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Topical Antiparasitic Agents
Questions
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Q44.1 What is the mechanism of action for (1) permethrin, (2) ivermectin, (3) malathion, and (4) spinosad? (Pgs. 506, 507, 508)
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Q44.2 What is the first-line treatment for patients with scabies? (Pg. 506)
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Q44.3 What is the permethrin treatment protocol for patients infested with scabies? (Pg. 506)
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Q44.4 What specific plant contact sensitization predisposes patients to a cross-reaction with topical pyrethroids? (Pg. 506)
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Q44.5 What topical antiparasitic agent is known to be flammable? (Pg. 507x2)
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Q44.6 What are the first-line agents for pediculosis capitis for children over the age of 6? (Pg. 507)
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Q44.7 What are several of the severe adverse effects that led to lindane being of primarily historical significance in the treatment of scabies and lice? (Pg. 508)
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Q44.8 What are some of the nonpharmacologic measures to remove nits from children with head lice? (Pg. 509)
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Q44.9 What is the current typical school policy for children infested with pediculosis capitis before returning to school? (Pg. 509)
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Q44.10 Concerning topical albendazole, what is/are (1) the mechanism of action, (2) the method of compounding, and (3) indications for use? (Pg. 509)
Abbreviations used in this chapter
AE
Adverse effect(s)
FDA
US Food and Drug Administration
GABA
γ-Aminobutyric acid
IL-1β
Interleukin 1β
kdr
Knockdown resistance
PGE 2
Prostaglandin E2
TNF-α
Tumor necrosis factor α
Introduction
Cutaneous parasites are ubiquitous worldwide, resulting in a tremendous burden on healthcare systems. Systemic and topical antiparasitic medications play an important role in treating cutaneous parasitic infections. The focus of this chapter will be on topical antiparasitic medications for the three major types of parasitic infection encountered in dermatology: (1) scabies, (2) pediculoses, and (3) cutaneous larva migrans. This chapter presents an update for clinicians on the use of the agents in the treatment of cutaneous parasitic infections. For a summary of the topical antiparasitic agents discussed in the chapter see Table 44.1 .
Table 44.2
Permethrin at a Glance
| Indications | Scabies (US FDA-approved) Pediculosis capitis and pubis Demodex folliculitis |
| Dosage forms | Permethrin 5% cream (Elimite) Permethrin 1% cream (Nix) |
| Dosing | Scabies: Apply for 8 hours overnight from the neck down. Repeat in 1 week. Pediculosis capitis: Apply to scalp and neck overnight and rinse in the morning. Repeat in 1 week. |
| Pregnancy category | B |
| Cost | Permethrin 5% cream 60 g US$60.73 |
| Adverse effects | Pruritus Mild and transient burning and stinging |
Permethrin and Pyrethrins
Pharmacology
Pyrethrins are organic compounds originally derived from a flower species of the genus Compositae , which is related to the chrysanthemum. Pyrethrin is available as a 0.33% shampoo (Rid) with 4% piperonyl butoxide added to stabilize and prolong the effectiveness of pyrethrin. After application to dry hair and other affected body parts, it should be allowed to sit for 10 minutes before being formed into a lather and rinsed. Care should be taken in patients with an allergy to ragweed as cross-reactions may occur.
Synthetic pyrethroids such as permethrin were developed to have a greater effectiveness and a wider range of activity against lice, scabies, ticks, and many other arthropods.
Permethrin is a synthetic pyrethroid used as an approximate 2:3 mixture of the 3-phenoxybenzyl (6) cis - and trans -3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate ( Fig. 44.1 ). Key pharmacologic concepts for permethrin are listed in Table 44.2 .
Table 44.1
Antiparasitic Agents
| Drug | Trade Name | Formulations | Sizes | Clinical Indications |
|---|---|---|---|---|
| Permethrin | Elimite Nix a |
5% cream 1% cream rinse |
60 g 60 mL |
Scabies Head lice, pubic lice |
| Ivermectin | Sklice | 0.5% Lotion | 117 g | Scabies, head lice |
| Pyrethrins | Rid, A200 LiceMD Licide |
0.33% shampoo 0.33% gel 0.33% shampoo |
118 mL, 120 mL 118 mL 120 mL |
Head lice, pubic lice |
| Lindane | None | 1% shampoo 1% lotion |
59 mL 59 mL |
Head lice, pubic lice, scabies |
| Crotamiton | Eurax | 10% cream 10% lotion |
60 g 60 mL, 480 mL |
Scabies |
| Malathion | Ovide | 0.5% lotion | 59 mL | Head lice, pubic lice |
| Benzyl benzoate | None | 10%–25% solution | — | Scabies |
| Albendazole | Eskazole | Tablets Lipophilic base 10% compounded |
200 mg | Cutaneous larva migrans |
| Precipitated sulfur | None | 6% ointment compounded | Various | Scabies |
| Spinosad | Natroba | 0.9% topical suspension | 120 mL | Head lice |
Permethrin is available as a 5% cream (Elimite) for the total body topical treatment of scabies and as a 1% cream rinse (Nix) for treatment of head lice.
After application of the permethrin 5% cream, mean systemic absorption is less than 1% to 2%, owing to its minimal percutaneous absorption. In studies using permethrin 5% lotion (not commercially available), the majority of test subjects had undetectable levels of permethrin in plasma samples where the maximum absorption was 0.032% of the applied dose. Permethrin is metabolized through ester cleavages and virtually all of the absorbed permethrin is excreted in the urine within 1 week.
Mechanism of Action
Q44.1 Pyrethrin and pyrethroids inhibit closure of voltage-gated sodium channels, thereby inhibiting nerve repolarization. The constant influx of sodium leads to repetitive firing of the nerves, placing the insect into what is called a state of knockdown. Paralysis and death of the mite soon follow this state of knockdown.
Resistance
Permethrins preferentially bind to voltage-gated sodium channels at a site away from the pore when it is in an open or active state. Mutations in the sodium channel have led to several species of scabies and lice to become resistant to permethrins because of a knockdown resistance (kdr) mechanism. Several mutations cause some of the channels to maintain a closed state, thereby reducing the binding affinity. An increase in kdr-type mutations has increased from 37% in 2001 to 98% in 2015. This correlates to a decline in lice-free patients after the use of permethrin from close to 100% in 1998 to 25% in 2011.
Clinical Use
Indications
Scabies
Q44.2 Multiple compiled trials comparing permethrin 5% cream or lotion, topical ivermectin 1% lotion, and oral ivermectin suggest that all are equally as effective in the treatment of scabies, as noted by a 2018 Cochrane review. Q44.3 Permethrin should be applied to all body surfaces from the neck down. Particular care should be paid to the hands and fingernail areas, because these sites harbor the greatest concentration of mites. In addition, intertriginous sites (including between digits) need careful application. A majority of the studies in the Cochrane review had more than one application and as a result infested patients should be treated with two overnight applications 1 week apart.
Permethrin cream is approved for use in patients 2 months of age and older. Because scabies can affect the scalp and face of infants and young children, the cream should be applied to these areas as well.
Pruritus can often persist for up to 1 month after treatment and should not be taken alone as a symptom of persistent infection. In severe cases, topical or systemic corticosteroids are prescribed to control the persistent itch.
In contrast to pediculosis, the scabies mite cannot survive off the body for extended periods. Therefore, it is unnecessary to constantly wash bed linen and clothing when beginning scabies treatment. It is reasonable to have patients machine wash with hot water any clothes and bed linen used in the previous 24 hours. All close contacts should be treated with one overnight application of permethrin 5% cream.
Pediculosis
Pyrethrins with piperonyl butoxide (Rid, A-200, Proto, R & C shampoo, End Lice) and permethrin 1% cream rinse (Nix) are approved by the US Food and Drug Administration (FDA) for the treatment of head lice and are available over the counter.
Although permethrin 1% (Nix) and pyrethroids (Rid, etc.) are marketed as a single-application treatment for head lice, they should be reapplied in 7 to 10 days because neither is reliably ovicidal. Hair should be washed with shampoo alone because conditioners impair permethrin’s adherence to the hair shaft, resulting in decreased efficacy. Once the hair is towel-dried, the entire scalp, hair, and retroauricular areas should be saturated for 10 minutes with the medication and subsequently rinsed with warm water.
Permethrin 5% cream (Elimite) can also be used in the treatment of head and pubic lice, particularly when resistance to the 1% cream rinse (Nix) is a problem. Two overnight applications to the scalp and neck 1 week apart are recommended.
Adverse Effects
There have been no reported adverse effects (AE) other than local irritation, which is common to all topical applications on inflamed skin. Q44.4 It should be noted that persons with sensitivity to Compositae should not use pyrethrins because of the potential for cross-reactions.
Pregnancy and Lactation Prescribing Status
These medications are thought to be safe to use in pregnancy and in breastfeeding women. Of note, permethrin has been linked to the generation of a t(11:19) translocation within the mixed-lineage leukemia (MLL) oncogene in mouse and human lymphocyte studies. This same translocation was observed in a case of leukemia discovered in a preterm infant whose mother used excessive amounts of permethrin throughout her pregnancy.
It is not known whether permethrin is secreted in human milk; however, the manufacturers suggest that nursing should be discontinued if the drug will be used while the patient is nursing.
Ivermectin—Topical ( Table 44.3 )
Pharmacology
Ivermectin is available as a 0.5% lotion (Sklice) for the treatment of head lice. Avermectin is a naturally occurring compound produced from Streptomyces , from which ivermectin is synthetically derived. It works by binding to ligand-gated, mainly glutamate and γ-aminobutyric acid (GABA), chloride channels, increasing permeability and allowing an influx of chloride into the cells. The resulting hyperpolarization leads to paralysis and death.
Table 44.3
Topical Ivermectin at a Glance
| Indications | Pediculosis capitis (FDA-approved), scabies (non-FDA-approved) |
| Dosing | Apply to dry scalp and hair. Leave on for 10 minutes and then rinse thoroughly with warm water |
| Pregnancy category | C |
| Cost | 117 g tube US$340.00 |
| Adverse effects | Localized burning Skin irritation |
FDA, US Food and Drug Administration.
Clinical Use
Indications
Scabies
Topical ivermectin is not FDA-approved for the treatment of scabies. However, a 2018 Cochrane review comparing the effectiveness of topical permethrin to topical ivermectin showed equal efficacy. One to three applications of 1% lotion or solution applied to affected areas spaced 1 week apart was sufficient to clear 96% of patients at 4 weeks.
Pediculosis
In 2012 the FDA approved ivermectin 0.5% lotion (Sklice) to treat pediculosis in individuals older than 6 months. Ivermectin 0.5% lotion is applied to the scalp and hair while dry and after 10 minutes the hair is rinsed with warm water. Shampoos and conditioners should be avoided for 24 hours after application to avoid decreasing efficacy. Although not ovicidal, because of the prolonged half-life, it is approved as a one-time use. Nit combing is not required. After a single treatment, 95% of patients have been found to be louse-free after 2 days. Topical ivermectin, malathion, and spinosad have all demonstrated similar safety and efficacy and can be considered first-line agents.
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