Emergence of Mycobacterium leprae Rifampin Resistance Evaluated by Whole-Genome Sequencing after 48 Years of Irregular Treatment

Abstract

A case of Mycobacterium leprae rifampin resistance after irregular antileprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Keywords: Mycobacterium leprae; leprosy; relapse emergence; resistance; rifampin; treatment; whole-genome sequencing.

FIG 1

Information collected from medical records and observation of a relapsed leprosy patient with irregular treatment over 48 years. (A) Timeline of the patient’s abandonment and retreatment cycles over 48 years. Treatment abandonment, treatment failure, and positive disease outcome are shown in red, blue, and green, respectively. BI, bacillary index; DDS, dapsone; ENL, erythema nodosum leprosum; fBI, final BI after treatment; iBI, initial BI at treatment implementation; MDT, multidrug therapy; RFT, release from treatment; RIF, rifampin; *, date for which whole-genome sequence is available. (B, C, D, G) Histological analysis of retrieved skin biopsy specimens consistent with leprosy diagnosis from 2002 to 2017. (B) Superficial and deep perivascular, periadnexal, and perineural lymphohistiocytic infiltrate. Macrophages containing abundant granular to foamy cytoplasm compatible with subpolar lepromatous leprosy. Hematoxylin and eosin, 20× (2002). (C) High density of granular and intact AFB, occasionally arranged in globi. LIB, 6+; Wade, 100× (2015). (D) Presence of a few granular and intact AFB after 12 MDT doses. LIB, 1+; Wade, 100× (2016). (G) Fragmented and intact AFB arranged in globi. LIB, 3.6+; Wade, 100× (2017). (E, F, H, I) Clinical features of the patient at the resistance confirmation in 2016 and after 24 months of treatment (2019). Patient’s hands (E) and back (F) as presented to the Fiocruz clinic in November 2016, with several nodules and infiltrated plaques spread all over the body and with edematous hands and feet, in addition to increasing paresthesia of upper and lower limbs consistent with lepromatous form of the disease. Release from treatment in 2019 with complete remission of symptoms in the hands (H) and back (I).