Chapter 29. Antifungal and Antiparasitic Agents

In the most general scientific sense, a “parasite” includes all of the known infectious agents such as viruses, bacteria, fungi, protozoa (single-celled eukaryotes of the animal kingdom), and helminths (worms) that live in or on host tissue, generally at the expense of the host. Certain species of parasites cause human infections. Some infections, especially fungal, are common in both industrialized and underdeveloped nations and cause varying degrees of illness and debility. Diseases caused by protozoan and helminthic parasites are among the leading causes of disease and death in tropical and subtropical regions. Many of these infections are intensified by inadequate water sanitation and hygiene, and their management is hampered by difficulty in controlling the vector (e.g., mosquito, in the case of malaria). This chapter describes the most commonly used drugs to treat fungal, protozoan, and helminthic infections.

Most human mycoses—diseases caused by fungal infections—are minor or superficial. However, the incidence and severity of human fungal infections have increased dramatically over the last few decades. This shift reflects the enormous number of immunocompromised patients (secondary to HIV and immunosuppressive drugs) who are at increased risk for invasive fungal infections, as well as the widespread use of broad-spectrum antimicrobials, which eliminate competitive nonpathogenic bacteria. In addition, fungi (especially Candida species) may be introduced into tissues that are normally resistant to invasion by, for example, central intravascular devices or hemodialysis.

Fungal infections are difficult to treat for several reasons. First, selective toxicity against fungal cells (and not the human host’s cells) is more difficult to achieve than for bacteria. Second, many antifungal agents suffer from problems with solubility, stability, and absorption. Third, fungi readily develop resistance.

For years, the mainstay of pharmacotherapy against systemic fungal infections has been the polyene class of drugs, especially amphotericin B. These drugs are toxic and azole agents (a different chemical class) have been developed as alternative antifungal drugs. However, owing to widespread use, azole-resistant organisms are becoming more widespread. Recently, the newest class of antifungals—the echinocandins—has demonstrated improved safety, efficacy, and tolerability.

Antifungals are generally classified on the basis of their target site of action. The major classes of antifungal agents—azoles, polyenes, echinocandins, and terbinafine—kill fungi by disrupting the synthesis or function of fungal cellular membranes. In contrast, the fungicidal actions of the less important agents, flucytosine and griseofulvin, are due to interference with intracellular functions (Figure 29–1 and 29–2). Clinically, antifungal drugs fall into several categories: drugs (oral or parenteral) for systemic infections, oral drugs for mucocutaneous infections (mucous membranes and skin), and topical drugs for mucocutaneous infections (Table 29–1).

Drugs for Systemic Fungal Infections

Amphotericin B

Chemistry and Pharmacokinetics

Amphotericin B is a polyene agent and one of the most important drugs for the treatment of systemic mycoses. It is available in oral, topical, and parenteral forms. Because it is poorly absorbed, oral amphotericin B is only effective against fungi in the lumen of the gastrointestinal tract. Topical forms are used for oral or cutaneous candidiasis. Amphotericin B is generally administered intravenously as a nonlipid colloidal suspension, as a lipid complex, or in a liposomal formulation. Development of the latter form has reduced its nephrotoxicity by decreasing nonspecific binding to human cell membranes, permitting the use of larger doses. Amphotericin B is widely distributed to all tissues except the central nervous system (CNS). Therefore, treatment of CNS fungal infections may necessitate intrathecal administration. Amphotericin B is primarily eliminated by hepatic metabolism. Hepatic impairment, renal impairment, and dialysis have little effect on drug concentrations.

Mechanism of Action and Clinical Uses

Amphotericin B kills fungi by binding to ergosterol (a major sterol constituent unique to fungal cell membranes) and forming pores, which results in leakage of cellular contents and cell death (Figure 29–2). Some binding to human cellular membranes occurs, probably accounting for amphotericin B’s serious toxicity.

Amphotericin B has the widest antifungal spectrum of any agent. It is considered the drug (or co-drug) of choice for treating almost all life-threatening systemic infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor. It is often used as the initial agent within a treatment regimen for serious fungal infections, and is then replaced by an azole for chronic treatment or relapse prevention. Amphotericin B is typically administered by slow intravenous infusion continued to a defined total dose rather than a defined time span. Doses vary depending on the particular infection, but it is not uncommon for patients to receive daily IV treatment for 6 to 12 weeks.

Toxicity

Toxic side effects of amphotericin B are divided into two categories: immediate reactions related to drug infusion and reactions that occur more slowly. Infusion-related adverse effects of amphotericin B are extremely common. These include fever, chills, vomiting, muscle spasms, headache, and significant hypotension occurring during infusion of the drug. Slowing the infusion rate or decreasing the daily dose may reduce these effects. In addition, premedication with antipyretics, antiemetics, antihistamines, meperidine (an opioid analgesic), or glucocorticoids may be provided to partially overcome infusion-related effects.

The most significant slower toxicity associated with amphotericin B is renal damage. Nearly all patients experience some renal impairment, with reversible and irreversible components. The irreversible form of nephrotoxicity usually results from prolonged administration. Strategies to decrease nephrotoxicity include concomitant saline infusion, dose reduction (made possible by adding another antifungal agent), and the use of liposomal formulations of amphotericin B. Anemia may also result because of decreased renal production of erythropoietin. Intrathecal administration may cause seizures and neurologic damage.

Azoles

Chemistry and Pharmacokinetics

The azoles are a class of antifungals named after the five-membered carbon-nitrogen ring in their structure. The azoles used for systemic fungal infections include ketoconazole, fluconazole, itraconazole, posaconazole, andvoriconazole. Fluconazole, posaconazole, and voriconazole are more reliably absorbed orally than the other azoles. The azoles are distributed to most body tissues, but drug levels achieved in the CNS are very low (with the exception of fluconazole and possibly posaconazole). The liver metabolizes ketoconazole, itraconazole, posaconazole, and voriconazole, and the kidneys eliminate fluconazole.

Mechanism of Action

The azoles disrupt membrane function of fungal cells by interfering with the synthesis of ergosterol (Figure 29–2), a process utilizing cytochrome P450 enzymes similar to human P450 isoforms. Resistance to azoles is becoming more widespread owing to increased use of this class of drugs for long-term prophylaxis of systemic mycoses in immunocompromised and neutropenic patients.

Toxicity

As a group, the azoles are relatively nontoxic. The most common adverse effects include minor gastrointestinal disturbances and rash. Varying degrees of hepatotoxicity may occur, especially in patients with impaired liver function. All azoles inhibit human hepatic cytochrome P450s to some extent because of their similarity to the fungal target enzymes. Thus, patients taking azoles (especially ketoconazole) in combination with other drugs may have higher plasma concentrations of drugs that are primarily metabolized by the cytochrome P450 system. In addition, inhibition of human cytochrome P450 (especially by ketoconazole) interferes with synthesis of adrenal and other steroids, which may lead to gynecomastia, menstrual irregularities, or infertility. Because it causes more adverse effects than the other azoles, ketoconazole is rarely used for systemic fungal infections, and is now mostly used for chronic mucocutaneous and dermatologic fungal infections.

Specific Azoles

Fluconazole

Because of its high oral bioavailability, relatively good gastrointestinal tolerance, and fewer effects on hepatic enzymes, fluconazole has the highest therapeutic index of all the azoles. Fluconazole is the treatment of choice for initial treatment and secondary prophylaxis for cryptococcal meningitis, and is also used in treating active infection due to Cryptococcusneoformans. It is effective against esophageal and oropharyngeal candidiasis, vaginal candidiasis, candidemia, and most infections caused by Coccidioides.

Itraconazole

Itraconazole is effective against many systemic fungal infections caused by Blastomyces and Sporothrix and for subcutaneous chromoblastomycosis (chronic, localized skin and subcutaneous tissue infection that follows traumatic implantation of one of several different fungal species). It can be used as the primary or alternative drug for treating infections caused by Aspergillus, Coccidioides, Cryptococcus, and Histoplasma. It is also used extensively in the treatment of dermatophytoses and onychomycosis.

Posaconazole

This newest azole has been recommended for prophylaxis of invasive aspergillosis in high-risk immunocompromised patients and for treatment of oropharyngeal candidiasis, including cases refractory to itraconazole and fluconazole. The full clinical usefulness and toxic potential of posaconazole are not yet established.

Voriconazole

Voriconazole is well absorbed orally and has an even wider spectrum of antifungal activity than itraconazole. It is replacing amphotericin B for the treatment of invasive aspergillosis because of greater efficacy with less toxicity. Voriconazole has also been used as an alternative drug in candidemia and in AIDS patients for the treatment of candidal esophagitis and stomatitis. In addition to the adverse effects common to the azoles, voriconazole has been reported to cause transient visual disturbances in more than 30% of patients.

Flucytosine

Chemistry and Pharmacokinetics

Flucytosine (5-fluorocytosine, 5-FC) is related to the anticancer drugfluorouracil. Unlike amphotericin B, it is effective orally and is distributed to most body tissues, including the CNS. To avoid toxic accumulation, serum concentrations are monitored regularly and dose reductions are made for patients with renal impairment.

Mechanism of Action and Clinical Uses

Flucytosine is preferentially taken up by fungal cells, where it is enzymatically converted to a compound that inhibits deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, thus preventing formation of fungal proteins (Figure 29–2). When used as a single-drug therapy, resistance to flucytosine emerges rapidly. Co-treatment with amphotericin B decreases the likelihood of resistance and produces synergistic fungicidal effects.

The antifungal spectrum of flucytosine is fairly narrow; it is active against yeasts such as Cryptococcus neoformans and some Candida species. To provide optimal fungicidal effects and reduce resistance, flucytosine is given in combination with amphotericin B or fluconazole. These drug combinations may be used to treat susceptible candidal septicemia, endocarditis and urinary tract infections, cryptococcal meningitis (one of the most common opportunistic CNS infections in AIDS patients), and pulmonary infections.

Toxicity

The most common adverse effects result from the metabolism of flucytosine to the anticancer drugfluorouracil. Reversible impairment of bone marrow function results in anemia, leukopenia, and thrombocytopenia. Less commonly, flucytosine causes liver dysfunction. Patients’ blood concentrations and renal function are monitored during drug therapy to avoid toxic accumulation.

Echinocandins

Chemistry and Pharmacokinetics

Echino-candins represent the newest class of antifungal agents, with a novel mechanism of action. Currently, three agents are available in this category: caspofungin, micafungin, and anidulafungin. Because these drugs are not well absorbed orally, they are only administered intravenously. Caspofungin distributes widely to most tissues except the cerebrospinal fluid (CSF). However, despite low CSF concentrations, positive results have been reported with caspofungin in the treatment of cerebral aspergillosis. Doses are decreased in patients with severe hepatic impairment.

Mechanism of Action and Clinical Uses

The echinocandins inhibit an enzyme present in fungal, but not mammalian cells. The result is impaired synthesis of β(1–3) glucan, an essential component of fungal cell walls. The echinocandins are used for the treatment of patients with candidemia and other forms of Candida infections (esophageal candidiasis, peritonitis, and intra-abdominal abscess). Early studies suggest that the potential for development of resistance to the echinocandins is low, suggesting that this class of antifungal agents may be used as therapy in life-threatening fungal infections (e.g., invasive aspergillosis) with strains that are no longer susceptible to conventional antifungals such as amphotericin B and the azoles.

Toxicity

To date, excellent tolerability and safety have been reported with the echinocandins. Compared with the other systemic antifungal agents, very few drug interactions have been reported with caspofungin.

Systemic Drugs Used in Mucocutaneous Fungal Infections

Mucocutaneous fungal infections include the superficial infections of skin, mucous membranes (including the oropharynx and vagina), and the nails. These disorders are confined to the cutaneous surface, with little likelihood for systemic proliferation. Commonly, these include infections with Candida organisms, usually C albicans. The severity of diseases may range from relatively minor cosmetic inconveniences such as onychomycosis (chronic fungal infection that affects toenails more commonly than fingernails) to oral thrush, which is a painful candidal infection that is often the first manifestation of local or systemic immunosuppression. Although mucocutaneous fungal infections are superficial, topical drug application alone is often ineffective because of insufficient penetration into affected tissues. This is especially true with onychomycosis, in which topical antifungal agents are unlikely to penetrate through all nail layers.

Griseofulvin

Griseofulvin is used to treat dermatophytoses—fungal infections of the skin, hair, and nails. Griseofulvin’s oral absorption is variable, but can be optimized when patients take ultramicrosize formulations with a high-fat meal. Griseofulvin interferes with microtubule formation in dermatophytes (Figure 29–2). It is deposited in keratin precursor cells, which are gradually exfoliated and replaced with noninfected tissue. Griseofulvin remains bound to new keratin, protecting the skin from new infection. To allow for replacement of infected keratin by newly resistant keratin, griseofulvin must be administered for long periods of time: 2 to 6 weeks for skin and hair infections and for at least 6 months for toenail infections. However, the use of griseofulvin is plagued by high relapse rates, especially for onychomycosis. The most common adverse reactions include skin rashes and urticaria (hives). Other side effects include gastrointestinal irritation, mental confusion, headache, and photosensitivity. Drug interactions occur with warfarin, phenobarbital, and alcohol. In addition, griseofulvin may increase the rate at which hepatic enzymes metabolize estrogens, possibly decreasing effectiveness of contraceptives and producing menstrual irregularities.

Terbinafine

Terbinafine has generally replaced griseofulvin in the treatment of onychomycosis. Terbinafine inhibits a fungal enzyme and results in accumulation of a substance toxic to the fungus. Terbinafine offers a shorter treatment regimen, higher cure rate, lower relapse rate, and fewer adverse effects than griseofulvin. Daily oral treatment for 12 weeks may result in a clinical cure rate as high as 60 to 75%. Adverse reactions include gastrointestinal upset, headache, rash, and taste disturbances. Rare cases of hepatic failure have been reported with the use of terbinafine in individuals with and without preexisting liver disease. Consequently, liver enzyme levels and a complete blood count are obtained before terbinafine is initiated and repeated every 4 to 6 weeks during treatment.

Topical Antifungal Drugs

A number of dermatologic fungal infections such as ringworm, jock itch, and athlete’s foot as well as some localized (oral, vaginal) candidal infections may be successfully treated with topical antifungal agents. Topical agents can be divided into three major categories: polyenes, azoles, and allylamines.

Nystatin is a polyene agent similar to amphotericin B. It acts by disrupting fungal cell membrane permeability, resulting in cell death. Because its toxicity precludes systemic use, nystatin is only used topically; the drug is not significantly absorbed from skin or mucous membranes. Nystatin (as powder, cream, ointment, or vaginal tablet) is commonly used to treat localized candidal infections in the oropharynx, in the vagina, and in areas where opposing skin surfaces may rub together, such as around the perineum or under the breasts. Localized infections can be cured rapidly, often within 24 to 72 hours after treatment initiation.

The most common topical azole agents are clotrimazole and miconazole. Both are available with a prescription as well as over-the-counter (OTC) as creams, powders, sprays, or vaginal suppositories. Clotrimazole and miconazole creams are used for the effective treatment of tinea pedis (athlete’s foot), tineacruris (jock itch), and tinea corporis (ringworm). Vaginal clotrimazole suppositories are used in the treatment of vaginal yeast infections. Oral clotrimazole lozenges (called troches) are used to treat oral candidiasis infections that commonly occur in immunocompromised individuals. Systemic absorption is minimal and adverse effects are rare.

Topical allylamine creams are available by prescription for the treatment of dermatologic fungal infections such as tinea cruris and tinea corporis. These include terbinafine, naftifine, and butenafine hydrochloride.

A large number of protozoa and helminths are capable of infecting humans. Drugs designed to kill these parasites must take into account their complex life cycles and the differences between their metabolic pathways and those of the host. Thus, drugs acting against protozoa are usually inactive against helminths and vice versa. Because protozoa and helminths are eukaryotes, they are metabolically more similar to humans than are bacteria. Although some antibacterial agents have antiprotozoal activity (e.g., metronidazole and doxycycline), most are ineffective against eukaryotic parasites.

Rational approaches to antiparasitic chemotherapy use the principle of selective toxicity, which exploits the biochemical and physiologic differences between parasite and human host cells. Many antiparasitic agents act on targets (usually enzymes) that are either unique to the parasite, or that possess sufficient differences between host and parasite to allow safe drug activity. Despite differences between host and parasite, many of the more effective antiparasitic drugs have significant toxicity and their use has to balance benefit against risk.

Climatic changes and international travel have facilitated the spread of many parasitic diseases, while starvation and poor sanitation that accompany poverty and war have promoted the reemergence of others. Drug resistance has also dramatically influenced the ability to treat and control many parasitic diseases.

Antiprotozoal Drugs

Protozoa are unicellular eukaryotic organisms. The parasitic protozoa that cause disease in humans either require the invasion of a suitable host to complete all or part of their life cycle, or they present as free-living protozoa that may become pathogenic in immunocompromised individuals. Conditions caused by protozoa include malaria, amebiasis, toxoplasmosis, pneumocystosis, trypanosomiasis, and leishmaniasis (Figure 29–3).

Drugs for Malaria

In terms of annual mortality, malaria remains the most important tropical parasitic disease. The World Health Organization estimates that malaria kills over 2.5 million people yearly, with the majority of deaths occurring in children under the age of 5 years in sub-Saharan Africa. Although four Plasmodium species infect humans (P falciparum, P malariae, P ovale, P vivax), P falciparum is responsible for the most serious life-threatening complications and death. Transmission most commonly occurs when an infected mosquito injects the infectious form of the parasite, the sporozoite, into the individual’s blood. Sporozoites circulate to the liver and infect liver cells. Here, they reproduce to form merozoites, which eventually leave the liver, reenter the bloodstream, and invade red blood cells (RBCs). Parasites mature within RBCs, are released, and continue infecting more RBCs. At this stage of infection, clinical disease is manifested by recurrent flu-like attacks, fever, severe anemia, and, in some cases, cerebral malaria and death.

In P falciparum and P malariae infections, only one cycle of liver cell invasion and multiplication occurs. Liver infection ceases spontaneously in less than 4 weeks. In this case, drugs that eliminate parasites within RBCs (e.g., chloroquine, quinine) can cure most of these infections if the parasite is not drug resistant. On the other hand, P ovale and P vivax can remain dormant in the liver for months or years. Subsequent malaria relapses can occur after successful pharmacotherapy directed against the erythrocytic parasites. To cure these infections, an antimalarial agent that eliminates liver parasites must be used in conjunction with agents that eliminate erythrocytic parasites. No single available antimalarial agent can reliably bring about a radical cure; that is, eliminate both hepatic and erythrocytic stages.

The major drugs used in malarial prophylaxis and treatment are shown in Table 29–2. For many agents, antimalarial activity is due to either intracellular accumulation of a compound toxic to the parasite (e.g., chloroquine), interference with parasitic DNA replication (e.g., quinine), or inhibition of critical enzymes involved in folic acid synthesis (e.g., pyrimethamine, proguanil, sulfadoxine). For other drugs, the antimalarial mechanism of action is not clear (e.g., halofantrine and doxycycline). Since parasites are increasingly resistant to multiple drugs, no chemoprophylactic regimen is fully protective, and treatment for malaria depends on knowledge of changing resistance patterns.

The first line of defense against malaria is limiting contact with mosquitoes by using mosquito repellent, keeping arms and legs covered, staying indoors during mosquitoes’ feeding hours (dusk and throughout the night), and sleeping under mosquito netting. Physical therapists involved in the Peace Corps, Health Volunteers Overseas, or other international organizations are likely to practice in malaria endemic areas. Prior to leaving home, individuals should consult the Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/travel/destinat.htm; or telephone 877-FYI-TRIP) for current recommendations regarding specific antimalarial chemoprophylaxis, resistance patterns, and treatment if malaria is contracted.

Chloroquine, Mefloquine, and Antifolate Agents (Pyrimethamine/Sulfadoxine)

Chloroquine, long considered the drug of choice for prophylaxis and treatment of malaria, is no longer considered the first-line antimalarial agent in many countries owing to worldwide prevalence of chloroquine-resistant parasites. In regions where P falciparum is not resistant, chloroquine is used for chemoprophylaxis and for acute attacks of falciparum and nonfalciparum malaria. Chloroquine is generally well tolerated, even with prolonged use. The most common adverse effects are gastrointestinal upset, skin rash or itching, and headaches. Consumption of calcium- and magnesium-containing antacids should be avoided because they significantly decrease oral chloroquine absorption. Dosing after meals may reduce some adverse effects. Long-term administration of high doses may cause severe skin lesions, peripheral neuropathies, myocardial depression, retinal damage, auditory impairment, and toxic psychosis.

Common alternatives for treating chloroquine-resistant strains include mefloquine, combined pyrimethamine/sulfadoxine (antifolate agents), and atovaquone/proguanil (Malarone), but resistance is emerging to mefloquine in some regions (parts of Southeast Asia), and significant resistance to the antifolate agents is now common for P falciparum and less common for P vivax. Malarone is becoming the preferred prophylactic agent for travelers to Africa and has shown efficacy for treatment of active malaria. Common adverse effects of mefloquine and the antifolate compounds include gastrointestinal distress and rash. Mefloquine causes headache and dizziness. Severe neuropsychiatric disturbances such as depression, confusion, acute psychosis, or seizures have also been reported with mefloquine. Toxicities for the antifolate compounds include hemolysis and kidney damage. The toxicity of malarone includes gastrointestinal disturbances, headache, and rash.

Quinine

Quinine is the original antimalarial drug that is derived from the bark of the native South American cinchona tree. Quinine remains the drug of choice for life-threatening malaria. Quinine acts rapidly against all four species of human malaria parasites in erythrocytes. Its main use is in treating chloroquine-resistant falciparum malaria. However, quinine is often used in combination with a second drug (doxycycline or clindamycin) to limit toxicity by shortening its duration of use (generally to 3 days). Quinine is generally not used in chemoprophylaxis because of toxicity and potential increases in parasitic resistance to these agents. Therapeutic doses of quinine commonly cause cinchonism. Milder symptoms of cinchonism such as gastrointestinal distress, headache, vertigo, blurred vision, and tinnitus do not warrant discontinuation of the drug. Higher doses of quinine result in cardiac conduction disturbances. In some individuals with hypersensitivity, severe blood disorders can occur. Therapy is discontinued in hypersensitive patients and those with severe cinchonism.

Primaquine

Primaquine is the only drug available to eradicate liver stage parasites of P vivax and P ovale and should be used in conjunction with an antimalarial effective against parasites within RBCs. It is generally well tolerated, but sometimes causes nausea, headache, and epigastric pain. Because it can produce severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, persons for whom this agent is being considered must be evaluated for G6PD enzyme levels and the drug should not be used in those who are G6PD deficient.

Artemisinin

The most important newer antimalarial compounds are derivatives of artemisinin (an extract of the Chinese herbal remedy quinghaosu). These agents combine rapid antimalarial activity with an absence of clinically important resistance: they are the only drugs reliably effective against quinine-resistant strains. Because of their short half-lives, artemisinin and its analogs artesunate and artemether are generally used with another antimalarial agent and are not useful in chemoprophylaxis. Although they appear to be better tolerated than most antimalarials, the artemisinins are currently available in the United States and Canada only on special request, but are widely available in Africa and Asia.

Drugs for Amebiasis

Amebiasis is infection with Entamoeba histolytica. Although amebiasis occurs worldwide, it is most prevalent in tropical and subtropical areas, especially in crowded and unsanitary living conditions. The organism lives and reproduces on the mucosal surface of the large intestine. Encysted forms periodically pass out in the feces, and can survive in the external environment and act as infective forms. Infection with E histolytica occurs as a result of inadequate sanitation, or when food or drink is contaminated by infected food handlers. Ingested cysts adhere to intestinal epithelial cells and invade the mucosal lining. E histolytica can cause asymptomatic intestinal infection, mild to moderate colitis, mild diarrhea, severe intestinal infection (amebic dysentery), liver abscess, and other extraintestinal infections.

Drugs for amebiasis (Table 29–3) include tissue amebicides (chloroquine, emetines, metronidazole), which act on organisms in the bowel wall and the liver; and luminal amebicides (diloxanide furoate, iodoquinol, paromomycin), which act only in the lumen of the bowel. Drug choice depends on the type of amebic infection.

Diloxanide Furoate

For asymptomatic disease (carriers with no symptoms in nonendemic areas), diloxanide furoate is the first choice. This drug is well tolerated, with usually mild gastrointestinal symptoms.

Metronidazole

For mild to severe intestinal infection, liver abscess, and other extraintestinal amebic disease, metronidazole is generally used in conjunction with a luminal amebicide. Adverse effects of metronidazole include gastrointestinal irritation, headache, and, less frequently, leukopenia, dizziness, and ataxia. (See Chapter 30 for further discussion of metronidazole.)

Emetine and Dehydroemetine

Emetine and dehydroemetine may still be used as back-up drugs for treatment of severe intestinal or hepatic amebiasis in hospitalized patients. However, because they may cause severe toxicity (including gastrointestinal distress, muscle weakness, and cardiovascular dysfunction), they have been mostly replaced by metronidazole.

Drugs for Pneumocystosis and Toxoplasmosis

Pneumocystis jiroveci (formerly called P carinii) is the cause of human pneumocystosis. Although now recognized as a fungus, P jiroveci is responsive to antiprotozoaldrugs, not antifungals. Commonly found in normal humans, the fungus causes symptomatic disease only in immune-deficient individuals. Thus, there is a high incidence of P jiroveci pneumonia in patients receiving immunosuppressive therapy and in patients with AIDS.

Trimethoprim Plus Sulfamethoxazole

Trimethoprim plus sulfamethoxazole (TMP-SMZ) is the first-line therapy for P jiroveci pneumonia. TMP-SMZ is also used as a chemoprophylactic drug combination for prevention of P jiroveci infection in immunocompromised individuals. While chemoprophylactic doses are generally much better tolerated than treatment for active infection, high-dose therapy entails significant toxicity in up to 50% of AIDS patients. Important toxicities include gastrointestinal distress, rash, fever, neutropenia, and thrombocytopenia. These adverse effects may be severe enough to warrant discontinuance of TMP-SMZ. Because of the high prevalence of serious adverse effects with TMP-SMZ, several drugs have been used as alternative agents against P jiroveci infection. Notably, none is as effective as TMP-SMZ.

Pentamidine

Pentamidine is a well-established alternative drug for P jiroveci infection. For prophylaxis, pentamidine is administered as an inhaled aerosol. Although well tolerated in this form, it is not as effective as daily TMP-SMZ. For treatment of active P jiroveci infection, pentamidine must be administered parenterally. Serious adverse effects result from parenteral administration, including respiratory stimulation followed by respiratory depression, severe hypotension, hypoglycemia, anemia, neutropenia, hepatitis, and pancreatitis.

Atovaquone

Atovaquone is an oral drug initially developed as an antimalarial, but it has also been approved for the treatment of mild to moderate P jiroveci pneumonia. Although less effective than TMP-SMZ or pentamidine, it is better tolerated. Adverse effects include fever, rash, cough, nausea, vomiting, diarrhea, and abnormal liver function tests.

Drugs for Toxoplasmosis

Toxoplasmosis is infection with Toxoplasma gondii. Infection occurs by ingesting oocysts released in the feces of infected cats (primary hosts) or by eating raw meat containing tissue cysts. Infection with this protozoan is widespread, but is not serious unless it is acquired (or reactivated) in immunosuppressed patients or acquired during pregnancy, when the organism invades all fetal tissues, especially the CNS. Damage to the eye is the most common consequence, although the brain may also be affected.

The antifolate agents pyrimethamine with sulfadiazine (or with clindamycin in patients allergic to sulfonamides) are used for treatment of congenital toxoplasmosis and acute infection in immunocompromised individuals. In AIDS-related Toxoplasma encephalitis, high-dose treatment must be given for many weeks and is associated with gastric irritation, neurologic symptoms (headaches, insomnia, tremors, seizures) and serious blood abnormalities. Spiramycin is an antibiotic that is used to treat toxoplasmosis acquired during pregnancy. Treatment lowers the risk of development of congenital toxoplasmosis.

Drugs for Trypanosomiasis

The protozoan genus Trypanosoma contains three species that cause human disease. Infections with T gambiense and T rhodesiense cause African trypanosomiasis (African sleeping sickness), and T cruzi infection causes American trypanosomiasis (Chagas disease). Trypanosomiasis is transmitted by the bite of infected insect vectors, which are the tsetse fly for African trypanosomiasis and reduviid bugs for American trypanosomiasis. Currently available drugs for all forms of trypanosomiasis are seriously deficient in both efficacy and safety. Availability of these drugs is also a concern: the CDC classifies several of these drugs as investigational agents, supplying them only upon request. Some of these drugs include bithionol, dehydroemetine, diethylcarbamazine, melarsoprol, nifurtimox, sodium stibogluconate, and suramin.

Suramin and Pentamidine

After a bite by an infected tsetse fly, widespread lymph node enlargement occurs and the organism establishes in the blood and rapidly multiplies. Suramin is the first-line therapy for this acute hemolymphatic stage of African trypanosomiasis. Because suramin does not enter the CNS, it is not effective against advanced disease when the CNS becomes involved. Suramin is administered intravenously and causes adverse effects including skin rashes, gastrointestinal distress, and neurologic complications. Pentamidine may be used as an alternative to suramin or in combination with suramin for the early hemolymphatic stage. Adverse effects (described above for its use against pneumocystosis) are noted in half of patients receiving therapeutic doses.

Melarsoprol and Eflornithine

Once African trypanosomiasis has infected the CNS, drugs that cross the blood-brain barrier must be administered. Even though melarsoprol is extremely toxic (it is an arsenic derivative), it is still considered the drug of choice because of the severity of African trypanosomiasis at this stage. Immediate toxicity includes fever, vomiting, abdominal pain, and arthralgias. The drug may also cause a reactive encephalopathy that can be fatal. To avoid the toxicity of melarsoprol as well as increasing treatment failures that may be due to drug resistance, eflornithine has been introduced as a second option for treating advanced disease. It is available orally and intravenously, and is effective against some forms of African trypanosomiasis. Toxicity is markedly less than that from melarsoprol, but adverse effects still include gastrointestinal distress, blood abnormalities, and seizures.

Nifurtimox and Benznidazole

Chagas disease, caused by T cruzi infection, is one of the main causes of death due to heart failure in Latin American countries. T cruzi primarily invades cardiac muscle cells and macrophages. Initial infection usually results in a transient febrile illness. After invasion of host cells, the disease pursues a very slow course. The two major symptoms of Chagas disease, myocarditis and intestinal tract dilation, can take years to develop. Two drugs are available to treat Chagas disease: nifurtimox and benz-nidazole. Both drugs are commonly used to treat the acute infection, but are often unsuccessful at complete eradication of the protozoan, thus allowing progression to the cardiac and gastrointestinal syndromes. The toxicities of both drugs, including gastrointestinal irritation and severe CNS effects, are a major drawback in their use, frequently forcing discontinuation of the treatment. Benznidazole is not commercially available in the United States and Canada.

Drugs for Leishmaniasis

Leishmania parasites are transmitted by the bite of infected sandflies. Infection results in cutaneous (skin), mucocutaneous (skin, nose, mouth), or visceral (liver and spleen) leishmaniasis. More than 12 million people are known to be infected with leishmaniasis, with the cutaneous and mucocutaneous forms being much more prevalent than the life-threatening visceral disease. The cutaneous disease is particularly prevalent in Afghanistan, Algeria, Brazil, Iraq, Iran, Peru, Saudi Arabia, and Syria. More than 90% of the world’s cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. The disease is often known by many local names (e.g., Oriental sore, espundia, Baghdad boil, Delhi sore, and kala-azar). Those at increased risk of leishmaniasis (particularly cutaneous leishmaniasis) include Peace Corps volunteers, people who do research outdoors at night, and soldiers. The cutaneous and mucocutaneous leishmania infections range from localized self-healing ulcers to disseminated lesions that give rise to chronic disfiguring conditions. Lesions may eventually heal with significant scarring, but will leave the individual relatively immune to reinfection. In contrast, visceral infection develops slowly and is characterized by hepatomegaly and splenomegaly. Left untreated, visceral leishmaniasis almost always results in death.

Sodium Stibogluconate

This drug, based on the heavy metal antimony, has been the mainstay of treatment for leishmaniasis. The drug must be administered parenterally (intravenous or intramuscular), and intramuscular injections can be very painful. Although few adverse effects occur initially, the toxicity of sodium stibogluconate increases over the course of therapy. The most commonly encountered adverse effects include gastrointestinal symptoms, fever, headache, myalgias, arthralgias, and rash. It is potentially cardiotoxic (QT prolongation), but these effects are generally reversible. Cure rates for the cutaneous and mucocutaneous forms are generally good with several weeks of therapy. However, treatment for the visceral disease (kala-azar) is ineffective at times, has shown increasing resistance, and is associated with treatment-related deaths in a small percentage of cases. Alternative drugs such as pentamidine and miltefosine (for visceral leishmaniasis), fluconazole or metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis) have been used when therapy is ineffective.

Miltefosine

This drug, originally developed as an antineoplastic drug, is the first effective oral drug used in the treatment of cutaneous and visceral leishmaniasis. The cure rate of miltefosine, especially for the visceral disease, is very promising, and the drug is generally well tolerated. Adverse effects include nausea and vomiting. Because the drug has demonstrated teratogenicity, miltefosine should not be given to pregnant women. Miltefosine is currently not approved for use in the United States.

Anthelmintic Drugs

The helminths include all groups of parasitic worms. Three main groups parasitize human organs, most often the gastrointestinal tract: tapeworms (Cestoda), flukes (Trematoda or Digenea), and roundworms (Nematoda). Tapeworms and flukes are relatively flat and have specialized structures to secure attachment to the host’s intestine or blood vessels. Roundworms have long cylindrical bodies and generally lack specialized attachment structures. Transmission may be direct by swallowing infective stages or by larvae actively penetrating the skin or indirect by injection from infected insect vectors. Some of the drugs used in helminthic infections are outlined in Figure 29–4, and listed in Table 29–4.

Drugs That Act Against Nematodes (Roundworms)

It is estimated that more than 1 billion people worldwide are infected by intestinal nematodes, with much higher prevalence in moist subtropical and tropical climates. Medically important intestinal nematodes responsive to anthelminticdrugs include Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (roundworm), Ancylostoma and Necator species (hookworms), and Strongyloides stercoralis (threadworm). Pinworms are the most common intestinal nematode in developed countries and are also the least pathogenic. Eggs that are laid on the perianal skin cause itching, and transmission generally occurs from contaminated fingers. While hookworm (Ancylostoma and Necator species) infections are rare in the United States, threadworm (Strongyloides stercoralis) infections are endemic in rural areas of the southeastern states and the Appalachian region. Not as common as intestinal nematodes, tissue nematodes still infect over a half billion people worldwide. Tissue nematodes responsive to anthelmintic therapy include Ancylostoma, Dracunculus, Onchocerca, and Toxocara species and Wuchereria bancrofti.

Albendazole

This is an oral drug with a wide anthelmintic spectrum. It is the drug of choice for roundworm (ascariasis), hookworm, pinworm, and whipworm infections. It is an alternative drug for threadworm and filariasis (endemic in some tropical areas and responsible for elephantiasis when the lymphatics are infected) infections. Dosing of albendazole varies depending on the parasitic infection being treated. During short courses of therapy, albendazole has relatively few adverse effects.

Mebendazole

This is another primary drug for ascariasis, pinworm, and whipworm infections, with cure rates of 90 to 100%. It has a low incidence of adverse effects, primarily limited to gastrointestinal irritation. Its use is contraindicated in pregnancy, as it may be embryotoxic.

Ivermectin

This is the drug of choice for onchocerciasis, a chronic disease endemic in West and sub-Saharan Africa, as well Saudi Arabia and Yemen. Chronic infection often results in serious ophthalmologic complications, including blindness. Ivermectin immobilizes sensitive parasites by inhibiting neurotransmitter function in parasites. It does not cross the blood-brain barrier, and does not interfere with human neurotransmission. Ivermectin is generally given as a single-dose oral therapy. Adverse effects include fever, headache, dizziness, rash, pruritus, tachycardia, hypotension, and pain in joints, muscles, and lymph glands. These symptoms are often of short duration and manageable with antihistamines and nonsteroidal anti-inflammatory drugs (NSAIDs).

Drugs That Act Against Trematodes (Flukes)

The medically important trematodes include several parasites that have an enormous impact on human populations, such as Clonorchis sinensis (human liver fluke, endemic in Southeast Asia), Schistosoma species (blood flukes, estimated to affect more than 200 million persons worldwide), and Paragonimus westermani (lung fluke, endemic in Asia and India).

Praziquantel

This drug has a wide anthelmintic spectrum. It kills susceptible worms by increasing cell membrane permeability, resulting in paralysis of their musculature, and eventual phagocytosis by human immune cells and death. Praziquantel is the safest and most effective drug for treating schistosomiasis (all species) and most other trematode and cestode infections. It is effective against adult worms and immature stages. Common mild and transient adverse effects include headache, dizziness, and malaise. These generally do not require treatment, but may be more frequent or serious in patients with heavy worm burdens.

Drugs That Act Against Cestodes (Tapeworms)

Cestode eggs are passed into soil from a primary host (humans in most cestode infestations), and ingested by and hatched in an intermediate host (e.g., cow, pig) in which they enter tissue and encyst. Primary hosts then ingest cysts in the flesh of the intermediate host. In some cestodes (Echinococcus and Spirometra species), humans are the intermediate hosts and larvae live within tissues and migrate through different organ systems. The four medically important cestodes are Taenia saginata (beef tapeworm), Tsolium (pork tapeworm, which can cause larval forms in the brain and eyes), Diphyllobothriumlatum (fish tapeworm), and Echinococcus granulosus (dog tapeworm, which is endemic in South America, Iceland, Australia, New Zealand, and southern parts of Africa and can cause cysts in the liver, lungs, and brain). The primary drugs for treatment of cestode infections are praziquantel (see above) and niclosamide. Niclosamide is used to treat infections caused by beef, pork, and fish tapeworms. It is not effective in cysticercosis, an infection caused by the pork tapeworm T solium (albendazole or praziquantel is used) or disease caused by E granulosus (albendazole is used). Toxic effects are mild, but include gastrointestinal distress, headache, rash, and fever.

This chapter includes an extremely broad spectrum of antiparasitic agents—from antifungal drugs to antimalarial and anthelmintic drugs. Most physical therapists will treat patients taking antifungal agents, whether it is the athlete using a topical antifungal for athlete’s foot or the AIDS patient receiving an intravenous agent to treat a systemic mycosis. Less commonly, physical therapists will encounter infections such as malaria and leishmaniasis that are endemic in tropical regions throughout the world. However, therapists traveling to these regions or caring for returning military personnel will often be involved in the management of infected individuals. For example, many individuals in malarial endemic regions will be receiving chemoprophylaxis or treatment for active malaria while participating in rehabilitation programs. An understanding of the medications’ potential adverse effects allows the therapist to optimize the delivery (e.g., intensity and timing) of therapy sessions. In some cases, individuals suffering from advanced stages of these diseases are not appropriate rehabilitation candidates. However, the physical therapist still serves as a valuable member of the health-care team in providing education regarding limiting the spread of infection.

Adverse Drug Reactions

Systemic Drugs Used for Fungal Infections

• • Amphotericin B almost always produces infusion-related adverse effects including fever, chills, vomiting, muscle spasms, headache, and significant hypotension.
• • Amphotericin B may cause anemia.
• • Flucytosine may cause reversible anemia and thrombocytopenia.
• • All azole agents inhibit hepatic drug-metabolizing enzymes (cytochrome P450s) to some extent.
• • Voriconazole may cause transient visual disturbances.

Antiparasitic Drugs

• • At therapeutic doses, many antiparasitic agents produce skin rashes, varying degrees of gastrointestinal distress, and neurologic complications ranging from headaches and tremors to confusion, acute psychosis, and seizures.

Anthelmintic Drugs

• • Many anthelmintics cause dizziness, tachycardia, hypotension, joint and muscle pain, and malaise.

Effects Interfering with Rehabilitation

Systemic Drugs Used for Fungal Infections

• • Infusion-related effects of amphotericin B can limit patients’ ability to participate in rehabilitation.
• • Anemia and thrombocytopenia may result in decreased capacity to exercise and to control bleeding after injury, respectively.
• • Inhibition of cytochrome P450s can cause higher plasma concentrations of other drugs, resulting in a potential increase or prolongation of therapeutic or adverse effects.
• • Transient visual disturbances can interfere with functional performance of patients participating in rehabilitation.

Antiparasitic Drugs

• • The severity of many parasitic infections, as well as adverse effects of the drugs used to treat them, can interfere with functional performance of patients.

Anthelmintic Drugs

• • Many anthelmintics cause dizziness, tachycardia, hypotension, joint and muscle pain, and malaise.

Possible Therapy Solutions

Systemic Drugs Used for Fungal Infections

• • If a patient is receiving intravenous amphotericin B, rehabilitation services should be scheduled away from this time.
• • If decreased exercise tolerance or excessive bruising is noted with patients receiving amphotericin B or flucytosine, contact the referring health-care provider.
• • If a patient taking any azole agent demonstrates new symptoms or if a patient is considering (or currently) taking an OTC drug or herbal supplement, contact the referring health-care provider for concerns regarding drug interactions.
• • Visual disturbances should be reported to the referring health-care provider.

Antiparasitic Drugs

• • Therapy may need to be postponed until parasitic infection has been brought under control.

Anthelmintic Drugs

• • During short courses of therapy, adverse effects of many anthelminticdrugs are usually short in duration. Rehabilitation can be postponed until adverse effects cease or improve.

Brief History: The patient is a 22-year-old male who returned from a military rotation in Iraq 2 months ago. He was admitted to a military rehabilitation hospital 4 days ago for an amputee rehabilitation program. He sustained a below the knee amputation (BKA) of the right lower extremity 1 week ago, secondary to a traumatic injury that occurred during a military operation. Prior to his injury, he was functionally independent and an avid basketball player.

Current Medical Status and Drugs: At admission, the patient was noted to have several crusted raised lesions that were up to 1 inch in diameter on his face, neck, and left forearm. The patient reported that the lesions were much larger and painful several weeks ago. An infectious disease physician sampled skin scrapings of the lesion and diagnosed the condition as cutaneous leishmaniasis, commonly known as “Baghdad boil.” The patient was started on a 20-day intravenous course of sodium stibogluconate, which he receives once per day, immediately prior to afternoon physical therapy sessions. Rehabilitation precautions include non-weight-bearing on the right stump. The patient’s current drugs include pain medication as needed.

Rehabilitation Setting: The patient is very motivated to return to his prior level of function and has been participating in rehabilitation therapy twice per day since the first day of admission. During the first week of rehabilitation, the patient met each therapy goal regarding edema control, stump maintenance, stretching, strengthening, and pregait activities. He was making remarkable gains in therapy, until 5 days after he started IV sodium stibogluconate. His energy level began declining, and he has been unable to complete an hourly physical therapy session. Today, while exercising in the parallel bars, he had to sit down twice secondary to dizziness. He complains of severe hip and knee pain, as well as gluteal, quadriceps, and back muscle soreness. Although some of the patient’s complaints may be due to his vigorous participation in rehabilitation, the therapist notes that some symptoms may be adverse effects of the drug therapy for cutaneous leishmaniasis. The therapist encourages the patient that these symptoms are likely to dissipate once the full course of drug therapy has ended. The patient states that the drug treatment “has been far worse than these little sores.” He states his intention to tell the doctor that he is no longer going to take the prescribed medication, so that he can “get on with rehab.”

Problem/Clinical Options: The physician should be notified of the patient’s symptoms, as well as their limiting impact on physical rehabilitation goals. Over half of patients receiving IV sodium stibogluconate experience fatigue, arthralgias, and myalgias. While symptoms necessitate interruption of treatment in only a small percentage of cases, these side effects are generally reversible. First, the patient should be educated about the cost to benefit ratio of continuing drug therapy. Untreated cutaneous leishmaniasis lesions can leave large, unsightly scars. In some cases, localized skin infections can spread to the mouth or nose (mucosal leishmaniasis) and cause potentially disfiguring scars. Second, attempts should be made to schedule therapy sessions as far apart from IV drug sessions as possible to determine whether adverse effects are attenuated during therapy sessions. Finally, the therapist can encourage and reassure the patient that the drug therapy is limited to a maximum of 20 days, and that the distressing symptoms will likely not persist or interfere with long-term rehabilitation goals.

Antifungal Agents

Amphotericin B

Parenteral:

Conventional formulation (Amphotericin B, Fungizone): 50-mg powder for injection

Lipid formulations:

(Abelcet): 100 mg/20 mL suspension for injection

(AmBisome): 50-mg powder for injection

(Amphotec): 50-, 100-mg powder for injection

Topical: 3% cream, lotion, ointment

Butaconazole (Femstat, Mycelex-3)

Topical: 2% vaginal cream

Butenafine (Mentax)

Topical: 1% cream

Caspofungin (Cancidas)

Parenteral: 50-, 70-mg powder for injection

Clotrimazole (Lotrimin, Others)

Topical: 1% cream, solution, lotion; 100-, 200-mg vaginal suppositories

Econazole (Spectazole)

Topical: 1% cream

Fluconazole (Diflucan)

Oral: 50-, 100-, 150-, 200-mg tablets; powder for 10, 40 mg/mL suspension

Parenteral: 2 mg/mL in 100- and 200-mL vials

Flucytosine (Ancobon)

Oral: 250-, 500-mg capsules

Griseofulvin (Grifulvin, Grisactin, Fulvicin P/G)

Oral microsize: 125-, 250-mg capsules; 250-mg tablets, 125 mg/5 mL suspension

Oral ultramicrosize1: 125-, 165-, 250-, 330-mg tablets

Itraconazole (Sporanox)

Oral: 100-mg capsules; 10 mg/mL solution

Parenteral: 10 mg/mL for IV infusion

Ketoconazole (Generic, Nizoral)

Oral: 200-mg tablets

Topical: 2% cream, shampoo

Miconazole (Micatin, Others)

Topical: 2% cream, powder, spray; 100-, 200-mg vaginal suppositories

Naftifine (Naftin)

Topical: 1% cream, gel

Natamycin (Natacyn)

Topical: 5% ophthalmic suspension

Nystatin (Generic, Mycostatin)

Oral: 500,000-unit tablets

Topical: 100,000 units/g cream, ointment, powder; 100,000 units vaginal tablets

Oxiconazole (Oxistat)

Topical: 1% cream, lotion

Sulconazole (Exelderm)

Topical: 1% cream, lotion

Terbinafine (Lamisil)

Oral: 250-mg tablets

Topical: 1% cream, gel

Terconazole (Terazol 3, Terazol 7)

Topical: 0.4%, 0.8% vaginal cream; 80-mg vaginal suppositories

Tioconazole (Vagistat-1)

Topical: 6.5% vaginal ointment

Tolnaftate (Generic, Aftate, Tinactin)

Topical: 1% cream, gel, solution, aerosol powder

Voriconazole (Vfend)

Oral: 50-, 200-mg tablets

Parenteral: 200-mg vials, reconstituted to a 5 mg/mL solution

Antiparasitic Agents

Albendazole (Albenza)

Oral: 200-mg tablets

Atovaquone (Mepron)

Oral: 750 mg/5 mL suspension

Atovaquone-Proguanil (Malarone)

Oral: 250 mg atovaquone + 100 mg proguanil tablets; pediatric 62.5 mg atovaquone + 25 mg proguanil tablets

Chloroquine (Generic, Aralen)

Oral: 250-, 500-mg tablets (equivalent to 150, 300 mg base, respectively)

Parenteral: 50 mg/mL (equivalent to 40 mg/mL base) for injection

Clindamycin (Generic, Cleocin)

Oral: 75-, 150-, 300-mg capsules; 75 mg/5 mL suspension

Parenteral: 150 mg/mL for injection

Dehydroemetine2

Doxycycline (Generic, Vibramycin)

Oral: 20-, 50-, 100-mg capsules; 50-, 100-mg tablets; 25 mg/5 mL suspension; 50 mg/5 mL syrup

Parenteral: 100, 200 mg for injection

Eflornithine (Ornidyl)

Parenteral: 200 mg/mL for injection

Halofantrine (Halfan)

Oral: 250-mg tablets

Iodoquinol (Yodoxin)

Oral: 210-, 650-mg tablets

Mefloquine (Generic, Lariam)

Oral: 250-mg tablets

Melarsoprol (Mel B)2

Metronidazole (Generic, Flagyl)

Oral: 250-, 500-mg tablets; 375-mg capsules; extended-release 750-mg tablets

Parenteral: 5 mg/mL

Nifurtimox2

Nitazoxanide (Alinia)

Oral: powder for 100 mg/5 mL oral solution

Paromomycin (Humatin)

Oral: 250-mg capsules

Pentamidine (Pentam 300-, Pentacarinat, Pentamidine Isethionate)

Parenteral: 300-mg powder for injection

Primaquine (Generic)

Oral: 26.3 mg (equivalent to 15 mg base) tablet

Pyrimethamine (Daraprim)

Oral: 25-mg tablets

Quinidine Gluconate (Generic)

Parenteral: 80 mg/mL (equivalent to 50 mg/mL base) for injection

Quinine (Generic)

Oral: 260-mg tablets; 200-, 260-, 325-mg capsules

Sodium Stibogluconate2

Sulfadoxine and Pyrimethamine (Fansidar)

Oral: 500 mg sulfadoxine plus 25 mg pyrimethamine tablets

Suramin2

Anthelmintic Agents

Albendazole (Albenza, Zentel)3

Oral: 200-mg tablets; 100 mg/5 mL suspension

Bithionol (Bitin)4

Oral: 200-mg tablets

Diethylcarbamazine (Hetrazan)4

Oral: 50-mg tablets

Ivermectin (Mectizan, Stromectol)5

Oral: 3-, 6-mg tablets

Levamisole (Decaris, Ethnor, Ketrax, Solaskil)

Oral: 50-, 150-mg tablets and syrup

Mebendazole (Generic, Vermox)

Oral: 100-mg chewable tablets; outside the United States, 100 mg/5 mL suspension

Metrifonate (Trichlorfon, Bilarcil)6

Oral: 100-mg tablets

Niclosamide (Niclocide)6

Oral: 500-mg chewable tablets

Oxamniquine (Vansil, Mansil)

Oral: 250-mg capsules; outside the United States, 50mg/mL syrup

Oxantel Pamoate (Quantrel)6; Oxantel/Pyrantel Pamoate (Telopar)6

Oral: tablets containing 100 mg (base) of each drug; suspensions containing 20 or 50 mg (base) per mL

Piperazine (Generic, Vermizine)

Oral: piperazine citrate tablets equivalent to 250 mg of the hexahydrate; piperazine citrate syrup equivalent to 500 mg of the hexahydrate per 5 mL

Praziquantel (Biltricide; Others Outside the United States)

Oral: 600-mg tablets (other strengths outside the United States)

Pyrantel Pamoate (Antiminth, Combantrin, Pin-Rid, Pin-X)

Oral: 50 mg (base)/mL suspension; 62.5 mg (base) capsules (available without prescription in the United States)

Suramin (Bayer 205, Others)4

Parenteral: ampules containing 0.5- or 1-g powder to be reconstituted as a 10% solution and used immediately

Thiabendazole (Mintezol)

Oral: 500-mg chewable tablets; suspension, 500 mg/mL

1Ultramicrosize formulations of griseofulvin are approximately 1.5 times more potent, milligram for milligram, than the microsize preparations.

2Available in the United States only from the Drug Service, CDC, Atlanta (404-639-3670).

3Albendazole is approved in the United States for the treatment of cysticercosis and hydatid disease.

4Not marketed in the United States but is available from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta: 404-639-3670.

5Approved for use in the United States for the treatment of onchocerciasis and strongyloidiasis. See Chapter 1 for comment on the unlabeled use of drugs.

6Not available in the United States.