Scabies Review

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Am. J. Trop. Med. Hyg.,94(2), 2016, pp. 258266doi:10.4269/ajtmh.14-0515Copyright 2016 by The American Society of Tropical Medicine and Hygiene

Review Article

Therapeutic Potential of Tea Tree Oil for Scabies

Jackson Thomas,* Christine F. Carson, Greg M. Peterson, Shelley F. Walton, Kate A. Hammer, Mark Naunton,Rachel C. Davey, Tim Spelman, Pascale Dettwiller, Greg Kyle, Gabrielle M. Cooper, and Kavya E. Baby

University of Canberra, Faculty of Health, Bruce, Canberra, Australia; Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia,

Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland, Australia; School of Medicineand Pharmacology, The University of Western Australia and Translational Renal Research Group, Harry Perkins Institute

of Medical Research, Nedlands, Western Australia; Burnet Institute, Melbourne, Victoria, Australia; School of Medicine,Flinders University, Katherine, Northern Territory, Australia; Private Practice, Charnwood, Canberra, Australia

Abstract. Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks inhealth institutions and vulnerable communities result in a significant economic burden. A review of the literature demon-strates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently avail-able scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patientcohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also beensuccessfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did notrespond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold stan-dard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entitiesis doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTOmay have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications.

This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existingdata for TTO, larger scale, randomized controlled clinical trials are warranted.

SCABIES INFECTION

Epidemiology.Scabies is a contagious, parasitic dermatosis(skin disease) caused by the acarine itch mite Sarcoptes scabieivar. hominis, affecting 300 million individuals worldwide eachyear, including all age groups and social classes.13

A World Health Organization (WHO) review estimated aglobal prevalence of 0.224%.4 However, the condition ismore prevalent in tropical regions, particularly for pediatricscabies. In Australia, scabies is a major public health problem

in Indigenous communities, with a prevalence of 25% in adultsand about 3065% in children.5,6 It is usually contracted byclose, prolonged personal contact with an infected person andtherefore is very common among family members and oftenseen in institutional settings.7,8 It is prevalent among youngchildren and remains frequent in older children and youngadults, possibly due to the absence of immunity and increasedexposure and cross infection between children.9,10

Disease morbidity. Sarcoptes scabiei releases antigens thatdiffuse into the outer skin layer resulting in local inflammatoryand immune reactions, leading to severe pruritus and skinabrasion.11,12 Breaks in the epidermis serve as an entry pointfor pathogenic bacteria (usually streptococci or staphylococci),which complement inhibitors from scabies mites and promote

bacterial growth.13 The scabies mites secrete a number ofendogenous molecules that inhibit the host immune system.13,14

This process is believed to protect the invaded mites fromhost defense mechanism. Molecular studies have also revealedthat scabies mites produce a variety of endogenous complementinhibitors (e.g., scabies miteinactivated protease paralogues Iland Dl and scabies mite serpins such as SMSB3 and SMSB4),

which interfere with different stages of host defense compli-ment cascades and promote the formation of bacterial patho-gens (e.g., Staphylococcus aureus and Streptococcus pyogenes)in the patients body favoring the establishment of secondarybacterial coinfections.1416 Superinfected lesions may developinto cellulitis or impetigo and may contribute to abscess forma-tion. These sequelae predispose the infected individuals to sep-sis and other nonsuppurative invasive infections, as explainedin Figure 1.17 A more severe or crusted form of infestationis associated with extreme incapacity and with disorders ofthe immune system, for example, human immunodeficiencyvirus infection.

In Australia, the Indigenous population has been found tosuffer from streptococcal septicemia (with infectious diseasesdriven by impetigo and associated scabies being the majorcause in rural and remote areas) at a five times greater ratethan the general population.18 This contributes to an estimatedlife expectancy gap of 13 years (2012 data) between Indige-nous and non-Indigenous Australians.19 Furthermore, a clearlink between scabies and bacterial pyoderma has been iden-tified as the causative factor for rheumatic fever and heartdisease, skin sepsis, and renal disease in Aboriginal andTorres Strait Islander communities in Australia.20

Economic burden of disease. A 2004 U.S. study estimatedthe annual economic burden for scabies management atUS$10.4 million.21 In Australia, the estimated annual (2013data) cost associated with the management of pediatric scabiesand pyoderma per patient was AU$10,000. This is the mini-mum cost associated with hospitalizations as no further dataor comprehensive estimates of the annual economic burdenare available.6,22,23

Current treatments. Topical treatments for scabies includesulfur, benzyl benzoate, allethrin, thiabendazole, crotamiton,monosulfiram, malathion, lindane, and permethrin. Oral treat-ments are limited to ivermectin. All scabies treatments arepotentially hazardous and associated with moderate to severe

*Address correspondence to Jackson Thomas, Faculty of Health,University of Canberra, Kirinari Street, Bruce, Canberra ACT 2601,Australia. E-mail: [email protected]

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side effects (Table 1).2,8,41,4547 The most frequent complication

of topical scabicides is persisting post-scabies eczema (general-ized eczematous dermatitis) from the various formulations.12

Further, it may be difficult to treat patients with secondaryeczematization, erosions, or ulcers using topical scabicidalagents, as they can cause serious cutaneous and systemicside-effects, resulting in poor treatment uptake.48

Ivermectin (the sole oral treatment) is delivered to theinfective organisms via ingested intraepidermal fluids. Hence,young children, the elderly (particularly women), individualswith asteatotic skin (e.g., taking estrogens or retinoids), anddiabetic individuals are at increased risk for treatment failuredue to minimum sebum production.49 No currently availableacaricides for scabies possess ovicidal activity, so re-treatmentis sometimes needed, to kill newly hatched mites. This prob-

lem is further exacerbated by increasing acaricide resistanceleading to treatment failures.50

Acaricide resistance. In vitro and in vivo studies completedin Australia and elsewhere have raised concerns about increas-ing resistance to ivermectin (Australian authors reportedstrains that were totally resistant to ivermectin) and permeth-rin.1,31,5155 A 1994 in vitro study reported 100% mortality ofscabies mites after 1 hour exposure to 5% permethrin; how-ever, a study conducted 6 years later showed > 3-fold increasein tolerance to permethrin.1,7,50,56 More recent studies haveconfirmed that permethrin is now the slowest acting acaricidein vitro in this region (Northern Territory, Australia).50 A2013 review article cited seven incidents of ivermectin resis-tance leading to treatment failures in northern Australia.7

Clinical and in vitro ivermectin resistance has also been docu-mented in crusted scabies patients.7 In vitro sensitivity datafrom the past 10 years indicate that median survival times forivermectin have doubled since its introduction.56 A 2009 clini-cal trial in Senegal reported poor therapeutic response toivermectin for the management of scabies in children. Therewas a cure rate of 24.6% with a single dose of ivermectin150200 g/kg, although the study has been criticized for thevariability of dose administered. The authors have also nowindicated the possibility of ivermectin resistance in the treatedpatient cohort resulting from the previous use of ivermectinin the mass treatment program for onchocerciasis, a parasiticdisease also known as river blindness caused by filarial worm

Onchocerca volvulus.57 Further, when ivermectin is used

alone, it is not effective against crusted scabies, requiringcoadministration of topical agents such as scabicidal prepara-tions or keratolytics. In addition, resistance to other acari-cides, such as lindane and crotamiton, has also been reportedworldwide.1,3,7,46,56,58

An ideal acaricide would possess ovicidal, antibacterial,anti-inflammatory, and/or antipruritic properties, and wouldbe effective in preventing treatment relapse (resulting fromnewly hatched mites), inflammatory skin reactions (from miteantigens), and pyodermal progression. It would have a lowincidence of resistance and would not contribute to thedevelopment of resistance to other agents. The long-term use-fulness of ivermectin and permethrin for the treatment of sca-bies is uncertain because they fail to meet these requirements.

It is doubtful that new chemical entities will be developed inthe near future. Though there may be potential for immuno-logical control, the development of a vaccine may be decadesaway.7 Veterinary vaccines are available (e.g., TickGARD,GAVAC) for the management of ectoparasitic conditions suchas cattle tick (Boophilus microplus).59 Development of ascabies vaccine seemed feasible, since animals that recoverfrom the infection possess protective immunity against mitereinfestation.6062 Vaccination using dust mite extracts providedprotection for immunized animals from mite challenge63;however, several obstacles have hindered development of ascabies vaccine.63 Further studies are required to identify theprotective antigens and/or antibodies, and deliver a detailedunderstanding of how the bodys immune system controls

scabies, including increased understanding of immune patho-genesis of crusted scabies.63 Preexisting immune responses toselected antigens in endemic areas (e.g., indigenous commu-nities in Australia) also need careful consideration.63,64 Com-pliance to vaccination could be a potential limiting factor incommunity settings; latest advancements in the field such asneedle-free skin vaccination could be an attractive option toadminister vaccine in mass immunization programs to eradi-cate this highly debilitating infection.63,65

Another important consideration is that patients with crustedscabies are often identified as core transmitters of scabies toothers in the community, and therefore the spread of acaricide-resistant mites may jeopardize the future of current treatment

FIGURE 1. Complications of scabies infection, modified from Engelman and others.3

259TOPICAL TEA TREE OIL FOR SCABIES MANAGEMENT


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TABLE1

AnoverviewofclassicaltreatmentsindicatedforthemanagementofscabiesinAustralia

Drugs

Dosage

Treatmentregimen

Contraindicatio

n

Disadvantages

Indicativecurerates

Comments

Topical

Benzylbenzoate

25%

solution

Oneorseveral

consecutive24-hour

applications

Pregnantwomen

andinfants

Burningorstinging,

pruritus,dermatitis

86%

(72/86)24;daily

applicationforthree

consecutivedays;

curerateatweek4

Inusesince19

30s;neurological

complication

swithmisuse;

withdrawnin

theEuropeanUnion

duetoneuro

toxicityconcerns

Permethrin

5%

cream

Applyovernight

(814hour)then

washoff

Infantsaged

0.5) tostandard care (Johnsons Baby Softwash) in preventingMRSA colonization

AUS = Australia; MRSA = methicillin-resistant Staphylococcus aureus; TTO = tea tree oil.

Adapted from Carson and others,70

Barker and others,73

and Blackwood and others.74

262 THOMAS AND OTHERS


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and light. In typical in-use conditions, TTO will have noappreciable degradation for up to 12 months.89,93

The chemical composition of TTO has been widely studiedand well defined. TTO consists largely of cyclic monoterpenes,of which about 50% are oxygenated and 50% are hydrocar-bons.95 The international standard ISO 4730 for Melaleuca,terpinene-4-ol type (TTO) contains three major components:

terpinen-4-ol,-terpinene, and -terpinene comprising about70% of whole oil, while -cymene, terpinolene, -terpineol,and -pinene account for about 15% of the oil.95,96 Becauseof high volatility, 90% of the TTO is removed quickly fromthe skin surface, minimizing the potential for TTO componentsto travel into the deeper layers of the skin and to be absorbedinto the bloodstream.97 Under nonoccluded conditions, pene-tration of TTO components through the skin is limited butterpinen-4-ol and - terpineol (the chief bioactive constitu-ents96,98) are able to penetrate the epidermal layer (3.68.0%and 3.68.4% of the applied amount, respectively, over 25-hourperiod after application of the pure oil97) of the skin suffi-ciently to provide antimicrobial, anti-inflammatory, and acari-cidal effects.70,99 However, when 20% TTO formulation (in

ethanol) was tested, only terpinene-4-ol (< 0.05% of the appliedformulation) was able to fully penetrate the epidermis.97

Resistance to TTO. Since its introduction in the 1920s,resistance to TTO per se has not yet been reported. It hasbeen postulated that the multiple active components in TTOmay reduce the potential for resistance to occur spontaneously,since multiple simultaneous mutations would be required toovercome all the actions of the individual components.70 TTOis known to affect multiple properties and functions associatedwith the cell membrane (similar to membrane-active biocides),meaning numerous targets would have to adapt to overcomethe effects of the oil.70

DISCUSSION

Scabies was listed as a neglected tropical disease by theWorld Health Organization (WHO) in 2013.100 Preventingand decreasing morbidity associated with scabies infestation isa national public health priority in some countries. WHO hascalled for an international alliance for research into the con-trol of scabies. In the developed world, outbreaks in healthinstitutions and vulnerable communities result in a significanteconomic burden.17 In 2010, it was estimated that the directeffects of scabies infestation on the skin alone led to morethan 1.5 million years lived with disability, and the indirecteffects of complications on renal and cardiovascular functionwere found to be far greater. The antibacterial properties,together with wound healing effects,101,102 of TTO could pre-

vent the disease progression to pyoderma, secondary sepsis,and other suppurative and nonsuppurative bacterial complica-tions associated with scabies infestation, especially in children.Furthermore, the anti-inflammatory and antipruritic activity ofTTO could reduce the inflammatory immune reactions seenas a response to mite antigens.

Preclinical investigations have demonstrated superiorscabicidal properties of TTO when compared with widelyused scabicidal agents, such as permethrin 5% cream andivermectin. Hence, it is reasonable to assume that a TTO-containing formulation ( 5%) could be useful for the man-agement of scabies infestations in humans and would beless likely to cause cutaneous and/or systemic side effects.

Intuitively, this approach could lead to the development ofa topical treatment option for the therapeutic managementof ectoparasitic infestations in humans and in animals (onehealth approach). TTO formulated for topical use wouldhave the added advantage of being cost-effective, simple touse, and could be implemented in remote communities as atraditional medicine for the long-term management of sca-

bies and pyoderma in children.Despite the fact that TTO has a relevant spectrum ofactivity against scabiesmites, proven antimicrobial and anti-inflammatory activities, putative anti-itch properties, and prom-ising preliminary clinical evidence of safety and effectiveness,it is unlikely to be investigated and developed as a treatmentof scabies by the usual commercial mechanisms. This isbecause the intellectual property associated with these prop-erties is already in the public domain and TTO would notmeet the novelty requirement for a patent. Although patentsare not the only mechanism that may be used to protectintellectual property, they are a cornerstone of the commercialdrug development process.103 Without a patent or other simi-lar means to protect the intellectual property associated with

developing and using TTO to treat scabies, there is little com-mercial incentive for anyone to bear the risk and cost associ-ated with product development and safety and efficacy testing.103

Consequently, the evaluation of a potentially useful, low-cost,nonproprietary treatment may continue to be overlooked.Ironically, the burden of scabies disease is borne dispropor-tionately by the poor,104 a group likely to benefit the most fromthe availability of nonproprietary treatments such as TTO.

Received August 12, 2014. Accepted for publication May 8, 2015.

Published online January 19, 2016.

Authorsaddresses: Jackson Thomas, Mark Naunton, Rachel Davey,Greg Kyle, and Gabrielle Cooper, Faculty of Health, University ofCanberra, Canberra, Australia, E-mails: jackson.thomas@canberra

.edu.au, [email protected], [email protected], [email protected], and [email protected]

.au. Christine F. Carson and Kate Hammer, School of Medicine, TheUniversity of Western Australia, Western Australia, Australia, E-mails:[email protected] and [email protected] M. Peterson, School of Medicine, University of Tasmania,Tasmania, Australia, E-mail: [email protected]. Shelley F. Walton,Faculty of Science, Health, Education and Engineering, University ofSunshine Coast, Queensland, Australia, E-mail: [email protected] Spelman, Center of Bio medical Research, Burnet Research Insti-tute, Victoria, Australia, E-mail: [email protected]. Pascale Dettwiller,School of Medicine, Flinders University, Northern Territory, Australia,E-mail: [email protected]. Kavya E. Baby, Private Prac-tice, Canberra, Australia, E-mail: [email protected].

This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the

original author and source are credited.

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Scabies Review