Rapid emergence ofMycobacterium tuberculosisbedaquiline resistance: lessons to avoid repeating past errors

Bedaquiline (BDQ) has demonstrated potent clinical activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis complex strains [1–3]. It has now been used in >50 countries, and it is estimated that ∼2500 patients had been treated with BDQ by the end of 2015. In spite of its recent clinical use, there are few reports of BDQ-resistant strains [4, 5]. Mutations in the rv0678 gene encoding the MmpL5 efflux pump repressor generate low-level BDQ resistance and clofazimine (CFZ) cross-resistance [6]. To our knowledge, this is the sole mechanism of BDQ resistance described in clinical strains [4, 5]. Despite its introduction in France in 2011 for XDR- and MDR-tuberculosis (TB) treatment, we report herein four BDQ-resistant cases, and discuss strategies to avoid a surge of BDQ resistance. Bedaquiline resistance appears rapidly both after treatment and in patients that have never been treated The members of CNR MyRMA (Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux) are as follows: Emmanuelle Cambau, Laurent Raskine and Faïza Mougari (Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Lariboisière-Saint Louis, Service de Bactériologie, Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France). The members of the Tuberculosis consilium of the CNR MyRMA are as follows: Claire Andrejak (Service de Pneumologie et de Réanimation Respiratoire, CHU Sud, Amiens, France), Mathilde Fréchet-Jachym (Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France), Guillaume Thouvenin (Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris (AP-HP), Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris, France and Inserm UMRS928, Université Pierre et Marie Curie, Sorbonne Universités, Paris), Katarina Chadelat (Hôpital d'Enfants Armand-Trousseau, AP-HP, Paris), Bertrand Dautzenberg (Hôpitaux Universitaires Pitié-Salpêtrière-Charles-Foix, AP-HP, Université Pierre-et-Marie-Curie, Paris), Najoua Helali (Clinical Microbiology Unit, Saint-Joseph Hospital Network, Paris) and Bénedictine Rivoire (Samu Social, Paris).