Low-Level Delamanid and Bedaquiline Resistance in Extensively Drug-Resistant TB

In a brief report published in Clinical Infectious Diseases, researchers reported a case of drug resistance against 2 recently approved antitubercular medications: delamanid and bedaquiline. Researchers presented a patient with extensively drug-resistant tuberculosis (TB), and highlighted the potential for the emergence and transmission of resistant Mycobacterium tuberculosis complex strains with more frequent use of these relatively new drugs.

In December 2016, a patient with a history of pulmonary TB diagnosed in 1993 who had a second episode in 2012, was seen in a hospital in Berlin, Germany. The patient had extensively drug-resistant TB and significant hearing loss caused by previous treatment with aminoglycosides. Based on previous drug exposures, the patient was started on an empiric regimen with p-aminosalicylic acid, clofazimine, linezolid, cycloserine, trimethoprim/sulfamethoxazole, and delamanid.

Drug susceptibility testing was performed using agar dilution method on Middlebrook 7H10 and/or the mycobacterium growth indicator tubes, and demonstrated resistance to isoniazid, moxifloxacin, prothionamide, capreomycin, ethambutol, linezolid, and pyrazinamide. Drug susceptibility testing and whole-genome sequencing were conducted for isolates at baseline and at weeks 22, 32, 42, and 64 of treatment.

Drug susceptibility testing of the first M tuberculosis isolate showed resistance to isoniazid, moxifloxacin, prothionamide, capreomycin, ethambutol, linezolid, and pyrazinamide and susceptibility to amikacin. The regimen was adjusted accordingly, with subsequent changes being made as a result of adverse effects.

Isolates from baseline and week 22 showed susceptibility to delamanid in mycobacterium growth indicator tubes and revealed low minimal inhibitory concentration using the colorimetric resazurin microtiter assay (REMA). Whole-genome sequencing data showed wild type for ddn and a silent mutation in fbiB.

The isolates from weeks 32, 42, and 64 showed resistance to delamanid in mycobacterium growth indicator tubes and showed an increased minimum inhibitory concentration value of 0.25 mg/L in REMA. Whole-genome sequencing indicated the presence of heteroresistance in the week 32 isolate, revealing ddn G53D mutation in 78%, 99%, and 100% of reads at weeks 32, 42, and 64, respectively.

Once delamanid resistance was detected, bedaquiline was added to the drug regimen. Using phenotypic drug susceptibility testing and whole-genome sequencing, researchers retrospectively investigated isolates from weeks 22, 32, 42, and 64 for bedaquiline and clofazimine susceptibility. Whole-genome sequencing revealed an insertion in Rv0678 in 48%, 87%, 87%, and 92% of reads at week 22, 32, 42, and 64, respectively. Using the World Health Organization’s recommended critical concentrations, drug susceptibility testing in mycobacterium growth indicator tubes showed bedaquiline and clofazimine resistance for the isolates of weeks 22, 32, 42, and 64. In addition, researchers found up to an 8-fold increased minimum inhibitory concentrations for bedaquiline and clofazimine in REMA when compared with baseline isolate.

Because of limited treatment options, a lobectomy was performed on the patient at week 79 of treatment to remove the diseased lung.

Researchers highlighted that this case showed the need for “regular and repeated quality-controlled [drug susceptibility testing] for both delamanid and bedaquiline before and during treatment.” In addition, they noted that this case provides “evidence that much lower [minimum inhibitory concentrations] levels than previously reported may lead to clinically relevant delamanid resistance and treatment failure.” Researchers concluded, “Future interpretation of molecular and phenotypic delamanid [drug susceptibility testing] results will need to take this into consideration.”

Reference

Polsfuss S, Hofmann-Thiel S, Merker M, et al. Emergence of low-level delamanid and bedaquiline resistance during extremely drug-resistant tuberculosis treatment [published online February 2, 2019]. Clin Infect Dis. doi:10.1093/cid/ciz074