Abstract
BackgroundRecent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Previous findings have implicated detoxification pathways in developing resistance to these acaricides. We investigated the contribution of Glutathione S-transferase (GST) enzymes to permethrin and ivermectin tolerance in scabies mites using biochemical and molecular approaches.ResultsIncreased in vitro survival following permethrin exposure was observed in S. scabiei var. hominis compared to acaricide naïve mites (p < 0.0001). The addition of the GST inhibitor diethyl maleate restored in vitro permethrin susceptibility, confirming GST involvement in permethrin detoxification. Assay of GST enzymatic activity in mites demonstrated that S. scabiei var. hominis mites showed a two-fold increase in activity compared to naïve mites (p < 0.0001). Increased transcription of three different GST molecules was observed in permethrin resistant S. scabiei var. canis- mu 1 (p < 0.0001), delta 1 (p < 0.001), and delta 3 (p < 0.0001). mRNA levels of GST mu 1, delta 3 and P-glycoprotein also significantly increased in S. scabiei var. hominis mites collected from a recurrent crusted scabies patient over the course of ivermectin treatment.ConclusionsThese findings provide further support for the hypothesis that increased drug metabolism and efflux mediate permethrin and ivermectin resistance in scabies mites and highlight the threat of emerging acaricide resistance to the treatment of scabies worldwide. This is one of the first attempts to define specific genes involved in GST mediated acaricide resistance at the transcriptional level, and the first application of such studies to S. scabiei, a historically challenging ectoparasite.
Highlights
Recent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin
The addition of 30 mM DEM to 5% permethrin significantly reduced mean survival time of the var. hominis mites from 6 hours to 1.5 hours
We extend on this by a) characterising the in vitro permethrin sensitivity and Glutathione S-transferase (GST) enzyme activity in S. scabiei collected from a patient with a history of extensive acaricide treatment, including permethrin, over ten years; b) confirming that the increased GST activity observed in permethrin resistant mites is correlated with up regulation of specific GST transcripts; and c) demonstrating that up regulation of GSTs and P-glycoprotein occurs in scabies mites over the course of ivermectin treatment
Summary
Recent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Limited sustainability of recent interventions [4] and anecdotal reports of treatment failure in some communities suggest the emergence of permethrin resistance as a possible cause for treatment failure This is supported by observations that S. scabiei maintained on a laboratory animal model under permethrin selection developed resistance to this drug [8]. These sustainability concerns have directed the development of alternative programs utilising the macrocyclic lactone drug ivermectin, with clinical trials targeting scabies and strongyloides in northern Australia due to commence in 2010 [2,9]
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