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Should we declare a state of emergency?

February 5, 2015 - 21:38 -- Bart G.J. Knols

Last week the Roll Back Malaria Vector Control Working Group organised its 10th meeting in Geneva. Close to 200 vector control specialists from more than 30 countries attended the three-day event. What started as a small gathering years ago has grown to become what could be considered the equivalent of the annual ASTMH meeting but with an exclusive focus on vectors. And although this 10th meeting was ample reason for celebration, it wasn't. The meeting was officially addressed by WHO's Global Malaria Programme Director Dr. Pedro Alonso, who recently took office. His opening statements were clear: Insecticide resistance is as much a threat to continued successful malaria control, if not more, than the current Asian threat of artemisinin resistance. Pyrethroids were great and have undoubtedly saved many thousands of lives, but the era in which we could safely rely on them, is coming to an end. And that's bad news.

Pyrethroids, after all, are the only class of insecticide that is currently recommended by WHO for bednet impregnation. We have nothing else that is as safe as this class of chemicals. Bednet manufacturers, however, have developed nets with dual treatments. But these have not yet received the full label of approval from WHO.

Meanwhile, the map of Africa is now littered with red dots. Dots that indicate some level of resistance in malaria vector populations. But that's not all. Apparently the intensity of resistance is on the rise. Where there was 2-fold resistance in certain West African strains years ago, this has risen to 1000-fold resistance. Evolution is doing its work in front of our very eyes. On top of that, hybrids between different forms of mosquitoes in Mali have been reported recently as 'super bugs', again laughing at pyrethroids. This study was apparently of such big impact that even TIME magazine wrote a story on it.

These developments caused arousal in the audience. There was even a suggestion to declare a state of emergency. Perhaps we should, and if we don't do so now, we will in the near future. Should we be surprised that we ended in this situation? No.

Malaria vector control has been relying on monotherapy. Spraying of a single chemical and treatments of bednets with one pyrethroid. Where combination therapy for treatment of malaria entered the public health arena and became standard practice already back in 2002, in vector control we still rely on single chemicals.

Obviously participants suggested to move away from monotherapy in vector control as soon as possible. But will combination therapy bring us what we need or is this merely buying us time before evolution once more catches up with us?

Interestingly, Prof. Norbert Becker presented amazing data during his talk in the larval source management working stream session. He showed convincing data that in spite of 35 years of use, mosquito larvae in the German Rhine Valley have not developed the least bit of resistance to Bacillus thuringiensis israelensis (Bti). A biological control agent that attacks mosquito larvae after ingestion by producing at least four toxins. So what does this tell us?

First, that combination therapy works if conducted well. Four toxins from a biological control agent are superior to individual chemicals many to which larvae have developed full-blown resistance (e.g. temephos, used against Aedes in many countries).

Second, that the mere development of new insecticides will deliver the same result as what we see today. More resistance problems. Even if new chemicals will be used wisely and according to resistance management plans, we can bet that there will be problems. Unless we start combining two of them, but preferably more. But getting cocktails of chemicals approved for public health use will undoubtedly be a long and tedious route to take. Human safety first.

Of the various chemical industry companies present in the meeting, such as Bayer and BASF, several have realised the problems with over-reliance on chemicals. In their agricultural pest control products portfolio, they have shown increased interest for biological options. But for vector control no such thing has emerged.

This is surprising. After all, besides Bti various groups around the world have been working for over a decade on entomopathogenic fungi for adult malaria mosquito control. And have shown that it would take many decades before any possible resistance might emerge. So why aren't we using it?

The criticism originates from the fact that we don't want to work with anything that has less than 6 months of residual activity after application. At least, that is the official 'gold standard'. In spite of this, apart from DDT perhaps, only few of the currently recommended insecticides for indoor residual spraying remain active for this period. One of the presentations in the meeting showed that bendiocarb only lasted for 1-2 months on certain wall types.

Fungal spores can remain viable for 2-3 months, so can exceed the residual activity of bendiocarb. Could we increase the residual activity of fungi? Most certainly. So why don't we?

Getting a strain of fungus that will remain viable for longer periods is a matter of selecting for it and developing the right formulation to apply it. This requires funding of course, but perhaps more importantly, the confidence in our vector control community that this can be done and that biologicals against adult mosquitoes can become an important tool in the future.

In my country, The Netherlands, pest control in greenhouse crops in the 1980s was almost entirely based on spraying of chemicals. In spite of an intense lobby by pesticide manufacturers, those that developed biologicals got a fair chance (read: funding). It took less than two decades to reach the state whereby more than 95% of all pest control in greenhouses was based on biologicals. Greener, safer, without risks of insecticide resistance.

What are we waiting for? 




Ole Skovmand's picture
Submitted by Ole Skovmand on

dear Bart
first, there is still no documentation to my knowledge that shows that the pyrethroid resistance has a signficant impact on transmission. There are several reasons for this: kdr resisant mosquitoes sit longer on a pyrethroid net, so even they will show good survival in 3 min cone test, this is irrelevant, because they will search on the net till they get repelled, meaning till they have collected enough insecicide to overcome their resistance. Secondly, mixed function oxidase is age dépendent, it works a lot better in Young mosquitoes (that are used for resistant testing) than in in old mosquitoes, and only the old ones transmit malaria. Old ones are also more likely to bite indoor, so all in all, there is probably good reason that the impact on malaria transmission is limited.
That said, I agree with you that it is high time that biologicals get a chance, especially Bti with its 4 toxins. The Bti story is better than that. The biggest of the four in percentage is the 28 Kda toxin that can serve as a binding site for the other toxins and its binds to any cell surface. Resistanc mechanisms against Bt toxins is often a change in the binding site molecule, so the toxin no longer binds and therefore never makes the pores in the target cells. The 28 kda protein prevent this mechanism, which is why laboratory developed resistance to thet other toxins do not work against the full Bti cocktail
Finally, I do not like the monotherapy terminology, though tempting. Pbo is not an insecticide in the dosage used, so a pyr-pbo combination is not a combination of two insecticides, it is a combination where the mixed function oxidase is blocked by a better binding to pbo than to the pyr plus pbo has some penetrating accelerating activity for fat soluble insecicides. Still, toxicity rely on the first insecticide and target mutations are not influenced by pbo. If you want to compare a pbo combination with something from the medical world, it should be a vaccine booster, not two medical products with different mode of action