Cost-comparison of DDT and alternative insecticides for malaria control

In anti-malaria operations the use of DDT for indoor residual spraying has declined substantially over the past 30years, but this insecticide is still considered valuable for malaria control, mainly because of its low cost relative to alternative insecticides. Despite the development of resistance to DDT in some populations of malaria vector Anopheles mosquitoes (Diptera: Culicidae), DDT remains generally effective when used for house-spraying against most species of Anopheles, due to excitorepellency as well as insecticidal effects. A 1990 cost comparison by the World Health Organization (WHO) found DDT to be considerably less expensive than other insecticides, which cost 2 to 23 times more on the basis of cost per house per 6 months of control. To determine whether such a cost advantage still prevails for DDT, this paper compares recent price quotes from manufacturers and WHO suppliers for DDT and appropriate formulations of nine other insecticides (two carbamates, two organophosphates and five pyrethroids) commonly used for residual house-spraying in malaria control programmes. Based on these 'global' price quotes, detailed calculations show that DDT is still the least expensive insecticide on a cost per house basis, although the price appears to be rising as DDT production declines. At the same time, the prices of pyrethroids are declining, making some only slightly more expensive than DDT at low application dosages. Other costs, including operations (labour), transportation and human safety may also increase the price advantages of DDT and some pyrethroids vs. organophosphates and carbamates, although possible environmental impacts from DDT remain a concern. However, a global cost comparison may not realistically reflect local costs or effective application dosages at the country level. Recent data on insecticide prices paid by the health ministries of individual countries showed that prices of particular insecticides can vary substantially in the open market. Therefore, the most cost-effective insecticide in any given country or region must be determined on a case-by-case basis. Regional coordination of procurement of public health insecticides could improve access to affordable products.     

Parasites and progress: ethical decision-making and the Santee-Cooper Malaria study, 1944-1949

As part of a mid-1940s malaria research program, U.S. Public Health Service researchers working in South Carolina chose to withhold treatment from a group of subjects while testing the efficacy of a new insecticide. Research during World War II had generated new tools to fight malaria, including the insecticide DDT and the medication chloroquine. The choices made about how to conduct research in one of the last pockets of endemic malaria in the United States reveal much about prevailing attitudes and assumptions with regard to malaria control. We describe this research and explore the ethical choices inherent in the tension between environmentally based interventions and the individual health needs of the population living within the study domain. The singular focus on the mosquito and its lifecycle led some researchers to view the humans in their study area as little more than parasite reservoirs, an attitude fueled by the frustrating disappearance of malaria just when the scientists were on the verge of establishing the efficacy of a powerful new agent in the fight against malaria. This analysis of their choices has relevance to broader questions in public health ethics.     

Wartime research on malaria chemotherapy

Malaria was a major problem for the opposing forces in World War II. During the first year of operations in the South West Pacific the casualties caused by this disease greatly exceeded the numbers of battle casualties. In response to this situation comprehensive research and development programs to discover new antimalarial drugs were undertaken in the United States and Britain. In both countries compounds synthesised by co-operating chemical laboratories were screened against bird malaria and those with high activity and low toxicity were tested in man. The wartime program in America was funded by the Office of Scientific Research and Development and co-ordinated through a specially designated body under the Committee on Medical Research of the National Research Council. It was an enormous undertaking involving a massive co-operative effort between pharmacologists, chemists, and clinical research scientists from American universities, the US Public Health Service, and the laboratories of commercial pharmaceutical companies. The British program, on a much smaller scale, was based on a co-operative arrangement between the research laboratories of Imperial Chemical Industries at Manchester, the Liverpool School of Tropical Medicine and the British Medical Research Council. The wartime programs in both countries identified a number of promising leads but lacked the resources to permit their rapid clinical evaluation against field strains of human malaria. This deficiency was overcome by experiments conducted by the Land Headquarters Medical Research Unit of the Australian Army in Cairns, Queensland with the use of army volunteers. Large scale clinical trials of the most promising compounds which emerged from the American and British programs were carried out in Australia. This co-operative endeavour among allied scientists resulted in a range of new drugs which have had an enduring influence on malaria chemotherapy.     

The Innovative Vector Control Consortium: improved control of mosquito-borne diseases

Few new insecticides have been produced for control of disease vectors for public health in developing countries over the past three decades, owing to market constraints, and the available insecticides are often poorly deployed. The Innovative Vector Control Consortium will address these market failures by developing a portfolio of chemical and technological tools that will be directly and immediately accessible to populations in the developing world. The Bill and Melinda Gates Foundation has supported this new initiative to enable industry and academia to change the vector control paradigm for malaria and dengue and to ensure that vector control, alongside drugs, case management and vaccines, can be better used to reduce disease.     

Malaria: an intra-erythrocytic neoplasm?

Drug resistance is a serious problem in malaria, and prospects for new drugs are not optimistic. In 1963, the US Army began a huge programme to develop new antimalarials; they screened over 235 000 compounds, but very few were sufficiently active and safe for use in humans. Part of the problem is that not enough is known about the biochemical properties of malaria parasites, especially the metabolic differences between them and their host cells which could offer targets for specific chemotherapy. An important characteristic of malaria infection is the rapid growth of the parasite population, and changes in host metabolism that result from this. A similar effect occurs in many cancers. In this article, Ya Zhang argues that malaria parasites also have metabolic similarities with tumour cells, and suggests that careful comparison of these two could provide insight for new drug development.     

The London School of Hygiene and Tropical Medicine: a new century of malaria research

The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools--drugs, vaccine and insecticides--are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.     

Malaria control priorities and constraints

Each year, there are still between 300-500 million clinical cases of malaria and over one million deaths due to the disease, 90% of which occur in Africa south of the Sahara. In all continents, malaria risk is highest in remote rural areas where poverty abounds, population densities are low and the quality and coverage of the health services are poor or in existent. A sustained impact on the malaria burden can only be achieved through the cost-effective use of current tools, by including malaria in health sector development and inter-sectorial action, by mobilizing malaria control within communities and by investing in new and more effective tools. This paper highlights some of the constraints faced by countries in controlling malaria and outlines the priority activities that are being carried out to address these constraints within both communities and the health services. It aims to be set the scene for the papers of this Centenary book which address some of these issues in more detail.     

Biodiversity and insecticide susceptibility status of major Anopheline fauna in three malariogenically stratified districts of Odisha,India

Understanding the species composition and biodiversity of anopheles mosquito population is a vital part of any malaria control intervention. Similarly, an effective malaria control strategy relies primarily on insecticides. The Anopheline diversity, composition, distribution as well as insectide susceptibility/resistance status were surveyed in three districts of Odisha viz. Kalahandi (southern hyper –endemic district), Bargarh (western meso-endemic district) and Cuttack (sub-coastal hypo-endemic district) which significantly differ from each other according to the malariogenic stratification. Anopheline fauna showed a higher species richness and diversification in Kalahandi followed by Cuttack and Bargarh. An. culicifacies, the most abundant primary vector in Odisha, showed resistant to DDT as well as malathion in all three districts with a higher knockdown time in Kalahandi. Except Bargarh and Cuttack, the vector species also showed resistance to deltamethrin in Kalahandi district. The species found susceptible to deltamethrin in Cuttack while in Bargarh, its response was under ‘verification required’. In contrast, the secondary vector, An. annularis showed resistance to DDT in all three districts and to malathion in only Kalahandi district. In Cuttack and Bargarh district, their response against the insecticide malathion was under verification required. The deltamethrin susceptible populations were detected in Cuttack and Bargarh district where as in Kalahandi they came under verification required category. The current study constitutes an essential step for understanding the dynamics of malaria transmission in relation to vector diversification and their resistant status to various insecticides that can provide guide to intervention policies and programmes in the fight against malaria.     

Rural Development and Malaria Control in Sub-Saharan Africa

The rapidly expanding population of Sub-Saharan Africa has led to an increased demand for land in which to live and grow food. The process of rural development continues to change the physical landscape, increasing mosquito breeding and biting rates of the chief vector of malaria in Africa, Anopheles gambiae, a mosquito exquisitely adapted for exploiting people. At the same time, development alters the social environment, affecting wealth, inequality, household entitlements, and male and female workloads, which lead to changes in coping and caring strategies. Despite the fact that malaria is sensitive to changes in the physical and social environment, most control tools use only chemicals (antimalarials and insecticides), not biophysical environmental modifications nor strengthening social systems. While antimalarials and insecticides are extremely effective weapons, they are probably not sustainable in the long term due to the emergence of resistant organisms. Here we suggest that environmental and social management should be considered as part of the suite of interventions against malaria, since these are likely to be effective in specific settings and represent a sustainable approach to malaria control in rural Africa.     

Distribution and spread of pyrethroid and DDT resistance among the Anopheles gambiae complex in Tanzania

The development of insecticide resistance is a threat to the control of malaria in Africa. We report the findings of a national survey carried out in Tanzania in 2011 to monitor the susceptibility of malaria vectors to pyrethroid, organophosphate, carbamate and DDT insecticides, and compare these findings with those identified in 2004 and 2010. Standard World Health Organization (WHO) methods were used to detect knock‐down and mortality rates in wild female Anopheles gambiae s.l. (Diptera: Culicidae) collected from 14 sentinel districts. Diagnostic doses of the pyrethroids deltamethrin, lambdacyhalothrin and permethrin, the carbamate propoxur, the organophosphate fenitrothion and the organochlorine DDT were used. Anopheles gambiae s.l. was resistant to permethrin in Muleba, where a mortality rate of 11% [95% confidence interval (CI) 6–19%] was recorded, Muheza (mortality rate of 75%, 95% CI 66–83%), Moshi and Arumeru (mortality rates of 74% in both). Similarly, resistance was reported to lambdacyhalothrin in Muleba, Muheza, Moshi and Arumeru (mortality rates of 31–82%), and to deltamethrin in Muleba, Moshi and Muheza (mortality rates of 28–75%). Resistance to DDT was reported in Muleba. No resistance to the carbamate propoxur or the organophosphate fenitrothion was observed. Anopheles gambiae s.l. is becoming resistant to pyrethoids and DDT in several parts of Tanzania. This has coincided with the scaling up of vector control measures. Resistance may impair the effectiveness of these interventions and therefore demands close monitoring and the adoption of a resistance management strategy.     

Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels

1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), the first organochlorine insecticide, and pyrethroid insecticides are sodium channel agonists. Although the use of DDT is banned in most of the world due to its detrimental impact on the ecosystem, indoor residual spraying of DDT is still recommended for malaria control in Africa. Development of resistance to DDT and pyrethroids is a serious global obstacle for managing disease vectors. Mapping DDT binding sites is necessary for understanding mechanisms of resistance and modulation of sodium channels by structurally different ligands. The pioneering model of the housefly sodium channel visualized the first receptor for pyrethroids, PyR1, in the II/III domain interface and suggested that DDT binds within PyR1. Previously, we proposed the second pyrethroid receptor, PyR2, at the I/II domain interface. However, whether DDT binds to both pyrethroid receptor sites remains unknown. Here, using computational docking of DDT into the K_v1.2-based mosquito sodium channel model, we predict that two DDT molecules can bind simultaneously within PyR1 and PyR2. The bulky trichloromethyl group of each DDT molecule fits snugly between four helices in the bent domain interface, whereas two p-chlorophenyl rings extend into two wings of the interface. Model-driven mutagenesis and electrophysiological analysis confirmed these propositions and revealed 10 previously unknown DDT-sensing residues within PyR1 and PyR2. Our study proposes a dual DDT-receptor model and provides a structural background for rational development of new insecticides.     

The re-emergence of the bed bug as a nuisance pest: implications of resistance to the pyrethroid insecticides

A global resurgence of bed bugs (Hemiptera: Cimicidae) has led to renewed scientific interest in these insects. The current bed bug upsurge appears to have started almost synchronously in the late 1990 s in Europe, the U.S.A. and Australia. Several factors have led to this situation, with resistance to applied insecticides making a significant contribution. With a growing number of insecticides (DDT, carbamates, organophosphates etc.) being no longer available as a result of regulatory restrictions, the mainstay chemistry used for bed bug control over the past few decades has been the pyrethroid insecticides. With reports of increasing tolerance to pyrethroids leading to control failures on the rise, containing and eradicating bed bugs is proving to be a difficult task. Consequently, several recent studies have focused on determining the mode of action of pyrethroid resistance in bed bug populations sourced from different locations. Correct identification of the factor(s) responsible for the increasing resistance is critical to the development of effective management strategies, which need to be based, wherever possible, on firm scientific evidence. Here we review the literature on this topic, highlighting the mechanisms thought to be involved and the problems currently faced by pest control professionals in dealing with a developing pandemic.     

The insecticide DDT targets the OSCP and subunit D of the Apis mellifera ATP synthase

1,1-bis (p-chlorophenyl)-2, 2, 2-trichloroethane (DDT) has been used for control of malaria mosquitoes and other insect vectors of human diseases since 1945. Its use poses an environmental dilemma and efforts to replace it have been hampered by lack of information about its molecular target. This work identifies the 23 kDa band responsible for the DDT sensitivity in bees, as the OSCP and subunit "d" of the ATP synthase. The OSCP of the bee's ATP synthase contained 207 amino acids compared to 190 in bovine, which is insensitive to DDT, and the identities were only 47%. Subunit "d" of the bees had no counterpart in the bovine. Whether DDT is interacting only with OSCP, only with subunit "d", or with both subunits, remains to be assessed. Identification of the molecular target of DDT will lead the way to new target based insecticides aimed to protect plant, combat malaria and other insect transmitted diseases.     

Malaria and World War II: German malaria experiments 1939-45

The epidemiological and pharmacological fight against malaria and German malaria research during the Nazi dictatorship were completely under the spell of war. The Oberkommando des Heeres (German supreme command of the army) suffered the bitter experience of unexpected high losses caused by malaria especially at the Greek front (Metaxes line) but also in southern Russia and in the Ukraine. Hastily raised anti-malaria units tried to teach soldiers how to use the synthetic malaria drugs (Plasmochine, Atebrine) properly. Overdoses of these drugs were numerous during the first half of the war whereas in the second half it soon became clear that it would not be possible to support the army due to insufficient quantities of plasmochine and atebrine. During both running fights and troop withdrawals at all southern and southeastern fronts there was hardly any malaria prophylaxis or treatment. After war and captivity many soldiers returned home to endure heavy malaria attacks. In German industrial (Bayer, IG-Farben) and military malaria laboratories of the Heeres-Sanit?ts-Akademie (Army Medical Academy) the situation was characterised by a hasty search for proper dosages of anti-malaria drugs, adequate mechanical and chemical prophylaxis (Petroleum, DDT, and other insecticides) as well as an anti-malaria vaccine. Most importantly, large scale research for proper atebrine and plasmochine dosages was conducted in German concentration camps and mental homes. In Dachau Professor Claus Schilling tested synthetic malaria drugs and injected helpless prisoners with high and sometimes lethal doses. Since the 1920s he had been furiously looking for an anti-malaria vaccine in Italian mental homes and from 1939 he continued his experiments in Dachau. Similar experiments were also performed in Buchenwald and in a psychiatric clinic in Thuringia, where Professor Gerhard Rose tested malaria drugs with mentally ill Russian prisoners of war. Schilling was put to death for his criminal research in 1946, Rose was condemned to lifelong imprisonment in 1947, though, not for his malaria research but for his dreadful experiments with epidemic typhus sera which he also had performed in concentration camps and with prisoners of war in Russia.     

Multiple insecticide resistance: an impediment to insecticide-based malaria vector control program

Background

Indoor Residual Spraying (IRS), insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs) are key components in malaria prevention and control strategy. However, the development of resistance by mosquitoes to insecticides recommended for IRS and/or ITNs/LLINs would affect insecticide-based malaria vector control. We assessed the susceptibility levels of Anopheles arabiensis to insecticides used in malaria control, characterized basic mechanisms underlying resistance, and evaluated the role of public health use of insecticides in resistance selection.

Methodology/Principal findings

Susceptibility status of An. arabiensis was assessed using WHO bioassay tests to DDT, permethrin, deltamethrin, malathion and propoxur in Ethiopia from August to September 2009. Mosquito specimens were screened for knockdown resistance (kdr) and insensitive acetylcholinesterase (ace-1^R) mutations using AS-PCR and PCR-RFLP, respectively. DDT residues level in soil from human dwellings and the surrounding environment were determined by Gas Chromatography with Electron Capture Detector. An. arabiensis was resistant to DDT, permethrin, deltamethrin and malathion, but susceptible to propoxur. The West African kdr allele was found in 280 specimens out of 284 with a frequency ranged from 95% to 100%. Ace-1^R mutation was not detected in all specimens scored for the allele. Moreover, DDT residues were found in soil samples from human dwellings but not in the surrounding environment.

Conclusion

The observed multiple-resistance coupled with the occurrence of high kdr frequency in populations of An. arabiensis could profoundly affect the malaria vector control programme in Ethiopia. This needs an urgent call for implementing rational resistance management strategies and integrated vector control intervention.     

The campaign against malaria in central western Madagascar: comparison of lambda-cyhalothrin and DDT house spraying. II--Parasitological and clinical study]

For malaria vector control in Madagascar, 10 WP (lambda-cyhalothrin 10% wettable powder) was compared with DDT 75% WP for house-spraying, from November 1997 to September 1998. This study was implemented at the fringe of the malaria epidemic zone, in villages on western slopes of the central highlands, outside the area covered for the past five years by routine DDT house-spraying (OPID). Four types of treatment were compared in different areas: 1) DDT 2 g ai/m2 and 2) lambda-cyhalothrin 30 mg ai/m2 in previously unsprayed villages, 3) no intervention (control); 4) yearly DDT spraying (OPID fifth cycle). To investigate the malariological impact of spraying, cross-sectional surveys of the village populations were performed in each study area at intervals of two months, before and after spraying. In the newly sprayed areas, from December to June, malaria indices decreased by 62% in the ICON area and 44% in the DDT area, whereas in the unsprayed village malaria increased by 32% during the same season. There was a similar decrease in the number of gametocyte carriers in the newly sprayed areas. Active malaria case detection among febrile individuals was performed fortnightly in each village outside the OPID area. Results showed decreased malaria incidence from February (two months post-spraying) in the sprayed villages, despite the rainy season, whereas in the unsprayed area the decline occurred only after the main transmission season. This study demonstrated that, parasitologically as well as entomologically, house-spraying with residual insecticide (DDT or ICON) was an effective method for controlling malaria on the western fringes of the Madagascar highlands epidemic zone. Both products were effective, but ICON had slightly better impact than DDT, i.e. more reduction of malaria indices and of vector longevity, less irritancy of mosquitoes. For best results in this area of transition between stable and unstable malaria, we recommend earlier annual spraying (as soon as November) and extension of the OPID barrier towards western and northern slopes of the Plateau.     

Antimalarial drug development and new targets

The Molecular Approaches to Malaria (MAM2000) conference, Lorne, Australia, 2-5 February 2000, brought together world-class malaria research scientists. The development of new tools and technologies - transfection, DNA microarrays and proteomic analysis - and the availability of DNA sequences generated by the Malaria Genome Project, along with more classic approaches, have facilitated the identification of novel drug targets, the development of new antimalarials and the generation of a deeper understanding of the molecular mechanism(s) of drug resistance in malaria. It is hoped that combinations of these technologies could lead to strategies that enable the development of effective, efficient and affordable new drugs to overcome drug-resistant malaria, as discussed at MAM2000 and outlined here by Ian Macreadie and colleagues.     

Responses of Anopheles culicifacies sibling species A and B to DDT and HCH in India: implications in malaria control

Differential responses of Anopheles culicifacies Giles sibling species A and B to DDT were evident from higher survival rate of species B in laboratory bioassays and greater proportions of species B in DDT-sprayed villages of northern India, compared with those under HCH pressure. Both species A and B have become almost completely resistant to HCH in this area due to regular house-spraying with HCH for about the last 10 years. Because species A predominates in northern India, where it has been incriminated as an important vector of malaria, and species A is more susceptible than species B to DDT, it is suggested that DDT would control malaria transmission more effectively than HCH in this situation. Monitoring of insecticide resistance in species A is therefore recommended as the basis for future choice of insecticides to be used by the National Malaria Eradication Programme.     

The multifaceted mosquito anti-Plasmodium response

Plasmodium development within its mosquito vector is an essential step in malaria transmission, as illustrated in world regions where malaria was successfully eradicated via vector control. The innate immune system of most mosquitoes is able to completely clear a Plasmodium infection, preventing parasite transmission to humans. Understanding the biological basis of this phenomenon is expected to inspire new strategies to curb malaria incidence in countries where vector control via insecticides is unpractical, or inefficient because insecticide resistance genes have spread across mosquito populations. Several aspects of mosquito biology that condition the success of the parasite in colonizing its vector begin to be understood at the molecular level, and a wealth of recently published data highlights the multifaceted nature of the mosquito response against parasite invasion. In this brief review, we attempt to provide an integrated view of the challenges faced by the parasite to successfully invade its mosquito host, and discuss the possible intervention strategies that could exploit this knowledge for the fight against human malaria.