**10. Resistance management strategies**

DDT-resistant population [149]. *An. Nuneztovari*, a secondary malaria vector, is resistant to

Insecticide resistance has been perceived to have the potential to undermine efforts to control vector-borne diseases including malaria [151, 152]. However, the impact of resistance on the ability of malaria control intervention to reduce disease transmission is poorly understood [153]. Insecticide resistance triggers a chain reaction that through deteriorated efficacy leads to vector control failure and disease control failure may be expected [153]. Evidence linking the potential of ITNs increasing phenotypic resistance and kdr frequency [154, 155] that threaten to compromise their effectiveness exists [86]. However, whether these various forms of resistance have an impact on the effectiveness of ITNs in malaria control remains a topic of debate among policy makers and researchers [60]. Conclusive evidence of insecticide resist‐ ance impacting on the efficacy of vector control interventions in decreasing disease transmis‐ sion is by large still absent. However, minimal evidence of an effect of resistance on entomological indicators having an impact on disease transmission exist [60]. The number of studies aimed at evaluating the operational significance of insecticide resistance on epidemio‐ logical outcomes of malaria remains nominal. This could be ascribed to multiple confounding factors capable of complicating the interpretation of data. The most available evidence is laboratory or experimental huts-based and harnessing entomological outcomes to assess the impact resistance on mosquito biting rates, blood feeding rates, or insect mortality [153]. Conflicting findings on the impact of resistance on vectorial capacity has been reported with some results indicating an increasing effect [156–160] while others present decreasing out‐

Mostly, the impact of pyrethroid resistance is not clearly observable in entomological and epidemiological terms. For instance, in areas with detected kdr resistance the distribution of LLINs has been shown to successfully reduce malaria transmission [161]. Insecticide resistance has only been directly implicated in operational control failure of pyrethroids in *An. funestus* in South Africa [162]. In 1996, pyrethroid resistance compromised malaria control in KwaZulu Natal following a switch of IRS insecticides from using DDT to deltamethrin [163]. The reintroduction of IRS with DDT controlled the pyrethroid resistant *An. funestus* population and malaria cases dropped by 91% [164]. In Bioko Island, IRS with pyrethroid had no impact on kdr-mediated resistant *An. gambiae* population, but had significant impact on transmission index and malaria cases [39, 42]. After switching to IRS with a carbamate, the mosquito population declined [42]. In Burundi, programmatic IRS with pyrethroids and ITNs markedly reduced Anopheles density by 82% and transmission intensity by 90% and occurrence of clinical episodes by 43% in children despite high kdr frequencies in *An. gambiae* s.s. [40, 165]. In Côte d'Ivoire, ITN-randomised controlled trials demonstrated a significant reduction on the entomological inoculation rate (55%) [166] and on malaria incidence in children <5 (56%) [167]

despite the presence of kdr-based pyrethroid resistance.

organophosphate and pyrethroids [150].

166 Insecticides Resistance

**9. Resistance and vector control**

comes [159, 160].

The long-term control of vectors is threatened by insecticide resistance, which is occurring at a faster pace than new insecticides are being developed. Pre-emptive action to mitigate the development and spread of insecticide resistance is critical in preserving the limited arsenal of insecticides available for public health [143]. With only four classes of insecticides currently recommended for vector control, implementation of effective resistance management strat‐ egies remains inevitable [29]. Resistance management can be defined as "the containment of the frequency of resistance genes below an acceptable threshold by means of strategic choices of insecticide, dosage, mode of application, or frequency of use"[173]. The mutant alleles that confer insecticide resistance are generated by random events. In the absence of insecticide selection pressure, resistance management strategies take advantage of the adverse fitness costs of resistance genes, to the insects carrying them. Though generally selected against in the absence of selection pressure, alleles with strong pleiotropic effects increase in frequency when insecticide selection pressure is applied. However, the outcome of resistance management strategies can be affected by dominance status of the trait [29, 143].

Resistance management entails the development and implementation of control interventions that minimise the likelihood that vectors will evolve strong resistance to important insecticides [169]. The aim is to prevent or delay the onset of resistance in populations exposed to an insecticide, or develop management programmes that cause existing resistance in populations to decline, through rotating or alternating insecticides as a resistance management strategy before resistance reaches measurable levels [174]. The use of combined classes of insecticides, rotations of insecticides, or mosaic design has shown to overcome resistance problems effectively than using a single class of insecticide [175, 176]. Temporal rotation over time of two, or preferably more, insecticide classes with different modes of action applied in an alternating sequence is also based on the assumption that an individual mosquito does not carry two resistant alleles [177]. Rotations are particularly effective if the resistance gene has an associated fitness cost [87] and assumes that if resistance to each insecticide is rare, then multiple resistances will be extremely rare [178]. The "mosaic" approach refers to applications of different compounds against the same insect in spatially segregated locations [55] and aim to preserve susceptibility by spatial restriction of insecticides [7]. Larger scale mosaics have been shown to be effective for the management of pyrethroid resistance in *An. albimanus* in Mexico [143, 179]. An alternative is simultaneous utilisation of a mixture of two or more insecticides of unrelated mode of action, the aim being that resistance will evolve more slowly to both insecticides than if either had been used on its own [180]. Unlike rotations, the effectiveness of mixtures is not directly related to the degree of fitness cost. Mixtures of insecticides require the expected frequency of resistant alleles at two different genetic loci to be low and that individual mosquitoes carrying both alleles are rare [181]. The other approach is through combinations of two vector control tools, such that a mosquito that survives contact with one (e.g., LLIN) is exposed to the other one (e.g., IRS) [182]. The success of combinations in effectively managing resistance depends on the ability to kill the vector despite the existence of resistance by using another intervention or insecticide [183]. However, caution should be exercised not to increase selection pressure by combining insecticides with same mode of action (e.g., avoid pyrethroids for both IRS and LLINs) [86].

Ideally, insecticide resistance management should be undertaken using insecticide-based approaches in conjunction with other non-insecticidal vector control methods, in the context of IVM [3]. However, resistance surveillance is a fundamental step and insecticide suscepti‐ bility an indispensable resource of resistance management; it provides baseline data for program planning and insecticide selection before the commencement of control operations, facilitates detection of resistance at an early stage so that timely management can be imple‐ mented, and enables continuous monitoring of the effect of control strategies on resistance. Establishing international, multi-disciplinary technical working groups with a clear reporting system and defined responsibilities to facilitate data collation and rational policy transforma‐ tion is critical for optimal IRM strategies. This would require the presence of a multiplicity of partners with vested interest in insecticide resistance, demand close collaboration and sustained coordination of local and external technical experts, and require good stewardship for them to succeed. Availability of entomological resources provides an ideal opportunity to develop a rational IRM plan underpinned by entomological and epidemiological baseline data to facilitate tracking of spatial and temporal resistance profiles of malaria vectors and evalu‐ ating its impact on the efficacy of control interventions. There remains a paucity of evidence on the utility of conventional resistance management strategies (e.g., insecticide rotations, mosaics, mixtures, and combinations) in restoring the susceptibility of malaria vectors. There is also a need for well-designed assessments of the operational impact of combinations of insecticidal and non-insecticidal interventions, including larval source management ap‐ proaches [87].
