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Research Letter |

Longitudinal Evidence of Increasing In Vitro Tolerance of Scabies Mites to Ivermectin in Scabies-Endemic Communities FREE

Kate E. Mounsey, PhD; Deborah C. Holt, PhD; James S. McCarthy, MBBS, FRACP; Bart J. Currie, MBBS, FRACP, DTM&H; Shelley F. Walton, PhD
Arch Dermatol. 2009;145(7):840-841. doi:10.1001/archdermatol.2009.125.
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Published online

Scabies remains a prominent cause of morbidity in remote Aboriginal communities in northern Australia. Secondary bacterial infection of skin lesions caused by scabies is linked to high rates of rheumatic fever and rheumatic heart disease in affected communities.1 Because the sustainability of community scabies eradication programs using topical permethrin, 5%, is problematic, oral ivermectin has been proposed as an alternative acaricide for mass drug administration.

While ivermectin is used routinely for the management of crusted scabies (CS) in northern Australia, reports of clinical and in vitro resistance2 indicate that prospective monitoring is required to detect the further emergence of ivermectin resistance. Herein, we report the results of a longitudinal study of in vitro acaricide sensitivity of Sarcoptes scabiei to ivermectin in a region under increasing drug selection pressure.

Specimens were obtained by gently scraping the skin of patients infected with CS who were admitted to the Royal Darwin Hospital. The scrapings were then examined for the presence of S scabiei using a dissecting microscope. If numerous live mites were found in the sample, acaricide sensitivity assays were performed using methods previously described.3 To maintain mite viability for the duration of the assay, mites were tested within 3 hours of collection and incubated at 28°C. From 1997 through 2006, sufficient mite numbers for analysis were obtained from 16 individual patients on 31 occasions (Table). Through a statistical comparison of data, we tested the null hypothesis that survival curves between years were identical.

Table Graphic Jump LocationTable. Aggregate Ivermectin In Vitro Survival Times, 1997-2006

Survival times of mites exposed to ivermectin increased from 1997 through 2006 (P < .001) (Table), while survival times remained unchanged over 10 years for the negative control emulsifying ointment. Even when we excluded the 2 patients with previously documented resistance2 from the analysis, we found that the trend for increasing ivermectin survival time remained significant (P = .006) (Table). Results from a single patient with recurrent CS and previously documented ivermectin resistance are of note (Figure). When this patient was treated again in 2006 with 3 doses of ivermectin (200 μg/kg), no noticeable reduction in mite numbers was observed (unpublished observations). A significant increase in mite survival time was observed when mites collected after 8 days and 3 doses of ivermectin were compared with those collected prior to the commencement of ivermectin therapy (P = .003).

Place holder to copy figure label and caption
Figure.

Kaplan-Meier survival analysis of mites exposed to ivermectin. The data were collected from a patient with recurrent crusted scabies during an 8-day treatment regimen in 2006 and show significantly increasing median survival times (P = .003 by treatment day 8) over the course of ivermectin treatment, indicating selection for subpopulations of ivermectin-tolerant mites. “n” Indicates number of mites used in each in vitro assay.

Graphic Jump Location

Mite survival times in the presence of in vitro ivermectin doubled over the 10-year study period. Furthermore, sequential data collected from a single patient over a course of ivermectin treatment confirms that selection for ivermectin-tolerant mites can occur rapidly and persist once established. These observations support concerns regarding the sustainability of mass drug administration scabies control programs using ivermectin. Surveillance of CS is important, not only to the individual but also to the community as a whole. As ordinary and crusted scabies are caused by the same variety of mite, patients with CS serve as core transmitters in many communities and may limit the success of community control programs.4 We are concerned by the potential for core transmitters serving as reservoirs of mites with increasing ivermectin tolerance, thus threatening the success of mass drug administration programs based on ivermectin

Increased monitoring for the development of drug resistance is urgently needed within the community setting. Because the applications of in vitro assays are limited, the development of molecular-based diagnostic techniques that are more sensitive and amenable to community application is imperative. It should also be recognized in Australian Aboriginal communities and elsewhere that addressing the underlying causes of persisting high rates of scabies (eg, overcrowding, socioeconomic disadvantage, poor sanitation facilities5) will effect a broader improvement in health as well as assist in control of scabies.

ARTICLE INFORMATION

Correspondence: Dr Mounsey, Clinical Tropical Medicine Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, QLD 4029 Australia (kate.mounsey@qimr.edu.au).

Author Contributions:Study concept and design: Mounsey, Currie, and Walton. Acquisition of data: Mounsey, Holt, Currie, and Walton. Analysis and interpretation of data: Mounsey, Holt, McCarthy, Currie, and Walton. Drafting of the manuscript: Mounsey and Holt. Critical revision of the manuscript for important intellectual content: Mounsey, Holt, McCarthy, Currie, and Walton. Statistical analysis: Mounsey and Holt. Obtained funding: Mounsey, Holt, McCarthy, Currie, and Walton. Study supervision: Mounsey, Currie, and Walton.

Financial Disclosure: None reported.

Funding/Support: This study received funding support from the Australian National Health and Medial Research Council, Cooperative Research Centre for Aboriginal Health, and the Channel 7 Children's Research Foundation of South Australia.

Additional Contributions: We are indebted to the patients and nursing staff of Royal Darwin Hospital for their continued support of this research. We thank members of the Skin Pathogens Research Laboratory at the Menzies School of Health Research, Charles Darwin University, Darwin, Australia, for assistance with in vitro assays.

Carapetis  JRCurrie  BJ Group A streptococcus, pyoderma, and rheumatic fever. Lancet 1996;347 (9010) 1271- 1272
Link to Article
Currie  BJHarumal  PMcKinnon  MWalton  SF First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin Infect Dis 2004;39 (1) e8- e12
PubMed Link to Article
Walton  SFMcKinnon  MPizzutto  SDougall  AWilliams  ECurrie  BJ Acaricidal activity of Melaleuca alternifolia (tea tree) oil: in vitro sensitivity of Sarcoptes scabiei var hominis to terpinen-4-ol. Arch Dermatol 2004;140 (5) 563- 566
PubMed Link to Article
Currie  BJConnors  CKrause  V Scabies programs in Aboriginal communities. Med J Aust 1994;161 (10) 636- 637
PubMed
Currie  BJCarapetis  JR Skin infections and infestations in Aboriginal communities in northern Australia. Australas J Dermatol 2000;41 (3) 139- 145
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Kaplan-Meier survival analysis of mites exposed to ivermectin. The data were collected from a patient with recurrent crusted scabies during an 8-day treatment regimen in 2006 and show significantly increasing median survival times (P = .003 by treatment day 8) over the course of ivermectin treatment, indicating selection for subpopulations of ivermectin-tolerant mites. “n” Indicates number of mites used in each in vitro assay.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Aggregate Ivermectin In Vitro Survival Times, 1997-2006

References

Carapetis  JRCurrie  BJ Group A streptococcus, pyoderma, and rheumatic fever. Lancet 1996;347 (9010) 1271- 1272
Link to Article
Currie  BJHarumal  PMcKinnon  MWalton  SF First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin Infect Dis 2004;39 (1) e8- e12
PubMed Link to Article
Walton  SFMcKinnon  MPizzutto  SDougall  AWilliams  ECurrie  BJ Acaricidal activity of Melaleuca alternifolia (tea tree) oil: in vitro sensitivity of Sarcoptes scabiei var hominis to terpinen-4-ol. Arch Dermatol 2004;140 (5) 563- 566
PubMed Link to Article
Currie  BJConnors  CKrause  V Scabies programs in Aboriginal communities. Med J Aust 1994;161 (10) 636- 637
PubMed
Currie  BJCarapetis  JR Skin infections and infestations in Aboriginal communities in northern Australia. Australas J Dermatol 2000;41 (3) 139- 145
PubMed Link to Article

Correspondence

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