Ivermectin

Abstract

Ivermectin, an anti-parasitic agent widely used for onchocerciasis in humans, is emerging as an oral antiscabietic that is as safe and effective as the topical antiscabietics. In the recent reports, all groups of population responded to ivermectin in the treatment of scabies, including immunocompetent, immunocompromised, and other high-risk populations such as individuals with Down's syndrome. This report reviews the efficacy, the mechanism of action, and the safety profile of ivermectin in the treatment of scabies, particularly its utility in crusted scabies and outbreaks of scabies in institutional settings.

Introduction

The standard therapy for scabies consists of topical antiscabietics such as precipitated sulfur, crotamiton, lindane, and permethrin. Permethrin 5% has become the antiscabietic of choice in the United States because of reports of resistance to and central nervous system (CNS) toxicity of lindane. In fact, lindane has recently been added to the Food and Drug Administration (FDA) MedWatch list because inappropriate usage and suicidal ingestion have resulted in three deaths (1). Oral antiscabietic, namely ivermectin, has been introduced within the last decade as an alternative to the topical agents. Ivermectin is a derivative of a class of compounds known as the avermectins. Avermectins were first discovered in mid 1970s in fermentation broth of a soil actinomycete, Streptomyces avermitilis (2). Specifically, ivermectin is a semi-synthetic derivative of avermectin B1a, a macrolytic lactone structurally similar to the macrolide antibiotics but with no known antibacterial activity (Figure 1). It was initially developed as an insecticide for crop management and was subsequently found to be a safe and effective treatment for infections and infestations in livestock and domestic animals by nematodes and arthropods, including insects, ticks, and mites (2). Ivermectin has since gained wide acceptance for use in humans as the treatment of choice for onchocerciasis, a filarial infection responsible for river blindness in many developing countries. The drug has also proven to be effective against a host of other human infections, including Wuchereria bancrofti, Brugia malayi, Strongyloides stercoralis, Enterobius vermicularis, cutaneous larva migrans, and head and body lice (3-5). In 1996, ivermectin was approved in the United States for treating the intestinal stage of strongyloides and onchocerciasis. Although the medicine is widely used in veterinary medicine for mite infestation, referred to as mange, ivermectin has no indication in humans for scabies as of yet in the United States. There is no indication for patients weighing less than 15 kilograms for any disease due to lack of experience and studies in this subset of the population.

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Pharmacology and Mechanism of Action

The pharmacokinetic profile of ivermectin has been investigated since the 1980s. In the dosage range of 6-15 mg, ivermectin exhibits linear pharmacokinetics achieving peak plasma concentration at 4 hours (6). The drug is 93% bound to plasma proteins, metabolized in the liver by isoform cytochrome P450-3A47. Its plasma half-life is at least 16 hours with complete excretion occurring in approximately 12 days almost exclusively in feces. Ivermectin has a large volume of distribution, that is, wide tissue distribution, including the skin. The highest concentration, however, is found in the adipose tissue (8). In cases of onchocerciasis involving the skin, single oral doses of 100, 150, and 200 micrograms achieve therapeutic level in the skin to decrease the number of microfilariae by 60 to 80% within 3 to 4 days (6).

Ivermectin binds to ligand-gated chloride ion channels including glutamate, glycine, and gammaaminobutyric acid (GABA) gated chloride ion channels in nerve and muscle cells. Its selective activity against human parasites is due to its high affinity for glutamate-gated chloride ion channels found in the peripheral nervous system of invertebrates (9). The binding of ivermectin to this ion channel in the nerve and muscle cells results in increased permeability of the cell membrane to chloride ions, leading to hyperpolarization with subsequent paralysis and death of the parasite. Because ivermectin does not readily cross the mammalian blood-brain barrier, where ligand-gated chloride ion channels are found in mammals, humans are spared from adverse CNS effects of the drug (10-12). Nevertheless, within the realm of veterinary medicine there have been reports of severe toxicity of ivermectin affecting collies, demonstrating that drug can access the CNS in mammals (13).

Scabies

Several studies have demonstrated that ivermectin is just as safe and effective as topical antiscabietics. In these studies, single oral therapy with dosages ranging from 100 to 200 [micro]g/kg resulted in cure rates that ranged from 70% to 100% (14-17). In a study comparing oral ivermectin and permethrin 5% cream, two 200 [micro]g/kg doses two weeks apart were required to achieve the cure rate of a single application of permethrin, which was 97.8% (18). Despite these studies, the optimal dosage for scabies has not been established due to paucity of randomized trials and the lack of longterm experience of the drug in humans for scabies. Data from the limited number of studies indicate that two doses of 200 mg/kg of ivermectin 1 to 2 weeks apart achieve the comparable cure rates of topical antiscabietics. Single dose failure is assumed to be, in part, due to survival of the eggs leading to re-infestation. Some report successful experience with single 250 [micro]g/kg and 400 [micro]g/kg dosages, which avoids the second dosage (19).

The advantages of oral versus topical therapy, some investigators assert, are convenience and better compliance. Indeed, in cases of uncooperative or uncontrollable patients, ivermectin may offer an advantage (20). In most cases, however, ivermectin does not offer a distinct advantage over topical antiscabietics in uncomplicated scabies.

Crusted Scabies

Immunosuppressed patients either from therapy or human immunodeficiency virus infection, patients with neurologic disorders such as Down's syndrome, and debilitated patients found in nursing homes comprise the groups at risk for this highly contagious form of scabies. Prompt eradication of the infestation is necessary since these patients may be at risk for bacterial sepsis because of their significantly compromised skin barrier. Re-infestation occurs frequently due to poor control of the spread of the disease primarily due to inadequate fomite control. Eradication of the infestation may pose a therapeutic challenge, requiring multiple treatments with topical antiscabietics and keratolytics. Ivermectin in this setting may provide a distinctive advantage over topical antiscabietics. In fact, some investigators have declared ivermectin as the therapy of choice for this form of infestation (21). Data on efficacy of ivermectin for crusted scabies are mostly from case reports rather than clinical trials. In most of these reports, effective regimen required more than two to three doses of 200 mg/kg with and without concomitant topical keratolytics and antiscabietics (22-32). In an open-label study by Huffam and Currie, 20 aboriginal patients with crusted scabies recalcitrant to topical antiscabietics were treated with 1 to 3 doses (200 mg/kg) of ivermectin two weeks apart, along with topical antiscabietics and keratolytics (33). Only 8 of the 20 patients had complete response to a single dose, 9 had partial response, and 3 had minimal improvement. One patient received 10 doses over a period of 12 months. The authors concluded that those who received 3 doses of ivermectin had the best clinical response. None of the investigators reported any significant side effects. Although single dose has been reported to be effective, multiple doses are required for most cases of crusted scabies. The number doses and the addition of topical keratolytics or antiscabietics will depend on the extent of the infestation, since the patients at risk for crusted scabies represent a heterogeneous group that may present with minimal crusting to extensive crusting of the body. Symptoms, especially pruritus, may subside within hours to days, but a complete response to ivermectin generally ranged from 2 to 6 weeks.

Institution Setting

Prompt eradication of scabies outbreak in institutional settings such as prisons, nursing homes, and homes for the mentally handicapped can be challenging. Meticulous application of topical antiscabietics can be difficult and time consuming, especially with uncooperative patients either due to mental incapacity or physical debilitations such as contractures. More reports of experience with ivermectin in these settings are emerging. Several authors have reported successful eradication of scabies in these settings (20,34-36). The usual regimen has been two doses of 200 mg/kg 1 to 2 weeks apart, although in one study in a prison setting, a large number of prisoners were treated using single dose of 150 mg/kg successfully (37). The investigators emphasize the safety, high efficacy, and the ease of administration and, thus, high compliance rate. Ivermectin in these settings may provide a distinctive advantage over topical antiscabietics.

Adverse Effects

Ivermectin has been used in the treatment of millions of people with parasitic diseases worldwide with minimal adverse effects. Headache, myalgia, rash, anorexia, hypotension, itching, fever, chills, and joint or facial edema comprise of the minor documented adverse events in the treatment of onchocerciasis, which usually occurred within three days of the administration of the first dose, rarely occurring after subsequent doses. Some of the rare severe side effects reported are severe postural hypotension, dyspnea, laryngeal edema, and more recently, encephalopathy (38,39). A presumed immunologic reaction to the dead filaria and their toxic products known as Mazzotti-reaction, which consists of fever, headache, itching, nausea, and hypotension, has been described in those patients who were treated with ivermectin (40).

In the recent experience of the drug against scabies, serious side effects such as Mazzotti-like reaction or encephalopathy have not been reported in patients treated with ivermectin. Most authors have reported no adverse reaction to ivermectin. The few side effects that were reported were mild and transient, which included facial edema, worsening of pruritus, hypotension, abdominal pain, and vomiting (17,24,41). Barkwell et al., in 1997 reported an increased death rate in 47 elderly patients treated with ivermectin following a scabies epidemic in a nursing home facility (42). Six months after the treatment, 15 of the 47 residents died compared to only 5 of 47 age and sex matched controls over the same period, leading the investigators to suggest that ivermectin had a role in their demise. Many have criticized the method and the conclusion of the study (43-45). Experiences of ivermectin usage in geriatric population by other investigators have not confirmed the observation made by Barkwell and Shield (34,46,47). In addition, a review of the study by the FDA found no association between these deaths and ivermectin (45). A recent study in humans demonstrated that higher and more frequent doses than currently approved for human use of ivermectin were well tolerated (48).

Although the experience of ivermectin in the treatment of scabies in the pediatric population is very limited, successful treatment in this population has been reported even in children under the age of five with minimal or no side effects (24,27-29,49,50). In regards pregnant woman, a follow-up study of hundreds of pregnant women inadvertently treated with ivermectin revealed no increased risk of fetal damage over controls (51). Central nervous system toxicity, specifically seizures, has been demonstrated in young mice that have yet to form a CNS blood-brain barrier. Therefore, CNS toxicity to the fetus theoretically may occur if ivermectin is administered before the blood-brain barrier is completely developed, which in humans it is thought form prenatally (52,53).

Conclusion

The addition of ivermectin to the clinician's armamentarium should be welcomed as a powerful tool for the treatment of scabies. The rapid course of action in the treatment of the associated pruritus, the low incidence of side effects, and the superior efficacy of the drug compared to other forms of treatment for the crusted variety of scabies are all compelling reasons for this new confidence in ivermectin. With an availability of effective topical antiscabietics, however, ivermectin should be reserved for those situations where a topical agent may not be suitable or optimal. Other investigators who fear eventual emergence of resistance if widespread usage of the drug is adopted have legitimately raised concerns over resistance.

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ADDRESS FOR CORRESPONDENCE:

Jason B Lee MD

Clinical Assistant Professor

Jefferson Medical College

Department of Dermatology and Cutaneous Biology

833 Chestnut Street, Suite 740

Philadelphia, PA 19107

E-mail: Jason.B.Lee@mail.tju.edu

Tel: (215) 503-4256

Fax: (215) 503-4317

ANTHONY F SANTORO MD (1)

MARK A REZAC MD (2)

JASON B LEE MD (3)

(1.) PRIVATE PRACTICE, WESTCHESTER, PENNSYLVANIA

(2.) WILL'S EYE HOSPITAL, PHILADELPHIA, PENNSYLVANIA

(3.) DEPARTMENT OF DERMATOLOGY AND CUTANEOUS BIOLOGY JEFFERSON MEDICAL COLLEGE, PHILADELPHIA, PENNSYLVANIA

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