**5. Insecticide resistance in malaria vectors**

indoor residual spraying (IRS). More recently, pyrethroids have been widely used for malaria control. They are the only class of insecticides recommended by the WHO for impregnation of long-lasting insecticidal bed nets (LLINs) [24] and are also available for IRS. Pyrethroids, such as permethrin and deltamethrin, and the pseudo-pyrethroid etofenprox, including DDT and its analogues, share a similar mode of action of targeting the sodium channels of the nerve membranes. Carbamates, such as bendiocarb, share the same mode of action as organophos‐ phates, such as pirimiphos methyl, malathion, and temephos, binding to acetylcholinesterase at the nerve junction [27]. Chlorfenapyr has a different mode of action involving disruption of oxidative phosphorylation and consequently the disruption of the conversion of ADP to ATP in mitochondria [28]. Although insecticides from different chemical classes are available as larvicides (e.g., temephos), the arsenal of insecticides recommended for IRS is limited to four classes only [29]. The selection of DDT resistance in malaria vectors resulted in the declining political and financial support for the Global Malaria Eradication Campaign launched by the

Vector control, personal protection, and community participation are the pillars of WHO strategies for insect-transmitted disease control. IVM has been advocated for as a recommend‐ ed approach for combating vector-borne diseases in the past decade [31]. IVM is defined as "a rational decision-making process for optimal use of resources for vector control". The objective of vector control is to reduce and/or interrupt transmission of malaria by preventing human contact with malaria-bearing mosquitoes, eliminating breeding sites, killing the mosquito larvae, or reducing the longevity of adult mosquitoes [30]. The use of IRS and LLINs are the mainstream contemporary malaria vector control interventions [32, 33]. The efficacy of these two methods has been evaluated in different epidemiological settings [34] at experimental field trial [35, 36] and community-wide levels [37, 38]. In reducing abundance and infectivity of malaria vectors, these tools reduce overall transmission and protect all individuals within a community [35], albeit with variation in responsiveness amongst vector populations. Present‐ ly, there is mounting evidence that combining IRS and insecticide treated nets (ITNs) affords enhanced protection to exposed populations compared to using one method alone [39]. As such, deployment of these interventions together in high malaria risk areas has been advocated [35, 40, 41]. Although these two interventions have been critical in providing community protection, the optimal policy for their co-implementation still remains to be determined. Moreover, the growing resistance of malaria vectors to available insecticides is a major cause for concern and an increasing threat to such essential and effective interventions [24, 42, 43].

In light of the inherent heterogeneity in the responsiveness of malaria vectors to control, the core interventions can be supplemented in specific locations by larval source management (LSM) strategies (e.g., larviciding, biological control, and environmental management) in the context of IVM [44, 45]. Larvivorous fishes or bacterial pathogens such as *Bacillus thuringien‐ sis israelensis* and *Bacillus sphaericus* are examples of biological agents that are used to kill larvae [46]. Temephos is the commonly used chemical larvicide. The environmental meth‐ ods to prevent malaria include elimination of breeding sites by drainage or by applying locally grown plants. With the selection of resistance, new insecticides, and novel ap‐ proaches to vector control must be developed. Effective and sustained malaria vector control requires clear commitment from national authorities, including long-term support from funding partners [47]. Several malaria control programmes have fragmentary empirical

WHO [30].

158 Insecticides Resistance

The selection of insecticide resistance in malaria vectors has the potential to compromise effective control of vector-borne diseases. Resistance is defined as "the development of an ability in a strain of some organism to tolerate doses of a toxicant that would prove lethal to a majority of individuals in a normal population of the same species" [27, 29]. Alternatively, a resistant phenotype has been defined as an insect that survives a dose of insecticide that would normally have killed it [50, 51]. This heritable change in the sensitivity of a vector population is reflected in the repeated failure of a product to achieve the expected level of control when used according to the label recommendation for that disease vector species [52]. The biological phenomenon is a genetically inherited characteristic that develops as a result of selective effects of the relevant insecticidal compound or its analogue and increases in the vector population [15]. In mosquitoes, genetic and phenotypic resistance results from a mutation or gene duplication leading to the alteration of a normal physiology, morphology, or behaviour of the individual phenotype. In this regard, the sensitivity of the nervous system to the insecticide is reduced or the process of detoxification of the insecticide is enhanced. When an insecticide is applied, susceptible individuals are less likely to survive relative to the resistant individuals. The consequence is the propagation and exponential increase in the frequency of the resistance gene within the population over time [29].

Resistance is a multidimensional biological phenomenon that depends for its development on the interaction of multiple influences [27]. The evolution of insecticide resistance is complex and depends on several genetic, biological, and operational factors [53, 54]. The genetic factors include the intrinsic characteristics of the resistant genes (e.g., mono versus polygenic resist‐ ance, dominance, fitness cost, and gene interaction), while the biological factors relate to the life cycle of the insect (e.g., rate of reproduction, number of generation/offspring, and rate of migration and isolation). Behavioural/ecological encompass, migration in and out of exposed population, avoidance of the insecticide, effects of age and natural inducers on degradative enzymes, and endophagy/exophagy. Operational factors concern the treatment itself, includ‐ ing the method and frequency of application, dosage, and residual activity of the insecticides as well as insecticide coverage [55]. Among known and potential factors affecting the evolution of resistance, the operational factors are the only ones open to manipulation by man. Therefore, investigation on the development of resistance should ideally take into account of all these factors.

The level of resistance in insect populations is dependent on the amount and frequency of insecticides used, and the inherent characteristics of the insect species selected. Mosquitoes, for instance, are endowed with all attributes suited for rapid resistance development including high reproductive potentials and short life cycles producing several generations per season with abundant progeny [27, 52]. Mostly resistance in a particular species is considered to occur throughout the control area, but in reality, insecticide resistance can be focal in nature and is very heterogeneous even over very small distances. It often develops within a small part of the population of one species of *Anopheles* and assumes different patterns depending on the type of selection pressure [27]. In Guatemala, sampling sites for *Anopheles albimanus* only a few kilometres apart varied not only by presence or absence of resistance, but also by level of resistance and the mix of mechanisms responsible for resistance [56]. The WHO Global Technical Strategy for Malaria 2016–2030 highlights insecticide resistance as a major obstacle to achieving malaria control targets [57]. The current major emphasis in research into vector resistance is double pronged. The first approach strives towards understanding the molecular mechanisms underlying resistance with the view of developing novel vector-control methods that avoid or minimise resistance problems. The second approach to research involves rational resistance management, which is developing and implementing control methods that mini‐ mise the likelihood that vectors will evolve strong resistance to important insecticides [58].
