Pyrethroid susceptibility reversal in Aedes aegypti: a longitudinal study in Tapachula, Mexico

Pyrethroid resistance in Aedes aegypti has become widespread after almost two decades of frequent applications to reduce the transmission of mosquito-borne diseases. Because few insecticide classes are available for public health use, insecticide resistance management (IRM) is proposed as a strategy to retain their use. A key hypothesis of IRM assumes that negative fitness is associated with resistance, and when insecticides are removed from use, susceptibility is restored. In Tapachula, Mexico, pyrethroids (PYRs) were used exclusively by dengue control programs for 15 years, thereby contributing to selection for high PYR resistance in mosquitoes and failure in dengue control. In 2013, PYRs were replaced by organophosphates—insecticides from a class with a different mode of action. To test the hypothesis that PYR resistance is reversed in the absence of PYRs, we monitored Ae. aegypti’s PYR resistance from 2016 to 2021 in Tapachula. We observed significant declining rates in the lethal concentration 50 (LC50), for permethrin and deltamethrin. For each month following the discontinuation of PYR use by vector control programs, we observed increases in the odds of mosquitoes dying by 1.5% and 8.4% for permethrin and deltamethrin, respectively. Also, knockdown-resistance mutations (kdr) in the voltage-gated sodium channel explained the variation in the permethrin LC50s, whereas variation in the deltamethrin LC50s was only explained by time. This trend was rapidly offset by application of a mixture of neonicotinoid and PYRs by vector control programs. Our results suggest that IRM strategies can be used to reverse PYR resistance in Ae. aegypti; however, long-term commitment by operational and community programs will be required for success. Author summary The mosquito Aedes aegypti is the principal urban vector of the viruses that cause three globally significant diseases: dengue fever, chikungunya, and Zika fever, for which vaccines and effective treatments are currently absent. The only way to control dengue, chikungunya, and Zika fever outbreaks is to diminish vector populations. During epidemics, the most frequent way of targeting adult mosquitoes is outdoor spatial spraying of insecticides. Control of Ae. aegypti is difficult because limited insecticide classes are available for public health, leading to operational practices that overuse single molecules for long periods of time, imposing great selection pressure on mosquito populations for insecticide resistance. Insecticide resistance management (IRM) is proposed as a strategy to prevent resistance and avoid depleting the susceptibility resource in mosquito populations. IRM strategies assume that alternation of insecticides with different toxicological modes of action will prevent the selection of resistance. Unfortunately, very few field evaluations have reported IRM schemes to control Ae. aegypti. In our study, the exclusive use of pyrethroids in vector control programs in Mexico from 1999 to 2013, led in the selection of knockdown resistance (kdr) to pyrethroid insecticides. To address this issue, vector control programs temporarily phased out pyrethroids from 2013 to 2019, substituting them with an insecticide class with a different mode of action: organophosphates (OPs). During six years, we monitored pyrethroid resistance in 24 mosquito populations from Tapachula, Mexico. We show that discontinuing pyrethroids for six years led in pyrethroid resistance reversal in Ae. aegypti in the field. However, high levels of pyrethroid resistance continue to jeopardize operational application, necessitating longer periods of pyrethroid cessation and novel IRM strategies to achieve lower resistance thresholds.