Efficacy and tolerance of oral ivermectin in scabies

Journal of the European Academy of Dermatology and Venereology 11 (1998) 247–251

Efficacy and tolerance of oral ivermectin in scabies Assen Dourmishev*, Dimitrina Serafimova, Lyubomir Dourmishev Department of Dermatology and Venereology, Medical University, Sofia 1431, Bulgaria

Abstract Objective The aim of this open-label study was to investigate the therapeutic effect and adverse reactions of oral ivermectin in scabies patients. Background There is much confusion over reports of efficacy, adverse reactions and relapses after oral treatment of scabies with ivermectin. Methods Nineteen patients, ten otherwise healthy outpatients with scabies, and nine inpatients with scabies and another skin disease (dermatomyositis, 3; pemphigus, 2; bullous pemphigoid, 1; pyoderma, 1; HIV, 1; Behc¸et’s disease, 1) were treated with an oral dose of 0.2 mg/kg ivermectin (1% water solution) on days 1 and 8. The presence of live mites and ova in the patient’s skin was investigated before, during and after the treatment. Results None of the 19 patients with scabies had evidence of scabies after the second dose of ivermectin. In seven patients we noted the enhancement of pruritus 24–72 h after the first administration of ivermectin. In three patients the skin manifestation, vesicle-pustular rash increased between the second and the fourth day. Conclusion The advantages of oral ivermectin treatment in scabies patients are: high therapeutic efficacy against Sarcoptes scabiei, good tolerance and influence of the drug on the whole skin surface and on clinical symptoms. The administration of the drug is easy and quick.  1998 Elsevier Science B.V. All rights reserved Keywords: Scabies; Oral treatment; Ivermectin

1. Introduction Anecdotal reports of improvement in scabies patients suggest that ivermectin has antiscabicide activity [1]. In domestic animals with sarcoptic mange ivermectin has been administered as a subcutaneous injection, orally or topically with very good results [2–12]. However, earlier studies in humans indicate that doses of ivermectin below 0.2 mg/kg of body weight for the treatment of scabies was less efficacious [13–15]. Recent reports demonstrated that ivermectin given as a single oral dose of 0.2

mg/kg is effective for the treatment of ordinary scabies, mange in AIDS patients and crusted scabies [16,17]. However, a single oral dose of 0.2 mg/kg of ivermectin cures most cases of ordinary and uncomplicated scabies, but crusted or other stubborn cases require additional treatment [16]. Therefore we consider it a matter of interest to report our clinical trial in patients with different forms of scabies successfully treated with 0.2 mg/kg oral ivermectin on the first and eighth days of therapy.

2. Patients and methods * Corresponding author. Tel./fax: +359 2 544879; e-mail: [email protected]

0926-9959/98/$ - see front matter PII S0926-9959 (98 )0 0075-0

An open-label study of 19 patients (13 males and

 1998 Elsevier Science B.V. All rights reserved

248

A. Dourmishev et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 247–251

six females; age range between 18 and 73 years; mean, 45.3 years) with scabies was conducted in Sofia Dermatology Clinic between September, 1995 and February, 1998. The patients were divided into two groups: the first consisted of ten otherwise healthy outpatients with scabies, and the second of nine inpatients with scabies and another skin disease (dermatomyositis, 3; pemphigus, 2; bullous pemphigoid, 1; pyoderma, 1; HIV, 1; Behc¸et’s disease, 1). In the past, relapses of the scabies in patients of the group had been treated repeatedly with a local scabicide with a temporary effect. None of them had used a scabicide for 2 months before their entry into the trial. Some of the patients from this group continued maintenance therapy with corticosteroids. The severity of scabies was recorded as ordinary (,50 lesions), severe or widespread (.50 lesions), and crusted (Table 1). A physical examination of the inpatients included measurement of weight, pulse, temperature and blood pressure. Blood, liver and kidney function analyses were also conducted. Scrapings of lesions in 40% lactic acid were examined microscopically for live mites, ova and faecal pellets before, during and after treatment. Ivermectin (1% water solution) was administered after informed consent of the patients as an oral dose of 0.2 mg/kg on the first and on the eighth days without local treatment. The patients in the first group were seen once weekly and those in the second group daily. A 26-year-old air-hostess was treated with a single oral dose of ivermectin and continued the treatment voluntarily abroad with benzyl benzoate; she was not included in our trial because this was protocol violation. The patients were interviewed about subjective evidence and adverse reactions. Clothing and bedclothes were disinfested by hot cycle at the end of treatment. Treated patients were followed-up 3 weeks after the second oral dose of ivermectin. Contact subjects of the scabies patients were treated with a topical 30% benzyl benzoate emulsion to reduce the risk of reinfection.

3. Results None of the 19 patients with scabies had evidence of scabies after the second dose of ivermectin. At the

end of the 8-day period we noted disappearance of pruritus, improvement of sleep and emotion in all patients. In seven patients we recorded an increase of pruritus 24–72 h after the first administration of ivermectin. Three patients experienced adverse skin reactions, vesicle-pustular rash, between the second and the fourth days (Table 2).

4. Discussion Ivermectin is an antiparasitic agent with a structure similar to the macrolide antibiotics, but without antibacterial activity [11]. It is a synthetic derivative of abamectin (natural fermentation product of Streptomyces avermitis). Ivermectin has been used against a wide range of endo- and ectoparasites of animals [11], and humans [18]. The drug is successfully used for the treatment of sarcoptic mange in different animals, in particular cats [11,12], dogs [2,3,11], foxes [4], pigs [5–8], wild boars [8] and camels [9,10], administered as a subcutaneous injection [9, 10], orally with feed [6,8] and topically[12]. In humans, ivermectin was introduced against Onchocerca volvolus infection by Aziz et al., in 1982 [19]. Oral ivermectin is highly effective for treatment of loiasis and brancroftian filariasis [18]. There are few data on the effectiveness of ivermectin in scabies patients. The first studies of oral ivermectin application in scabies patients indicate that doses below 0.2 mg/kg were not efficacious [13– 15]. Macotela-Ruiz and Pefia-Gonzalez in a doubleblind study reported that 79.3% scabies patients were cured 1 week after a single dose of 0.2 mg/kg ivermectin, compared with 15.4% of patients in a placebo group [1]. Meinking et al., conducted an open-label study in which ivermectin was administered as a sinTable 1 The severity of scabies Group

Lesions

Males

Females

Scabies and another skin disease

I. Ordinary II. Severe III. Crusted Total

,50 lesions .50 lesions – –

9 4 0 13

2 1 3 6

3 3 3 9

249

A. Dourmishev et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 247–251 Table 2 Characteristics of patients and side effects of ivermectin Age

Sex

Disease

Scabies

Side effects

68 48 21 33 18 59 18 60 38 40 34 65 55 56 43 48 73 18 66

M M M M M M F M M M M F F F F M F M M

Healthy Healthy Healthy Healthy Healthy Healthy Eczema mammae Healthy Healthy Healthy HIV infection Dermatomyositis, Ca pancreatisa Dermatomyositisa Dermatomyositis, Ca mammaea Pemphigus, diabetes mellitus Pemphigus, diabetes mellitus Bullous pemphigoid Pyoderma Morbus Behc¸et’s

Severe Ordinary Ordinary Ordinary Ordinary Ordinary Severe Ordinary Ordinary Ordinary Ordinary Crusted Crusted Crusted Ordinary Severe Ordinary Severe Severe

Pruritus + rash 0 0 Pruritus + rash Pruritus + rash Pruritus Pruritus 0 0 0 Pruritus 0 0 0 0 0 0 0 0

a

Decreased cell mediated immunity; M, male; F, female.

gle oral dose of 0.2 mg/kg in two groups: the first consisting of 11 otherwise healthy patients with ordinary scabies and the second of 11 HIV-infected patients with scabies, the majority of whom had AIDS [16]. By the time of the 4-week follow-up evaluation all patients of the first group and eight of 11 (73%) of the HIV-positive patients were cured. Two patients required a second dose 2 weeks after the first treatment and were also cured. The authors concluded that a single oral dose of 0.2 mg/kg of body weight ivermectin cures most cases of ordinary and uncomplicated scabies, but crusted or other stubborn cases require additional treatment. Aubin and Humbert reported that a single dose of 0.2 mg/kg ivermectin was enough for the cure of two patients with crusted scabies [17]. However, Youssef et al., reported that in scabies patients, ivermectin was found to have a curative effect after a single topical application, but in 50% of the cases, another application was needed five days later [20,21]. The conflicting data on relapses in scabies patients [1,14,16] and high efficacy in animal mange [3,4,8– 10] led us to use 0.2 mg/kg ivermectin two-fold within a 7-day interval. In our study all patients with scabies were successfully cured by this drug.

The mode of action of ivermectin against Sarcoptes scabiei, however, remains elusive. The simplest explanation for how ivermectin works is that it specifically increases membrane chloride ion permeability of target organism [22]. Ivermectin has an endectocidal effect (simultaneously against endo- and ectoparasites) causing paralysis by suppressing the conduction of the nervous impulses in the interneuronic synapses of parasites. This is accomplished by stimulation of g-aminobutiric acid (GABA) release from presynaptic nerve endings and enhancement of the binding to the postsynaptic receptors. In this way the conduction of the nerve impulses is ceased and paralysis and death of the parasites occur. Ivermectin is well tolerated by mammals as GABA is localized only in the CNS, and a much higher concentration is needed, compared with nematodes or arthropodes, to affect neurological function [23]. Another explanation of the low toxicity of the drug in mammals is the lack of a specific, high affinity site associated with neuronal function or to the relatively poor penetration of this large molecular weight compound through the haematoencephalic barrier [23]. The 15-year ivermectin history for control of millions of people suffering from microfilaria diseases

250

A. Dourmishev et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 247–251

indicates that it is a safe medicine [16,18,24–26]. The results from several trials of ivermectin in the Onchocerciasis Control Programme in West Africa show a low prevalence of adverse reactions [24,25]. Transient and mild adverse reactions have been reported in 24% of patients with filarial diseases like anorexia, asthenia, headache, arthralgia, myalgia, fever and eosinophilia. Mazzotti reactions of the release of degradation products of microfilaria were observed. Macular and papular rash and pruritus were also reported [26]. High rates of adverse reactions have been reported in expatriates treated with ivermectin [26–28]. Serious reactions after mass treatment of onchocerciasis were reported in 1.1 of 10 000 patients [29]. On the basis of a statistical study Barkwell and Shields [30] suggest possible death in elderly patients associated with a single oral dose of ivermectin (0.15–0.2 mg/kg weight body) for treatment of scabies. Fifteen out of 47 patients who had been consecutively treated topically with crotamiton, repeatedly with lindane and once with oral ivermectin died in a 6month period. The fatal outcomes were preceded by changes in the behaviour of these individuals with anorexia, listlessness and lethargy. The final causes of death were not verified by autopsy. In our study an enhancement of pruritus was observed in seven patients 24–72 h after the first administration of ivermectin. In three patients the skin manifestation, vesicle-pustular rash, increased between the second and the fourth day. These mild adverse skin reactions in our patients did not necessitate the interruption of treatment. In the second group of patients with another skin disease and maintenance therapy with corticostroids no side effects were observed. A 65-year-old woman with paraneoplastic dermatomyositis died 6 months after the treatment of scabies from disseminated cancer of the pancreas. Metastases had been confirmed before the treatment and according to us the death is not associated with ivermectin therapy. In conclusion, the benefits of oral ivermectin treatment of scabies patients are high therapeutic efficacy against S. scabiei, good tolerance and influence of the drug over clinical symptoms (decrease of pruritus, improvement of emotion and sleep). Administration is quick and easy. This treatment is convenient for persons who are not self-sufficient or are bed-ridden, forbidden to move (with myocardial infarction etc).

What is very important for patients with another skin disease is the lack of the local iritant action of topical scabicides. Oral treatment with ivermectin for eradication of scabies might defeat mysterious relapsing of parasitosis because the drug operates over the whole body and there are no neglected areas [31]. The disadvantages of this treatment are the slow onset of therapeutic effect; transitory enhancement of itching and rash; and lack of safeguards against reinfestation. Further investigation is necessary to evaluate the optimal regimen of this treatment in patients with different forms of scabies and immunodeficiency, the possibility of its use for prophylaxics in risk groups, interference with topical scabicides (lindan etc.) in elderly patients and the incidence of serious adverse reactions.

References [1] Macotela-Ruiz E, Pefia-Gonzalez G. Tratamiento de la escabiasis con ivermectina por via oral. Gaseta Med de Mexico 1993;129:201–205. [2] Yazvinski TA, Pote L, Tilley W, et al., Efficacy of ivermectin against Sarcoptes scabiei and Otodectes cynotis infestations of dogs. Vet Med Small Anim Clinic, 1981;76:1751. [3] Scheidt VJ, Medleau L, Seward RL, et al., An evaluation of ivermectin in the treatment of sarcoptic mange in dogs. Am J Vet Res1984;45:1201–1202. [4] Berge GH, Smeds E. Efficacy of ivermectin against S. scabiei infestations of foxes. Nord Vet Med1984;36:156–161. [5] Courtney CH, Ingalls WL, Stitzlein SL. Ivermectin for the control of swine scabies: relative values of prefarrowing treatment of sows and weaning treatment of pigs. Am J Vet Res1983;44:1220–1223. [6] Primm ND, Hall WF, Di Pietro JA, et al., Efficacy of an infeed preparation of ivermectin against endoparasites and scabies mites in swine. Am J Vet Res 1992;53:508–512. [7] Seaman JT, Thompson DR, Barrick RA. Treatment with ivermectin of sarcoptic mange in pigs. Aust Vet J 1993;70:307– 308. [8] Kutzer E. Zur behandlung der Sarcoptesraude bei wild- und hausschweinen mit ivermectin. Dtsch tiearztl Wschr 1986; 93:426–429. [9] Opferham RR. Treatment of sarcoptic mange in a dromedary camel. J Am Vet Med Assoc 1985;187:1240–1241. [10] Hasim DH, Wasfi IA. Invermectin treatment of camels naturally infected with sarcoptic mange. World Anim Rev 1986;57:26–29. [11] Campbell WC. Use of ivermectin in dogs and cats. In: Campbell WC editors. Ivermectin and abamectin. New York: Springer-Verlag, 1989:245–259. [12] Soll MD, d’Assonville JA, Smith CJ. Efficacy of topically

A. Dourmishev et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 247–251

[13]

[14]

[15] [16] [17] [18]

[19] [20]

[21]

[22]

applied ivermectin against sarcoptic mange (Sarcoptes scabies var. bovis) of cattle. Parasitol Res 1992;78:120–122. Dunne CL, Malone CJ, Whithworth J. A field of the effects of ivermectin on ectoparasites of man. Trans R Soc Trop Med Hyg 1991;85:550–551. Glaziou P, Cartel JL, Alzieu P, et al., Comparison of ivermectin and bezyl benzoate for treatment of scabies. Trop Med Parasitol 1993;44:331–332. Kar SK, Mania J, Patnaik S. The use of ivermectin for scabies. Natl Med J India, 1994;7:15–16. Meinking TL, Taplin D, Jorge L, et al., The treatment of scabies with ivermectin. N Engl J Med 1995;332:26–30. Aubin F, Humbert P. Ivermectin for crusted (Norwegian) scabies. N Engl J Med 1995;332:612. Green BM, Brown KR, Taylor HR. Use of ivermectin in humans. In: Campbell WC editor. Ivermectin and abamectin. New York: Springer-Verlag, 1989;311–323. Aziz MA, Diallo S, Diop IM, et al., Efficacy and tolerance of ivermectin in onchocerciasis. Lancet 1982;2:171–173. Youssef MY, Sadaka HA, Eissa MM, et al., Topical application of ivermectin for human ectoparasites. Am J Trop Med Hyg 1995;53:652–653. Fink DW, Porra AG. Pharmacokinetics of ivermectin in animals and humans. In: Campbell WC editor. Ivermectin and abamectin. New York: Springer-Verlag, 1989;113–130. Turner MJ, Schaeffer JM. Mode of action of ivermectin. In: Campbell WC editor. Ivermectin and abamectin. New York: Springer-Verlag, 1989;73–88.

251

[23] Lankas GR, Gordon LR. Toxicology. In: Campbell WC editor. Ivermectin and abamectin. New York: Springer-Verlag, 1989;91. [24] De Sol G, Dadzie KY, Giese J, et al., Lack of adverse reactions in ivermectin treatment for onchocerciasis. Lancet 1990;335:1106–1107. [25] Pacque M, Munoz B, Green BM, et al., Safety of and compliance with community-based ivermectin therapy. Lancet 1990;335:1377–1380. [26] Withworth J, Mande GH, Unty A. Expatriates treated with ivermectin. Lancet 1991;337:625–626. [27] Davidson RN, Godfrey-Faussett L, Bryceson HD. Adverse reaction in expatriates treated with ivermectin. Lancet 1990;336:1005. [28] Bryan RT, Stokes SL, Spencer HC. Expatriates treated with ivermectin. Lancet 1991;337:304. [29] Gardon J, Gardon-Wendel N, Demanga-Ngougne ON, et al., Serious reactions after mass treatment of Onchocerciasis with ivermectin in an area endemic for Loa Ioa infection. Lancet 1997;350:18–22. [30] Barkwell R, Shields S. Deaths associated with ivermectin treatment of scabies. Lancet 1997;349:114–1145. [31] Dourmishev AL, Serafimova DK, Dourmishev LA, Mualla MA, Papaharalambous V, Malchevsky T. Crusted scabies with scalp location in dermatomyositis patients: three cases treated with oral ivermectin. Int J Dermatol 1998;37:231– 234.