Clinical Update on Resistance and Treatment of Pediculosis capitis

Supplements and Featured Publications, Definitive Management of Head Lice in the Era of Pediculicide Resistance, Volume 10, Issue 9 Suppl

The anatomy and physiology of head lice makethem extremely adaptable to their human hosts butalso difficult to eradicate. Their coloring and smallsize make them difficult to see, and the larvae, ornymphs, have multiple exoskeletons for protection.When exposed to pediculicides, a nymph can shedits outer exoskeleton and receive only a sublethaldose. Through natural selection, head lice havedeveloped resistance to commonly used pediculicides,making it increasingly difficult to eliminateinfestations.

Other contributors to resistance include changesin formulations of pediculicides and improper use.Over the last 20 years, the efficacy of pyrethrins hasdeclined because of necessary safety changes in formulationsand unintentional effects of new packagingon chemical components of these products.Pediculicides designed to be applied to wet hair maybecome too diluted to produce the desired effect.Patients also may use too little product to conservecosts. The combination of decreased product efficacyand exposure of head lice to diluted or insufficientamounts of pediculicides has reduced theireffectiveness substantially. Studies comparing thecurrent efficacy of several over-the-counter and prescriptionpediculicides with effectiveness in the1980s has shown that OVIDE® (malathion) Lotion,0.5% is the only product that has retained its efficacyover time. The efficacy of over-the-counter pyrethrinproducts had declined significantly, and lindane,another prescription product, was least effective ofall products tested both in the 1980s and in morerecent studies. In addition to retaining its efficacy,malathion 0.5% also is effective when applied foronly 20 minutes. The shorter application time is saferfor children and also decreases the likelihood thatresidual product remains in the hair, further contributingto resistance.

(Am J Manag Care. 2004;10:S264-S268)

Lice Anatomy and Physiology

Pediculus humanus capitis

, or head lice,have lived among humans for thousands ofyears. Their anatomy and physiology haveevolved to make these ectoparasites welladapted to their human hosts. Figure 1shows a family of lice. The female (left) isdistinguished from the male (center) by herlarger size and by the posterior protrusionsthat create an invaginated "V" structure,which she uses to clasp around the hair shaftto lay eggs. The male has dark brown bandsacross his back. Unlike the larvae of someother insects, the louse larva, called a nymphor instar (right), looks like a miniature adultlouse. The nymph has multiple exoskeletons,which it progressively sheds as it goesthrough 3 molting cycles before becomingan adult. There are 3 or 4 days between eachmolt.1 Third stage instar nymphs are themost difficult to kill with pediculicidesbecause they are protected by their layeredexoskeletons. A nymph that has beenexposed to a pediculicide can shed itsexoskeleton and receive only a sublethaldose, which contributes to resistance.Nymphs that have just molted are most vulnerableto pediculicides. The developmentof pediculicide resistance might vary duringdifferent stages of louse development andmolting. At any given time, lice will exist onthe host's head at various stages of molting,so they will not all die at once after exposureto a pediculicide.

Lice that have just hatched and have notfed on the host's blood are nearly transparent.The blood of a nymph, called hemolymph, isclear. The red color of a recently fed nymphis due to the host's blood meal. Nymphs areextremely small, at about the size of a 12-point font period at the end of a sentence.Their transparency and size make newlyhatched nymphs extremely difficult to seeduring examination. Nits, the eggs laid bylice, are attached to the hair shaft with anadhesive substance. Since they are stationary,nits are actually easier to find andremove than nymphs.

The feeding structures of lice are complex,including the haustellum, a proboscis-liketube with teeth, which is used to piercethe host's skin, and a cibarial pump thatdraws blood through the haustellum. Theteeth of the haustellum anchor it to thehost's skin while the louse feeds. There are 3stylets within the haustellum, as shown inFigure 2. Two of the stylets inject a substanceto make feeding easier, including ananticoagulant and a vasodilator, while thethird is used to draw back the blood to feed.The mouthparts retract when the louse isnot feeding.1 The ability of lice to anchorthemselves while feeding, as well as theircolor and small size, make it nearly impossibleto identify and remove them manuallythrough nit combing.

Bartonella quintana.

There is no information to date suggestingthat head lice spread disease, but research isongoing. Body lice are known to spread diseasessuch as typhus, relapsing fever, andtrench fever, a reemerging disease in theUnited States caused by Information about disease transmissionwas derived from colonies of body licethat have been maintained and studied onrabbits, but no similar colony of head liceexists. Although attempts have been made,head lice will feed only on human blood.

Contributors to Resistance

Over the last 2 decades, pediculicidepackaging and formulations have changed,contributing to resistance. The synergizedpyrethrin RID® was originally packaged inbrown glass bottles. When permethrin 1%(Nix®) was introduced to the market in aplastic bottle and received favorable consumerattention, the manufacturers of RIDrepackaged their product in plastic. Theydid not realize that plastic affected the formulation,decreasing its efficacy. Anotherpyrethrin, A-200®, caused irreversiblecorneal damage in some patients, so the formulationwas modified. Neither product is asefficacious as it was during studies conductedin the 1980s.2

Another contributor to resistance is thedilution of pediculicides that are designed tobe applied to wet, towel-dried hair. Theamount of water left in towel-dried hair isvery subjective, and some hair types naturallyretain more water than others. Patientsalso may apply too little product, oftenbecause more than 1 family member isinfested. Conserving product also conservescosts. When pediculicides are diluted or areused too sparingly, lice are exposed to sublethaldoses and eventually develop resistance.Conversely, patients may use toomuch product or may use it as preventivetreatment when there is no lice infestation.Resistance may develop from overexposureto pediculicides.

Clinical Efficacy of Pediculicides

An in vitro study was conducted in April2000 to assess the extent to which the efficacyof pediculicides had changed since theearly 1980s because of alterations in theirformulations.2 The pediculicidal and ovicidalactivities of 5 head lice products were evaluatedusing head lice and eggs harvested fromhealthy children in Panama, where lice arestill sensitive to most therapies. Results fromthis study were compared with an earlier1984 study evaluating pediculicide efficacyin Panama.3 The comparative ranking of theproducts is presented in Table 1. There wasno change from 1984 to 2000 in the rankingof malathion 0.5% as the most effective product.Permethrin 1% was not marketed in1984 for the first study. In the second study,permethrin 1% was evaluated in diluted andundiluted form because the product isapplied to damp hair and, as stated, dilutionmay affect efficacy. A follow-up study wasconducted from July through November2000 to assess the efficacy of the same 5products in killing lice harvested from peoplein a south Florida clinic. The Floridastudy was a replication of the Panama protocol,using the same products and methods.However, people attending the south Floridaclinic had treated themselves before seekingcare, so the lice collected were thought toinclude both sensitive and treatment-resistantspecimens. The main outcome measurewas the percentage of lice dead at regularobservation intervals between 5 minutes and3 hours of continuous exposure to the pediculicides.Results are presented in Table 2.

Of the 5 products tested, malathion 0.5%produced the fastest and most effectiveresult, killing 88% of lice at 10 minutes and100% at 20 minutes. The second most effectiveproduct, the pyrethrin A-200, killed 60%of lice at 20 minutes, 82% at 1 hour, and100% at 3 hours. Although synergizedpyrethrin has the same active ingredients asA-200, it killed only 8% of lice in 20 minutesand only 34% after 3 hours of continuousexposure. It is likely that the disparity inefficacy between these 2 products is becauseof differences in formulations and methodsof delivery. The slowest and least effectiveproduct was 1% lindane shampoo, whichkilled only 2% of lice at 20 minutes, 8% at 1hour, and only 17% after 3 hours of continuousexposure.3

Efficacy of Adjunctive Nit Combing

Another study evaluated the efficacy ofcombing as an adjunct to treatment withpermethrin.4 The study was performedbecause it is commonly believed thatrepeated combing with a fine-toothed combis an effective way to eradicate lice. TheNational Pediculosis Association, a consumerorganization, promotes wet combingalone as adequate therapy and markets anit-removal comb (LiceMeister). Thepatient population for this study was locatedin south Florida. All 95 patients in thestudy were treated with permethrin 1%, andone third were given a nit-removal comband instructed in its proper daily use. Eachperson in a household was given an individual,numbered comb and instructed not toshare it to prevent the transmission of licefrom the comb. The group that did notreceive combs was asked to not manuallyremove nits (using fingers or other types ofcombs). Patients were evaluated at 8 and 15days. If lice were observed at day 8, patientsreceived a second treatment with permethrin.Results are presented in Figure 3. Atday 8, nearly 46% of patients who receivedpermethrin treatment alone were free oflice, compared with 33% of those usingadjunctive combing. At day 15, a higherpercentage of patients in the permethrin-onlytreatment group were lice-free,although the difference between the groupswas not statistically significant. Overall, thecombing group had a higher treatment failurerate compared to patients who did notcomb. Nit removal combing performed bycaregivers and advocated in the UnitedStates by many schools and consumerorganizations was not effective as anadjunct to treatment with pediculicides andtherefore is not an appropriate method oflice eradication when used alone.4

Residual Pediculicide Effects:A Contributor to Resistance

Pediculicides often have residual effectseven after being rinsed from the hair. Theseeffects were previously viewed as beneficial,providing continued protection from infestation.Over time, lice exposed to sublethalresidual pediculicides adapted and becameresistant to some agents. Residual effects arenow considered undesirable because of theirlong-term contribution to pediculicideresistance.

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One approach to reducing residual effectsis limiting the amount of time the pediculicideis left on the hair and scalp, therebypotentially reducing residue. Decreasingexposure time raises the question ofwhether pediculicide efficacy declines, however.A study was recently conducted toevaluate the efficacy of malathion 0.5%applied for 20 minutes and permethrin 1%applied as labeled for 10 minutes. The originallabeling for malathion 0.5% dates to theproduct's introduction to the market andrecommends an application time of 8 to 12hours specifically to promote residualeffects. A second objective of the study wasto determine whether the 10-minute applicationfor permethrin 1% retained the sameefficacy it had when it was introduced in1986. Patients were treated with eithermalathion 0.5% or permethrin 1% and wereevaluated at 8 and 15 days for the presenceof live lice and viable nits. Among the 66patients enrolled in the study, 44 were treatedwith malathion 0.5% and 22 were treatedwith permethrin 1%. At day 15, 98% ofpatients treated with malathion 0.5% and55% of patients treated with permethrin 1%were free of lice and viable nits ( <.0001).Malathion 0.5% applied for 20 minutes waseffective without producing residual effects.Permethrin 1% demonstrated decreased efficacycompared to its documented pediculicidaleffects in 1986.5,6 Malathion 0.5% iseffective in killing lice and nits during allstages of parasitic development and molting.

Conclusions

Head lice are extremely host-specific,feeding only on humans, and have demonstratedincreased resistance to pediculicides.Current clinical data demonstratethat most pediculicides do not meet advertisingclaims of "killing lice on contact."Slow pediculicidal action, ineffective formulations,and sublethal residue on the hairand scalp have contributed to resistanceover time. Malathion 0.5% is the only pediculicidethat has retained its efficacy, killingboth lice and nits.2,3 Other commonly usedproducts have demonstrated resistance inthe United States. Although malathionresistance has been documented in theUnited Kingdom, the formulations thereare very different from OVIDE that is soldin the United States. The US formulationincludes synergistic components to deterthe development of resistance. When US-manufacturedOVIDE was tested onmalathion-resistant lice from the UnitedKingdom, it maintained its efficacy.7 Recentdata suggest that a decreased applicationtime for OVIDE is effective without producingresidual effects.5 The reduced applicationtime is beneficial for the pediatricpopulation, particularly in terms of limitingthe risk for potential adverse events, such asitching or burning of the scalp.

Of particular interest is the failure of nitcombing to produce better outcomes, evenwhen used as an adjunct to pediculicidetherapy.4 Schools and organizations oftenadvocate nit combing as a safe and effectiveway to eradicate lice and nits. Study resultssuggest that nit combing is not effective.

The clinical history of pediculicides andthe increase in resistance over time stronglysuggest the need for better management oftherapies that remain efficacious, such asmalathion 0.5%. Currently, it is the onlypediculicide to demonstrate no resistanceand no change in efficacy; however, overuseof malathion 0.5% may lead to resistance inthe United States as it has in other countries.Since malathion 0.5% is a prescriptionproduct, physicians are urged to regulate itsuse and to educate patients and others, suchas school administrators and public healthpolicy developers, about the proper use ofpediculicides.

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3. Meinking TL, Serrano L, Hard B, et al. Comparativein vitro pediculicidal efficacy of treatments in a resistanthead lice population in the United States. 2002;138:220-224.

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4. Meinking TL, Clineschmidt CM, Chen C, et al. Anobserver-blinded study of 1% permethrin creme rinsewith and without adjunctive combing in patients withhead lice. 2002;141:665-670.

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5. Meinking TL, Vicaria M, Eyerdam DH, et al. Efficacyof a reduced application time of OVIDE&#174; Lotion (0.5%malathion) compared to Nix&#174; Cr&#232;me Rinse (1% permethrin)for the treatment of head lice. In press:

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6. Taplin D, Meinking TL, Castillero PM, Sanchez R.Permethrin 1% Cr&#232;me Rinse for the treatment ofPediculus humanus var caputis infestation. 1986;3:344-348.

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7. Downs AM, Stafford KA, Harvey II, Coles GC.Evidence for double resistance to permethrin andmalathion in head lice: reply from authors. 2000;142:1067.