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Head Lice: New Approaches May Help Overcome Pediculicide Resistance

W. Steven Pray, PhD, DPh
Bernhardt Professor, Nonprescription Products and Devices

College of Pharmacy, Southwestern Oklahoma State University

Weatherford, Oklahoma


3/19/2010

US Pharm. 2010;35(3):10-15. 

There is a nearly universal revulsion of parasites, especially those that prey on human blood, such as fleas and bedbugs. Most blood-sucking parasites feed for a few seconds (e.g., mosquitoes) to a few days (e.g., ticks, chiggers). This month’s column is concerned with just such a parasite—the head louse. However, this creature is different from most others in that it creates colonies on the human head that could potentially last for the life of the infested individual. The head louse species is Pediculus humanus var capitis.1,2 This group of insects has no wings, and they cannot jump to others. Rather, they depend on six legs to move, each of which terminates in a claw that is able to grasp human hair. Head lice can crawl through hair at 12 inches per minute. 

The Life Cycle of the Head Louse

Female head lice live for 17 to 22 days, potentially laying 10 eggs daily, or perhaps about 200 eggs per female, assuming she can locate a sexually mature male when fertilization is required.1,2 She lays eggs (nits) on the hair shaft, in most cases right at the point where the hair exits the scalp, known as the skin-hair shaft junction. Female head lice affix their eggs to the hair with extremely strong cement that allows the nits to remain attached to the hair during normal combing and washing. Nits are oval-shaped egg cases composed of waxy chemicals that protect the maturing larva. The top of the case has several perforations to allow respiration. Larvae inside nits mature in 6 to 9 days; body heat radiating from the scalp keeps them warm enough to maintain viability. After the nymph hatches, it must obtain a blood meal within 24 hours or it cannot survive. Following birth, the nymph reaches sexual maturity in 7 to 10 days. When it comes into contact with a sexually mature louse of the opposite gender, the life cycle continues. 

Older Pesticides and Resistance

Physicians and pharmacists have often relied on older neurotoxic pediculicides (pesticides) to kill lice. These include prescription lindane and malathion (Ovide), as well as nonprescription synergized pyrethrins (Rid, Pronto, A-200) and permethrin (Nix). However, they may now be unwise choices in light of potential resistance. 

Pharmacists are well aware of the phenomenon of resistance. Pathogenic microorganisms have become resistant to many antibiotics. It should come as no surprise that rapidly reproducing insects such as head lice will inevitably develop resistance to the pesticides used to combat them.3,4 Resistance has been characterized as “a growing problem” that is “daunting.”5,6 One of its dangers is that patients will resort to multiple treatments with pesticides, reexposing children needlessly to potentially toxic chemicals. 

Reports of resistance to lindane have accelerated since the 1970s.7,8 The mechanism for development of resistance is hypothesized to be alterations in amino acids located at the nerve sheath sodium channel; this phenomenon may also confer resistance to pyrethrins and permethrin.9 Lindane users have experienced seizures, lethargy, slurred speech, and neck and extremity stiffness.10,11 

Malathion is an odorous, flammable pesticide that must remain on hair until it is dry, perhaps 8 to 12 hours later. It can sting and irritate skin. Although the product marketing claims there is a residual effect, the manufacturer suggests that patients undergo a second exposure if lice remain after 7 to 9 days. Malathion has had a checkered marketing history in the United States, having been known as Prioderm and Ovide. It was discontinued but remarketed in 1999.10 Treatment failures were reported as early as 1990, with early reports emanating from Australia and England, where it is a nonprescription product.12-14 Early reports cited a failure rate of 8%, but reports from 1999 gave the figure as 64%.15-17 In 2001, a Cochrane Review concluded that resistance was widespread in the United Kingdom (UK); resistance in the U.S. has not been widely reported but may eventually develop with continued use, given its emergence in other countries.7,18,19 

Pyrethrins are chrysanthemum derivatives that must be synergized with piperonyl butoxide, a petroleum derivative, to retain efficacy. They cannot be used in patients allergic to ragweed. Reports of resistance to this nonprescription pesticide began in 1986, growing in scope until 1997 when the Medical Letter reported that treatment failures had become common.20-22 In 1999, researchers reported that synergized pyrethrin’s efficacy was questionable in light of the accelerating number of anecdotal reports of resistance.23 As case reports of resistance continued to accumulate, dermatologists suggested that multiple resistance had appeared, and that those patterns would undoubtedly be seen throughout the world.24,25  

Permethrin was a prescription product (Nix) in the U.S. from 1986-1990, when it was switched to OTC status. The first reports of resistance to permethrin emerged in 1990, with later reports coming from Israel, the Czech Republic, and Britain in 1995.12,21,26-28 In 1997, the Medical Letter stated that resistance was increasing.22 Resistance was reported in Washington State in 1998.29 In 1999, it was reported to be virtually useless in the UK; even very high concentrations had no effect on resistant lice.16,29,30 Allegations of resistance continued to accumulate; resistance figures as high as 87% were quoted for the UK.18,19,24,31-33 A 1999 study indicated possible resistance in the U.S.; this was demonstrated again in 2003.23,34 Permethrin resistance may develop through several mechanisms. If the knockdown resistance (kdr) gene is involved, no strength of permethrin will be effective, which eliminates consideration of the 5% prescription concentration (e.g., Elimite). 

Resistance as a Cumulative Phenomenon

Resistance is the development of mechanisms to survive potentially deadly onslaughts. Once these successful mutations are incorporated into the DNA of the living being, they will continue to be passed to succeeding generations. The numbers of resistant organisms can only stabilize or grow in the face of continual challenge by the provocative agent. Thus, any figure for the percentage of resistant members of a population is outdated; the actual percentage of resistant louse strains can only stabilize or increase. Given the dynamic nature of organism adaptation, increase is the only logical conclusion, meaning that any figure for percentage is of necessity lower than reality.

Survey of Pharmacists

A survey of pharmacists discovered that 81.7% of respondents had encountered patients with apparent treatment failures after use of synergized pyrethrins; 78.6% had seen failure following use of permethrin.35 Treatment failures occurred once or twice weekly in 58.1% of pharmacists’ practices, often causing patients to treat themselves more frequently or in higher doses with pesticides. 

Manufacturer Explanations of Resistance

The manufacturers of topical pesticides for lice state that they have reports of efficacy. Some reports result from use of laboratory-bred lice. However, lab-bred lice are different from free-living lice in the U.S. at large. Data from lab-bred lice populations cannot necessarily be extrapolated to the hardier lice typically found on human heads.36 Manufacturers also blame the patient for resistance by suggesting that the patient failed to apply the pesticide for a second time, that too little product was used, that the patient was reexposed, or by stating that the patient did not remove nits or clean the environment properly. 

Innovative Resistance-Free Approaches

Pharmacists who wish to recommend a nonprescription product for detection and/or treatment of lice may stock and sell the FDA-registered medical device known as the LiceMeister Comb, developed by the nonprofit National Pediculosis Association.37 Preliminary research has demonstrated that the LiceMeister is superior to other plastic and metal combs due to its unique construction, having 32 closely spaced, rigid, stainless steel teeth.31 In contrast to the use of pesticides, combing with the LiceMeister presents no risk of pesticide absorption or toxicity, presents no danger to the environment, and can simultaneously detect and treat an infestation. 

Hot Air Treatment: A prescription FDA-registered medical device known as the LouseBuster kills lice and nits in a single 30-minute treatment using controlled warm air.38 Resistance cannot develop as hot air destroys all stages of lice and eggs. 

Benzyl Alcohol: A prescription product containing 5% benzyl alcohol (Ulesfia Lotion) was approved by the FDA for treatment of head lice in April 2009.39 It does not act in the same manner as traditional neurotoxins, and it kills lice by a novel method. Following application, benzyl alcohol renders head lice incapable of closing their respiratory spiracles, allowing the product’s vehicle to obstruct them, resulting in death by asphyxiation. Its lack of ovicidal activity means that it does not kill nits, making a second treatment a necessity 7 days after the first treatment. It possesses several important advantages over the traditional treatments. It is not a neurotoxin, making it a safer alternative for humans. Due to its mechanism of action, lice cannot adapt via the development of detoxification pathways, as is the case with the four older pesticides. Therefore, resistance should never develop. Unlike malathion, it is not flammable. It is not indicated for patients under the age of 6 months or older than 60 years. If the product contacts the eyes, they should be immediately flushed with water. Patients must wash their hands after application. The agent may cause contact dermatitis, in which case the patient should immediately rinse with water and discontinue application until the irritation subsides. If irritation persists, the patient should contact a physician. 

The most common adverse reactions at the site of application are irritation (2%), anesthesia/hypoesthesia of the application site (2%), and pain (1%). Other reactions include pruritus (12%), erythema (10%), pyoderma (7%), and ocular irritation (6%).39 Patients should be directed to apply Ulesfia Lotion to dry hair, being sure to use sufficient lotion to fully saturate the scalp and hair to ensure that each louse is coated with product, waiting for a carefully timed 10 minutes to allow asphyxiation to occur, rinsing the product from the scalp, and repeating the treatment in 7 days. For complete coverage, the lotion must also be applied behind the ears and to the back of the neck. There are no studies of Ulesfia Lotion in pregnant women, and its ability to pass into breast milk is unknown. 

Spinosad: An innovative product known as NatrOVA (0.9% spinosad) is of low toxicity to humans and has a method of action different from older pesticides.40 As a result, it should be effective in lice resistant to older pesticides. It was found to be significantly more effective than permethrin under actual-use conditions in two studies.41 The FDA is currently reviewing the new drug application (NDA) for spinosad. 


How to Detect Head Lice

For decades, parents have been given instructions on how to detect head lice. This traditional procedure involved placing gloves on the hands, parting the hair with small wooden paddles under strong light, and looking for tan insects about the size of a sesame seed. Parents also looked for tiny whitish eggs (nits) tightly attached to the hair, especially in the “hot spots” such as the crown of the head, the nape of the neck, and behind the ears. However, a newer method has proven far simpler and better at detection. The LiceMeister comb is available online for a nominal charge from a nonprofit organization known as the National Pediculosis Association ( www.headlice.org/licemeister). When used as directed, this comb removes live lice and nits, serving as an excellent detection tool and also as a treatment method, since both lice and their eggs are combed out. 

Treating Head Lice

Some older lice treatments are outdated and should no longer be used. They include prescription lindane and malathion and nonprescription Rid, Nix, Pronto, and A-200. These lotions and shampoos present medical risks to the patient, and lice may also have become resistant to them (i.e., the treatments will no longer work effectively). A new prescription product known as Ulesfia Lotion is a safer alternative, and resistance has not been demonstrated. As previously mentioned, the LiceMeister comb is also a good treatment option, as lice cannot develop resistance to it, and the device is harmless to both humans and the environment. 

Products to Avoid

Sprays are available that treat pillows, beds, and mattresses for lice. Any head lice found away from the head will die shortly since they cannot get the blood they need to survive. You can vacuum thoroughly if you wish, but you should not use sprays, as they are of unknown safety. Your child might breathe in the fumes all night if you cover the bedding with them. 

Also avoid products that promise to kill or remove lice but contain nothing more than diluted table salt in water (labeled as Natrum Muriaticum), neon paint, or dimethicone, and products containing herbs such as rue, tea tree oil, pawpaw, sage, rosemary, thyme, pennyroyal, and essential oils. None of these is yet proven safe and effective. 

You should avoid so-called “suffocating treatments” that advise you to cover the head with olive oil, salad dressing, full-fat mayonnaise, petrolatum, or some other thick, gooey, or oily substance. You may be instructed to leave the substance on overnight beneath several layers of plastic wrap. Removal of such greasy matter can involve several courses of regular shampoo, which can irritate the scalp. These methods have never been proven to kill head lice in any case. 

Never resort to potentially deadly treatments such as gasoline, kerosene, and lantern oil. These have all exploded in flash fires in people’s homes, causing severe burns and even death. Never use any type of garden or pet insecticide, and never use any industrial strength chemicals. 

Remember, if you have questions, Consult Your Pharmacist. 

REFERENCES

1. Pray WS. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.
2. Pray WS. Head lice: perfectly evolved human predators. Am J Pharm Educ.

3. Burgess IF. Human lice and their control. Annu Rev Entomol. 2004;49:457-481.
4. Wendel K, Rompalo A. Scabies and pediculosis pubis: an update of treatment regimens and general review. Clin Infect Dis. 2002;35(suppl 2):S146-S151.
5. Heukelbach J, Feldmeier H. Ectoparasites—the underestimated realm. Lancet. 2003;363:889-891.
6. Ko LJ, Elston DM. Pediculosis. J Am Acad Dermatol. 2004;50:1-14.
7. Meinking TL, Serrano L, Hard B, et al. Comparative in vitro pediculicidal efficacy of treatments in a resistant head lice population in the United States. Arch Dermatol. 2002;138:220-224.
8. Meinking TL, Taplin D. Advances in pediculosis, scabies, and other mite infestations. Adv Dermatol.

9. Jones KN, English JC III. Review of common therapeutic options in the United States for the treatment of pediculosis capitis. Clin Infect Dis. 2003;36:1355-1361.
10. Malathion for treatment of head lice. Med Lett. 1999;41:73-74.
11. Kassirer JP, Kopelman RI. Lest we become smug. Hosp Pract. 1990;25:33-35,39,47.
12. Goldsmid JM. Head louse treatment: is there an insecticide resistance problem [letter]? Med J Aust.

13. Kyle DR. Comparison of phenothrin shampoo and malathion lotion in the treatment of head louse infection. J Roy Soc Health. 1990;110:622-663.
14. Burgess I. Malathion lotions for head lice—a less reliable treatment than commonly believed. Pharm J. 1991;247:630-632.
15. Chosidow O, Chastang C, Brue C, et al. Controlled study of malathion and d-phenothrin lotions for Pediculus humanus var capitis-infested schoolchildren. Lancet. 1994;344:1724-1727.
16. Downs AM, Stafford KA, Coles GC. Head lice: prevalence in schoolchildren and insecticide resistance. Parasit Today. 1999;15:1-4.
17. Downs AM, Stafford KA, Harvey I, Coles GC. Evidence for double resistance to permethrin and malathion in head lice. Br J Derm. 1999;141:508-511.
18. Downs AM, Stafford KA, Hunt LP, et al. Widespread insecticide resistance in head lice to the over-the-counter pediculocides in England, and the emergence of carbaryl resistance. Br J Dermatol.

19. Dodd CS. Interventions for treating headlice. Cochrane Database Syst Rev. 2001;(2):CD001165.
20. Rasmussen JE. Pediculosis treatment and resistance. Adv Dermatol. 1986;1:109-125.
21. Mumcuoglu KY, Hemingway J, Miller J, et al. Permethrin resistance in the head louse Pediculus capitis from Israel. Med Vet Entomol. 1995;9:427-432,447.
22. Drugs for head lice. Med Lett. 1997;39:6-7.
23. Pollack RJ, Kiszewski A, Armstrong P, et al. Differential permethrin susceptibility of head lice sampled in the United States and Borneo. Arch Pediatr Adolesc Med. 1999;153:969-973.
24. Bailey AM, Prociv P. Persistent head lice following multiple treatments: evidence for insecticide resistance in Pediculus humanus capitis. Australas J Dermatol. 2000;41:250-254.
25. de Berker D, Sinclair R. Getting ahead of head lice. Australas J Dermatol. 2000;41:209-212.
26. Rupes V, Moravec J, Chmela J, et al. A resistance of head lice (Pediculus capitis) to permethrin in Czech Republic. Centr Eur J Pub Health. 1995;3:30-32.
27. Concern over development of resistance to pyrethroid head lice treatments. Pharm J. 1995;255:490.
28. Burgess IF, Peock S, Brown CM, Kaufman J. Head lice resistant to pyrethroid insecticides in Britain [letter]. BMJ. 1995;311:752
29. Bell TA. Treatment of Pediculus humanus var capitis infestation in Cowlitz County, Washington, with ivermectin and the Licemeister Comb. Pediatr Infect Dis J. 1998;17:923-924.
30. Dawes M, Hicks NR, Fleminger M, et al. Evidence based case report: treatment for head lice. BMJ.

31. Picollo MI, Vassena CV, Mougabure Cueto GA, et al. Resistance to insecticides and effect of synergists on permethrin toxicity in Pediculus capitis (Anoplura: Pediculidae) from Buenos Aires. J Med Entomol. 2000;37:721-725.
32. Dodd C. Treatment of head lice. BMJ. 2001;323:1084.
33. Meinking TL, Clineschmidt CM, Chen C, et al. An observer-blinded study of 1% permethrin creme rinse with and without adjunctive combing in patients with head lice. J Pediatr. 2002;141:665-670.
34. Yoon KS, Gao JR, Lee SH, et al. Permethrin-resistant human head lice, Pediculus capitis, and their treatment. Arch Dermatol. 2003;139:994-1000.
35. Pray WS. Pediculicide resistance in head lice: a survey. Hosp Pharm. 2003;38:241-246.
36. Burgess IF. Shampoos for head lice treatment—comparative in vitro tests. Pharm J.

37. The LiceMeister Comb. National Pediculosis Association. www.headlice.org/licemeister/ 1999;63(summer):204-209. 1990;5:131-150. 1990;153:233-234. 2002;146:88-93. 1999;318:385-386. 1996;257:188-190.
index.htm. Accessed January 20, 2010.
38. The LouseBuster. Larada Sciences. www.lousebuster.com. Accessed January 20, 2010.
39. Ulesfia Lotion. Shionogi Pharma, Inc. www.ulesfialotion.com/ulesfia/
default.aspx. Accessed January 20, 2010.
40. Overview of Spinosad. ParaPRO LLC. www.parapro.com/overview.aspx. Accessed January 20, 2010.
41. Stough D, Shellabarger S, Quiring J, Gabrielsen AA Jr. Efficacy and safety of spinosad and permethrin creme rinses for pediculosis capitis (head lice). Pediatrics. 2009;124:e389-e395.
42. Speare R, Koehler JM. A case of pubic lice resistant to pyrethrins. Aust Fam Physician. 2001;30:572-574. 

To comment on this article, contact rdavidson@uspharmacist.com.

Feedback on Head Lice Column (March 2010)

In his discussion of pediculicide resistance, Dr. Pray raises questions regarding the continued efficacy of Ovide (malathion) lotion 0.5%.1 As Dr. Pray notes, resistance to pyrethroid head lice products developed in the 1990s. In response to the emergence of resistant head lice, the CDC in 1999 specifically requested the reintroduction of prescription malathion.2 Subsequent, direct, clinical head-to-head studies in the United States have shown that malathion provides 97% to 98% cure rate, compared to 45% to 55% for a leading OTC pyrethroid product.3,4 An assessment of cholinesterase inhibition in patients receiving malathion showed no evidence of systemic absorption or effect.4 Dr. Pray also highlights the emergence of malathion resistance in Europe, particularly the UK. Nonetheless, the most recent published comparative study of head lice treatments, which included UK sites, continues to show that treatment with malathion lotion 0.5% provides approximately 90% efficacy even in patients with resistant lice.5 

Comparative clinical data represent the best approach to assess the efficacy of various head lice treatments. The absence of head-to-head clinical trial data makes it difficult to assess the potential efficacy of newer treatments such as Ulesfia (benzyl alcohol) in comparison to established treatments with documented, clinical trial comparative efficacy data. 

Just as a reminder, Ovide is indicated for the treatment of pediculosis capitis infestation of the scalp with head lice and their ova. The approved treatment regimen is an 8- to 12-hour application with a repeat treatment in 7 to 9 days only if live head lice are noted. Irritation to the skin and scalp is the most common adverse reaction. Accidental contact with the eyes can result in mild conjunctivitis. Ovide lotion is contraindicated for neonates and infants. Because this product contains isopropyl alcohol, it is flammable. Parents and patients should be instructed to keep away from heat sources (i.e., hair dryers, cigarettes) or open flame while the hair is wet. See the full Prescribing Information for complete safety information.6 

Howard Rutman, MD, Medical Affairs
Kate Shattuck, RPh, Pharmacy Policy
Taro Pharmaceuticals, U.S.A., Inc.
Hawthorne, New York
Taro Pharmaceuticals distributes Ovide (malathion) lotion 0.5% in the U.S.

REFERENCES

1. Pray WS. Head lice: new approaches may help overcome pediculicide resistance. US Pharm. 2010;35(3):10-15.
2. Jackson EM. Medicis asked to reintroduce Ovide (malathion) lotion 0.5% for head lice. Cosmet Dermatol. 2000;13:43-44.
3. Meinking TL, Vicaria M, Eyerdam DH, et al. Efficacy of a reduced application time of Ovide lotion (0.5% malathion) compared to Nix creme rinse (1% permethrin) for the treatment of head lice. Pediatr Dermatol. 2004;21:670-674.
4. Meinking TL, Vicaria M, Eyerdam DH, et al. A randomized, investigator-blinded, time-ranging study of the comparative efficacy of 0.5% malathion gel versus Ovide Lotion (0.5% malathion) or Nix Crème Rinse (1% permethrin) used as labeled, for the treatment of head lice. Pediatr Dermatol. 2007;24:405-411.
5. Chosidow O, Giraudeau B, Cottrell J, et al. Oral ivermectin versus malathion lotion for difficult-to-treat head lice. N Engl J Med. 2010;362:896-905.
6. Ovide (malathion) lotion 0.5% package insert. Hawthorne, NY: Taro Pharmaceuticals, U.S.A., Inc; January 2007. 

Author’s Response
I appreciate Dr. Rutman’s and Ms. Shattuck’s clarifications regarding Ovide. I would stress that the degree of louse resistance to a pesticide such as malathion is not static, and I urge Taro to conduct more current studies in the U.S. for dissemination to the profession.
W. Steven Pray, PhD, DPh
Southwestern Oklahoma State University


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