Miltefosine and emerging Leishmania (Mundinia) in Southeast Asia: Molecular insights, therapeutic challenges, and future strategic implementation.

Miltefosine, the only oral antileishmanial drug with regulatory approval, has expanded treatment options in several endemic settings but shows variable efficacy across Leishmania species, clinical forms, and host immune contexts. In Southeast Asia, where Leishmania (Mundinia) martiniquensis and L. (M.) orientalis are increasingly reported, amphotericin B formulations remain the main treatment despite toxicity, relapse, and implementation constraints. This review evaluates miltefosine's clinical relevance, mechanisms of action, and resistance pathways, with emphasis on Thailand and neighboring Southeast Asian settings. A Thai compassionate-use case using miltefosine with liposomal amphotericin B for refractory L. martiniquensis infection achieved repeated clinical improvement and culture negativity after combination induction, although monotherapy was insufficient to maintain remission in advanced immunosuppression. Evidence from other endemic regions indicates that poor adherence, unregulated access, prolonged subtherapeutic exposure, and inadequate monitoring can reduce treatment durability and favor reduced susceptibility. Mechanistic studies in non-Mundinia species identify transport disruption, lipid and sterol remodeling, mitochondrial stress adaptation, redox buffering, and host-parasite effects as resistance-relevant axes, while regional data raise concern for amphotericin B-associated reduced miltefosine susceptibility in L. martiniquensis. Wider implementation should therefore be linked to species-resolved diagnostics, baseline susceptibility testing, longitudinal phenotype-genotype surveillance, drug stewardship, and One Health monitoring. Miltefosine should be considered a rational but carefully monitored therapeutic addition for emerging Southeast Asian leishmaniasis.