Part 1The threat of <strong><strong>in</strong>secticide</strong> <strong>resistance</strong>The characteristics of the four classes of <strong><strong>in</strong>secticide</strong> currently recommended <strong>for</strong> IRS and LLINs are summarized <strong>in</strong> Figure 5.Figure 5: Characteristics of the four classes of <strong><strong>in</strong>secticide</strong> currently recommended <strong>for</strong> <strong>in</strong>door residual spray<strong>in</strong>g and long-last<strong>in</strong>g<strong>in</strong>secticidal netsInsecticide cost: Estimated approximate cost range perhousehold sprayed aCurrent LLINproductsCurrent IRSproductsMoleculesrecommended<strong>for</strong> use <strong>in</strong> IRSHazardclassificationDuration ofeffect per spray(months) bPyrethroids6Class Ib / II /U c3–6OrganophosphatesOrganochlor<strong>in</strong>es(DDT)1 Class II 6–123 Class II / III d 2–3Carbamates2 Class II 2–6051015(US$)From references (12-14)LLIN, long-last<strong>in</strong>g <strong>in</strong>secticidal net; IRS, <strong>in</strong>door residual spray<strong>in</strong>gHazard classification (active <strong>in</strong>gredient): Class Ib: Highly hazardous; Class II: Moderately hazardous; Class III: Slightly hazardous; Class U: Unlikely to present acute hazard <strong>in</strong> normal usea Analysis calculated <strong>for</strong> a household of 5 people (150 m 2 sprayed) and based on WHOPES spray<strong>in</strong>g guidel<strong>in</strong>es and PMI cost data (14).b Duration as based on typical <strong>for</strong>mulation <strong>for</strong> use <strong>in</strong> <strong>malaria</strong> control.c Cyfluthr<strong>in</strong> is WHO class Ib, Alpha-cypermethr<strong>in</strong>, Bifenthr<strong>in</strong>, Deltamethr<strong>in</strong>, Lambda-cyhalothr<strong>in</strong> and Permethr<strong>in</strong> are WHO class II and Etofenprox is WHO class U.d Fenitrothion and Pirimiphos-methyl are class II and Malathion is class III.26GLOBAL PLAN FOR INSECTICIDE RESISTANCE MANAGEMENT IN MALARIA VECTORS (GPIRM)
1.2 Status of<strong><strong>in</strong>secticide</strong><strong>resistance</strong>1.2.1 Def<strong>in</strong>itions and types of <strong>resistance</strong>There are three ways of look<strong>in</strong>g at <strong><strong>in</strong>secticide</strong> <strong>resistance</strong>,each of which is useful <strong>in</strong> a different context.Insecticide <strong>resistance</strong> is the term used to describe the situation<strong>in</strong> which the <strong>vectors</strong> are no longer killed by the standard doseof <strong><strong>in</strong>secticide</strong> (they are no longer susceptible to the <strong><strong>in</strong>secticide</strong>)or manage to avoid com<strong>in</strong>g <strong>in</strong>to contact with the <strong><strong>in</strong>secticide</strong>. Theemergence of <strong><strong>in</strong>secticide</strong> <strong>resistance</strong> <strong>in</strong> a vector population is anevolutionary phenomenon.Molecular genotyp<strong>in</strong>g of <strong>resistance</strong> is the identification ofthe underly<strong>in</strong>g genes that confer the <strong>in</strong>herited trait of <strong>resistance</strong>(15). Identification of a <strong>resistance</strong> gene provides evidence ofthe underly<strong>in</strong>g evolutionary process. Depend<strong>in</strong>g on the typeof <strong>resistance</strong> mechanism, this provides understand<strong>in</strong>g of boththe degree of <strong>resistance</strong> expressed <strong>in</strong> <strong>in</strong>dividual <strong>in</strong>sects withthe <strong>resistance</strong> gene, and the frequency of such <strong>in</strong>sects <strong>in</strong> thepopulation. 1Phenotypic <strong>resistance</strong> is the basic expression of the geneticcause of <strong>resistance</strong>, shown by a vector’s ability to resist and survivethe effects of the <strong><strong>in</strong>secticide</strong>. Phenotypic <strong>resistance</strong> is measured<strong>in</strong> a susceptibility test of vector mortality when subjected to astandard dose of the <strong><strong>in</strong>secticide</strong>. WHO has def<strong>in</strong>ed phenotypic<strong>resistance</strong> as “development of an ability, <strong>in</strong> a stra<strong>in</strong> of <strong>in</strong>sects,to tolerate doses of toxicants, which would prove lethal to themajority of <strong>in</strong>dividuals <strong>in</strong> a normal population of the same species”(16). Phenotypic <strong>resistance</strong> is the phenomenon most commonlyreferred to <strong>in</strong> public health.Resistance lead<strong>in</strong>g to control failure - while phenotypic<strong>resistance</strong> provides an <strong>in</strong>dication of the effects of <strong>resistance</strong> onthe vector, the most <strong>in</strong><strong>for</strong>mative way of look<strong>in</strong>g at <strong>resistance</strong> is asan epidemiological phenomenon, <strong>in</strong> which <strong>resistance</strong> is identifiedas the cause of <strong>in</strong>creas<strong>in</strong>g <strong>malaria</strong> transmission. In the notion of<strong>resistance</strong> lead<strong>in</strong>g to control failure, evidence of resistant <strong>vectors</strong>is l<strong>in</strong>ked directly to the failure of vector control programmes <strong>in</strong>the field. Resistance lead<strong>in</strong>g to control failure can be def<strong>in</strong>ed asthe “selection of heritable characteristics <strong>in</strong> <strong>in</strong>sect population thatresults <strong>in</strong> repeated failure of an <strong><strong>in</strong>secticide</strong> product to provide<strong>in</strong>tended level of control when used as recommended.” 2 (15)Resistance lead<strong>in</strong>g to control failure is the phenomenon most1 Different <strong>resistance</strong> mechanisms have different strengths and possibly different capacity to drivecontrol failure.2 Def<strong>in</strong>ition from the Insecticide Resistance Action Committee (IRAC).commonly referred to <strong>in</strong> agriculture. National <strong>malaria</strong> controlprogrammes should not, however, wait <strong>for</strong> control failure to occurbe<strong>for</strong>e implement<strong>in</strong>g strategies to manage <strong><strong>in</strong>secticide</strong> <strong>resistance</strong>.There is no acceptable level of control failure <strong>in</strong> public health, andwait<strong>in</strong>g could result <strong>in</strong> delay<strong>in</strong>g action until it is too late.Four types of <strong>resistance</strong> mechanisms have beenidentified.Resistance mechanisms can be grouped <strong>in</strong>to four categories,target-site <strong>resistance</strong> and metabolic <strong>resistance</strong> be<strong>in</strong>g the primaryfocus of this document.Target-site <strong>resistance</strong> occurs when the site of action of an<strong><strong>in</strong>secticide</strong> (typically with<strong>in</strong> the nervous system) is modified<strong>in</strong> resistant stra<strong>in</strong>s, such that the <strong><strong>in</strong>secticide</strong> no longer b<strong>in</strong>dseffectively and the <strong>in</strong>sect is there<strong>for</strong>e unaffected, or less affected,by the <strong><strong>in</strong>secticide</strong>. Resistance mutations, known as knock-down<strong>resistance</strong> (kdr) mutations, can affect acetylchol<strong>in</strong>esterase, whichis the molecular target of organophosphates and carbamates, orvoltage-gated sodium channels (<strong>for</strong> pyrethroids and DDT) (15, 17).Metabolic <strong>resistance</strong> is related to the enzyme systems thatall <strong>in</strong>sects possess to detoxify <strong>for</strong>eign materials. It occurs when<strong>in</strong>creased or modified activities of an enzyme system preventthe <strong><strong>in</strong>secticide</strong> from reach<strong>in</strong>g its <strong>in</strong>tended site of action. Thethree ma<strong>in</strong> enzyme systems are: esterases, mono-oxygenasesand glutathione S-transferases. While metabolic <strong>resistance</strong> isimportant <strong>for</strong> all four <strong><strong>in</strong>secticide</strong> classes, different enzymes affectdifferent classes 3 (15, 17).Although most <strong>resistance</strong> mechanisms (especially kdr <strong>resistance</strong>)have been studied <strong>for</strong> decades <strong>in</strong> previous cases of <strong>resistance</strong>,the detailed study of mono-oxygenase metabolic <strong>resistance</strong> isrelatively new, and our understand<strong>in</strong>g of it is fairly limited. Indeed,cases of mono-oxygenase <strong>resistance</strong> <strong>in</strong> mosquitoes were unknownbe<strong>for</strong>e its identification <strong>in</strong> South Africa <strong>in</strong> 2000–2001 (see section1.2.3 <strong>for</strong> details). 4As described below, metabolic and target site <strong>resistance</strong> can bothoccur <strong>in</strong> the same vector population and sometimes with<strong>in</strong> thesame <strong>in</strong>dividual mosquito. The two types of <strong>resistance</strong> appear tohave different capacities to reduce the effectiveness of <strong><strong>in</strong>secticide</strong>basedvector control <strong>in</strong>terventions, with metabolic <strong>resistance</strong> be<strong>in</strong>gthe stronger and more worry<strong>in</strong>g mechanism (see section 1.2.3 <strong>for</strong>details).3 The most important enzyme systems are mono-oxygenases and then esterases <strong>for</strong> pyrethroids,glutathione S-transferases and then mono-oxygenases <strong>for</strong> DDT and carbamates, and esterases andmono-oxygenases <strong>for</strong> organophosphates.4 Mono-oxygenase <strong>resistance</strong> is exceptionally difficult to study because more than 100 candidate<strong>resistance</strong> genes could be responsible <strong>for</strong> <strong>resistance</strong> and specific mutations are often difficult tolocate. Metabolic <strong>resistance</strong> genes occur when the specificity of an enzyme is altered, when genesare duplicated or when there is a promoter gene. The last is particularly difficult to identify.27
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