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extensive and innovative in vivo work (thereby TIMELINE — TROPICAL INFECTIOUS DISEASES complementing the in vitro work done in Japan) and had the resources to push promis- ing compounds through the -develop- The life and times of — ment pipeline. By the early 1970s, the testing of synthetic chemicals at the MSD commercial a success story research laboratories was beginning to realize diminishing returns2, so the company was keen to explore and take advantage of the Satoshi Õmura and Andy Crump new research directions that were proposed by the Japanese group. Consequently, the Abstract | Since its introduction more than 20 years, improving the lives of hundreds of link between Õmura and Tishler, with his 20 years ago, ivermectin has proved to be millions of the world’s poorest and worst connections to MSD, formed the basis for the one of the most successful therapeutic afflicted in the process (TIMELINE). new Kitasato–MSD collaboration, which was in veterinary medicine, as well as the formally created in 1973. basis of one of the most successful public- The partnership When the partnership was founded, only health programmes of the past century. For most of the important breakthroughs a few of the several thousand active fermen- The drug arose from a unique international in medical research, serendipity has an tationproducts that had been isolated had collaboration between the public and private important role, and so it proved in the case of activity. Compounds of signifi- sectors. The development process also the drug ivermectin. Researchers at the cance included anthelmycin, anthelvencin, incorporated the world’s first and largest Kitasato Institute in Tokyo had established a the complex S-15-1, aspiculomycin, drug-donation programme and involved a worldwide reputation for their expertise in the axenomycins, G-418, hygromycin B, the unique association between governments, detecting bioactive compounds produced by destomycins, myxin, and the non-governmental organizations and microorganisms that are mainly found in the thiamycins. Only one compound, hygromycin, industry. The drug is now being used, free of environment. Novel techniques were devel- was considered suitable for further develop- charge, in two global disease-elimination oped and screening systems were established ment3.To address this shortage, the new, programmes that are benefiting millions of to increase the chances of accurately detecting goal-oriented research initiative was focused the world’s poorest people. minute samples of active compounds1.In towards discovering a drug that would be 1971, one of the authors (S.O.) took a sabbat- effective against helminth parasites2. In 1973, a research partnership was established ical from the Kitasato Institute to take up a between the Kitasato Institute in Japan and research post working with Max Tishler, who, Discovery and isolation the Merck, Sharpe and Dohme (MSD) after a successful career at MSD, had moved All of the cultures sent from Japan under the research laboratories in the United States. The from industry to Wesleyan University in the terms of the research partnership were from outcome of this alliance led to an important United States. The Kitasato team were eager soil samples that were collected and processed advance in animal health products, through to find an industrial partner to participate by well-established and sophisticated screen- the development of an extremely safe drug in a new line of research to discover micro- ing systems. These procedures established the with a broad spectrum of activity organisms that produce potentially useful morphological features and physiological — a drug that has also provided significant compounds with unique chemical structures. properties of organisms and compounds benefits to human health for more than Researchers at MSD routinely carried out produced in fermentation broths and in vitro

Timeline | Development of ivermectin (1995–1996) APOC formed (Late 1990s) (1982–1986) Phase (1982–1986) World Bank, WHO, and ComDT identified as being Ivermectin and (1972–1973) Satoshi Õmura proposes I–IV clinical studies. TDR and OCP become involved and safe and highly effective. , and research activities to discover novel field trials are carried out in Africa. ivermectin and antibiotic agents from natural organisms. MSD researchers report activity Mectizan Donation (1995–1996) Use of mass combination (1972–1973) Agreement of collaboration First publication against Onchocerca volvulus, revealing Programme established donation programmes of treatments used to between Satoshi Õmura and MSD on the the possibility of using the drug in (first ever mass drug- ivermectin become central eliminate lymphatic laboratories. . human public-health/disease control. donation programme). to the APOC. filariasis.

1972 1973 1974 1979 1981 1982 1987 1988 1992 1995 1999 2001

(1973–1974) Streptomyces (1974–1975) Samples /ivermectin The French government OEPA is Cloning of (2001–2003) avermectinius collected from sent to MSD for testing marketed as veterinary drug approves drug for established. genes involved Genome sequence single site in Japan. in novel mouse model. and becomes a best-seller. human use. in avermectin of S. avermectinius biosynthesis. completed. (1973–1974) Identification (1974–1975) MSD agree to donate (1987 onwards) of antiparasitic activity Anthelmintic activity ivermectin free to help Mectizan used in through screening systems. discovered. eliminate river blindness. OCP programme.

984 | DECEMBER 2004 | VOLUME 2 www.nature.com/reviews/micro PERSPECTIVES evaluations of the chemical products were In 1999, the Kitasato group reported that carried out. In the second year of the collabo- 17 genes of S. avermectinius encode enzymes ration, the Kitasato team isolated an organism that are involved in avermectin biosynthesis. — Streptomyces avermitilis,which is a species Of these, those encoding four types of I poly- of actinomycete (FIG. 1) — from soil near a ketide synthases are concerned with lactone golf course bordering the ocean at Kawana, formation, via 12 cycles and 53 steps. The near Ito City in the Shizuoka region. (In remainder act on pathway-specific regulation, 2002, the Kitasato research group published with 12 genes being involved in modification morphological, physiological, biochemical of the lactone ring, biosynthesis of oleandrose and phylogenetic evidence arguing for the and its glycosylation53. reclassification of the original microorganism In 2003, the Kitasato team sequenced the and rename it Streptomyces avermectinius 4). S. avermectinius genome, which is the largest The isolated culture was sent, together with bacterial genome sequence reported so far11,12. 53 other promising microbial samples, to the Analysis of the genome allowed identification MSD laboratories in 1974. MSD researchers of the gene cluster involved in secondary screened the samples in a novel mouse 5 µm metabolite production, shedding light on the model of helminth in which mice biology of microbial secondary metabolite were infected with the worm Figure 1 | Micrograph of Streptomyces synthesis at the genetic level. avermectinius. S. avermectinius is the only Nematospiroides dubius.Originally identified organism that has been found to produce the as OS-3153, the most promising microbial avermectins. Mode of action sample was a S. avermectinius strain that was Initially, owing to its rapid and specific anti- shown to have potent anthelmintic activity parasitic and anthelmintic action, it was pro- with little or no toxicity. The compound Avermectins are a complex of 16-membered posed that ivermectin was an agonist for responsible for the activity was named aver- macrocyclic lactones, and fermentation of neurotransmitter function. Experimental mectin3 (FIG. 2).Further studies demonstrated S. avermectinius produces a mixture of eight studies confirmed this proposal when it was that avermectin had biocidal activity against a avermectin compounds (A1a,A1b,A2a,A2b,B1a, shown that inhibition occurred via gluta- diverse range of , insects and B1b,B2a and B2b) (FIG. 2).Compounds of the mate-gated chloride ion channels in nerve arachnids. Moreover, the mode of action of B-series containing a 5′-hydroxyl group are and muscle cells13.Ivermectin interacts with avermectin was both unique and robust, and markedly more active than those of the these channels, preventing their closure. was 25 times more potent than all currently A-series, which contain a 5′-methoxyl group. Consequently, synapse membranes become available . The unique ability of The 1-series and 2-series have similar activity increasingly permeable to chloride ions, avermectin to kill both ecto- and endopara- against many parasites8.An interdisciplinary which leads to hyperpolarization of the neu- sites gave rise to the new class of compounds team at MSD, headed by William Campbell, ronal membrane and decreases, or prevents, called ‘endectocides’.In 1979, the first papers investigated the eight active compunds, of neuronal transmission. This, in turn, leads to on avermectin and its derivatives were pub- which avermectins B1a and B1b were found paralysis of the somatic muscles, particularly lished, describing the molecules as a series of to have the highest activity. Reduction of the pharyngeal pump, causing the death of 14,15 γ macrocyclic lactone derivatives that lacked the C22–C23 double bond of B1a and B1b com- the parasite . -aminobutyric acid (GABA)- antibacterial and activity but which pounds with Wilkinson’s catalyst improved related chloride ion channels, which are pre- had powerful anthelmintic properties5–7. both the spectrum of activity and safety sent only in nematodes, insects and ticks, are (resulting in very low mammalian toxicity), only inhibited with greater drug concentra- 16–18 and the resulting 22,23-dihydro B1 complex tions .In mammals, GABA receptors and (as a mixture of 80% B1a and 20% B1b) was neurons are found in the central nervous sys- selected for further commercial development tem, whereas in arthropods and nematodes under the generic, non-proprietary name, they are located in the peripheral nervous ivermectin9.Although structurally similar system. This, coupled with the relatively low Japanese government to macrolide and antifungal dose concentrations needed, ensures that approves use of macrocyclic polyenes, the avermectins have mammals can ingest ivermectin with a high ivermectin for treating strongyloidiasis. no antibacterial or antifungal activities. degree of safety. Further analysis revealed that ivermectin was highly efficacious against mite, tick and Animal health botfly ectoparasites, which are organisms that Ivermectin was introduced to the market in 2002 2003 2004 cause massive economic losses in the livestock 1981 as a veterinary antiparasitic drug and industry. MSD researchers also observed that soon proved to be the most effective, broad- the compound had remarkable activity spectrum antiparasitic drug ever developed. It

Taxonomy of Twenty-fifth against endo- as well as ectoparasites in horses, quickly became a remarkable success, rapidly S. avermectinius anniversary of the cattle, pigs and sheep. Ivermectin was also capturing a large portion of the global veteri- elucidated. first avermectin publication. found to be successful in treating larval heart- nary antiparasitic market, and became the worms, but not adult worms, and could be market leader within two years — the drug used to treat mange and other conditions in has maintained that position ever since, with dogs. However, no activity was found against annual sales of about US$1 billion. Since the flatworms, , or fungi10. introduction of ivermectin, several other

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OCH3 in the body, causing a variety of symptoms HO (FIG. 3).The bite of infected blackflies (Simulium spp.) transmits immature larval O O R1 R2 X–Y forms of the worms from human to human. OCH3 Avermectin A1a Me Et CH=CH Adult worms, which take a year to mature, O Avermectin A Me Me CH=CH Y 1b lodge in nodules under the skin, releasing H X Avermectin A Me Et CH CH(αOH) OOH 2a 2 millions of microfilariae into surrounding α O Avermectin A2b Me Me CH2CH( OH) tissues, which then migrate through the Avermectin B HEtCH=CH R2 1a body, living for 9–18 months. When the O O Avermectin B1b HMeCH=CH α microfilariae die, the resulting residue causes HO Avermectin B2a HEtCH2CH( OH) α visual impairment and blindness, skin rashes, Avermectin B2b HMeCH2CH( OH lesions, intense itching and depigmentation O H of the skin, lymphadenitis and general OR 1 debilitation. is found in 35 Figure 2 | Structure of the avermectins. The inclusion of different groups at positions R , R , X and Y 1 2 countries, including 28 nations in tropical create the eight different avermectin compounds A , A , A , A , B , B , B and B . 1a 1b 2a 2b 1a 1b 2a 2b Africa where 99% of infected people live (FIG. 4).Isolated foci also occur in Latin endectocides have appeared but none have Public health America and Yemen. Each year, approximately replaced ivermectin as the market leader. At the time the collaboration between the 18 million people are infected, with more Five years after its introduction, iver- Kitasato Institute and MSD was being set up than 6.5 million people suffering from severe mectin was registered for use in 46 countries and becoming operational in the mid-1970s, itching, dermatitis and impaired visual acuity, and was being used worldwide to treat onchocerciasis (or river blindness) had long and 270,000 patients suffering from complete approximately 320 million cattle, 151 million been a major global health problem. The blindness. The disease is estimated to be sheep, 21 million horses and 5.7 million disease results from infection with Onchocerca responsible for the loss of 1 million disability- pigs19.Most horses in the United States were volvulus, which is a that lives adjusted life years (DALYs) annually. In the treated with the drug to the extent that the in the human body. Adult female worms live early 1970s, the only drugs that were available horse nematode Onchocerca cervicalis has for up to 14–15 years, producing millions of to treat the disease were , which is a now virtually disappeared. microscopic larvae (microfilariae) that migrate highly toxic molecule that had to be adminis- tered in repeated injections over a period of several weeks, and diethylcarbamazine, which Penetrates stomach wall also had to be administered over several weeks. Diethylcarbamazine can also cause severe side effects due to the accumulation of Ingested by blackfly Migrates to head and proboscis dead parasitic tissue, a process that can result Simulium spp. in blindness. By the mid-1970s, it was clear that both drugs could actually worsen eye lesions and so the use of for onchocerciasis was stopped20. There was hope, however, for a new and effective treatment. The MSD research in horses had demonstrated that ivermectin killed Onchocerca cervicalis,which are nema- todes that are closely related to Onchocerca Microfilariae O. volvulus enters volvulus, so work began to investigate the in skin skin through fly bite possible use of ivermectin in humans. MSD joined forces with the World Health Organization (WHO), the Special Programme for Research and Training in Tropical Diseases (TDR) and the Onchocerciasis Control Migrates to Programme in West Africa (OCP) to carry out subcutaneous tissue Mate and produce Human host an extensive collaborative research programme microfilariae in humans. This proved to be an early example of the so-called public–private partnerships Figure 3 | Schematic representation of the life cycle of Onchocerca volvulus. When a parasitized (PPPs) that are now being created in increasing female blackfly (Simulium spp.) takes a meal, infective Onchocerca larvae pass into the host through numbers to coordinate the production and the fly-bite wound. Larvae enter subcutaneous tissue, where they migrate, aggregate in nodules, mature distribution of effective therapies for diseases into adult worms and mate. After mating, eggs in female worms develop into immature larvae for which there is little likelihood of a financial (microfilariae), each worm is capable of producing 1,000 microfilariae per day. Many thousands of microfilariae are released to migrate in subcutaneous tissue. When they die, they cause skin rashes, return on investment. lesions, intense itching and skin depigmentation. Microfilariae also migrate to the eye and can cause visual In 1981, clinical trials of ivermectin, which impairment and blindness. When the infected host is bitten by another female fly, microfilariae pass into was produced under the brand name the blackfly, where they develop into infective larvae, and the life cycle continues. ‘Mectizan’,began in Senegal21,22.Over the next

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marginalized communities. In 1987, after receipt of consent from the Kitasato Institute, which agreed to forego royalties, P. Roy Vagelos, the then chief executive of MSD, announced that ivermectin (under the brand name Mectizan) would be provided free of charge for the treatment of river blindness for “as long as it is needed”, a pledge that has been honoured ever since. The advent of this drug donation has trans- formed the treatment of onchocerciasis to a point where elimination of the disease has become an achievable goal.

Disease present Community-directed treatment Also in 1987, the TDR began to fund pio- Figure 4 | Global distribution of onchocerciasis. Data obtained from the WHO. neering research on the concept of ‘commu- nity-based treatment’ using ivermectin. The rationale behind this concept was that the four years, large-scale field trials involving than annually, could have a sterilizing effect on drug was so safe and easy to use that affected hundreds of thousands of individuals were adult female worms and reduce their lifespan34. communities should be able to organize their undertaken in Ghana, Guatemala, Cote Nevertheless, taking the drug over the lifespan own drug distribution and treatment. In the d’Ivoire, Liberia, Mali, Senegal and Togo. Phase of the adult worms effectively prevents patients field, community-directed treatment proved to II studies reported that local inflammatory from developing the disease. be remarkably successful and, in 1989, the responses in ocular tissue were less severe with Following the work of a truly international WHO announced that ivermectin could be ivermectin than with diethylcarbamazine, partnership involving the public and private administered “with minimal supervision”.It thereby avoiding the unwanted Mazzotti sectors, governments of disease-endemic was subsequently noted that ivermectin cover- reaction — by which the accumulation of countries and affected communities, the age was greatest when affected communities dead parasitic material can induce blindness. human formulation of ivermectin was reg- were allowed to design and implement their Results showed that a single annual dose of istered for use by French regulators in 1987 own drug-distribution programme40.The 200 µg per kg of body weight eradicated with mass drug administrations commencing TDR went on to develop the community- microfilarial worms from the eye and skin after in 1988. directed treatment with ivermectin (ComDT) one month, and patients remained worm-free The use of ivermectin can cause adverse procedure, which became the operational basis for up to 12 months after treatment23–25. Later, side effects, the most common being oedema, of the African Programme for Onchocerciasis large-scale community trials in various epi- fever, pruritus and pain35,36.They are generally Control (APOC). Established in 1995, the aim demiological conditions, including hyper- and mild and transient, however, and can be easily of APOC is to create sustainable community- meso-endemic areas, found that ivermectin treated by primary healthcare workers or directed distribution systems using mass reduced the levels of skin microfilaria by trained lay members of the community. distribution of ivermectin to all those eligible 96–99% within the first few months of Indeed, the incidence of adverse reactions in by 2007, ultimately covering 59 million people therapy26.It has been repeatedly shown that follow-up studies on distribution pro- in African countries where the disease ivermectin has little impact on adult worms grammes has actually been less than that remains a serious public-health problem and and that multiple doses do not have much observed during clinical trials37.Ivermectin where 15 million people are heavily infected. impact on oogenesis27.Adult worms can con- can also have serious effects on individuals The goal is to eliminate the disease in the tinue to reproduce, so ivermectin is suppressive heavily infected with Loa loa,which causes 17 African nations where it still persists after rather than curative; however, treatment leads severe encephalopathy that can prove fatal38. the successful control of the disease in the to a marked reduction in the number of Consequently, it is essential to take appro- 11 west-African nations covered by the OCP. immature worms and reduces microfilarial priate safety measures to exclude any such Meanwhile, the Onchocerciasis Elimination loads after each course of treatment21,28.Several people from mass drug-administration pro- Programme in the Americas (OEPA), which follow-up studies have shown that the marked grammes.A comprehensive review of serious was launched in 1992, is based on the premise reduction in both prevalence and intensity of adverse events following Mectizan treatment that mass administration of Mectizan tablets microfilaridermia is maintained, even after five carried out in 1989–2001 found 207 cases can rid the region of the disease relatively years of treatment29–31.Ivermectin has the from a reported 165 million treatments, quickly, as the vector blackflies in this region added benefits of allowing the body to repair representing an incidence ratio of 1 per transmit the parasite with reduced efficiency. minor eye lesions and reduces the severity of 800,000 treatments39. The programme is expected to achieve its goal itching and the prevalence of skin lesions32. of eliminating the disease from the region by Some researchers argue that ivermectin alters Drug donation 2007 (REF.20).Community-directed treatment the mechanisms by which adult worms locate During the latter stages of human trials, is producing excellent results in the fight each other and that this explains why fewer discussions took place between the public against onchocerciasis.Affected villages collect males are found in nodules after multiple and private sectors to determine a suitable Mectizan tablets, deliver them to all those treatments33.More frequent administration of price for the drug, bearing in mind that the eligible and report back to health authorities ivermectin, for example bi-annually rather end-users of the product would be poor and — and meet all the costs involved themselves

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(the drug being provided free to district health ivermectin may soon be routinely used in spe- posts). The correct dosage can be calculated The success of ivermectin does not stop with cial circumstances, such as in homes for the simply by measuring the height of the recipi- the potential elimination of onchocerciasis as elderly to help control the incidence of scabies. ent. In 2003, approximately 56 million a public-health threat. Combinations of iver- Perhaps of greater significance, ivermectin Africans were taking a single annual dose of mectin and albendazole or ivermectin and became available at a time when resistance to ivermectin41.The overall goal of these pro- diethylcarbamazine have been adopted as the other similar drugs, such as and grammes is to eliminate onchocerciasis as a basis of mass treatment in the Global Alliance , was common. Very few cases of public-health problem globally by 2010. to Eliminate Lymphatic Filariasis, which was resistance to ivermectin have been reported initiated by the WHO in 1997. The efficacy of and any future development of widespread Economic aspects the ivermectin and albendazole combination resistance is thought to be unlikely16.Parasites Mectizan is viewed by some as one of the therapy for bancroftian filariasis was first that are resistant to the avermectins are also finest public-health success stories of the past reported in 1997 (REF.46).Lymphatic filariasis resistant to the and it is likely that century, and a model for all future public and is one of the most prevalent tropical diseases, P-glycoproteins (plasma-membrane-associated private sector partnerships. However, analysis with an estimated 120 million people being drug efflux transporters) are involved in the of the economics indicates that success infected annually. The disease is responsible resistance mechanism50.It is also postulated depends on financial commitment from both for 5 million DALYs lost each year, ranking it that resistance could be mediated by muta- sectors. Cost-effective analyses of the mass third among tropical diseases in terms of tions in the gene encoding the α-subunit of distribution of ivermectin have identified a DALYs, after malaria and tuberculosis. Almost glutamate-gated chloride channels; However, cost of US$14–30 per DALY that is prevented42. 1 in 5 of the world population are at risk of the exact resistance mechanism is still a matter This compares reasonably well with other infection and the disease remains a major of conjecture51. control programmes for priority diseases, but impediment to socio-economic development The discovery, development and deploy- the benefit ratio in this case is only possible in endemic areas — India loses an estimated ment of ivermectin through the efforts of due to the huge financial commitment from US$1 billion annually as a result of lymphatic Merck & Co. and the Kitasato Institute, aided Merck& Co., which pays the production costs filariasis. In an effort to curb this disease, by a group of international partners from a of Mectizan, the costs of transport from the Merck & Co. confirmed that they would range of disciplines, has been hailed by some manufacturing facility in France to the recipi- donate Mectizan free of charge to the elimi- commentators as one of the greatest medical ent countries and the related customs and nation programmes in regions where achievements of the twentieth century52. other handling costs. In total, more than 250 onchocerciasis and lymphatic filariasis co- Vigilance is now needed to ensure that the million doses of ivermectin have been admin- exist. GlaxoSmithKline, the manufacturers of progress that has been made against several istered since the start of the Mectizan donation albendazole, also announced that they would devastating diseases is maintained. The strain programme. In 2000, APOC devoted 63% of donate this drug for lymphatic filariasis con- of Streptomyces found in Japan remains the its total annual budget of US$9.4 million to trol programmes, which are working towards only microorganism that produces aver- ivermectin distribution programmes. Using the goal of eliminating the disease by 2020. mectin. The Kitasato Institute, and similar the US$1.50 figure claimed by the Mectizan New uses for ivermectin continue to be organizations, remain dedicated to the search Donation Programme as being the cost of a found. For example, in 2003, ivermectin was for further microbiological treasures for use single tablet, the value of the ivermectin con- registered for the treatment of strongyloidia- in public health from among the myriad of tributed by Merck & Co. in 2001 is estimated sis, an intestinal that is widely substances produced by the world’s reservoir to be US$143.6 million for APOC countries distributed in the tropics and subtropics and of environmental microorganisms. alone. This can be compared with the total which is prevalent in south-east Asia and Satoshi Õmura is at the Kitasato Institute, 5-9-1 15-year costs of the APOC programme, which southern Japanese islands. More than 10 mil- Shirokane, Minato-ku, Tokyo 108-8642, Japan. 43 are estimated to be US$182.5 million . lion people are infected with the causative Andy Crump is at 6-2-4-403 Shinjuku, APOC and others are working towards microorganism. Shinjuku-ku, Tokyo 160-0022, Japan. reducing the actual costs of ‘free drug’ dona- Correspondence to S.O. tion programmes, with APOC focusing on a Future use e-mail: [email protected] target distribution cost of US$0.20 per treat- A microorganism from a single site in Japan doi:10.1038/nrmicro1048 ment43.A study oftwo villages in Nigeria has provided a drug that has proved to be one found that 92–93% of inhabitants were of the most successful tools in human and 1. Õmura, S. Philosophy of new drug discovery. Microbiol. Rev. 50, 259–279 (1986). willing to pay US$0.30 and US$0.28, respec- animal health, and one that has been the 2. Campbell, W. C. in Inventive Minds (eds Weber, R. J. & tively, to meet their ivermectin distribution mainstay of several of the most successful Perkins, D. N.) Chapter 11, 192–214 (Oxford Univ. Press, New York, 1992). needs. The actual costs of treatment in the disease-control programmes in the history of 3. Burg, R. W. & Stapley, E. O. in Ivermectin and two villages were calculated as US$0.13 and public health. Moreover, the benefits continue (ed. Campbell, W. C.) 24–32 (Springer, New York, 1989). 44,45 4. Takahashi, Y. et al. Streptomyces avermectinius sp. nov., US$0.17, respectively ,which bodes well to accrue. It is common knowledge that mal- an avermectin-producing strain. Int. J. Syst. Evol. for maintaining sustainable, long-term mass nutrition and undernutrition are major causes Microbiol. 52, 2163–2168 (2002). 5. Burg, R. W. et al. Avermectins, new family of potent anthel- distribution programmes for the period of of ill health in Africa and throughout the mintic agents: producing organisms and fermentation. time that is needed to achieve disease elimi- developing world, particularly among young Antimicrob. Agents Chemother. 15, 361–367 (1979). 6. Miller, T. W. Avermectins, new family of potent anthelmintic nation. The continuing, concerted and long- children. Ivermectin is known to be particu- agents: isolation and chromatographic properties. term commitment of donors (led by the larly effective against infection with Ascaris Antimicrob. Agents Chemother. 15, 368–371 (1979). World Bank), non-governmental organiza- worms and reasonably effective against hook- 7. Egerton, J. R. et al. Avermectins, new family of potent anthelmintic agents: efficacy of the B1A component. tions, governments, health services and worm and Trichuris 47,48.Furthermore, the Antimicrob. Agents Chemother. 15, 372–378 (1979). 8. Sunazuka, T. et al. in Macrolide Antibiotics — Chemistry, affected communities will be essential if the prevalence of head lice is markedly reduced in Biology and Practice 2nd ed. (ed. S. Õmura) 99–180 elimination goal is to be achieved. children taking ivermectin tablets49.In Japan, (Academic Press, 2002).

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The increasing prevalence of antibiotic- In 1995, the American Society for Micro- Arch. Opthalmol. 104, 863–870 (1986). 1 35. Pacqué, M. et al. Community-based treatment of resistant microorganisms is now an issue of biology , and in 1998, a House of Lords onchocerciasis with ivermectin: safety, efficacy and major public concern. Newspaper headlines Select Committee in the United Kingdom2, acceptability of yearly treatment. J. Infect. Dis. 163, 381–385 (1991). and media reports regularly feature details of issued reports that have been influential in 36. Chijioke, C. P. & Okonkwo, P. Adverse events following their impact on individuals as well as raising establishing national strategies. In the United mass ivermectin therapy for onchocerciasis. Trans. R. Soc. 3 Trop. Med. Hyg. 86, 284–286 (1992). the spectre of widespread and untreatable States, a task force was established .The 37. De Sole, G. et al. Adverse reactions after large-scale drug-resistant infections. 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