Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 50
Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections

Humans host a wide variety of protozoal parasites that can be transmitted by insect vectors, directly from other mammalian reservoirs or from one person to another. The immune system plays a crucial role in protecting against the pathological consequences of protozoal infections. Thus, opportunistic infections with protozoa are prominent in infants, individuals with cancer, transplant recipients, those receiving immunosuppressive drugs or extensive antibiotic therapy, and persons with advanced human immunodeficiency virus (HIV) infection. Because effective vaccines are unavailable, chemotherapy has been the only practical way to both treat infected individuals and reduce transmission. Many effective antiprotozoal drugs are toxic at therapeutic doses, a problem exacerbated by increasing drug resistance.

INTRODUCTION TO PROTOZOAL INFECTIONS OF HUMANS

AMEBIASIS. Amebiasis affects ~10% of the world’s population, commonly individuals living in poverty, crowded conditions, and areas with poor sanitation. Three morphologically identical but genetically distinct species of Entamoeba (i.e., E. histolytica, E. dispar, and E. moshkovskii) have been isolated from infected persons, with E. histolytica responsible for ~10% of human infections. Only E. histolytica causes disease and requires treatment.

Humans are the only known hosts for these protozoa, which are transmitted almost exclusively by the fecal-oral route. Ingested E. histolytica cysts from contaminated food or water survive acid gastric contents and transform into trophozoites that reside in the large intestine. The outcome of E. histolytica infection is variable. Many individuals remain asymptomatic but excrete the infectious cyst form, making them a source for further infections. In other individuals, E. histolytica trophozoites invade into the colonic mucosa with resulting colitis and bloody diarrhea (amebic dysentery). In a smaller proportion of patients, E. histolytica trophozoites invade through the colonic mucosa, reach the portal circulation, and travel to the liver, where they establish an amebic liver abscess.

The cornerstone of therapy for amebiasis is metronidazole or its analogs tinidazole and ornidazole. Because metronidazole is so well absorbed in the gut, levels may not be therapeutic in the colonic lumen, and the drug is less effective against cysts. Hence patients with amebiasis (amebic colitis or amebic liver abscess) also should receive a luminal agent to eradicate any E. histolytica trophozoites residing within the gut lumen. Luminal agents are also used to treat asymptomatic individuals found to be infected with E. histolytica. The nonabsorbed aminoglycoside paromomycin and the 8-hydroxyquinoline compound iodoquinol are effective luminal agents. Diloxanide furoate, previously considered the luminal agent of choice for amebiasis, is no longer available in the U.S. Nitazoxanide (ALINIA), approved in the U.S. for treatment of cryptosporidiosis and giardiasis, is also active against E. histolytica.

GIARDIASIS. Giardiasis, caused by the flagellated protozoan Giardia intestinalis, is prevalent worldwide and is the most commonly reported intestinal protozoal infection in the U.S. Infection results from ingestion of the cyst form of the parasite, which is found in fecally contaminated water or food.

Infection with Giardia results in 1 of 3 syndromes: an asymptomatic carrier state, acute self-limited diarrhea, or chronic diarrhea. Chemotherapy with a 5-day course of metronidazole usually is successful, although therapy may have to be repeated or prolonged in some instances. A single dose of tinidazole (TINDAMAX, others) probably is superior to metronidazole for the treatment of giardiasis. Paromomycin(HUMATIN, others) has been used to treat pregnant women to avoid any possible mutagenic effects of the other drugs. Nitazoxanide (ALINIA), N-(nitrothiazolyl) salicylamide, and tinidazole are approved for the treatment of giardiasis in immune-competent children <12 years of age. Furazolidone has been discontinued in the U.S.

TRICHOMONIASIS. Trichomoniasis is caused by the flagellated protozoan Trichomonas vaginalis. This organism inhabits the genitourinary tract of the human host, where it causes vaginitis in women and, uncommonly, urethritis in men. Trichomoniasis is a sexually transmitted disease and has been associated with an increased risk of acquiring HIV infection. Only trophozoite forms of T. vaginalis have been identified in infected secretions.

Metronidazole remains the drug of choice for the treatment of trichomoniasis. Tinidazole, another nitroimidazole, appears to be better tolerated than metronidazole and has been used successfully at higher doses to treat metronidazole-resistant T. vaginalis.

TOXOPLASMOSIS. Toxoplasmosis is a zoonotic infection caused by Toxoplasma gondii. Although cats and other feline species are the natural hosts, tissue cysts (bradyzoites) have been recovered from all mammalian species examined. Common routes of infection in humans are:

• Ingestion of undercooked meat containing tissue cysts

• Ingestion of contaminated vegetable matter containing infective oocysts

• Direct oral contact with feces of cats shedding oocysts

• Transplacental fetal infection with tachyzoites from acutely infected mothers

The acute illness is usually self-limiting, and treatment rarely is required. Individuals who are immunocompromised, however, are at risk of developing toxoplasmic encephalitis from reactivation of tissue cysts deposited in the brain. The primary treatment for toxoplasmic encephalitis consists of the antifolates pyrimethamine (DARAPRIM) and sulfadiazine along with folinic acid (leucovorin). Therapy must be discontinued in ~40% of cases because of toxicity owing primarily to the sulfa compound; clindamycin can be substituted for sulfadiazine without loss of efficacy. Alternative regimens combining azithromycin, clarithromycin, atovaquone, or dapsone with either trimethoprim-sulfamethoxazole or pyrimethamine and folinic acid are less toxic but also less effective. Spiramycin, which concentrates in placental tissue, is used for the treatment of acute acquired toxoplasmosis in pregnancy to prevent transmission to the fetus. If fetal infection is detected, the combination of pyrimethamine, sulfadiazine, and folinic acid is administered to the mother (only after the first 12-14 weeks of pregnancy) and to the newborn in the postnatal period. Spiramycin is not available in the U.S.

CRYPTOSPORIDIOSIS. Cryptosporidia are coccidian protozoan parasites that can cause diarrhea. Cryptosporidium parvum and the newly named C. hominis appear to account for almost all infections in humans. Infectious oocysts in feces may be spread either by direct human-to-human contact or by contaminated water supplies.

After ingestion, the mature oocyte is digested, releasing sporozoites that invade host epithelial cells. In most individuals, infection is self-limited. However, in AIDS patients and other immunocompromised individuals, the severity of diarrhea may require hospitalization. The most effective therapy for cryptosporidiosis in AIDS patients is restoration of their immune function through highly active antiretroviral therapy (HAART) (see Chapter 59). Nitazoxanide has shown activity in treating cryptosporidiosis in immunocompetent children and is possibly effective in immunocompetent adults. Its efficacy in children and adults with HIV infection and AIDS is not clearly established.

TRYPANOSOMIASIS. African trypanosomiasis, or “sleeping sickness,” is caused by subspecies of the hemoflagellate Trypanosoma brucei that are transmitted by bloodsucking tsetse flies of the genus Glossina. Largely restricted to sub-Saharan Africa, the infection causes serious human illness and also threatens livestock (nagana), leading to protein malnutrition. In humans, the infection is fatal unless treated. An estimated 500,000 Africans carry the infection, and >50 million people are at risk for the disease.

The parasite is entirely extracellular, and early human infection is characterized by the finding of replicating parasites in the bloodstream or lymph without CNS involvement (stage 1); stage 2 disease is characterized by CNS involvement. Symptoms of early-stage disease include febrile illness, lymphadenopathy, splenomegaly, and occasional myocarditis that result from systemic dissemination of the parasites. There are 2 types of African trypanosomiasis: the East African (Rhodesian; T. brucei rhodesiense) variety produces a progressive and rapidly fatal form of disease marked by early involvement of the CNS and frequent terminal cardiac failure; the West African type (Gambian; T. brucei gambiense) causes illness characterized by later involvement of the CNS and a more long-term course that progresses to the classical symptoms of sleeping sickness over months to years. Neurological symptoms include confusion, sensory deficits, psychiatric signs, disruption of the sleep cycle, and eventual progression into coma and death.

Standard therapy for early-stage disease is pentamidine for T. brucei gambiense and suramin for T. brucei rhodesiense. Both compounds must be given parenterally over long periods and are not effective against late-stage disease. The CNS phase has traditionally been treated with melarsoprol (available from the CDC), a highly toxic agent that causes a fatal reactive encephalopathy in 2-10% of treated patients. Moreover, lack of response to this agent is leading to increasing numbers of treatment failures. Eflornithine, an inhibitor of ornithine decarboxylase, a key enzyme in polyamine metabolism, offers the only alternative for the treatment of late-stage disease. It has efficacy against both early and late stages of human T. brucei gambiense infection; however, it is ineffective as monotherapy for infections ofT. brucei rhodesiense. Notably, eflornithine has significantly fewer side effects than melarsoprol and is more effective than melarsoprol for treatment of late-stage Gambian trypanosomiasis, suggesting that eflornithine is the best available first-line treatment for this form of the disease. Nifurtimox-eflornithine combination therapy (NECT) allows a shorter exposure to eflornithine with good efficacy and a reduction in adverse events.

American trypanosomiasis, or Chagas disease, a zoonotic infection caused by Trypanosoma cruzi, affects ~15 million people from Mexico to Argentina and Chile. The chronic form of the disease in adults is a major cause of cardiomyopathy, megaesophagus, megacolon, and death. Blood-sucking triatomid bugs infesting poor rural dwellings most commonly transmit this infection to young children; transplacental transmission also may occur in endemic areas. Two nitroheterocyclic drugs, nifurtimox (available from the CDC) and benznidazole are used to treat this infection. Both agents suppress parasitemia and can cure the acute phase of Chagas disease in 60-80% of cases; both drugs are toxic and must be taken for long periods.

LEISHMANIASIS. Leishmaniasis is a complex vector-borne zoonosis caused by ~20 different species of intramacrophage protozoa of the genus Leishmania. Small mammals and canines generally serve as reservoirs for these pathogens, which can be transmitted to humans by the bites of female phlebotomine sandflies.

In increasing order of systemic involvement and potential clinical severity, major syndromes of human leishmaniasis have been classified into cutaneous, mucocutaneous, diffuse cutaneous, and visceral(kala azar) forms. Cutaneous forms of leishmaniasis generally are self-limiting, with cures occurring in 3-18 months after infection. However, this form of the disease can leave disfiguring scars. The mucocutaneous, diffuse cutaneous, and visceral forms of the disease do not resolve without therapy. Visceral leishmaniasis caused by L. donovani is fatal unless treated. The classic therapy for all species ofLeishmania is pentavalent antimony (sodium antimony gluconate; sodium stibogluconate; PENTOSTAM); resistance to this compound is widespread in India, although it remains useful in other parts of the world. As an alternative, liposomal amphotericin B is a highly effective agent for visceral leishmaniasis, and it is currently the drug of choice for antimony-resistant disease. Treatment of leishmania has undergone major changes owing to the success of the first orally active agent, miltefosine. The drug also appears to have promise for the treatment of the cutaneous disease and for the treatment of dogs, an important animal reservoir of the disease. Paromomycin has been used with success as a parenteral agent for visceral disease, and topical formulations of paromomycin have efficacy against cutaneous disease.

OTHER PROTOZOAL INFECTIONS. Just a few of the many less common protozoal infections of humans are highlighted here.

Babesiosis, caused by either Babesia microti or B. divergens, is a tick-borne zoonosis that superficially resembles malaria in that the parasites invade erythrocytes, producing a febrile illness, hemolysis, and hemoglobinuria. This infection usually is mild and self-limiting but can be severe or even fatal in asplenic or severely immunocompromised individuals. Currently recommended therapy is with a combination of clindamycin and quinine for severe disease, and the combination of azithromycin and atovaquone for mild or moderate infections.

Balantidiasis, caused by the ciliated protozoan Balantidium coli, is an infection of the large intestine that may be confused with amebiasis. Unlike amebiasis, this infection usually responds to tetracyclinetherapy.

Isospora belli, a coccidian parasite, causes diarrhea in AIDS patients and responds to treatment with trimethoprim-sulfamethoxazole. Cyclospora cayetanensis causes self-limited diarrhea in normal hosts and can cause prolonged diarrhea in individuals with AIDS.

Microsporidia are spore-forming unicellular eukaryotic fungal parasites that can cause a number of disease syndromes, including diarrhea in immunocompromised individuals. Infections with microsporidia have been treated successfully with albendazole, an inhibitor of β-tubulin polymerization (see Chapter 51). Immunocompromised individuals with intestinal microsporidiosis due to E. bieneusi (which does not respond as well to albendazole) have been treated successfully with the antimicrobial fumagillin.

ANTIPROTOZOAL DRUGS

For ease of reference, the myriad agents used to treat nonmalarial protozoal diseases are presented alphabetically.

AMPHOTERICIN B

The pharmacology, formulation, and toxicology of amphotericin B are presented in Chapter 57.

Antiprotozoal Effects. Amphotericin B (AMBISOME) is a highly effective antileishmanial agent that cures >90% of the cases of visceral leishmaniasis and is the drug of choice for antimonial-resistant cases. It is a second-line drug for cutaneous or mucosal leishmaniasis, where it has been shown effective for the treatment of immunocompromised patients. The lipid preparations of the drug have reduced toxicity, but the cost of the drug and the difficulty of administration remain a problem in endemic regions.

Mechanism of Action. The basis of amphotericin B action against leishmania is similar to that for the drug’s antifungal activities (see Chapter 57). Amphotericin complexes with ergosterol precursors in the cell membrane, forming pores that allow ions to enter the cell. Leishmania has similar sterol composition to fungal pathogens, and the drug binds to these sterols preferentially over the host cholesterol. No significant resistance to the drug has been encountered after nearly 30 years of use as an antifungal agent.

Therapeutic Uses. Typical regimens of 10-20 mg/kg total dose given in divided doses over 10-20 days by intravenous infusion have yielded >95% cure rates. In the U.S., the FDA recommends 3 mg/kg intravenously on days 1-5, 14, and 21 for a total dose of 21 mg/kg. Recent data suggest that a single dose of 5 mg/kg followed by 7-14 days treatment with oral miltefosine was effective at curing visceral leishmaniasis, and this dosing scheme warrants additional study.

CHLOROQUINE

The pharmacology and toxicology of chloroquine are presented in Chapter 49 (antimalarials). Chloroquine does have an FDA-approved use for extra-intestinal amebiasis at a dose of 1 g (600 mg base) daily for 2 days, followed by 500 mg daily for at least 2-3 weeks. Treatment is usually combined with an effective intestinal amebicide.

DILOXANIDE FUROATE

Diloxanide furoate (FURAMIDE, others) is a derivative of dichloroacetamide. Diloxanide furoate is a very effective luminal agent for the treatment of E. histolytica infection but is no longer available in the U.S.

EFLORNITHINE

Eflornithine (α-D,L difluoromethylornithine, DFMO, ORNIDYL) is an irreversible catalytic (suicide) inhibitor of ornithine decarboxylase, the enzyme that catalyzes the first and rate-limiting step in the biosynthesis of polyamines (putrescine, spermidine, and spermine) that are required for cell division and for normal cell differentiation. In trypanosomes, spermidine is required for the synthesis of trypanothione, a conjugate of spermidine and glutathione that replaces many of the functions of glutathione in the parasite.

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Eflornithine currently is used to treat West African (Gambian) trypanosomiasis caused by T. brucei gambiense; the drug is largely ineffective for East African trypanosomiasis. Eflornithine’s difficult treatment regimen limits its use. Eflornithine is no longer available for systemic use in the U.S. but is available for treatment of Gambian trypanosomiasis by special request from the CDC. Eflornithine is safer and more efficacious than melarsoprol for late-stage gambiense sleeping sickness, and is the recommended first-line treatment for this disease when adequate care can be provided for its administration.

Antitrypanosomal Effects. Eflornithine is a cytostatic agent that has multiple biochemical effects on trypanosomes, all of which are a consequence of polyamine depletion. The parasite and human enzymes are equally susceptible to inhibition by eflornithine; however, the mammalian enzyme is turned over rapidly, whereas the parasite enzyme is stable, and this difference likely plays a role in the selective toxicity. T. brucei rhodesiense cells are less sensitive to eflornithine inhibition than T. brucei gambiense cells; studies in vitro suggest that the effective doses are increased by 10-20 times in the refractory cells. The molecular basis for the higher dose requirement in T. brucei rhodesiense is not understood.

ADME. Eflornithine is given by intravenous infusion. The drug does not bind to plasma proteins but is well distributed and penetrates into the CSF, where estimated concentrations of at least 50 μM must be reached to clear well distributed and penetrates into the CSF. Renal clearance after intravenous administration is rapid (2 mL/min/kg), with >80% of the drug cleared by the kidney largely in unchanged form. Some studies indicate that suramin enhances eflornithine uptake into the CNS and could lower the dose requirements for eflornithine.

Therapeutic Uses. Eflornithine is used for the treatment of late-stage West African trypanosomiasis caused by T. brucei gambiense. The preferred regimen for adult patients is 100 mg/kg given intravenously every 6 h as a 2-h infusion for 14 days. Response rates exceed 90% in the late-stage patients. Children (<12 years of age) receive higher doses of eflornithine (150 mg/kg given intravenously every 6 h for 14 days) based on prior findings that eflornithine trough concentrations in both the CSF and blood were significantly lower among children than in adults. The treatment course for eflornithine has been reduced to 7 days in combination with nifurtimox. This combination protocol, NECT, uses a shortened course of eflornithine with oral nifurtimox, with dosing as follows: 400 mg/kg/day given intravenously every 12 h by 2-h infusion for 7 days plus nifurtimox (orally at 15 mg/kg/day in 3 divided doses [every 8 h]) for 10 days. Eflornithine is less successful for treating AIDS patients with West African trypanosomiasis, presumably because host defenses play a critical role in clearing drug-treated T. brucei gambiense from the bloodstream.

Toxicity and Side Effects. Eflornithine causes adverse reactions that are generally reversible on withdrawal of the drug. Abdominal pain and headache are the predominant complaints, followed by reactions at the injection sites. Tissue infections and pneumonia are also observed. The most severe reactions reported include fever peaks (6%), seizures (4%), and diarrhea (2%). The case fatality rate for eflornithine (~1.2%) is significantly lower than for melarsoprol (4.9%), and overall eflornithine is superior to melarsoprol with respect to both safety and efficacy. Reversible hearing loss can occur after prolonged therapy with oral doses. Therapeutic doses of eflornithine are large and require coadministration of substantial volumes of intravenous fluid. This poses significant practical limitations in remote settings and can cause fluid overload in susceptible patients.

FUMAGILLIN

Fumagillin (FUMIDIL B, others) is an acyclic polyene macrolide. Fumagillin and its synthetic analog TNP-470 are toxic to microsporidia.

Fumagillin is used topically to treat keratoconjunctivitis caused by E. hellem at a dose of 3-10 mg/mL in a balanced salt suspension. For the treatment of intestinal microsporidiosis caused by E. bieneusi, fumagillin is used at a dose of 20 mg orally 3 times daily for 2 weeks. Adverse effects of fumagillin may include abdominal cramps, nausea, vomiting, and diarrhea. Reversible thrombocytopenia and neutropenia also have been reported. Fumagillin has not been approved for the systemic treatment of microsporidia infection in the U.S.

Fumagillin is used widely to treat the microsporidian Nosema apis, a pathogen of honey bees. Fumagillin and TNP-470 also inhibit angiogenesis and suppress tumor growth. TNP-470 is undergoing clinical trials as an anticancer agent (see Chapter 61). Human methionine-aminopeptidase-2 (MetAP2) is the target for the drugs’ antitumor activity, and a gene encoding MetAP2 has been identified in the genome of the microsporidian parasite E. cuniculi.

8-HYDROXYQUINOLINES

The halogenated 8-hydroxyquinolines iodoquinol (diiodohydroxyquin) and clioquinol (iodochlorhydroxyquin) have been used as luminal agents to eliminate intestinal colonization with E. histolytica.

Iodoquinol (YODOXIN) is the safer and is the only one available for use as an oral agent in the U.S. When used at appropriate doses (never to exceed 2 g/day and duration of therapy not greater than 20 days in adults), adverse effects are unusual. However, the use of these drugs, especially at doses exceeding 2 g/day for long periods carries significant risk. The most important toxic reaction, ascribed primarily to clioquinol, is subacute myelo-optic neuropathy. Peripheral neuropathy is a less severe manifestation of neurotoxicity owing to these drugs. Administration of iodoquinol in high doses to children with chronic diarrhea has been associated with optic atrophy and permanent loss of vision.

Because of its superior adverse-event profile, paromomycin is preferred as the luminal agent for amebiasis; however, iodoquinol is a reasonable alternative. Iodoquinol is used in combination with metronidazole to treat individuals with amebic colitis or amebic liver abscess but may be used as a single agent for asymptomatic individuals found to be infected with E. histolytica. For adults, the recommended dose of iodoquinol is 650 mg orally 3 times daily for 20 days, whereas children receive 10 mg/kg of body weight orally 3 times a day (not to exceed 1.95 g/day) for 20 days.

MELARSOPROL

Despite the fact that it causes an often fatal encephalopathy in 2-10% of the patients, melarsoprol is the only drug for the treatment of late (CNS) stages of East African trypanosomiasis caused by T. brucei rhodesiense. Although melarsoprol is also effective against late-stage West African trypanosomiasis caused by T. brucei gambiense, eflornithine has become the first-line treatment for this disease. The continued use of melarsoprol in the field is indicative of the paucity of alternative therapies for late-stage sleeping sickness.

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Melarsoprol (MEL B; ARSOBAL) is supplied as a 3.6% (w/v) solution in propylene glycol for intravenous administration. It is available in the U.S. only from the CDC.

Mechanism of Action; Antiprotozoal Effects. Melarsoprol is metabolized to melarsen oxide, the active drug. Arsen-oxides react avidly and reversibly with vicinal sulfhydryl groups and thereby inactivate many enzymes. Melarsoprol reacts with trypanothione, the spermidine-glutathione adduct that substitutes for glutathione in these parasites. Binding of melarsoprol to trypanothione results in a melarsen oxide-trypanothione adduct that inhibits trypanothione reductase. Both the sequestering of trypanothione and the inhibition of trypanothione reductase would have lethal consequences to the cell; however, this mode of action remains unproven. Treatment failure owing to resistance of trypanosomes to melarsoprol has risen sharply and some of the resistant strains are an order of magnitude less sensitive to the drug. Resistance to melarsoprol likely involves transport defects. The adenine-adenosine transporter termed the P2 transporter is 1 example. It has activity on melarsoprol as well as pentamidine and berenil; point mutations in this transporter are found in melarsoprol-resistant isolates. Another transporter, HAPT1, has been identified, and the concomitant loss of both the P2 and HAPT transporters led to high-level cross-resistance to both melarsen and pentamidine.

ADME. Melarsoprol is always administered by slow intravenous injection, with care to avoid leakage into the surrounding tissues because the drug is intensely irritating. Melarsoprol is a prodrug and is metabolized rapidly (t1/2 = 30 min) to melarsen oxide, the active form of the drug. A small but therapeutically significant amount of the drug enters the CSF and has a lethal effect on trypanosomes infecting the CNS. The compound is excreted rapidly, with 70-80% of the arsenic appearing in the feces.

Therapeutic Uses. Melarsoprol is the only effective drug available for treatment of the late meningoencephalitic stage of East African (Rhodesian) trypanosomiasis, which is 100% fatal if untreated. The drug is also effective in the early hemolymphatic stage of these infections, but because of its toxicity, it is reserved for therapy of late-stage infections. Patients infected with T. brucei rhodesiense who relapse after a course of melarsoprol usually respond to a second course of the drug. In contrast, patients infected with T. brucei gambiense who are not cured with melarsoprol rarely benefit from repeated treatment with this drug. Such patients often respond well to eflornithine.

For T. brucei gambiense a continuous 10-day course of 2.2 mg/kg/day is equivalent to the longer course treatment and is now recommended. For T. brucei rhodesiense, the CDC recommends 3 series of 3 daily doses with a 7-day rest period between series. The first series gives 1.8, 2.7, and 3.6 mg/kg on days 1, 2, and 3, respectively. The subsequent series are 3.6 mg/kg daily. Encephalopathy develops more frequently in patients with T. brucei rhodesiense compared to T. brucei gambiense. Concurrent administration of prednisolone is frequently employed throughout the treatment course.

Toxicity and Side Effects. Treatment with melarsoprol is associated with significant toxicity and morbidity. A febrile reaction often occurs soon after drug injection, especially if parasitemia is high. The most serious complications involve the nervous system. A reactive encephalopathy occurs 9-11 days after treatment starts in ~5-10% of patients, leading to death in about half of these. Peripheral neuropathy occurs in ~10% of patients receiving melarsoprol. Hypertension and myocardial damage are not uncommon, although shock is rare. Albuminuria occurs frequently, and evidence of renal or hepatic damage may necessitate modification of treatment. Vomiting and abdominal colic also are common, but their incidence can be reduced by injecting melarsoprol slowly into the supine, fasting patient.

Precautions and Contraindications. Melarsoprol should be given only to patients under hospital supervision. Initiation of therapy during a febrile episode has been associated with an increased incidence of reactive encephalopathy. Administration of melarsoprol to leprous patients may precipitate erythema nodosum. Use of the drug is contraindicated during epidemics of influenza. Severe hemolytic reactions have been reported in patients with deficiency of glucose-6-phosphate dehydrogenase. The drug may be used in pregnancy.

METRONIDAZOLE

Metronidazole and related nitroimidazoles are active in vitro against a wide variety of anaerobic protozoal parasites and anaerobic bacteria. Metronidazole is clinically effective in trichomoniasis, amebiasis, and giardiasis, as well as in a variety of infections caused by obligate anaerobic bacteria, including Bacteroides, Clostridium, and microaerophilic bacteria such as Helicobacter and Campylobacter spp. Metronidazole manifests antibacterial activity against all anaerobic cocci and both anaerobic gram-negative bacilli, includingBacteroides spp., and anaerobic spore-forming gram-positive bacilli. Nonsporulating gram-positive bacilli often are resistant, as are aerobic and facultatively anaerobic bacteria.

MECHANISM OF ACTION AND RESISTANCE. Metronidazole is a prodrug requiring reductive activation of the nitro group by susceptible organisms. Unlike their aerobic counterparts, anaerobic and microaerophilic pathogens (e.g., the amitochondriate protozoa T. vaginalis, E. histolytica, and G. lamblia and various anaerobic bacteria) contain electron transport components that have a sufficiently negative redox potential to donate electrons to metronidazole. The single electron transfer forms a highly reactive nitro radical anion that kills susceptible organisms by radical-mediated mechanisms that target DNA. Metronidazole is catalytically recycled; loss of the active metabolite’s electron regenerates the parent compound. Increasing levels of O2 inhibit metronidazole-induced cytotoxicity because O2competes with metronidazole for electrons generated by energy metabolism. Thus, O2 can both decrease reductive activation of metronidazole and increase recycling of the activated drug. Anaerobic or microaerophilic organisms susceptible to metronidazole derive energy from the oxidative fermentation of ketoacids such as pyruvate. Pyruvate decarboxylation, catalyzed by pyruvate-ferredoxin oxidoreductase (PFOR), produces electrons that reduce ferredoxin, which, in turn, catalytically donates its electrons to biological electron acceptors or to metronidazole.

Clinical resistance to metronidazole is well documented for T. vaginalis, G. lamblia, and a variety of anaerobic and microaerophilic bacteria. Resistance correlates with impaired oxygen-scavenging capabilities, leading to higher local O2 concentrations, decreased activation of metronidazole, and futile recycling of the activated drug. Other resistant strains have lowered levels of PFOR and ferredoxin, perhaps explaining why they may still respond to higher doses of metronidazole. In the case of Bacteroides spp., metronidazole resistance has been linked to a family of nitroimidazole (nim) resistance genes that can be encoded chromosomally or episomally. These nim genes appear to encode a nitroimidazole reductase capable of converting a 5-nitroimidazole to a 5-aminoimidazole, thus stopping the formation of the reactive nitroso group responsible for microbial killing.

ADME. Preparations of metronidazole are available for oral, intravenous, intravaginal, and topical administration. The drug usually is absorbed completely and promptly after oral intake and distributed to a volume approximating total body water; less than 20% of the drug is bound to plasma proteins. A linear relationship between dose and plasma concentration pertains for doses of 200-2000 mg. Repeated doses every 6-8 h result in some accumulation of the drug. The t1/2 of metronidazole in plasma is ~8 h. With the exception of the placenta, metronidazole penetrates well into body tissues and fluids, including vaginal secretions, seminal fluid, saliva, breast milk, and CSF. After an oral dose, >75% of labeled metronidazole is eliminated in the urine, largely as metabolites formed by the liver from oxidation of the drug’s side chains, a hydroxy derivative and an acid; ~10% is recovered as unchanged drug. Two principal metabolites result. The hydroxy metabolite has a longer t1/2 (~12 h) and has ~50% of the antitrichomonal activity of metronidazole. Formation of glucuronides also is observed. Small quantities of reduced metabolites are formed by the gut flora. The urine of some patients may be reddish brown owing to the presence of unidentified pigments derived from the drug. Oxidative metabolism of metronidazole is induced by phenobarbital, prednisone, rifampin, and possibly ethanol and is inhibited by cimetidine.

THERAPEUTIC USES. Metronidazole cures genital infections with T. vaginalis in both in >90% of cases. The preferred treatment regimen is 2 g metronidazole as a single oral dose for both males and females. Tinidazole, which has a longer t1/2 than metronidazole, is also used at a 2-g single dose and appears to provide equivalent or better responses. When repeated courses or higher doses of the drug are required for uncured or recurrent infections, it is recommended that intervals of 4-6 weeks elapse between courses. Leukocyte counts should be carried out before, during, and after each course of treatment. Treatment failures owing to the presence of metronidazole-resistant strains of T. vaginalis are becoming increasingly common. Most of these cases can be treated successfully by giving a second 2-g dose to both patient and sexual partner. In addition to oral therapy, the use of a topical gel containing 0.75% metronidazole or a 500- to 1000-mg vaginal suppository may be beneficial in refractory cases.

Metronidazole is the agent of choice for the treatment of all symptomatic forms of amebiasis, including amebic colitis and amebic liver abscess. The recommended dose is 500-750 mg metronidazole taken orally 3 times daily for 7-10 days, or for children, 35-50 mg/kg/day given in 3 divided doses for 7-10 days. Amebic liver abscess has been treated successfully by short courses (2.4 g daily as a single oral dose for 2 days) of metronidazole or tinidazole. E. histolytica persist in most patients who recover from acute amebiasis after metronidazole therapy, so it is recommended that all such individuals also be treated with a luminal amebicide. Although effective for the therapy of giardiasis, metronidazole has yet to be approved for treatment of this infection in the U.S. However, tinidazole is approved for the treatment of giardiasis as a single 2-g dose and is appropriate first-line therapy.

Metronidazole is a relatively inexpensive and versatile drug with efficacy against a broad spectrum of anaerobic and microaerophilic bacteria. It is used for the treatment of serious infections owing to susceptible anaerobic bacteria, including Bacteroides, Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus, Eubacterium, and Helicobacter. The drug is also given in combination with other antimicrobial agents to treat polymicrobial infections with aerobic and anaerobic bacteria. Metronidazole achieves clinically effective levels in bones, joints, and the CNS. It can be given intravenously when oral administration is not possible. Metronidazole is used as a component of prophylaxis for colorectal surgery and is employed as a single agent to treat bacterial vaginosis. It is used in combination with other antibiotics and a proton pump inhibitor in regimens to treat infection with H. pylori (see Chapter 45). Metronidazole is used as primary therapy for Clostridium difficile infection, the major cause of pseudomembranous colitis. Metronidazole is also used in the treatment of patients with Crohn disease who have perianal fistulas and colonic disease.

Toxicity, Contraindications, and Drug Interactions. Common side effects are headache, nausea, dry mouth, and a metallic taste. Vomiting, diarrhea, and abdominal distress are experienced occasionally. Dizziness, vertigo, and very rarely, encephalopathy, convulsions, incoordination, and ataxia are neurotoxic effects that warrant discontinuation of metronidazole. The drug also should be withdrawn if numbness or paresthesias of the extremities occur. Reversal of serious sensory neuropathies may be slow or incomplete. Urticaria, flushing, and pruritus are indicative of drug sensitivity that can require withdrawal of metronidazole. Metronidazole is a rare cause of Stevens-Johnson syndrome, which may be more common among individuals receiving high doses of metronidazole and concurrent therapy with the antihelminthic mebendazole. Dysuria, cystitis, and a sense of pelvic pressure have been reported. Metronidazole has a disulfiram-like effect, and some patients experience abdominal distress, vomiting, flushing, or headache if they drink alcoholic beverages during or within 3 days of therapy with this drug. Metronidazole and disulfiram or any disulfiram-like drug should not be taken together because confusional and psychotic states may occur. Metronidazole should be used cautiously in patients with active disease of the CNS because of potential neurotoxicity. The drug also may precipitate CNS signs of lithium toxicity in patients receiving high doses of lithium. Metronidazole can prolong the prothrombin time of patients receiving therapy with warfarin (COUMADIN) anticoagulants. The dosage of metronidazole should be reduced in patients with severe hepatic disease. Metronidazole use during the first trimester generally is not advised.

MILTEFOSINE

Miltefosine (IMPAVIDO) is an alkylphosphocholine (APC) analog developed originally as an anticancer agent. It is highly curative against visceral leishmaniasis and also appears to be effective against the cutaneous forms of the disease. Its main drawback is its teratogenicity; it must not be used in pregnant women.

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Antiprotozoal Effects. Miltefosine is the first orally available therapy for leishmaniasis. It is a safe and effective treatment for visceral leishmaniasis and has shown >90% efficacy against some species of cutaneous leishmaniasis. The mechanism of action of miltefosine is not yet understood. Studies in Leishmania suggest that the drug may alter ether-lipid metabolism, cell signaling, or glycosylphosphatidylinositol anchor biosynthesis. Mutations in a P-type ATPase that belongs to the aminophospholipid translocase subfamily apparently decrease drug uptake and confer drug resistance.

ADME. Miltefosine is well absorbed orally and distributed throughout the human body. Detailed pharmacokinetic data are lacking, with the exception that miltefosine has a long t1/2(1-4 weeks). Plasma concentrations are proportional to the dose.

Therapeutic Uses. Oral miltefosine is registered for use in India for the treatment of visceral leishmaniasis: for adults >25 kg, 100 mg daily divided into 2 parts, and for adults <25 kg, 50 mg daily in 1 dose for 28 days; for children, 2.5 mg/kg/day in 2 divided doses. In the U.S., the recommended dose for both visceral and cutaneous disease is 2.5 mg/kg/day (maximum dose of 150 mg/day) for 28 days, given in 2 divided doses. The compound cannot be given intravenously because it has hemolytic activity.

Toxicity and Side Effects. Vomiting and diarrhea have been reported as frequent side effects in up to 60% of the patients. Elevations in hepatic transaminases and serum creatinine also have been reported. These effects are typically mild and reversible. Because of its teratogenic potential, miltefosine is contraindicated in pregnant women.

NIFURTIMOX AND BENZNIDAZOLE

Nifurtimox and benznidazole are used to treat American trypanosomiasis caused by T. cruzi. Nifurtimox (Bayer 2502, LAMPIT), a nitrofuran analog, and benznidazole (Roche 7-1051, ROCHAGAN), a nitroimidazole analog, can be obtained in the U.S. from the CDC.

Antiprotozoal Effects and Mechanisms of Action. Nifurtimox and benznidazole are trypanocidal against both the trypomastigote and amastigote forms of T. cruzi. Nifurtimox also has activity against T. brucei and can be curative against both early- and late-stage disease (see earlier discussion on nifurtimox-eflornithine combination therapy). The trypanocidal effects of nifurtimox and benznidazole derive from their activation by a NADH-dependent mitochondrial nitroreductase to nitro radical anions that are thought to account for the trypanocidal effects. The generated nitro anion radicals form covalent attachments to macromolecules leading to cellular damage that includes lipid peroxidation and membrane injury, enzyme inactivation, and damage to DNA.

ADME. Nifurtimox is well absorbed after oral administration, with peak plasma levels observed after ~3.5 h. Less than 0.5% of the dose is excreted in urine. The elimination t1/2 is ~3 h. High concentrations of several unidentified metabolites are found, and nifurtimox undergoes rapid biotransformation, probably via a presystemic first-pass effect. Whether the metabolites have any trypanocidal activity is unknown.

Therapeutic Uses. Nifurtimox and benznidazole are employed in the treatment of American trypanosomiasis (Chagas disease) caused by T. cruzi. Because of toxicity, benznidazole is the preferred treatment. Both drugs markedly reduce the parasitemia, morbidity, and mortality of acute Chagas disease, with parasitological cures obtained in 80% of these cases. In the chronic form of the disease, parasitological cures are still possible in up to 50% of the patients, although the drug is less effective than in the acute stage. The clinical response of the acute illness to drug therapy varies with geographic region; parasite strains in Argentina, southern Brazil, Chile, and Venezuela appear to be more susceptible than those in central Brazil. The current recommendations are that patients <50 years of age with either acute- or recent chronic-phase disease, without advanced cardiomyopathy, should be treated. In patients >50 years of age, treatment is optional because of lowered drug tolerability. Therapy is strongly encouraged for patients who will receive immunosuppressive therapy or who are HIV positive. Therapy with nifurtimox or benznidazole should start promptly after exposure for persons at risk of T. cruzi infection from laboratory accidents or from blood transfusions.

Both drugs are given orally. For nifurtimox, adults (>17 years of age) with acute infection should receive 8-10 mg/kg/day in 3 to 4 divided doses for 90 days; children 1-10 years of age should receive 15-20 mg/kg/day in 3 to 4 divided doses for 90 days; for individuals 11-16 years old, the daily dose is 12.5-15 mg/kg given according to the same schedule. For benznidazole, the recommended treatment for adults (>13 years) is 5-7 mg/kg/day in 2 divided doses for 60 days, with children up to 12 years receiving 10 mg/kg/day. If gastric upset and weight loss occur during treatment, dosage should be reduced. The ingestion of alcohol should be avoided. Nifurtimox is used in combination with eflornithine in treating late stage T.b. gambiense sleeping sickness.

Toxicity and Side Effects. Side effects are common and range from hypersensitivity reactions (e.g., dermatitis, fever, icterus, pulmonary infiltrates, and anaphylaxis) to dose- and age-dependent complications primarily referable to the GI tract and both the peripheral and central nervous systems. Nausea and vomiting are common, as are myalgia and weakness. Peripheral neuropathy and GI symptoms are especially common after prolonged treatment; the latter complication may lead to weight loss and preclude further therapy. Because of the seriousness of Chagas disease and the lack of superior drugs, there are few absolute contraindications to the use of these drugs.

NITAZOXANIDE

Nitazoxanide (N-[nitrothiazolyl] salicylamide, ALINA) is an oral synthetic broad-spectrum antiparasitic agent (see Chapter 51). Nitazoxanide is FDA-approved for the treatment of cryptosporidiosis and giardiasis in children.

Antimicrobial Effects. Nitazoxanide and its active metabolite, tizoxanide (desacetyl-nitazoxanide), inhibit the growth of sporozoites and oocytes of C. parvum and inhibit the growth of the trophozoites of G. intestinalis, E. histolytica, and T. vaginalis in vitro. Nitazoxanide also demonstrated activity against intestinal helminths.

Mechanism of Action. Nitazoxanide interferes with the PFOR enzyme-dependent electron-transfer reaction, which is essential to anaerobic metabolism in protozoan and bacterial species.

ADME. Following oral administration, nitazoxanide is hydrolyzed rapidly to its active metabolite, tizoxanide, which undergoes conjugation to tizoxanide glucuronide. Bioavailability after an oral dose is excellent, and maximum plasma concentrations of the metabolites occur 1-4 h following administration. Tizoxanide is >99.9% bound to plasma proteins. Tizoxanide is excreted in the urine, bile, and feces; tizoxanide glucuronide is excreted in the urine and bile.

Therapeutic Uses. In the U.S., nitazoxanide is approved for the treatment of G. intestinalis infection (therapeutic efficacy of 85-90% for clinical response) and for the treatment of diarrhea caused by cryptosporidia (therapeutic efficacy, 56-88% for clinical response) in adults and children >1 year of age. The efficacy of nitazoxanide in children (or adults) with cryptosporidia infection and AIDS has not been clearly established. For children ages 12-47 months, the recommended dose is 100 mg nitazoxanide every 12 h for 3 days; for children ages 4-11 years, the dose is 200 mg nitazoxanide every 12 h for 3 days. A 500-mg tablet, suitable for adult dosing (every 12 h), is available. Nitazoxanide has been used as a single agent to treat mixed infections with intestinal parasites (protozoa and helminths). Effective parasite clearance after nitazoxanide treatment was shown for G. intestinalis, E. histolytica/E. dispar, B. hominis, C. parvum, C. cayetanensis, I. belli, H. nana, T. trichiura, A. lumbricoides, and E. vermicularis, although more than 1 course of therapy was required in some cases. Nitazoxanide has been used to treat infections with G. intestinalis that are resistant to metronidazole and albendazole.

Toxicity and Side Effects. Adverse effects appear are rare with nitazoxanide. A greenish tint to the urine is seen in most individuals taking nitazoxanide. Nitazoxanide is a pregnancy Category B agent, based on animal teratogenicity and fertility studies.

PAROMOMYCIN

Paromomycin (aminosidine, HUMATIN) is an aminoglycoside that is used as an oral agent to treat E. histolytica infection, cryptosporidiosis, and giardiasis. A topical formulation has been used to treat trichomoniasis; parenteral administration has been used for visceral leishmaniasis.

Mechanism of Action; ADME. Paromomycin shares the same mechanism of action as neomycin and kanamycin (binding to the 30S ribosomal subunit) and has the same spectrum of antibacterial activity. The drug is not absorbed from the GI tract and thus the actions of an oral dose are confined to the GI tract; 100% of the oral dose is recovered in the feces. Paromomycin is available only for oral use in the U.S.

Antimicrobial Effects; Therapeutics Uses. Paromomycin is the drug of choice for treating intestinal colonization with E. histolytica and is used in combination with metronidazole to treat amebic colitis and amebic liver abscess. Adverse effects are rare with oral usage but include abdominal pain and cramping, epigastric pain, nausea and vomiting, steatorrhea, and diarrhea. Rarely, rash and headache have been reported. Dosing in adults is 500 mg orally 3 times daily for 10 days, whereas children have been treated with 25-30 mg/kg/day in 3 divided oral doses. Paromomycin formulated as a 6.25% cream has been used to treat vaginal trichomoniasis in patients in whom metronidazole therapy has failed. Cures have been reported, but vulvovaginal ulcerations and pain can complicate treatment. Paromomycin is also efficacious as a topical formulation containing 15% paromomycin in combination with 12% methylbenzonium chloride for the treatment of cutaneous leishmaniasis. The drug has been administered parenterally alone or in combination with antimony to treat visceral leishmaniasis. Paromomycin has been advocated as a treatment for giardiasis in pregnant women, when metronidazole is contraindicated and as an alternative agent for metronidazole-resistant isolates of G. intestinalis.

PENTAMIDINE

Pentamidine is a positively charged aromatic diamine. It is a broad-spectrum agent with activity against several species of pathogenic protozoa and some fungi.

Pentamidine as the di-isethionate salt is marketed for injection (PENTAM 300, others) or for use as an aerosol (NEBUPENT). The di-isethionate salt is highly water soluble; however, solutions should be used promptly because pentamidine is unstable in solution.

Antiprotozoal and Antifungal Effects. Pentamidine is used for the treatment of early-stage T. brucei gambiense infection but is ineffective in the treatment of late-stage disease and has reduced efficacy against T. brucei rhodesiense. Pentamidine is an alternative agent for the treatment of cutaneous leishmaniasis. Pentamidine is an alternative agent for the treatment and prophylaxis of Pneumocystis pneumonia caused by Pneumocystis jiroveci. Diminazene (BERENIL) is a related diamidine that is used as an inexpensive alternative to pentamidine for the treatment of early African trypanosomiasis.

Mechanism of Action and Resistance. The mechanism of action of the diamidines is unknown. The compounds display multiple effects on any given parasite and act by disparate mechanisms in different parasites. Multiple transporters are responsible for pentamidine uptake, and this may account for the fact that little resistance to this drug is observed in field isolates despite its years of use as a prophylactic agent.

ADME. Pentamidine isethionate is fairly well absorbed from parenteral sites of administration. Following a single intravenous dose, the drug disappears from plasma with an apparent t1/2 of several minutes to a few h and maximum plasma concentrations after intramuscular injection occurring at 1 h. The t1/2 of elimination is long (weeks to months); the drug is 70% bound to plasma proteins. This highly charged compound is poorly absorbed orally and does not cross the blood-brain barrier, explaining its ineffectiveness against late-stage trypanosomiasis. Inhalation of pentamidine aerosols is used for prophylaxis of Pneumocystis pneumonia; delivery of drug by this route results in little systemic absorption and decreased toxicity compared with intravenous administration.

Therapeutic Uses. Pentamidine isethionate is used for the treatment of early-stage T. brucei gambiense and is given by intramuscular injection in single doses of 4 mg/kg/day for 7 days. Pentamidine has been used successfully in courses of 15-20 intramuscular doses of 4 mg/kg every other day to treat visceral leishmaniasis. This compound provides an alternative to antimonials, lipid formulations of amphotericin B, or miltefosine but it is overall the least well tolerated.

Pentamidine is one of several drugs or drug combinations used to treat or prevent Pneumocystis infection. Pneumocystis pneumonia (PCP) is a major cause of mortality in individuals with AIDS and can occur in patients who are immunosuppressed by other mechanisms. Trimethoprim-sulfamethoxazole is the drug of choice for the treatment and prevention of PCP (see Chapter 52). Pentamidine is reserved for 2 indications: (1) as a 4 mg/kg single daily intravenous dose for 21 days to treat severe PCP in individuals who cannot tolerate trimethoprim-sulfamethoxazole and are not candidates for alternative agents (e.g., atovaquone or the combination of clindamycin and primaquine); (2) as a “salvage” agent for individuals with PCP who fail to respond to initial therapy (usually trimethoprim-sulfamethoxazole; pentamidine may be less effective than the combination of clindamycin and primaquine or atovaquone for this indication).

Pentamidine administered as an aerosol preparation is used for the prevention of PCP in at-risk individuals who cannot tolerate trimethoprim-sulfamethoxazole and are not deemed candidates for either dapsone (alone or in combination with pyrimethamine) or atovaquone. Candidates for PCP prophylaxis are individuals with HIV infection and a CD4 count of <200/mm3 and individuals with HIV infection and persistent unexplained fever or oropharyngeal candidiasis. For prophylaxis, pentamidine isethionate is given monthly as a 300-mg dose in a 5-10% nebulized solution over 30-45 min. Although convenient, aerosolized pentamidine has several disadvantages, including its failure to treat any extrapulmonary sites of Pneumocystis, the lack of efficacy against any other potential opportunistic pathogens, and a slightly increased risk for pneumothorax.

Toxicity and Side Effects. Approximately 50% of individuals receiving the drug at recommended doses show some adverse effect. Intravenous administration of pentamidine may be associated with hypotension, tachycardia, and headache. These effects are probably secondary to the binding of pentamidine to imidazoline receptors and can be ameliorated by slowing the infusion rate. Hypoglycemia, which can be life threatening, may occur at any time during pentamidine treatment. Careful monitoring of blood sugar is key. Paradoxically, pancreatitis, hyperglycemia, and the development of insulin-dependent diabetes have been seen in some patients. Pentamidine is nephrotoxic (~25% of treated patients show signs of renal dysfunction), and if the serum creatinine concentration rises >1.0-2.0 mg/dL, it may be necessary to withhold the drug temporarily or change to an alternative agent. Other adverse effects include skin rashes, thrombophlebitis, anemia, neutropenia, and elevation of hepatic enzymes. Intramuscular administration of pentamidine is associated with the development of sterile abscesses at the injection site, which can become infected secondarily; most authorities recommend intravenous administration. Aerosolized pentamidine is associated with few adverse events.

SODIUM STIBOGLUCONATE

Sodium stibogluconate (sodium antimony gluconate, PENTOSTAM) is a pentavalent antimonial compound that has been the mainstay of the treatment of leishmaniasis. Increasing resistance to antimonials has reduced their efficacy and they are no longer useful in India, where lipid-based amphotericin B and miltefosine are now recommended instead. In the U.S., sodium stibogluconate can be obtained from the CDC.

Mechanism of Action. The relatively nontoxic pentavalent antimonials act as prodrugs that are reduced to the more toxic Sb+ species that kill amastigotes within the phagolysosomes of macrophages. Following reduction, the drugs seem to interfere with the trypanothione redox system, Sb+ induces a rapid efflux of trypanothione and glutathione from the cells, and also inhibits trypanothione reductase, thereby causing a significant loss of thiol reduction potential in the cells.

ADME. The drug is given intravenously or intramuscularly; it is not active orally. The agent is absorbed rapidly, distributed in an apparent volume of ~0.22 L/kg, and eliminated in 2 phases. The first has at1/2 of ~2 h, and the second is much slower (t1/2 = 33-76 h). The prolonged terminal elimination phase may reflect conversion of the Sb+ to the more toxic Sb+ that is concentrated and slowly released from tissues. The drug is eliminated in the urine.

Therapeutic Uses. Sodium stibogluconate is given parenterally. The standard course is 20 mg/kg/day for 21 days for cutaneous disease and for 28 days for visceral leishmaniasis. Increased resistance has greatly compromised the effectiveness of antimonials, and the stibogluconate is now obsolete in India. Liposomal amphotericin B is the recommended alternative for treatment of either visceral leishmaniasis (kala azar) in India or mucosal leishmaniasis in general; the orally effective compound miltefosine is likely to see much wider use. Intralesional treatment has also been advocated as a safer, alternative method for treating cutaneous disease. Children usually tolerate the drug well at the same dose per kilogram used for adults. Patients who respond favorably show clinical improvement within 1-2 weeks of initiation of therapy. The drug may be given on alternate days or for longer intervals if unfavorable reactions occur in especially debilitated individuals. Patients infected with HIV present a challenge because they usually relapse after successful initial therapy with either pentavalent antimonials or amphotericin B.

Toxicity and Side Effects. In general, high-dose regimens of sodium stibogluconate are fairly well tolerated; toxic reactions usually are reversible, and most subside despite continued therapy. Adverse effects noted most commonly include pain at the injection site; chemical pancreatitis in nearly all patients; elevation of serum hepatic transaminase levels; bone marrow suppression manifested by decreased red cell, white cell, and platelet counts in the blood; muscle and joint pain; weakness and malaise; headache; nausea and abdominal pain; and skin rashes. Reversible polyneuropathy has been reported. Hemolytic anemia and renal damage are rare manifestations of antimonial toxicity, as are shock and sudden death.

SURAMIN

Suramin sodium (BAYER 205, formerly GERMANIN, others) is a water-soluble trypanocide; solutions deteriorate quickly in air and only freshly prepared solutions should be used. In the U.S., suramin is available only from the CDC.

Antiparasitic Effects. Suramin is a relatively slow-acting trypanocide (>6 h in vitro) with high clinical activity against both T. b. gambiense and T. b. rhodesiense. Its mechanism of action is unknown. Selective toxicity is likely to result from the ability of the parasite to take up the drug by receptor-mediated endocytosis of the protein-bound drug, with low-density lipoproteins the most important interacting proteins for this event. Suramin inhibits many trypanosomal and mammalian enzymes and receptors unrelated to its antiparasitic effects. No consensus for the mechanism of action has emerged, and the lack of any significant field resistance points to multiple potential targets.

ADME. Because it is not absorbed after oral intake, suramin is given intravenously to avoid local inflammation and necrosis associated with subcutaneous or intramuscular injections. After its administration, the drug displays complex pharmacokinetics with marked interindividual variability. The drug is 99.7% serum protein bound and has a terminal elimination t1/2 of 41-78 days. Suramin is not appreciably metabolized; renal clearance accounts for elimination of ~80% of the compound from the body. Very little suramin penetrates the CSF, consistent with its polar character and lack of efficacy once the CNS has been invaded by trypanosomes.

Therapeutic Uses. Suramin is the first-line therapy for early-stage T. brucei rhodesiense infection. Because only small amounts of the drug enter the brain, suramin is used only for the treatment of early-stage African trypanosomiasis (before CNS involvement). Treatment of active African trypanosomiasis should not be started until 24 h after diagnostic lumbar puncture to ensure no CNS involvement, and caution is required if the patient has onchocerciasis (river blindness) because of the potential for eliciting a Mazzotti reaction (i.e., pruritic rash, fever, malaise, lymph node swelling, eosinophilia, arthralgias, tachycardia, hypotension, and possibly permanent blindness). Suramin is given by slow intravenous injection as a 10% aqueous solution. The normal single dose for adults with T. brucei rhodesienseinfection is 1 g. It is advisable to employ a test dose of 200 mg initially to detect sensitivity, after which the normal dose is given intravenously (e.g., on days 1, 3, 7, 14, and 21). The pediatric dose is 20 mg/kg, given according to the same schedule. Patients in poor condition should be treated with lower doses during the first week. Patients who relapse after suramin therapy should be treated with melarsoprol.

Toxicity and Side Effects. The most serious immediate reaction consisting of nausea, vomiting, shock, and loss of consciousness is rare (~1 in 2000 patients). Malaise, nausea, and fatigue are also common immediate reactions. The most common problem encountered after several doses of suramin is renal toxicity, manifested by albuminuria, and delayed neurological complications, including headache, metallic taste, paresthesias, and peripheral neuropathy. These complications usually disappear spontaneously despite continued therapy. Other, less prevalent reactions include vomiting, diarrhea, stomatitis, chills, abdominal pain, and edema. Patients receiving suramin should be followed closely. Therapy should not be continued in patients who show intolerance to initial doses, and the drug should be employed with great caution in individuals with renal insufficiency.