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Antiparasitic Therapy

  • Shanthi Kappagoda
    Affiliations
    Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA

    Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA

    Center for Primary Care and Outcomes Research, Stanford University School of Medicine, Stanford, CA
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  • Upinder Singh
    Affiliations
    Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA

    Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA
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  • Brian G. Blackburn
    Correspondence
    Address correspondence to Brian G. Blackburn, MD, Stanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine, 300 Pasteur Dr, Grant Bldg, Room S-101, Stanford, CA 94305-5107. Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com
    Affiliations
    Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA

    Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA
    Search for articles by this author
      Parasitic diseases affect more than 2 billion people globally and cause substantial morbidity and mortality, particularly among the world's poorest people. This overview focuses on the treatment of the major protozoan and helminth infections in humans. Recent developments in antiparasitic therapy include the expansion of artemisinin-based therapies for malaria, new drugs for soil-transmitted helminths and intestinal protozoa, expansion of the indications for antiparasitic drug treatment in patients with Chagas disease, and the use of combination therapy for leishmaniasis and human African trypanosomiasis.
      Parasitic diseases cause substantial morbidity and mortality worldwide, taking the heaviest toll among the world's poorest people. This article reviews the treatment of the major protozoan and helminth infections in humans.

      PROTOZOA AND THE DISEASES THEY CAUSE

      Protozoa are single-celled eukaryotes that cause a diverse array of human diseases. They are generally categorized as systemic or intestinal and usually do not cause eosinophilia.

      Systemic Protozoa

      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.
      • Centers for Disease Control and Prevention (CDC)
      Guidelines for treatment of malaria in the United States.
      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.
      • Maude RJ
      • Plewes K
      • Faiz MA
      • et al.
      Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria?.
      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.
      • Centers for Disease Control and Prevention (CDC)
      Guidelines for treatment of malaria in the United States.
      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.
      • Dondorp A
      • Nosten F
      • Stepniewska K
      • Day N
      • White N
      Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
      • Dondorp AM
      • Fanello CI
      • Hendriksen IC
      • et al.
      Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial.
      In the United States, artesunate is available from the Centers for Disease Control and Prevention for severe malaria in patients who meet certain criteria.
      • Centers for Disease Control and Prevention (CDC)
      Notice to readers: new medication for severe malaria available under an investigational new drug protocol.
      Artesunate is combined with atovaquone-proguanil, doxycycline, clindamycin, or mefloquine to prevent recurrent parasitemia.
      • Dondorp A
      • Nosten F
      • Stepniewska K
      • Day N
      • White N
      Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
      Artesunate is well tolerated, with adverse effects similar to artemether. At high doses, it may cause neutropenia.
      • Bethell D
      • Se Y
      • Lon C
      • et al.
      Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.
      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.
      • Centers for Disease Control and Prevention (CDC)
      Guidelines for treatment of malaria in the United States.
      • Daneshvar C
      • Davis TM
      • Cox-Singh J
      • et al.
      Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections.
      Resistance. 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.
      • World Health Organization (WHO)
      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.
      • Dondorp AM
      • Nosten F
      • Yi P
      • et al.
      Artemisinin resistance in Plasmodium falciparum malaria.
      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.
      • World Health Organization (WHO)
      Treatment failure rates with AL of more than 20% have occurred only in Cambodia.
      • World Health Organization (WHO)
      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.
      • World Health Organization (WHO)
      The Worldwide Antimalarial Resistance Network has developed an online database of malaria resistance.
      Worldwide Antimalarial Resistance Network (WWARN).
      Treatment regimens for all types of malaria are summarized in Table 1.
      TABLE 1Treatment Regimens for Protozoal Infections in Adults
      BP = blood pressure; CDC = Centers for Disease Control and Prevention; CNS = central nervous system; DS = double-strength; ECG = electrocardiography; GAE = granulomatous amebic encephalitis; G6PD = glucose-6-phosphate dehydrogenase; HAART = highly active antiretroviral therapy; IM = intramuscular; IV = intravenous; TMP-SMX = trimethoprim-sulfamethoxazole; PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory; US = United States.
      MedicationDoseAdverse effectsAdditional information
      First-line treatment
      Second-line treatment
      Systemic protozoa
      Malaria—uncomplicated
      Plasmodium falciparum or species unknown
      Chloroquine-resistant area (everywhere except Central America west of Panama Canal. Haiti, Dominican Republic, and parts of the Middle East)Atovaquone-proguanil250 mg/100 mg, 4 adult tablets orally every day for 3 dNausea, vomiting, hepatitisShould be taken with food
      OR Artemether-lumefantrine20 mg/120 mg, 4 tablets oral starting dose, followed by 4 tablets orally 8 h later, followed by 4 tablets orally twice a day for 2 dHeadache, dizziness, vomitingShould be taken with fatty foods
      OR Quinine
      Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      625 mg salt orally 3 times a day for 7 d for patients infected in Southeast Asia or for 3 d in other patientsCinchonism,
      Symptoms of cinchonism include nausea, vomiting, dizziness, tinnitus, and high-frequency hearing loss.
      hypo-glycemia
      plus Doxycycline100 mg orally twice a dayNausea, vomiting, abdominal pain, candidiasis, photosensitivity
      or Tetracycline250 mg orally 4 times a day
      or Clindamycin6-7 mg/kg orally 3 times a day for7dNausea, vomiting, diarrhea, abdominal pain
      Mefloquine
      Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      750 mg salt oral loading dose followed by 500 mg salt orally 6-12 h after initial doseNausea, vomiting, vivid dreams, dysphoria, mood changes, QT prolongation
      Chloroquine-sensitive area (Central America west of Panama Canal, Haiti, Dominican Republic, and parts of the Middle East)Chloroquine
      Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      1000 mg salt oral loading dose followed by 500 mg salt orally at 6 h, 24 h, and 48 hNausea, vomiting, headache, dizziness, pruritis (usually in African patients), photosensitivity
      Hydroxychloroquine
      Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      800 mg salt oral loading dose followed by 400 mg salt orally at 6 h, 24 h, and 48 hRetinal toxicity unlikely with short-term use
      Malaria—severeArtesunate per CDC protocol2.4 mg/kg IV at 0 h, 12 h, 24 h, and 48 h, then once per day if IV still necessaryCan be requested from CDC Malaria Hotline
      CDC Malaria Hotline (770-488-7788 M-F 9:00 am to 5:00 pm EST or 770-488-7100 other hours).
      Usually P falcipariumplus Atovaquone-proguanil, doxycycline, clindamycin, or mefloquine
      Quinidine
      Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      Loading dose of 10 mg/kg salt IV over 1-2 h followed by 0.02 mg/kg/min salt continuous infusion for 24 hInfusion-related hypotension, QT and QRS prolongation, arrhythmias, hypoglycemiaContinuous ECG and close BP and blood glucose monitoring mandatory
      Once improved, switch to oral quinine625 mg salt orally 3 times a day
      plus Doxycycline100 mg IV/orally twice daily for 7 d
      or Tetracycline250 mg orally 4 times daily for 7 d
      or Clindamycin10 mg/kg IV loading dose then 5 mg/kg IV every 8 h (or oral dose as above) for7d
      Total duration of quinidine/quinine therapy is 7 d for patients infected in Southeast Asia, 3 d for elsewhere
      Malaria—uncomplicatedChloroquineSee P falciparium
      Plasmodium vivax or Plasmodium ovaleFollowed by primaquine52.6 mg salt orally every day for 14 dNausea and vomiting. hemolytic anemia with G6PD deficiency
      All regions except Papua New Guinea and Indonesia (or other areas with documented chloroquine resistance)
      Hydroxychloroquine Followed by primaquineSee P falciparium
      Malaria—uncomplicatedQuinineSee P falciparium
      P vivax or P ovaleplus Doxycycline, tetracycline, or clindamycin
      Chlor oquine-resistant areas (Papua New Guinea and Indonesia)
      Followed by primaquineSee P falciparium
      or Atovaquone-proguanil
      Followed by primaquine
      Mefloquine Followed by primaquineSee P falciparium
      Malaria—uncomplicatedChloroquineSee P falciparium
      Plasmodium malariae or Plasmodium knowlesior Hydroxychloroquine
      African trypanosomiasisPentamidine4mg/kg/dIMfor7-10dHypotension (with IV infusion), hypoglycemia, hepatitis, pancreatitis, leukopenia, sterile abscesses, nephrotoxicity
      Early (hemolymphatic stage)
      Trypanosoma brucei gambiense
      Suramin100-200 mg IV (test dose) followed by 1 g IV on days 1, 3, 7, 14, and 21Nephrotoxicity, rash (including exfoliative dermatitis), fatal hyper-sensitivity reaction (lin 20,000 doses), peripheral neuropathy myelosuppressionAvailable from CDC Drug Service
      CDC Drug Service (404-639-3670).
      Trypanosoma brucei rhodesienseSuraminDosed as above
      Late (CNS stage)
      T b gambienseEflornithine100 mg/kg IV every 6 h for 14 dFever, seizures, myelosuppression, peripheral neuropathy, diarrhea, hypertension, rashGiven as prolonged infusion. Contact CDC Drug Service regarding availability
      • Bethell D
      • Se Y
      • Lon C
      • et al.
      Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.
      or Eflornithine200 mg/kg IV every 12 h for 7 d
      plus Nifurtimox5 mg/kg orally 3 times a day for 10 dNausea, vomiting, anorexia, abdominal pain, insomnia, peripheral neuropathy hepatitis. Avoid alcoholAvailable from CDC Drug Service
      • Bethell D
      • Se Y
      • Lon C
      • et al.
      Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.
      Melarsoprol2.2mg/kg/dIVfor 10 dVomiting, nephrotoxicity, hepatitis, myocardial damage, peripheral neuropathy, fever, thrombocytopenia, reactive encephalopathy (often fatal). Encephalopathy risk reduced by coadmin-istration of corticoste-roids. Contraindicated with G6PD deficiencyAvailable from CDC Drug Service
      • Bethell D
      • Se Y
      • Lon C
      • et al.
      Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.
      T b rhodesienseMelarsoprol2.0-3.6 mg/kg/d IV for 3 d. Repeat course after 7 d and then again 7 d after the completion of the 2nd courseAvailable from CDC Drug Service
      CDC Drug Service (404-639-3670).
      American trypanosomiasis (Chagas disease)Benznidazole2.5-3.5 mg/kg orally twice a day for 60 dNausea, vomiting, anorexia, insomnia, peripheral neuropathy dermatitis, myelo-suppression. Disulfiram-like reaction with alcoholContact CDC Drug Service
      CDC Drug Service (404-639-3670).
      regarding availability
      Should be taken with food
      Nifurtimox2-3 mg/kg orally every 6-8 h for 90 dShould be taken after meals
      Available from CDC Drug Service
      Symptoms of cinchonism include nausea, vomiting, dizziness, tinnitus, and high-frequency hearing loss.
      Leishmaniasis
      VisceralLiposomal amphotericinImmunocompetent adults:3 mg/kg IV once a day on days 1-5, 14, and 21Nephrotoxicity, electrolyte wasting, hypertension, infusion reaction, chills/rigorsMultiple regimens used, including shorter-course amphotericin-based regimens and combination regimens
      Immunocompromised adults: 4 mg/kg IV once a day on days 1-5, 10, 17, 24, 31, and 38
      Sodium stibogluconate20 mg/kg IV or IM once a day for 28 d
      or Miltefosine2.5 mg/kg/d (maximum 150 mg/d) orally for 28 dNausea, vomiting, severe vertigo, headache, diarrheaNot commercially available in the US; contact Caligor Rx, Inc. for availability
      Caligor Rx, Inc, New York, NY (212-369-6000 or for emergencies 917-692-0195).
      or Paromomycin15 mg/kg/d IM for 21 dNephrotoxicity, ototoxicity, hepatitis
      CutaneousSodium stibogluconate20 mg/kg/d IV or IM for 20 dPentavalent antimonials: nausea, vomiting, abdominal pain, pancreatitis, hepatitis, myalgias, myelo-suppression, ECG abnormalitiesAvailable from CDC Drug Service
      CDC Drug Service (404-639-3670).
      Decision whether to use systemic therapy for cutaneous leishmaniasis is complex. When used, most appropriate drug depends in part on infecting species and region acquired
      Miltefosine2.5 mg/kg/d (maximum 150 mg/d) orally for 28 d
      or Fluconazole200 mg orally once a day for 6 wkHeadache, anorexia, hepatitis, alopecia
      or Liposomal amphotericin3 mg/kg IV once a day on days 1-5, 14, and 21Optimal dosing regimen not defined
      or Pentamidine2-3 mg/kg IV or IM once a day or every other day for 4-7 d
      MucocutaneousSodium stibogluconate20 mg/kg/d IV or IM for 28 d
      Liposomal amphotericin3 mg/kg IV once a dayMultiple regimens used
      or Amphotericin deoxycholate0.5-1.0 mg/kg IV once a day for 1 mo
      or Miltefosine2.5 mg/kg (maximum 150 mg/d) orally once a day for 28 d
      Babes iosisAtovaquone750 mg orally twice a dayRash, abdominal pain, diarrhea, nausea, vomiting, headache, insomnia, methemoglobinemia, hepatotoxicityHigher doses, longer duration of therapy for immunosuppressed patients (see text)
      plus Azithromycin500 mg orally for 1 d then 250 mg orally once a day for 7-10 dNausea, vomiting, abdominal pain, diarrhea, headache, hepatotoxicity
      Quinine650 mg orally 3 times a day
      plus Clindamycin300-600 mg IV every 6 h or 600 mg orally 3 times a day for 7-10 d
      ToxoplasmosisPyrimethamine200 mg orally once followed byMyelosuppression, abdominal pain, rash, headaches, dysgeusiaNo treatment for acute illness in nonpregnant/immunocompetent patients
      50 mg (if <60 kg) or 75 mg (if >60 kg) orally once a day
      plus Sulfadiazine1 g/kg (if <60 kg) or 1.5 g/kgMyelosuppression, rash, crystal-induced nephropathyDuration of therapy based on clinical situation
      (if >60 kg) orally 4 times a day
      plus Folinic acid10-25 mg orally once a day
      TMP-SMX5/25 mg/kg orally or IV every 12 hRash, urticaria, nausea, vomiting, myelo-suppression. Rarely: Stevens -Johnson syndrome, renal insufficiency, hyper-kalemia, hepatitisConsider concomitant systemic corticosteroids for chorioretinitis
      Higher doses have been used in some cases
      For patients with sulfa allergy
      Pyrimethamine
      plus Folinic acidDoses as above
      plus either
      Clindamycin600 mg IV every 6 h or 450 mg orally 4 times a day
      or Atovaquone750 mg orally every 6 h
      Acquired during pregnancyConsider spiramycinSpiramycin: nausea, abdominal pain, diarrheaCommercially unavailable in the US but can be obtained from PAMF-TSL
      PAMF-TSL (650-853-4828).
      or Pyrimethamine/sulfadiazine depending on clinical situation and gestational age (see text)
      Suggest expert consultation (see box to right)
      CongenitalConsider prolonged pyrimethamine/sulfadiazineUniversity of Chicago Congenital Toxoplasmosis Study Group may be able to provide clinical guidance
      University of Chicago Congenital Toxoplasmosis Study Group (773-834-4152).
      Suggest expert consultation (see box to right)
      Intestinal/genitourinary protozoa
      GiardiasisTinidazole2 g orally onceAnorexia, metallic taste, alcohol-induced disulfiram-like reaction, headache, peripheral neuropathy, seizures, neutropenia
      or Metronidazole250 mg orally 3 times a day for 5-7 d
      Nitazoxanide500 mg orally twice a day for 3 dNausea, vomiting, abdominal pain, diarrhea
      Amebiasis (Entamoeba histolytica)Luminal agent: Paromomycin8-12 mg/kg orally 3 times a day for7dNausea, vomiting, abdominal pain
      Asymptomatic carrieror Iodoquinol650 mg orally 3 times a day for 20 dNausea, vomiting, diarrhea, pruritis, headache
      Diloxanide500 mg orally 3 times a day for 10 dCommercially unavailable in the US but may be available through Abbott India Ltd
      Diloxanide may be available from Abbott India Ltd, Mumbai, India (+91 22 67978888).
      Amebic colitisMetronidazole500-750 mg orally 3 times a day for 10 d
      or Tinidazole Followed by luminal agent (see above)2 g orally once a day for 3 d
      Amebic liver abscess or other disseminated diseaseMetronidazole or Tinidazole750 mg orally or IV 3 times daily 2 g orally once a dayLength of metronidazole or tinidazole component of therapy often based on clinical response
      Followed by luminal agent (see above)
      Cryptosporidiosis
      Non-AIDS -associatedNitazoxanide500 mg orally twice a day for 3 d
      AID S-associatedHAART
      Consider nitazoxanide
      Cyclosporiasis
      Non-AIDS -associatedTMP-SMX1 DS tablet orally twice a day for 7-10 d
      AID S-associatedTMP-SMX1 DS tablet orally 4 times a day for 10 d followed by twice a day for 3 wk
      Ciprofloxacin500 mg orally twice a day for 7 d followed by 1 tablet orally 3 times a week for 2 wkNausea, vomiting, abdominal pain. Rarely: tendinopathy, neuropsychiatrie effects
      Isosporiasis
      Non-AIDS -associated AID S-associatedTMP-SMX1 DS tablet orally twice a day for 10 d
      TMP-SMX1 DS tablet orally 4 times a day for 10 d followed by twice a day for 3 wk
      Ciprofloxacin500 mg orally twice a day for 7 d
      DientamoebiasisIodoquinol650 mg orally 3 times a day for 20 d
      Blastocystis hominisNitazoxanide500 mg orally twice a day for 3 dTreatment controversial
      TrichomoniasisTinidazole2 g orallySexual partners should be treated
      Metronidazole2 g orally once or 500 mg orally twice a day for 7 d
      Free-living amebae
      Naegleria fowledTherapy should include amphotericin B
      Consider intrathecal amphotericin
      Combination systemic therapy is essential: consider addition of azoles, rifampin, or other antimicrobial agents (see text)
      Acanthamoeba species
      GAE and disseminated diseaseCombination therapy is essential and should include pentamidine, azoles. sulfonamides, and possibly flucytosine (see text)
      Acanthamoeba keratitisTopical chlorhexidine0.02%May be available via compounding pharmacies
      A compounding pharmacy that specializes in ophthalmic drugs is Leiter's Park Avenue Pharmacy in San Jose, CA (800-292-6773).
      Polyhexamethylene biguanide0.02%
      Balamuthia mandrillarisCombination therapy is essential and should likely include flucytosine. pentamidine, fluconazole. sulfadiazine, macrolides (see text)
      a BP = blood pressure; CDC = Centers for Disease Control and Prevention; CNS = central nervous system; DS = double-strength; ECG = electrocardiography; GAE = granulomatous amebic encephalitis; G6PD = glucose-6-phosphate dehydrogenase; HAART = highly active antiretroviral therapy; IM = intramuscular; IV = intravenous; TMP-SMX = trimethoprim-sulfamethoxazole; PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory; US = United States.
      b Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.
      c Symptoms of cinchonism include nausea, vomiting, dizziness, tinnitus, and high-frequency hearing loss.
      d CDC Malaria Hotline (770-488-7788 M-F 9:00 am to 5:00 pm EST or 770-488-7100 other hours).
      e CDC Drug Service (404-639-3670).
      f Caligor Rx, Inc, New York, NY (212-369-6000 or for emergencies 917-692-0195).
      g PAMF-TSL (650-853-4828).
      h University of Chicago Congenital Toxoplasmosis Study Group (773-834-4152).
      i Diloxanide may be available from Abbott India Ltd, Mumbai, India (+91 22 67978888).
      j A compounding pharmacy that specializes in ophthalmic drugs is Leiter's Park Avenue Pharmacy in San Jose, CA (800-292-6773).
      New Developments. Arterolane, a synthetic trioxolane derived from artemisinins, is undergoing phase 3 clinical trials in combination with piperaquine for P falciparum malaria.
      • Valecha N
      • Looareesuwan S
      • Martensson A
      • et al.
      Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial.
      In 2 recent clinical trials, both once-daily pyronaridine-artesunate and azithromycin plus artesunate were noninferior to AL for P falciparum malaria.
      • Tshefu AK
      • Gaye O
      • Kayentao K
      • et al.
      Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial.
      • Thriemer K
      • Starzengruber P
      • Khan WA
      • et al.
      Azithromycin combination therapy for the treatment of uncomplicated falciparum malaria in Bangladesh: an open-label randomized, controlled clinical trial.
      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 (Table 1).
      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.
      • Brun R
      • Blum J
      • Chappuis F
      • Burri C
      Human African trypanosomiasis.
      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.
      • Brun R
      • Blum J
      • Chappuis F
      • Burri C
      Human African trypanosomiasis.
      Coadministration of corticosteroids lowers the risk of encephalopathy.
      • Pepin J
      • Milord F
      • Guern C
      • Mpia B
      • Ethier L
      • Mansinsa D
      Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness.
      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.
      • Priotto G
      • Kasparian S
      • Mutombo W
      • et al.
      Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.
      Another trial found that melarsoprol-nifurtimox combination therapy was more effective than melarsoprol alone.
      • Bisser S
      • N'Siesi FX
      • Lejon V
      • et al.
      Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness.
      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.
      • Priotto G
      • Fogg C
      • Balasegaram M
      • et al.
      Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda.
      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 (Table 1).
      • Brun R
      • Blum J
      • Chappuis F
      • Burri C
      Human African trypanosomiasis.
      Resistance. Up to 30% of patients infected with T b gambiense do not respond to melarsoprol,
      • Brun R
      • Schumacher R
      • Schmid C
      • Kunz C
      • Burri C
      The phenomenon of treatment failures in Human African Trypanosomiasis.
      and 6% to 8% may receive no benefit from eflornithine in some regions.
      • Priotto G
      • Pinoges L
      • Fursa IB
      • et al.
      Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study.
      Suramin and melarsoprol resistance have occurred in clinical isolates of T b rhodesiense from Tanzania.
      • Kibona SN
      • Matemba L
      • Kaboya JS
      • Lubega GW
      Drug-resistance of Trypanosoma b. rhodesiense isolates from Tanzania.
      Drugs in Development. Clinical trials with fexinidazole, an oral 5-nitroimidazole active against T b gambiense and T b rhodesiense, are under way.

      Torreele E. Fexinidazole: a rediscovered nitroimidazole drug candidate moving into clinical development for HAT. Presented at 57th ASTMH Annual Meeting. New Orleans, LA: December 7-11, 2008.

      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 (Table 1). Benznidazole is better tolerated and generally considered the drug of choice.
      • Bern C
      • Montgomery SP
      • Herwaldt BL
      • et al.
      Evaluation and treatment of Chagas disease in the United States: a systematic review.
      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.
      • Lauria-Pires L
      • Braga MS
      • Vexenat AC
      • et al.
      Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives.
      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.
      • Bern C
      • Montgomery SP
      • Herwaldt BL
      • et al.
      Evaluation and treatment of Chagas disease in the United States: a systematic review.
      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.
      • Urbina JA
      Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches.
      Recent studies suggest that benznidazole for indeterminate or early chronic Chagas disease may improve parasite clearance rates
      • de Andrade AL
      • Zicker F
      • de Oliveira RM
      • et al.
      Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection.
      • Sosa Estani S
      • Segura EL
      • Ruiz AM
      • Velazquez E
      • Porcel BM
      • Yampotis C
      Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease.
      and prevent progression to cardiomyopathy.
      • Viotti R
      • Vigliano C
      • Lococo B
      • et al.
      Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a non-randomized trial.
      A multicenter, placebo-controlled trial involving benznidazole for the treatment of chronic Chagas disease is under way.
      • Marin-Neto JA
      • Rassi Jr, A
      • Avezum Jr, A
      • et al.
      The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease.
      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.
      • Urbina JA
      Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches.
      A phase 2 clinical trial of posaconazole vs benznidazole for chronic Chagas disease is under way.

      National Institutes of Health, National Library of Medicine, US Department of Health and Human Services. Clinical trial for the treatment of chronic Chagas disease with posaconazole and benznidazole (CHAGASAZOL). ClinicalTrials.Gov Web site. http://clinicaltrials.gov/ct2/show/NCT01162967. Accessed April 29, 2011.

      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 (Table 1). 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.
      • Sundar S
      • Chakravarty J
      • Agarwal D
      • Rai M
      • Murray HW
      Single-dose liposomal amphotericin B for visceral leishmaniasis in India.
      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.
      • Sundar S
      • Jha TK
      • Thakur CP
      • et al.
      Oral miltefosine for Indian visceral leishmaniasis.
      Adverse effects include nausea, vomiting, vertigo, diarrhea, hepatitis, renal insufficiency, and teratogenicity. There is concern that monotherapy may lead to drug resistance.
      • Murray HW
      • Berman JD
      • Davies CR
      • Saravia NG
      Advances in leishmaniasis.
      Pentavalent antimonial agents, such as sodium stibogluconate, were previously the therapeutic choice for VL. Currently, resistance limits their use, especially in South Asia.
      • Sundar S
      • More DK
      • Singh MK
      • et al.
      Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic.
      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.
      • Sundar S
      • Jha TK
      • Thakur CP
      • Sinha PK
      • Bhattacharya SK
      Injectable paromomycin for visceral leishmaniasis in India.
      Adverse effects include ototoxicity, nephrotoxicity, and hepatotoxicity.
      Combination therapy for VL may shorten treatment duration, decrease toxicity, and prevent resistance.
      • van Griensven J
      • Balasegaram M
      • Meheus F
      • Alvar J
      • Lynen L
      • Boelaert M
      Combination therapy for visceral leishmaniasis.
      In Sudan, paromomycin plus antimony was more effective than antimony alone.
      • Melaku Y
      • Collin SM
      • Keus K
      • Gatluak F
      • Ritmeijer K
      • Davidson RN
      Treatment of kala-azar in southern Sudan using a 17-day regimen of sodium stibogluconate combined with paromomycin: a retrospective comparison with 30-day sodium stibogluconate monotherapy.
      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.
      • Sundar S
      • Sinha PK
      • Rai M
      • et al.
      Comparison of short-course multi-drug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial.
      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 (Table 1). Combination therapy with allopurinol or pentoxifylline plus antimonial agents may be more effective than antimonial agents alone.
      • Gonzalez U
      • Pinart M
      • Rengifo-Pardo M
      • Macaya A
      • Alvar J
      • Tweed JA
      Interventions for American cutaneous and mucocutaneous leishmaniasis.
      A 4-week course of miltefosine was as effective as antimonial agents in Colombia but less effective than antimonial agents in Guatemala.
      • Soto J
      • Berman J
      Treatment of New World cutaneous leishmaniasis with miltefosine.
      Pentamidine has been used for CL caused by Leishmania guyanensis in French Guyana, Surinam, and Brazil but is toxic and less effective.
      • van der Meide WF
      • Sabajo LO
      • Jensema AJ
      • et al.
      Evaluation of treatment with pentamidine for cutaneous leishmaniasis in Suriname.
      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 (Table 1). 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.
      • Alrajhi AA
      • Ibrahim EA
      • De Vol EB
      • Khairat M
      • Faris RM
      • Maguire JH
      Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major.
      • Morizot G
      • Delgiudice P
      • Caumes E
      • et al.
      Healing of Old World cutaneous leishmaniasis in travelers treated with fluconazole: drug effect or spontaneous evolution?.
      Miltefosine has been used successfully to treat Old World CL.
      • van Thiel PP
      • Leenstra T
      • Kager PA
      • et al.
      Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military personnel returning from northern Afghanistan.
      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 agents
      • Miranda-Verastegui C
      • Tulliano G
      • Gyorkos TW
      • et al.
      First-line therapy for human cutaneous leishmaniasis in Peru using the TLR7 agonist imiquimod in combination with pentavalent antimony.
      ; however, no benefit was seen in a similar trial in Iran.
      • Firooz A
      • Khamesipour A
      • Ghoorchi MH
      • et al.
      Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial.
      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.
      • Wortmann G
      • Zapor M
      • Ressner R
      • et al.
      Liposomal amphotericin B for treatment of cutaneous leishmaniasis.
      Mucocutaneous Leishmaniasis. 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 (Table 1).
      • Murray HW
      • Berman JD
      • Davies CR
      • Saravia NG
      Advances in leishmaniasis.
      Cure rates with antimonial agents plus pentoxifylline were higher than with antimonial agents alone in Brazil.
      • Machado PR
      • Lessa H
      • Lessa M
      • et al.
      Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis.
      Amphotericin and pentamidine have also been used. Oral miltefosine cured 83% of patients with mild ML and 58% with more extensive ML in Bolivia.
      • Soto J
      • Toledo J
      • Valda L
      • et al.
      Treatment of Bolivian mucosal leishmaniasis with miltefosine.
      Resistance. Resistance to pentavalent antimonial agents occurs in 40% to 60% of patients with VL in Bihar, India.
      • Sundar S
      • More DK
      • Singh MK
      • et al.
      Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic.
      Resistance has also been reported from Sudan.
      • Maltezou HC
      Drug resistance in visceral leishmaniasis.
      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).
      • Wasunna MK
      • Rashid JR
      • Mbui J
      • et al.
      A phase II dose-increasing study of sitamaquine for the treatment of visceral leishmaniasis in Kenya.
      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.
      • Wormser GP
      • Dattwyler RJ
      • Shapiro ED
      • et al.
      The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.
      For mild to moderate illness, atovaquone plus azithromycin is as effective (and better tolerated) than the previous standard, oral quinine plus clindamycin (Table 1).
      • Krause PJ
      • Lepore T
      • Sikand VK
      • et al.
      Atovaquone and azithromycin for the treatment of babesiosis.
      Severe disease can be treated with a 7- to 10-day course of oral quinine plus intravenous clindamycin.
      • Wormser GP
      • Dattwyler RJ
      • Shapiro ED
      • et al.
      The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.
      Relapse is common in immunocompromised patients, and some authors recommend 6 or more weeks of therapy (including 2 weeks after blood smears are negative).
      • Krause PJ
      • Gewurz BE
      • Hill D
      • et al.
      Persistent and relapsing babesiosis in immunocompromised patients.
      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.
      • Wormser GP
      • Prasad A
      • Neuhaus E
      • et al.
      Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection.
      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 (Table 1). 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.
      • Soheilian M
      • Sadoughi MM
      • Ghajarnia M
      • et al.
      Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis.
      • Torre D
      • Casari S
      • Speranza F
      • et al.
      Italian Collaborative Study Group
      Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS.
      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 (Table 1),
      • Montoya JG
      • Remington JS
      Management of Toxoplasma gondii infection during pregnancy.
      although its efficacy is controversial.
      • Thiebaut R
      • Leproust S
      • Chene G
      • Gilbert R
      Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data.
      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 (Table 1).
      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 (Table 1), which cures more than 90% of cases.
      • Busatti HG
      • Santos JF
      • Gomes MA
      The old and new therapeutic approaches to the treatment of giardiasis: where are we?.
      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.
      • Busatti HG
      • Santos JF
      • Gomes MA
      The old and new therapeutic approaches to the treatment of giardiasis: where are we?.
      Nitazoxanide, an oral nitrothiazolyl-salicylamide, appears to inhibit pyruvate:ferredoxin oxidoreductase. A 3-day course cures 80% to 85% of patients.
      • Busatti HG
      • Santos JF
      • Gomes MA
      The old and new therapeutic approaches to the treatment of giardiasis: where are we?.
      • Rossignol JF
      Cryptosporidium and Giardia: treatment options and prospects for new drugs.
      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.
      • Solaymani-Mohammadi S
      • Genkinger JM
      • Loffredo CA
      • Singer SM
      A meta-analysis of the effectiveness of albendazole compared with metronidazole as treatments for infections with Giardia duodenalis.
      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 (Table 1). 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.
      • Gonzales ML
      • Dans LF
      • Martinez EG
      Antiamoebic drugs for treating amoebic colitis.
      Cure rates of greater than 90% have been seen with nitazoxanide,
      • Rossignol JF
      • Kabil SM
      • El-Gohary Y
      • Younis AM
      Nitazoxanide in the treatment of amoebiasis.
      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 (Table 1).
      • Cabada MM
      • White Jr, AC
      Treatment of cryptosporidiosis: do we know what we think we know?.
      In patients with AIDS, initiation of antiretroviral agents, particularly protease inhibitors, improves symptoms.
      • Cabada MM
      • White Jr, AC
      Treatment of cryptosporidiosis: do we know what we think we know?.
      Paromomycin, nitazoxanide, macrolides, and rifamycins appear to be ineffective in HIV-infected patients.
      • Abubakar I
      • Aliyu SH
      • Arumugam C
      • Hunter PR
      • Usman NK
      Prevention and treatment of cryptosporidiosis in immunocompromised patients.
      Several thiazolides have in vitro activity against C parvum.
      • Gargala G
      • Le Goff L
      • Ballet JJ
      • Favennec L
      • Stachulski AV
      • Rossignol JF
      Evaluation of new thiazolide/thiadiazolide derivatives reveals nitro group-independent efficacy against in vitro development of Cryptosporidium 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 (Table 1). Ciprofloxacin is a less effective alternative; limited data suggest nitazoxanide may also be effective.
      • Verdier RI
      • Fitzgerald DW
      • Johnson Jr, WD
      • Pape JW
      Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients: a randomized, controlled trial.
      • Zimmer SM
      • Schuetz AN
      • Franco-Paredes C
      Efficacy of nitazoxanide for cyclosporiasis in patients with sulfa allergy.
      Isosporiasis. 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 (Table 1). Ciprofloxacin, pyrimethamine (with folinic acid),
      • Weiss LM
      • Perlman DC
      • Sherman J
      • Tanowitz H
      • Wittner M
      Isospora belli infection: treatment with pyrimethamine.
      and nitazoxanide
      • Romero Cabello R
      • Guerrero LR
      • Munoz Garcia MR
      • Geyne Cruz A
      Nitazoxanide for the treatment of intestinal protozoan and helminthic infections in Mexico.
      are alternatives.
      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 (Table 1).
      • Stark D
      • Barratt J
      • Roberts T
      • Marriott D
      • Harkness J
      • Ellis J
      A review of the clinical presentation of dientamoebiasis.
      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.
      • Rossignol JF
      • Kabil SM
      • Said M
      • Samir H
      • Younis AM
      Effect of nitazoxanide in persistent diarrhea and enteritis associated with Blastocystis hominis.
      Therapeutic options include nitazoxanide, metronidazole, and iodoquinol (Table 1).
      Trichomonas vaginalis. 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 (Table 1).
      • Workowski KA
      • Berman S
      • Centers for Disease Control and Prevention (CDC)
      Sexually transmitted diseases treatment guidelines, 2010.
      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.
      • Schwebke JR
      • Barrientes FJ
      Prevalence of Trichomonas vaginalis isolates with resistance to metronidazole and tinidazole.
      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.
      • Workowski KA
      • Berman S
      • Centers for Disease Control and Prevention (CDC)
      Sexually transmitted diseases treatment guidelines, 2010.
      Other successful regimens have included high-dose tinidazole plus doxycycline or ampicillin with clotrimazole pessaries
      • Mammen-Tobin A
      • Wilson JD
      Management of metronidazole-resistant Trichomonas vaginalis—a new approach.
      and intravaginal paromomycin.
      • Tayal SC
      • Ochogwu SA
      • Bunce H
      Paromomycin treatment of recalcitrant Trichomonas vaginalis.

      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.
      • Schuster FL
      • Visvesvara GS
      Opportunistic amoebae: challenges in prophylaxis and treatment.
      • Vargas-Zepeda J
      • Gomez-Alcala AV
      • Vasquez-Morales JA
      • Licea-Amaya L
      • De Jonckheere JF
      • Lares-Villa F
      Successful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin.
      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 (Table 1). 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 (Table 1). Almost all patients who survived received combination chemotherapy.
      • Schuster FL
      • Visvesvara GS
      Opportunistic amoebae: challenges in prophylaxis and treatment.
      • Saxena A
      • Mittal S
      • Burman P
      • Garg P
      Acanthameba meningitis with successful outcome.
      • Aichelburg AC
      • Walochnik J
      • Assadian O
      • et al.
      Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine.
      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.
      Balamuthia mandrillaris. 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.
      • Centers for Disease Control and Prevention (CDC)
      Notes from the field: transplant-transmitted Balamuthia mandrillaris—Arizona, 2010.
      • Schuster FL
      • Yagi S
      • Gavali S
      • et al.
      Under the radar: Balamuthia amebic encephalitis.
      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 (Table 1).
      • Deetz TR
      • Sawyer MH
      • Billman G
      • Schuster FL
      • Visvesvara GS
      Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases.
      • Martinez DY
      • Seas C
      • Bravo F
      • et al.
      Successful treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement.

      HELMINTHS AND THE DISEASES THEY CAUSE

      Helminths are multicellular worms that do not reproduce in humans (with the exceptions of Strongyloides and Capillaria). They often provoke an eosinophilic response in their human hosts, particularly when they invade tissue. Helminths are broadly categorized as cestodes, trematodes, or nematodes.

      Cestodes (Tapeworms)

      Cestodes cause disease as segmented, ribbon-like adult tapeworms in the gastrointestinal lumen or as juvenile tissue cysts. The preferred treatment is praziquantel for most intestinal cestodes and benzimidazoles for tissue/larval cestodes.
      Taenia saginata. Also known as beef tapeworm, T saginata is the most common Taenia species that infects humans. It is found worldwide, with highest prevalence in Latin America, Africa, the Middle East, and Central Asia. Humans become infected after consuming undercooked/raw infested beef. Most infections are asymptomatic, but some patients have abdominal cramps or malaise. Treatment is with praziquantel; niclosamide and nitazoxanide are alternatives (Table 2).
      • Lateef M
      • Zargar SA
      • Khan AR
      • Nazir M
      • Shoukat A
      Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide.
      Praziquantel is very effective for taeniasis. It is an oral pyrazinoisoquinolone derivative that damages the tegument and causes paralysis. Adverse effects include dizziness, headache, abdominal pain, vomiting, diarrhea, and hepatitis. Niclosamide works by uncoupling oxidative phosphorylation. Adverse effects include nausea and abdominal pain.
      TABLE 2Treatment Regimens for Helminth Infections in Adults
      CDC = Centers tor Disease Control and Prevention; DbC = diethylcarbamazine; FA1K = percutaneous puncture, aspiration, injection, reaspiration.
      MedicationDoseAdverse effectsAdditional information
      First-line treatment
      Second-line treatment
      Cestodes
      Intestinal tapeworm infectionPraziquantel5-10 mg/kg orally onceDizziness, headache, abdominal pain, nausea, hepatitis
      Taenia saginata
      Taenia solium
      Diphyllobothrium latum
      Niclosamide2 g orally onceNausea, vomiting, diarrhea, headacheNot commercially available in the US but may be obtained from Expert Compounding Pharmacy
      Expert Compounding Pharmacy, Lake Balboa, CA (800-247-9767).
      Tablets should be chewed before swallowing
      or Nitazoxanide500 mg orally twice a day for 3 dNausea, vomiting, abdominal pain, diarrhea
      Hymenolepsis nanaPraziquantel25 mg/kg orally once
      Niclosamide2 g orally once, followed by 1.5 g orally once a day for 6 d
      or Nitazoxanide500 mg orally once a day or twice a day for 3 d
      CysticercosisAlbendazole400 mg orally twice a day for 2-4 wk with corticosteroids given before. during, and after treatment to decrease seizure riskAbdominal pain, nausea, vomiting, myelo-suppression, alopecia, hepatitis. Can precipitate seizures in patients with neurocysticercosisShould be taken with food
      (see above for intestinal T solium infection)Decision regarding whether to treat is complex (see text). Ocular cysticercosis should be excluded before initiating systemic therapy
      Praziquantel33 mg/kg orally 3 times a day for 1 d followed by 15 mg/kg orally 3 times a day for 2-4 wk with corticosteroids given before, during, and after treatment to decrease seizure riskCan precipitate seizures in patients with neurocysticercosis
      Echinococcosis
      Echinococcus granulosusAlbendazole400 mg orally twice a day for 1-6 mo; consider PAIRTreatment decision is complex; management strategies depend in part on cyst stage (see text)
      Echinococcus multilocularisConsider albendazole: definitive therapy is surgical
      Trematodes
      Schistosomiasis
      Schistosoma mansoni, Schistosoma haematobium, or Schistosoma intercalatumPraziquantel20 mg/kg orally twice a day for 1 d
      Schistosoma japonicum or Schistosoma mekongiPraziquantel20 mg/kg orally 3 times a day for 1 d
      FascioliasisTriclabendazole10 mg/kg orally once or twiceAbdominal painContact CDC Drug Service regarding availability°
      Bithionol30-50 mg/kg orally every other day for 20-30 dNausea, vomiting, abdominal pain, pruritis, urticariaUnavailable in US
      or Nitazoxanide500 mg orally twice a day for 7 d
      Clonorchiasis/opisthorchiasisPraziquantel25 mg/kg orally 3 times a day for 2 d
      Albendazole10 mg/kg/d orally for 7 d
      ParagonimiasisPraziquantel25 mg/kg orally 3 times a day for 2 d
      Triclabendazole or Bithionol10 mg/kg orally twiceContact CDC Drug Service regarding availability
      Contact CDC Drug Service (404-639-3670).
      30-50 mg/kg orally every other day for 20-30 dUnavailable in US
      Intestinal flukesPraziquantel25 mg/kg orally 3 times a day for 1 d
      Nematodes
      Intestinal nematodes
      AscariasisAlbendazole400 mg orally once
      or Mebendazole500 mg orally once or 100 mg orally twice a day for 3 d
      Ivermectin150-200 μg/kg orally onceNausea, diarrhea, hepatitis, or dizziness
      or Pyrantel pamoate11 mg/kg (maximum 1 g) orally for 3dAbdominal pain, nausea, vomiting, diarrheaCan be obtained from Expert Compounding Pharmacy
      Expert Compounding Pharmacy, Lake Balboa, CA (800-247-9767).
      Trichuriasis (whipworm)Albendazole400 mg orally once a day for 3-7 d
      or Mebendazole100 mg orally twice a day for 3-7 d
      Ivermectin200 μg/kg orally once a day for 3 d
      HookwormAlbendazole400 mg orally once
      (Necator americanus, Ancylostoma duodenale)or Mebendazole100 mg orally twice a day for 3 d
      Pyrantel pamoate11 mg/kg (maximum 1 g) orally once a day for 3 d
      Enterobiasis (pinworm)Albendazole400 mg orally onceTreatment course should be repeated 2 wk later
      or Mebendazole100 mg orally once
      Ivermectin200 μg/kg orally once
      Strong y loidiasis
      Chronic intestinal infectionIvermectin200 μg/kg orally once a day for 2d
      Albendazole400 mg orally twice a day for 10-14 d
      or Thiabendazole25 mg/kg orally twice a day for 3-7 dSimilar to albendazole
      Disseminated/hyperinfectionIvermectin200 μg/kg orally once a day until
      Possible role for subcutaneous (veterinary) formulations of ivermectin or combination ivermectin/albendazole regimens7-14 d after clearance of parasite
      Extra-intestinal nematodes
      TrichinellosisAlbendazole400 mg orally twice a day for 8-14 dConsider concomitant corticosteroids
      or Mebendazole200-400 mg orally 3 times a day for 3 d, followed by 400-500 mg orally 3 times a day for 10 d
      Toxocariasis
      Visceral larva migransAlbendazole400 mg orally twice a day for 5 dConsider concomitant corticosteroids
      or Mebendazole100-200 mg orally twice a day for 5 d
      Ocular larva migransAlbendazole400-800 mg orally twice a day for 28 d
      Filarial infections
      Lymphatic filariasisDEC2 mg/kg orally 3 times a day for 1 d 12 dNausea, fever, asthma-or like symptoms, and arthralgias
      Ivermectin With or without albendazole150-400 μg/kg orally once
      400 mg orally once
      Possible role for doxycycline200 mg/d for 4-8 wk
      Tropical pulmonary eosinophiliaDEC2 mg/kg orally 3 times a day for 2-3 wk
      OnchocerciasisIvermectin150 μg/kg orally once, repeated every 6-12 mo until asymptomatic 200 mg/d for 4-8 wkDEC contraindicated
      Possible role for doxycycline
      LoaiasisDEC2-3 mg/kg orally 3 times a day for 2-3 wkAvailable from CDC Drug Service
      Contact CDC Drug Service (404-639-3670).
      Antiparasitic therapy associated with encephalopathy in patients with high-grade parasi-temia; consider pretreatment apheresis
      Albendazole200 mg orally twice a day for 3 wk
      Other tissue nematodes
      Cutaneous larva migransAlbendazole400 mg orally once a day for 3 d
      Ivermectin200 μg/kg orally once a day for 1-2 d
      Angiostrongylus cantonensis (eosinophilic meningitis)Albendazole400 mg orally twice a day for 2-3 wk (plus corticosteroids)
      BaylisascariasisAlbendazole400 mg orally twice a day for 1-2 wk (plus corticosteroids)
      Gnathostomias isAlbendazole400 mg orally twice a day for 21 d
      Ivermectin200 μg/kg orally once a day for 2 d
      CapillariasisMebendazole200 mg orally twice a day for 20 d
      Albendazole400 mg orally twice a day for 10 d
      a CDC = Centers tor Disease Control and Prevention; DbC = diethylcarbamazine; FA1K = percutaneous puncture, aspiration, injection, reaspiration.
      b Expert Compounding Pharmacy, Lake Balboa, CA (800-247-9767).
      c Contact CDC Drug Service (404-639-3670).
      Taenia solium. Also known as pork tapeworm, T solium is endemic to Latin America, sub-Saharan Africa, and Asia, where free-range pigs are raised. Taeniasis, intestinal infection with the adult tapeworm, results from eating undercooked pork containing cysticerci (larval cysts). Cysticercosis (tissue infection with T solium larval cysts) results from ingestion of T solium eggs, which are spread from a person with intestinal taeniasis or via fecal-oral autoinfection. Cysticercosis involving subcutaneous tissue or skeletal muscle is usually asymptomatic. With neurocysticercosis (NCC), cysts in the CNS can cause seizures, hydrocephalus, or chronic meningitis.
      Although T solium intestinal infection is usually asymptomatic, patients are treated to prevent cysticercosis. Praziquantel is first-line treatment, and niclosamide is an alternative (Table 2). The decision to treat NCC with antiparasitic agents is complex; the location, number, and type of cysts and clinical manifestations should be considered. Corticosteroids are given concurrently to decrease the inflammatory response and risk of seizures as the parasite degenerates. In general, patients with intraparenchymal cysts should be treated with albendazole plus corticosteroids. Patients with only intraparenchymal calcifications generally do not require antiparasitic therapy. Patients with subarachnoid cysts should generally receive prolonged courses of albendazole plus corticosteroids. Surgical removal is indicated for intraventicular, intraocular, and spinal cysts. Intraocular cysts should be excluded before initiating antiparasitic therapy for cysticercosis. If present, intraocular cysts should be surgically removed before administration of antiparasitic treatment to avoid irreversible eye damage due to the resulting inflammatory response.
      Albendazole is a broad-spectrum benzimidazole that inhibits microtubule formation. It can cause nausea, abdominal pain, rash, alopecia, leukopenia, and hepatitis. Emerging evidence suggests that antiparasitic therapy decreases seizures in patients with live intraparenchymal cysts.
      • Garcia HH
      • Pretell EJ
      • Gilman RH
      • et al.
      A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis.
      Praziquantel is a second-line agent for NCC. Disadvantages of praziquantel include lower efficacy, lower drug levels when coadministered with corticosteroids, and more drug-drug interactions.
      Dwarf Tapeworm. The dwarf tapeworm Hymenolepsis nana is found worldwide, with highest prevalence in Asia, southern/eastern Europe, Latin America, and Africa. Transmission is usually fecal-oral. Infections are usually asymptomatic, but some patients have abdominal discomfort and diarrhea. Treatment is with praziquantel at higher doses and longer courses than for taeniasis (Table 2). Niclosamide and nitazoxanide are alternatives.
      • Romero Cabello R
      • Guerrero LR
      • Munoz Garcia MR
      • Geyne Cruz A
      Nitazoxanide for the treatment of intestinal protozoan and helminthic infections in Mexico.
      • Chero JC
      • Saito M
      • Bustos JA
      • Blanco EM
      • Gonzalvez G
      • Garcia HH
      Hymenolepis nana infection: symptoms and response to nitazoxanide in field conditions.
      Diphyllobothrium latum. Infection with D latum results from eating raw or undercooked fish. Outbreaks have occurred in South America, Japan, Siberia, Europe, and North America. Infection is usually asymptomatic, but some patients have weakness, dizziness, salt craving, diarrhea, and passage of proglottids in their stool. The parasite interferes with vitamin B12 absorption and can cause megaloblastic anemia. Treatment is with praziquantel or, alternatively, niclosamide (Table 2).
      Drugs in Development. Tribendimidine is a diamidine derivative of amidantel, an older acetylcholine receptor agonist used to treat hookworm. Treatment with tribendimidine has yielded cure rates similar to albendazole for intestinal taeniasis.
      • Xiao SH
      • Hui-Ming W
      • Tanner M
      • Utzinger J
      • Chong W
      Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China.
      Echinococcosis. Echinococcus granulosus and Echinococcus multilocularis cause cystic and alveolar echinococcosis, respectively. E granulosus infection results from ingesting food or water contaminated with Echinococcus eggs or from contact with infected dogs. The disease affects pastoral communities, particularly in South America, the Mediterranean littoral, Eastern Europe, the Middle East, East Africa, Central Asia, China, and Russia. After infection, the parasites encyst, usually in the liver, or less commonly in the lungs. Initially, cysts are asymptomatic, but over the course of months to years they enlarge and cause symptoms. Cyst rupture can cause anaphylaxis. With E multilocularis infection (which is less common than E granulosus), cysts usually form in the liver. They are aggressive, eventually invading contiguous structures with tumor-like progression and can metastasize, usually to the lungs and brain.
      Management strategies depend on the cyst stage and include percutaneous puncture, aspiration, injection, and reaspiration (PAIR); surgery; antiparasitic chemotherapy; and expectant management.
      • Brunetti E
      • Kern P
      • Vuitton DA
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      Select patients may be treated with albendazole alone (Table 2). A prolonged course is recommended to prevent recurrence after surgery or percutaneous treatment. There may be some benefit to combination praziquantel plus albendazole before and after surgical interventions.
      • Bygott JM
      • Chiodini PL
      Praziquantel: neglected drug? ineffective treatment? or therapeutic choice in cystic hydatid disease?.

      Trematodes (Flatworms)

      With the exception of fascioliasis, the preferred treatment for trematodes (flukes) is praziquantel.
      Schistosomiasis. More than 200 million people globally are infected by Schistosoma species. The 3 species of primary medical importance are Schistosoma mansoni (found primarily in Africa, the Arabian Peninsula, and South America), Schistosoma japonicum (China, the Philippines, Southeast Asia, and Indonesia), and Schistosoma haematobium (Africa and the Arabian peninsula).
      Infection occurs after skin contact with infested fresh water; 1 to 2 days later, patients may develop a papular, pruritic rash. About 1 to 2 months later, a minority develop Katayama fever, with myalgias, cough, eosinophilia, abdominal pain, fever, and hepatosplenomegaly. S mansoni and S japonicum can cause chronic hepatic/intestinal disease (abdominal pain, hepatic fibrosis, and portal or pulmonary hypertension). S haematobium can cause genitourinary disease (hematuria, genital lesions, urinary strictures/obstruction, and bladder cancer). In endemic areas, schistosomiasis contributes to anemia and growth retardation in children.
      The treatment of choice for schistosomiasis is praziquantel (Table 2).
      • Gryseels B
      • Polman K
      • Clerinx J
      • Kestens L
      Human schistosomiasis.
      Higher doses are recommended for S japonicum (and Schistosoma mekongi) infections compared with the other Schistosoma species. Praziquantel has little activity against eggs or immature worms (schistosomulae) and cannot abort early infection. Patients treated early in their infection must be retreated with praziquantel after the adult worms have matured (usually in 6 to 12 weeks). Although artesunate has activity against schistosomulae, it is not usually used for schistosomiasis, in part because of concern about causing artemisinin-resistant malaria.
      • Boulanger D
      • Dieng Y
      • Cisse B
      • et al.
      Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks.
      For Katayama fever, corticosteroids are often coadministered with praziquantel.
      • Ross AG
      • Vickers D
      • Olds GR
      • Shah SM
      • McManus DP
      Katayama syndrome.
      S mansoni resistance to praziquantel has been observed.
      • Ismail M
      • Botros S
      • Metwally A
      • et al.
      Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers.
      S mansoni can also be treated with oxamniquine, and S haematobium with metrifonate (Table 2); however, these drugs are not currently available in the United States.
      • Ferrari ML
      • Coelho PM
      • Antunes CM
      • Tavares CA
      • da Cunha AS
      Efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infection: a controlled trial.
      Fascioliasis. Fascioliasis, caused mainly by Fasciola hepatica, is endemic to more than 60 countries and is most highly prevalent in sheep-raising areas of Peru, Bolivia, France, Portugal, Egypt, and Iran. Infection results from eating freshwater plants infested with metacercariae. About 6 to 12 weeks after infection, larvae enter the liver. This acute (migratory) stage of infection can last 2 to 4 months and presents with marked eosinophilia, abdominal pain, fever, and weight loss. Computed tomography reveals multiple migratory, branching hepatic abscesses. F hepatica later moves to the bile ducts, where it produces eggs after 3 to 4 months. Some patients develop intermittent biliary obstruction, but many are asymptomatic during the chronic (biliary) stage of infection. Unlike other trematodes, F hepatica responds poorly to praziquantel, and triclabendazole (a benzimidazole that inhibits microtubule formation) is the treatment of choice (Table 2). Efficacy is 80% to 90%, but resistance has been reported.
      • Moll L
      • Gaasenbeek CP
      • Vellema P
      • Borgsteede FH
      Resistance of Fasciola hepatica against triclabendazole in cattle and sheep in The Netherlands.
      Triclabendazole is well tolerated aside from abdominal pain. Bithionol is an alternative but requires longer courses and causes more adverse effects. Cure rates are 60% with a 7-day course of nitazoxanide and 70% with a 10-day course of artesunate.
      • Favennec L
      • Jave Ortiz J
      • Gargala G
      • Lopez Chegne N
      • Ayoub A
      • Rossignol JF
      Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru.
      Clonorchiasis and Opisthorchiasis. The Opisthorchiidae family of liver flukes contains 3 major species: Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus. Infection results from eating undercooked freshwater fish infested with metacercariae. C sinensis is endemic primarily to East Asia, O viverrini to Southeast Asia, and O felineus to Russia and other former Soviet re publics. Adult worms deposit eggs in the biliary system; symptoms are uncommon, but patients may have fever, abdominal pain, hepatomegaly, and eosinophilia. Complications include ascending cholangitis, pancreatitis, and biliary pigment stones. Infection may increase the risk of cholangiocarcinoma. The treatment of choice is praziquantel (Table 2)
      • Bunnag D
      • Harinasuta T
      Studies on the chemotherapy of human opisthorchiasis in Thailand: I. Clinical trial of praziquantel.
      ; albendazole is an alternative.
      • Liu YH
      • Wang XG
      • Gao P
      • Qian MX
      Experimental and clinical trial of albendazole in the treatment of Clonorchiasis sinensis.
      Tribendimidine preliminarily appears to be as efficacious as praziquantel.
      • Soukhathammavong P
      • Odermatt P
      • Sayasone S
      • et al.
      Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, tribendimidine, and praziquantel in patients with Opisthorchis viverrini: a randomised, exploratory, open-label, phase 2 trial.
      Paragonimiasis. Paragonimiasis is caused by Paragonimus species lung flukes, of which Paragonimus westermani is the best described. It is most common in East and Southeast Asia. Infection results from eating undercooked crabs or crayfish infested with metacercariae. Adult worms lay eggs in the lung, and acute infection can cause diarrhea, abdominal pain, fever, chest pain, eosinophilia, and cough. Subsequently, patients may develop eosinophilic pleural effusions or bronchiectatic and cavitary lung disease with cough and hemoptysis, often mimicking tuberculosis. Less commonly, lesions develop in the CNS, skin, or other sites. Treatment with praziquantel results in rapid clinical improvement and has high cure rates (Table 2).
      • Udonsi JK
      Clinical field trials of praziquantel in pulmonary paragonimiasis due to Paragonimus uterobilateralis in endemic populations of the Igwun Basin, Nigeria.
      Triclabendazole is also effective.
      • Calvopina M
      • Guderian RH
      • Paredes W
      • Chico M
      • Cooper PJ
      Treatment of human pulmonary paragonimiasis with triclabendazole: clinical tolerance and drug efficacy.
      Bithionol is an alternative but requires longer courses and is more toxic.
      • Kim JS
      Treatment of Paragonimus westermani infections with bithionol.
      Intestinal Flukes. More than 60 flukes infect the human intestinal tract. The best known are Fasciolopsis buski, Heterophyes heterophyes, Metagonimus yokogawai, and Echinostoma species. Most cases occur in Asia, but there are foci in Africa and the Middle East. All intestinal flukes are food-borne, and most result in asymptomatic infection. Praziquantel is the preferred treatment; however, triclabendazole is also effective (Table 2).
      • Bunnag D
      • Radomyos P
      • Harinasuta T
      Field trial on the treatment of fasciolopsiasis with praziquantel.

      Nematodes (Roundworms)

      Nematodes are a diverse group of parasites that are among the most prevalent of human infections. They are categorized as intestinal or extraintestinal. Except for Strongyloides and filarial infections, benzimidazoles are the treatments of choice.

      Intestinal Nematodes

      Soil-Transmitted Helminths. The most common intestinal nematodes are Ascaris lumbricoides, Trichuris trichiura (whipworm), and the human hookworms Ancylostoma duodenale and Necator americanus. These organisms are also termed soil-transmitted helminths (STHs) because their eggs or larvae must develop in soil before becoming infectious. More than 1 billion people are infected with Ascaris, and nearly as many with whipworm or hookworm, most commonly in tropical areas with poor sanitation. Humans acquire Ascaris and Trichuris primarily through the fecal-oral route and hookworm primarily by walking barefoot on infested soil. Although pulmonary symptoms can occur early after infection with Ascaris or hookworm, adult worms in the bowel lumen generally cause no symptoms or only mild abdominal pain, nausea, or diarrhea. Ascaris can rarely cause intestinal or biliary obstruction, appendicitis, and intestinal perforation. Whipworm can cause rectal prolapse, and hookworm causes chronic anemia. Chronic infection with the STHs can impair growth and cognitive development in children and adversely affect pregnancies.
      Short-course albendazole (or mebendazole) cures 88% to 95% of infections with Ascaris (Table 2).
      • Keiser J
      • Utzinger J
      Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis.
      For Trichuris, short-course cure rates are low, and patients should receive 3 to 7 days of therapy.
      • Knopp S
      • Mohammed KA
      • Speich B
      • et al.
      Albendazole and mebendazole administered alone or in combination with ivermectin against Trichuris trichiura: a randomized controlled trial.
      Preliminary data suggest mebendazole may be superior to albendazole for whipworm and that combination therapy with ivermectin may be superior to benzimidazole monotherapy.
      • Knopp S
      • Mohammed KA
      • Speich B
      • et al.
      Albendazole and mebendazole administered alone or in combination with ivermectin against Trichuris trichiura: a randomized controlled trial.
      For hookworm, albendazole is preferred over mebendazole.
      • Keiser J
      • Utzinger J
      Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis.
      Soil-transmitted helminths may be developing resistance to benzimidazoles.
      • Albonico M
      • Bickle Q
      • Ramsan M
      • Montresor A
      • Savioli L
      • Taylor M
      Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar.
      None of the available alternative therapies is superior to albendazole or mebendazole for all 4 STH species. The acetylcholine receptor agonist pyrantel pamoate is an alternative for Ascaris and hookworm, and ivermectin is an alternative for Ascaris and whipworm. Newer treatments include nitazoxanide for Ascaris and whipworm and tribendimidine for Ascaris and hookworm.
      • Galvan-Ramirez ML
      • Rivera N
      • Loeza ME
      • et al.
      Nitazoxanide in the treatment of Ascaris lumbricoides in a rural zone of Colima, Mexico.
      • Diaz E
      • Mondragon J
      • Ramirez E
      • Bernal R
      Epidemiology and control of intestinal parasites with nitazoxanide in children in Mexico.
      Enterobius vermicularis. E vermicularis (pinworm) causes enterobiasis, which occurs worldwide and does not disproportionately affect residents of tropical countries. The worms live in the proximal colon and migrate to the perianal region to lay eggs that become infectious after 6 hours. Transmission is mainly person-to-person, often via fecal-oral contamination of hands or fomites. Institutional or familial spread is common. Although most infections are asymptomatic, perianal pruritis can be severe. Single-dose albendazole or mebendazole is highly effective (Table 2).
      • Wen LY
      • Yan XL
      • Sun FH
      • Fang YY
      • Yang MJ
      • Lou LJ
      A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China.
      Alternatives include ivermectin or pyrantel pamoate. Household and other close contacts should be treated, and treatment should be repeated after 2 weeks because of frequent reinfection and autoinfection.
      • Matsen JM
      • Turner JA
      Reinfection in enterobiasis (pinworm infection). Simultaneous treatment of family members.
      Strongyloides stercoralis. Strongyloidiasis is caused by S stercoralis, an intestinal nematode usually acquired by walking barefoot on infested soil. S stercoralis is found in the tropics, subtropics, and limited foci in the United States and Europe, where poor sanitation and a warm, moist climate coexist. Unlike nearly all other helminths, Strongyloides can complete its life cycle within humans, allowing for amplification of the parasite, person-to-person transmission, and lifelong persistence. Chronic infection is usually asymptomatic, although abdominal pain, nausea, eosinophilia, and diarrhea can occur. Acute infection causes eosinophilia and sometimes rash or cough. In immunosuppressed patients, hyperinfection (a dramatic increase in the worm burden) and dissemination can occur, causing abdominal pain, diarrhea, polymicrobial sepsis, bronchopneumonia, or meningitis. Hyperinfection risk is highest in patients receiving corticosteroids or cancer chemotherapeutics, and in those coinfected with human T-cell lymphotropic virus.
      Uncomplicated strongyloidiasis should be treated with oral ivermectin, which cures 70% to 85% of chronically infected patients (Table 2).
      • Igual-Adell R
      • Oltra-Alcaraz C
      • Soler-Company E
      • Sanchez-Sanchez P
      • Matogo-Oyana J
      • Rodriguez-Calabuig D
      Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis.
      This monocyclic lactone binds chloride channels in helminth nerve and muscle cells, resulting in paralysis and death. Ivermectin is well tolerated, only rarely causing nausea, diarrhea, hepatitis, or dizziness when used for intestinal nematodes. Resistance is rare. Less effective alternatives include thiabendazole and albendazole.
      • Marti H
      • Haji HJ
      • Savioli L
      • et al.
      A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children.
      Hyperinfection or disseminated strongyloidiasis should be treated with oral ivermectin, usually in prolonged courses.
      • Keiser PB
      • Nutman TB
      Strongyloides stercoralis in the immunocompromised population.
      Experimental use of veterinary parenteral ivermectin has been successful in treating disseminated strongyloidiasis.
      • Turner SA
      • Maclean JD
      • Fleckenstein L
      • Greenaway C
      Parenteral administration of ivermectin in a patient with disseminated strongyloidiasis.
      • Marty FM
      • Lowry CM
      • Rodriguez M
      • et al.
      Treatment of human disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin.
      Patients have also been successfully treated with ivermectin plus albendazole.
      • Pornsuriyasak P
      • Niticharoenpong K
      • Sakapibunnan A
      Disseminated strongyloidiasis successfully treated with extended duration ivermectin combined with albendazole: a case report of intractable strongyloidiasis.
      Screening should be considered in anyone (particularly patients with current or impending immunosuppression) with any history of exposure to endemic areas, even if many years before. Due to the risk of hyperinfection, all patients infected with Strongyloides should be treated.

      Extraintestinal (Tissue) Nematodes

      Trichinellosis. Trichinellosis is caused by multiple species in the Trichinella genus, of which Trichinella spiralis is the best described. Infection results from eating undercooked meat containing Trichinella cysts (traditionally pork, but most US cases are now due to bear or other wild game meat). Symptoms include diarrhea, myositis, periorbital edema, conjunctivitis, fever, and eosinophilia. Rarely, patients can die of myocarditis or encephalitis. The benefit of antiparasitic therapy is uncertain, but most patients are treated with albendazole (or mebendazole) plus corticosteroids (Table 2).
      • Watt G
      • Saisorn S
      • Jongsakul K
      • Sakolvaree Y
      • Chaicumpa W
      Blinded, placebo-controlled trial of antiparasitic drugs for trichinosis myositis.
      Toxocariasis. Toxocariasis is usually caused by Toxocara canis or Toxocara cati. The eggs of T canis or T cati, which are the most common causes of toxocariasis, are passed in dog or cat (respectively) feces into the environment, where they become infectious after 3 to 4 weeks. Human infections, which result from ingesting eggs in contaminated soil, can be asymptomatic (covert toxocariasis) or present as a larva migrans syndrome. Visceral larva migrans (VLM) occurs most commonly in young children. It is usually asymptomatic but can cause cough, fever, and wheezing. Visceral larva migrans causes eosinophilia and often hepatomegaly; splenomegaly and lymphadenopathy are less common. It is usually self-limited, and treatment with antihelminthic agents is controversial. If antiparasitics are used, albendazole is the drug of choice (Table 2); alternatives include mebendazole, thiabendazole, ivermectin, or the piperazine diethylcarbamazine (DEC).
      • Sturchler D
      • Schubarth P
      • Gualzata M
      • Gottstein B
      • Oettli A
      Thiabendazole vs. albendazole in treatment of toxocariasis: a clinical trial.
      • Magnaval JF
      Comparative efficacy of diethylcarbamazine and mebendazole for the treatment of human toxocariasis.
      Corticosteroids are usually added in severe cases. Ocular larva migrans usually presents as a chorioretinal granuloma. Albendazole may be effective but in higher doses and longer courses than for VLM (Table 2).
      • Barisani-Asenbauer T
      • Maca SM
      • Hauff W
      • et al.
      Treatment of ocular toxocariasis with albendazole.
      Surgery is sometimes required.
      Filariasis. The filariae are vector-borne tissue nematodes generally found in residents of endemic areas, although travelers occasionally become infected.
      Lymphatic filariasis (LF) is caused by the mosquitoborne helminths Wuchereria bancrofti and Brugia species. More than 120 million people have LF, mainly in Southern Asia, sub-Saharan Africa, Oceania, and parts of Latin America. Adult worms reside in lymphatics and release microfilariae, which circulate nocturnally in the blood. These parasites harbor rickettsia-like Wolbachia endosymbionts, which female worms require to reproduce. Most patients have asymptomatic eosinophilia, but fever, adenolymphangitis, lymphedema, hydrocele, or elephantiasis can occur. Some patients develop tropical pulmonary eosinophilia, with nocturnal asthma, cough, fever, weight loss, and high-grade eosinophilia.
      Parasitemic patients should receive DEC. A 1-day course appears to be as effective as the traditional 12-day regimen (Table 2).
      • Centers for Disease Control and Prevention (CDC)
      Parasites—lymphatic filariasis: guidance for evaluation and treatment.
      Antiparasitic treatment in patients with lymphedema or elephantiasis who are not actively infected is controversial. Patients with tropical pulmonary eosinophilia should receive a 2- to 3-week course of DEC. Adverse effects include nausea, fever, asthma-like symptoms, and arthralgias. Therapy for all filarial infections may be associated with allergic-like reactions resulting from degenerating filariae and Wolbachia, for which anti-histamines and corticosteroids may be useful. Diethylcarbamazine kills microfilariae but has only modest activity against adult worms. It should not be given to persons from areas coendemic for onchocerciasis or Loa loa unless these infections have been excluded. Alternatives for LF include ivermectin and albendazole. Prolonged courses of doxycycline (which kills and sterilizes adult worms as a result of anti-Wolbachia activity) may have a role.
      • Hoerauf A
      Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis.
      Onchocerciasis, also known as river blindness, is caused by Onchocerca volvulus. Transmitted by Simulium blackflies, onchocerciasis is found in equatorial Africa and limited foci in Latin America and the Arabian Peninsula. Infection can cause dermatitis, subcutaneous nodules, keratitis, chorioretinitis, and blindness. Ivermectin is the treatment of choice (Table 2), although it kills only microfilariae, not adult worms.
      • Udall DN
      Recent updates on onchocerciasis: diagnosis and treatment.
      Ivermectin must be used with caution if coinfection with L loa is possible. The adverse effects of ivermectin include fever, rash, dizziness, pruritis, myalgias, arthralgias, and lymphadenopathy, mostly due to dying filariae and Wolbachia. Suramin is active against adult worms, but toxicity precludes use in most cases. Moxidectin, a drug in development that is closely related to ivermectin (but with higher potency), is also active against onchocerciasis.
      • Taylor MJ
      • Hoerauf A
      • Bockarie M
      Lymphatic filariasis and onchocerciasis.
      Prolonged doxycycline therapy may have a role because of its anti-Wolbachia activity. Diethylcarbamazine should not be administered to persons infected with onchocerciasis because blindness can result from the subsequent ocular inflammatory response.
      Loaiasis is caused by L loa, a helminth that is transmitted by Chrysops flies and is endemic to Central and West Africa. Adult worms migrate in subcutaneous tissues, and microfilariae circulate diurnally in the blood. L loa does not harbor Wolbachia. Most infected persons have asymptomatic eosinophilia; some have urticaria, Calabar swellings (migratory, subcutaneous, angioedematous lesions), and visible “eye worms” migrating across the conjunctivae. Hematuria, proteinuria, and encephalitis (usually precipitated by treatment) also occur. Diethylcarbamazine is effective against loaiasis, although multiple courses may be necessary (Table 2).
      • Padgett JJ
      • Jacobsen KH
      Loiasis: African eye worm.
      Treatment can cause pruritis, arthralgias, Calabar swellings, fever, eye worms, diarrhea, and renal failure. Patients with detectable microfilaremia (particularly >2500 microfilariae/mL) are at risk of treatment-associated encephalopathy, which may be ameliorated by pretreatment apheresis. Ivermectin is active against L loa, but albendazole (which acts more slowly) is associated with a lower risk of encephalopathy than DEC or ivermectin.
      • Klion AD
      • Massougbodji A
      • Horton J
      • et al.
      Albendazole in human loiasis: results of a double-blind, placebo-controlled trial.

      Other Tissue Nematodes

      Cutaneous Larva Migrans. Migration of dog and cat hookworms (eg, Ancylostoma braziliense) in the dermis can cause a serpiginous rash termed cutaneous larva migrans. The rash occurs after skin contact with infested soil and is usually seen on the lower extremities. Cutaneous larva migrans can be associated with eosinophilia or pulmonary infiltrates but is self-limited. Albendazole or ivermectin may hasten resolution (Table 2).
      • Albanese G
      • Venturi C
      • Galbiati G
      Treatment of larva migrans cutanea (creeping eruption): a comparison between albendazole and traditional therapy.
      Angiostrongylus cantonensis. Human infection with A cantonensis occur after ingesting snails, slugs, or leafy vegetables containing snails, slugs or slime trails with larvae. Endemic primarily to Asia and Oceania, infection can cause a prolonged (but usually self-limited) eosinophilic meningitis. Although antiparasitic therapy is controversial, albendazole plus corticosteroids is often used (Table 2).
      • Chotmongkol V
      • Wongjitrat C
      • Sawadpanit K
      • Sawanyawisuth K
      Treatment of eosinophilic meningitis with a combination of albendazole and corticosteroid.
      Baylisascaris procyonis. B procyonis (ie, raccoon roundworm) can rarely cause a form of VLM. Human infections result from contact with soil contaminated with raccoon feces. Severe meningoencephalitis can occur, usually in children. Treatment is not well defined, but albendazole plus corticosteroids has been used successfully (Table 2).
      • Pai PJ
      • Blackburn BG
      • Kazacos KR
      • Warrier RP
      • Begue RE
      Full recovery from Baylisascaris procyonis eosinophilic meningitis.
      Gnathostoma spinigerum. G spinigerum, which is acquired by eating undercooked freshwater fish, chicken, or pork, is the most common cause of gnathostomiasis. Although it is endemic primarily to Southeast Asia, infections also occur in Latin America and elsewhere. Symptoms include eosinophilia, migratory subcutaneous swellings, and (rarely) fulminant meningoencephalitis. Treatment is with albendazole or ivermectin (Table 2).
      • Nontasut P
      • Bussaratid V
      • Chullawichit S
      • Charoensook N
      • Visetsuk K
      Comparison of ivermectin and albendazole treatment for gnathostomiasis.
      Capillaria philippinensis. C philippinensis is the most common cause of capillariasis, which results from eating infected freshwater fish. Endemic primarily to Southeast Asia and the Middle East, the parasite inhabits the small bowel, causing diarrhea, malabsorption, and (uncommonly) fever and eosinophilia. As with Strongyloides, these helminths can multiply in humans, sometimes causing overwhelming infection. Mebendazole or albendazole can be life-saving (Table 2).
      • Cross JH
      Intestinal capillariasis.

      CONCLUSION

      A wide array of parasites infect humans, causing some of the most prevalent infectious diseases globally. Recent advances in the treatment of malaria, leishmaniasis, and Chagas disease have brought needed improvements to the management of these diseases. Helminth infections are managed with a smaller pharmaceutical armamentarium than protozoal infections, but good treatment options are now available for many trematode, intestinal cestode, and intestinal nematode infections. Despite a relatively narrow therapeutic pipeline for new antiparasitic drugs, there have been significant improvements in the treatment of these widespread infections in the past 2 decades.

      CME Materials

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