Reply to Decroo et al.: High-Dose First-Line Treatment Regimen for Recurrent Rifampicin-Susceptible Tuberculosis

Abstract

GenoType MTBDRplus. rpoB mutations outside the 81-bp rifampicin resistance determining region are not covered by these commercial assays. Another, not unusual cause of missed rifampicin resistance is heteroresistance resulting from a mixed population of both susceptible and resistant TB bacilli (3). If patients with resistance to isoniazid and missed rifampicin resistance were treated with the World Health Organization levofloxacin-strengthened first-line regimen, resistance to fluoroquinolone would emerge rapidly. Because the efficacy of second-line TB treatment relies on a fluoroquinolone as a core drug, treatment options would be dramatically reduced. Finally, as shown by Dooley and colleagues, as well as by previous studies (4), high-dose isoniazid may overcome mutations that confer resistance to isoniazid and render normal doses ineffective (4). Excluding isoniazid, which has the highest early bactericidal activity of all first-line drugs, increases the risk of acquiring rifampicin resistance, as mutant bacilli may survive the early phase of TB treatment. Moreover, Boeree and colleagues showed that high-dose rifampicin (35 mg/kg) was safe and reduced time to culture conversion when compared with normal-dose rifampicin (10 mg/kg) (5). Although isoniazid is used for its bactericidal activity against actively replicating bacilli, rifampicin has both a bactericidal effect against rapidly replicating bacilli and a sterilizing effect against dormant bacilli. Both types of action are needed to ensure a relapse-free cure (6). Globally, about 11.6% of patients with recurrent TB have rifampicin-susceptible/isoniazid-resistant TB. Studies should compare high-dose first-line regimens with normal-dose regimens in terms of safety, treatment success, and acquired rifampicin resistance in patients with rifampicin-susceptible/isoniazid-resistant TB. If it is shown to be safe and efficacious, high-dose first-line treatment could be used in all patients with recurrent rifampicin-susceptible TB, regardless of initial isoniazid resistance, thus avoiding delays in retreatment. Such an improved use of first-line anti-TB drugs would have major advantages. No additional susceptibility testing beyond rifampicin testing would be required and there would be no delay between a diagnosis of rifampicin-susceptible recurrent TB and initiation of treatment. If first-line treatment could rely on first-line drugs only, second-line treatment options would be maximally safeguarded. n

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline

“…As noted for other drugs discussed in this practice guideline, QT interval prolongation may occur with delamanid use, and routine ECG monitoring is recommended. A recent evaluation of the cardiac safety of delamanid and bedaquiline given together as part of multidrug therapy for MDR-TB concluded that the combined effect on the corrected QT interval (QTc) using the Fridericia formula (QTcF) is clinically modest and no more than additive (ClinicalTrials.gov Identifier: NCT02583048), with mean change in QTcF from baseline at 11.9 milliseconds (95.1% CI, 7.4–16.5 ms) in the bedaquiline arm, 8.6 milliseconds (95.1% CI, 4.0–13.2 ms) in the delamanid arm, and 20.7 milliseconds (95.1% CI, 16.1–25.4 ms) in the combined bedaquiline and delamanid arm (136).…”