Malaria. Human malaria is caused by the mosquitoborne parasites Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi, which parasitize red blood cells and cause hemolytic anemia. Malaria kills nearly 1 million people and causes almost 300 million symptomatic illnesses annually. It is found in sub-Saharan Africa, Asia, Oceania, and Latin America. Uncomplicated malaria can manifest as fever, anemia, thrombocytopenia, myalgias, cough, and diarrhea. Severe malaria is defined in part by respiratory distress, renal failure, altered mental status or seizures, intolerance of oral medications, metabolic acidosis or hypoglycemia, and parasitemia greater than 5%. The mortality rate of severe malaria is high.
Treatment of Uncomplicated P falciparum Malaria.
The preferred treatment for uncomplicated P falciparum
malaria acquired in areas with chloroquine resistance is atovaquone-proguanil, artemether-lumefantrine (AL), or oral quinine plus doxycycline.1
Atovaquone-proguanil is a well-tolerated, oral fixed-dose combination. Atovaquone inhibits parasite mitochondrial electron transport. Proguanil inhibits the dihydrofolate reductase step in purine synthesis and lowers the concentration of atovaquone necessary to kill Plasmodium species. Adverse effects include nausea, vomiting, abdominal pain, and hepatitis.
Artemether-lumefantrine is an oral fixed-dose combination recently approved in the United States. Artemether is a semisynthetic derivative of artemisinin, a sesquiterpene lactone. Lumefantrine, a fluorene derivative, may interfere with heme metabolism. Artemether-lumefantrine is rapidly effective against all erythrocytic stages of malaria. Adverse effects include nausea, vomiting, dizziness, headache, and possibly QT prolongation.2
It should be taken with fatty foods to increase absorption.
Oral quinine plus doxycycline (or plus tetracycline or clindamycin) is effective for uncomplicated malaria. Quinine is an aryl-amino alcohol, which may cause toxic heme accumulation in the parasite. It can cause cinchonism (nausea, vomiting, tinnitus, high-frequency hearing loss, and dizziness). Both tetracyclines and clindamycin inhibit expression of the Plasmodium apicoplast genome. Adverse effects include nausea, vomiting, abdominal pain, candidiasis, and photosensitivity for doxycycline and nausea, vomiting, abdominal pain, and diarrhea for clindamycin.
Mefloquine, an aryl-amino quinoline, has the same mechanism of action as quinine. Due to resistance, it is not recommended for patients infected in much of Southeast Asia. It can cause neuropsychiatric disturbances and QT prolongation at treatment doses and is a second-line agent.
Chloroquine is recommended for uncomplicated P falciparum
malaria acquired in areas without chloroquine resistance. It is a 4-aminoquinoline and may act by disrupting heme metabolism. Adverse effects include nausea, vomiting, diarrhea, headache, and blurred vision. Pruritis also occurs, mostly in African patients. Hydroxychloroquine is an acceptable alternative.1
Treatment of Severe Malaria.
Severe malaria (usually caused by P falciparum
) should be treated with parenteral medications, such as intravenous artesunate, quinine, or quinidine. Artesunate is preferred because it works faster, is more effective, and is better tolerated than quinine.3,4
In the United States, artesunate is available from the Centers for Disease Control and Prevention for severe malaria in patients who meet certain criteria.5
Artesunate is combined with atovaquone-proguanil, doxycycline, clindamycin, or mefloquine to prevent recurrent parasitemia.3
Artesunate is well tolerated, with adverse effects similar to artemether. At high doses, it may cause neutropenia.6
Quinidine gluconate, which has the same mechanism of action as quinine, is available for severe malaria in the United States. Patients should be monitored with telemetry and have blood glucose and drug levels followed up closely. Adverse effects include infusion-related hypotension, QT prolongation, torsades de pointes, and hypoglycemia. Although less cardiotoxic than quinidine, parenteral quinine is not available in the United States. It can cause infusion-related hypotension, hypoglycemia, and cinchonism. Both quinine and quinidine should be combined with doxycycline, tetracycline, or clindamycin, and patients can transition to oral therapy after improvement.
Treatment of Uncomplicated Non-falciparum Malaria.
Chloroquine plus primaquine is effective for uncomplicated P vivax
and P ovale
malaria in most of the world. Patients infected in areas with chloroquine-resistant P vivax
and P ovale
(particularly Papua New Guinea and Indonesia) should be treated with atovaquone-proguanil, mefloquine, or quinine plus doxycycline. Patients infected with P vivax
or P ovale
should receive primaquine (an 8-aminoquinolone) for 14 days to prevent relapse. Because primaquine can cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient patients, G6PD levels should be measured before use. Other adverse effects include nausea and vomiting. P malariae
or P knowlesi
infections can usually be treated with chloroquine.1,7
Chloroquine resistance is widespread. Due to resistance, mefloquine is not recommended for malaria acquired in much of Southeast Asia. Parts of South America and equatorial Africa also have high mefloquine treatment failure rates.8
Atovaquone-proguanil–resistant P falciparum
is rare. The World Health Organization recommends that artemisinins be used exclusively in combination regimens, but strains of P falciparum
with decreased sensitivity to artemisinins have emerged along the border between Cambodia and Thailand, in part because of long-standing monotherapy practices.9
Of 22 African countries, 2 (Ghana and Burkina Faso) had failures in more than 10% of P falciparum
cases treated with AL in one study.8
Treatment failure rates with AL of more than 20% have occurred only in Cambodia.8
Chloroquine-resistant P vivax
occurs primarily in Southeast Asia and Oceania, but cases have been reported in South America, Ethiopia, and the Solomon Islands. P vivax
treatment failure rates of more than 10% with AL have occurred in Papua New Guinea.8
The Worldwide Antimalarial Resistance Network has developed an online database of malaria resistance.10
Treatment regimens for all types of malaria are summarized in .
Treatment Regimens for Protozoal Infections in Adultsa
Arterolane, a synthetic trioxolane derived from artemisinins, is undergoing phase 3 clinical trials in combination with piperaquine for P falciparum
In 2 recent clinical trials, both once-daily pyronaridine-artesunate and azithromycin plus artesunate were noninferior to AL for P falciparum
African Trypanosomiasis. Human African trypanosomiasis (HAT, or sleeping sickness) is caused by 2 subspecies of Trypanosoma brucei that are endemic only to Africa and transmitted by tsetse flies. In the United States, only 1 or 2 cases occur annually (among returning travelers). T brucei rhodesiense causes a rapidly progressive disease in Eastern and Southern Africa, whereas T brucei gambiense causes a more indolent disease in West and Central Africa. Initially, patients develop fever, lymphadenopathy, hepatosplenomegaly, and rash. Later, a chronic meningoencephalitis occurs with headaches, listlessness, disordered sleep, and neuromuscular dysfunction. Drugs for HAT are toxic; however, left untreated, the disease is fatal.
T b gambiense. Pentamidine and suramin are available for early-stage T b gambiense disease. Neither drug crosses the blood-brain barrier, and for late-stage (central nervous system [CNS]) disease, eflornithine and melarsoprol are used ().
Pentamidine, an aromatic diamidine, is preferred for early-stage disease. Pentamidine reduces the mitochondrial membrane potential and binds to nucleic acids. It is given intramuscularly and can cause hypotension, hypoglycemia, leukopenia, nephrotoxicity, hepatitis, and pancreatitis.
Suramin, a sulfonated naphthylamine, inhibits multiple trypanosome metabolic enzymes. It is a second-line treatment for early-stage disease because of toxicity, including exfoliative dermatitis, peripheral neuropathy, nephrotoxicity, myelosuppression, and a potentially fatal hypersensitivity reaction. Suramin is active against Onchocerca volvulus
, and reactions (from dying parasites) can occur in coinfected patients.14
Eflornithine, which inhibits ornithine decarboxylase, is the preferred drug for late-stage T b gambiense disease. It is less toxic than melarsoprol but not reliably effective against T b rhodesiense. Adverse reactions include fever, myelosuppression, hypertension, rash, peripheral neuropathy, and diarrhea.
Melarsoprol, an organic arsenical agent, remains the most widely used drug against late-stage HAT despite being the most toxic. Its mechanism of action is unknown. The most feared adverse effect is reactive encephalopathy, which occurs in 5% to 10% of patients and is fatal in half of cases.14
Coadministration of corticosteroids lowers the risk of encephalopathy.15
Other adverse effects include vomiting, abdominal pain, thrombophlebitis, peripheral neuropathy, fever, and thrombocytopenia.
Nifurtimox-eflornithine combination therapy was more effective than eflornithine monotherapy for late-stage T b gambiense
and enabled shorter treatment courses in 2 clinical trials.16
Another trial found that melarsoprol-nifurtimox combination therapy was more effective than melarsoprol alone.17
However, a subsequent study found that patients with late-stage T b gambiense
disease who were treated with melarsoprol-nifurtimox had higher death rates than those treated with other combination regimens.18
T b rhodesiense.
There is little new clinical evidence regarding the treatment of T b rhodesiense
. Suramin is used for early-stage disease, and melarsoprol is used for late-stage disease ().14
Up to 30% of patients infected with T b gambiense
do not respond to melarsoprol,19
and 6% to 8% may receive no benefit from eflornithine in some regions.20
Suramin and melarsoprol resistance have occurred in clinical isolates of T b rhodesiense
Drugs in Development.
Clinical trials with fexinidazole, an oral 5-nitroimidazole active against T b gambiense
and T b rhodesiense
, are under way.22
American Trypanosomiasis. American trypanosomiasis (Chagas disease) is caused by Trypanosoma cruzi, which is endemic only to Latin America and is usually transmitted by blood-feeding triatomine insects. Acute infection is often asymptomatic, but patients may have unilateral palpebral edema or an erythematous, indurated skin lesion with regional lymphadenopathy. Fever, diffuse lymphadenopathy, hepatosplenomegaly, and (less commonly) meningoencephalitis and myocarditis may occur. Acute disease is generally self-limited. Most patients are subsequently asymptomatic (a state termed indeterminate Chagas). Years to decades later, 20% to 40% of cases progress to chronic Chagas disease, which affects the heart (eg, cardiomyopathy, chronic heart failure, and arrhythmias) and the gastrointestinal tract (eg, achalasia, megaesophagus, constipation, obstruction, and megacolon).
The nitroheterocyclic compounds nifurtimox and benznidazole are used to treat Chagas disease (). Benznidazole is better tolerated and generally considered the drug of choice.23
Contraindications to treatment include pregnancy and renal and hepatic insufficiency.
Nifurtimox is a 5-nitrofuran derivative; its mechanism of action is not well understood. Adverse effects include anorexia, abdominal pain, vomiting, insomnia, paresthesias, peripheral neuropathy, and hepatitis. Discontinuation due to intolerance is common.24
During therapy, clinicians should screen for peripheral neuropathy, monitor liver and renal function, and obtain a complete blood cell count (CBC).
Benznidazole is a nitroimidazole derivative that may increase phagocytosis. Adverse effects include vomiting, anorexia, dermatitis, and myelosuppression. Dose-dependent peripheral neuropathy, severe rash, fever, or lymphadenopathy should prompt discontinuation. Clinicians should check for rash and monitor CBCs as well as liver and renal function test results during treatment.
Although clinical evidence supporting treatment for Chagas disease is limited, most authorities recommend treatment for acute and congenital infections, infections in children, and reactivated infections in immunocompromised patients.23
The role of therapy in indeterminate and chronic Chagas disease in adults is more controversial, but evidence is emerging that select patients in these groups may benefit.25
Recent studies suggest that benznidazole for indeterminate or early chronic Chagas disease may improve parasite clearance rates26,27
and prevent progression to cardiomyopathy.28
A multicenter, placebo-controlled trial involving benznidazole for the treatment of chronic Chagas disease is under way.29
Resistance and Drugs in Development.
Although strains of T cruzi
resistant to both nifurtimox and benznidazole can be generated in vitro, documentation of clinical resistance is scarce. Several new triazoles, squalene synthase inhibitors, and cysteine protease inhibitors have shown efficacy in animal models.25
A phase 2 clinical trial of posaconazole vs benznidazole for chronic Chagas disease is under way.30
Leishmaniasis. Leishmania species are transmitted primarily by sandflies and cause 3 clinical syndromes: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (ML).
Visceral Leishmaniasis. Visceral leishmaniasis is caused predominantly by Leishmania donovani on the Indian subcontinent and East Africa and by Leishmania infantum/chagasi elsewhere. Infection with these species results in subclinical infection in most patients and kala-azar (fever, weight loss, hepatosplenomegaly, hyperglobulinemia, neutropenia, and death) in a minority. Ninety percent of VL cases occur in India, Bangladesh, Nepal, Sudan, and Brazil. The drug of choice for VL in the United States is liposomal amphotericin (). Multiple dosing schedules and other treatment regimens are used globally.
Liposomal amphotericin, a polyene, forms pores in cell membranes. In India, single-dose liposomal amphotericin was as effective as 29 days of amphotericin B deoxycholate in a recent trial.31
Amphotericin causes nephrotoxicity, electrolyte loss, fever, and rigors; however, these occur less frequently with liposomal formulations.
Miltefosine, a synthetic phospholipid analogue and the only orally available drug for VL, causes apoptosis-like cell death. Cure rates appear similar to those obtained with amphotericin in India.32
Adverse effects include nausea, vomiting, vertigo, diarrhea, hepatitis, renal insufficiency, and teratogenicity. There is concern that monotherapy may lead to drug resistance.33
Pentavalent antimonial agents, such as sodium stibogluconate, were previously the therapeutic choice for VL. Currently, resistance limits their use, especially in South Asia.34
Antimonial agents inhibit several parasitic enzymes, but they are poorly tolerated. Adverse effects include anorexia, vomiting, pancreatitis, hepatitis, myalgias, cytopenias, QT prolongation, and arrhythmias. Renal and liver function tests, CBCs, amylase/lipase measurements, and electrocardiography should be monitored during treatment. Response rates are variable and relapses common.
Paromomycin, an aminoglycoside that inhibits metabolism and mitochondrial respiration, is an alternative for VL. Paromomycin was noninferior to amphotericin in India in a recent study.35
Adverse effects include ototoxicity, nephrotoxicity, and hepatotoxicity.
Combination therapy for VL may shorten treatment duration, decrease toxicity, and prevent resistance.36
In Sudan, paromomycin plus antimony was more effective than antimony alone.37
Single-dose liposomal amphotericin plus short-course miltefosine was effective and well tolerated in India, as was single-dose liposomal amphotericin plus short-course paromomycin and short-course miltefosine plus paromomycin.38
Cutaneous Leishmaniasis. Cutaneous leishmaniasis usually presents as nodular skin lesions that slowly enlarge and ulcerate. Ninety percent of CL cases occur in Afghanistan, Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru. Because the lesions of CL usually heal spontaneously, the decision to treat depends on lesion location and size, the region of acquisition and infecting species, the risk of progression to ML (limited to some New World CL infecting species), and patient preference.
New World CL is commonly caused by Leishmania braziliensis, Leishmania mexicana
, and Leishmania panamensis.
When the decision is made to treat, antimonial agents are usually used (). Combination therapy with allopurinol or pentoxifylline plus antimonial agents may be more effective than antimonial agents alone.39
A 4-week course of miltefosine was as effective as antimonial agents in Colombia but less effective than antimonial agents in Guatemala.40
Pentamidine has been used for CL caused by Leishmania guyanensis
in French Guyana, Surinam, and Brazil but is toxic and less effective.41
Old World CL is caused mainly by Leishmania major, Leishmania tropica
, or Leishmania aethiopica.
When systemic treatment is deemed necessary, antimonial agents are usually used (). Fluconazole cured 79% of CL patients in Saudi Arabia with L major
at 3 months; however, a subsequent observational study showed no benefit from fluconazole.42,43
Miltefosine has been used successfully to treat Old World CL.44
Topical therapy, such as 15% paromomycin-12% methylbenzethonium ointment and intra-lesional antimonial agents, may be an alternative treatment option for Old World CL. Imiquimod, a topical immunomodulator, improved cure rates in Peru when given with parenteral antimonial agents45
; however, no benefit was seen in a similar trial in Iran.46
Amphotericin (particularly liposomal formulations) has been used successfully in a growing number of CL patients infected in both the Old and New World. Infections caused by at least 5 different Leishmania
species have been successfully treated with liposomal amphotericin; however, experience remains limited, and the optimal dosing regimen has not yet been determined.47
Patients with CL caused by certain New World Leishmania
species (eg, L braziliensis
) can develop ML (ulcerative lesions in the nose, mouth, and pharynx). Mucocutaneous leishmaniasis is usually treated with a 28-day course of antimonial therapy, but response rates are variable and relapses common ().33
Cure rates with antimonial agents plus pentoxifylline were higher than with antimonial agents alone in Brazil.48
Amphotericin and pentamidine have also been used. Oral miltefosine cured 83% of patients with mild ML and 58% with more extensive ML in Bolivia.49
Resistance to pentavalent antimonial agents occurs in 40% to 60% of patients with VL in Bihar, India.34
Resistance has also been reported from Sudan.50
Drugs in Development.
Sitamaquine (an oral 8-aminoquinoline) cured 50% to 90% of patients with VL in phase 2 trials. Adverse effects included nephrotoxicity and methemoglobinemia (with G6PD deficiency).51
Trials with azithromycin, amphotericin, miltefosine, and low-dose antimonial agents for CL are ongoing.
Babesiosis. Babesia microti
is the most common cause of babesiosis. This predominantly tick-borne zoonosis is endemic to southern New England, New York, the north central American Midwest, and Europe. Babesia
species parasitize red blood cells. Infections are commonly asymptomatic but can be associated with a mild to moderate febrile illness or fulminant hemolytic anemia (usually in patients with immunosuppression or splenectomy). Treating asymptomatic, immunocompetent patients is generally unnecessary unless parasitemia persists for 3 months or more.52
For mild to moderate illness, atovaquone plus azithromycin is as effective (and better tolerated) than the previous standard, oral quinine plus clindamycin ().53
Severe disease can be treated with a 7- to 10-day course of oral quinine plus intravenous clindamycin.52
Relapse is common in immunocompromised patients, and some authors recommend 6 or more weeks of therapy (including 2 weeks after blood smears are negative).54
Exchange transfusion is indicated for severe babesiosis (parasitemia of 10% or more; significant hemolysis; or renal, hepatic, or pulmonary compromise). Coinfection with Lyme disease or anaplasmosis should be considered in patients with babesiosis because the same tick transmits all 3 pathogens.
Atovaquone monotherapy can induce resistance in animal models, and resistance emerged during atovaquone and azithromycin treatment in 3 immunocompromised patients.55
Toxoplasmosis. Toxoplasmosis is most commonly acquired by consuming undercooked meat or other food or water containing Toxoplasma gondii cysts. After acute infection, T gondii remains latent and persists for life. Although acute infection is usually asymptomatic, 10% to 20% of patients develop lymphadenopathy or a self-limited mononucleosis-like syndrome. T gondii can also cause chorioretinitis. Immunocompromised patients can develop toxoplasmic encephalitis (usually reactivation of latent disease) and, less commonly, disseminated disease. Toxoplasmosis acquired during pregnancy can cause spontaneous abortion, hydrocephalus, intracranial calcifications, mental retardation, and seizures in the baby. Nonpregnant, immunocompetent patients with acute toxoplasmosis generally do not require antimicrobial therapy. For eye disease, treatment usually includes anti-Toxoplasma agents plus systemic corticosteroids. Immunocompromised patients with toxoplasmosis should be treated with 2 antimicrobial agents.
Pyrimethamine (the most effective anti-Toxoplasma
agent available) plus sulfadiazine (with folinic acid) is preferred (). Pyrimethamine inhibits dihydrofolate reductase, depleting folate and impairing nucleic acid synthesis. Adverse effects include dose-dependent myelosuppression (which can be ameliorated with concurrent folinic acid), abdominal pain, rash, and headaches. Pyrimethamine is combined with sulfadiazine, another folate antagonist. In addition to rash and myelosuppression, sulfadiazine can cause crystal-induced nephropathy. Trimethoprim-sulfamethoxazole (TMP-SMX) has similar efficacy to pyrimethamine-sulfadiazine for toxoplasmic encephalitis and chorioretinitis; however, unlike pyrimethamine-sulfadiazine, it is also available intravenously. 56,57
Pyrimethamine plus clindamycin is also effective. If none of these drugs can be used, clarithromycin, azithromycin, atovaquone, and dapsone are alternatives.
Toxoplasmosis During Pregnancy
. In the United States, spiramycin is generally recommended for toxoplasmosis acquired during pregnancy to reduce the risk of congenital toxoplasmosis (),58
although its efficacy is controversial.59
Spiramycin, a macrolide that inhibits protein synthesis, is well tolerated. Its main adverse effects are abdominal pain and diarrhea. When maternal infection occurs at 18 weeks of gestation or later, or fetal transmission is confirmed, pyrimethamine-sulfadiazine plus folinic acid is usually recommended. Congenitally infected infants are generally treated for 12 months with pyrimethamine-sulfadiazine plus folinic acid ().
New Developments. A clinical trial comparing spiramycin with pyrimethamine-sulfadiazine for the prevention of congenital toxoplasmosis in the babies of women infected at 14 weeks of gestation or later is under way.
Intestinal and Genitourinary Protozoa
Giardiasis. Giardia lamblia (also called Giardia duodenalis and Giardia intestinalis) infects the small intestine. It is found worldwide and is a common cause of travelers' diarrhea and childhood diarrhea in areas with poor sanitation. Water-borne transmission is most common, followed by person-to-person and food-borne spread. Some infections are asymptomatic, but most cause diarrhea (often lasting several weeks). Abdominal cramps, bloating, flatulence, weight loss, lactose intolerance, and malabsorption with oily, foul-smelling stools can occur.
Giardiasis can be treated with a single dose of tinidazole (), which cures more than 90% of cases.60
This 5-nitroimidazole is converted into toxic radicals that damage DNA. Adverse effects include dysgeusia, nausea, abdominal discomfort, and alcohol-induced disulfiram-like reactions. Rarely, peripheral neuropathy, seizures, and neutropenia occur. Metronidazole, widely used to treat giardiasis in the United States, has a similar mechanism of action and similar adverse effects; a 5- to 7-day course has slightly lower efficacy.60
Nitazoxanide, an oral nitrothiazolyl-salicylamide, appears to inhibit pyruvate:ferredoxin oxidoreductase. A 3-day course cures 80% to 85% of patients.60,61
It is generally well tolerated but can cause nausea and vomiting. A recent meta-analysis found that albendazole had comparable efficacy and was better tolerated than metronidazole.62
Amebiasis. Entamoeba histolytica
, a protozoan transmitted by the fecal-oral route, is most common in tropical regions. Most infected persons remain asymptomatic, but 10% annually develop invasive disease that presents as nonbloody diarrhea or amebic dysentery. Most adults have gradually worsening diarrhea and abdominal pain; rare complications include liver abscess, toxic megacolon, and ameboma. Asymptomatic persons infected with E histolytica
are treated to prevent transmission and invasive disease (). For asymptomatic infections, a “luminal agent” (that is active against cysts), such as paromomycin or iodoquinol, is sufficient. Iodoquinol is an 8-hydroxyquinoline; both it and paromomycin are poorly absorbed and can cause nausea and abdominal cramps. Optic and peripheral neuropathy can occur with prolonged use. Diloxanide is an alternative luminal agent. Symptomatic infections should be treated with a tissue amebicide (eg, metronidazole or tinidazole) plus a luminal agent. Tinidazole may be better tolerated and more effective than metronidazole.63
Cure rates of greater than 90% have been seen with nitazoxanide,64
but comparative data with nitroimidazoles are limited.
Cryptosporidiosis. Cryptosporidium parvum
and Cryptosporidium hominis
, the most common causes of cryptosporidiosis, are found worldwide. They cause diarrhea, which is usually self-limited in immunocompetent hosts. In immunocompromised hosts (particularly patients with AIDS), diarrhea may be severe and persistent. Nitazoxanide accelerates symptom resolution in human immunodeficiency virus (HIV)–negative patients, but results have been mixed in HIV-infected patients, with efficacy greatest in those with CD4
cell counts higher than 50/μL ().65
In patients with AIDS, initiation of antiretroviral agents, particularly protease inhibitors, improves symptoms.65
Paromomycin, nitazoxanide, macrolides, and rifamycins appear to be ineffective in HIV-infected patients.66
Several thiazolides have in vitro activity against C parvum
Cyclosporiasis. Cyclospora cayetanensis
is found worldwide, with highest prevalence in Haiti, Guatemala, Peru, and Nepal. It causes watery diarrhea with abdominal cramps, fatigue, and anorexia. Diarrhea can persist for months, particularly in HIV-infected patients. Cyclosporiasis is treated with TMP-SMX (). Ciprofloxacin is a less effective alternative; limited data suggest nitazoxanide may also be effective.68,69
Found most commonly in tropical and subtropical regions, isosporiasis is caused by Isospora belli
. Symptoms are similar to those of cyclosporiasis. Diarrhea is often self-limited in immunocompetent hosts but may be prolonged in those who are immunocompromised. Treatment is with TMP-SMX, and, as with cyclosporiasis, higher doses are used in patients with AIDS (). Ciprofloxacin, pyrimethamine (with folinic acid),70
Dientamoeba fragilis. D fragilis
is a trichomonad that may cause diarrhea and may be associated with irritable bowel syndrome. Iodoquinol is the preferred treatment; metronidazole, paromomycin, and tetracyclines have also been used successfully ().72
Blastocystis hominis. B hominis
is a protozoan that has also been linked to irritable bowel syndrome. Whether it truly causes disease is controversial, but some evidence supports a trial of antiparasitic therapy in infected patients with abdominal pain or diarrhea and no alternative explanation for their symptoms.73
Therapeutic options include nitazoxanide, metronidazole, and iodoquinol ().
Trichomoniasis is a common sexually transmitted infection caused by T vaginalis
. In women, T vaginalis
can cause vaginal discharge and pruritis, but 50% of infections may be asymptomatic. In men, infections are usually asymptomatic but can cause urethritis. Treatment with a single dose of tinidazole cures 86% to 100% of patients; metronidazole is an alternative ().74
Sexual partners should also be treated.
In one study, 10% of Trichomonas
isolates were resistant to metronidazole and less than 1% were resistant to tinidazole.75
Patients who do not respond to single-dose metronidazole should be treated with 500 mg of metronidazole twice daily for 7 days. If no improvement is seen, 2 g of metronidazole or tinidazole daily for 5 days is recommended.74
Other successful regimens have included high-dose tinidazole plus doxycycline or ampicillin with clotrimazole pessaries76
and intravaginal paromomycin.77
Free-Living Amebae Naegleria fowleri. N fowleri
is a thermophilic protist found worldwide in soil and fresh water. It causes primary amebic meningoencephalitis, which is almost universally fatal within days of infection via the nasopharynx from warm fresh water. Symptoms may begin with altered taste or smell, followed by fever, vomiting, and rapid progression to confusion, coma, and death. Most survivors have received amphotericin, and drugs used successfully in combination with amphotericin include miconazole, fluconazole, ornidazole, rifampin, sulfisoxazole, and chloramphenicol.78,79
Miltefosine, voriconazole, and chlorpromazine have been effective in experimental settings.
Treatment should include intravenous amphotericin and consideration of intrathecal amphotericin in confirmed or highly suspect cases (). Combination antimicrobial therapy seems warranted; the addition of azoles, rifampin, or other antimicrobial agents should be considered.
Acanthamoeba Species. Acanthamoeba
species are found worldwide in soil, dust, and fresh water. They cause granulomatous amebic encephalitis and disseminated disease, which usually occur in immunocompromised persons, and amebic keratitis, which occurs in immunocompetent hosts with contact lens use or ocular trauma. Granulomatous amebic encephalitis presents insidiously, with altered mental status, focal neurologic deficits, fever, headache, seizures, and CNS mass lesions, and is usually fatal. The drugs used most frequently in successfully treated cases are pentamidine, azoles, sulfonamides, and possibly flucytosine (). Almost all patients who survived received combination chemotherapy.78,80,81
Amebic keratitis is a vision-threatening infection that causes corneal ulceration and blindness if not treated promptly. Topical chlorhexidine or polyhexamethylene biguanide appear to be the most effective medical treatments.
Found worldwide in soil, B mandrillaris
causes a subacute or chronic meningoencephalitis in immunocompromised and immunocompetent hosts. Patients may present with skin lesions, fever, headache, vomiting, seizures, CNS mass lesions, and focal neurologic deficits. Clusters of disease have recently been reported in patients with previously unexplained encephalitis and in transplant recipients.82,83
Only 8 cases of successfully treated infections with Balamuthia
species have been reported; all received a prolonged course of combination chemotherapy. Successful treatment regimens have included flucytosine, pentamidine, fluconazole, sulfadiazine, and a macrolide; albendazole and itraconazole; and albendazole, fluconazole, and miltefosine ().84,85