Systemic Antiparasitic Agents

Mechanism of Action

Q12.2 Ivermectin binds selectively to glutamate and gamma-aminobutyric (GABA)-gated chloride ion channels found in invertebrate nerve and muscle cells. Binding results in increased permeability of cell membranes to chloride ions, with hyperpolarization of the nerve or muscle cells resulting in death of the parasite. Ligand-gated ion channels represent the primary ivermectin targets in invertebrates. Ivermectin positively modulates central nervous system (CNS) adenosine triphosphate (ATP)-gated purinergic P2X4 receptors and is believed to act in the same region as ethanol, which has spurred research into its use for alcohol abuse disorders.

Approved Indications

Q12.3 Labeled indications include the treatment of intestinal strongyloidiasis caused by Strongyloides stercoralis and onchocerciasis caused by Onchocerca volvulus . It should be noted that US Food and Drug Administration (FDA)-reviewed trials have only established that ivermectin is active against the microfilaria of O. volvulus and the intestinal forms of S. stercoralis .

Off-Label Indications

Ivermectin is most widely used in dermatology for the treatment of scabies, and to a lesser extent for the treatment of pediculosis, demodicosis, and cutaneous larva migrans. A single dose of ivermectin has been used empirically to reduce pruritus in homeless populations. Worldwide, it has also been used to treat infestations caused by Ascaris lumbricoides , Enterobius vermicularis (pinworm), Mansonella ozzardi , Gnathostomia spingerum , Mansonella streptocera , and Trichuris trichiura (whipworm), as well as both bancroftian and brugian filariasis. Interestingly, recent literature shows a potential role for ivermectin in multidrug therapy for malaria, as the drug has ‘cidal’ antimalarial activity through inhibition of import of signal recognition peptides required by plasmodium in addition to mosquitocidal activity, which prevents transmission of the disease after treatment.

Therapeutic Guidelines

Dosages range from 150 to 400 μg/kg. In the treatment of scabies, 200 μg/kg (which is roughly 1 mg/10 pound body weight) is commonly given as a single dose, and repeated in a week to 10 days as the drug has only scabicidal and not ovicidal activity. For lice, a single 400 μg/kg dose has been given on day 1 and day 8. Q12.1 Q12.4 In the setting of crusted scabies (common in immunocompromised patients), ivermectin should generally be used in conjunction with keratolytics and topical therapy, but dosing is otherwise the same as in immunocompetent patients. It is recommended to be given in three, five, or seven doses. Ivermectin has been used in the control of hospital and institutional outbreaks of scabies and to decrease disease burden in highly endemic countries, and may be superior to topical treatment in the setting of mass infestation. ( Table 12.1 )

Adverse Effects

More than 350 million people have been safely treated with ivermectin worldwide, and there are few significant adverse reactions. Rare deaths and severe encephalopathy have most often been associated with high levels of Loa microfilaremia. A study looking at World Health Organization pharmacovigilance data from the Democratic Republic of Congo found that serious and potentially fatal encephalopathy has been reported in patients coinfected with loiasis, even with low blood concentrations. Encephalopathy following the administration of ivermectin in other patients has demonstrated vascular pathology in the brain similar to that in previously reported cases of L. loa -associated death following diethylcarbamazine treatment.

Q12.5 Cutaneous and systemic reactions in patients with onchocerciasis are termed Mazzoti reactions and may include rash, systemic symptoms, and ophthalmological reactions. These may be the result of allergic and inflammatory responses to the death of microfilariae or to microorganisms within the worms. Doxycycline can eliminate endosymbiotic bacteria within filarial worms, reducing the incidence of Mazotti reactions ( Box 12.1 ).

The following reactions to ivermectin have been reported in >10% of patients in the setting of helminthic infestations. They are markedly less common in the setting of scabies infestation.

• 1.

  Mazzotti-type reaction: The overall incidence of rashes, including edema and urticaria, is 23% in the setting of helminthic infestation.

• 2.

  Pruritus (28% in the setting of helminthic infestation).

• 3.

  Fever (23% in the setting of helminthic infestation).

• 4.

  Lymphadenopathy or lymph node tenderness (1%–14%).

Less frequent reactions include tachycardia, facial edema, orthostatic hypotension, diarrhea, and nausea. CNS symptoms and Stevens–Johnson syndrome (SJS) are rare. Liver function test abnormalities have been reported. A single Canadian report of increased deaths among nursing home patients using ivermectin has not been confirmed in other trials. Q12.6 P-glycoprotein restricts the entry of ivermectin across the blood–brain barrier by an ATP-driven efflux mechanism, and deficiencies have been implicated as a risk factor for neurotoxicity. In dogs with a homozygous mutation, ivermectin accumulates in the brain, producing neurotoxicosis and even death. In this animal model, selamectin is safer than ivermectin. In knockout mice, both drugs have been shown to be substrates of P-glycoprotein, but selamectin accumulates to a much lesser degree than ivermectin in the absence of P-glycoprotein. Mutations in the P-glycoprotein multidrug resistance gene ABCB1 (MDR1) are responsible for the severe neurotoxicity seen in collie dogs treated with ivermectin, and this transporter has been shown to have similar affinity for avermectins in human and mouse cell lines. However, the same mutations do not appear to be responsible for the subchronic neurotoxicity seen in other breeds following macrocyclic lactone treatment for generalized demodicosis, suggesting that other genes or other mechanisms of toxicity may be important.

Ivermectin is routinely used to treat parasitic infestations in cattle. There have been ongoing concerns about residual drug present in milk products, and single nucleotide polymorphisms in transport proteins may result in higher residual amounts in milk from certain cows. This has raised concerns about the potential for hypersensitivity reactions and the emergence of resistance.

Drug Interactions

Ivermectin may enhance the anticoagulant effect of vitamin K antagonists such as warfarin. There is some potential for interaction with drugs that affect levels of CYP3A4, although metabolism by this enzyme system is relatively minor. Rifampicin (rifampin) and phenobarbital enhance CYP3A4 activity, and alter ivermectin gastrointestinal disposition via enhanced P-glycoprotein-mediated intestinal transport. Of the two, phenobarbital had the greater effect in a rat model. Ketoconazole-mediated CYP3A4 inhibition led to a 3-fold increase in the time ivermectin dose remained above therapeutic levels in a minipig model.

Resistance

Q12.7 Suboptimal responses to ivermectin in onchocerciasis control efforts in Ghana have raised concern about the development of resistance to ivermectin. Although ivermectin remains a potent microfilaricide, adult parasite populations resistant to ivermectin’s antifecundity effects are emerging, which could eventually lead to recrudescence of the disease. Increased expression of ABC transport proteins is associated with nematode resistance to ivermectin. Resistant strains can demonstrate a multidrug resistance phenotype mediated by active drug transport with cross-resistance to moxidectin, levamisole, and pyrantel. Ivermectin resistance in O. volvulus may be related to single nucleotide polymorphisms of P-glycoprotein-like protein.

Emerging evidence suggests that scabies mites are also becoming resistant to oral ivermectin, particularly in heavily endemic areas, prompting the study of alternatives as well as synergists that could be used in conjunction with ivermectin. Piperonyl butoxide, S,S,S -tributyl phosphorotrithioate, and diethyl maleate show promise as synergists for pyrethroids. There is mounting concern about the emergence of both permethrin and ivermectin resistance in scabies mites. Sarcoptes scabiei var. hominis mites from scabies-endemic communities in northern Australia have shown increasing resistance to both 5% permethrin and oral ivermectin, based on increased drug metabolism and efflux mechanisms. Ivermectin-resistant ticks are also emerging, posing a problem for cattle farmers and making ivermectin a somewhat less attractive option for the treatment of humans with massive tick infestation.

Pregnancy Prescribing Status: Category C

Teratogenic effects have been observed in some animal studies. The manufacturer states that ivermectin should not be used during pregnancy, as safety in pregnancy has not been established. Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given repeatedly at doses of respectively 0.2, 8.1, and 4.5 times the maximum recommended human dose. In animals, developmental effects were found only at or near doses that were toxic to the pregnant female, suggesting that the drug is not selectively toxic to the developing fetus.

Lactation

Q12.8 The drug enters breast milk, and safety and efficacy for use in children weighing less than 15 kg have not been established; therefore, ivermectin use is not recommended during lactation. It is not recommended for children weighing under 15 kg. Limited data available in this patient population demonstrates tolerability without serious or long-term adverse effects (AE), but further study is warranted to establish safety.