major diagnostic gap. The aim of this analysis was to describe the prevalence and profile of drug resistance among bacteriologically confirmed TB patients subjected to reflex Xpert MTB/XDR testing. We conducted an analysis of programmatic data from a four-week active drug-resistant TB case finding surge in May 2025, implemented across 39 high-TB burden facilities in five provinces of Zambia. We re-evaluated eligible Xpert MTB/RIF Ultra positive TB patients using the Xpert MTB/XDR platform regardless of Rifampicin resistance to identify additional drug resistance beside rifampicin. We analyzed patient demographics, characteristics, and the distribution of drug resistance drug-resistance categories descriptively. Of 509 TB patients identified, 70.9%(n = 360) were bacteriologically confirmed by Xpert MTB/RIF Ultra among whom 92.8%(n = 336) were eligible for reflex Xpert MTB/XDR testing. Of the eligible, 89.3% (n = 313) underwent reflex Xpert MTB/XDR testing. Results were successfully retrieved for 282 (90.1%). Overall, 8.5%(n = 24) of patients with XDR results had a form of drug-resistant tuberculosis. Mono-resistance to rifampicin (3.5%, n = 10) or isoniazid (3.2%, n = 9) was more prevalent than multi-drug-resistant tuberculosis (1.1%, n = 3), while only 0.4% (n = 1) had Pre-XDR TB. Non-rifampicin resistant drug-resistance, including isoniazid mono-resistance and isoniazid combined with fluoroquinolone or ethionamide resistance, were detected in 3.2% (n = 9) of all patients with XDR TB results (37.5% of all DR-TB cases). Reflex Xpert MTB/XDR testing enabled rapid identification of non-rifampicin-resistance drug-resistant TB cases that would have been missed by rifampicin-centric diagnostics. Strengthening the integration of MTB/XDR into routine diagnostic algorithms can improve early drug-resistant tuberculosis detection, guide individualized treatment, and prevent amplification of resistance in high-burden settings.