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Emerging head lice resistance sparks new pharmacotherapy conversation
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The pharmacotherapy of head lice has been a frequent topic of this column, owing to its commonality, therapeutic controversies and nature of the clinical problem. Recently published literature and management reviews, including a 2015 clinical report by the AAP, have increasingly discussed resistance by head lice to over-the-counter (OTC) products. How resistance patterns and their concerns relate to clinical-use applications of OTC and prescription products are not well defined, however.
Treatment recommendations from professional medical organizations, including the AAP, the American Academy of Dermatology, and the CDC, continue to recommend pyrethroid OTC products, permethrin (such as Nix, MedTech) or pyrethrin (such as Rid, Bayer), as primary treatment. Permethrin- and pyrethrin-based products are inexpensive and easily available in pharmacies. However, the main concern with their use, as increasingly discussed in the medical literature, relates to reports of declining efficacy, and likely the result of drug resistance by head lice.
Earlier clinical studies of permethrin, from the 1980s to 1990s, demonstrated high efficacy rates of 80% or more for eradicating head lice. Several recent studies, from 2000 to 2010, have demonstrated permethrin efficacy of 50% or less. Although the exact cause of this declining efficacy has not been fully elucidated, published molecular studies and several recent literature reviews have suggested an increasing presence of drug susceptibility gene mutations as the main cause.
Leading the resistance
The development of organic mechanisms of resistance to insecticides, including the pyrethroids, is well known and has increasingly been studied in head lice. The permethrin mechanism of action as a pediculicide and insecticide is to act as a neuroexcitant at the voltage-sensitive sodium channel in the head louse nervous system, resulting in prolonged nerve depolarization and fatal muscle paralysis — this is referred to as knockdown effects. Possible mechanisms of resistance to the pyrethroids include reduced drug penetration, enhanced xenobiotic detoxification, and target site insensitivity. It is this latter mechanism that has been a focus of recent research.
Several gene mutations at the pyrethroid site of action, the neuron voltage-sensitive sodium channel, have been identified and are described as knockdown resistance, or kdr. The kdr phenotype results in nerve insensitivity to pyrethroids and other insecticides. Recently, three point mutations in the nerve sodium channel of head lice have been identified, with one mutation, TI, resulting in complete insensitivity of the sodium channel to permethrin. Recently developed laboratory techniques have allowed researchers to more easily identify the presence of these sodium channel gene mutations in collected head lice samples.
Numerous recent studies have evaluated the presence of knockdown resistance allele frequencies in collected head lice samples. A 2014 study published in the Journal of Medical Entomology evaluated 291 samples of head lice from 12 states, and demonstrated an increasing prevalence of the kdr TI mutation, increasing from 84.4% to 99.6% over the period 1999 to 2009. A larger study published in 2016 by Gellatly and colleagues evaluated 1,925 head lice samples collected from 48 states during 2013 to 2015. The presence of three distinct sodium channel point mutations were identified in these samples. The overall mean percent resistance allele frequency in these samples was 98.3%.
Although these studies demonstrate an increasing frequency of pyrethroid susceptibility gene mutations, it may be premature to unequivocally state that pyrethroid drugs no longer have a role in the daily treatment of head lice infestation in children. Although the assumption stated in several published studies, that an increasing presence of drug susceptibility gene mutations correlates with decreasing permethrin clinical efficacy demonstrated in separate studies, is logical, many unknowns continue to exist. These unknowns include information on specific geographic and local drug resistance gene mutation patterns in head lice, qualitative relationships between specific point mutation types and drug susceptibilities, practical issues of regional and local laboratory testing capabilities and availability for identifying resistance mutations, and perhaps most important, a well-defined treatment strategy correlating the presence of drug susceptibility gene mutations with clinical uses of pyrethroids.
Authors of the studies discussed here have stated that the presence of kdr resistance alleles alone may not directly correlate with clinical treatment success, and some published evidence supports this contention. In an observational study of 112 German children with head lice carrying kdr mutations and treated with permethrin, Bialek and colleagues demonstrated that clinical cure was still achieved in 93%. In another related study of German children with head lice carrying kdr mutations, use of pyrethrin resulted in a clinical cure rate of 74%.
Available by prescription
Fortunately, resistance to the pediculicides available by prescription has not been widely reported in the United States and is not clinically significant. Four FDA–labeled topical products are available in the United States: malathion (Ovide; TaroPharma), spinosad (Natroba, Parapro), ivermectin (Sklice, Arbor Pharmaceuticals), and benzyl alcohol (Ulesfia, Shionogi). No direct comparative efficacy studies have been published of these agents. Differences among these pediculicides include age labeling: malathion (6 years, although some nonlabeled evidence additionally supports its use in ages 2-5 years); spinosad (4 years); ivermectin (6 months); and benzyl alcohol (6 months).
All of the prescription pediculicide products are relatively expensive, with approximate cash costs (without insurance) ranging from $100 (malathion) to more than $300 (ivermectin). Comparatively, OTC permethrin sells for $5 to $10. One well-done published clinical study demonstrated good efficacy of orally administered ivermectin tablets (400 µg/kg for 2 doses, 7 days apart) in children weighing 15 kg or more who have head lice, although this use is off label. Other off-label use products are available OTC, but little evidence from controlled studies exist to document their efficacy, including Cetaphil (a facial cleanser applied as an occlusive) and dimethicone (LiceMD; Reckitt Benckiser Pharmaceuticals) which is an emollient.
Recently published evidence documents an increasing presence of gene mutations conferring mechanistic resistance to OTC permethrin and pyrethrin products. Additional studies have demonstrated decreasing clinical efficacy of these commonly used products. It is reasonable to surmise a relationship between the presence of these gene mutations and decreasing clinical efficacy. How these separately reported data are related, however, have not been well defined.
Although the presence of drug resistance mutations has been shown to be widespread throughout the United States, regional and local patterns can be difficult to determine. Testing for the presence of pyrethroid resistance mutations is not widely available, and anecdotal claims by parents or health care professionals of pyrethroid product treatment failure due to resistance are difficult to substantiate. Treatment failure may result from several causes, including improper product use and application (including lack of a second dose treatment), reinfestation or true resistance. Additional studies are needed to quantify and qualify the relationship between the presence of drug resistance gene mutations and product clinical efficacy. Thus, recently published recommendations, including guidelines from the AAP, continue to be relevant. The use of permethrin or pyrethrin products are a reasonable first choice for primary treatment of active infestations. If treatment failure occurs, and causes of treatment failure other than product efficacy have been ruled out, prescribers may choose from four FDA–labeled prescription pediculicide products.
- References:
- Bialek R, et al. N Engl J Med. 2011; doi: 10.1056/NEJMc1007171.
- Devore CD, et al. Pediatrics. 2015; doi: 10.1542/peds.2015-2696.
- Durand R, et al. Clin Microbiol Infect. 2012; doi: 10.1111/j.1469-0691.2012.03806.
- Gellatly KJ, et al. J Med Entomol. 2016;53:653-659.
- Koch E, et al. Pediatr Dermatol. 2016; doi: 10.1111/pde.12982.
- Yoon KS, et al. J Med Entomol. 2014 Mar;51(2):450-7.
- For more information:
- Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.