Several different avermectin-"resistant" developmental and physiological phenotypes have been described, but definitive relationships among these phenotypes and native avermectin receptor subtypes, locations, numbers, and binding affinities require clarification (Hejmadi et al., 2000; Sangster and Gill, 1999). Alterations in genes encoding ATP-dependent P-glycoprotein transporters that bind avermectins and in those encoding putative components of the glutamate-gated Cl− channel have been associated with the development of resistance in Haemonchus contortus (Xu et al., 1998). A significant increase in low-affinity glutamate binding has been detected in ivermectin-resistant nematodes, but how this relates to drug resistance is unclear (Hejmadi et al., 2000).
Glutamate-gated Cl− channels probably are one of several sites of ivermectin action among invertebrates (Zufall et al., 1989). Avermectins also bind with high affinity to γ-aminobutyric acid (GABA)-gated and other ligand-gated Cl− channels in nematodes such as Ascaris and in insects, but the physiological consequences are less well defined. Lack of high-affinity avermectin receptors in cestodes and trematodes may explain why these helminths are not sensitive to ivermectin (Shoop et al., 1995). Avermectins also interact with GABA receptors in mammalian brain, but their affinity for invertebrate receptors is ~100-fold higher (Schaeffer and Haines, 1989).
In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial counts in the skin and ocular tissues that lasts for 6-12 months (Newland et al., 1988). The drug has little discernible effect on adult parasites, even at doses as high as 800 μg/kg (Molyneux et al., 2003) but affects developing larvae and blocks egress of microfilariae from the uterus of adult female worms (Court et al., 1985). By reducing microfilariae in the skin, ivermectin decreases transmission to the Simulium black fly vector (Cupp et al., 1989). Regular treatment with ivermectin also has been conjectured to act prophylactically against the development of Onchocerca infection (Molyneux et al., 2003).
Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B. malayi, L. loa, and M. ozzardi. The drug exhibits excellent efficacy in humans against Ascaris lumbricoides, Strongyloides stercoralis, and cutaneous larva migrans. Other GI nematodes are either variably affected (Trichuris trichura and Enterobius vermicularis), or unresponsive (Necator americanus and Ancylostoma duodenale).
Absorption, Fate, and Excretion. In humans, peak levels of ivermectin in plasma are achieved within 4-5 hours after oral administration. The long terminal t1/2 (~57 hours in adults) primarily reflects a low systemic clearance (~1-2 L/hour) and a large apparent volume of distribution. Ivermectin is ~93% bound to plasma proteins. The drug is extensively converted by hepatic CYP3A4 to at least 10 metabolites, mostly hydroxylated and demethylated derivatives (Zeng et al., 1998). Virtually no ivermectin appears in human urine in either unchanged or conjugated form (Krishna and Klotz, 1993). Studies in transgenic mice lacking a P-glycoprotein efflux pump showed neurotoxicity, indicating that this drug transporter, located in the endothelium of brain microvasculature, reduces ivermectin penetration to the CNS (Schinkel et al., 1994). This, and the relatively lower affinity of ivermectin for mammalian CNS receptors, may explain the paucity of CNS side effects and the relative safety of this drug in humans.
Onchocerciasis. Ivermectin administered as a single oral dose (150 to 200 μg/kg) given every 6-12 months is the drug of choice for treatment of onchocerciasis, in adults and children ≥5 years of age (Goa et al., 1991). Ivermectin given in mass drug administration programs has become a critical component of onchocerciasis control programs in the Americas and in sub-Saharan Africa. Equally important, such therapy results in reversal of inflammatory changes in ocular tissues and arrests the development of further ocular pathology due to microfilariae. Marked reduction of microfilariae in the skin results in major relief of the intense pruritus that is a feature of onchocerciasis. Clearance of microfilariae from skin and ocular tissues occurs within a few days and lasts for 6-12 months; the dose then should be repeated. The drug is not curative, however, because ivermectin has little effect on adult O. volvulus. Ivermectin has been used since 1987 as the mainstay for onchocerciasis control programs in all of Africa and in the Middle East and Latin America, where the disease is endemic. Nearly 20 million people have received at least one dose of the drug, and many have received six to nine doses (Dull and Meredith, 1998). The Onchocerciasis Elimination Programme in the Americas (OEPA) has effectively reduced transmission in the endemic nations of the Americas, Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela through biannual treatment with ivermectin (Molyneux et al., 2003), and there is interest in extending biannual ivermectin coverage to the endemic regions of sub-Saharan Africa. Annual doses of the drug are quite safe and substantially reduce transmission of this infection (Boatin et al., 1998; Brown, 1998). How long such therapy should continue is unknown.
Resistance to ivermectin and the related agent moxidectin have been reported in a variety of parasites of veterinary importance, as have poor parasitological responses to ivermectin in the onchocerciasis control program (Osei-Atweneboana et al., 2007). Recent laboratory work with C. elegans has shown that exposure to increasing doses of ivermectin resulted in the development of a stable multidrug resistance phenotype with cross-resistance to the related drug moxidectin and to other antihelmintics, levamisole and pyrantel, but not albendazole (James and Davey, 2009). The potential for the development of similar resistance in human parasites exists, particularly in the setting of mass treatment campaigns.
Lymphatic Filariasis. Initial studies indicated that single annual doses of ivermectin (400 μg/kg) was both effective and safe for mass chemotherapy of infections with W. bancrofti and B. malayi (Ottesen and Ramachandran, 1995). Ivermectin is as effective as DEC for controlling lymphatic filariasis, and unlike DEC, it can be used in regions where onchocerciasis, loiasis, or both are endemic. Although ivermectin as a single agent can reduce W. bancrofti microfilaremia, the duration of treatment required to eliminate LF at 65% coverage of the affected population presumably would be >6 years (Molyneux et al., 2003). More recent evidence indicates that a single annual dose of ivermectin (200 μg/kg) and a single annual dose of albendazole (400 mg) are even more effective in controlling lymphatic filariasis than either drug alone (www.filariasis.org). The duration of treatment is at least 5 years, based on the estimated fecundity of the adult worms. This dual-drug regimen also reduces infections with intestinal nematodes. Facilitated by corporate donation of ivermectin and albendazole, the drug combination now serves as the treatment standard for mass chemotherapy and control of lymphatic filariasis (Ottesen et al., 1999).
Strongyloidiasis. Ivermectin administered as a single dose of 150 to 200 μg/kg is the drug of choice for treatment of human strongyloidiasis (Marti et al., 1996). It is at least as active as the older drug of choice, thiabendazole, and significantly better tolerated. It is generally recommended that a second dose be administered a week following the first dose. It is more efficacious than a 3-day course of albendazole (Marti et al., 1996). In the life-threatening Strongyloides hyperinfection syndrome where GI absorption of oral dose may be poor, parenteral veterinary ivermectin has been administered "off-label" to human subjects by the subcutaneous route (Chiodini et al., 2000).
Infections with Other Intestinal Nematodes. Ivermectin also is variably effective against other intestinal nematodes. It is more effective in ascariasis and enterobiasis than in trichuriasis or hookworm infection (Keiser and Utzinger, 2008). In the latter two infections, although it is not curative, it significantly reduces the intensity of infection.
Other Indications. Although ivermectin has activity against microfilaria (but not adult worms) of L. loa and M. ozzardi, it is not used clinically to treat infections with these parasites. Taken as a single 200-μg/kg oral dose, ivermectin is a first-line drug for treatment of cutaneous larva migrans caused by dog or cat hookworms. Ivermectin, administered orally in a dose of 200 μg/kg, is an effective treatment of scabies. In uncomplicated scabies, two doses should be administered, 1-2 weeks apart. It should be used in severe (crusted) scabies in repeated doses, with one recommended regimen entailing 7 doses of 200 μg/kg given with food, on days 1, 2, 8, 9, 15, 22, and 29 (Roberts et al., 2005). The drug appears to be effective against human head lice as well.
Toxicity, Side Effects, and Precautions. Ivermectin is well tolerated by uninfected humans.
In filarial infection, ivermectin therapy frequently causes a Mazzotti-like reaction to dying microfilariae. The intensity and nature of these reactions relate to the microfilarial burden. After treatment of O. volvulus infections, these side effects usually are limited to mild itching and swollen, tender lymph nodes, which occur in 5-35% of people, last just a few days, and are relieved by aspirin and antihistamines (Goa et al., 1991). Rarely, more severe reactions occur that include high fever, tachycardia, hypotension, prostration, dizziness, headache, myalgia, arthralgia, diarrhea, and facial and peripheral edema; these may respond to glucocorticoid therapy. Ivermectin induces milder side effects than does DEC, and unlike the latter, it seldom exacerbates ocular lesions in onchocerciasis. The drug can cause rare but serious side effects including marked disability and encephalopathies in patients with heavy L. loa microfilaria (Gardon et al., 1997). Loa encephalopathy is associated with ivermectin treatment of individuals with Loa microfilaremia levels ≥30,000 microfilariae per milliliter of blood (Molyneux et al., 2003). There is little evidence that ivermectin is teratogenic or carcinogenic.
Possible adverse interactions of ivermectin with other drugs that are extensively metabolized by hepatic CYP3A4 have yet to be evaluated. Because of its effects on GABA receptors in the CNS, ivermectin is contraindicated in conditions associated with an impaired blood-brain barrier (e.g., African trypanosomiasis and meningitis). Ivermectin is not approved for use in children <5 years of age or in pregnant women. Lactating women taking the drug secrete low levels in their milk; the consequences for nursing infants are unknown. Currently, the WHO recommends against ivermectin treatments in mass drug administration campaigns for pregnant women, lactating women in the first week after birth, children <90 cm in height (~15 kg in body weight), and the severely ill (WHO, 2006).