7.

26 Overview of Parasitic Infections

P J Rosenthal, University of California, San Francisco, CA, USA
& 2007 Elsevier Ltd. All Rights Reserved.

7.26.1 Introduction 750

7.26.2 Disease Burden from Parasitic Diseases 750
7.26.3 Protozoan Infections 752
7.26.3.1 Malaria 752
7.26.3.1.1 Biology of malaria parasites 752
7.26.3.1.2 Epidemiology of malaria 752
7.26.3.1.3 Clinical manifestations of malaria infection 754
7.26.3.1.4 Drugs to treat malaria 754
7.26.3.2 Leishmaniasis 756
7.26.3.2.1 Biology of leishmanial parasites 756
7.26.3.2.2 Epidemiology of leishmaniasis 756
7.26.3.2.3 Clinical manifestations of leishmanial infection 756
7.26.3.2.4 Drugs for leishmaniasis 756
7.26.3.3 African Trypanosomiasis 756
7.26.3.3.1 Biology of African trypanosomes 756
7.26.3.3.2 Epidemiology of African trypanosomiasis 757
7.26.3.3.3 Clinical manifestations of African trypanosomiasis 757
7.26.3.3.4 Drugs for African trypanosomiasis 757
7.26.3.4 American Trypanosomiasis (Chagas Disease) 757
7.26.3.4.1 Biology of American trypanosomes 757
7.26.3.4.2 Epidemiology of Chagas disease 757
7.26.3.4.3 Clinical manifestations of Chagas disease 757
7.26.3.4.4 Drugs for Chagas disease 758
7.26.3.5 Gastrointestinal and Genitourinary Protozoan Infections 758
7.26.3.5.1 Biology of gastrointestinal and genitourinary protozoan infections 758
7.26.3.5.2 Epidemiology of gastrointestinal and genitourinary protozoan infections 758
7.26.3.5.3 Clinical manifestations of gastrointestinal and genitourinary protozoan infections 758
7.26.3.5.4 Drugs for gastrointestinal and genitourinary protozoan infections 758
7.26.3.6 Toxoplasmosis 758
7.26.3.6.1 Biology of Toxoplasma gondii 758
7.26.3.6.2 Epidemiology of toxoplasmosis 759
7.26.3.6.3 Clinical manifestations of toxoplasmosis 759
7.26.3.6.4 Drugs for toxoplasmosis 759
7.26.4 Helminth Infections 759
7.26.4.1 Intestinal Nematode (Round Worm) Infections 759
7.26.4.1.1 Biology of nematodes 759
7.26.4.1.2 Epidemiology of nematode infections 759
7.26.4.1.3 Clinical manifestations of nematode infections 759
7.26.4.1.4 Drugs for nematode infections 760
7.26.4.2 Tissue Nematode Infections 760
7.26.4.2.1 Biology of tissue nematodes 760
7.26.4.2.2 Epidemiology of tissue nematodes 760
7.26.4.2.3 Clinical manifestations of tissue nematode infections 760
7.26.4.2.4 Drugs for tissue nematodes 760
7.26.4.3 Trematode Infections 760
7.26.4.3.1 Biology of trematode infections 760
7.26.4.3.2 Epidemiology of trematodes 761
7.26.4.3.3 Clinical manifestations of trematode infections 761

749
750 Overview of Parasitic Infections

7.26.4.3.4 Drugs for trematode infections 761

7.26.4.4 Cestode (Tapeworm) Infections 761
7.26.4.4.1 Biology of cestode infections 761
7.26.4.4.2 Epidemiology of cestodes 761
7.26.4.4.3 Clinical manifestations of cestode infections 761
7.26.4.4.4 Drugs for cestode infections 761
7.26.5 The Future of Drug Discovery and Development for Parasitic
Infections 761
References 762

7.26.1 Introduction
Parasitic organisms are responsible for a huge number of illnesses in humans (for detailed discussions of parasitic
infections and the biology of human parasites, see 1). Although all infectious pathogens can be considered human
parasites, the term parasite is generally restricted to two large groups of eukaryotic organisms that inflict human
disease: unicellular protozoans and multicellular helminths. Among these are species responsible for many of the most
widespread and devastating human infections. In general, protozoan parasites reproduce in human hosts, leading to the
generation of large numbers of parasites in the body, and serious illnesses. Malaria, leishmaniasis, African
trypanosomiasis, American trypanosomiasis, and amebiasis are among the most deadly human infections. Effective
treatment of protozoan infections generally requires complete eradication of infecting parasites. Most helminths do not
reproduce in humans, so disease is the consequence of infection with large numbers of organisms. Some helminths are
quite benign, only occasionally causing disease, but the very high prevalence of infection with, for example, a number of
roundworms, leads to important morbidities, even though most infections are asymptomatic. Other helminths are less
prevalent, but nonetheless infect millions, and are responsible for significant human morbidity and mortality.
Treatment of some helminth infections requires parasite eradication, but for a number of infections antiparasitic drugs
are most widely used to control infections both in individuals and populations, without necessarily fully eradicating
infecting worms.
It so happens that most, although not all, parasitic infections disproportionately affect the most economically
disadvantaged populations in the world. Many parasites that are rarely, if ever, encountered in the developed world are
extremely common in developing countries. The consequence of this fact is that, for most parasitic diseases, the
incentive for drug discovery is low, as it is difficult for pharmaceutical companies to generate profits from drugs for
developing world populations. For this reason, our ability to treat parasitic infections is remarkably inadequate. Many of
the earliest anti-infective therapies were directed against parasites, for example quinine, which was developed in the
early nineteenth century as an antimalarial drug.2 Yet, in the early twenty-first century we lack highly effective
therapies for many parasitic infections. For some diseases, such as malaria, effective therapies are available, but for
complex reasons, including the high cost of newer agents, most infected individuals still receive older drugs that are
suboptimal due to drug resistance and toxicity. For other diseases, including African and American trypanosomiasis,
available therapies are poor, due to limited efficacy, resistance, and unacceptable toxicity. New drugs are greatly needed
for many human parasitic diseases, but development efforts have been slow. Recently, some progress has been seen on
this front, with increased funding for antiparasitic drug discovery from industry and publicprivate partnerships, and
the future for antiparasitic drug development has become a bit more promising.
Another population that is disproportionately affected by parasitic infections is immunocompromised individuals.
A number of protozoan parasites cause most illnesses in the immunocompromised. For example, toxoplasmosis is
usually a harmless chronic infection and cryptosporidial infections are generally mild in most healthy individuals, but
these and other parasites cause a range of serious and at times deadly manifestations in immunocompromised hosts.
Another important reason for antiparasitic drug discovery is the need to improve therapies for infections in
immunocompromised individuals in both developed and developing countries.

7.26.2 Disease Burden from Parasitic Diseases

The burden of parasitic diseases of humans is enormous (Table 1). It is quite difficult to ascertain accurate
epidemiologic data, as most infections occur in underserved populations with limited healthcare infrastructures.
Table 1 Summary of human parasitic diseases

Disease Key species Vectors Geographic distribution Prevalencea Annual incidencea Annual mortalitya

Malaria Plasmodium falciparum, P. vivax, P. ovale, P. malariae Anopheline mosquitoes Most of tropics 2 777 000 213 743 000 856 000
Leishmaniasis Leishmania spp. Sand flies Much of tropics 1 278 000 414 000 50 000
African trypanosomiasis Trypanosoma brucei Tsetse fly Sub-Saharan Africa 267 000 60 000 47 000
American trypanosomiasis Trypanosoma cruzi Triatome insects Latin America 15 785 000 728 000 19 000
Amebiasis Entamoeba histolytica Worldwide, especially tropics
Toxoplasmosis Toxoplasma gondii Worldwide
Giardiasis Giardia lamblia Worldwide, especially tropics
Trichomoniasis Trichomonas vaginalis Worldwide
Babesiosis Babesia spp. Scattered locations
Cryptosporidiosis Cryptosporidum spp. Worldwide, especially tropics
Isosporiasis Isospora belli Worldwide, especially tropics
Hookworm Ancylostoma duodenale, Necator americanus Worldwide, especially tropics 1 298 000 000 159 000 000 65 000
Ascariasis Ascaris lumbricoides Worldwide, especially tropics 1 472 000 000 335 000 000 60 000
Trichuriasis Trichuris trichuria Worldwide, especially tropics 1 049 000 000 220 000 000 10 000
Strongyloidiasis Strongyloides stercoralis Worldwide, especially tropics 70 000 000
Trichinellosis Trichinella spiralis Worldwide
Drancunculiasis Dracunculus medinensis Copepods Africa 80 000
Filariasis Wuchereria bancrofti, Brugia malayi, Brugia timori Mosquitoes Worldwide in tropics 120 000 000 44 000 000
Loiasis Loa loa Tabanid flies Africa 13 000 000
Onchocerciasis Onchocerca volvulus Blackflies Africa, Latin America 17 660 000 270 000 45 000
Schistosomiasis Schistosoma species Worldwide in tropics 201 380 000 20 000 000 20 000

Overview of Parasitic Infections

Liver flukes Clonorchis sinensis, Opisthorchis species, Fasciola hepatica Worldwide, especially Asia 19 740 000
Intestinal flukes Fasciolopsis buski and others Worldwide, especially Asia 1 110 000
Lung flukes Paragonimus westermani and others Worldwide, especially Asia 20 680 000
Fish tapeworm Diphyllobothrium latum Worldwide 9 000 000
Beef tapeworm Taenia saginata Worldwide 77 000 000
Pork tapeworm Taenia solium Worldwide 10 000 000
Dwarf tapeworm Hymenolepsis nana Worldwide 75 000 000
Echinococcosis Echinococcus spp. Scattered areas worldwide 2 700 000
a
Estimates of prevalence, incidence, and mortality vary quite widely. The estimates provided here are from 27 for protozoan infections in 1990 and 46 for helminth infections.

751
752 Overview of Parasitic Infections

Nonetheless, significant effort has gone into estimating the impact of the most important parasitic infections. In many
cases, most notably for protozoan infections such as malaria, the burden consists of acute infections, with extensive
acute morbidity and mortality. In other cases, in particular a number of helminth infections such as schistosomiasis,
chronic disease ensues after infection with large numbers of organisms. In addition, many asymptomatic individuals are
infected with helminths, serving as potential future sufferers of chronic diseases and as reservoirs for the transmission
of infections. In some cases, such as malaria, leishmaniasis, and trypanosomiasis, case-mortality is high. In other cases,
despite limited mortality, morbidity may be extensive, such as with many helminth infections. In addition, for
infections where prevalence is extremely high, even quite low case-mortality levels can lead to important morbidity and
mortality. The data on infection and disease prevalence, incidence, and mortality in Table 1 are from a number of
sources, and of varied reliability, but nonetheless they provide insight into the profound importance of parasitic
infections of humans. Some data are quite old, but sadly this fact is of little importance, as progress against most
parasitic diseases has been very limited in recent years. Additional epidemiologic data for diseases of particular
importance are provided in sections on individual infections below.

7.26.3 Protozoan Infections

Protozoan infections are the leading causes of morbidity and mortality among parasitic infections of humans. The most
important human protozoan infections are summarized in Tables 1 and 2. Additional information is provided on
infections of greatest importance in drug discovery efforts.

7.26.3.1 Malaria
7.26.3.1.1 Biology of malaria parasites
Human malaria is caused by four species of apicomplexan parasites, Plasmodium falciparum, P. vivax, P. ovale, and
P. malariae. P. falciparum is by far the most medically important parasite, as it is the only malaria parasite that commonly
causes severe disease and death. The virulence of P. falciparum is due to a number of biological factors, including its
ability to infect erythrocytes of all ages and the binding of P. falciparum-infected erythrocytes to human endothelial
cells, which mediates various disease processes.3 P. vivax is about as common as P. falciparum, but is generally not
responsible for severe disease. The other two plasmodial species are quite uncommon.
All malaria parasites have a similar life cycle.3 Human infection is initiated by inoculation of sporozoites during
the bite of an anopheline mosquito. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue
schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes, where
parasites divide asexually. Repeated cycles of erythrocyte infection can lead to the infection of many erythrocytes
and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where
they develop into infective sporozoites.
Clinical illness is caused only by the erythrocytic cycle of malaria parasites. Antimalarial therapy focuses on
eradicating parasites at this stage of their life cycle.4 Most drugs are not effective against other stages, but some offer
activity against liver stages, to facilitate chemoprophylaxis, or against gametocytes, to offer benefit in diminishing
parasite transmission to others.
In P. falciparum and P. malariae infections, only one cycle of liver cell invasion and multiplication occurs, and liver
infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure
these infections. In P. vivax and P. ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most
drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of
both erythrocytic and hepatic parasites is required to cure these infections.

7.26.3.1.2 Epidemiology of malaria

Malaria is the most deadly protozoan infection of humans. Hundreds of millions of cases of malaria occur annually, and
infections with P. falciparum, the most virulent human malaria parasite, probably lead to over a million deaths each
year.5,6 Indeed, a recent analysis suggested that prior estimates of incidence were low, and that 515 million episodes of
clinical P. falciparum infection occurred in 2002.7 Most severe disease and deaths from malaria are in children; it has
been estimated to cause 10.7% of all deaths in children under 5 years of age.8 Despite extensive control efforts, the
incidence of malaria is not decreasing in most endemic areas of the world, and in some areas it is clearly increasing.9
A major reason for the persistence of the severe malaria problem is the increasing resistance of parasites to available
 Overview of Parasitic Infections 753

Table 2 Available drugs and key drug needs for parasitic infections

Disease Available drugs Key drug needs

Malaria Chloroquine, amodiaquine, quinine, mefloquine, Inexpensive, orally bioavailable, safe

primaquine, sulfadoxinepyrimethamine and compounds for combination therapy for
other antifolates, artemisinins (including uncomplicated malaria, including that
combination regimens), atovaquone, caused by highly drug-resistant parasites;
doxycycline and other antibiotics, halofantrine improved drugs for chemoprophylaxis
Leishmaniasis Pentavalent antimonials, amphotericin B, Inexpensive, nontoxic drugs active against
pentamidine, miltefosine drug-resistant disease
African Pentamidine, suramin, melarsoprol, eflornithine Drugs with efficacy against resistant parasites
trypanosomiasis and decreased toxicity compared to current
agents
American Nifurtimox, benznidazole Drugs with ability to eradicate fully early
trypanosomiasis infections and to provide benefit when
used in chronic and advanced infections
Amebiasis Metronidazole or tinidazole

Toxoplasmosis Pyrimethamine plus sulfadiazine or clindamycin Therapies with decreased toxicity

Giardiasis Tinidazole or metronidazole Therapies with improved efficacy

Trichomoniasis Metronidazole Therapy for metronidazole-resistant

infections
Babesiosis Quinine plus clindamycin

Cryptosporidiosis Nitazoxanide Therapies with improved efficacy

Isosporiasis Trimethoprimsulfamethoxazole

Hookworm Albendazole or mebendazole

Ascariasis Albendazole or mebendazole or pyrantel pamoate

Trichuriasis Albendazole or mebendazole

Strongyloidiasis Ivermectin or thiabendazole or albendazole

Trichinellosis Mebendazole or albendazole (uncertain benefit)

Drancunculiasis Thiabendazole or metronidazole and worm

removal
Filariasis Diethylcarbamazine or ivermectin

Loiasis Diethylcarbamazine or ivermectin

Onchocerciasis Ivermectin or diethylcarbamazine

Schistosomiasis Praziquantel

Liver flukes Praziquantel or albendazole or triclabendazole

Intestinal flukes Praziquantel

Lung flukes Praziquantel

Fish tapeworm Praziquantel or niclosamide

Beef tapeworm Praziquantel or niclosamide

Pork tapeworm Praziquantel or niclosamide or albendazole

(cysticercosis)
Dwarf tapeworm Praziquantel or niclosamide

Echinococcosis Albendazole and cyst removal

754 Overview of Parasitic Infections

chemotherapeutic agents. Resistance to chloroquine, the most widely used antimalarial over the last half-century, is
now very common, and other available antimalarials are limited by resistance, high cost, and toxicity.10
Malaria is endemic throughout most of the tropics. However, its epidemiology varies greatly in different endemic
regions. Malaria is most highly endemic in sub-Saharan Africa, which suffers the bulk of worldwide malarial morbidity
and mortality. The particularly high prevalence of malaria in Africa is probably due to the high transmission efficiency of
local anopheline vectors and other environmental factors. The level of transmission of malaria in much of sub-Saharan
Africa is truly remarkable; in many areas individuals are infected, on the average, more than once each day. With
increasing transmission comes increasing levels of antimalarial immunity. Immunity is never complete, but in areas with
high transmission malaria is primarily a disease of young children, with older children and adults relatively protected
against severe disease. A second reason for the particular severity of malaria in Africa is that in this area, the disease is
nearly all due to P. falciparum, the most virulent parasite; in most other endemic areas P. vivax is as common or more
common than P. falciparum as a cause of disease. Nonetheless, although numbers are lower than in Africa, falciparum
malaria causes large numbers of illnesses and deaths in South America, South Asia, and parts of Oceania.
A key factor in understanding the current epidemiology of malaria is the epidemiology of drug resistance. Drug
resistance is primarily a problem with P. falciparum. Most important are resistance to chloroquine, the mainstay for
antimalarial therapy from about 1950 until recently, and to antifolates, the most common replacements for chloroquine.
Chloroquine resistance was first seen in the late 1950s in South America and Southeast Asia, spread quite slowly around
the world, but is now deeply seated in nearly all malarious areas.10 Resistance to antifolates is also now a large and
increasing problem.

7.26.3.1.3 Clinical manifestations of malaria infection

Although it is the most common cause of death from parasitic infection, malaria most commonly presents as a relatively
mild febrile illness. Millions of episodes of malaria are treated with self-administered drugs, drugs provided by health
workers or shopkeepers with limited medical training, or in clinics without laboratory diagnostic capabilities. On the
other hand, a subset of infections, particularly those caused by P. falciparum, will progress to severe disease. The
progression to severe illness is much more likely in an individual without prior antimalarial immunity, such as a traveler
to the tropics from a nonendemic area. The most common presentation of malaria is fever accompanied by nonspecific
symptoms including headache, weakness, sweats, chills, arthralgias, and myalgias. Common manifestations of severe
malaria are profound anemia, most commonly in children in endemic areas, cerebral malaria, with progressive
neurological dysfunction, and severe pulmonary disease, each of which can commonly progress to death. Many organ
systems can be affected by malaria; heart failure secondary to anemia, renal failure, respiratory failure, and hepatic
dysfunction are all common. However, prompt therapy of severe malaria is often followed by excellent therapeutic
outcomes.

7.26.3.1.4 Drugs to treat malaria

Numerous drugs are available to treat malaria.4,11,12 However, many drugs suffer from one or more of three main
concerns: diminishing efficacy due to the spread of drug-resistant parasites, toxicity, and high cost that limits use in
developing countries. It is important to consider antimalarial drugs based on three quite different indications. The
greatest need is for safe, inexpensive, oral drugs for the therapy of uncomplicated malaria in developing countries. For
this indication drugs must be very inexpensive and safe enough for use in unsupervised settings. Considering the
challenges of assuring patient compliance in settings with limited healthcare infrastructures, they should also ideally be
effective when used over brief courses (generally up to 3 days) with once-daily dosing. A second need is for rapidly
acting drugs to treat severe malaria; these drugs are typically given intravenously, but other routes (e.g., per rectal) are
of interest in some settings with limited technology.13 Cost is less of a concern for the treatment of severe malaria, as
the number of doses needed is much lower than for uncomplicated disease. A third need is for chemoprophylaxis
against infection, most commonly used in travelers from nonendemic to endemic countries. In this case, much higher
costs can be tolerated. However, drugs used for chemoprophylaxis should be extremely safe and should be effective
when used with weekly or once-daily dosing.

7.26.3.1.4.1 Drugs to treat uncomplicated malaria

Most difficulties in the treatment of malaria are with P. falciparum. Infections with other species are generally
successfully treated with chloroquine, although increasing resistance of P. vivax to chloroquine has been observed.14 For
P. vivax and P. ovale infections, primaquine must also be given to eradicate liver hypnozoites and prevent subsequent
relapse of infection.
 Overview of Parasitic Infections 755

For many years chloroquine was an outstanding drug for uncomplicated malaria, offering a very cheap, very safe,
rapidly acting, and highly effective therapy for falciparum malaria. However, chloroquine resistance has gradually spread
around the world, such that the use of this drug is now appropriate in only a few areas. Despite decreasing efficacy, due
to its low cost and the familiarity of patients and clinicians with this drug, it is still widely used, especially in Africa.
However, there is a growing consensus that in nearly all areas chloroquine should be replaced by other drugs for the
routine treatment of malaria. Related drugs, including amodiaquine and mefloquine, offer much better efficacy in most
areas, although resistance to these drugs is also a problem in some areas. Quinine retains excellent efficacy in most
areas, but it is fairly expensive and toxic, relegating its use for uncomplicated malaria primarily to second-line therapy
after the failure of another regimen. Antifolates offer potent antimalarial activity, and sulfadoxinepyrimethamine
(Fansidar), which inhibits dihydrofolate reductase and dihydropteroate synthase, has been used as an inexpensive
replacement for chloroquine. However, resistance to sulfadoxinepyrimethamine has been seen to develop rapidly after
widespread use.10 In Southeast Asia, where resistance to chloroquine and sulfadoxinepyrimethamine was seen earlier
than in Africa, other drugs are now routinely used. In Thailand, the use of mefloquine was followed by the
identification of parasites resistant to this drug, but the use of a combination of mefloquine and artesunate has shown
excellent efficacy against highly resistant parasite.15 Artesunate is one of a growing class of antimalarials derived from
artemisinin, a natural product developed in China.16,17 These drugs offer very rapid antimalarial activity and are not yet
limited by drug resistance. However, they have very short half-lives, so must be used in combination with longer-acting
drugs to avoid unacceptable levels of late recrudescences. Artemisinin-based combination therapy (ACT) is rapidly
becoming the standard for the therapy of uncomplicated malaria.14,18 Although mefloquineartesunate has been
successful in Thailand, it is probably too toxic and too expensive for widespread use in more disadvantaged populations,
such as Africa. Other ACT regimens currently under study (and increasingly used) are amodiaquineartesunate,
lumefantrineartemether, and piperaquinedihydroartemisinin.19 However, ACTs remain much more expensive than
older drugs, are of uncertain safety in pregnant women, and have to date been relatively little tested in Africa, where
the need for new therapies is greatest.20 Particularly in Africa, most therapies for uncomplicated malaria will be used
outside of medical supervision, meaning that many doses of antimalarials may be used when the true cause of fever is
not malaria, and it is unclear if ACT regimens are appropriate or affordable enough for this widespread use. Other non-
ACT combination regimens can play a role in some settings. In particular, amodiaquinesulfadoxinepyrimethamine has
shown surprisingly good efficacy, even in areas with moderate resistance to the individual components of the
combination.21 Additional antimalarial drugs that show efficacy but are of limited utility in developing countries due to
high cost and/or toxicity concerns are halofantrine and the combination of atovaquone and proguanil. The field of
antimalarial drug discovery is now increasingly active,22 and it is anticipated that a number of artemisin-based and other
new antimalarial drugs will be undergoing clinical testing in the near future.

7.26.3.1.4.2 Drugs for complicated malaria

The standard therapy for complicated malaria has for many years been parenteral quinine. Courses of quinine, which is
quite poorly tolerated, can be shortened by adding doxycycline or clindamycin; these antibiotics are slow acting, but
effective in combination. Recent studies have shown a number of artemisinins to offer equivalent efficacy to quinine
for severe malaria, and it is likely that these new regimens, if affordable, will play important roles in the treatment of
severe disease.

7.26.3.1.4.3 Drugs for chemoprophylaxis against malaria

It has been standard practice for many years for travelers from nonendemic to endemic regions to receive medication to
prevent malaria.23 Weekly dosing of chloroquine was the standard for this indication, but resistance to this drug in
nearly all malarious areas now mandates the use of other drugs for most travelers. Most commonly used at present are
mefloquine, which is effective but relatively poorly tolerated, atovaquoneproguanil, a new quite expensive regimen,
and doxycycline, which is limited by photosensitivity and gastrointestinal toxicity. Improved chemoprophylactic agents
are needed. Ironically, although this need is tiny compared to that for therapies for the millions infected with drug-
resistant malaria parasites, this is the only indication for which antimalarial drug development may be profitable, and so
the development of drugs for chemoprophylaxis may drive the identification of new therapies.
Chemoprophylaxis for malaria is not deemed appropriate for widespread use in endemic countries due to high costs,
potential toxicities, difficulties of assuring compliance, and potential to select for resistant parasites. However, another
use of chemoprophylaxis is for endemic populations at particular risk for severe malaria, notably young children and
pregnant women. Intermittent preventive therapy of pregnant women with chloroquine was used previously, and the
use of sulfadoxinepyrimethamine for this indication has offered benefit.24 More recently, intermittent treatment of
756 Overview of Parasitic Infections

infants with sulfadoxinepyrimethamine diminished malarial morbidity.25 However, benefits of chloroquine and
sulfadoxinepyrimethamine for these indications may in large part be due to the unusually long half-lives of these
drugs, and with increasing resistance, it is not clear which other drugs can fill this role.

7.26.3.2 Leishmaniasis
7.26.3.2.1 Biology of leishmanial parasites
Leishmanial parasites cause three quite different clinical syndromes, depending on the infecting species. Visceral
leishmaniasis (kala azar) is the most important, as it is a severe disseminated disease that is commonly fatal. Cutaneous
leishmaniasis is a common cause of chronic skin ulcers. Mucocutaneous leishmaniasis is an uncommon syndrome
involving mucosal lesions of the respiratory tract after prior cutaneous disease. Leishmaniasis is transmitted by sand
flies of the genus Lutzomyia or Phlebotomus. The flies transmit promastigotes to humans, which develop into amastigotes
in human macrophages. In visceral disease, infected macrophages disseminate, leading to infection of the entire
reticuloendothelial system. In cutaneous disease infected macrophages cause only local skin disease, except for some
species which can occasionally progress to distant mucocutaneous involvement.

7.26.3.2.2 Epidemiology of leishmaniasis

Visceral leishmaniasis is endemic in the Indian subcontinent, other regions of central Asia, and parts of Africa, the
Middle East, and Latin America, a total of 62 countries. Over 90% of cases occur in five countries, India, Bangladesh,
Nepal, Sudan, and Brazil. Recent estimates are that 200 million people are at risk, and that there are 500 000 episodes
each year, leading to over 40 000 recorded and likely many additional unreported deaths.26 Importantly, the incidence of
visceral leishmaniasis has been increasing in recent years. Cutaneous leishmaniasis is endemic in scattered areas around
the world, with an estimated worldwide incidence of 1.5 million in 1990.27 It is particularly important in regions of the
Middle East, the Mediterranean, Africa, India, Asia, and Central and South America. Mucocutaneous leishmaniasis
occurs only Central and South America.
Drug resistance is an important concern for visceral leishmaniasis. Notably, 40% of cases in India are reportedly now
resistant to pentavalent antimony, although resistance in other areas is uncommon.28

7.26.3.2.3 Clinical manifestations of leishmanial infection

Visceral leishmaniasis causes a febrile wasting illness with progressive hepatosplenomegaly. Untreated, the disease
progresses slowly until death from anemia, malnutrition, bleeding, or secondary infections. Cutaneous leishmaniasis
presents with large painless skin ulcers that heal slowly, over months to over a year, often with residual scarring.
Mucocutaneous disease presents with destructive mucosal lesions of the mouth, nose, larynx, or trachea.

7.26.3.2.4 Drugs for leishmaniasis

Standard drugs for all forms of leishmaniasis are pentavalent antimonials (sodium stibogluconate and meglumine
antimonate). These drugs generally have good efficacy, but they require a long course of parenteral therapy and entail
significant toxicity. In addition, resistance is an increasing problem, as noted above.28,29 Alternative therapies for
visceral leishmaniasis include amphotericin B, another parenteral therapy with significant toxicity. Lipid-associated
formulations of amphotericin B decrease toxicity and allow a shortened treatment course, but costs are prohibitive for
developing countries.30 Pentamidine is a third parenteral therapy with major toxicities, and its use is limited also by
increasing drug resistance. Two important new drugs for leishmaniasis are miltefosine and paromomycin. Miltefosine,
which was registered in India in 2002, is an effective oral agent for visceral leishmaniasis, although concerns with this
drug include the rapid selection of resistant parasites and genotoxicity, and its overall role is not yet clear.30
Paromomycin appears to be promising as an alternative parenteral therapy, but funding constraints have delayed
development of the drug for this indication. For cutaneous leishmaniasis, pentavalent antimonials are generally used,
although in some cases no therapy may be needed. Miltefosine may offer a simpler therapy. Multiple new approaches to
antileishmanial chemotherapy are under investigation.29,30

7.26.3.3 African Trypanosomiasis

7.26.3.3.1 Biology of African trypanosomes
African trypanosomiasis is caused by two subspecies of Trypanosoma brucei. The parasites are transmitted by tsetse
flies. The insects inoculate trypomastigotes during a blood meal. Disease is caused by parasites that live and
 Overview of Parasitic Infections 757

multiply extracellularly in the bloodstream and other spaces. African trypanosomes are thus unusual for human
protozoan parasites in successfully surviving as free forms in the bloodstream despite an immune response against the
parasite.

7.26.3.3.2 Epidemiology of African trypanosomiasis

Two similar syndromes, both referred to as sleeping sickness, are caused by African trypanosomes. West African
trypanosomiasis is caused by T. brucei gambiense and transmitted in tropical rain forests of West and Central Africa. East
African trypanosomiasis is caused by T. brucei rhodesiense and transmitted in wooded and savanna regions of Central and
East Africa. Overall, approximately 50 million Africans are at risk of sleeping sickness, with a recent estimate of 100 000
cases and 66 000 deaths each year.31 Of concern, the incidence of African trypanosomiasis appears to be increasing.32

7.26.3.3.3 Clinical manifestations of African trypanosomiasis

West African trypanosomiasis is characterized by a chronic febrile illness, which may not begin until months after the
acquisition of infection. Meningoencephalitic disease may ensue months to years after the onset of infection, with the
development of irritability, personality changes, somnolence, and headaches. Progressive neurological abnormalities end
in death. East African trypanosomiasis has a much more acute course, with the illness typically presenting a few days
after an infectious bite. The disease progresses more rapidly, but with similar findings to West African trypanosomiasis,
ending in death from severe neurological dysfunction.

7.26.3.3.4 Drugs for African trypanosomiasis

Available treatments for African trypanosomiasis are remarkable in that they are mostly very old and very toxic. The
limited armamentarium for this disease is a major concern.32 Disease that has not yet involved the central nervous
system responds fairly well to therapy. Pentamidine (used since 1940) is quite effective for West African disease,
although the therapy is parenteral and quite toxic. Suramin (used since the 1920s) is effective against early East
African disease, but it is also quite toxic. Three drugs are available for advanced central nervous system disease.
Melarsoprol (used since 1949) can be used for both subspecies, and is the only reliable drug for East African disease. It
is very toxic, and in addition suffers from decreasing efficacy in some areas, probably due to parasite drug resistance.32
An important relatively new drug is eflornithine, which has been available since the 1990s. Eflornithine is an effective
therapy for advanced West African, but not East African trypanosomiasis. Although clearly less toxic than melarsoprol, it
does have some important safety concerns. It requires parenteral dosing, although an oral formulation is under
development.

7.26.3.4 American Trypanosomiasis (Chagas Disease)

7.26.3.4.1 Biology of American trypanosomes
Trypanosoma cruzi, the cause of American trypanosomiasis, is transmitted by a number of species of triatome insects
(kissing bugs). Transmission occurs when mucous membranes or skin breaks are contaminated with insect feces
containing infective trypomastigotes. In the human host parasites invade multiple cell types, transform into
amastigotes, and multiply intracellularly. The parasite can also be transmitted by blood transfusions. The most heavily
parasitized tissue is muscle, with most disease manifestations due to infection of cardiac and smooth muscle. Chronic
infection leads to gradual destruction of cardiac and gastrointestinal smooth muscle over many years.

7.26.3.4.2 Epidemiology of Chagas disease

Chagas disease is a zoonosis that occurs through most of Latin America. The parasite infects many mammalian species,
and humans are an incidental host. The disease is transmitted principally in areas where primitive housing is used,
allowing cohabitation of humans and disease vectors. Thus, Chagas disease is primarily a problem of poor rural
inhabitants of Latin America. Recent extensive efforts to control the disease have had success, and transmission has
decreased markedly in much of South America. Despite these advances, Chagas disease was recently estimated to be
responsible for 1012 million infections and up to 45 000 deaths each year.33

7.26.3.4.3 Clinical manifestations of Chagas disease

Acute infections with T. cruzi are commonly asymptomatic, but may include swelling at the site of inoculation followed
by fever, malaise, other nonspecific findings and, rarely, serious neurological or cardiac disease. The major public health
758 Overview of Parasitic Infections

importance of Chagas disease is chronic infection. Disease manifestations often present many years after primary
infection. Chronic infection progresses to serious clinical problems, including severe heart failure, arrhythmias, and
extreme dilatation of the esophagus or colon.

7.26.3.4.4 Drugs for Chagas disease

Available therapies for Chagas disease consist of just two drugs, and these are clearly inadequate.34 Nifurtimox, an oral
agent, reduces the severity and duration of acute Chagas disease, but long courses are required, adverse events are
common, and parasitological cure is not achieved in 30% of patients. Benznidazole, another oral agent, has similar
efficacy and limitations. It is not clear whether it is beneficial to treat chronic Chagas disease with either nifurtimox or
benznidazole.34 New therapeutic approaches for Chagas disease are under investigation.34

7.26.3.5 Gastrointestinal and Genitourinary Protozoan Infections

7.26.3.5.1 Biology of gastrointestinal and genitourinary protozoan infections
Infections with Entamoeba histolytica, Giardia lamblia, Cryptosporidium parasites, Isospora belli, and other gastrointestinal
protozoans are initiated by ingestion of infectious cysts or oocysts. Amebiasis causes an invasive, inflammatory enteritis,
but the other pathogens cause noninflammatory diarrhea. Entamoeba can also invade other tissues, most commonly the
liver. Trichomonas vaginalis is primarily transmitted sexually and causes genitourinary disease.

7.26.3.5.2 Epidemiology of gastrointestinal and genitourinary protozoan infections

Amebiasis is most common in developing countries. It causes approximately 50 million cases and 100 000 deaths each
year.35 Giardiasis and cryptosporidiosis are unusual among protozoans, in causing significant disease, mostly related to
contaminated water, in both developed and developing countries. Trichomoniasis is among the most common sexually
transmitted diseases in women and a fairly common cause of urethritis in men.

7.26.3.5.3 Clinical manifestations of gastrointestinal and genitourinary protozoan infections

Amebiasis most commonly presents with colitis and diarrhea, and can progress to severe dysentery. Amebiasis can also
cause extraintestinal disease, most notably liver abscesses. Other intestinal protozoans cause diarrhea, which can be
severe in immunocompromised individuals infected with Cryptosporidium, Isospora, and some other parasites.
Trichomoniasis causes vaginitis in women and urethritis in men.

7.26.3.5.4 Drugs for gastrointestinal and genitourinary protozoan infections

Amebiasis, giardiasis, and trichomoniasis are usually treated with metronidazole or tinidazole36 Drug resistance is of
uncertain significance, but appears to be an increasing problem with Trichomonas.37 Cryptosporidiosis is usually self-
limited in those with normal immunity, but the treatment of severe disease in immunocompromised hosts has been
very challenging. Nitazoxanide was recently approved for the treatment of cryptosporidiosis and giardiasis, although
efficacy against severe cryptosporidiosis in AIDS patients has not clearly been demonstrated.38 Isospora infection is
treated with trimethoprimsulfamethoxazole, which is quite effective, even in AIDS patients.

7.26.3.6 Toxoplasmosis
7.26.3.6.1 Biology of Toxoplasma gondii
Toxoplasma gondii infects many species of mammals and birds. The only definitive hosts are various species of cats; all
others, including humans, are intermediate hosts. Humans are infected by ingesting undercooked meat containing
tissue cysts, by ingestion of water or food contaminated with oocysts from cat feces, or by congenital transmission. In
the intestines, sporozoites released from oocysts or bradyzoites released from tissue cysts invade and multiply within
epithelial cells as tachyzoites, and spread to other locations via the lymphatics and bloodstream. Tachyzoites
subsequently invade many cell types, leading to rapid replication and cell destruction. Some tachyzoites differentiate
to bradyzoites, which replicate slowly and form tissue cysts. In immunocompetent individuals, infection is followed by
a chronic subclinical infection. With immune compromise, latent infections become active, and rapid proliferation of
tachyzoites leads to destructive lesions, most commonly in the brain, eyes, heart, and lungs.
 Overview of Parasitic Infections 759

7.26.3.6.2 Epidemiology of toxoplasmosis

Toxoplasmosis is a worldwide zoonosis. In different regions the relative importance of transmission due to the ingestion
of undercooked meat and the ingestion of food contaminated by cat feces may vary. Toxoplasmosis is most important as
a cause of disease after reactivation in immunocompromised individuals. Presentations differ with different types of
immune deficiency. With AIDS, encephalitis due to toxoplasmosis is one of the most important opportunistic
infections, and may occur in up to half of patients who do not receive antiretroviral or antiparasitic therapy.39
Involvement of other organs, in particular the lungs and heart, is more common in patients immunocompromised due
to organ transplantation. Congenital toxoplasmosis occurs after acute infection during pregnancy and is an important
cause of both neonatal disease and long-term sequellae of infection.

7.26.3.6.3 Clinical manifestations of toxoplasmosis

Acute toxoplasmosis is usually asymptomatic, but may present with lymphadenopathy or a mild febrile illness in
immunocompetent hosts. In patients with AIDS, toxoplasmosis usually presents with a severe encephalopathy. In
patients with other forms of immunodeficiency, encephalopathy, pneumonitis, and myocarditis are common.

7.26.3.6.4 Drugs for toxoplasmosis

Available drugs do not eradicate encysted bradyzoites, but act against tachyzoites to control active disease. The
standard therapy is pyrimethamine plus either sulfadiazine or clindamycin. Trimethoprimsulfamethoxazole, which is
used for prophylaxis against a number of infections in immunocompromised individuals, is effective for the prevention
of toxoplasmosis.40

7.26.4 Helminth Infections

A great many different worm species, including nematodes, trematodes, and cestodes, are important human pathogens.
In general, drug needs are less for helmintic infections, as most of the infections are usually less serious than the most
important protozoan infections and some excellent drugs active against multiple helminth species are already available.
However, effective drugs can be of great importance for both the treatment and control of helminth infections.
Helminths of importance for drug discovery are detailed in Tables 1 and 2, and important infections are described in
more detail below.

7.26.4.1 Intestinal Nematode (Round Worm) Infections

7.26.4.1.1 Biology of nematodes
Nematodes infect humans after the ingestion of eggs (ascariasis and trichuriasis) or the passage of infective larvae
through the skin (hookworm infections and strongyloidiasis). Worms migrate through the gut or other tissues to the
intestines. Infections can persist for years, and can be particularly prolonged in strongyloidiasis.

7.26.4.1.2 Epidemiology of nematode infections

Intestinal nematode infections are very common in developing countries. Over 80% of populations may be infected
with Ascaris.41 For all of the nematodes, low-level infections are very common, but probably not of clinical consequence.
Heavy infections are much less common, but lead to clinical disease. Deaths are uncommon, but can result from
abdominal complications. In addition, it is estimated that severe anemia secondary to hookworm infection is
responsible for about 60 000 deaths per year.42

7.26.4.1.3 Clinical manifestations of nematode infections

Ascariasis and trichuriasis are typically asymptomatic, but Ascaris can cause pulmonary symptoms during passage of
larvae through the lungs. Heavy infections can lead to gastrointestinal symptoms and occasional obstructive processes.
Although serious manifestations are very uncommon, these infections are so prevalent that they are a common cause of
surgical admission for abdominal disease in the tropics. Hookworm can cause gastrointestinal symptoms; the major
consequence of infection is chronic anemia, which can be severe. Strongyloidiasis can also cause acute pulmonary
symptoms. Chronic infection is usually asymptomatic, but can include intestinal symptoms due to adult worms and
nonspecific symptoms due to migrating larvae. Uniquely among the nematodes, Strongyloides can replicate in the human
host; this process is of particular relevance in immunodeficient individuals, in whom hyperinfection syndromes with
multisystem involvement, bacterial superinfection, and high levels of mortality can be seen.43
760 Overview of Parasitic Infections

7.26.4.1.4 Drugs for nematode infections

A number of effective drugs are available for nematode infections. Indications vary for the different parasites.
Important agents include albendazole, mebendazole, thiabendazole, pyrantel pamoate, and ivermectin. Short courses
are generally highly effective, although Strongyloides hyperinfection requires prolonged therapy.

7.26.4.2 Tissue Nematode Infections

7.26.4.2.1 Biology of tissue nematodes
Trichinosis results from ingestion of Trichinella larvae in undercooked meat. The larvae circulate in the bloodstream and
invade skeletal muscle. Dracunculiasis occurs after drinking water contaminated with small crustaceans infected with
Dracunculus medinensis. Larvae are released in the stomach and penetrate the intestinal mucosa. Worms subsequently
develop and mate in the retroperitoneum, followed by migration to subcutaneous tissues, protrusion of worms, and
release of larvae upon contact with water. Filariasis is transmitted by mosquitoes. Infective larvae develop in lymph
nodes into adult worms, which can live for years, releasing microfilariae into the bloodstream. Loiasis is transmitted by
tabanid flies. Larvae develop into adult worms, which migrate through subcutaneous tissues, causing painless soft
tissue swellings. Onchocerciasis is transmitted by black flies. Larvae develop into adult worms, which become
surrounded by an inflammatory reaction in connective tissues, and which release microfilariae into the circulation.

7.26.4.2.2 Epidemiology of tissue nematodes

Trichinosis occurs worldwide, but uncommonly. Dracunculiasis occurs in sub-Saharan Africa; the incidence of the
disease has decreased markedly due to successful control efforts. Different species of filarial worms have different
distributions, but overall filarial infections are seen in most of the tropics. Overall prevalence of these parasites is
estimated at 120 million. Loiasis occurs in parts of West and Central Africa. Onchocerciasis occurs in West and Central
Africa and parts of the Middle East and Latin America. The disease is believed to be prevalent in millions of Africans.
Most importantly, it is the second leading cause of preventable blindness in the world, with an estimated prevalence of
500 000 for visual impairment and 270 000 for blindness.44

7.26.4.2.3 Clinical manifestations of tissue nematode infections

Trichinosis is usually subclinical, but can present with fever, periorbital edema, myositis, and many nonspecific
symptoms. Drancunculiasis causes a painful ulcer, usually on the legs, often with a visible protruding worm. Filarial
disease presents most commonly as lymphangitis progressing to chronic manifestations of lymphatic obstruction,
including elephantiasis. Loiasis causes transient subcutaneous swellings; adult worms may be noticed passing through
subconjunctival tissue in the eye. Early onchocerciasis presents most commonly with a pruritic rash. Chronic infection
progresses to inflammatory eye disease, and eventually blindness.

7.26.4.2.4 Drugs for tissue nematodes

No therapy effectively eradicates Trichinella larvae in tissue, although mebendazole or albendazole may offer some
benefit. Dracunculiasis is treated with thiabendazole or metronidazole, followed by physical removal of infected worms.
Treatment of filariasis, loiasis, and onchocerciasis with diethylcarbamazine or ivermectin reduces circulating
microfilariae, but does not reliably kill adult worms, and can be complicated by serious acute inflammatory processes.
For onchocerciasis, ivermectin is the safer therapy, and offers benefit with repeated therapy to destroy microfilariae and
gradually reduce numbers of adult worms.44 Intermittent therapy with ivermectin has also been used for the control of
onchocerciasis, with good success.44 An interesting new approach now under investigation is to use antibiotics, in
particular doxycycline, to eradicate the bacterial symbiont Wolbachia, and thereby control onchocerciasis.44

7.26.4.3 Trematode Infections

7.26.4.3.1 Biology of trematode infections
Schistosomiasis occurs after invasion of human skin by cercariae released from infected fresh-water snails.
Schistosomulae subsequently migrate to the lungs and liver, mature to adult worms, and migrate to mesenteric (or,
for S. hematobium, urinary tract) veins. Disease is caused primarily by inflammatory responses to eggs and larvae near the
location of adult worms. Liver flukes are transmitted by ingestion of undercooked fish (Clonorchis, Opisthorchis) or
aquatic vegetation (Fasciola), followed by maturation in the biliary tract, where worms can live for decades. Intestinal
flukes (Fasciolopsis and other species) are acquired after ingestion of contaminated plants; adult flukes inhabit the small
intestine. Paragonimus, the lung fluke, is acquired from ingestion of undercooked fresh-water crayfish and crabs; adults
migrate to the lungs.
 Overview of Parasitic Infections 761

7.26.4.3.2 Epidemiology of trematodes

The most important trematode infection is schistosomiasis. Different species of schistosomes are distributed
throughout the tropics. The worldwide prevalence of infection was estimated at 208 million, leading to 8000 deaths in
1990.27 Other fluke infections have varied geographic distributions; in particular, many flukes are prevalent in Asia.

7.26.4.3.3 Clinical manifestations of trematode infections

Schistosomiasis generally presents with disease in the liver or urinary tract after chronic infection with large numbers of
flukes. Important late manifestations are portal vein fibrosis, gastrointestinal bleeding, liver disease, and genitourinary
disease. Liver fluke infections lead to biliary tract inflammation and obstruction. Lung flukes cause chronic pulmonary
disease, often with nodular or cystic disease, productive cough, and other nonspecific pulmonary symptoms. For many
fluke infections, acute disease from small numbers of migrating worms can also be seen, and disease at sites distant
from the usual locations of individual species can occur. In some cases, inflammatory processes linked to chronic
infections have been associated with increased risks of malignancy.

7.26.4.3.4 Drugs for trematode infections

Schistosomiasis, intestinal flukes, and lung flukes are generally treated with praziquantel. Liver flukes are treated with
praziquantel or albendazole, except for fascioliasis, which is treated with triclabendazole.

7.26.4.4 Cestode (Tapeworm) Infections

7.26.4.4.1 Biology of cestode infections
Tapeworm infections are all acquired by ingesting worm cysts or eggs. The most common infections result from
undercooked fish (Diphyllobothrium latum), beef (Taenia saginata), and pork (Taenia solium). Other tapeworms can be
spread person-to-person (Hymenolepsis nana) or with contamination of food by feces from infected dogs (Echinococcus
species). Mature worms reside in the gut, releasing large numbers of eggs, but usually causing little disease.

7.26.4.4.2 Epidemiology of cestodes

Tapeworm infections are common, particularly in the tropics, but clinical consequences of infection are much less
common. However, cysticercosis, a consequence of T. solium infection, is an important cause of seizures and other
neurological disease in certain areas, including parts of Latin America and Southeast Asia.

7.26.4.4.3 Clinical manifestations of cestode infections

Infections with the fish, beef, and pork tapeworms are usually asymptomatic. Diphyllobothrium latum infection can lead to
vitamin B12 deficiency. An important syndrome related to T. solium infection is cysticercosis. This syndrome is due to
tissue infection with parasite cysts, most often in the brain, following ingestion of food contaminated with parasite eggs
from pig feces. Neurocysticercosis causes inflammatory brain lesions, with seizures, meningitis, and other neurological
sequellae. Echinococcosis causes large cysts (hydatid disease), most commonly in the liver and lung.

7.26.4.4.4 Drugs for cestode infections

Tapeworm infections are generally treated with niclosamide or praziquantel. Neurocysticercosis can be treated with
praziquantel or albendazole. However, the killing of active cysts can be accompanied by inflammatory changes,
with worsening of neurological symptoms, and therefore the advisability of treating neurocysticercosis remains unclear.
With antiparasitic treatment, corticosteroids are often coadministered to limit inflammation. Hydatid disease is treated
by careful surgical resection of cysts, with perioperative administration of albendazole.

7.26.5 The Future of Drug Discovery and Development for Parasitic Infections
Of tremendous importance in considerations of drug development for parasitic diseases is the general lack of a
traditional market for drugs for these indications. Huge amounts of drugs are used for these common diseases, but the
vast majority of this usage is in developing countries, so opportunities for profits are minimal. Contrasts between
healthcare spending in developing and developed countries are enormous, leading to striking, at times perhaps obscene
parallels. For example, eflornithine is a promising and potentially life-saving new drug for African trypanosomiasis, but
for some years it was only available as an expensive topical cream for removal of unwanted facial hair. However, despite
continued disparities in wealth, there are some reasons for optimism regarding drug development for parasitic diseases.
762 Overview of Parasitic Infections

First, advances in medical science and chemistry promise the possibility of more cheaply discovering, developing, and
producing drugs. Second, transportation and communication advances continue to lead to increased contact between all
world populations, and it is increasingly difficult for those in the developed world to ignore health problems of poor
countries. Some of these health problems present in developed countries and are at risk to increase there, many are
risks to travelers from developed to developing countries, and all impact on attempts to improve health and social
circumstances in the poorest countries. Thus, programs to attack major infectious diseases of developing countries are
increasingly promoted by governments of developed countries and nongovernmental organizations. Third, academic
interest in research on parasitic diseases and drug targets remains high. Academicians realize that diseases which are of
relatively little interest among industry groups offer niches for productive research. Fourth, some companies are
increasingly interested in research on diseases of underserved populations, perhaps to ease public perceptions that
their business practices are not adequately serving the public. Finally, the concept of publicprivate partnerships has
emerged, whereby major drug discovery and development efforts are supported by a combination of public funding,
industrial partners, and dedicated funding agencies.45 Despite the reasons for cautious optimism, there is no call for
complacency. Massive disparities in healthcare spending persist, spending for modern diseases such as heart disease
and cancer still far outweighs that for parasitic diseases that affect millions, and the incidence of many of the most
important parasitic diseases is not decreasing. More than ever, aggressive drug discovery efforts directed against leading
parasitic diseases are needed.

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Biography

Philip J Rosenthal, MD, is a professor in the Department of Medicine at the University of California, San Francisco.
He received a BS in Biochemistry from the State University of New York at Stony Brook, an MD from New York
University, training in Internal Medicine at the University of Michigan, and then training in Infectious Diseases at the
University of California, San Francisco. His research interests include the biochemistry of malaria parasites, antimalarial
drug discovery, and translational studies of antimalarial drug efficacy and resistance.

& 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II
No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6
in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying,
recording or otherwise, without permission in writing from the publishers ISBN (Volume 7) 0-08-044520-9; pp. 749763