Public Health Journal 18 (2007) by Bayer Vector Control

Public Health Bayer Environmental Science Journal

INSECTICIDE RESISTANCE Resistance against insecticides is an increasing challenge wherever diseases are transmitted by arthropod vectors. Many factors need to be considered to successfully implement effective long-term resistance management.

No. 18 November 2006

CONTENT

Editorial Column: Christian Verschueren

Why effective insecticide resistance management is important

COVER STORY Important aspects to be considered in arthropod pest management.

Insecticide resistance in public health pests

A challenge for effective vector control

by Ralf Nauen R E S I S TA N C E M A N A G E M E N T

Pyrethroid resistance in malaria vectors

Operational implications in Africa

by Pierre F. Guillet

Insecticide resistance management in a multiresistant malaria vector scenario

A Mexican trial shows sustainability

by A.D. Rodriguez, R.P. Penilla, M.H. Rodriguez, J. Hemingway

Combatting resistance to insecticides in malaria control

Gains made in India by A.P. Dash, K. Raghavendra, M.K.K. Pillai

30 2

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CONTENT

Malaria control on Bioko Island, Equatorial Guinea

Surpassing original targets

VECTOR CONTROL

Chikungunya outbreaks in Indian Ocean islands

Mosquito-borne viral disease by Michael B. Nathan

Ethiopia: Support from UNICEF in the fight against malaria

Focus on distributing insecticidetreated nets

NGO

Non-governmental organizations

Their help is increasingly important

NGO Profile: PSI

Success with measurable health impact

Interview with Desmond Chavasse on page 56

Aid project in the Ssese Islands

Mosquito nets for orphans Notes CD-ROM Cover photo: Corbis

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57 58 63

KEY FACTS

Biochemical target sites Nerve transmission

Fenthion O

OM e OM e P S

Organophosphates & Carbamates Bendiocarb

AChE

HN O

O O O

MACE

Abbreviations: AChE = Acetylcholinesterase Ach = Acetylcholine ChAT = C MACE = Modified Acetylcholinesterase kdr = knock-down re

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of synthetic insecticides ONLY FOUR different chemical classes of synthetic insecticides are used to treat adult mosquitoes: organochlorines, organophosphates, carbamates and pyrethroids. These insecticides act on two different target sites with three modes of action: organophosphates and carbamates induce phosphorylation and carbamylation. Both inhibit acetylcholinesterase, an enzyme of crucial importance in terminating nerve pulses. Synthetic pyrethroids and DDT are modulators of voltage-gated sodium channels and in most cases with fast knock-down properties.

Deltamethrin O Br

CN O

O Br

Pyrethroids & DDT

vg-Na+ channel kdr

Choline Acetyl-Transferase esistance

Cl Cl

DDT

vg-Na+ channel = voltage-gated sodium channel

Available as poster on the enclosed Public Health CD-ROM PUBLIC HEALTH JOURNAL 18/2006

EDITORIAL

Dear Readers, Insecticide resistance is an overall issue concerning not only pests in agriculture, but also disease transmitting vectors and other insects important in public health. These PASCAL HOUSSET include flies, cockroaches, fleas, bedbugs, Chagas bugs, Head of sandflies â&#x20AC;&#x201C; and especially mosquitoes. The problem is Bayer Environmental Science particularly severe in vector control because although the agricultural industry has put new insecticides on the market, no new active ingredient classes are suitable for targeting adult mosquitoes. This means we have to live with the tools we have and to use them responsibly and carefully. Many of the articles in this issue of the Public Health Journal No. 18 describe strategies for managing malaria vector control in the face of growing insecticide resistance. The reports come from Africa, Mexico, India and other regions where the burden of malaria and other insect-borne diseases is still a major health problem and a cause of poverty. The articles by various experts in the field emphasize the importance of resistance monitoring, rotation or mosaic spraying schemes to delay or avoid resistance development. One cornerstone is the introduction of bendiocarb for indoor residual spraying in cases where pyrethroid and DDT resistances are already presenting operational challenges. Insecticide Resistance Management (IRM) has become an important part of the strategy of Bayer Environmental Science. We are pursuing this with the support of many institutions such as national health authorities, academia and the WHO. Besides our main theme of Insecticide Resistance Management we also focus on other themes in this edition â&#x20AC;&#x201C; such as the recent chikungunya outbreaks. We have also started a new feature series where we highlight the important contribution of non-profit organizations (NGOs) in efforts to combat public health issues. We wish you pleasant reading.

Pascal Housset

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Dr Christian Verschueren

Why effective insecticide resistance management is important Dr Christian Verschueren is the Director General of CropLife International*. In the following article he explains how the effective management of invertebrate pest populations important in public health, veterinary, agricultural and horticultural issues depends on a variety of inputs. One major area is the use of efficacious synthetic insecticides according to the principles of Integrated Pest and Vector Management. or over half a century the responsible plant science industry has strived to develop products to meet the increasing global demands for improved public health and the availability of food and fiber. A key challenge for the industry has thus been to expand the toolbox of available products by maintaining a steady flow of new, ever-more effective insecticides with novel modes of action that also meet the increasingly stringent regulatory standards for human and environmental safety.

It has proved equally challenging to protect and maximize the benefits of developing new insecticides by maintaining the effective life of these products in the field. This is because with their abundant numbers and generally short life-cycles, pest insects under continuous selection pressure can develop resistance to the insecticides used against them. By 2005, the number of species of insects that had developed resistance to one or more groups of insecticides was estimated to be well over 500. More recently, a number of pest species of public health importance have evolved resistance, as insecticide use in these sectors has expanded. Moreover, a number of cases of insecticide resistance are currently critical with some key species having few or no available effective classes of insecticide available. Given the inherent ability of

insect populations to evolve resistance, it is imperative to develop and implement effective insecticide resistance management (IRM) strategies at an early stage in the commercial life of an insecticidal product, so that resistance is prevented or delayed. Similar strategies may be employed to solve existing resistance problems, although it is acknowledged that it is much easier to proactively prevent the development of resistance than it is to solve resistance problems once they have developed. Effective IRM is vital and one of the most challenging issues in modern applied entomology. This is illustrated by the fact that insecticide resistance issues are central to manâ&#x20AC;&#x2122;s efforts to control major vector-borne diseases and improve agricultural production. The socio-economic burden associated with tropical diseases such as malaria, dengue, filariasis and trypanosomiasis is a serious impediment to development in many tropical countries, and most of these diseases are not

* CropLife International is a global federation representing the plant science industry and a network of regional and national associations in 91 countries. www.croplife.org

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only major health concerns but also a major cause of poverty. It is estimated that malaria alone has reduced the gross national product of the African continent by more than 20% over the past 15 years. Vector-borne diseases account for a very significant part of total morbidity due to infectious diseases, and occur not only in the tropics but also in many temperate countries. Recent estimates indicate that, annually, there are 300-500 million clinical cases of malaria, leading to more than one million deaths, mostly children. In high-transmission areas (which include most parts of Africa) malaria incidence cannot be reduced if, in parallel with early diagnosis and treatment, transmission is not controlled through very effective vector-control and/or personalprotection interventions. Accordingly, insecticides remain the most important element of integrated approaches to vector control. Although public health accounts for only a very small fraction of overall insecticide quantities applied, many vector species of public health importance have already developed resistance to one or more insecticides.

â&#x20AC;&#x153;

The massive efforts currently developed to control malaria, especially in Africa, may be jeopardized by the widespread development of pyrethroid resistance due to the permanent exposure of adult mosquitoes to this class of insecticides.

â&#x20AC;?

While the use of IRM strategies employing a number of compounds with different modes of action is ideal, the control of adult mosquitoes depends entirely on insecticides with just two target sites in the insect nervous system (see diagram on cover flap). The loss of useful compounds and the development of widespread resistance to existing compounds highlight the urgent need for a new mosquito adulticide. New technologies such as insecticide-treated bed nets (ITNs) and insecticide-treated materials (ITMs) are now highly promoted and used to

protect particularly children and pregnant women. However, ITNs still remain highly dependent on a single class of insecticides: the synthetic pyrethroids. It is also important to understand that almost all public health insecticide classes are also used in agriculture. When vectors breed within or close to agricultural crops, they can be exposed to the same or similar insecticidal compounds and develop resistance. This phenomenon is of particular relevance for malaria vectors. Such considerations underline the importance of resistance experts in both sectors working together to manage resistance. At one time it was believed that the industry could always invent ways out of resistance problems by developing new insecticides with novel modes of action which would be unaffected by pre-existing resistance mechanisms. Such an approach assumed that an endless supply of such new compounds was possible, and that it was acceptable to use new insecticides indiscriminately until they failed. Modern, more enlightened approaches acknowledge that it is hugely expensive, very time-consuming and not at all easy to develop new insecticides. Estimates from CropLife America and the European Crop Protection Association (ECPA) in 2003 suggest that the cost of developing a new active ingredient is US$ 185 million. Registered compounds should therefore be regarded as valuable resources, and protected from resistance developing to them. An essential feature of modern, successful IRM strategies is the availability of a toolbox of insecticidal compounds with a broad range of modes of action. Experience has shown that all effective insecticide resistance management strategies work by reducing the selection for resistance from any one type of insecticide or mode of action. This can be achieved by various means including the use of sequences, alternations, rotations, mixtures or mosaics of insecticides. The major manufacturers of insecticides are all committed to good product stewardship to

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Photo: Elisabeth Friedrich

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sustain and prolong the effective commercial life of their products. The development and implementation of successful IRM strategies form a key part of this effort. The knowledge gained from research studies on resistance helps to sustain valuable effective products in the market place. Depending on the individual resistance management issues concerned, companies may collaborate to harmonize the IRM requirements for compounds from a single mode of action group, even though they are developed and marketed by different companies. This is vital if growers and pest control professionals are to understand the IRM strategies they are required to implement at a practical level. At an all industry level, the Insecticide Resistance Action Committee (IRAC) is a Specialist Technical Group under the umbrella of CropLife International. IRAC is also recognized by The Food and Agriculture Organization (FAO) and the World Health Organization (WHO) of the United Nations as an advisory body on matters pertaining to resistance to insecticides. The group’s activities are coordinated by the IRAC International Committee, and Country or Regional Committees with the information disseminated through conferences, meetings, workshops, publications, educational materials and the IRAC

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Website (see page 29). IRAC International is comprised of key technical personnel from the agrochemical companies affiliated with CropLife through membership in the relevant National Associations (ECPA, CropLife America, etc). Current member companies are BASF, Bayer CropScience, Dow AgroSciences, DuPont, FMC, Sumitomo and Syngenta. The International Committee supports resistance management project teams and also provides a central coordination role to regional, country and technical groups around the world. More recently, much attention has been focused on the need for effective vector control, highlighted by the development of widespread resistance to the key insecticide classes used for vector control. To tackle this problem WHO, the Innovative Vector Control Consortium (IVCC) funded by the Bill & Melinda Gates Foundation and IRAC are joining forces. IRAC has responded recently by forming a specialist Public Health Team to work with these bodies and to provide the technical inputs necessary to help combat insecticide resistance in key vector species. One of the IRAC Public Health team’s first actions has been to develop a manual on the ‘Prevention and Management of Insecticide Resistance in Vectors and Pests of Public Health Importance’. Clearly, the manufacturers of insecticides put great efforts into sustaining the effectiveness of their products and avoiding resistance problems. As indicated earlier, this is done not only as a part of responsible product stewardship, but also because susceptibility to particular modes of action is valuable, and once lost they may be hard or impossible to recover. Strict adherence to IRM guidelines and application requirements, consultation with local IRM experts and integration of good integrated crop and pest management systems will help preserve susceptibility.

This column is an excerpt from a longer article by Dr Christian Verschueren. You can find the whole article on the enclosed Public Health CD-ROM.

Photo: Iconotec

Photo: Flat Earth

Photo: Corbis

INSECT-BORNE DISEASES are a problem worldwide, made worse by increasing resistance of the vectors to insecticides. To control chagas disease in Bolivia, malaria in Africa or sandflies in the Middle East, which transmit leishmaniasis, it is essential that resistance management strategies are implemented.

Photo: Tobias Gremme / Das Fotoarchiv

A challenge for

PUBLIC HEALTH JOURNAL 18/2006

COVERSTORY

Insecticide resistance in public health pests

effective vector control How resistance emerges, what mechanisms are involved, what is done to monitor resistance and what are possible options to manage insecticide resistance. These are essential aspects in dealing with disease-transmitting insect pests in Public Health.

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n public health many diseases are WHO, regulatory bodies and the transmitted by arthropod vectors, public sector) as an issue that needs e.g. mosquitoes (malaria, dengue a proactive approach. In this direcfever, yellow fever, encephalitis, tion the Insecticide Resistance filariasis, West Nile fever and chikunAction Committee (IRAC) coordigunya), ticks (e.g. Lyme disease) and nates a private sector response to sandflies (leishmaniasis). It has been either preventing or at least delaying The author: demonstrated in the past that the use the development of insecticide Dr RALF NAUEN of insecticides can dramatically reduce resistance. IRAC not only facilitates Chairman IRAC Public Health Working Group, the risk of insect-borne diseases. This communication and education on all Bayer CropScience is well documented by the WHO and aspects of insecticide resistance, but in numerous scientific investigations and reports, also promotes the development of resistance particularly concerning the most widespread and management guidelines (see page 29: IRAC). important disease, malaria. How resistant populations develop Serious threat of insecticide resistance Frequent applications of the same insecticide will Since the introduction of synthetic insecticides to select for those individuals in a population that are control arthropod pests the selection pressure on able to survive recommended levels of the populations has increased drastically, with many compounds due to a stable genetic change. If one species developing mechanisms to withstand does not switch between different modes of action insecticide treatments. There is little doubt that (or chemical classes) in application regimes, the number of less susceptible individuals will increase. Over a certain period of time (it may Insecticide resistance is defined as a heritable take months or even years) such one-sided insecchange in the sensitivity of a pest population ticide administration will result in a resistant that is reflected in the repeated failure of a population. This is even more likely if combined product to achieve the expected level of control with high reproductive potentials and short life cycles producing several generations per season. when used according to the label recommen-

dation for that disease vector species. insecticide resistance has evolved to all classes of insecticides and is counteracting the control of many invertebrate pests of agricultural importance, disease vectors and other insects important in public health. The list of public health pests resistant to insecticides has been growing for decades and includes disease vectors such as many known mosquito species, fleas and ticks, as well as cockroaches, bedbugs, houseflies and more recently also Chagas bugs and sandflies.

Complicated by cross-resistance In most cases a resistant pest population usually also shows resistance to other compounds within the same chemistry class, e.g. resistance against one pyrethroid usually results in resistance against the whole group of pyrethroids. This is known as cross-resistance. Sometimes, depending on the nature of the resistance mechanism, cross-resistance may even arise between chemical classes, e.g. organophosphates and carbamates (see Fig. 2 page 14: Major biochemical mechanisms of resistance).

Insecticide resistance is viewed as an extremely serious threat in crop protection and vector control, and is considered by many parties (industry,

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COVERSTORY

Furthermore, resistance development due to selection pressure in disease vectors is complicated by an additional (sometimes neglected) aspect: frequent application of similar synthetic insecticides to control important agricultural pests may indirectly affect the susceptibility of insects important in public health. Surveillance is essential Once insecticide resistance is established in a population it can profoundly affect public health by the possible reemergence of vector-borne diseases. When resistance is monitored in suspected cases it is often too late. Focusing on surveillance wherever possible is essential in order to react proactively as soon as a regional population seems to be changing its susceptibility towards synthetic insecticides. For this purpose the WHO has published numerous monographs on methods to ensure the surveillance of resistance development to many different insecticides, e.g. by diagnostic dose bioassays for mosquitoes (see list of monographs on www.who.int). A diagnostic dose tested in insecticide-coated glass vials

usually provides 100% mortality of a susceptible population within one hour. In contrast, resistant populations survive such doses, at least to a certain extent. Insecticide classes are limited Another major aspect in terms of selection pressure on important public health insect species is the fact that only a limited number of insecticide classes are available. Only four different chemical classes of synthetic insecticides are (or have been) used to treat adult mosquitoes, i.e. organochlorines, organophosphates, carbamates and pyrethroids. Even the original compound (permethrin) of the synthetic pyrethroids has been available for more than 30 years (see Fig. 1 below). It is important to note that these four chemical classes address only three different modes of action. Therefore, there is much less target-site diversity for the control of public health pests (see diagram on cover flap) than in the agricultural sector. In principle, all insecticidal classes have their biochemical target sites in the insectâ&#x20AC;&#x2122;s

Insectides for mosquito control WHO approved insecticides

Years 1940-45

DDT

1946-50

Lindane

1951-55

Malathion

1956-60 1961-65

Fenitrothion

1966-70

Chlorpyrifos-methyl

1971-75

Pirimiphos-methyl

1976-80

Cypermethrin

1981-85

Alpha-cypermethrin

Propoxur Bendiocarb

Permethrin

Only a limited number of insecticide classes are available for adult mosquito control. No new malaria mosquito adulticide has been approved by the WHO in the last 15 years.

Cyfluthrin

Lambda-cyhalothrin Deltamethrin Bifenthrin 1986-90

Etofenprox

1991-95 1996-00 2001-05 Organochlorines Organophosphates

Carbamates Pyrethroids

Fig. 1 PUBLIC HEALTH JOURNAL 18/2006

COVERSTORY

central nervous system, i.e. cholinergic nerve transmission, which is one of the reasons why they act quite rapidly. Pyrethroids have excellent properties Insecticide classes used to control adult mosquitoes as malaria vectors have to meet specific requirements, i.e. excellent contact action, a rapid knock-down effect and selective toxicology. This is why the pyrethroids in particular were most successfully used in mosquito control over the last decades, with economic values of ca. 60% and 80% in residual use and space spray, respectively. Due to their excellent properties they account for 100% of global bednet treatments. Adding up all these numbers one could easily imagine that the pyrethroid selection pressure on many pests of importance in public health is considerable, particularly on malaria vectors. The risk of resistance development to pyrethroid insecticides in mosquitoes is therefore quite high.

Behavioral resistance Insecticide resistance in mosquitoes is not always based on biochemical mechanisms such as metabolic detoxification or target-site mutations, but may also be conferred by behavioral changes in response to prolonged spraying programs. Behavioral resistance does not have the same importance as physiological resistance, but can be considered a contributing factor, leading to the avoidance of lethal doses of an insecticide. A behavioral response is either dependent or independent on a stimulus. If mosquitoes avoid a treated place due to sensing the insecticide it is considered to be a behavioral change dependent on a stimulus, whereas the selective occupation of an untreated area can be considered a stimulus independent response.

Mechanisms of resistance Extensively studied in the past, resistance mechanisms in mosquitoes can be divided into two groups, metabolic (degradation of the active ingredient by detoxification enzymes) and targetsite resistance (mutations in the target proteins). Both mechanisms can be quite specific, although there is a tendency for metabolic mechanisms to be more versatile with regard to cross resistance between chemical classes. A compilation of the major mechanisms of resistance and their respective importance for the different chemical classes used in malaria vector control is given in Figure 2 (see page 14: Major biochemical mechanisms of resistance). Resistance to pyrethroids and organochlorines Mosquitoesâ&#x20AC;&#x2122; resistance to pyrethroids and DDT is either conferred by a mutation in the voltagegated sodium channel (kdr) or by elevated levels of microsomal monooxygenases. Several monooxygenase genes have been associated with pyrethroid resistance, particularly relating to permethrin. DDT resistance is also specifically conferred by the so-called DDT-dehydrochlorinase, a glutathione S-transferase. In addition, rdl (resistance to dieldrin, a mutation in the GABAgated chloride channel) results in resistance to organochlorines other than DDT. In contrast to pest insects of agricultural importance, esterases have not yet been shown to play a major role in conferring pyrethroid resistance in mosquitoes. Resistance to organophosphates and carbamates In contrast to pyrethroids, over-expression of esterases by gene amplification provides considerable organophosphate (and to a certain extent carbamate) resistance in mosquitoes. This has been reported as an evolutionary response to selection by organophosphates and carbamates. A second mechanism of importance is MACE. Both organophosphates and carbamates are

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affected by this target-site mutation in acetylcholinesterase. Monooxygenases only play a minor role in organophosphate and – if any – in carbamate resistance. Monooxygenase-based cross resistance to carbamates has been described as unusual in mosquitoes. It was only reported for propoxur as a notable exception, whereas bendiocarb against the very same mosquito strains gives excellent control at diagnostic doses. This is likely to be due to the structural uniqueness of bendiocarb, which carries a bis-methylated methylenedioxymotif possibly resilient to attack by insect cytochrome P-450 enzymes. In other words, although these carbamates share the same mode of action as organophosphates they are structurally different and may select for different mechanisms of resistance. Resistance management a challenge The management of insecticide resistance, or more precisely, the management of arthropod pest susceptibility is crucial. It should be considered as one of the most challenging issues in modern applied entomology. The effective management of malaria vectors by only a limited number of insecticide chemical classes is a challenge in itself. As briefly outlined here, the chemical options for a resistance management strategy in adult mosquitoes are limited. Currently there are only four chemical classes of insecticides addressing just two different insect target sites!

Mosquito larvae carry the same resistance genes as adults. Therefore, they are also resistant to the same compounds, although the extent of the resistance might differ between adults and larvae. However, there are also various new classes of larvicides for controlling immature insect populations (see page 45: Chikungunya). One class, called insect growth regulators (IGRs) has various biological modes of action. So far IGRs are usually detoxified by metabolic enzymes such as

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Photo: gettyimages

Larvicides provide new options

ENCEPHALITIS transmitting mosquitoes often breed in rice fields – use of agricultural insecticides can trigger the development of resistance in vector control.

COVERSTORY

microsomal monooxygenases. No cases of targetsite resistance have yet been described for any IGR. Biologicals such as bacterial endotoxins are also an option. Resistance to Bacillus sphaericus toxin has been described in field populations and laboratory selected strains of different species of mosquitoes. This resistance is due to the toxin failing to bind to the specific mid-gut receptors, which is caused by several mutations in the binding protein. Usually, no cross-resistance to Bacillus thuringiensis (BTI) is seen, because the toxins of these bacteria bind to different mid-gut receptor proteins.

than alternating members of one chemical class or different chemical classes addressing the same target site. Possible implications of resistance mechanisms on such strategies can be worked out from Figure 2. For example, the presence of kdr resistance renders DDT and pyrethroids less effective, whereas carbamates such as bendiocarb or organophosphates such as fenthion can still be used. If the MACE mechanism is not a problem, one may even think about the rotational use of carbamates and organophosphates. This might increase the chances of regaining pyrethroid susceptibility. However, this should be carefully monitored.

Rotation recommended Most recommendable is the rotational use of chemicals with different modes of action, rather

Furthermore, it seems much more likely to select for cross-resistance to organophosphates than to pyrethroids when using carbamates in alternation

Major biochemical mechanisms of resistance

Target-site

Metabolic Esterases

Monooxygenases

GSH S-Transferases

kdr

MACE

Pyrethroids DDT

Carbamates Organophosphates

Fig. 2: The metabolic detoxification enzymes described to confer insecticide resistance in mosquitoes are: esterases, monooxygenases and glutathione S-transferases (in blue). Two major target-site mechanisms are relevant today: kdr (knock-down resistance), a mutation in the voltage-gated sodium channel (in pink), and MACE (modified acetylcholinesterase) (in green). The respective importance of each resistance mechanism is indicated by the size of the circle.

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with pyrethroids, particularly due to possible selection for MACE-based resistance. In conclusion, both organophosphates and carbamates, particularly bendiocarb are useful as rotational partners in resistance management strategies in order to sustain pyrethroid susceptibility in mosquitoes.

Article on the enclosed Public Health CD-ROM

CONCLUSION Effective long-term resistance management is necessary, but many factors need to be considered to successfully implement strategies. This is not only achieved by the availability of insecticides but is also driven by other factors, e.g. training courses and educational material on disease prevention, or by vector control personnel in general educating management principles, to ensure proper implementation and surveillance. Of course, new active ingredients with new modes of action would be most welcome in order to diversify the vector control toolbox and extend the life cycle of all available insecticides, thus lowering the risk of reemerging vector-borne diseases.

(HQ & AFRO) and scientists involved in vector resistance (UK, Mexico). Detailed questions for further research were addressed. Some recommendations made during the meeting:

1st International Workshop on Resistance Management South Africa, 29-30 June 2004 A meeting on malaria vector resistance was organized in South Africa by the Medical Research Council. The objectives of the meeting were to review the current situation of resistance in Southern Africa, mechanisms involved and practical implications for vector control in the region. This meeting was sponsored by Bayer Environmental Science. About 40 people participated from 9 countries, including South Africa, Swaziland and Mozambique, and managers of 5 Malaria Control Programs, representatives of WHO

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• WHO to coordinate the development of guidelines for resistance management with special reference to Southern Africa, and with the target audience being program managers. • Industry to develop new formulations (OPs, carbamates, pyrethroids), which would last for 12 months on all surfaces, including mud and cement. • Pesticide industry to contribute to resistance monitoring within the framework of product stewardship (modalities to be further discussed).

The document regarding “Recommended actions to support research and control strategies” can be found on the enclosed Public Health CD-ROM

R E S I S TA N C E M A N A G E M E N T

Pyrethroid resistance in malaria vectors

Operational implications in Africa Widespread insecticide resistance in African malaria vectors raises concerns about chemical-based vector control interventions. WHO expert Dr Pierre F. Guillet outlines the challenges malaria vector control programs now face. In particular, to ensure that a chosen insecticide provides the expected efficacy for the calculated duration, as well as how to use insecticides in a way that minimizes development of resistance.

yrethroid resistance in African malaria vectors page 18: kdr mutations). Metabolic resistance has was first detected in Côte d’Ivoire in a major also been reported from Kenya, Cameroon and vector species, Anopheles gambiae. At that time, suspected in Nigeria. But due to problems associthe use of pyrethroid treated nets or any other vec- ated with the complexity and reliability of tor control intervention in this area was almost biochemical assays, especially for oxidases, metanon-existent. It was suggested that resistance bolic resistance in An. gambiae has most likely came from using these insecticides been under-reported. Oxidasein agriculture and/or households. based resistance has been found in This met with skepticism and the another major vector, An. funestus potential implications of such resistin South Africa as well as in ance were grossly underestimated, if Mozambique. not ignored. In 1998, a quick survey was carried out in six countries of Carbosulfan (carbamate) resistance West, Central and Southern Africa. was recently reported from West It confirmed the presence of strong Africa in Côte d’Ivoire. It has been resistance to permethrin and DDT in attributed to modified acethylThe author: three West African countries, resistcholinesterase (AChE), a major DR PIERRE F. GUILLET ance to DDT in one Central African gene conferring resistance to carbaWHO, Vector Control & country and susceptibility to both mate and organophosphate insectiPrevention, Global Malaria permethrin and DDT in one cides (see page 8: Coverstory). Programme Southern African country. Recent Data from preliminary surveys data gathered through the African Network for done in West Africa showed the presence of the Vector Resistance (ANVR) showed that AChE mutation at a low frequency in Benin but at pyrethroid and DDT resistance is not only a relatively high frequency (around 50%) in widespread over West and Central Africa, but also Burkina Faso, Côte d’Ivoire and Sierra Leone. It present in Eastern Africa, involving different is also suspected in Ghana. There is no known resistance mechanisms. evidence of any recent tests made with organophosphate insecticides. Common resistance mechanisms Testing the impact of resistance Knock-down resistance (kdr) is the most frequently found mutation in African malaria vectors Resistance can be interpretated in different ways, belonging to the An. gambiae complex (see box either biologically (e.g. the presence of a

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Photo: Elisabeth Friedrich

INCIDENCES of malaria attacks were reduced by 50% in children protected by permethrin treated nets compared to unprotected children.

resistance gene) or operationally (failure of a vector control intervention). The presence of resistance does not necessarily imply that an intervention has lost its efficacy or effectiveness. The overall public health impact of any insecticide is not just related to its efficacy but also to additional interacting factors, which result in a dramatic reduction of target insects acting as vectors and in transmission. Monitoring insecticide resistance is an essential part of any chemical-based vector control intervention. Once resistance has been found and the mechanism identified, it is essential to understand its potential impact on efficacy and eventually on the effectiveness of insecticide-based vector control interventions. A number of steps and complex investigations should be carried out in laboratory, then small-scale field experiments, followed by village-scale trials.

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Laboratory and small-scale field experiments Mortality and blood feeding inhibition induced by pyrethroid treated nets are only moderately reduced by the kdr mutation as observed in a number of laboratory investigations. It has been shown that kdr resistant mosquitoes landing on treated netting can stay 10 to 20 times longer than susceptible ones, since mutation dramatically reduces the knock-down effect of pyrethroids as well as their irritant effect on mosquitoes. As a consequence, female mosquitoes can stay longer on the treated netting and finally pick up enough insecticide to inhibit blood feeding and to be killed. Laboratory and experimental hut studies with carbamate resistant An. gambiae have shown that carbosulfan treated nets in experimental huts

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(free-flying mosquitoes) are highly effective despite a high level of resistance. On the contrary, mortality was dramatically reduced when resistant mosquitoes were exposed to treated surfaces. It is possible that the limited impact of kdr on the efficacy of pyrethroid treated nets might also apply to other resistance mechanisms and insecticides. This needs to be investigated further.

detectable impact on the vector population, e.g. reducing densities and/or infectivity. The conclusion was that permethrin treated nets do provide good personal protection against malaria vectors even in areas with a high level of pyrethroid resistance. The lack of entomological impact could be attributed to kdr resistance and/or the use of permethrin, which tends to repel rather than kill mosquitoes.

Village-scale trials Confirming the results Laboratory and experimental hut investigations provide valuable information on the impact of resistance on vector behavior and survival. However, they do not provide evidence about the possible impact under real life situations, so a necessary further step is large-scale field trials. Such trials are difficult, long and expensive, therefore evidence on the impact of resistance on insecticide-treated net (ITN) efficacy has been limited so far. In a first trial in an area of Côte d’Ivoire with a very high frequency of the kdr mutation (over 85%), the use of permethrin treated nets reduced the incidence of malaria attacks (morbidity) in protected children by 50% compared to unprotected children. However, treated nets made no

kdr mutations Knock-down resistance (kdr) mutations occur in sodium channels, the target site for DDT and pyrethroids (see diagram on cover flap). A quick survey in Côte d’Ivoire and Burkina Faso showed that the kdr mutation was widespread and commonly occurring at high to very high levels. Interestingly, the mutation was found only in one particular form of An.gambiae, the savannah (S) form, but absent from another closely related form, Mopti (M). A similar situation has been found in Nigeria. Later on, the kdr mutation was detected in the M form in Benin and Burkina Faso. Between 1999 and 2003, a rapid increase in

A larger-scale field trial involving eight paired villages was carried out in an area of high kdr frequency (over 95%) in northern Côte d’Ivoire to assess the efficacy of lambda-cyhalothrin (treated nets versus no net). The protective efficacy of treated nets for children under the age of 5 was 56%, equivalent to what is seen in a similar savannah area with susceptible vectors. But here ITNs had a dramatic impact on An. funestus populations, interrupting transmission by this species. In addition to being fully susceptible to pyrethroids, this species is very sensitive to indoor residual spraying (IRS) and ITNs because of its lower sensitivity to the excito-repellent effect of DDT and pyrethroids compared to An. gambiae. ITNs also made a significant impact on An. gambiae

the kdr frequency was observed in Côte d’Ivoire, starting from the Atlantic coast and rapidly moving northward in savannah areas. A different kdr mutation was found in An. gambiae from East Africa. This East Africa mutation (kdrE) induces a lower level of pyrethroid resistance than the West Africa mutation (kdrW) but a higher level of DDT resistance. It was discovered later that the two mutations were overlapping in large parts of Africa. In Libreville, Gabon, the two mutations were found at a frequency of 100% (37% kdrW, 63% kdrE). Almost 50% of mosquitoes carried both mutations. kdrW was also found far to the east, in Uganda, where both mutations were also found in a single mosquito.

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Photos: Reiner Pospischil

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ANOPHELES STEPHENSI

populations, dramatically reducing but not interrupting malaria transmission. These trials confirmed the results from laboratory and experimental hut investigations that kdr resistance has marginal impact on the protective efficacy of pyrethroid treated nets. Therefore, this resistance should not be seen as an immediate obstacle to deploying and scaling up ITN interventions. Evidence on the impact of metabolic resistance is limited. In a preliminary trial ITN efficacy was significantly reduced in an area with oxidasebased resistance in Cameroon. It is worth noting than the same metabolic resistance in An. funestus in Southern Africa has a dramatic impact on reducing the efficacy of IRS programs using pyrethroids, forcing malaria control programs to revert to DDT spraying, or to using costly alternatives. It is interesting to note that in an area with kdr resistance (Burkina Faso) a newly developed permethrin impregnated film tested in experimental huts was much less effective with resistant mosquitoes than with sensitive ones for both mortality and blood feeding inhibition. Does vector control select for insecticide resistance? The answer is undoubtedly yes. Most long-term chemical-based vector control programs, including malaria, have faced resistance problems. However, resistance prospects depend on very complex factors and differ from one program to the other depending on the insecticide used, vector

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CULEX QUINQUEFASCIATUS

behavior (especially in avoiding the insecticide), bio-ecology, population dynamics and the life stage targeted (larvae or adults). DDT, for example, has been used against malaria vectors for more than 50 consecutive years in a number of eco-epidemiologic settings without facing significant resistance problems. Although DDT resistance is widespread, after more than 50 years of use, e.g. in South Africa, major vectors never developed resistance, or only at low levels. This is due to the impact of the treatment on vector population dynamics and the fact that the product exerts only a limited selection pressure on the vector. For example, it targets only endophilic females and is strongly excito-repellent, meaning it diverts vectors to animals more than killing them or selecting resistance. In contrast, today kdr frequencies are more than 80% over very wide areas where no serious or sustained vector control program has been implemented. This is because selective pressure by DDT and by pyrethroids has been high due to contamination of larval breeding sites by agricultural insecticides, which also explains why AChE has been selected to a high frequency in addition to kdr. If we have more and better information on target site mutation resistance this is only because the tools for monitoring this resistance are much better than those for monitoring metabolic resistance. The impact of resistance also depends on the type of intervention and which specific physiological vector stage is targeted. Both DDT and pyrethroids act on the same target-site (see diagram on

Photo: Iconotec

VILLAGE-SCALE studies are needed to assess the impact of resistance on vector behavior and survival in real life situations.

cover flap) and have a similar impact on vector behavior. Whether sprayed on walls or nets, these products target only female mosquitoes (the only ones biting humans) and within females, the endophilic (resting indoors) and endophagic (feeding on humans indoor) ones. With ITNs, the primary target is a hungry host-seeking mosquito. The search for a blood meal is a vital process: if a female mosquito is unable to take a blood meal during the night following egg laying her survival chances are significantly reduced. This means a host-seeking female mosquito will tend to be very persistent, flying on and around an ITN desperately trying to get a blood meal. In doing so, she will easily pick up a lethal dose of insecticide. ITNs are therefore a trap with the most attractive bait for major malaria vectors.

susceptible and can be killed even after very brief exposure, mosquitoes will tend to leave the treated houses and eventually survive. This behavioral avoidance of insecticide has long been identified as having important implications in IRS interventions based on DDT or pyrethroid spraying. In addition, because of the excito-repellent effect of these insecticides, an important fraction of the target mosquitoes deterred or repelled outside are forced to feed on cattle or other domestic animals. As a result, the selective pressure exerted by these insecticides on adult malaria vector populations is limited and in some circumstances might not be enough to induce resistance development. However, once resistance has developed, the insecticide may still protect human populations, for example by diverting vectors to rest outside and feed on domestic animals.

Avoidance behavior Know the vector biology Conversely, the primary targets for IRS are fed female mosquitoes looking for a resting site after a blood meal. They tend to avoid treated surfaces if the insecticide has any irritant effect, such as DDT and some pyrethroids. Unless they are fully

In contrast, selective pressure is relatively high with larvicides since all individuals in the treated area are exposed and larvae cannot avoid the insecticide. The importance of vector ecology in

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Will the use of ITNs select for pyrethroid resistance? Again, the overall answer is likely yes, with some nuances. Two studies carried out in experimental huts in an area with high pyrethroid resistance in Côte d’Ivoire showed selection of resistance to alpha-cypermethrin and etofenprox. Two other studies carried out in the same area and an area with lower resistance (Benin) showed that resistance is unlikely to be selected by permethrin, especially if resistance is still at an early stage of development. As long as the kdr mutation is absent or present at low frequencies, it seems unlikely that ITNs will either select or dramatically accelerate the development of this resistance. Little can be said at this stage concerning other resistance mechanisms, especially detoxification. Is resistance management with ITNs feasible?

insecticide resistance selection is exemplified by An. gambiae and An. funestus, two major malaria vectors in Africa. In West Africa, the S form of An. gambiae larvae preferentially breed in rain puddles, possibly located near crop fields (e.g. cotton) that are repeatedly sprayed with insecticides. As a result, these breeding sites are often contaminated by agricultural insecticides. Larvae of the M form breed in more permanent waterways or in rice fields where relatively little insecticides are sprayed. Significantly, widespread and high level DDT and pyrethroid resistance has been found in the S but not the M form. An. funestus breeds in permanent water bodies shaded by vegetation, also usually not exposed to agricultural insecticides. Until now An. funestus has remained fully susceptible in most parts of Africa, including the West Africa cotton belt. The link between larval ecology, agriculture and vector resistance has also been particularly obvious in Mexico and Turkey.

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Although kdr resistance does not appear as an immediate obstacle to large-scale deployment of ITNs, pyrethroid resistance in malaria vectors remains a major concern globally. As long as insecticides play a key role in malaria transmission control there is a need to choose interventions that are effective despite resistance. A number of tactics have been proposed, the most common being the use of mixtures or mosaic treatments or rotation of unrelated insecticides over time. Can non-pyrethroid insecticides be used on nets? Nets treated with organophosphate (pirimiphosmethyl) or carbamate (carbosulfan) insecticides are very effective in killing vector mosquitoes, including the nuisance mosquito Culex quinquefasciatus. However, since organophosphates do not prevent blood-feeding, nets treated with these insecticides do not provide any personal protection against malaria vectors, in contrast to carbosulfan (and of course pyrethroids). In addition, these two insecticides do not last long enough on nets (especially the very volatile organophosphates) for practical application, unless residual

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WHOPES

Need for a generic risk assessment model Pyrethroid insecticides have been used for several years for the treatment of bednets to protect against malaria-carrying mosquitoes. The effectiveness of such bednets in reducing morbidity and mortality from malaria has been documented elsewhere (WHO, 2000). The WHO Roll Back Malaria (RBM) project has made insecticide-treated bednets one of the cornerstones of the effort to reduce malaria, setting the goal in October 1999 of ensuring coverage of 60 million African families with insecticide-treated mosquito nets over a five-year period. The present consensus is that pyrethroids – at the levels currently employed – are generally of low risk to human health, both for operators and for users of treated bednets. The WHO Pesticide Evaluation Scheme (WHOPES) currently recommends a number of insecticides, all pyrethroids, for the treatment of bednets (Najera & Zaim, 2002). A review of the safety of pyrethroid-treated bednets has been published (Zaim et al., 2000), and in a detailed risk assessment on the use of deltamethrin on bednets, Barlow; Sullivan & Lines (2001) support the safety-in-use of this particular insecticide.

However, detailed assessments of the other WHOPES-approved compounds have yet to be published. Because of the development of insect resistance to the commonly used pyrethroids, there is now a need to consider the use of alternative insecticide classes for vector control in the treatment of bednets. Alternatives under consideration include organophosphates and carbamates, which differ from the pyrethroids in their mode of action and are inherently more acutely toxic and less stable. Thus there is an urgent need for safety assessment of such treatments before they are used in the field. There is also a need to assess the risks from the various methods of bednet treatment that may be used, including the types of insecticide formulation used and the newer, more persistent insecticide treatments. A generic risk assessment model is therefore needed, based on typical scenarios for the preparation and use of insecticide-treated bednets and on average or “worst case” values for environmental and human parameters, which are applicable to any insecticide.

Quoted from paragraph 2.1 in: “A generic risk assessment model for insecticide treatment of mosquito nets and their subsequent use“ (WHO/CDS/WHOPES/GCDPP/2004.6) You can find the whole article at: www.who.int/whopes/guidelines/en/

activity can be increased in the future using longer-lasting formulations. In addition, the use of carbamate alone tended to actively select resistance mediated by modified acethylcholinesterases. The same would likely occur with organophosphates. Another limitation to the use of non-pyrethroids on nets is the human safety issue. OPs and particularly carbamate insecticides can potentially cause greater harm to ITN users than pyrethroids, both during treatment and net use. It is therefore desirable to find solutions that take advantage of non-pyrethroids, while

overcoming their limitations. This has been addressed by combining pyrethroids and nonpyrethroids on a single net. Combining insecticides on one net Combinations can be either a mosaic or insecticide mixture. The concept of combining insecticides on nets was introduced to restore efficacy against resistant mosquitoes, while preventing further development of resistance. Combination of a pyrethroid (bifentrin) on the lower part of the net

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Photo: Iconotec

and a carbamate (carbosulfan) on the upper part and the roof (mosaic treatment) fully restored net efficacy against resistant An. gambiae (kdr and modified acethylcholinesterase) as well as multiresistant Culex quinquefasciatus. Experimental hut investigations with various insecticide combinations and locations showed that the full benefit of insecticide combination is obtained by treating the roof with a non-pyrethroid and the four sides with a pyrethroid insecticide. Combinations can also use a mixture of two insecticides, and might have a practical interest for treating mosquito nets, especially if there is a synergy between the products used. Pyrethroids and organophosphates effectively have a synergic effect when used as a mixture on nets, which raised interesting prospects for ITNs. Unfortunately, it appeared that the synergistic effect does not occur with pyrethroid resistant mosquitoes in the laboratory, nor in the field. Interestingly, it seems that neither the mixture nor the mosaic treatment using a carbamate and a pyrethroid selected for both modified AChE and kdr, while the non-selection of kdr by pyrethroid alone was again confirmed. Recent investigations on the behavior of vector mosquitoes flying around a net have confirmed the important role of the roof in the insecticidal action of ITNs. Since mosquitoes come in contact with several parts of a treated net while trying to seek out a blood meal, the mosaic treatment can be seen as equivalent to a mixture, except that mosquitoes are exposed to 2 different chemicals in turn (mosaic) instead of simultaneously (mixtures). A big advantage of the mosaic approach is that each insecticide can be used at the full operational dose without serious financial and safety implications. A potential limitation of a mixture, in addition to safety considerations, is the rate of decay of the two

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products: if this is not identical at some time point during the net's usable life, treatment no longer represents a mixture. Industry is currently addressing the challenge of adapting the long-lasting treatment technologies to the use of non-pyrethroid insecticides. This would require an available insecticide with the required efficacy and safety to treat the whole net, which is not yet the case, as well as strict control over users. However, rotation of insecticides is almost unfeasible with ITNs. LNs usually last for 3 to 5 years, which does not fit with the time-scale for a rotation approach usually planned on a shorter basis. CONCLUSION Scaling up vector control interventions in Africa, either ITNs or IRS, will require significant strengthening of resistance monitoring, e.g. through the African Network for Vector Resistance (ANVR). The choice of insecticides will have to rely on detailed mapping of resistance, identification of resistance mechanisms and an understanding of potential operational implications of resistance. It will also require adoption of pragmatic resistance management tactics supported by a strong component of operational research. This should be directly linked to operations to assess local field situations in real time and guide programs in their efforts to sustain effective vector control programs. This article is an excerpt from a longer contribution by Dr Pierre F. Guillet. You can find the complete article including the references on the enclosed Public Health CD-ROM.

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Insecticide resistance management in a multi-resistant malaria vector scenario

A Mexican trial shows sustainability A large-scale field trial in Mexico evaluated resistance management strategies for dealing with, delaying or even stopping insecticide resistance selection. Biological and biochemical assays showed that high level resistance development was reduced and kept at low levels by using rotation or mosaic schemes rather than single insecticide regimes. nsecticide resistance is an important issue in the use of larvicides, such as organophosphates, malaria control, with some vectors already or space sprays. Although alternatives such as multi-resistant. Agricultural usage of bio-insecticides and insect growth The authors: insecticides has also increased the regulators (IGR) are available, their selection pressure on disease vectors DR A. D. RODRIGUEZ, higher costs often prevent their use in DR R. P. PENILLA, that rest and breed on the crops. The developing countries. Since only a DR M. H. RODRIGUEZ use of insecticides is currently the Centro de Investigaci贸n few new molecules for vector control major method of prevention and conare being developed, new approaches de Paludismo, Mexico trol of many vector-borne diseases. PROF J. HEMINGWAY to retain efficacy of currently availDengue control, for example, relies on able public health insecticides are Liverpool School of

Tropical Medicine, UK

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Photo: Adalberto Rios Szalay / Sexto Sol / gettyimages

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clearly needed. Resistance management strategies are an option that could delay or in the most favorable scenario, stop resistance development while maintaining disease control. To establish whether predicted methods of resistance management would work under operational conditions, the IRAC public health group sponsored an ambitious resistant management program against Anopheles albimanus, the multiresistant New World malaria vector (see box page 29: IRAC). Designing operational conditions In the coastal plain of Chiapas, Mexico, a largescale field trial was undertaken from 1996-2002 to evaluate rotations and mosaics of insecticides

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MAP OF THE STUDY AREA indicating the groups of villages and the treatments. MOS = mosaic application, PYR = single use of a pyrethroid, DDT = single use of DDT, ROT = annual rotation of insecticides.

(see map above). The site was chosen because of the history of insecticide use in Mexico. Extensive agricultural and public health insecticide use during the 1960’s and 1970’s selected multiple insecticide resistance mechanisms in An. albimanus, the main coastal malaria vector. Subsequent changes in land use, the reduction in cotton farming and the success of malaria control activities consequently decreased insecticide use. This resulted in a well-documented regression towards insecticide susceptibility in An. albimanus to all insecticides except DDT – as measured by diagnostic WHO mortality tests (see table page 26: Experimental design). DDT resistance was maintained by continued use of this insecticide for malaria control activities in Mexico.

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Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Traditional

Traditional

Rotation

Mosaic

DDT

Single

DDT

DDT insecticide Single insecticide

EXPERIMENTAL DESIGN Four treatment regimes were assigned to the selected villages:

PYR

CAR

PYR

PYR insecticides

A B A B A B A B A

A: OP

B: PYR

Twenty-four villages were selected and grouped into sets of three villages, which were randomly assigned to one of four treatment regimes (see map page 25). All insecticides involved in the study were applied as part of normal anti-malarial activities three times per year, with the exception of DDT, which was sprayed twice per year. Insecticides were sprayed with a Hudson X-Pert® sprayer with

Unrelated

A B A B A B A B A

Two unrelated insecticides

PYR = pyrethroid (deltamethrin) OP = organophosphate (pirimiphos-methyl) CAR = carbamate (bendiocarb)

nozzle No. 8002. Wall bioassays to monitor residual efficacy of insecticides were conducted one day and then every month, after spraying. Good killing effect of mosquitoes was achieved with all products at the applied dosages (pirimiphos-methyl) at 2 g a.i./m2, deltamethrin at 0.025 g a.i./m2, bendiocarb at 0.4 g a.i./m2 and DDT at 2 g a.i./m2), with mosquito mortalities averaging around 75% four months after insecticide application.

Mortality of Anopheles albimanus Mortality (%) Insecticide DDT Malathion Fenitrothion Fenthion Chlorphoxim Propoxur Deltamethrin Cypermethrin Bendiocarb Pirimiphos-methyl

Concentration (%) 4 5 1 2.5 4 0.1 0.025 0.1 0.1 4

1982

1983

1990

1997

38 84 44 97 98 89 64

39 93 57 100 99 95 57 82 87 99

47 99 99

40 100 100 99 100 100 99 100 100 100

100 86

MORTALITY of Anopheles albimanus from the Chiapas coastal plain to WHO diagnostic adult doses of different insecticides during the early 1980’s and late 1990’s.

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Photo: Cuauhtemoc Villarreal

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A NUMBER OF VILLAGES were selected for a largescale field trial.

Field-caught mosquitoes in the lab The frequency of all resistance mechanisms was monitored before and during the intervention period by biochemical assays, along with WHO diagnostic bioassays using insecticide impregnated papers. Field samples of mosquitoes were collected on a regular basis approximately three months after each spray round and the F1 generation reared from the field-caught mosquitoes were used for all assays. When few mosquitoes were available, priority was given to biochemical assays since this method was the most sensitive for detection of small changes in resistance. Biochemical assay results were compared with the susceptible An. albimanus Panama strain. Logistic regression analyses were used to determine the effect of the different treatment regimes on the frequency of different resistance mechanisms. Pyrethroid treatment and pre-spray were set as reference variables in the analysis. Since no changes were observed in DDT resistance levels

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under any treatment scheme during the whole study period, data from DDT treated villages were excluded from the analyses. It had been anticipated that DDT resistance should have declined over time when the DDT selection pressure was relaxed. It did not. There are two possible reasons for this. Either the DDT still on the walls (given the longevity of the active agent) was sufficient to maintain positive selection â&#x20AC;&#x201C; or perhaps more likely the resistance had been selected so long ago and then maintained that any negative selection associated with DDT resistance genes had been counterbalanced by other genetic changes, thus removing the negative fitness costs of the resistance genes. Rotation or mosaic schemes more effective? Bioassays showed that continuous use of a pyrethroid gradually increased pyrethroid

resistance in the mosquito field population over the first four years: resistance then remained stable for the next two years. In the rotation and mosaic schemes, pyrethroid and organophosphate resistance were selected at low levels and remained stable. No carbamate resistance was observed in the rotation scheme. The biochemical assays (see box below) showed that although enzyme activity patterns varied, the chances of high level resistance development using a rotation or a mosaic regime were significantly lower than the rate at which resistance was selected using a pyrethroid alone. Delaying resistance selection Both the rotation and mosaic strategies performed well operationally and were accepted by the local

Photo: Cuauhtemoc Villarreal

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population. Hence, rotations or mosaics should be implemented as part of normal malaria control operations, to reduce the likelihood of resistance development. Even in areas where resistance is already present these strategies may still work well and delay high level resistance selection.

Resistance biochemistry Organophosphate and carbamate resistance in Anopheles is often due to a change in the insecticide's target site, acetylcholinesterase (AChE). Odds ratios for individuals with altered AChE above the normal insecticide susceptible range were significantly higher for the rotation and mosaic treatments compared to the single pyrethroid treatment during most of the study period, and after the application of both organophosphate and carbamate in the rotation system. Altered AChE was the main mechanism conferring resistance against organophosphates and carbamates in Mexico and resistance increased slightly due to this mechanism with both the rotation and mosaic regime. Esterase-based organophosphate and pyrethroid resistance is also common in mosquitoes. Odds ratio for individuals with esterase levels (measured with the substrate ρNPA) above the normal susceptible range

indicated that the rotational regime kept that mechanism at or below “acceptable” levels, as compared to the single use of a pyrethroid. This suggests that esterases play an important role in conferring pyrethroid resistance in An. albimanus. Odds ratios for individuals with esterase levels using α-naphthyl acetate as a substrate were above the normal susceptible range for both the rotation and mosaic regimes, hence they selected for individuals with this type of resistance mechanism. The odds ratios for individuals with cytochrome P450s above the normal susceptible range also indicated that by the fourth year of using the pyrethroid or the rotation, a significantly higher frequency of individuals with this resistance mechanism were selected. There was no evidence of selection of a glutathione transferase-based mechanism by any of the four treatments.

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Insecticide Resistance Action Committee WAITING FOR the house to be sprayed after moving goods and furniture outside.

The format of the rotation scheme should take into account the previous history of insecticide resistance or insecticide use. Where resistance management is undertaken resistance levels should be monitored regularly. In the course of this trial the biochemical assays, although variable, were more reliable and practical than the bioassays. More insects could be processed compared to the WHO method and a greater amount of information was generated per mosquito when sample numbers were low.

IRAC is an inter-company group formed in 1984 to provide insecticide and acaricide resistance management strategies to help reduce the development of resistance in insect and mite pests. The key to managing resistance is to reduce selection pressure caused by the over-use or misuse of an insecticide, because this could result in the selection of resistant forms of the pest and the consequent evolution of populations that are resistant to that insecticide. IRAC believes that Resistance Management should be an integral part of Integrated Pest Management and provides for sustainable agriculture and improved public health.

New public health insecticides have been brought to market at a slower rate than insecticide resistance has developed, and regulatory issues have further reduced the available insecticide choice. Better resistance management of current and new public health insecticides, to delay or even stop resistance selection, is needed if vector control is to be sustainable in the long-term. Article (with plots of odds ratios) on the enclosed Public Health CD-ROM

Photo: IRAC

CONCLUSION

IRAC is acting as a Specialist Technical Group of CropLife.

www.irac-online.org

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Combatting resistance to insecticides in malaria control

Gains made in India Eradication programs in the 1950s dramatically reduced malaria cases in India. This remarkable success was possible using DDT. Then in the 1970s malaria resurged in India, largely due to the development of insecticide resistance in malaria vectors. But with continued application of well-targeted insecticides India succeeded in reducing the disease burden again and maintaining this over the last 25 years. Now managing the spread of resistance is of primary importance for sustaining insecticide-based vector control.

significant breakthrough in the 20th century has been the spectacular success in controlling human malaria and an ever-lengthening list of vector-borne diseases through a well-structured vector control program coupled with curative

Photo: Iconotec

treatment. The discovery of the insecticidal properties of DDT during the Second World War facilitated the development of successful vector control programs worldwide. A classical example has been the success story of malaria control in

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India solely relying on DDT. The launching of the National Malaria Eradication Program in the 1950s indeed dramatically reduced the abysmal figure of 75 million malaria cases per year to a remarkable low of 49 thousand cases by the year 1962, with no recorded deaths. This was evidently possible with the use of DDT, which could effectively control the malaria vectors due to its broadspectrum toxicity coupled with excito-repellency. However, this success could not be sustained for long and India witnessed malaria resurgence in the 1970s. The situation was further aggravated by the emergence and re-emergence of many other vector-borne diseases. Setback in malaria control The Modified Plan of Operations (MPO) launched in 1977, continued to deploy powerful well-targeted insecticides along with other tools. This strategy brought down the disease burden in

India to a stable level of two million reported cases of malaria per annum by 1980 and has kept this under control for the last two and a half decades. This remarkable achievement has been recognized as yet another successful story, a distinction the National Vector Borne Disease Control Program (NVBDCP) of India shares with Brazil, Eritrea and Vietnam. The authors: The severe setback in DR A.P. DASH, malaria control witnessed DR K. RAGHAVENDRA in India during the 1970s National Institute was largely due to the of Malaria Research development of resistance (Indian Council of to insecticides by malaria Medical Research) vectors. It is a recognized DR M.K.K. PILLAI fact that mosquitoes have Former Head, Department of Zoology, the innate ability to University of Delhi mutate and outwit any ingenious insecticide developed to decimate them. Indeed, it will be a Herculean task for the national program not only to achieve further reduction in malaria but also to sustain the gains achieved so far. This necessarily warrants a paradigm shift in the operation of insecticide-based vector control strategies so as to prolong their useful life. This indeed, is the need of the hour mainly due to the lack of globally available new insecticides for vector control.

Insecticides effective in vector control Insecticides are effectively used in diverse ways to target vectors and produce optimum control based on the insectsâ&#x20AC;&#x2122; behavioral traits. Indoor residual spraying (IRS) using wettable powder (WP) formulations are targeted against adult mosquitoes, while emulsifiable concentrates (EC) are used for larval control. In addition, fogging or space sprays (ULV or thermal) are deployed during epidemics. Also insecticide impregnated bed nets, including long-lasting insecticidal nets

RURAL AREAS face different problems in terms of vector ecology and the logistics of implementing control programs.

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(LNs), have recently been introduced as an effective tool to control malaria. Organochlorine insecticide DDT was initially introduced in 1944 on an experimental basis in the allied forces camps on the Assam-Burma front during the Second World War and subsequently in civilian areas in Orissa and Karnataka states. In the 1950s, the National Malaria Eradication Program (NMEP) was launched relying on the standard protocol of deploying DDT in indoor residual spraying at 1 g/sqm for two rounds per year. Wherever DDT was found ineffective HCH

Historic events • DDT introduced in 1944 on the AssamBurma front during the Second World War. • The National Malaria Eradication Program (NMEP) launched in the 1950s was based solely on DDT spraying. • Use of DDT dramatically reduced the malaria burden up to the mid-1960s. • Setbacks began in 1966 due to vectors developing resistance to DDT and HCH. • Malathion introduced in 1969 to combat DDT-HCH-resistant mosquitoes. • First reports of resistance to malathion in 1973 – malaria resurgence peaks in 1976. • Modified Plan of Operations (MPO) launched in 1977 deploying well-targeted insecticides and other tools. • Pyrethroids (first deltamethrin, then others) introduced into the national program in the mid-1990s. • During the last two decades pyrethroid formulations developed for impregnating mosquito nets. • HCH withdrawn from the national program in 1997 due to health concerns. • Deltamethrin resistance first detected in 2002, followed by low level resistance to other synthetic pyrethroids.

(hexachlorocyclohexane, another insecticide in the group of organochlorines) was used at 2 g/sqm for three rounds per year. Setbacks in the eradication program began in 1966 due to cross resistance to DDT and HCH first reported in the early 1960s. This situation led to the more logical option of introducing malathion in the states of Gujarat and Maharashtra in 1969 to combat DDT-HCH-resistant An. culicifacies. Within four years of its introduction the first reports of resistance to malathion in An. culicifacies came from these states. Simultaneously, India was witnessing a severe resurgence of malaria in many parts of the country. This became full-blown by 1976, when 6.47 million cases were reported, the largest number ever since the introduction of DDT. Thus, it was necessary to explore new strategies and the national program looked to introduce new insecticide molecules to contain the triple resistant An. culicifacies. Synthetic pyrethroids showed promise with their remarkable insecticidal activity and low mammalian toxicity. The National Institute of Malaria Research (NIMR, formerly known as Malaria Research Centre) has the distinction of evaluating the field efficacy of deltamethrin (synthetic pyrethroid) for the first time in India. By the mid1990s this insecticide had been introduced into the national program. During the last two decades, besides deltamethrin, other structurally related and equally effective pyrethroids, such as cyfluthrin, lambda-cyhalothrin and alpha-cypermethrin, were field evaluated and regularly used for IRS. At the same time suitable formulations of these pyrethroid insecticides were made available for impregnating mosquito nets. This intervention is part of vector control at community levels in areas with increased risk of malaria. The national program has also accepted in principle the introduction of LNs. A tablet formulation for converting nets into LNs is available and under field trials 1 with NIMR . These efforts would facilitate largescale use of LNs especially in areas where the operation of IRS is not feasible.

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Photo: Nicholas Pitt / gettyimages

MALARIA VECTORS IN INDIA Fifty-eight of the 450 anopheline species reported so far in the world are recorded in India. Of these, only ten species of Anopheles are known to be vectors of malaria, although six of them are considered to be primary vectors having distinct geographical distribution, with diverse ecological niches and transmission dynamics (see table below). With the exception of An. stephensi, other vectors are species complexes comprising sibling species or isomorphic species differing in vectorial competence, insecticidal susceptibility, ecological traits and behavior. Proper understanding of these factors has become imperative to elucidate their transmission dynamics and initiate innovative control strategies. The primary vector, An. culicifacies with wide-spread distribution, efficiently transmits both Plasmodium vivax and P. falciparum malaria. It breeds prolifically during monsoons and often causes sporadic localized epidemics in different parts of the country. Indeed 60 to 70% of malaria incidence in India is transmitted by An. culicifacies and an equivalent proportion of the annual budget for malaria control in India is spent on controlling this species. An. stephensi is an urban malaria vector and accounts for about 12% of malaria cases annually. This species, which perennially transmits

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malaria, is an important vector in arid zones of Rajasthan. In this region this species has a unique characteristic of breeding proficiently in underground water tanks (Tankas) prevalent in villages and urban areas. Furthermore, in some of these arid areas increased precipitation facilitates prolific breeding of An. culicifacies which can often lead to localized outbreaks of malaria. An. fluviatilis inhabiting hilly regions of the country contributes to about 15% of cases annually, while the other three species, An. minimus and An. dirus confined to northeastern regions and An. sundaicus in Andaman and Nicobar Islands, together contribute to about 8-9% of cases. Species

Prevalence

An. culicifacies An. stephensi An. fluviatilis An. minimus An. dirus An. sundaicus An. annularis* An. philippinensis* An. jeyporiensis* An. varuna*

Rural plains and peri-urban areas Mainly urban areas Hills and foothills North eastern states North eastern states Adaman and Nicobar Islands Eastern region North eastern states Eastern region Eastern region and sporadic in southern region

Primary vectors

* Secondary vectors/local importance

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Geographical distribution of insecticide resistance in An. culicifacies

In a national program for larval control, organophosphate insecticides temephos, fenthion and pirimiphos-methyl are used. Bacterial endotoxin formulations from Bacillus thuringiensis israelensis H-14 are also used selectively in breeding habitats. Status of insecticide resistance in malaria vectors Malaria control in India currently only uses organochlorine, organophosphates and synthetic pyrethroids. Carbamate insecticides used elsewhere are yet to be introduced into the Indian anti-malaria program.

Quadruple resistance to DDT, dieldrin, malathion and deltamethrin Triple resistance to DDT, dieldrin and malathion

DDT resistance was first reported in An. culicifacies in 1958 in Gujarat and later from various other states. Development of resistance in this important vector species necessitated withdrawal of DDT from many parts of the country (see table on page 36: Insecticide resistance in An. culicifacies). HCH introduced in 1958, registered the first case of resistance in 1962 and soon resistance became widespread in many states. The vector achieved the unique distinction of double resistance to DDT and HCH in 233 districts in 16 states and in two union territories. Owing to human health concerns HCH was subsequently withdrawn from the program in 1997. DDT is designated as an â&#x20AC;&#x153;exemptedâ&#x20AC;? insecticide for use in public health sprays within the mandated quantity of production of 10,000 MT for exclusive use to contain kala-azar and malaria in certain areas.

Double resistance to DDT and dieldrin Resistance to DDT Reports not available

Malathion resistance in An. culicifacies was first reported from Gujarat in 1973 and later became widespread throughout the country. The resistance problem was aggravated when An. culicifacies acquired triple resistance to DDT, HCH and malathion in 182 districts in 13 states and in 1 union territory. In certain areas it was also found that agricultural use of malathion induced resistance in An. culicifacies in the states of Andhra Pradesh, Madhya Pradesh and Maharashtra where malathion was never used in public health.

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Synthetic pyrethroids were introduced to counteract triple resistance in An. culicifacies in many states by 1990. However, contrary to expectations An. culicifacies exhibited deltamethrin resistance in Surat and Rameshwaram by 2002. Recent monitoring in different states has revealed low levels of resistance to different pyrethroids in Maharashtra, Gujarat, Madhya Pradesh, Karnataka and Tamil Nadu. This indeed indicates the possibility of resistance to synthetic pyrethroids becoming widespread in the near future and might result in a setback in sustaining malaria control in India. Moreover, extensive use of synthetic pyrethroids in agriculture and the practice of enhanced use of pyrethroid impregnated bed nets will accelerate the selection of resistance to pyrethroids in An. culicifacies, putting insecticide-based vector control at a turning point. Increasing mosquito vector tolerance

An. fluviatilis is responsible for transmission of about 15% of new malaria cases annually in hilly and foot hill regions of Orissa, Madhya Pradesh, Uttaranchal and Chhattisgarh.

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Photo: Corbis

An. stephensi, though a vector of urban malaria, also prevails in peri-urban areas. In urban areas only larvicides are used and this vector has not developed resistance to any insecticide or bacterial pesticides (Bti) used in larval control. However, adults have shown resistance to DDT alone, to DDT and HCH, and to DDT, HCH and malathion, mainly in peri-urban areas (see table on page 36: Insecticide resistance in An. stephensi). A slight increase in tolerance to synthetic pyrethroids was also reported from periurban areas and where this is additionally subjected to selection pressure from IRS used against An. culicifacies.

This species was found mostly susceptible to DDT except for a few stray reports of resistance from some states. This species was found to be resistant to DDT in two districts of Orissa and one district each in Uttar Pradesh and Uttaranchal. A 1997 survey showed DDT resistance in 11 districts in 4 states. But it was susceptible to malathion and deltamethrin. It is worth mentioning that in Koraput (Orissa) the species was found to be susceptible to DDT. An. minimus and An. dirus are the main vectors of the north-eastern states of India. Both species are reported to be susceptible to DDT. An. sundaicus, the exclusive vector of Andamans and Nicobar Islands, is also reported to be susceptible to DDT. Management of resistance essential The insecticide resistance problem is of serious concern in India with regard to An. culicifacies, which is responsible for more than 60-70% of the malaria burden in this country, with intermittent outbreaks/epidemics. It is apparent from recent surveys that this species has acquired resistance to DDT and malathion and is at the threshold of developing widespread resistance to the whole spectrum of synthetic pyrethroids currently in use for malaria control. Thus An. culicifacies, an omnipresent vector in most parts of India, is currently subjected to intense selection pressure from various synthetic pyrethroids used in public health for IRS and impregnated bed nets, in addition to intense selection pressure from the extensive deployment of synthetic pyrethroids in agriculture. Hence, vector control solely based on synthetic pyrethroids may not be promising in the near future. The problem is compounded by the fact that no newer, safer

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Insecticide resistance in An. culicifacies

Insecticide resistance in An. stephensi

Type of resistance

DDT Double* Triple** Quadruple***

Number of states

Number of districts

18 16 13 2

286 233 182 2

DDT Double* Triple**

Number of states

Number of districts

7 6 3

34 27 8

* Double resistance to DDT and dieldrin ** Triple resistance to DDT, dieldrin and malathion *** Quadruple resistance to DDT, dieldrin, malathion and deltamethrin.

insecticides are available for use in public health now or in the near future. This scenario evidently requires an immediate consideration of managing the existing and future spread of resistance as a primary solution to sustaining insecticide-based vector control. Existing practices of substitution with more effective insecticides on an ad hoc basis to counteract resistance has always failed, since resistance is a natural evolutionary outcome from environmental stress caused by continued pesticide onslaught. Therefore, to sustain insecticide-based vector control and to mitigate resistance, the primary aim should be to delay the onset of resistance to pesticides and thereby increase their useful life. This is possible by drastically altering operational strategies in vector control programs, based on a better understanding of the chemical traits of the insecticides, their modes of action and their vulnerability to detoxifications rendering them ineffective. Vector control has to focus on selecting the right insecticide in resistant areas to prevent or slow down development and geographical spread of resistance.

Rotation strategies sustain susceptability The many strategies suggested for the management of resistance include a time bound rotation of chemically unrelated insecticides differing in mode of action and susceptibility to different enzymatic detoxification. WHO recommends a preplanned time bound rotation to effectively check the onset of resistance and sustain vector control with relative ease. This essentially requires a minimum of two, but preferably three insecticides to be rotated in tandem. One such successful campaign has been the Onchocerciasis Control Program (OCP) in West Africa involving rotation of temephos, phoxim and Bti (H14). Other success stories in malaria control include a campaign against malaria vectors in Mexico using an organophsophate compound, a synthetic pyrethroid and a carbamate, and in South Africa using synthetic pyrethroids, carbamate and DDT. The carbamate bendiocarb field trials in rotation with DDT and synthetic pyrethroids in Mexico and South Africa demonstrated a reversion to DDT and pyrethroid susceptibility in malaria vectors. In India, carbamates can be profitably used in resistance management of malaria vectors, especially An. culicifacies. Bendiocarb insecticide has the desirable residual efficacy and no long-term persistence in the environment as documented by

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WHO.2 In addition, this insecticide is not used in agriculture, an added advantage to vector control programs by avoiding the selection of resistance in disease vectors as non-target species of agricultural sprays.

Since the rapid development of resistance to synthetic pyrethroids is looming on the horizon, malaria control in India is at cross roads. The national program needs to seriously focus its attention on preventing or minimizing the development of pyrethroid resistance in An. culicifacies by resorting to a judicious and prudent strategy of insecticide rotation. At present, the national program has no alternative insecticide for effective vector control or for management of resistance. However, possibilities include selective use of any of the effective organophosphate or carbamate compounds. Bendiocarb 3, evaluated by NIMR and other institutions in India, was found to be effective against An. culicifacies. It is an ideal insecticide to be used against vectors in multiple resistant areas in rotation with the programâ&#x20AC;&#x2122;s existing insecticides, wherever needed, in order to sustain and effectively control malaria in the years to come in a cost-effective manner and retain the gains achieved so far in malaria control.

See page 59: Vector management in India

2 Pesticides and their application â&#x20AC;&#x201C; For the control of vectors and pests of public health importance. WHO/CDS/NTD/WHOPES/GCDPP/2006.1. Sixth Edition. 3

See page 59: Vector management in India

Photo: The authors

India at cross roads

NO ALTERNATIVE insecticides are available for effective vector control in India, so existing compounds will have to be used selectively and in rotation.

CONCLUSION Insecticide resistance is a serious problem in India. Malaria eradication programs must immediately consider managing the spread of resistance in order to sustain insecticide-based vector control. A rotational approach to managing insecticide resistance could open up new perspectives in vector control scenarios in global malaria control. It is needless to emphasize that concerted efforts of governmental, non-governmental and private sectors in this new endeavor could lead to achieving the final goal of a malaria-free society. Article on the enclosed Public Health CD-ROM

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Malaria control on Bioko Island, Equatorial Guinea

Photos: Marathon Oil Corporation

SURPASSING ORIGINAL TARGETS

WINDOW TRAPS confirm the effectiveness of the spraying program.

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The main strategy of the Bioko Island Malaria Control Project is indoor residual spraying with the goal of reducing the incidence of malaria and associated mortality by substantially reducing malaria transmission. Early emergence of knock-down resistance (kdr) to pyrethroids and DDT required switching to a carbamate. Preliminary results indicate a rapid and considerable impact with significant benefits particularly for the poor.

rior to the Bioko Island Malaria Control Project (BIMCP) malaria incidence was extremely high on Bioko Island, with reported Plasmodium falciparum parasite infection rates of over 50% among children aged 2 to 9 years. The principal vectors in Equatorial Guinea are An. gambiae and An. funestus, and malaria transmission was year-round.

Photo: Dex Image

The BIMCP started in 2003 with financial support from Marathon Oil Corporation, its partners and the Government of Equatorial Guinea. Departing from many other country strategies based mainly on personal protection using long-lasting insecticidal nets (LNs), the BIMCP relies on indoor residual spraying (IRS) as the principal control strategy.

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This is because the main objective of the BIMCP is not just to significantly reduce morbidity and mortality due to malaria (the objectives of Roll Back Malaria), but to achieve a substantial reduction or virtual elimination of malaria transmission on Bioko Island within five years. The main beneficiaries are children under 15 years of age and pregnant women, although all Biokans benefit directly from reduced transmission.

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Unique partnership The US$ 12 million, 5-year commitment is a unique, voluntary, multi-stakeholder partnership between: • The corporate sector (Marathon Oil and its partners). • The Government of Equatorial Guinea. • Civil society organizations (Medical Care Development International/MCDI) who serves as the lead implementing organization. • One World Development Group (OWDG). • Research institutes (the South African Medical Research Council/MRC and the Harvard School of Public Health). • The community of Bioko Island. Based on best practice The BIMCP strategy was originally designed by a team from the Harvard University School of Public Health in consultation with the South African MRC, working with the Ministry of Health of Equatorial Guinea and the Health Service Department of Marathon Oil. It was based on international evidence of best practice to reduce malaria transmission, including extensive and

highly successful previous experiences using IRS as a principal component of integrated malaria control initiatives. Particular attention was paid to the important role of IRS in eradication efforts during the 1950s and 60s. Also its effectiveness in malaria control initiatives in other high transmission areas (e.g. the humid coastal area of Tanga, the Pare-Tayeta region in Tanzania and the humid area of Nyanza in Kenya) was noted, in addition to the long-standing and highly successful use of IRS in Southern Africa. Setting up the project Launching of the BIMCP was greatly helped by the logistic and administrative capacities of Marathon Oil operating on Bioko Island, and their strong working relations with the Government. A total of 80 national spraymen and supervisors were trained and capacity building mechanisms were established. Bioko was divided into spraying areas by administrative district and satellite imagery helped establish the boundaries. An annual implementation plan was developed in consultation with the Ministry of Health. A specially chosen Information, Education and Communication (IEC) advance team notified

Principal BIMCP goals b Reduce transmission through indoor residual spraying (IRS) of all residential structures on the island. b Improve malaria diagnosis through a combination of enhanced microscopy and the introduction of rapid diagnostic tests (RDTs) at health centers without laboratories. b Improve case management through the introduction of artemisinin-based combination therapy (ACT), given a reported 56% failure rate for chloroquine. b Implement intermittent preventive therapy (IPT) during pregnancy. b Disseminate comprehensive information, education and communications (IEC) to support both IRS and case management. b Establish state-of-the-art monitoring and evaluation system. b Secure early and concerted investment in capacity-building and the full integration of BIMCP activities into the national Malaria Control Program as a necessary condition for sustainability.

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Indoor residual spraying 2005 Bendiocarb

104,000

Structures (rooms) sprayed

102,000

103,099

100,000 98,000

2004 Deltamethrin

96,000 96,353 94,000 92,000

IN 2005 the total number of structures treated with bendiocarb (two rounds) was significantly higher than with deltamethrin in 2004.

2005 Bendiocarb 92,440

90,000 88,000 86,000 Round 1

Round 2

communities throughout the island about impending spraying activity, meeting with community leaders to mobilize community support. Since sprayteams visit almost all households on Bioko, this contact also provides an important vehicle for spreading and reinforcing educational messages. For example, information on how to prevent exposure to insecticide, how to maximize the useful life of the residual spray, and where to seek help in case of fever and suspected malaria. The spraymen also obtain informed consent from households to have their homes sprayed and record important data on spray coverage. Baseline data An IRS spray database is used to track and regulate insecticide usage by spray point, sprayman and date. It records the number of rooms sprayed and surface area covered, and allows for detailed analysis of insecticide usage. This is compared with records on the number of insecticide sachets distributed by the central or provincial store per

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Round 3

day. Excessive (or sub-optimal) usage is quickly spotted so follow-up inspection and remedial action can be taken. 96 window traps were also installed in 16 sentinel sites located around the Island. Daily mosquito catches from these traps are counted and analyzed for malaria infectivity by species. A baseline survey of 575 households living in the environs of these same sentinel sites was completed in February 2004. This included data on all-cause infant and child mortality (under 5 years, data from 1,137 mothers); parasitemia and anemia analyzed in blood smears from 2,440 children under 15 years of age; IRS and insecticide-treated net coverage; self-reported morbidity requiring or undergoing anti-malarial treatment and prevention. Subsequent household surveys have been conducted annually. These surveys provide statistically significant comparisons between sentinel sites each year, as well as comparisons between years at the same site.

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Average no. mosquitoes / trap / 100 nights

Impact on malaria vector count island-wide 60

Round 2 Carbamate

Round 1 Pyrethroid

Round 3 Carbamate

40 30 20 10 0 12 01 02 03 04 05 06 07 08 09 10 11 12 01 02 03 04 05 06 07 08 2003

An. funestus An. gambiae

2005

2004

Average number An. gambiae and An. funestus per trap per 100 nights (December 2003 – August 2005)

GRAPH adapted from data produced by Medical Research Council, Durban, South Africa.

The baseline data indicated that one-fourth of the total trapped mosquitoes were malaria vectors. In addition, overall human infection with Plasmodium falciparum was about 45% with rural prevalence being somewhat higher than urban prevalence. Three-quarters of children aged 1-14 were anemic, with a significantly higher rate among children suffering from malaria. The baseline mortality for children under 5 years was estimated as 169 per thousand births.

By reducing the need to spend money on malaria treatment the BIMCP benefited all households, but in particular those who can least afford treatment. Analysis of malaria treatment costs before and after the first round of spraying revealed that IRS resulted in savings equaling about 8% of the poorest households’ total annual income and 3% of the wealthiest. Malaria control can clearly be viewed as an important component of national poverty alleviation in highly endemic countries.

Life saving results

Insecticide resistance necessitated alternatives

The 2004 IRS program was originally based on a single spray round using a long-lasting WP formulation of deltamethrin (K-Othrine® WP). The impact of the BIMCP on malaria transmission was based on the mosquito capture data from the 96 window traps. After the first round of spraying the average number of infected mosquitoes was reduced by 80%. The percentage of children on Bioko Island with malaria parasites in their blood was reduced by 30% (see box: Significant impact of IRS on malaria).

The window trap samples are also analyzed for the presence of the pyrethroid knock-down resistance genotype. The knock-down resistance genotype was first reported in malaria vectors collected on Bioko in 2002. After the first spray round in 2004 knock-down resistance was found to have emerged rapidly in the mosquito population of An. gambiae. On the contrary the spraying effect on An. funestus was drastic (see chart above). Since knock-down resistance genes also

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confer resistance to DDT, this compelled the BIMCP team to recommend a switch from deltamethrin to a WP formulation of bendiocarb (FICAM® WP), a carbamate insecticide. However, carbamates have an expected shorter residual life than pyrethroids, meaning the switch would require twice-yearly spraying, effectively doubling annual operating costs. Marathon Oil and its partners supported this switch and agreed to absorb the higher costs associated with the enhanced spraying campaign and more expensive bendiocarb product. Two rounds of spraying with bendiocarb were conducted in 2005 (see chart page 41: Indoor residual spraying), and the project initiated its fourth round of spraying with the product in February 2006. Rotation of insecticides back to pyrethroids is also being considered for future years. 4:1 benefit to cost ratio Total BIMCP expenditures in the 1st year of operations were roughly US$ 2.3 million, including training, equipment, etc., that will be used over the lifespan of the project. Estimated savings in treatment costs for averted malaria cases resulting from the first spraying round in 2004 were US$ 10.8 million. This represents a minimum benefit to cost ratio of 4:1 for the first year of the project – in other words US$ 4 in benefits for each US$ 1 invested by Marathon and the Government of Equatorial Guinea. In the short-term IRS is clearly a more expensive malaria control intervention than LNs. But the ability to achieve high coverage within a fairly short time, considerably reducing malaria transmission and hence the burden of malaria, makes it a relatively cost-effective alternative.

Significant impact of IRS on malaria Although detailed analyses of the impact of IRS are still underway, preliminary results are highly encouraging and fully consistent with expectations. The following data reflect the results obtained after the 1st sprayround of only using pyrethroids in 2004. • The total number of infective An. gambiae and An. funestus caught in window traps was reduced to 24% and 8%, respectively, of pre-spray levels. • Within 4 months the total number of An. gambiae in the window traps increased very rapidly giving a clear indication of resistance against the pyrethroid used. • Parasitemia prevalence among under 15 year olds was reduced from 46% in 2004 to 31% in 2005. • Anemia among under 15 year olds was reduced by 10%, from 76% in 2004 to 66% in 2005. • The self-reported probability of clinical malaria decreased by 67% between 2004 and 2005. • Registered malaria cases among oil workers decreased by 65% between 2004 and 2005.

will help ensure that transmission does not rebound and that the incidence of malaria remains low to non-existent. Lessons learned

Moreover, the savings in avoided treatment costs are also expected to have an important welfareenhancing effect on the population. It should release more of their income for other essential basic needs, goods and services. In turn, it is hoped this will eventually lead to improvements in housing and environmental conditions, which

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• IRS is very effective in reducing malaria transmission and associated parasitemia prevalence on Bioko Island, even after just one round of spraying. • IRS also has a significant impact on reducing anemia and the reported incidence of clinical malaria infection.

Photo: Marathon Oil Corporation

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WITH THE HELP of handheld wireless devices surveyors collect family medical data.

• The Bioko experience confirms that IRS is a cost-effective strategy for malaria transmission reduction in high transmission, hyper-endemic island contexts. • The benefit of IRS has an appreciable impact on poverty alleviation. • The impact of IRS on transmission reduction enhances the likelihood of sustainability of other integrated malaria control initiatives. • The BIMCP contract between Marathon Oil and the Government of Equatorial Guinea provides a framework for co-financing malaria control. • The unique multi-stakeholder partnership has greatly enhanced opportunities for achieving rapid and substantial success. Partnerships similar to the BIMCP offer international corporations a viable model for engaging in population-based health activities that are outside their line of business. The model shows how corporate socially responsible investments can maximize the positive impact on the people of the country or regions where they are working. • The BIMCP has direct benefits for Marathon Oil and its corporate partners (healthier workforce), which will enable it to continue to expand its activities on Bioko and improve work conditions for its employees.

As has been shown the use of IRS is an adequate and cost-effective tool to impact malaria. Nevertheless, it will fail when resistance occurs, such as pyrethroid / DDT kdr type. The rotational use of a non cross resistant chemical class (here a carbamate – bendiocarb) makes continuation of intervention possible. Because of the economical impact, a switch back to a pyrethroid (for example, when the resistance level has gone down) has to be an integral part of the plan. CONCLUSION Results after just two years indicate that the BIMCP is having a rapid and substantial impact on reducing transmission as well as the incidence of malaria on Bioko Island. This has attracted considerable international donor attention, encouraging further funding by the Global Fund to fight AIDS, Tuberculosis and Malaria to extend the BIMCP to the Island of Annobon and mainland Equatorial Guinea (starting in 2006). The newly launched US Presidential Malaria Initiative has also awarded a grant to MCDI to reinforce the capacity of the Ministry of Health and Social Welfare of Equatorial Guinea, particularly in the area of developing health information systems. When combined with the BIMCP resources, this will greatly enhance the potential for substantially reducing malaria transmission and associated malaria morbidity and mortality throughout Equatorial Guinea. This article is based on contributions by Dr Luis Benavente and Dr Christopher Schwabe (MCDI), and Dr Adel Chaouch (Marathon). You can find the article as well as the scientific report (and references) on the enclosed Public Health CD-ROM.

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VECTOR CONTROL

Chikungunya outbreaks in Indian Ocean islands

Mosquito-borne viral disease Chikungunya means “stooped walk” in Swahili, describing how someone suffering from the disease moves. Like dengue fever, chikungunya is a viral disease transmitted by mosquitoes. In 2005 and 2006 an epidemic of chikungunya spread among the islands of the South-West Indian Ocean, affecting the Comoros, Mayotte, La Réunion, Mauritius, Seychelles and Madagascar. a Réunion appears to have been the most seriously affected; the number of cases is estimated to have surpassed 260,000 – approximately one-third of the total population. The great majority of these occurred in the first few months of 2006. However, by mid-2006, the cooler, drier austral winter season, the incidence rate had declined to very low levels.

dengue-like syndrome, with sudden onset of fever and joint pains, particularly affecting the hands, wrists, ankles and feet. Severe chills, leucopenia and a maculopapular rash are also common, but the infection can also be symptomless.

The virus was first isolated in 1953 from a patient in Tanzania (the former Tanganyika), East Africa. It is an Alphavirus belonging to the family Togaviridae with a geographic distribution that includes sub-Saharan

Photo: Corbis

Long recognized as a self-limiting, often debilitating but rarely fatal illness, chikungunya manifests as a

The author: DR MICHAEL B. NATHAN Vector Ecology & Management, Department of Control of Neglected Tropical Diseases, WHO

VECTOR CONTROL

Africa, South-East Asia and the Indian sub-continent. It is transmitted by mosquitoes, evidence indicating the involvement of Aedes species, including Ae. furcifer and Ae. africanus in Africa, and Ae. aegypti and Ae. albopictus in Asia. The virus has been isolated from nonhuman primates in Africa but in Asia the zoonotic status is not well understood. Extension of geographical distribution Several key features of the recent epidemic have brought unprecedented attention to this arboviral disease. With the exception of the Seychelles, where serological evidence of chikungunya virus was previously reported1, the first is that the Indian Ocean event represents an extension of the geographical distribution of chikungunya virus. Indeed, not only was this essentially a “virgin soil” outbreak, but the public health services of the region had very limited prior experience with

the prevention and control of arboviruses, the exception being a major outbreak of dengue fever in the Seychelles in 1977, and a subsequent but small outbreak in La Réunion in 2004. Ae. albopictus was the probable vector on those occasions. Another striking feature was the explosive nature of the epidemic, especially in La Réunion, where there was an estimated peak incidence of more than 40,000 cases in the first week of February 2006. This is clearly indicative of a highly efficient vector population. Though relatively close to continental Africa, the main African vectors of chikungunya are either absent or rare in the cluster of Indian Ocean islands. In Mauritius Ae. aegypti is reportedly no longer present and in La Réunion, if it persists, it is only as isolated sylvatic populations. Its disappearance from these islands has been attributed to the anophelinetargeted malaria eradication campaigns of the 1960s and 1970s. Ae. aegypti has never been found in the Seychelles. By contrast, Ae. albopictus is widespread in these and neighbouring islands (in Madagascar it is confined to the littoral zone along the east coast) and is considered to have been the main and possibly the only vector. Before the rapid spread of this species to continental Africa, Europe and the Americas during the last three to four decades, the islands of the SouthWest Indian Ocean represented the westernmost limit of its distribution which otherwise was

SYMPTOMS appear 4 to 7 days after being bitten by an infected mosquito. High fever is accompanied by various flu-like symptoms, backache and pains in the muscles, joints or bones. The pain can be so severe that patients are unable to walk.

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Photo: L’ Express de Madagascar

Photo: Reiner Pospischil

THE CHIKUNGUNYA VIRUS is mainly transmitted by Aedes aegypti.

VECTOR CONTROL

Photo: Joerg Heckel

RAIN-FILLED containers such as abandoned tyres provide ideal breeding grounds for Ae. aegypti and Ae. albopictus mosquitoes. These tyres must be removed, destroyed or treated with insecticide.

confined to South-East Asia and some islands of the Western Pacific. Competitive mosquito species On the Indian Ocean islands Ae. albopictus typically breeds in shady and confined rain-filled natural habitats such as plant axils, bamboo nodes and rock holes, and in artificial container habitats such as abandoned tyres (see photo above), saucers under potted plants, and discarded food containers. It is an aggressive and largely outdoor, day-biting species. The fact that the domestic form of Ae. aegypti has been unable to re-colonize the abundant artificial container habitats typical of this species, may be due to factors related to interspecific competition from a long-established Ae. albopictus population. Suffering a range of symptoms From the perspective of clinical presentation, which was well-documented in La RĂŠunion, the severity of illness was particularly noteworthy.

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Neurological signs and fulminant hepatitis were reported among a number of patients with confirmed chikungunya infection. Moreover, among death certificates issued during the first six months of 2006, 240 made mention of chikungunya. However, it is to be noted that morbidity rates due to chronic diseases are high in La RĂŠunion and the majority of registered deaths were among the elderly. This suggests that the infection may have been a contributory factor leading to those deaths but that other underlying health conditions were the primary causes of mortality. Higher virus amplification Genetic studies during the epidemic linked the chikungunya virus to a strain from East Africa2. The researchers were also able to show how subtle changes in non-structural proteins occurred during the course of the epidemic. They hypothesized that these changes may have led to higher virus amplification in the mosquito host, which in turn may have contributed to the explosive increase in transmission during the 2006 rainy season.

VECTOR CONTROL

RECENT OUTBREAKS of chikungunya have been reported from the areas circled in red. See also page 59, Latest outbreaks: Mosquito-borne diseases spreading.

An increase in outbreaks Lastly, the epidemic yet again serves to illustrate how interconnected the world has become. Arbovirus epidemics such as this one cannot be seen as isolated events, even when they occur in areas of relative geographical isolation. Conversely, geographically isolated islands are clearly not without risk for the introduction of new viruses and vectors. There are cultural and trade links between some of the islands and mainland Africa, from where the virus may have been introduced on this occasion. There are also strong national, cultural and tourist links between the islands and mainland Europe as well as to the Indian sub-continent.

La RĂŠunion and Mayotte are overseas departments of France, while the Comoros and Madagascar are former French colonies. Mauritius and Seychelles were British before they gained independence. These links resulted in an estimated 1.5 million people travelling between the islands and mainland Europe in 2004, mostly 3 by air . Not surprisingly, in 2005-2006 the chikungunya virus has been repeatedly imported to Europe, including more than 300 confirmed cases in metropolitan France alone (beyond mainland Europe, cases were also imported to the island of Martinique in the Caribbean, to Canada, India and Hong Kong, among other places).

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VECTOR CONTROL

In Europe this has raised public health concerns about the risk of local transmission in areas where Ae. albopictus has become established and where meteorological conditions are seasonably favorable, e.g. on the south-east coast of France. Additionally, there are close cultural ties between Mauritius and India, where chikungunya has also spread this year. However, it is not clear whether there are any epidemiological links between the two events. Protective measures As with dengue, there is no public health vaccine, nor specific treatment for chikungunya. Measures to control the vector(s) and individual protection against mosquito bites are the only options available for prevention and control. These include chemical methods and, more importantly in the case of Ae. albopictus, the elimination or management of larval habitats that are close to human habitation. Effective implementation of these source reduction measures requires strong social mobilization and communication actions. With the continuing risk of seasonal transmission of chikungunya and of outbreaks of dengue and possibly other arboviruses, efforts are progressing among the islands of the sub-region to strengthen their disease surveillance network and vector control capabilities. CONCLUSION Since last year cases of the mosquito-borne viral disease chikungunya increased dramatically in regions around the Indian Ocean. The main outbreak control activity is mosquito control. In the case of epidemics Integrated Vector Management’s first task is to reduce the mosquito population as rapidly as possible to stop transmission. The long-term goal is to maintain the vector population at a low level with targeted monitoring systems and focused use of vector control measures. 1

Calisher et al. 1981, Bull. WHO, 59: 619-622 Schuffenecker et al. PLoS Medicine, 2006, 3: 263 3 Eurostat

Bayer Environmental Science

Joining forces With the chikungunya outbreak representing a major public health concern, Bayer Environmental Science coordinated with the local health authorities, the French Ministry of Health (La Réunion), the WHO and others in their intervention strategy to fight the further spread of the virus. The most effective and rapid way to control disease transmission is by reducing the mosquito population. Insecticides can dramatically reduce the risk of insectborne diseases. Following an emergency visit after the first awareness of the disease outbreak, Bayer Environmental Science sent a team of technical experts to both Mauritius and La Réunion at the end of March 2006 to advise the Ministry of Health, intervention teams and local authorities and decision makers in “best practice” issues. This included additional training to ensure the appropriate products (such as Aqua K-Othrine®) were used correctly according to label instructions and without risk for humans and the environment. Appropriate insecticides are best applied in intervals shorter than the incubation period of the pathogen in the vector, to prevent spreading of the disease to other regions.

Latest outbreaks of Chikungunya see notes on page 59. Article on the enclosed Public Health CD-ROM

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VECTOR CONTROL

Ethiopia: Support from UNICEF in the fight against malaria

Focus on distributing insecticidetreated nets UNICEF is one of the founding members of the Roll Back Malaria (RBM) partnership initiative and as such supports health authorities in malaria affected countries. Programs running in Ethiopia provide an example of how this support works in practice and which preferences play a role in the treatment of nets. UNICEF sees the focus of its work in the fight against malaria in Ethiopia as supporting the government in various aspects of malaria control, prevention and treatment. This ranges from the use of insecticide-treated nets (ITNs) to case management, involving diagnosis and treatment of malaria. The recently introduced rapid diagnostic tests, which like pregnancy tests can be used at home, represent a big shift in case management. UNICEF also works in social communication at the community level – training, discussion groups, distribution and treatment of nets. Distributing 2 million ITNs Programs focusing on the use of insecticide-treated nets for personal protection have proved highly successful. For example, in 2005 the Ethiopian government purchased 1.2 million nets and a further 1.8 million through UNICEF, including 1 million K-O TAB® 1-2-3 kits. This made it possible to distribute two million insecticide-treated nets throughout hundreds of emergency prone districts before the malaria season in September. In many cases, these nets were treated in front of the recipients, an important tool for health education. In addition, UNICEF consultants helped with distribution plans, micro-planning, training

for net treatment, monitoring and evaluation. A list was developed of all villages most prone to malaria, and the consultants worked out the number of nets needed for maximum coverage – two nets per household. In some villages the number of treated nets has now reached 80%. Different treatment methods used The regional health authorities decided how to treat the nets, choosing between three main methods. The first method was based on mass treatment – 4 thousand nets were treated in one place by 30 trained people. This process lasted 3-4 weeks and then the nets were distributed via health centers. However, this chosen method only involved a small proportion of the total nets. With the second method 325 emergency villages were chosen as a priority and it was decided to add the nets to existing distribution programs such as medicines. The nets were treated in front of the recipients. Women and children (particularly under 5) are the key targets here. This is important for health education, since the recipients, i.e. mothers and older children, SOME 200 CHILDREN saw nets being treated at each site every day.

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then go and put the nets up in their huts. Around 200 children per day at each site saw the nets being treated. The so-called intermediate method involved some nets at health centers. These nets were treated as they were distributed to ensure 100% treatment. This strategy was based on the general observation that in Ethiopia it is more difficult to get people to re-treat their old nets than elsewhere.

Photos: Melanie Renshaw

VECTOR CONTROL

Before the malaria season ® K-O TAB 1-2-3 played an important role in the treatment of nets, particularly in regions with a better capacity to treat nets. These treatment kits were also chosen because it was faster to treat and distribute such ITNs than to obtain pre-treated nets – ahead of the malaria season.

The use of a binder in the K-O TAB® 1-2-3 formulation means the insecticide remains active for up to 20 washes. This is a key point in a continent where as many as 120 million untreated nets already exist and where many people do not treat their nets regularly. Although not WHOPES approved (expected December 2006), studies on the wash resistance of such treated nets have been encouraging. These results certainly were an important factor in the Ethiopian government’s choice. CONCLUSION With children being one of the main groups affected by malaria, and as a member of the RBM partnership, UNICEF is closely involved in programs to combat this disease. In Ethiopia, where many people do not re-treat their old nets, UNICEF focuses on regional treatment programs to convert mosquito nets into long lasting insecticide-treated nets (LNs). This proved to be faster than obtaining pre-treated nets in order to provide as much personal protection as possible before the malaria season. Article on the enclosed Public Health CD-ROM

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MASS DIPPING OF NETS, drying and packing.

NGO

Non-governmental organizations

Their help is increasingly important Independent of governments, NGOs today make an invaluable contribution to international development. They typically focus on social, human rights, welfare, relief, health and environmental issues, and generally depend on donations and voluntary service. The following is a brief introduction to NGOs in general and marks the beginning of a series of specific portraits. he World Bank defines NGOs as “private organizations that pursue activities to relieve suffering, promote the interests of the poor, protect the environment, provide basic social services, or undertake community development”. However, the term NGO is very broad and covers many different types of associations, including private voluntary organizations (PVOs), communitybased organizations (CBOs, also known as grassroots organizations) and charities.

Two centuries of development Voluntary associations of citizens have existed throughout history, but NGOs as known today developed over the last two centuries. One of the

first was the International Committee of the Red Cross, established in 1863. The term “non-governmental organization” was introduced with the founding of the United Nations in 1945, and today many international NGOs act as consultants for various UN agencies. There are now thousands of NGOs of every size and form throughout the world: in 1995 a UN report estimated nearly 29,000 international NGOs, most created in the previous 30 years, and even more national ones (e.g. about 2 million in the US and 65,000 in Russia). Current estimates of national NGOs in developing countries lie between 6,000 and 30,000.

Photo: Knut Mueller / Das Fotoarchiv

THE MAIN MISSIONS of NGOs are addressing important public health issues helping disadvantaged populations access health care and putting an end to local and global poverty.

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NGO

Funding large budgets

Photo: Sebastian Bolesch / Das Fotoarchiv

In 1992 international NGOs channeled over US$ 7.6 billion of aid to developing countries. Today this sum is considerably more. Major sources of NGO funding include the sale of goods and services, private donations, and grants from international institutions or national governments. Although “NGO” implies independence from governments, some NGOs depend heavily on them for their funding. For example, about a quarter of the income of the famine relief organization Oxfam is usually funded by the British government and the EU, and Médecins Sans Frontières receives almost 50 percent of its income from government sources. NGOs’ strengths, roles and missions The specific strengths of NGOs lie in their strong grassroots links, field-based expertise, ability to innovate and adapt, application-oriented approaches, hands-on methods and tools, longterm commitment, and finally their cost-effectiveness. They also play an important role in employing people in developing countries, where local expertise is often undervalued. NGOs focus on humanitarian issues, developmental aid and sustainable development. Indeed, the vital role played by NGOs in sustainable development was recognized in Agenda 21 of the Rio de Janeiro Convention in 1992. Some NGOs act primarily as lobbyists, raising awareness, acceptance and knowledge, while others mainly conduct programs and activities – although these activities often overlap. Development NGOs notice immediate needs and respond to them, delivering services directly to those affected. They are actively involved in food distribution, disaster relief, homeless/refugee shelter, vaccination programs, family planning, pre- and post-natal care, and ultimately building up self-reliant, sustainable local action. Their main mission is putting an end to local/global poverty,

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MANY NGOs are actively involved in food distribution, disaster relief and refugee shelter, delivering services directly to those affected.

helping disadvantaged populations access health care and addressing important public health issues. Focusing on specific NGOs In this, and future editions of Public Health Journal we will be presenting short profiles of NGOs and non-profit organizations involved in issues relevant to the topics and fields addressed by Bayer Environmental Science. We are starting this series on the next page with a brief look at Population Services International (PSI). More www.coregroup.org/working_groups/malaria.cfm

Article on the enclosed Public Health CD-ROM

Photo: 2006 PSI Malaria Department

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CURRENTLY providing insecticide treated mosquito nets (ITNs) to 28 countries in Africa, Asia and South America, PSI is one of the largest distributors of ITNs in the world. Last year PSI delivered over 10 million insecticide treatment kits for converting nets in the field into ITNs (and LNs), making them one of Bayer’s primary customers for K-O TAB® and K-O TAB® 1-2-3.

NGO Profile: PSI

Success with measurable health impact PSI is one of the leading non-profit organizations in the world. This is effectively highlighted by its activities and successful projects in 70 countries, focusing on major health concerns such as HIV/AIDS, malaria, nutrient deficiencies, safe water and family planning. The following article provides a brief introduction to PSI. hereas business operations measure their success in financial assets, PSI measures its success in impact on health, disease and death. In 2004, PSI calculated that its programs directly prevented 650,000 HIV infections, 6.1 million unintended pregnancies, 11.5 million bouts of malaria and a variety of other global health problems.

program offices worldwide. Here, PSI actively supports Ministries of Health in 70 developing countries, offering a wide range of health products and services, and is involved in 30 malaria country programs. PSI delivers products and services to improve health and save lives in populations vulnerable to malaria, HIV/AIDS, contaminated water and other major public health concerns worldwide.

Global engagement to save lives Population Services International (PSI) is a nonprofit organization based in Washington D.C. But with only 151 US staff, its global engagement is reflected by the 7,000 local PSI staff working at its

Founded in 1970, PSI initially worked in family planning (hence the name Population Services International) in Bangladesh, Kenya, India, Pakistan and Sri Lanka. In 1980, PSI launched oral rehydration salts in Bangladesh and in 1988

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NGO

started its first HIV/AIDS prevention project in the Democratic Republic of Congo (DRC). PSI turned to the problems of malaria and safe water systems in the mid-1990s, pioneering one of the world’s first insecticide treated mosquito net (ITN) projects in the Central African Republic in 1995. PSI’s mission is “to promote health products and other types of healthy behavior that enable lowincome and other vulnerable people to lead healthier lives.” In particular, this involves numerous programs for targeting heavily subsidized prevention and treatment products directly to risk groups. Malaria control means prevention and treatment PSI’s numerous activities and global engagement in public health are exemplified by its contributions to combating malaria in many developing countries. PSI tailors its malaria control programs to fit the needs of each country, their Ministry of Health and the local RBM partnership. PSI programs focus on delivering insecticide treated mosquito nets (ITNs) and long lasting insecticidal nets (LNs) to malaria risk groups – especially pregnant women and children under five – as well as marketing a pre-packaged therapy (PPT) for treating malaria. Targeting of highly subsidized, or even free, malaria prevention and treatment products directly to the most vulnerable groups is combined in parallel with stimulating the commercial sector. Segmented delivery Such segmented delivery (based on population variables such as risk, access, socio-economic status, etc.) not only increases the availability of effective and affordable malaria products to all, but also maximizes efficient and sustained product delivery. When suitably managed, it can operate smoothly in parallel within the same country. Two examples of such programs are Smartnet in Tanzania and the Malawi ITN delivery model (see issue No. 17 of Public Health Journal).

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Today, PSI manages ITN projects in 28 countries in Africa, Asia and South America. In 2005 alone, PSI delivered more than 3.5 million malaria treatment kits, 8.5 million insecticide treated mosquito nets (50% LNs) and over 10 million insecticide treatment kits, making it one of the largest distributors of ITNs in the world and an important actor in the global Roll Back Malaria (RBM) partnership. Donors provide vital support As a non-profit organization PSI depends upon financial donations to support its, often highly subsidized, projects worldwide. Major PSI donors include US, UK, German and Dutch governments, the Global Fund to fight Aids, TB and Malaria (GFATM), UNICEF, the Bill and Melinda Gates Foundation and other private foundations. CONCLUSION The non-profit organization PSI carefully calculates its contribution to improving health and saving lives worldwide. Its combined product delivery strategies not only deliver prevention and treatment products and services to people most at risk, but also stimulate efficient and sustained product supplies. The recently launched PSI link to malaria provides a range of downloadable sources of malaria information (www.psi.org/ malaria/malaria-downloads.html). The paper on The Costs and Effects of the Malawi ITN Model (http://www.malariajournal.com/content/pdf/1475-2875-4-22.pdf) provides detailed figures for economically evaluating the cost-effectiveness of ITN programs. www.psi.org

Article on the enclosed Public Health CD-ROM

NGO

Interview with Desmond Chavasse, Global Director of Malaria Control

In malaria control – one size does not fit all Why did PSI decide to add malaria to its activities and how important is that area to PSI? Currently malaria control represents the fastest growing program area for PSI and is one of our core activities. We added malaria control to our activities because of the severity of the disease in the countries in which we have programs and because we have a comparative advantage in supporting Ministries of Health in the delivery of effective malaria prevention and treatment products accompanied by behavior change communications. Based in Nairobi, Kenya, Dr. Chavasse is responsible for PSI’s malaria control programs in 30 countries in Africa, Asia and Latin America. He has 19 years experience in the control of vector borne diseases, particularly malaria and the analysis of ITN delivery models in the field.

What are the reasons for PSI focusing on ITNs in its malaria control programs? Distribution of ITNs and LNs is an important part of PSI’s malaria control activities because our programs are able to leverage a broad range of public, private and NGO delivery channels appropriate for maximizing access to malaria vulnerable groups. PSI now focuses equally on increasing access to effective malaria treatment, particularly the new artemisinin-based combination therapies (ACTs), through delivery of prepackaged drugs in combination with provider training and communications campaigns to improve treatment seeking behavior.

ing ITNs across malaria affected countries vary immensely and this demands tailored approaches to delivery in line with national guidelines determined by Ministries of Health. Depending on the context, delivering nets free of charge as part of vaccination campaigns, sustained supply of nets or vouchers through antenatal clinics, distribution through NGO networks and supply through commercial channels all have a role and PSI practices all of them as the situation demands. You will never hear me describe PSI’s approach to ITN delivery as “social marketing”. We simply use our comparative advantage in procurement, distribution, marketing and communications to maximize access to vulnerable groups under prevailing local conditions. What was the basic rationale behind your decision to go ahead with the long lasting re-treatment, K-O TAB® 1-2-3, in Tanzania and Kenya? The decision was easy. There is no other product currently on the market which is able to increase the effective life of a traditionally treated mosquito ® net. While the effective life of K-O TAB 1-2-3 under field conditions has yet to be determined, there is already sufficient evidence to indicate that it will last longer than traditional treatments. Therefore, the bundling of traditional nets with ® K-O TAB 1-2-3 will provide significantly greater health impact than untreated nets bundled with traditional treatment kits when LNs cannot be considered. Furthermore, campaign treatment of nets in the field with K-O TAB® 1-2-3 can convert a crop of traditional nets to longer lasting insecticidal nets.

Is there a best model to get ITN/LNs to the people who need them? The quick answer is no – one size does NOT fit all. The opportunities and constraints to deliver-

PSI has reached an agreement with Bayer Environmental Science to implement several million units of K-O TAB® 1-2-3 in Tanzania.

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Photo: Elisabeth Friedrich

NGO

Aid project in the Ssese Islands

Mosquito nets for orphans With no publicity, limited resources, but considerable personal engagement, private initiatives are making a vital contribution to development aid. An example is an aid action for orphans in the Ssese Islands on Lake Victoria in Africa (Uganda) coordinated by a German midwife. lisabeth Friedrich makes it clear that her work is no more than “a drop in the ocean.” But in the villages on the Island of Bugala, as well as on the small neighboring islands this aid can save lives and improve chances for the future.

The high number of orphans can be explained by the fact that many parents die not only from malaria, but above all from AIDS. HIV-infected parents often move back to the island with their children. When the parents die the children remain there alone and urgently need help. Since 1999 this sprightly senior citizen has met the call from the episcopal house Masaka (Uganda) through the Senior Citizen Expert Service. In the meantime, with support from friends, projects include renovating the outpatient station as well as building a primary school and orphanage. A rainwater storage system was installed for the dry

season. A larger outpatients station with a laboratory is currently being built – although the project keeps being delayed due to a shortage of money. In her arduous travels over the island Elisabeth Friedrich searches for orphans living in huts in the scattered villages. Included in the aid provided are school exercise books and rolls of material for school uniforms, which are sewn by women’s groups – but above all mosquito nets to protect the children particularly at risk (up to the age of five) from malaria. Nets together with treatment kits (K-O TAB®) are provided by Bayer Environmental Science and its local partner Quality Chemicals. They are distributed locally by Elisabeth Friedrich through the women’s groups. Elisabeth Friedrich: “We rely on such help!” More www.ugandasseseisland.com (in German)

Article on the enclosed Public Health CD-ROM PUBLIC HEALTH JOURNAL 18/2006

NOTES

RBM Partners in Dakar: Countries identify resource requirements RBM Partners worked with fifteen countries in Dakar between 7-15 September 2006 to identify the resource requirements that would enable sustainable impact – and reduction in deaths from malaria by 2010/15. The World Bank held an intensive five-day Regional Workshop at

which partners developed the necessary strategies to address gaps – financial and programmatic – so as to provide harmonized support to country programs and to attract additional resources from major donors. In preparation for the Workshop, National Malaria Control

Malaria commitment: Clinton Global Initiative annual meeting RBM Partnership presented its commitment to heads of state, CEOs, religious leaders, philanthropists, NGOs and foundation heads at this years annual meeting of the Clinton Global Initiative (CGI) in New York, 20-22 September 2006. The commitment seeks to strengthen the capacity of 30 countries to foster a community-driven response to malaria, and to increase access to and use of current malaria interventions. First Lady Laura Bush backed

the malaria fight by announcing a US Malaria Summit, billed for December 2006. Quoted from RBM Newsletter

Managers undertook a procurement and supply chain management workshop and a detailed and comprehensive review of their country plans, sharing experiences and challenges to scaling-up malaria control. Quoted from RBM Newsletter

Asia: Countries vow to step up malaria fight Facing a resurgence of malaria in much of southern and southeastern Asia, health ministers from 11 countries in the region pledged after meeting in Bangladesh in August to bolster the fight against the disease. The ministers from such countries as India, Sri Lanka and Thailand said they would boost spending to prevent malaria and set a goal of giving 80% of households access to pesticide-treated mosquito nets by 2010. Quoted from UN Wire Newsletter

Erratum In our previous issue of Public Health Journal No. 17 we mentioned on page 23 that for nets which incorporate insecticides into the extruded fibers the label recommendation is to heat up the net to enhance faster migration. Sumitomo brought to our attention that this recommendation does not exist for the Olyset label and it is definitely not a recommendation of Sumitomo.

More www.unwire.org http://rbm.who.int/

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NOTES

India: Vector management

WHO: IRS as primary intervention against malaria On 15 September in Washington, the World Health Organization launched a Position Statement on the use of Indoor Residual Spraying (IRS) stressing that it must be considered a primary intervention against malaria,

together with insecticide treated nets, and artemisinin-based combination therapies (ACTs). WHO commits to work more closely with countries to expand and improve IRS interventions. Quoted from RBM website

As part of vector control programs in areas with increased risk of malaria, the National Institute of Malaria Research (NIMR) is conducting field trials on suitable formulations for converting nets into LNs using K-O TAB® 1-2-3 from Bayer Environmental Science (see page 32). In addition, bendiocarb WP 80% (Ficam) has recently been registered in India and will be introduced in malaria control programs for rotational use in resistance management – pending a TAC implementation decision (see page 37).

Latest outbreaks: Mosquito-borne diseases spreading Recent outbreaks of mosquitoborne diseases across India have caused many deaths and overwhelmed hospitals and clinics. With 71 deaths in the southern state of Kerala in September 2006, severe outbreaks of chikungunya reported from southern India and Pakistan suggest that it is rapidly moving north. The Indian Government took political steps and measures for Integrated Vector Management, including the use of space sprays to stop the outbreak. Health Ministers of boarder states attended a meeting at Bangalore from 18-20 July, where they requested Rs 800 million from the central

Government for chickungunya control. They also recommended establishing chickungunya referral laboratories in each affected state. The Joint Director of Health from Karnataka State had already issued a circular to all District Malaria Officers in March 2006 on how to tackle outbreaks of chikungunya. Experts assume that chikungunya is not a “new” disease, but that in the past many cases were thought to be dengue fever. However, dengue fever itself is also causing grave concern, with almost 600 cases and over 93 deaths reported in India over six weeks in August/September. On

October 5, the Guardian newspaper reported that three members of the prime minister's family were taken to hospital suffering from high fever symptomatic of dengue. Scenes of panic in Delhi earlier that week were due to doctors turning away patients suspected of having dengue fever because of a lack of blood supplies for transfusions. These mosquito-borne diseases are also on the increase in Asia. There have been more than 160 deaths from dengue fever in the Philippines this year, and Indonesia has recently reported an outbreak of chickungunya (see article on page 45).

Sources: WHO, UN Wire Newsletter, the Guardian

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NOTES

Yaoundé: Call to action on Malaria The Roll Back Malaria (RBM) Partners’ Forum V held 18-19 November 2005 in Yaoundé, Cameroon, aimed to refocus global efforts to fight malaria and overcome the barriers that are hindering progress. The key recommendations of the meeting were synthesized in the Yaoundé Call to Action, a commitment by all partners and stakeholders to ensure coordinated, harmonized and intensified activities over the next ten years.

NICEF Ambassador Yvonne Chaka Chaka, Assistant Director General of the World Health Organization (WHO) Dr. Anarfi AsamoahBaah, and AIDS activist Milly Katana were among those who urged the assembled Ministers, representatives of lead UN agencies, non-governmental organizations, the private sector, communities and key malaria stakeholders to use the current momentum to combine forces and accelerate scale-up of malaria control. “Today there is global recognition that this disease can and must be tackled as a matter of urgency,” stated Mr Olanguena Awono, the host Minister of Health. “All of us have the collective responsibility

to stop malaria claiming the lives of millions. We have the tools, there is increased funding – now we must act.” Focus on women and children The RBM partners were also challenged to look at malaria from a gender perspective. “It is critical that women at every level come together to create awareness of the magnitude of the problem and highlight the inequalities that impact women, as primary health care givers and sufferers of malaria. The integration of a gender perspective for effective malaria control is crucial,” said ChakaChaka, UNICEF Ambassador for malaria. And according to Dr Awa Marie Coll-Seck, Executive Secretary of the Roll Back Malaria Partnership: “The gender perspective on malaria research and all areas of malaria control implementation has been neglected in the current global response to the disease mainly because there is little understanding of the gender aspect of malaria.”

Photo: Bayer Imagebank

Taking the actions forward With a sense of urgency the RBM partners committed themselves, to take forward the actions agreed at the Yaoundé RBM Partners Forum, including the following priority actions, and to implementing the RBM Global Strategic Plan 2005-2015, holding each other accountable to its resource needs, targets and timelines:

WOMEN AND CHILDREN bear the greatest burden of malaria as primary health care givers and sufferers of the disease.

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NOTES

Key recommendations Under the banner “United against malaria to save lives and reduce poverty”, the participants of the RBM meeting expressed their commitment to work together to rapidly scale-up action against malaria. These are their key recommendations: Considering the magnitude of the disease, in particular its devastating impact on young children and pregnant women, and its economic consequences in Africa. Acknowledging that the implementation of effective interventions has enabled some countries to reduce the illness and death caused by malaria, we note with concern that the targets of the Abuja Declaration on Roll Back Malaria in Africa of April 2000 have not been achieved. Recognizing that these successes can be replicated provided sustained funding is available and is complemented by national leadership and mobilization of adequate human resources at all levels of the health system. Alarmed that current levels of global spending on malaria control are only 20% of the estimated US$ 3 billion needed annually, and deeply concerned about the lack of long-term predictability of funding that is provided. Acknowledging that adequate investment in, and incentives for, research and development are required to ensure new and effective medi-

• National governments should continue to develop national plans for scaled-up action, linked to health and development plans, through participatory mechanisms, establish broad based national coordinating mechanisms and scale-up programs. • In supporting national governments all other RBM partners, consistent with principles agreed in Paris in March 2005 (Paris Declaration on AID Effectiveness), should base their overall support on countries’ national strategies and implement, where feasible, common arrangements at country level for planning, funding, disbursement, moni-

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cines, diagnostics, vaccines, vector control tools and strengthened health systems. Building on all previous commitments and targets to roll back malaria, and recognizing that increased global attention to development and poverty reduction as expressed in the Millennium Development Goals, has created an unprecedented opportunity for rolling back malaria. Aware that the effects of malaria reach far beyond health and that the response requires the involvement of society as a whole. Emphasizing the importance of national leadership for a single coordinating authority, a single national plan and a single monitoring and evaluation framework. Our duty is to the people and communities that suffer most from malaria, but whose voices are all too often not heard. High-level commitment and action is needed by all partners led by the principle of local ownership of the challenges and solutions for reducing the devastating impact of malaria.

toring, evaluating and reporting to government on activities, progress and impact. • To rapidly establish monitoring mechanisms to ensure mutual accountability to these commitments, and joint review of progress towards them. The RBM partners who met in Yaoundé invited all those who share their commitment to engage in this Call to Action. More www.rollbackmalaria.org/forumV/

NOTES

History: Discovering the malaria parasite Plaguing mankind since prehistoric times, there had long been those who argued that the “ague” was caused by “pestiliferous miasmas” from swamps. Acquiring the name malaria in the 18th century, the disease was common in Ancient Asia, the Near East and early Europe – Roman soldiers even died of malaria in Scotland. But although continuing to be a major problem in warmer climates, it had virtually disappeared from Europe by 1880, the year Charles Louis Alphonse Laveran discovered the malaria parasite. Malaria (bad air), or “intermittent fever” had long been a concern of naval and army doctors because of its devastating effects on those involved in campaigns or explorations abroad and European colonialism. The Frenchman

SKETCH of an infected Anopheles mosquito by Ronald Ross, 1902.

Charles Louis Alphonse Laveran (1845-1922) came from a medical military background and was himself an army physician. Born in Paris, he went to Algeria with his family when he was very young. He returned to France when his father was appointed

professor at the École de Val-deGrâce, a position Laveran later held twice. Seen through a microscope However, it was during the period between these two appointments, when posted to Algeria (1878-83) that he decided to study malaria. Thanks to the discovery of the microscope he managed to observe the malaria parasite in the blood of malaria patients. In 1882 he visited Rome to confirm that the blood parasites he had observed in Algeria were present in malaria patients from Campagna, Italy. He concluded that these protozoa were the cause of malaria. Although initially met by skepticism, his results were subsequently confirmed by scientists from many countries.

Charles Louis Alphonse Laveran

He continued his research into disease-causing protozoa and in 1907 was awarded the Nobel Prize in medicine for his work. His interest in malaria continued and he was the first to suggest that the malaria parasite must exist outside the human body. Linking mosquitoes with malaria The life cycle of the parasite was determined by Camillo Golgi, and the mosquito’s role in its transmission by Ronald Ross, Patrick Manson, Amico Bignami and others. Laveran was closely involved in investigating relationships between Anopheles and malaria. Armed with this information, he could then focus on campaigns to combat this endemic disease, particularly in swamps in Corsica and Algeria.

Sources The Fever Trail: In search of the cure for malaria by Mark Honigsbaum Mosquito: The Story of Man’s Deadliest Foe by Andrew Spielman, Michael D’Antonio Dictionary of the History of Science, Macmillan Press Ltd. http://nobelprize.org/medicine/laureates/1907/laveran-bio.html

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Link List

Events

With reference to the topics in this issue of Public Health Journal we include a summary of the main Internet links, where you can find further information, the latest reports and statements.

2nd International Workshop on Resistance Management 22 - 24 November 2006, Durban, South Africa

AFRICA MALARIA DAY / REPORT 2006 www.rbm.who.int/amd2006/index.html Bill & Melinda Gates Foundation www.gatesfoundation.org Centers for Disease Control and Prevention www.cdc.gov/malaria CORE (NGOs) www.coregroup.org CropLife International www.croplife.org DFID Department for International Development (UK) www.dfid.gov.uk Insecticide Resistance Action Committee (IRAC) www.irac-online.org International Federation of Red Cross and Red Crescent Societies www.ifrc.org Liverpool School of Tropical Medicine www.liv.ac.uk/lstm London School of Hygiene and Tropical Medicine (LSHTM) www.lshtm.ac.uk Malaria Research Council (MRC) South Africa www.malaria.org.za National Institute of Malaria Research (ICMR) Delhi www.mrcindia.org NetMark www.netmarkafrica.org PMI (Presidentâ&#x20AC;&#x2122;s Malaria Initiative) www.fightingmalaria.gov PSI (Population Services International) www.psi.org The Global Fund to fight AIDS, tuberculosis and malaria www.theglobalfund.org The United Nations Foundation www.unfoundation.org The World Bank www.worldbank.org/malaria UNICEF www.unicef.org United Nations Development Programme www.undp.org USAID www.usaid.gov WORLD MALARIA REPORT 2005 www.rbm.who.int/wmr2005/ WHO / Global Malaria Programme (GMP) www.who.int/malaria/ WHO / WHOPES www.who.int/whopes/

5th European Congress on Tropical Medicine and International Health 24 - 28 May 2007, Amsterdam, Netherlands www.trop-amsterdam2007.com

Bayer Environmental Science

FOR INFORMATION PLEASE CONTACT Business Manager Vector Control Dr Gerhard Hesse email: gerhard.hesse@ bayercropscience.com Australia / Pacific Justin McBeath email: justin.mcbeath@ bayercropscience.com CARTSEE Muge Yagcioglu email: muge.yagcioglu@ bayercropscience.com India Dr Anil Makkapati email: anilkumar.makkapati@ bayercropscience.com Latin America Claudio Teixeira email: claudio.teixeira@ bayercropscience.com MENAP Ashraf Shebl email: ashraf.shebl@ bayercropscience.com Southeast Asia Jason Nash email: jason.nash@ bayercropscience.com Dr Nai Pin Lee email: naipin.lee@ bayercropscience.com Sub-Saharan Africa Mark Edwardes email: mark.edwardes@ bayercropscience.com

You can find all links on the enclosed Public Health CD-ROM PUBLIC HEALTH JOURNAL18/2006

RESISTANCE

is not only an issue concerning mosquitoes and Chagas bugs as vectors of important tropical diseases, but also a problem affecting a whole range of public health pests. In various countries the control of cockroaches and houseflies, as carriers of various disease causing bacteria, fungi, etc., has become very difficult due to rapidly spreading resistance. Even decades ago head lice and bedbugs were among the first pests to develop resistance.

A Business Operation of Bayer CropScience