Rapid emergence of<i>Mycobacterium tuberculosis</i>bedaquiline 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 <http://ow.ly/mxEM30604OF> 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).