Ineffectiveness of permethrin in human scabies treatment: A multicenter study of kdr gene mutations

BACKGROUND: Scabies remains a widespread parasitic skin disease with increasing reports of treatment failure associated with permethrin, the first-line therapy. Emerging evidence suggests that genetic variation in the voltage-gated sodium channel (VGSC) may be associated with reduced susceptibility to pyrethroids, although its contribution to clinical treatment failure in human scabies remains incompletely characterized. OBJECTIVES: To investigate the presence and frequency of knockdown resistance (kdr) gene mutations associated with permethrin treatment failure in S. scabiei collected from patients in multiple centres across Europe and Africa. METHODS: Mite samples were obtained from patients with clinically diagnosed scabies in France, Belgium, Tunisia and Madagascar between 2023 and 2025. Genomic DNA was extracted and PCR amplification of the voltage-sensitive sodium channel (VSSC) gene was performed, followed by bidirectional sequencing to identify single nucleotide polymorphisms (SNPs). Detected mutations were analysed and correlated with clinical treatment outcomes. RESULTS: Out of 61 suspected cases, 45 were confirmed as scabies infestations. Molecular analysis identified three mutations-M918L, G733D and S916S-in 25 (55.5%) specimens, which were detected in patients with documented permethrin treatment failure. In contrast, 20 out of 45 patients without these mutations experienced successful treatment outcomes. M918L was the most frequent and widely distributed mutation. These genetic findings were consistent with the observed treatment ineffectiveness. This study is the first to report these mutations in Belgium, Tunisia and Madagascar. CONCLUSIONS: This pilot multicentre study identified an association between specific VGSC polymorphisms and documented permethrin treatment failure in human scabies. M918L, G733D and S916S represent candidate resistance-associated variants, whereas the functional significance of the synonymous S916S substitution requires further investigation. Regarding the multifactorial nature of scabies treatment, the increasing occurrence of VGSC nucleotide substitutions highlights an emerging challenge in scabies management and underscores the urgent need for ongoing resistance monitoring, molecular surveillance and the development of alternative therapeutic strategies.