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Published in final edited form as: Pestic Biochem Physiol. 2021 Dec 16;181:105013. doi: 10.1016/j.pestbp.2021.105013

New chemistries for the control of human head lice, Pediculus humanus capitis: a mini-review

John M Clark a,*
PMCID: PMC8795694  NIHMSID: NIHMS1766154  PMID: 35082036

Abstract

Pediculus lice represent one of the longest and most prevalent parasitic infestations of humans. Head lice are an economic and social concern whereas body lice pose a more serious public health threat. Significant progress has been made in the study of human lice over the last 10 years, allowing for new approaches in their control. An in vitro rearing system has made it possible to maintain insecticide-susceptible and -resistant reference strains, which allowed an in depth study of pediculicide resistance, including its underlying molecular mechanisms and the detection and monitoring of resistance. The generation of inbreed strains facilitated the efficient sequencing, assembly and annotation of the genomes and transcriptomes of both lice. The use of functional genomics and reverse genetics elucidated the genetics involved in the evolution of resistance and the discovery of novel target sites for the development of new pediculicides. In this review, four new effective pediculicide products, each with different mode of action and unique chemistries, will be presented. They have been found to be safe and selective, and control resistant lice. As such, they meet the criteria necessary to be used in rotations as a sustainable resistance management strategy.

Keywords: Human head lice; pediculicides, Dimethicone; Ivermectin; Spinosad; Abametapir

Graphical abstract

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1. Introduction

Pediculus lice are wingless insects in the order Phthiraptera (lice), suborder Anoplura (sucking lice), family Pediculidae (human blood feeding lice), which includes a single genus (Pediculus) consisting of two highly related species/ecotypes: the human head louse (Pediculus humanus capitis) and the body louse (Pediculus humanus humanus). Both are obligatory ectoparasites feeding solely on human blood (Pennisi, 2004). Body lice diverged from head lice when humans began wearing clothing (Kittler, 2003) and are highly related genetically (Kang et al. 2015; Olds et al. 2012). Nevertheless, there are significant differences between them, leading to significant impacts on humans.

Pediculus lice differ in their lifestyles, morphologies and disease vectoring abilities. Head lice live on the human scalp, mate and lay eggs on hair strands. After hatching, larvae undergo three successive molts, becoming reproductive adults. All walking stages feed numerous times each day. In contrast, body lice are found on non-head regions of humans, mate and lay eggs on clothing, only coming onto the human body intermittently to feed. Body lice are generally larger than head lice and are competent vectors human diseases whereas head lice are not (Light et al. 2008; Bonilla et al. 2009).

In this review, advances over the past 10 years will be summarized based on the impact that they have had on the suppression of louse infestations. The tools and methods necessary to accomplish this, including the development of an in vitro louse rearing system, the genomic sequencing of both the head and body louse genomes and the use of functional genomics and reverse genetics to study pediculicidal resistance will be presented. The discovery of new target sites for pediculicide action, their mechanisms of action and the marketing of novel acting pediculicides with the possibility of implementing sustainable resistance management strategies will be emphasized. To accomplish this in an efficient manner, the information in a number of current reviews (Clark et al. 2013; Pittendrigh et al. 2013; Clark et al. 2015; Divore and Schutze, 2015; Pittendrigh et al. 2015); Koch et al. 2016) will be used to guide our summarization, including information from a recently published book chapter written by the author (Clark, 2018).

2. Pediculosis and its medical implications

Pediculosis is the infestation of humans by blood-sucking Pediculus lice. Head louse infestations are more common in children whereas body louse infestations occur more often in homeless shelters and migrant camps (Gratz, 1999).

Head lice are not efficient disease vectors but still represent a major economic and social concern worldwide (Williams et al. 2001) and infestations can lead to secondary bacterial infections (Jones et al. 1996). Body lice, however, transmit several bacteria (Rickettsia prowazekii, Borrelia recurrentis, and Bartonella quintana) causing serious human diseases (epidemic typhus, louse-borne relapsing fever and trench fever, respectively) (Kelly et al. 2002). With the availability of antibiotics, outbreaks are now sporadic but do occur during times of famine, war and social unrest, and the body louse still serve as an important vector of re-emerging diseases in developed countries (Weiss, 1988).

Pediculosis is controlled in two ways: (1) proactive prevention or (2) post-infestation treatment. Emphasis is increasingly on prevention (education) and physical removal (combing or shaving) because a crisis exists in the chemical management of pediculosis. The choices of effective pediculicides are limited due to increasing levels of insecticide resistance. Thus, there is a critical need to identify unique target sites and to develop new and novel acting pediculicides.

3. Pediculicide resistance

The control of pediculosis has been largely dependent upon the availability of natural and synthetic insecticides starting with DDT and followed by the natural pyrethrins, the organochlorine lindane, the organophosphorus malathion, the carbamate carbaryl and synthetic pyrethroid permethrin (Durand et al., 2012).

In the USA, the pyrethrins/permethrin have dominated the over-the-counter (OTC) market, followed by the prescription only malathion-containing formulations, such as Ovide®. The pyrethrins/pyrethroids share a common target site in the nervous system, the voltage-sensitive sodium channel (VSSC), and act as agonistic neuroexcitants (Soderlund et al., 2002). Malathion is a phosphorodithioate-type organophosphorus insecticide, which is an indirect nerve toxin that acts as a competitive irreversible inhibitor of acetylcholinesterase associated with the insect cholinergic nervous system.

Insecticide resistance to currently-used pediculicides, including permethrin, PBO-synergized pyrethrins and malathion, has occurred worldwide, is increasing (Hodgdon et al. 2010; Marcoux et al. 2010; Gao et al, 2006; Lee et al. 2000; Mumcuoglu et al. 1995; Chosidow et al. 1994), and is certainly contributing to increased incidences of pediculosis (Clark, 2018).

4. Determination of resistance using the in vitro rearing system

The development of an in vitro rearing system allows for the first time the sustainable maintenance of head and body louse colonies without human infestation, and enables the large-scale rearing of pediculicide-susceptible and -resistant strains of lice (Takano-Lee et al. 2003). The efficacies of three commercially-available OTC formulations (Nix®, Rid®, Proto® Plus) were assessed using this system (Yoon et al. 2006). All products were highly effective (100% mortality) on the pediculicide-susceptible strain but differentially efficacious (62–84% mortality) on the pediculicide-resistant strain, validating previous anecdotal reports of resistance to permethrin- and pyrethrin-based pediculicide formulations.

5. Louse genomes and transcriptomes

Sequencing of the body louse genome revealed that despite its small size (Johnson et al. 2007) the genome retained a remarkably complete basal insect repertoire of 10,775 draft body louse gene models (Kirkness et al. 2010). Comparison of the transcriptional profiles of body and head lice using expressed sequence tags identified 10,771 body and 10,770 head louse transcripts (Olds et al. 2012). Interestingly, the numbers of detoxification genes involved in xenobiotic metabolism (e.g., cytochrome P450 monooxygenases, glutathione S-transferases, esterases) were dramatically reduced in both head and body lice compare with other insects, indicating that the decreased number of detoxification genes and small genome size would make human lice an efficient model to study insecticide resistance (Lee et al. 2010).

6. Mechanisms of resistance to permethrin and malathion

6.1. Three point mutations in the α-subunit gene of the VSSC cause knockdown resistance (kdr) and can be used for monitoring the extent and magnitude of resistance

Lee et al. (2000) found that head lice were resistant to a permethrin and exhibited in vivo responses in behavioral bioassays that were consistent with kdr (Busvine, 1951; Soderlund and Knipple, 2003). Three point mutations resulting in non-silent amino acid substitutions (M815I, T917I and L920F) in the VSSC α-subunit (numbered according to the head louse amino acid sequence) were identified only in permethrin-resistant head lice (Lee et al. 2003). Using site-directed mutagenesis, heterologous expression and two-electrode voltage clamp electrophysiology, Yoon et al. (2008) determined that all three mutations resulted in target site insensitivity by functioning as kdr-type mutations and contributes to permethrin resistance in the head louse.

6.2. Monitoring kdr in North America

The extent and frequency of a kdr-type resistance allele (T918I) in North American populations of head lice was initially determined from lice collected from 32 locations in Canada and the USA (Yoon et al. 2014). The T918I allele frequency in USA lice from 1999 to 2005 was 84.4%, increased to 99.6% from 2007 to 2009 and was 97.1% in Canadian lice in 2008. In a follow up study with lice collected from 138 geographical collection sites in 48 US states (Gellatly et al. 2016), the mean percent resistance allele frequency values (mean % RAF) across all three mutation loci (M/I, T/I, L/F) were determined using quantitative sequencing (Kwon et al. 2008). The overall mean % RAF (± S.D.) for all analyzed lice was 98.3 ± 10%. Forty-two states (88%) had mean % RAF of 100%. 132 of the 138 sites (95.6%) had a mean % RAF of 100%, five sites (3.7%) had intermediate values, all > than 50%, and only a single site had no mutations. The loss of efficacy of the Nix® formulation (containing permethrin) from 1998 to 2013 as determined by 12 clinical studies was highly correlated to the increase in kdr-type mutations over this same time frame (Gellatly et al. 2016). Thus, the frequency of kdr-type alleles in North American head louse populations was uniformly high, which appear to be due to the high selection pressure from the intensive and widespread use of the pyrethrins/pyrethroid-based pediculicides over many years, and is likely a main cause of the failure of pyrethrins/permethrin-based products in Canada and the USA, leading to increased pediculosis (Clark, 2018).

6.3. Malathion resistance is due to enhanced hydrolytic ester cleavage by malathion carboxylesterase

Malathion resistance in the head louse was previously reported to be due to enhanced malathion carboxylesterase (MCE) activity (Gao et al. 2006). The transcriptional profiles of five catalytically-active esterases were determined and compared between the malathion-resistant (BR-HL) and malathion-susceptible (KR-HL) strains (Kwon et al. 2014). Only one esterase gene, HLCbE3, exhibited a significantly higher transcription level (5.4-fold) in the resistant BR-HL strain. Comparison of the entire cDNA sequences of HLCbE3 revealed no sequence differences between the BR-HL and KR-HL strains. However, two copies of the HLCbE3 gene were found in BR-HL, implying that over-transcription of HLCbE3 is due to the combination of a gene duplication and up-regulated transcription. Knockdown of HLCbE3 expression by RNA interference (RNAi) in the BR-HL strain caused increased malathion susceptibility, confirming the identity of HLCbE3 as the MCE responsible for malathion resistance in head lice.

7. New and novel-acting pediculicides/medical devices

Given the widespread occurrence of resistant lice to the most commonly-used pediculicides, containing permethrin, pyrethrins or malathion, as discussed above, there has been a resurgence in the development of new pediculicide formulations over the past ~10 years. A new pediculicide needs to have novel chemistry and mechanism of action, be safe and selective, rapidly eliminate walking lice and viable eggs (ovicidal), show no cross-resistance, be easily used and affordable (Devore and Schutze, 2015). The following list of formulations includes commercially-available pediculicidal treatments that have been recently registered either in the USA or considered medical devices. They all have unique chemicals as their active ingredients, which do not overlap with the target sites used in the OTC- or malathion-containing formulations discussed above, indicating that cross-resistance is not likely. Only products that have had their active ingredient identified are discussed below.

7.1. Dimethicone-based formulations

There has been an increasing interest in the development of physical means to control head lice, mostly in Europe, because of increasing instances of resistance, particularly to neurotoxic pediculicides, and the increased scrutiny of the use of such products on children. Dimethicone-based anti-louse products (silicone oils) are medical devices that have low mammalian toxicity, novel physical modes of action (not neurotoxic) and the possibility that they will have a low potential for the development of resistance (multiple potential target sites and/or no main toxiphore).

Dimethicones are linear polydimethylsiloxanes (CH3SiO[SiO(CH3)2]nSi(CH3)2) of varying chain lengths, where n is the number of repeating monomeric dimethyl siloxanes [SiO(CH3)2], which influences their viscosity and spreading characteristics. The toxic action for the dimethicones is not definitively known (and may differ between products of differing chain lengths, see below) but they have been shown to be effective (Burgess, 2009; Burgess et al. 2013). Two dimethicone-based products, Hedrin® and NYDA,® are better characterized scientifically in terms of their effectiveness and probable modes of action.

Hedrin® 4% lotion (Thornton & Ross Ltd, Huddersfield, UK) is a 4% dimethicone lotion in 96% (w/w) decamethylcyclopentasiloxane (cyclomethicone D5). Treated head lice are rapidly immobilized but small movements in their extremities over several hours indicate that death is delayed. Scanning electron microscopy coupled with X-ray microanalysis revealed that Hedrin® 4% lotion was found in the spiracles, in some cases blocking the opening, and penetrated into the outer aspects of the tracheae (Burgess, 2009). Asphyxia is unlikely given the slow onset of mortality. The inability of the louse to excrete the excess water acquired during blood feeding by transpiration out of the spiracles has been suggested as a toxic action (Burgess et al. 2013).

The second dimeticone-based anti-louse product, NYDA® (G. Pohl-Boskamp GmbH & Co. Hohenlockstedt, Germany), contains a mixture of two dimeticones, one of low and the other of higher viscosity, at a final total concentration of dimeticones of 92% (w/w). Medium-chain length triglycerides, jojoba wax and two fragrances make up the remaining constituents. NYDA® rapidly enters the tracheal system due to its high spreading ability (Richling and Bockele, 2008). Death occurs rapidly and appears to be due to asphyxia. NYDA® is also an effective ovicide (Strycharz et al. 2012).

In the USA, the OTC product, Lice MD®, is currently available from Reckitt-Benckiser, Slough, England, and contains dimethicone as an emollient (Devore and Schutze, 2015).

7.2. Ivermectin-based formulations

Ivermectin is a 16-member macrocyclic lactone produced fermentatively by Streptomyces avermitilis and is a widely-used oral anthelmintic agent for both humans and animals (Chosidow et al. 2010; Clark. 2018). There are three major moieties attached to the central macrocyclic lactone: a benzofuran ring, a spiroketal group and a disaccharide (Fig. 1). Besides muscles used in motility, ivermectin also acts to paralyze the muscles associated with the pharyngeal pump, inhibiting the pumping action needed for feeding and attachment (Fisher and Mrozik, 1984; Brownlee et al. 1997). The concentration of ivermectin causing paralysis of the pharyngeal pump is 10- to 100-fold lower than the concentration needed to cause mortality (Gill et al. 1995).

Fig. 1.

Fig. 1.

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Chemical Structure of Ivermectin. Ivermectin consists of a mixture of two homologues: 5-O-dimethyl- 22,23-dihydroavermectin B 1a and B 1b in a ratio of 80:20. IUPAC Name: 22,23-dihydroavermectin B1a (C48H74O14) + 22,23-dihydroavermectin B1b (C47H72O14). This figure is a modified version of Fig.1 from Martin et al. Trends in Parasitology 37(1), 48–64, 2021. Copyright 2020, Elsevier.

Ivermectin increases chloride ion permeability in insect (Duce and Scott, 1985) and nematode (Dent et al. 1997) neurons and muscle membranes through binding primarily to glutamate-gated chloride ion channels and acting as an allosteric agonist. These channels are pentameric receptors with large extracellular domains where glutamate binds and activates the channel. Ivermectin binds in the transmembrane domain of the receptor where it interacts between adjacent subunits, each consisting of four transmembrane α-helixes (M1-M4) (Wolstenholme, 2012). The benzofuran ring of ivermectin enters the pore of the receptor and binds to the M1 and M2 α-helixes and positions the spiroketal group next to the M3 α-helix in the adjacent subunit, perturbing its positon and forcing the channel into a persistent conducting state.

Glutamate-gated chloride channels are highly expressed in the neuromuscular system of the pharyngeal pump in the mouthparts of the free living nematode, Caenorhabditis elegans, which has been shown to be highly sensitive to ivermectin (Pemberton et al. 2001). Action potentials recorded from pharyngeal muscles are reduced in amplitude and frequency by concentrations as low as 10 pM and the muscle membrane potential is maximally depolarized by 10 nM ivermectin causing paralysis. During de-worming, ivermectin paralyzes of the mouthparts of the nematode, causing it to detach from the mammalian gut and be excreted. A similar mode of action in head lice is expected, however, it has not been directly characterized.

Recently, oral ivermectin was used to treat hard-to-control head louse infestations (Chosidow et al. 2010). Successive treatments were necessary to kill nymphs that emerge from eggs present at the time of the initial treatment, indicating an absence of a direct ovicidal effect of oral ivermectin on eggs due to their external location on hair strands.

Ivermectin is also formulated as a topically-applied pediculicide as a 0.5% ivermectin cream formulation (Sklice ®, Arbor Pharmaceutical, Atlanta, GA) and was approved by the US FDA in 2012 as a prescription treatment in patient 6 months or older (Devore and Schutze, 2015). Sklice ® killed permethrin-resistant head lice (Strycharz et al. 2008) but was not directly ovicidal to treated eggs, as hatchability was not decreased (Strycharz et al. 2011). Nevertheless, the percent of hatched lice from treated eggs that took a blood meal was significantly decreased (80–95%) compared to lice that hatched from untreated eggs and all treated lice died within 48 h of hatching. Lice that hatched from eggs treated with non-lethal dilutions of Sklice® also fed significantly less than lice from untreated eggs. Using [3H] inulin uptake as a means to measure blood feeding, lice from eggs treated with non-lethal dilutions of Sklice® ingested significantly less blood than lice from untreated eggs. Thus, the failure of hatched instars to take a blood meal following egg treatments with Sklice® is responsible for its action as a post-eclosion nymphicide (Strycharz et al. 2011) and this action is likely due to the paralyzing action of ivermectin on the muscles of the pharyngeal pump as discussed above.

7.3. Spinosad-based formulation

Spinosad is a 12-member macrocyclic lactone insecticide produced fermentatively by a soil actinomycete bacterium, Saccharopolyspora spinosa. It has two active ingredients, spinosyn A and spinosyn D, in a 5 to 1 ratio. Spinosyn A has a structure consisting of a unique tetracyclic ring system, including the macrocyclic lactone, which is attached to an amino sugar (D-forosamine) and a neutral sugar (tri-O-methyl-L-rhamnose) (Fig. 2). Salgado first reported that spinosyn A acted on the cholinergic nervous system in insects, likely at the nicotinic acetylcholine receptor (AChR) (Salgado, 1998). Using American cockroach (Periplaneta Americana) thoracic ganglion nerve preparation, he further showed that 100 nM imidacloprid inhibited the desensitizing aspect of the acetylcholine-induced current (I nAChRD) carried by the nAChR, leaving the non-desensitizing current (I nAChRN) (Salgado and Saar, 2004). Spinosad A was found to be highly active on the non-desensitizing current (EC50 27 nM) whereas 1–10 mM spinosyn A only slightly effected the desensitizing current. Recently, spinosyn A has been shown to bind to the transmembrane aspect of the insect nAChR between adjacent subunits in a manner similar to ivermectin binding to the invertebrate glutamate-gated chloride channel but in much less detail (Bacci et al. 2016). In summary, spinosad is a neurotoxic allosteric agonist at the nAChR of the cholinergic nervous system where it selectively modifies the non-desensitizing aspect of the current flowing through this ligand-gated channel, causing prolonged excitability and then paralysis (Salgado and Saar, 2004). Spinosad is both pediculicidal and ovicidal (Villegas and Breitzka, 2012).

Fig. 2.

Fig. 2.

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Chemical structure of spinosyn A (C41H65NO10) and spinosyn D (C42H67NO10). Spinosad consists of a 5:1 ratio of A to D, respectively. This figure is modified from Fig. 1 in Salgado, Pestic. Biochem. Physiol. 60, 91–102, 1998. Copyright 1998, Elsevier.

Spinosad has been commercially formulated as a 0.9% viscous topical suspension and was approved by the FDA in 2011 as a prescription treatment for the treatment of pediculosis in patients 6 months or older (Natroba®, ParaPRO, LLC, Carmel, IN) (Devore and Schutze, 2015).

7.4. Abametapir-based formulation

A novel approach investigated egg hatching as a pathway to identify new sites of action for the development of novel ovicidal compounds (Bowles et al. 2007). A number of proteases were identified as metalloproteases and their presence from newly hatched louse eggs indicated that they may play a role in egg hatching. Eggs treated with a known metalloproteinase inhibitor, 1,10-phenanthroline, failed to hatch, indicating that metalloproteinase may function as novel ovicidal targets in lice. Metalloproteinases are known to play essential roles in insect development, including embryogenesis, egg hatching, growth and tissue remodeling (Nagase et al. 2006).

To better understand this phenomenon, 5,5’-dimethyl-2,2’-bipyridyl (a bipyridine metal chelating ligand formerly known as Ha44, now referred to as abametapir) was used to determine its ovicidal, larvicidal and adulticidal action on D. melanogaster as a model insect (Fig. 3) (Van Hiel et al. 2012). Bipyridyl is a well-established divalent metal chelator where three molecules form six coordinate covalent bonds with a single metal cation. Although toxic to both larvae and adults, abametapir was particularly active on eggs (LC50 250 μM) and arrested development at various stages of embryogenesis. The action abametapir on developing eggs was found to be reversed by the addition exogenous metal cations (Fe2+>Fe3+>Cu2+>Zn2+) and the enzyme activity of a zinc-containing matrix metalloprotease, meprin 1A, was inhibited by abametapir and two other well-established metal chelators ((N,N,N,N’-tetrakis(−)[2-pyridylmethyl]-ethylenediamine (TPEN) and ethylenediaminetetraacetic acid (EDTA) in vitro. Also, abametapir was shown to reduce the concentration of both copper and zinc in the digestive tract of flies in vivo using a GFP expression reporter assay.

Fig. 3.

Fig. 3.

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Chemical structure of abametapir (5,5’-dimethyl-2,2’-bipyridyl). Molecular weight 184.24 (C12H12N2). This figure is modified from Accessdata.fda.gov. PDF/ 206966Orig1s000.

Recently, abametapir in isopropanol and as a formulated lotion (Xeglyze™, 0.74% abametapir) was determined to be 100% ovicidal on both human head and body louse eggs (Bowles et al. 2016), was found in a clinical study to be an effective in clearing active human head louse infestation in vivo (Bowles et al. 2018) and ovicidal in an ex vivo study Bowles et al. 2019). Xeglyze™ Lotion was FDA-approved in 2020 as is a topical pediculicide for human head lice in patients 6 months and older.

8. Sustainable resistance management

Resistance management entails processes that reduce resistant allele frequencies, dominance, and fitness of the resistant genotypes (Leeper et al. 1986). Many non-chemical processes used to delay resistance in agricultural settings (e.g., natural enemies, insect disease, and host-plant resistance) are not applicable for human lice and limit the operational choices to a chemical management format coupled with nit removal. Insecticides are applied to manage resistance by moderation, saturation, or multiple attack strategies (Georghiou, 1983). Low tolerance of infestations and the “No-Nit” policy of some schools eliminate most moderation approaches. Saturation schemes that involve high concentrations of insecticides are not appropriate when treating children. Thus, only multiple attacks (e.g., mixtures, mosaics, and rotations of pediculicides) are available strategies. The use of mosaics on a human head is impractical and mixtures would entail manufacturers purchasing multiple formulations, reformulating and reregistering them, a costly and laborious process likely not to be undertaken any time soon. Rotating formulations containing active ingredients with different modes of action, however, have recently been suggested as an effective insecticide resistance management strategy using the Insecticide Resistance Action Committee (IRAC) / Mode of Action (MoA) Classification scheme (Sparks and Nauen, 2015).

In this current review, four new effective pediculicide products have been discussed, each with different MoA and unique chemistries. They have been proven to be safe and selective, are adulticidal, nymphicidal, either directly or indirectly ovicidal, and kill resistant lice. As such, they meet the criteria necessary to be used in rotations as discussed above as a resistance management strategy. For this to happen, however, there needs to be a level playing field on how these products are regulated both on a federal and state level. Most pediculicides are regulated as drugs by the US Food and Drug Administration (FDA) and must have a FDA-approved label due to their use on humans. States, however, decide which products will be available to their citizens. An important distinction is whether a drug is placed on a “preferred drug list”, allowing physicians to prescribe the drug without excessive paperwork. Having the above four pediculicidal products on a “preferred drug list” as antiparasitics would facilitate their use in rotation as a sustainable resistance management scheme.

Highlights.

  • Head lice are resistant to permethrin/pyrethrins due to 3 kdr-type mutations

  • Also resistant to malathion due to enhanced malathion carboxylesterase activity

  • Four new pediculicides products kill resistant lice

  • Each has novel chemistry and different modes of action

  • Their use in rotations is suggested as an effective resistance management strategy

Footnotes

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Declaration of Competing Interest

The author has no conflict of interest.

References

  1. Bacci L, Lupi D, Savoldelli S, Rossaro B 2016. A review of spinosyns, a derivative of biological acting substances as a class of insecticides with a broad range of action against many insect pests. J. Entomol. Acarol. Res 48, 5652. [Google Scholar]
  2. Bonilla DI, Kabeya H, Henn J, Kramer VI, et al. 2009. Bartonella quintana in body lice and head lice from homeless persons, San Francisco, California, USA, Emerg. Infect. Dis 15, 912–915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bowles VM, Young AR, Barker SC 2007. Metalloproteases and egg-hatching in Pediculus humanus, the body (clothes) louse of humans (Phthiraptera: Insecta). Parasitol 135, 125–130. [DOI] [PubMed] [Google Scholar]
  4. Bowles VM, Yoon KS, Barker SC, Tran C, et al. 2016. Ovicidal efficacy of abametapir against eggs of human head and body lice (Anoplura: Pediculidae). J. Med. Entomol 54, 167–172. Doi: 10.1093/jme/tjw132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bowles VM, Van Luvanee LJ, Alsop H, Hazan L, Shepherd K, Sidgiddi S, Allenby K, Ahveninen T, Hanegraaf S 2018. Clinical studies evaluating abametapir lotion, 0.74%, for the treatment of head louse infestation. Pediatric Dermatol 35: 616–621. Doi: 10.111/pde.13612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bowles VM, Hanegraaf S, Ahveninen T, Sidgiddi S, Allenby K, Alsop H 2019. Effect of a new head lice treatment, abametapir lotion, 0.74%, on louse eggs: a randomized, double-blind study. Global Pediatric Health 6, 1–7. Doi: 10.1177/2333794X19831295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brownlee DJ, Holden-Dye AL, Walker RJ 1997. Actions of the anthelmintic ivermectin on the pharyngeal muscle of the parasitic nematode, Ascaris suum. Parasitol 115, 553–561. [DOI] [PubMed] [Google Scholar]
  8. Burgess IF 2009. The mode of action of dimeticone 4% lotion against head lice, Pediculus capitis. BMC Pharmacol 9, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burgess IF, Brunton ER, Burgess NA 2013. Single application of 4% dimeticone liquid gel versus two applications of 1% permethrin crème rinse for treatment of head louse infestations; a randomized controlled trial. BMC Dermatol 13, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Busvine JR (1951) Mechanism of resistance to insecticide in houseflies. Nature, 168, 193–195. [DOI] [PubMed] [Google Scholar]
  11. Chosidow O, Chastang C, Brue C, Bouvet E, et al. 1994. Controlled study of malathion and d-phenothrin lotions for Pediculus humanus var capitis-infested schoolchildren. Lancet, 344, 1724–1727. [DOI] [PubMed] [Google Scholar]
  12. Chosidow O, Giraudeau B, Cottrell J, Ozri A, et al. 2010. Oral ivermectin versus malathion lotion for difficult-to-treat head lice. N. Engl. J. Med 362, 896–905. [DOI] [PubMed] [Google Scholar]
  13. Clark JM, Yoon KS, Lee SH, Pittendrigh BR 2013. Human lice: past present and future control. Pestic. Biochem. Physiol 106, 162–171. [Google Scholar]
  14. Clark JM, Yoon KS, Kim JH, Lee, et al. 2015. Utilization of the human louse genome to study insecticide resistance and innate immune response. Pestic. Biochem. Physiol 120, 125–132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Clark JM 2018. Chapter 6-New developments in the control of human lice, in Meng C, and Sluder A, (Eds.), Drug Discovery in Infectious Disease: Volume 6- Ectoparasites: Drug Discovery Against Moving Targets Wiley-VCH, pp. 119–137. [Google Scholar]
  16. Dent JA, Davis MW, Avery L 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. The EMBO Journal 16, 5867–5879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Devore CD, Schutze GE 2015. Head lice. Pediatrics, 135, e1356–e1361. [DOI] [PubMed] [Google Scholar]
  18. Duce IC, Scott RH, H. R 1985. Actions of dihydroavermectin B1a on insect muscle. Brit. J. Pharmacol 85, 395–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Durand R, Bouviesse S, Berdjane Z, Izri A, et al. 2012. Insecticide resistance in head lice: Clinical, parasitological and genetic aspects. Clin. Microbiol. Infect 18, 338–344. [DOI] [PubMed] [Google Scholar]
  20. Fisher MH and Mrozik H 1984. The avermectin family of macrolide-like antibiotics, in Omura A, (Ed), Macrolide Antibiotics, Academic Press, New York, NY. pp. 553–606. [Google Scholar]
  21. Gao J-R, Yoon KS, Frisbie RK, Coles GC, et al. 2006. Esterase-mediated malathion resistance in the human head louse, Pediculus capitis (Anoplura: Pediculidae). Pestic. Biochem. Physiol 85, 28–37. [Google Scholar]
  22. Gellatly KJ, Krim S, Palenchar DJ, Shepherd K, et al. 2016. Expansion of the knockdown resistance frequency map for human head lice (Phthiraptera: Pediculidae) in the United States using quantitative sequencing. J. Med. Entomol 23, 1–7, doi: 10.1093/jme/tjw023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Georghiou GP 1983. Management of resistance in arthropods, in Georghiou GP, Saito T, (Eds) Pest Resistance to Pesticides, Plenum Press, New York, NY. pp. 769–792. [Google Scholar]
  24. Gill JH, Redwin JM, Van Wyk JA, Lacey E 1995. Avermectin inhibition of larval development in Haomonchus contortus effects ivermectin resistance. Int. J. of Parasitol 25, 463–470. [DOI] [PubMed] [Google Scholar]
  25. Gratz NG 1999. Emerging and resurging vector-borne diseases, Ann. Rev. Entomol 44, 51–75. [DOI] [PubMed] [Google Scholar]
  26. Hodgdon HE, Yoon KS, Previte DJ, Kim HJ, et al. 2010. Serial invasive signal amplification reaction for the determination of kdr frequencies in global human head louse populations for efficient resistance monitoring. Pest Manag. Sci 66, 1031–1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Johnson JS, Yoon KS, Strycharz JP, Pittendrigh BR, et al. 2007. Body and head lice (Phthiraptera: Pediculidae) have the smallest genomes of any hemimetabolous insect reported to date. J. Med. Entomol 44, 1009–1012. [DOI] [PubMed] [Google Scholar]
  28. Jones DS, Wache S, Chhokar V 1996. Toxins produced by arthropod parasites: salivary gland proteins of human body lice and venom protein of chelonine wasps. Toxicon, 34, 1421–1429. [DOI] [PubMed] [Google Scholar]
  29. Kang JS, Cho YJ, Kim JH, Kim SH, et al. 2015. Comparison of the genome profiles between head and body lice. J. Asia-Pacific Entomol 18, 337–382. [Google Scholar]
  30. Kelly DJ, Richards AL, Temenak J, Strickman JD, et al. 2002. The past and present threat of rickettsial diseases to military medicine and international public health. Clin. Infect. Dis 34 (Suppl. 4), S245–S169. [DOI] [PubMed] [Google Scholar]
  31. Kirkness EF, Haas BJ, Sun W, Braig HR, et al. 2010. Genome sequences of the human body louse and its endosymbiont provide insights into the permanent parasitic lifestyle. PNAS, 107, 12168–12173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kittler R 2003. Molecular evolution of Pediculus humanus and the origins of clothing. Curr. Biol 13, 1414–1417. [DOI] [PubMed] [Google Scholar]
  33. Koch E, Clark JM, Cohen B, Meinking TL, et al. 2016. Management of head louse infestations in the United States- A literature review. Pediatric Dermatol, 33, 466–472. [DOI] [PubMed] [Google Scholar]
  34. Kwon DH, Yoon KY, Strycharz JP, Clark JM, and Lee SH 2008. Determination of permethrin resistance allele frequency of human head louse populations by quantitative sequencing. J. Medical Entomol 45, 912–920. [DOI] [PubMed] [Google Scholar]
  35. Kwon DK, Kim JH, Kim YH, Yoon KS, K. S, et al. 2014. Identification and characterization of the esterase involved in malathion resistance in the head louse, Pediculus humanus capitis. Pestic. Biochem. Physiol 112, 13–18. [DOI] [PubMed] [Google Scholar]
  36. Lee SH, Yoon KS, Williamson MS, Goodson SJ, et al. 2000. Molecular analysis of kdr-type resistance in permethrin-resistant strains of head lice, Pediculus capitis. Pestic. Biochem. Physiol 66, 130–143. [Google Scholar]
  37. Lee SH, Gao J-R, Yoon KS, Mumcuoglu KY, K. Y, et al. 2003. Sodium channel mutations associated with knockdown resistance in the human head louse, Pediculus capitis (De Geer). Pestic. Biochem Physiol 75, 79–91. [Google Scholar]
  38. Lee SH, Min JS, Yoon KS, Strycharz JP, et al. 2010. Decreased detoxification genes and genome size makes the human body louse an efficient model to study xenobiotic metabolism. Insect Mol. Biology, 19, 599–615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lee SH, Yoon KS, Williamson MS, Goodson SJ, Takano-Lee M, Edman JD, Devonshire AL, Clark JM, 2000. Molecular analysis of kdr-like resistance in permethrin-resistant strains of head lice, Pediculus capitis. Pestic. Biochem. Physiol 66, 130–143. [Google Scholar]
  40. Leeper JR, Rough JR, Reynolds HT 1986. Preventing or managing resistance in arthropods, in Pesticide Resistance: Strategies and Tactics for Management, National Academy Press, Washington, D.C., pp.335–346. [Google Scholar]
  41. Light JE, Toups MA, Reed DL 2008. What’s in a name: the taxonomic status of human head and body lice. Mol. Phylogenet. Evol 47, 1203–1216. [DOI] [PubMed] [Google Scholar]
  42. Marcoux D, Palma K, Kaul N, Hodgdon H, et al. 2010. Pyrethroid pediculicide resistance of head lice in Canada evaluated by serial invasive signal amplification reaction. J. Cutaneous Med. & Surg 14, 115–118. [DOI] [PubMed] [Google Scholar]
  43. Mumcuoglu KY, Hemingway J, Miller J, Ioffe-Uspensky I, Klaus S, Ben-Ishai F, Galun R, 1995. Permethrin resistance in the head louse Pediculus capitis from Israel. Med.Vet. Entomol 9, 427–432. [DOI] [PubMed] [Google Scholar]
  44. Nagase H, Visse R, Murphy G 2006. Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Res 69: 562–573. 10.1016/j.cardiores.2005.12.002. [DOI] [PubMed] [Google Scholar]
  45. Olds BP, Coates BS, Steele LD, Sun W, et al. 2012. Comparison of the transcriptional profiles of head and body lice. Insect Mol. Biol 21, 257–268. [DOI] [PubMed] [Google Scholar]
  46. Pemberton DJ, Franks CJ, Walker RJ, Holden-Dye L 2001. Characterization of glutamate-gated chloride channels in the pharynx of wild-type and mutant Caenorhabditis elegans delineates the role of the subunit GluCl-α2 in the function of the native receptor. Mol. Pharmacol 59, 1037–1043. [DOI] [PubMed] [Google Scholar]
  47. Pennisi E 2004. Human origins. Louse DNA suggests close contact between early humans. Science, 306, 210. [DOI] [PubMed] [Google Scholar]
  48. Pittendrigh BR, Olds BP, Yoon KS, Lee SH, et al. 2013. The genomics of human lice: from the genome to the potential for future control strategies. Pestic. Biochem. Physiol 106,172–176. [Google Scholar]
  49. Pittendrigh BR, Clark JM, Lee SH, Yoon KS, et al. 2015. Body lice: from genome project to functional genomics and reverse genetics, in Raman C, Goldsmith MR, Agunbiade TA (Eds.), Short Views on Insect Genomics and Proteomics, Entomology in Focus 3, Springer Int. Publish., Switzerland, pp. 1–18. DOI 10.1007/978-3-319-24235-4_1 [DOI] [Google Scholar]
  50. Richling I, Bockele W 2008. Lethal effects of treatment with a special dimeticone formula on head lice and house crickets (Orthoptera, Ensifera: Acheta domestica and Anoplura, Phthiraptera: Pediculus humanus)-Insights into physical mechanisms. Arzneimittelforschung, 58, 248–254. [DOI] [PubMed] [Google Scholar]
  51. Salgado VL 1998. Studies on the mode of action of spinosad: insect symptoms and physiological correlates. Pestic. Biochem. Physiol 60: 91–102. [Google Scholar]
  52. Salgado V, Saar R 2004. Desensitizing and non-desensitizing subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in cockroach neurons. J. Insect Physiol 50, 867–879. [DOI] [PubMed] [Google Scholar]
  53. Soderlund DM, Clark JM et al. 2002. Mechanisms of Pyrethroid Neurotoxicity: Implications for Cumulative Risk Assessment. Toxicology 171: 3–59. [DOI] [PubMed] [Google Scholar]
  54. Soderlund DM, Knipple DC 2003. The molecular biology of knockdown resistance to pyrethroid insecticides. Insect Biochem. Mol. Biol 33, 563–577. [DOI] [PubMed] [Google Scholar]
  55. Sparks TC, Nauen R 2015. IRAC: Mode of action classification and insecticide resistance management. Pestic. Biochem. Physiol 121:122–128. [DOI] [PubMed] [Google Scholar]
  56. Strycharz JP, Yoon KS, Clark JM 2008. A new ivermectin formulation topically kills permethrin-resistant human head lice (Anoplura: Pediculidae). J. Med Entomol 45, 75–81. [DOI] [PubMed] [Google Scholar]
  57. Strycharz JP, Berge NM, Alves AM, Clark JM 2011. Ivermectin acts as a post-eclosion nymphicide by reducing blood feeding of human head lice (Anoplura, Pediculidae) that hatched from treated eggs. J. Med. Entomol 48, 1174–1182. [DOI] [PubMed] [Google Scholar]
  58. Strycharz JP, Lao AR, Alves AM, Clark JM 2012. Ovicidal response of NYDA formulations on the human head louse (Anoplura, Pediculidae) using a hair tuft bioassay. J. Med. Entomol 49, 336–342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Takano-Lee M, Velten RK, Edman JD, Mullens BA et al. 2003. An automated feeding apparatus for in vitro maintenance of the human head louse, Pediculus humanus capitis, (Anoplura: Pediculidae). J. Med. Entomol 40, 795–799. [DOI] [PubMed] [Google Scholar]
  60. Van Hiel MB, Breugelmans B, Pagel CN, Williams AK et al. 2012. The ovicidal, larvicidal and adulticidal properties of 5,5’-dimethyl-2,2’-bipyridyl against Drosophila melanogaster. PLoS One, 7, e49961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Villegas SC, Breitzka RL 2012. Head lice and the use of spinosad. Clin. Ther 34, 14–23. [DOI] [PubMed] [Google Scholar]
  62. Weiss K 1988. The role of rickettsioses in history, in Walker DH (Ed), Biology of Rickettsial Diseases, Vol. 1., CRC, Boca Raton, FL. pp.1–14. [Google Scholar]
  63. Williams LK, Reichart A, MacKenzie WR, Hightower AW, et al. 2001. Lice, nits, and school policy. Pediatrics, 107, 1011–1015. [DOI] [PubMed] [Google Scholar]
  64. Wolstenholme AJ 2012. Glutamate-gated chloride channels. J. Biol. Chem 287, 40232–40238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yoon KS, Strycharz JP, Gao JR, Takano-Lee M, et al. 2006. An improved in vitro rearing system for the human head louse allows the determination of resistance to formulated pediculicides. Pestic. Biochem. Physiol 86, 195–202. [Google Scholar]
  66. Yoon KS, Symington SB, Lee SH, Soderlund DM et al. 2008. Three mutations identified in the voltage-sensitive sodium channel alpha-subunit gene of permethrin-resistant human head lice abolish permethrin sensitivity of the house fly Vssc1 expressed in Xenopus oocytes. Insect. Biochem. & Mol. Biol 38, 296–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yoon KS, Previte DJ, Hodgdon HE, Poole BC, et al. 2014. Knockdown resistance allele frequencies in North American head louse populations. J. Med. Entomol 51, 450–457. [DOI] [PMC free article] [PubMed] [Google Scholar]

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