Delamanid and Bedaquiline resistance in Mycobacterium tuberculosis ancestral Beijing genotype causing XDR-TB in a Tibetian refugee

Multi-drug resistant tuberculosis (MDR-TB) is posing a major threat to the achievements following world-wide efforts in fighting TB. Two new anti-TB drugs, bedaquiline (Sirturo™) and delamanid (Deltyba™), have recently been approved by international medical agencies and have become a new source of hope to get the epidemic of resistant TB under control. Here, we present a case with MDR-TB of whom the M. tuberculosis isolate (a Beijing genotype) has developed drug resistance towards both, bedaquiline and delamanid, under treatment with presumably efficient combination drug regimens in a Central European country. Amino acid exchange D49Y in FbiA has been identified as probable cause of resistance toward delamanid by comparative analysis of whole genome sequences of two isolates, one recovered before prescription and one after treatment failure of a delamanid containing regimenWe have developed and evaluated three technologies for drug susceptibility testing of new anti-TB agents which we applied to 250 isolates from Central Asia. Surprisingly, increased minimal inhibitory concentrations and full resistance occurred more frequently than expected although patients have never received and MTB isolates were never exposed to bedaquiline and delamanid. Stop-codon mutations in the ddn-gene were the most frequently encountered polymorphisms with probable causative association with delamanid resistance. Our findings alarmingly indicate that we soon might lose also these new, powerful drugs against MDR-TB to bacterial resistance if we are not able to imbed them in innovative programs of efficient drug-, patient- and infection control-management. Careful stewardship of the new antituberculotics is urgently required.

No conflict of interest has been declared by the author(s).