Resistance factor still relatively unknown in lice management

September 2007

As the school year begins, it is timely to review the drug therapy of head lice infestation and review the pertinent issues.

The most relevant issue relating to head lice treatment and the available drug products may be resistance to these agents. Several studies and review articles recently published have evaluated and discussed resistance by head lice and the potential effect upon available treatments. It is important to understand that drug resistance as applied to head lice has not been well defined or standardized. How drug resistance by head lice is determined, defined, and how it applies to the clinical use of a drug is not clear. Drug resistance may also vary widely geographically, which also has not been well studied. The clinical implications of these issues upon a patient population or specific patient are not clear. It may be easy to jump on the “resistance bandwagon” when drug treatment does not at first appear to be successful for a specific patient, yet other factors should be considered (Table).

Resistance to the pyrethroids, pyrethrin and permethrin may occur through several mechanisms. Genetic mutation of the neuronal sodium channel of head lice (knock-down resistance) is believed to be a major mechanism of resistance toward the pyrethroids. Other mechanisms of resistance may include increased production of drug metabolizing enzymes by head lice.

Many published studies have evaluated increased levels of resistance by head lice in various states, and in other countries. Studies published over the past 15 to 20 years have implicated a decline in clinical efficacy of, and laboratory sensitivity toward some of the agents of the pyrethroid class. Resistance to malathion (Ovide, TaroPharma) has not been reported in the United States; however, it has been reported in the United Kingdom and France. It is important to consider that malathion is relatively new to the commercial market in the United States (available less than 10 years), as opposed to the United Kingdom where it has been available longer and is also available without a prescription. Other agents available to clinicians, although not FDA-labeled for use in head lice treatment (eg, ivermectin) have not been as well studied for resistance trends.

Head lice medications

Despite documented resistance toward pyrethroids, treatment recommendations generally continue to favor the use of permethrin as a first-line agent in the treatment of head lice. Although resistance has been documented, the lack of standardization of resistance, and its implications for clinical drug therapy, are not well defined.

The pyrethroids include permethrin 1% (eg, Nix, Insight and generic), and pyrethrin 0.33%/piperonyl butoxide (eg, RID, Bayer, A-200, and generic). Pyrethrin is a natural extract derived from the flower of chrysanthemum, and permethrin is a synthetic pyrethroid. Some evidence from laboratory resistance and clinical studies indicate that permethrin may be more active than pyrethrin/piperonyl butoxide toward head lice. The 2006 Red Book lists permethrin or malathion as drugs of choice, with pyrethrin/piperonyl butoxide or ivermectin as alternatives. Permethrin is labeled for use in children 2 months of age and older. Pyrethrin/piperonyl butoxide is labeled for use in children 2 years and older. Permethrin and pyrethrin/piperonyl butoxide should be applied in two applications, separated by seven to 10 days. When considering the life cycle of head lice, it has been suggested that a third application at day 13 to 15 be considered to treat hatched eggs not killed by the first or second applications. Permethrin is also available as a 5% cream product (Elimite, Allergan), which is FDA-labeled for body application and treatment of scabies infection. This product may not be clinically useful, however, as head lice with knock-down resistance toward permethrin are likely to display resistance toward permethrin 5% as well.

Malathion is likely to be the most active and clinically effective head lice agent available, even demonstrating activity against permethrin-resistant head lice in one study. This may relate to several factors: malathion is relatively new to the commercial market in the United States; it is only available by prescription; Ovide contains two additional ingredients that may have activity toward head lice (isopropyl alcohol 78% and terpineol). Thus, head lice have likely not been exposed as often to malathion compared with the pyrethroids.

Disadvantages of malathion include the fact that it contains isopropyl alcohol and is flammable, it has a bad odor, and the medication’s expense (it is more than $100). Ovide package directions include application to the hair overnight, or for eight to 12 hours. A study published in 2004, however, demonstrated good efficacy with a shorter application time (20 minute application for one to two applications). Patients and caregivers should be informed of its proper use, including application away from any heat source that may potentially ignite isopropyl alcohol. Malathion has good ovicidal activity, and a second application may not be necessary. However, it is often recommended that a second application be considered in seven to 10 days, especially if live lice are seen eight to 12 hours after initial application. Thus, if permethrin or pyrethrin/piperonyl butoxide are not effective for a child with head lice, and after consideration of other potential factors for failed product use (Table), malathion should be used.

Lindane has been available as a pediculicide for many years. However, some evidence indicates that resistance is higher than the other agents discussed here. A black box warning is part of lindane’s labeling, as it has the potential for significant central nervous system toxicity (mostly associated with inappropriate use). Because of these concerns, lindane has little, if any, role in the treatment of head lice.

While other drug treatments are available for head lice, none are FDA-labeled for this use, nor are they well studied. Ivermectin is listed in the 2006 Red Book as alternative treatment (ie, third-line choice). Although no controlled trials are available, anecdotal evidence suggests that ivermectin may be effective (200 mcg/kg one dose, repeated in seven to 10 days). Ivermectin should not be given to children with weights less than 15 kg, as it may potentially cross the blood brain barrier in small children, resulting in central nervous system adverse effects. Trimethoprim/sulfamethoxazole may be also be used, and one trial demonstrated that a combination of permethrin and trimethoprim/sulfamethoxazole was more effective than either agent alone. Concerns expressed by some with trimethoprim/sulfamethoxazole use include the potential for adverse effects known to occur with this antibiotic (eg, Stevens-Johnson syndrome). Caregivers expressing interest in the use of a natural product may consider using HairClean 1-2-3, which contains anise oil, ylang ylang oil, coconut oil, and isopropyl alcohol. Little evidence exists for its effectiveness, however.

Mechanical removal of head lice and nits, without drug therapy, has also been used. This method is tedious and time consuming, and efficacy is likely to be lower than drug therapy. Formic acid (Step 2 Lice Egg Removal Kit) and vinegar (1:1 mixture with water) may be applied to hair for several minutes to help loosen nits. These products should not be used prior to topical drug therapy application to the hair, as they may adversely affect the topical drug product’s residual effect upon nits. Occlusion with petrolatum, mayonnaise or other similar products has been advocated by some in an attempt to suffocate head lice. However, no evidence other than anecdotal recommendations exists to support the use of these products. As lice do not have lungs or air sacs (they obtain oxygen by diffusion and through body channels), they can survive for an extended time period without air.

Conclusions

It is likely that some head lice in the United States have developed resistance toward many of the drug therapy treatments available to clinicians. The relative amount of resistance differs among these products, and malathion seems to be the least affected agent. However, many unknowns about resistance exist, including how resistance is determined, defined, and its application to the clinical use of head lice drugs. Resistance may also vary geographically. Because of these considerations, permethrin 1% should continue to be used initially for head lice infestation. Proper use of permethrin 1% and other products is important. Caregivers should be educated on product use and this should be assessed prior to concluding that treatment was not successful. Malathion is likely to provide good efficacy, and it should be used if permethrin fails. Pyrethrin/piperonyl butoxide products may be used alternatively, although it is possible that they are less effective.

For more information:

• Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.
• Committee on School Health and Committee on Infectious Diseases, AAP. Clinical report – head lice. Pediatrics. 2002;110:638-643.
• Lebwohol M. Therapy for head lice based on life cycle, resistance, and safety considerations. Pediatrics. 2007;119:965-974.
• Malcolm CE. Trying to keep ahead of lice: a therapeutic challenge. Skin Therapy Letter. 2006;11:1-6.
• Meinking TL. 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 Derm. 2004;21:670.
• Meinking TL. Comparative efficacy of treatments for pediculosis capitis infestations – update 2000. Arch Derm. 2001;137:287-292.
• Roberts RJ. Comparison of wet combing with malathion for treatment of head lice in the UK: a pragmatic randomized controlled trial. Lancet. 2000;356:540-544.
• Yoon KS. Permethrin-resistant human head lice, pediculosis capitis, and their treatment. Arch Derm. 2003;139:994-1000.