A History of Resistance in Mosquitoes

The Hunt for Long-Term Answers

The Aedes aegypti mosquito’s robustness and adaptability to domestic and urban environments has allowed it to spread worldwide. This is a serious matter since it is also one of the most significant vectors of human diseases, such as yellow fever, dengue, chikungunya and Zika. At the same time, traditional eradication methods are no longer as effective, mainly due to insecticide resistance. To improve global health, international researchers are working to better understand these resistance mechanisms in order to be able to develop effective solutions.

Science can, sometimes, make mosquitoes disappear. In 1904, when yellow fever and malaria were killing workers on the Panama Canal, researchers found a way to eradicate the vectors – mosquitoes. As there were no commercial insecticides available at that time, Chief Sanitary Inspector Joseph Augustin LePrince developed a larvacide mixture of carbolic acid, resin and caustic soda to fight mosquito larvae in the nearby waters. Other measures included grass cutting; draining or oiling of pools, ponds and swamps; and regular screenings in buildings and collecting mosquitoes from houses. For a ten-year period in the region, mosquitoes – and these diseases – were gone, and the canal was completed. The situation didn’t last, of course. In fact, the mosquitoes, and the diseases they carried, came back to the region with a vengeance. Still, scientists and governments in endemic regions have been, periodically, a step ahead of them. “The use of insecticides has played an essential role. At present, it is the most widely-used intervention method for reducing the populations of disease-transmitting mosquitoes,” says Dr. Lorenzo Cáceres Carrera, scientist at The Gorgas Memorial Institute for Health Studies (GMI) in Panama. While insecticides are needed to control vectors, the risk of over-using or even misusing them is high: After a period, their effectiveness could drop, and these disease vectors thrive. 

 

Dr. Lorenzo Cáceres Carrera, scientist at The Gorgas Memorial Institute for Health Studies (GMI) in Panama, reflects upon mosquito resistance to insecticides in Central America 

 

In 20th century Latin America, as insecticides developed, so did a vicious circle: For periods of time, regional mosquitoes seemed to disappear, but they eventually re-emerged as insecticide-resistant. Communities, then, faced a seemingly unstoppable vector. This has had devastating health consequences since malaria and an array of neglected tropical diseases (NTDs) – including dengue, filariasis, Zika and chikungunya – are carried by mosquitoes. “The emergence of resistance to different groups of chemical agents among pest and medically significant insect populations is one of the most serious undesired effects and technical problems in all parts of the world,” says Dr. Carrera. “Therefore, NTDs have continued to sicken and kill many people.”

 

 


All mosquitoes need water in which to complete their lifecycle. But not all mosquitoes prefer the same conditions. 

Some mosquito larvae develop in polluted or brackish water environments, and some prefer cleaner water. 

All sites of stagnant water – including swamps, drains, and even puddles and gutters –
can become hot spots for mosquitoes and need to be treated to control this vector. 


Central America: A Look at Past and Current Health Problems
In the Americas, selective pressure on mosquito populations through intensive, extensive and indiscriminate applications has led to the development of resistance to one or more major insecticides – including temephos, pirimiphos-methyl, deltamethrin and cyfluthrin. In Dr. Carrera’s report “Insecticide resistance in mosquito populations in Central America,” he explains the history of this development, back to the early 1960’s when the earliest known resistance research was conducted. 

 

Dr. Carrera notes the current rise of the incidence rate and prevalence of dengue in all tropical and subtropical endemic areas. There has also been a dramatic increase in cases in the Americas in recent decades. For Dr. Carrera, fighting mosquito populations is currently the only way to overcome the transmission of dengue. But there is a central problem: “Vector control programs in Central America are painfully lacking in resistance monitoring.” Following the re-emergence of dengue in the early 1990s, chikungunya in 2014 and Zika in 2015, most countries have turned their attention to health programs and, mainly, general vector control programs. The main tool remains the use of insecticides to prevent the transmission of these arboviruses. However, most of these countries lack effective control over populations of Aedes aegypti, and it has not been ruled out that resistance to different insecticides is the main cause of this problem.

 

Spotlight on Mexico

In 1962, Mexico was declared free of the mosquito Aedes aegypti, after eliminating the vector as part of yellow fever eradication. But by 1970, the eradication campaign was officially suspended due to the lack of political support, and Mexico became infested once more. By 1997, the distribution range of Aedes aegypti encompassed more countries in Latin America than prior to eradication. In Mexico today, control of dengue, chikungunya and zika continues to depend mainly on vector control to reduce mosquito population densities to a level where virus transmission is low enough to avoid epidemic outbreaks. 

 

“In most cases, resistance not only negatively affects the compound that is in use, but it also confers cross-resistance to other chemically-related compounds. This is because products from the same chemical group usually affect a common point of action, which is why it is considered that they share the same mode of action, as is the case of pyrethroids.”

Américo David Rodríguez, scientist at the Instituto Nacional de Salud Pública in Tapachula, Mexico

 

To achieve this status, environmental management methods can be used as well as the application of chemical or biological agents. “In Mexico, said measures mainly include the elimination of breeding grounds through social media campaigns for public awareness, larvae control by means of chemical and biological insecticides in non-disposable breeding sites, as well as the use of spatial application (ultra-low volume) and residual spraying insecticides to control adult mosquito populations,” states Américo D. Rodríguez, scientist at the Instituto Nacional de Salud Pública in Tapachula, Mexico. He and his research partners – R. Patricia Penilla Navarro, Alma D. López Solis, Francisco Solis Santoyo and Mario H. Rodríguez – presented their findings in their report “Development of insecticide resistance in the mosquito Aedes aegypti from Mexico and its related factors: from eradication to control.” Rodríguez concludes that “even with certain levels of resistance detected in mosquito populations, the use of insecticides is still being justified in many species of importance to public health.”

 


Space spraying of insecticides is an important measure to protect people from being bitten by disease-transmitting mosquitoes. The primary goal is to reduce the lifespan of the vectors and thereby reduce or interrupt disease transmission. 

Prevention team at work: This protective clothing shields human skin from drops of insecticide – to ensure a safe application. 

Insecticide spraying requires some basic equipment – and the availability of effective insecticide products.. 

Insecticides do not create resistance. Their resistant traits or ‘mutations’ are present in the insect population already at very low levels or appear randomly. Insecticides represent a selection pressure which allows resistant organisms to grow in numbers within a given population if the selection pressure is repeatedly applied. Testing a substance will show if it is killing mosquitoes effectively.

Treatment of a mosquito net with an appropriate insecticide improves the protective effect provided by the net. Otherwise, mosquitoes can bite through untreated nets if skin is adjacent to the netting material, or mosquitoes find holes in untreated, worn nets.

 

No Relief in Cuba and the Caribbean

In Latin America, several types of insecticides have been used for vector control. These include pyrethroids, which have been the most frequently used since the 90s. A research group at the Instituto de Medicina Tropical “Pedro Kourí” (IPK) in Havana, Cuba, has specialized on studying insecticide resistance in Cuba and the Caribbean. “In October 1981, at the end of the dengue epidemic, a campaign to eradicate the Aedes aegypti mosquito was carried out. The most widely-used insecticide was organophosphate malathion,” explains Dr. Juan Bisset Lazcano, Biologist and Head of Vector Control Department at the IPK. “As a result, the species was almost completely eradicated. However, due to the high selection pressure, the density of the southern house mosquito population – the Culex quinquefasciatus mosquito – began increasing. It had developed resistance to malathion.” This situation led to starting the use of cypermethrin in 1986, the first insecticide formulated using pyrethroid. 

 

Today, the Aedes aegypti mosquito has developed resistance to the active ingredients of different groups of insecticides – including organochlorines, organophosphates, pyrethroids and carbamates – in countries across the region. In their report, “A history of insecticide resistance in Cuba and the Caribbean, and the impact of rotation with pyrethroids, carbamates and organophosphates,” the IPK researchers explain the results of a study carried out with Aedes aegypti in Jamaica, Costa Rica, Panama, Nicaragua, Peru, Venezuela and Cuba. “We have revealed which mosquitoes and which larvae showed resistance to which specific insecticides,” summarizes Domingo Montada Dorta, Head of Chemical Control Laboratory at the IPK. Overall, resistance measures in larvae and adults to the same insecticides may differ, indicating that the mechanisms selected in larvae are not necessarily going to be manifested in adults.

 

Domingo Montada Dorta, Head of Chemical Control Laboratory at the IPK 

 

Resistance – a Multifactorial Phenomenon

The Instituto Nacional de Salud Pública in Mexico currently recognizes three types of factors that are affecting the development of resistance: genetic, biological and operational. Genetic factors are related to the frequency, number and dominance of the alleles related to resistance, among other important aspects. Biological factors consist of biotic aspects, mainly related to the reproduction potential and populational behavior of insects. The operational factors are the chemical agents and their application. The genetic and biological factors are intrinsic to the species and, therefore, cannot be changed. However, it is important to have a knowledge of their role as researchers can use this information to evaluate the likelihood of resistance in an insect population. Operational factors can be controlled through insecticide management programs.

 

Why Does Resistance Occur?

The experts in Mexico conclude that the development of resistance in Aedes aegypti is likely the result of a combination of factors. These are both intrinsic, given the highly domestic characteristics of the species, and operational, based on the manner of application. “The nature and formulation of the insecticide also play a major role. As well, there is a lack of migration of susceptible genes, due to the small dispersion of this species, on the one hand and, on the other, the lack of refuge of said susceptible genes when undertaking applications that broadly cover areas with arbovirus transmission problems,” explains Américo D. Rodríguez.

 

The research group concludes that it would be ideal to have other control tools and to depend less on the use of insecticides, or not risk so much on the success of spatial spraying outdoors. Rodríguez urges the continued promotion of improved vigilance, so a better system can be developed, such as one which focuses on indoor chemical control actions. “It could be by means of ultra-low volume (ULV) spraying – cold or thermal – where part of the insecticide impacts the front of the house and one part enters it, while the other part of the cloud moves toward the back patio over the roof of the house. Or it could be by means of residual spraying, using faster application equipment.”

  

 

In all of the investigations carried out in Central America and the Caribbean, the Aedes aegypti populations have developed resistance to one or more insecticides. These experts agree that there are different contributing factors. “When it comes to resistance, the cause, intensity and importance in the fight against disease vectors can vary greatly. It is a dynamic phenomenon that appears over very variable time lapses,” says Dr. Carrera. “It is well-known that resistance appears more slowly in some species than in others. Even in the same species, under certain conditions, resistance can develop rapidly, while under other conditions it evolves more slowly or simply never appears.” Resistance mechanisms occur in different species and in the same species when subjected to different intensities of insecticide application. 

 

Strategies Include Integrated Policies

As Dr. Carrera points out, “Research studies carried out in the different countries are very specific, and they do not follow one resistance monitoring policy, program or plan established by the vector control programs in each of the countries.” This situation calls for improved monitoring: This requires national policies for the correct use of insecticides; technicians with proper training about the use of susceptibility to bio-assay tests; and better equipment, supplies, laboratories, insectariums and work with universities, institutes and research centers that participate and offer support for the best use of insecticides as well as the monitoring and management of resistance. Adds Dr. Carrera, “There is a need for health programs and the companies that produce insecticide molecules and formulas, as well as the companies that manufacture and distribute equipment for the application of insecticides, to develop a closer and continuous relationship in order to optimize the use of the insecticides.”

 

 

 

To do its part, Bayer is already building a strong network with non-profit organizations like the Integrated Vector Control Consortium (IVCC) in the UK and the Institute of Medical Research (IMR) in Malaysia. As well, pooling knowledge in research is crucial: “Depending on the region of the world, even in the same country, resistance may develop at different speeds. The reasons for that are not clear yet,” says Frédéric Baur, Global Market Manager for Vector Control with Environmental Science at Bayer in Lyon, France. “We are working with different experts from everywhere in the world to try to understand with them what makes a certain strain of mosquito develop resistance quicker than other strains: Is it the poor quality of the insecticide application or something within the mosquito itself?” Baur explains that sometimes, when a product shows little effect, it is not actually a sign of resistance but the result of incorrect application. 

 

“Depending on the region of the world, even in the same country, resistance may develop at different speeds. The reasons for that are not clear yet.”

Frédéric Baur, Global Market Manager for Vector Control with Environmental Science, at Bayer in Lyon, France

 

It is important to bear in mind that there are few molecules and formulations available in the public health sector; at the same time, developing a new insecticide molecule takes companies time due to many factors, including the process for registration of new insecticides, intensive testing to ensure the safety of products for humans, the environment and non-target organisms, as well as the high costs involved. “To avoid the development of resistance in the first place, we advise rotation of insecticide modes of action, combination of interventions, mosaic spraying and/or use of insecticide mixtures,” explains Baur. Through closer cooperative efforts, and funding for research, everyone involved in resistance research will help protecting and prolonging the useful life of the efficiency of insecticide molecules. Effective vector control is the best help: “Diseases are not only words – they are pain, and they cause suffering,” says Baur. “Preventing them in the first place is a huge saving for individuals, communities and governments.” 

 

 

 

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