Ivermectin Resistance and Cross-Resistance with Current Insecticides in Malaria Vectors: Potential Mechanisms and Implications for Vector Control in Sub-Saharan Africa

Ivermectin has emerged as a promising complementary tool for malaria vector control in sub-Saharan Africa (SSA). Its primary target, in Anopheles mosquitoes, the glutamate-gated chloride channel, and its systemic insecticidal mechanism distinguish it from current contact-based insecticides, to which resistance is now widespread. However, prolonged use of ivermectin mass drug administration in neglected tropical disease control programs and use in veterinary programs in SSA may have exerted sub-lethal selective pressure on malaria vectors. Concurrently, there are concerns about cross-resistance with current insecticides, particularly in settings where metabolic resistance is already established. This review examines the potential development of ivermectin resistance and cross-resistance between ivermectin and the current insecticides. We synthesize evidence from existing studies to highlight possible cross-resistance pathways mediated by cytochrome P450s, detoxification enzymes, ATP-binding cassette transporters, shared regulatory mechanisms and microbiome interactions. Finally, we discuss the operational implications for integrated vector management in this setting and identify priority research areas that will help mitigate cross-resistance risks and sustain the efficacy of ivermectin as a malaria vector control tool.