Unlike other public health uses of insecticides, head louse treatments cannot afford to leave any survivors for clinical, aesthetic, and epidemiological reasons. Consequently, dilution of resistance traits by elimination of the most resistant insects and ingress of susceptible insects into the population, a fundamental component of the principles behind multiple pesticide tactics, does not and cannot apply to this condition. The ideal of complete elimination of an infestation presumably failed frequently with the result that surviving lice were selected for one or more of the traits identified here (Maunder, 1991).
The collections of head lice from around Britain indicate that acquired resistance arose in geographically separate localities more or less concurrently and increased in intensity over a relatively short period coincident with continued use of insecticide products. At the time, most health authorities used insecticide rotation policies based on the theoretical concept that changing from an insecticide with one mode of action to another with a different mode of action would dilute the resistance trait within the population (Tabashnik, 1989; Maunder, 1991). It assumed a) that resistance to any one insecticide was monogenic and did not cross-over to other insecticides from a different chemical class (Tabashnik, 1989); b) the usage of the insecticide products was thorough in terms of both application and dosage (Maunder, 1989); and c) that all products containing the same named active substance showed the same bioavailability and were equally effective, which was not the case (Burgess, 1991; Burgess, et al., 1992).
It was not surprising that any latent residual kdr-type mutations present in the UK louse population should be selected after the introduction of the pyrethroids, phenothrin and permethrin, in 1993 given the long history of use of DDT from the 1940s through to the 1980s. However, the speed of selection, less than 18 months, was surprising, as was the widespread distribution with contemporaneous reporting from several areas of the country, which eliminated the possibility that resistance was spreading through human trafficking of lice from the first identified focus in London to other regions. The initial selection was probably from widespread use of an inefficient, but market leading, phenothrin shampoo with further selection through widespread use of permethrin creme rinse that left diminishing residual deposits of insecticide on the hair (Burgess, et al, 1992; Burgess and Brown; 1999). Similarly, malathion resistance was identified in several locations a few months after the first report in mid-1995. This also was probably not surprising because the insecticide had been the mainstay of treatment since 1971, although the main products were fortified by a mixture of d-limonene and α-terpineol monoterpenes. However, in June 1988 terpenes were removed from one of the most used products and within weeks several health authorities received reports of treatment failures (Burgess, 1991), apparently because infestations re-established when not all louse eggs were killed.
Awareness of resistance to insecticides was slow to disseminate amongst health practitioners because the first systematic review of pediculicides, published one week before the first report of resistance in Britain, found only permethrin creme rinse had robust clinical evidence to support its use (Vander Stichele, et al., 1995) and as a result largely overshadowed any possibility that practitioners would doubt efficacy due to resistance. Consequently, prescribed pyrethroids dominated insecticide use for two to three more years, resulting in extensive selection for resistance traits nationwide. Such was the power of the systematic review that some prescribers failed to believe the evidence of treatment failure in their patients. For example, we were asked to advise in a case where the general practitioner had been prescribing 1% permethrin up to four times each week for more than a month in an attempt to treat a case of what he believed was repeated reinfestation. Furthermore, there was a deeply held underlying belief by some specialists that everything could be managed if only the right procedures were followed, and care givers used the right products thoroughly enough (the Stafford Group, 1998).
Once it became clear that treatment failures were not just the result of incomplete or inadequate treatment, some local public health departments instituted procedures to investigate the resistance status in their area. This intervention was patchily distributed and dependent upon the interest of individual paediatric consultants or communicable disease specialists. Although it did identify problems on a local basis, resulting in changes of policy for insecticide use, overall, it was too little action too late because, as we found in Cambridge with the switch from permethrin to malathion, some lice had already acquired traits of tolerance that were expressed as full resistance within a short period. Continued use of the insecticides resulted in a cross-over resistance between pyrethroids and malathion mediated by non-specific esterases (Gao, et al., 2006), although this appeared not to affect all areas (Thomas, et al., 2006). Over the next few years, it became possible to identify lice from this population by their diminutive size, with adult lice sometimes smaller that third stage nymphs of susceptible lice, presumably because over production of metabolising and sequestering enzymes depleted energy resources that would otherwise have been devoted to growth and fecundity. In parallel, a few lice were found to be tolerant of the original alcohol-based malathion lotion with added terpenoids, suggesting resistance to those chemicals also.
In mid-1996 the UK Department of Health issued policy guidance for treatment of infestations using wet combing with conditioner (Department of Health, 1996), which was rapidly taken up by some general practitioners who wished to stop an apparently endless cycle of prescribing. It is not known how effective this was for combatting resistance, but it did result in a significant reduction in the number of prescriptions for head louse treatments for a number of years (RCGP, 2007). Whether the public implemented the guidance to any degree is uncertain, but market data collected around that time indicate that insecticide sales did not diminish, which would have resulted in continued selection pressure for resistance until the introduction of the physically acting treatment products in 2005/6.
Despite cumulative clinical and other field collected evidence of resistance to insecticides and the associated failure of treatment products (Burgess, et al., 1995; 2007; 2012; 2013; 2014; Downs, et al., 1999; 2002; Thomas, et al., 2006), insecticide use in the United Kingdom still persists, albeit at a lowered level from the mid-1990s (Fig. S2) (Open Prescribing.org, 2021). Only two insecticide products remain on the UK market; 1% permethrin creme rinse, which has shown around 15–21% treatment success in clinical trials, and 0.5% malathion liquid that has proven only slightly more effective with between 33% and 47% success (Burgess, et al., 2007; 2012; 2013; 2014). These data indicate that resistance to permethrin has been more of a problem in Britain than in the United States of America, where clinical studies have consistently shown higher levels of efficacy despite widespread and high levels of kdr resistance allele frequency (Gellatly, et al., 2016) or in Denmark and Germany, where prevalence of kdr resistance genes exceeded 90% in epidemiologic and clinical studies (Kristensen, et al., 2006; Burow, et al., 2010; Bialek and Zelk, 2011) but failed to show a clinical impact in one German study (Burow, et al., 2010). The likely explanation for the difference in the UK is found in the bioassay evidence, which showed a parallel and high-level resistance to malathion in many samples, mediated by esterases that can also degrade permethrin. On that basis it is not surprising that resistance to permethrin is greater in Britain than the USA or Germany, neither of which have used malathion extensively. However, in Denmark malathion has long been used and shows levels of resistance similar to Britain but the underlying mechanisms have not yet been investigated (Kristensen, et al., 2006), so it is possible that resistance to permethrin in that country is also linked with malathion resistance, as has been shown in other isolates of lice from Britain (Thomas, et al., 2006).