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Antiparasitic Drugs

Article  in  New England Journal of Medicine · June 1996

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1178 THE NEW ENGLAND JOURNAL OF MEDICINE
REVIEW ARTICLE
DRUG THERAPY
ALASTAIR J. J. WOOD, M.D., Editor
ANTIPARASITIC DRUGS
LEO X. LIU, M.D., D.T.M.H.,
AND P ETER F. W ELLER , M.D.
I NFECTIONS with parasitic helminths and proto-
zoa are important causes of morbidity and mortal-
ity worldwide. Chemotherapy has an important role
not only in the treatment of individual patients but also,
in conjunction with public health and vector-control
measures, in reducing the transmission of parasitic in-
fections. At present, however, there are no vaccines for
human parasitic infections, the scientific knowledge nec-
essary to develop antiparasitic drugs is rudimentary,
and the mechanisms of action of most antiparasitic
drugs are poorly understood. Commercial incentives
for the production of drugs designed to fight infections
that are mainly endemic in developing countries are lim-
ited, and some proved antiparasitic drugs remain un-
available in the United States. New drugs that are ef-
fective against certain parasitic infections have been
developed in recent years; in this review we focus our
attention on these medications, as well as older drugs
that have recently been established to be effective against
specific parasites (Table 1). Older, established antipar-
asitic drugs1-3 and antimalarial drugs4 are not consid-
ered here.
ANTHELMINTIC DRUGS
Parasitic helminths, such as nematodes (roundworms),
cestodes (e.g., tapeworms), and trematodes (flukes), are
complex multicellular organisms with differentiated nerv-
ous systems and organs. In contrast to viruses, bacteria,
and protozoa, most helminths do not directly replicate in
the human body but reproduce sexually, giving rise to
eggs or larvae that pass out of the body. Anthelmintic
drugs often affect some of the more complex systems of
cellular physiology, such as microtubule formation or
neuromuscular function. The emergence of drug resist-
ance in helminths has been much more gradual and lim-
ited than in rapidly replicating protozoa, such as the ma-
larial parasite Plasmodium falciparum.
Albendazole
The benzimidazole drugs available for the treatment
of parasitic diseases in humans include thiabendazole,
From the Department of Medicine, Harvard Medical School, and the Infec-
tious Diseases Division, Beth Israel Hospital — both in Boston. Address reprint
requests to Dr. Weller at Beth Israel Hospital, DA-617, 330 Brookline Ave., Bos-
ton, MA 02215.
1996, Massachusetts Medical Society.
The New England Journal of Medicine
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May 2, 1996
mebendazole, and albendazole. By binding to free
b-tubulin, benzimidazoles inhibit the polymerization of
tubulin and the microtubule-dependent uptake of glu-
cose.5 Although resistance to benzimidazole due to a loss
of the drug’s high affinity for binding to tubulin6 devel-
ops in intensively treated livestock, resistance has not
yet been a problem in humans. The newest benzimi-
dazole, albendazole, has a broad range of activity against
many nematode and cestode parasites. In the United
States, it is available only on a compassionate-use basis
from the manufacturer, SmithKline Beecham. The side
effects of albendazole (Table 2) usually do not require
discontinuation of the drug.7 Its teratogenicity has not
been extensively studied, but all benzimidazoles should
be avoided, if possible, in women of childbearing age.
Echinococcosis
Albendazole has expanded the therapeutic options
for patients with cystic hydatid disease due to Echinococ-
cus granulosus.7 Surgery remains the definitive treatment
for this disease, but it carries the risks of operative mor-
bidity, recurrence of cysts, and spillage of fluid from the
cysts, which can lead to anaphylaxis or dissemination of
the infection. Albendazole reduces the viability of pro-
toscolices and cysts, and its hepatic metabolite, albenda-
zole sulfoxide, is also active against the larval cestodes.
The administration of albendazole before surgery has
been advocated in order to inactivate protoscolices and
minimize the likelihood of recurring cysts.8 Drug thera-
py is also indicated after the spontaneous or operative
rupture of cysts, and the spillage of their contents, to
prevent secondary dissemination.9 The usual four-week
course of treatment (Table 2) often needs to be repeated
two or more times. The absorption of albendazole is en-
hanced by taking it with fatty meals.10
Albendazole is indicated for patients with inopera-
ble, widespread, or numerous cysts of E. granulosus and
for patients with complicated medical problems who
are unsuitable candidates for surgery.7,11 Percutaneous
drainage has also been successfully used to treat hepat-
ic hydatid cysts, and when combined with albendazole
therapy, further reduces the size of cysts.12,13
Albendazole is also useful as adjunctive medical ther-
apy for alveolar hydatid disease due to E. multilocularis14,15
and may be effective against infection with E. vogeli.16
In infection with either E. granulosus or E. multilocularis,
however, the response to albendazole occurs only after
many months. Furthermore, in most treated patients the
cystic lesions do not resolve completely, although they
cease to enlarge.11 Thus, when feasible, surgical exci-
sion of echinococcal cysts remains the definitive therapy,
and albendazole should be administered in conjunction
with surgery or to patients who are not candidates for
surgery.
Intestinal Tapeworms and Cysticercosis
Infection with intestinal tapeworms can be treated
effectively with available anthelmintic drugs, including
Vol. 334 No. 18 DRUG THERAPY 1179

praziquantel and niclosamide.2 How- Table 1. Chemotherapy for Parasitic Diseases.

ever, tissue infection with the larval PARASITE AND INFECTION STANDARD TREATMENT POTENTIAL NEW TREATMENT
stage of Taenia solium (cysticercosis),
and especially neurocysticercosis, the Helminths
Intestinal nematodes
most prevalent helminthic infection Ascariasis Mebendazole, pyrantel pamoate Albendazole, ivermectin
of the brain, was for a long time ame- Trichuriasis Mebendazole Albendazole,* ivermectin*
nable only to surgical therapy. The Enterobiasis Mebendazole, pyrantel pamoate Albendazole,* ivermectin*
Hookworm infection Mebendazole, pyrantel pamoate* Albendazole*
therapeutic use of praziquantel, and Strongyloidiasis Thiabendazole Albendazole,* ivermectin*
more recently of albendazole, has Tissue nematodes
provided medical treatment for neu- Onchocerciasis Ivermectin
17 Trematodes
rocysticercosis. For patients with Schistosomiasis Praziquantel, oxamniquine (for
inactive disease and calcified tissue Schistosoma mansoni)
Fascioliasis Bithionol* Triclabendazole*
cysts, specific cesticidal therapy is not Other liver, lung, and Praziquantel*
needed. Active neurocysticercosis, intestinal flukes
however, with viable intraparenchy- Cestodes
Intestinal tapeworms Praziquantel*
mal cysts (which can be seen as low- Cysticercosis Surgery, praziquantel,* albendazole*
density cysts on computed tomogra- Echinococcosis Surgery Albendazole*
phy with little or no enhancement Protozoa
with contrast medium) requires drug Giardiasis Metronidazole* Albendazole*
treatment. Microsporidiosis in AIDS† None Albendazole,* fumagillin*
Cyclosporiasis Trimethoprim–sulfamethoxazole*
The administration of either pra- Isosporiasis Trimethoprim–sulfamethoxazole*
ziquantel or albendazole results in Cryptosporidiosis Supportive fluid and electrolyte Paromomycin*
therapy
the reduction or disappearance of
cysts in 80 to 90 percent of patients. *Not approved by the Food and Drug Administration for this indication.
In comparative trials albendazole †AIDS denotes acquired immunodeficiency syndrome.

(5 mg per kilogram of body weight

three times daily for 28 to 30 days) was more effective
than praziquantel in reducing the number and size of
cysts and in inducing overall clinical improvement.17-19
Adjunctive therapy with dexamethasone is recommend-
ed for patients with numerous cysts and for those in
whom neurologic symptoms or intracranial hyperten-
sion develops after the initiation of therapy against cys-
17
ticerci. Plasma concentrations of albendazole, but not
praziquantel, are higher in patients treated with corti-
costeroids.20 A shorter course of albendazole (8 days)
appears to be as effective as the traditional 28-to-30-day
course.17,21 Pharmacokinetic studies suggest that the rel-
atively long half-life of albendazole might allow for
22
twice-a-day dosing for this condition.
Medical therapy is definitely indicated for patients
with numerous viable cysts, acute meningitis, or in-
creased intracranial pressure, but it may be effective
23
even in patients with solitary cysts and seizures alone.
Clinical variability and a tendency toward spontaneous
resolution in neurocysticercosis, however, have contrib-
uted to continuing uncertainty about the precise indica-
tions for anthelmintic therapy — and even its overall
usefulness — in this disease.24 For patients with giant
subarachnoid cysts, albendazole, but not praziquantel,
25
has proved effective. For patients with ventricular, spi-
nal, or intraocular cysts, surgery is the preferred thera-
py, although concurrent therapy with albendazole is ad-
visable and, on occasion, treatment with albendazole
has obviated the need for surgery.17,26
Intestinal Roundworms
Soil-transmitted helminthiases — ascariasis, hook-
worm infection, and trichuriasis — are among the most
prevalent infections in the world. In areas in which they
are endemic, the efficacy of single doses of albendazole
or the older benzimidazole drug mebendazole has made
mass chemotherapy feasible for school-age children.
Such mass treatment has been advocated as a compo-
nent of control measures to reduce the number of worms
in individual children below pathogenic levels and has
improved children’s growth and academic perform-
ance.27,28 These two drugs have also been used exten-
sively in individually tailored therapy. Single doses of
both albendazole (Table 2) and mebendazole are high-
ly effective against ascariasis,29 although albendazole
appears to be more effective than mebendazole in hook-
worm infections.29 Neither drug in a single dose is high-
ly effective in eradicating Trichuris trichiura,30 although
in one study, three doses of albendazole resulted in an
80 percent rate of cure.31
Other Roundworms
Albendazole has also proved effective or promising
against a number of less common nematode infections
of tissue, including cutaneous larva migrans,32,33 gnath-
ostomiasis,34 intestinal capillariasis,35 clonorchiasis,36
and infection with lagochilascariasis minor,37 as well
as more recently recognized infections with Trichinella
pseudospiralis38 and Oesophagostomum bifurcum.39 Alben-
dazole (400 mg twice daily for three days) is moderate-
ly effective for chronic strongyloidiasis,40 but not as ef-
fective as ivermectin (see next page). The effectiveness
of albendazole has not been evaluated in patients with
the hyperinfection syndrome of strongyloidiasis, for
whom thiabendazole — despite its frequent side ef-
fects41 — remains the drug of choice. In infections with
filarial nematodes, onchocerciasis and loiasis, albenda-
zole has a limited ability to reduce the number of mi-
crofilariae,42,43 possibly because of an embryotoxic ef-
fect on the adult worms. Albendazole is not active

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1180 THE NEW ENGLAND JOURNAL OF MEDICINE May 2, 1996

Table 2. Newer Uses of Antiparasitic Drugs. the skin and eyes,47 thus dimin-
ishing the likelihood of disabling on-
DRUG AND INDICATION DOSAGE ADVERSE EFFECTS
chocerciasis. In areas where the dis-
Albendazole Abdominal pain, nausea, ease is endemic, the dose can be
Echinococcosis* 400 mg twice daily for 28 days, re- vomiting, alopecia, in-
peated as necessary creased serum amino-
repeated every 6 to 12 months to
Neurocysticercosis* 5 mg/kg three times daily for 8–30 transferase, neutropenia maintain suppression of both der-
days, repeated as necessary mal and ocular microfilariae.47 Af-
Ascariasis,* hookworm infection* 400 mg once
Trichuriasis* 400 mg once (repeated for 3 days in ter therapy with ivermectin, even
heavy infections) severe onchocercal dermatitis is re-
Enterobiasis* 400 mg once, repeated in 2 weeks duced, with amelioration of pruritus
Strongyloidiasis (uncomplicated)* 400 mg twice daily for 3 days
Microsporidiosis in AIDS*† 400 mg twice daily for 2–3 weeks but no resolution of depigmentation.48
Ivermectin Mild pruritus, rash, dizzi- Ocular disease also responds: dam-
Onchocerciasis* 150 mg/kg once ness
Ascariasis,* trichuriasis* 12 mg once
age to the optic nerve is lessened,
Strongyloidiasis* 200 mg/kg once daily for 1–2 days punctate keratitis and iritis are di-
Paromomycin Abdominal discomfort minished, and fewer microfilariae are
Giardiasis (during pregnancy) 8–10 mg/kg three times daily for
7 days released in the anterior chamber and
Cryptosporidiosis* 500 mg three to four times daily for cornea. However, there are no effects
2 weeks on sclerosing keratitis or chorioreti-
Praziquantel Headache, dizziness,
Schistosomiasis drowsiness, abdominal nitis.49,50
S. mansoni, S. haematobium 20 mg/kg twice daily for 1 day discomfort By decreasing the number of mi-
S. japonicum, S. mekongi 20 mg/kg three times daily for 1 day
Fluke infection
crofilariae in the skin of infected per-
Liver (Clonorchis sinensis, 25 mg/kg three times daily for 1 day sons, mass chemotherapy with iver-
Opisthorcis viverrini)* mectin reduces transmission of this
Lung (paragonimus)* 25 mg/kg three times daily for 2 days
Intestine (Fasciolopsis buski, 25 mg/kg three times daily for 1 day vector-borne disease. Ivermectin may
Heterophyes heterophyes, impair the fertility of female on-
Metagonimus yokogawai)* chocerca worms, but it does not kill
Nanophyetus salmincola* 20 mg/kg three times daily for 1 day
Neurocysticercosis* 15–20 mg/kg three times daily for 15 adult worms. A well-tolerated drug
days that is effective against adult on-
Intestinal tapeworm infection
Fish, beef, pork, and dog* 5–10 mg/kg once
chocerca worms has yet to be found.
Dwarf (Hymenolepsis nana)* 25 mg/kg once The side effects of ivermectin ther-
Oxamniquine apy for patients with onchocercia-
S. mansoni infection 15 mg/kg once; 30 mg/kg in East Af-
rica; 30 mg/kg for 2 days in Egypt sis (Table 2) are mainly due to host
and South Africa reactions to the dying microfilariae
Fumagillin and include pruritus, papular rash,
Microsporidial keratoconjunctivitis* Eye drops
dizziness, edema of the face and
*Not approved by the Food and Drug Administration for this indication. limbs, and — in rare cases — ocular
†AIDS denotes acquired immunodeficiency syndrome. inflammation.47 These side effects
are usually mild and less severe than
in infections with the filarial parasite Mansonella per- with diethylcarbamazine. No adverse effects have been
stans.44 observed in women inadvertently treated during preg-
nancy.51
Ivermectin
Ivermectin is an extremely potent, broad-spectrum, Other Filariases
anthelmintic drug that has been widely used in con- The effectiveness of ivermectin in onchocerciasis
trolling nematode infections in animals.45 In humans, it has led to field trials of the drug for cases of lymphat-
has been used most extensively against onchocerciasis ic filariasis, the other major filarial infection. In single
(river blindness), through supplies donated by the man- doses of between 100 and 440 mg per kilogram, iver-
ufacturer, Merck, to the Onchocerciasis Control Pro- mectin leads to clearance of the microfilariae of Wuchere-
gram of the World Bank and the World Health Organ- ria bancrofti and Brugia malayi from the blood, but it is
ization. In the United States, ivermectin is available on not active against adult filarial worms in the lymphat-
a compassionate-use basis from Merck. Ivermectin is ic system.51-54 A single dose of ivermectin is as effective
a semisynthetic macrocyclic lactone derived from av- as the traditional 14-day course of diethylcarbamazine
ermectins of the soil mold Streptomyces avermitilis.45 It in lowering the number of circulating microfilariae
appears to kill helminths by opening chloride-sen- and has far fewer side effects.52 However, the reduc-
sitive channels, and in the free-living nematode Cae- tion in microfilaremia is not sustained, and a single
norhabditis elegans the drug binds to a glutamate-gated dose of diethylcarbamazine appears to be as well tol-
chloride channel.46 erated and effective as ivermectin in inducing a sus-
tained reduction in microfilaremia.54 With respect to
Onchocerciasis other filarial parasites, ivermectin is effective against
A single oral dose of ivermectin (150 mg per kilo- M. ozzardi55 but not M. perstans.56 In Loa loa infections,
gram) greatly reduces the number of microfilariae in ivermectin decreases microfilaremia, but because it

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Vol. 334 No. 18
is not clearly effective against adult worms — the
stage of the parasite primarily responsible for human
symptoms — diethylcarbamazine remains the drug of
choice.2,57
Other Roundworms
Ivermectin is also effective against several common
intestinal parasitic nematodes, including ascaris, trich-
uris, and enterobius.58 It is ineffective against hook-
worms in humans,58 for which mebendazole is the treat-
ment of choice. A single 12-mg dose of ivermectin was
more effective than a single 400-mg dose of albenda-
zole for cutaneous larva migrans in one study.59 Iver-
mectin, in a daily dose of 200 mg per kilogram for one
or two days, is highly effective against chronic intestin-
al strongyloidiasis,58,60,61 a difficult infection to eradi-
cate. Side effects of treating strongyloidiasis with iver-
mectin are less frequent than with thiabendazole.60 In
one study of strongyloidiasis, ivermectin (150 to 200 mg
per kilogram, given as a single oral dose) cured 83 per-
cent of patients with the disease, as compared with a
rate of 38 percent with albendazole.61 Ivermectin has
also proved effective for strongyloidiasis in patients
with the acquired immunodeficiency syndrome (AIDS).62
A series of doses of ivermectin may be effective in the
hyperinfection syndrome of strongyloidiasis, but expe-
rience with its use in disseminated strongyloidiasis is
limited.
Ectoparasites
Ivermectin may be effective in treating ectoparasites
in humans, including scabies and head lice.63-65
Praziquantel
Praziquantel is an effective drug against a broad
range of trematode and cestode infections. Although
the drug has been in clinical use for over a decade, its
mode of action is still not clearly understood.66 Pra-
ziquantel appears to interfere with calcium homeo-
stasis and causes flaccid paralysis in adult flukes.67
Studies of parasitic schistosomes indicate that the im-
mune response of the host and the formation of specific
antibodies are necessary to create praziquantel’s ant-
helmintic effects.67 Perhaps by disrupting the surface
membrane of the parasite, praziquantel causes antigens
within the parasite to be exposed to the action of host
antibodies.
Schistosomiasis
Praziquantel is the drug of choice for all forms of
schistosomiasis (Table 2). In areas where schistosomi-
asis is endemic, treatment with praziquantel has en-
hanced patients’ physical fitness.68 In addition, mass
treatment with praziquantel has been used as a means
of control of the waterborne, snail-transmitted para-
sites that cause the disease. However, resistance to the
drug has been found in infected mice,66 and the drug
was ineffective in a few large-scale campaigns. In some
areas of endemic schistosomiasis the low rates of cure
attributable to praziquantel might be due to extremely
rapid reinfection rather than any intrinsic drug resist-
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DRUG THERAPY 1181
ance of the parasite. For infection with Schistosoma man-
soni, oxamniquine (Table 2) is an effective and cheaper
alternative to praziquantel.
Other Flukes
Praziquantel is also effective in the treatment of
most flukes (Table 2). The only fluke not responsive to
praziquantel is Fasciola hepatica (sheep-liver fluke), which
responds to bithionol (given at a daily dose of 30 to 50
mg per kilogram on alternate days for 10 to 15 doses)2
and, as seen in a few promising studies, to the veteri-
nary drug triclabendazole.69
Cestodes
For infection with intestinal tapeworms, praziquantel
(Table 2) in a single dose is effective.2 Treatment of in-
testinal Taen. solium infections can lead to neurologic re-
actions in patients who have occult neurocysticercosis,70
although patients with neurocysticercosis often have no
response to a single dose of praziquantel.71 As noted
above, a longer course of praziquantel is effective for
neurocysticercosis (Table 2), although albendazole may
be more efficacious.72 The bioavailability of praziquan-
tel is limited by extensive first-pass metabolism of the
drug; this limitation of metabolism is exacerbated by
dexamethasone and the antiepileptic drugs that are of-
ten given concomitantly with praziquantel for seizure
control in patients with neurocysticercosis.73 Phenytoin
and carbamazepine induce metabolism of praziquantel
by hepatic cytochrome P-450 and have contributed to
treatment failures.74 Cimetidine, which inhibits hepatic-
enzyme metabolism, increases the peak serum concen-
tration of praziquantel and lengthens the drug’s elimi-
nation half-life.75
ANTIPROTOZOAL DRUGS
Protozoan parasites belong to four distinct groups:
the amebae, the flagellates, the ciliates, and the sporo-
zoa. Unlike helminths, they are all single-cell organ-
isms and replicate, often rapidly, in the infected host.
Of the many diseases due to protozoan parasites, we re-
view some of those for which new, or older, drugs hold
promise as treatment.
Albendazole
Giardiasis
Albendazole, as noted above, binds to tubulin and
affects cytoskeletal microtubules; this property makes
it potentially useful in the treatment of some protozoan
infections in addition to its more established roles in
therapy for helminthic infections. Giardiasis, caused by
the flagellated protozoan Giardia lamblia (also known as
G. duodenalis), a pathogen of the small bowel, is one of
the most common diarrheal infections in the United
States, as well as in other countries. Giardiasis is cur-
rently treated with metronidazole (although the drug
is not approved for this indication by the Food and
Drug Administration), tinidazole (not available in the
United States), and quinacrine (no longer distributed in
the United States).2 In vitro, albendazole inhibits the
growth of trophozoites of G. lamblia and their adhesion
1182 THE NEW ENGLAND JOURNAL OF MEDICINE
to cultured intestinal epithelial cells and disrupts the
activity of microtubules and microribbons in the troph-
ozoite’s adhesive disk. The results of treatment of giar-
diasis with albendazole have been mixed. Albendazole,
in doses of 400 mg per day for five days, cured 97 per-
cent of infections in children in Bangladesh,76 but it was
ineffective in a study of adult travelers returning from
tropical areas.33
Microsporidiosis
Unlike giardiasis, for which there are effective drugs,
the various forms of microsporidiosis have until recent-
ly proved difficult to treat. Microsporidia are small,
spore-forming obligate intracellular protozoan parasites
that only rarely infect immunocompetent patients but
that may cause intestinal, ocular, or disseminated dis-
ease in patients with AIDS.77 Five genera of microspo-
ridia — enterocytozoon, encephalitozoon, septata, pleis-
tophora, and nosema — and some other unclassified
microsporidia cause human disease. Albendazole dis-
rupts the function of tubulin in microsporidia78 and has
antimicrosporidial activity both in vitro and in vivo.79-81
Although current clinical trials of albendazole in mi-
crosporidiosis have not been completed, patients with
AIDS who had intestinal microsporidial infections,
principally with Enterocytozoon bieneusi and Septata intesti-
nalis, had symptomatic improvement with albendazole,
with less frequent stools and often decreased fecal ex-
cretion of microsporidial spores.82-86 After the cessation
of albendazole therapy, however, symptomatic illness
often recurred, so longer-term suppressive treatment
may be needed.
Fumagillin
Ocular Microsporidiosis
Fumagillin is a water-insoluble antibiotic produced
by Aspergillus fumigatus. Over four decades ago, fumagil-
lin was found to inhibit the activity of intestinal proto-
zoa, including Entamoeba histolytica, the causative agent
of amebiasis.87 Fumagillin had not been used in human
infections, although a water-soluble form of the drug,
fumagillin bicyclohexylammonium salt, is used to con-
trol microsporidial disease due to Nosema apis in honey-
bees. Although the mechanism of action of fumagillin
has not been established, it suppresses the proliferation
of microsporidia in vitro.81 A topical suspension of fu-
magillin was effective in the treatment of microsporid-
ial keratoconjunctivitis due to Encephalitozoon hellem or
Enceph. cuniculi in several patients with AIDS.88-90 Main-
tenance therapy with twice-daily topical administration
of fumagillin was necessary to prevent symptomatic re-
lapses.88
Trimethoprim–Sulfamethoxazole
Cyclosporiasis
Cyclospora, a newly recognized coccidian protozoan
parasite,91 causes diarrheal illness, often prolonged, in
the United States and other countries. Trimethoprim–
sulfamethoxazole, by no means a new antimicrobial
preparation, is efficacious in treating diarrheal disease
caused by cyclospora.92-94 In immunocompetent pa-
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May 2, 1996
tients, treatment with a combination of 160 mg of
trimethoprim and 800 mg of sulfamethoxazole (i.e.,
a double-strength tablet) twice daily for seven days
ended diarrheal illness and led to clearance of the par-
asites.93 In patients infected with the human immuno-
deficiency virus, treatment with one double-strength
tablet of trimethoprim–sulfamethoxazole four times
a day for 10 days leads to a rapid resolution of diar-
rhea. Symptomatic cyclosporiasis may recur in the fol-
lowing weeks, but it can be prevented by the adminis-
tration of trimethoprim–sulfamethoxazole three times
weekly.94
Isosporiasis
Trimethoprim–sulfamethoxazole is also effective in
treating enteric infections with Isospora belli.95 The dou-
ble-strength tablet is given orally four times a day for
10 days and then twice a day for 3 weeks. In patients
with AIDS, in whom recurrences are common, long-
term maintenance therapy with double-strength tri-
methoprim–sulfamethoxazole tablets given three times
a week or a combination of 25 mg of pyrimethamine
and 500 mg of sulfadoxine given once a week can be
effective.96 Alternatively, for those intolerant of sulfa
drugs, pyrimethamine alone (75 mg per day, until the
infection is cleared) is effective and can be followed
with a maintenance dose of 25 mg per day to prevent
relapses.97
Paromomycin
Cryptosporidiosis
Cryptosporidium parvum is a common cause of diarrhea
in ungulate farm animals and a major cause of water-
borne outbreaks of diarrhea among humans. Crypto-
sporidiosis is usually a self-limited enteric infection in
immunocompetent patients but a potentially debilitat-
ing and chronic diarrheal illness in patients with AIDS
or other immunocompromised states. An effective anti-
parasitic drug for cryptosporidiosis in patients with
AIDS is greatly needed, but many drugs have proved
ineffective. Several recent studies suggest that an older
oral aminoglycoside, paromomycin, may be at least
partially effective in treating cryptosporidiosis. Cur-
rently, paromomycin is used as a secondary drug in
therapy for amebiasis2 and in pregnant women in whom
giardiasis is not severe enough to require therapy with
metronidazole. In both an open trial 98 and a small dou-
ble-blind trial 99 of paromomycin (in a dose of 500 mg
three or four times a day for two weeks) in patients with
AIDS who had cryptosporidiosis, the drug reduced di-
arrhea; in the double-blind study the fecal excretion of
cryptosporidiosis oocysts was also reduced.99 Paromo-
mycin given orally is not systemically absorbed, even in
patients with intestinal cryptosporidiosis.100 It is not
likely to be a definitive antiparasitic therapy, and con-
tinued treatment with 500 mg twice daily is needed to
prevent relapse.98
CONCLUSIONS
A variety of infections with protozoan and helmin-
thic parasites are prominent worldwide health prob-
Vol. 334 No. 18 DRUG THERAPY
lems, and several protozoa are increasingly encoun-
tered as the cause of opportunistic infections in patients
with AIDS. Newer drugs such as albendazole and iver-
mectin have proved to be effective against some of
these parasitic infections. However, there remains a
need for the continued development of new drugs to
counter the many parasitic infections for which there is
not yet effective treatment.
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