Treatment of InfectionsIII: Antifungal and

Antiparasitic Drugs

Antifungal Agents Fungi are plantlike microorganisms that exist ubiquitously

throughout the soil and air and in plants and animals. A disease caused by fungal infection is also referred to as a

mycosis Some fungal infections are relatively local or superficial,

affecting cutaneous and mucocutaneous tissue Often, fungal infections are relatively innocuous because

they can be destroyed by the body’s normal immune defense mechanisms

Fungal infections that are relatively easy to treat in the immunocompetent person may become invasive and life threatening in those who lack adequate immune function

Systemic Antifungal Agents

Amphotericin BClinical Use. is one of the primary drugs used to treat severe systemic fungal

infections This drug is often chosen to treat systemic infections and meningitis caused

by Candida, Cryptococcus,

Mechanism of Action. Amphotericin B appears to work by binding to specific steroidlike lipids

(sterols) located in the cell membrane of susceptible fungi.

Adverse Effects. Most patients experience problems such as headache, fever, muscle and joint

pain, muscle weakness, and gastrointestinal distress (nausea, vomiting, stomach pain or cramping).

FluconazoleClinical Use. This drug is often the primary treatment for urinary tract infections,

pneumonia, and infections of the mouth and esophagus caused by the Candida species of fungus.

Mechanism of Action. Fluconazole and similar agents (itraconazole, ketoconazole) inhibit certain enzymes in

fungal cells that are responsible for the synthesis of important sterols. also directly damages the fungal membrane by destroying certain membrane

components such as triglycerides and phospholipids

Adverse Effects. Hepatotoxicity is the most serious adverse effect of fluconazole Other common side effects include headache and gastrointestinal disturbances

(abdominal pain, nausea, vomiting)

FlucytosineClinical Use. This drug is used systemically to treat endocarditis, urinary tract infections, and the

presence of fungi in the bloodstream (fungemia) during candidiasis. is also used to treat meningitis and severe pulmonary infections caused by

cryptococcosis

Mechanism of Action. is incorporated into susceptible fungi, where it undergoes enzymatic conversion to

fluorouracil,7 which acts as an antimetabolite during RNA synthesis in the fungus

Adverse Effects. may cause hepatotoxicity and may also impair bone marrow function, resulting in anemia,

leukopenia, and several other blood dyscrasias.

GriseofulvinClinical Use. is used primarily in the treatment of common fungal infections of the skin

known as tinea, or ringworm.

Mechanism of Action. enters susceptible fungal cells and binds to the mitotic spindle during cell

division

Adverse Effects. Common side effects of griseofulvin administration include headaches—

which may be severe—and gastrointestinal disturbances (nausea, vomiting, diarrhea).

Skin photosensitivity (increased reaction to ultraviolet light) may also occur

ItraconazoleClinical Use. is an azole antifungal agent that is effective against many systemic fungal

infections may also be used as the primary or alternative treatment for other fungal

infections, such as aspergillosis, chromomycosis, coccidioidomycosis, and various infections caused by the Candida species

Mechanism of Action. These drugs disrupt membrane function of the fungal cell by inhibiting the

synthesis of key membrane components such as sterols, and by directly damaging other membrane components such as phospholipids.

Adverse Effects. Side effects associated with itraconazole include headache, gastrointestinal

disturbances (nausea, vomiting), and skin rash.

KetoconazoleClinical Use. is used to treat a variety of superficial and deep fungal infections.

Mechanism of Action. Ketoconazole selectively inhibits certain enzymes that are responsible for the

synthesis of important sterols in fungal cells.

Adverse Effects. Gastrointestinal disturbances (nausea, vomiting, stomach pain) are the most

common adverse effects when ketoconazole is administered systemically. Some degree of hepatotoxicity may occur, and severe or even fatal hepatitis

has been reported on rare occasions

EchinocandinsClinical Use. These drugs are administered intravenously to treat severe esophageal

infections caused by Candida. is also used to treat systemic aspergillosis infections in patients who cannot

tolerate other drugs such as amphotericin B or fluconazole

Mechanism of Action. These drugs inhibit the glucan synthase enzyme that is responsible for the

biosynthesis of beta-D-glucan—a component of the fungal cell membrane

Adverse Effects. Primary side effects of caspofungin and micafungin include gastrointestinal

disturbances (nausea, vomiting) and headache.

TerbinafineClinical Use. is effective against a broad spectrum of fungi and can be administered

systemically to treat infections in the toenails and fingernails (onychomycosis) that are caused by various fungi.

Mechanism of Action. Terbinafine inhibits a specific enzyme (squalene epoxidase) that is

responsible for sterol synthesis in the fungal cell membrane.

Adverse Effects. Systemic administration of terbinafine may cause a hypersensitivity

reaction (skin rashes, itching) and gastrointestinal problems such as nausea, vomiting, and diarrhea.

VoriconazoleClinical Use. Voriconazole has a broad antifungal spectrum, and is administered

systemically to treat aspergillosis and other serious fungal infections caused by Scedosporium apiospermum and Fusarium

Mechanism of Action. Inhibits sterol biosynthesis in fungal cell membranes

Adverse Effects. Skin rashes and vision disturbances (blurred vision, seeing bright spots) are

common during voriconazole administration, but these side effects are usually transient and fairly uneventful.

Topical Antifungal Agents

Topical Azole AntifungalsClinical Use. these drugs are valuable in controlling fungal infections in the skin

andmucocutaneous tissues

Mechanism of Action. antifungal azoles work by inhibiting the synthesis of key components of the fungal cell

membrane; that is, these drugs impair production of membrane sterols, triglycerides, and phospholipids

Adverse Effects. Gastrointestinal distress (cramps, diarrhea, vomiting) can occur if azole lozenges are

swallowed. Other problems associated with topical use include local burning or irritation of the

skin or mucous membranes.

Antiprotozoal Agents

Protozoa are single-celled organisms that represent the lowest division of the animal kingdom.

One relatively common disease caused by protozoal infection is malaria. Malaria is caused by several species of a protozoan parasite known as plasmodia

Antimalarial Agents

ChloroquineClinical Use. chloroquine (Aralen) has been one of the primary antimalarial drugs This drug provides a safe, effective, and relatively inexpensive method for treating

malaria, and is also administered routinely to individuals who are traveling to areas of the world where they may be exposed to malaria infection

Mechanism of Action. chloroquine may impair metabolic and digestive function in the protozoa by becoming

concentrated within subcellular vacuoles and raising the pH of these vacuoles

Adverse Effects. The most serious problem associated with chloroquine is the possibility of toxicity to

the retina and subsequent visual disturbances

Hydroxychloroquine Hydroxychloroquine (Plaquenil) is derived chemically from chloroquine and is similar

to it in clinical use, mechanism of action, and adverse effects.

MefloquineClinical Use. Mefloquine (Lariam) has emerged as one of the most important antimalarial agents. This drug is especially important in the prevention and treatment of malaria that is resistant

to traditional antimalarial drugs such as chloroquine and quinine

Mechanism of Action. mefloquine may exert antimalarial effects similar to chloroquine; that is, these drugs inhibit

hemoglobin digestion in malarial parasites, thus causing heme by-products to accumulate within the protozoa and cause toxicity and death of this parasite.

Adverse Effects. At higher doses, such as those used to treat infection, mefloquine may cause dizziness,

headache, fever, joint and muscle pain, and gastrointestinal problems (abdominal pain, nausea, vomiting, diarrhea).

PrimaquineClinical Use. Primaquine is typically used to treat the relapses of specific forms of malaria, and is generally

administered in acute or severe exacerbations

Mechanism of Action. appears to impair DNA function in susceptible parasites

Adverse Effects. Gastrointestinal disturbances (nausea, vomiting, abdominal pain), headache, and visual

disturbances

PyrimethamineClinical Use. is only of minor use in treating and preventing malaria. the antimalarial effectiveness of pyrimethamine is increased dramatically by

combining it with the antibacterial drug sulfadoxine

Mechanism of Action. Pyrimethamine blocks the production of folic acid in susceptible protozoa by

inhibiting the function of the dihydrofolate reductase enzyme.

Adverse Effects. Toxicity is fairly common when these drugs are given in high dosages for prolonged

periods, and adverse effects include gastrointestinal disturbances (vomiting, stomach cramps, loss of appetite), blood dyscrasias (agranulocytosis, leukopenia, thrombocytopenia), CNS abnormalities (tremors, ataxia, seizures), and hypersensitivity reactions (skin rashes, anaphylaxis, liver dysfunction).

QuinineClinical Use. Quinine is one of the oldest forms of antimalarial chemotherapy remains one of the most effective antimalarial drugs and is currently used to treat

severe malaria that is resistant to other drugs

Mechanism of Action. This drug probably exerts antimalarial effects similar to those of chloroquine—that is,

inhibition of hemoglobin digestion and subsequent accumulation of toxic heme by-products that lead to death in susceptible protozoa

Adverse Effects. This drug may produce disturbances in the CNS (headache, visual disturbances, ringing in

the ears), gastrointestinal system (nausea, vomiting, abdominal pain), and cardiovascular system (cardiac arrhythmias). Problems with hypersensitivity, blood disorders, liver dysfunction, and hypoglycemia may also occur in some individuals.

Other Antimalarials: Use of Artemisinin DerivativesClinical Use. These agents act rapidly and appear to be effective against all malarial parasites that

infect humans

Mechanism of Action. appear to work by a two-step process occurring within the malarial parasite first step, the drug is activated when it is cleaved by the heme-iron component within the

protozoa. second step, reacts with and destroys essential protozoal proteins.

Adverse Effects. Because these drugs are fairly new, the potential for side effects remains to be

determined fully.

Drugs Used to Treat Protozoal Infections in the Intestines and Other Tissues

AtovaquoneClinical Use. is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that

causes pneumocystis pneumonia in immunocompromised patients

Mechanism of Action. appears to selectively inhibit electron transport in susceptible microorganisms

Adverse Effects. may cause side effects such as fever, skin rash, cough, headache, and gastrointestinal

problems (nausea, vomiting, diarrhea).

Emetine and DehydroemetineClinical Use. are used primarily to treat protozoal infections in the intestinal tract and extraintestinal

sites such as the lungs and liver.

Mechanism of Action. These drugs exert a direct effect on susceptible protozoa by causing degeneration of

subcellular components

Adverse Effects. problems with cardiotoxicity may occur, as reflected by arrhythmias, palpitations, and

other changes in cardiac conduction and excitability.

IodoquinolClinical Use. is used primarily to treat protozoal infections within the intestinal tract,51 and it is

often combined with a second tissue amebicide, which kills protozoa at extraintestinal sites.

Mechanism of Action. The mechanism of action of iodoquinol as an amebicide is unknown.

Adverse Effects. Iodoquinol is neurotoxic and may produce optic and peripheral neuropathies when

administered in large dosages for prolonged periods.

MetronidazoleClinical Use. is effective against a broad spectrum of protozoa and is often the primary agent used

against protozoal infections in intestinal and extraintestinal tissues

Mechanism of Action. The exact mechanism of action of metronidazole is not known.

Adverse Effects. Gastrointestinal disturbances including nausea, vomiting, diarrhea, stomach pain, and

an unpleasant taste in the mouth are relatively common with metronidazole.

NitazoxanideClinical Use. is a relatively new agent that is used primarily to treat diarrhea caused by intestinal

cryptosporidia and giardia infections

Mechanism of Action. appears to inhibit electron transport in susceptible protozoa, thus inhibiting energy

metabolism in these parasites.

Adverse Effects. Gastrointestinal disturbances (vomiting, diarrhea) and headache

ParomomycinClinical Use. is an aminoglycoside antibacterial that is used primarily to treat mild to moderate

intestinal infections (amebiasis)

Mechanism of Action. Paromomycin acts selectively on protozoa within the intestinal lumen and destroys

these parasites by a direct toxic effect

Adverse Effects. problems with gastrointestinal distress (nausea, vomiting, abdominal pain) may

occur

PentamidineClinical Use. is effective against several types of extraintestinal protozoal infections, including

certain forms of trypanosomiasis (African sleeping sickness) and visceral infections caused by Leishmania protozoa

Mechanism of Action. Some possible antiprotozoal actions of this drug include the inhibition of protein and

nucleic acid synthesis, cellular metabolism, and oxidative phosphorylation in susceptible parasites.

Adverse Effects. The primary adverse effect of systemic pentamidine administration is renal toxicity.

Anthelmintics Infection from helminths, or parasitic worms, is the most common form of disease in

the world Worms can enter the body by various routes but often are ingested as eggs in

contaminated food and water Once in the body, the eggs hatch, and adult worms ultimately lodge in various

tissues, especially the digestive tract. The adult worms begin to steal nutrients from their human host and may begin to

obstruct the intestinal lumen or other ducts if they reproduce in sufficient numbers.

Albendazole is primarily used to treat infections caused by the larval form of certain cestodes

(tapeworms). albendazole is used as an adjunct to the surgical removal of these cysts or as the

primary treatment if these cysts are inoperable This drug is also effective against many gastrointestinal roundworms and hookwo Albendazole exerts its anthelmintic effects by acting on the intestinal cells of

parasitic worms and by inhibiting glucose uptake and glycogen storage by these parasites.

Long-term treatment for conditions such as hydatid disease may result in abnormal liver function tests (e.g., increased serum aminotransferase activity), and liver function

Diethylcarbamazine is used to treat certain roundworm infections of the lymphatics and connective

tissues, including loiasis, onchocerciasis, and Bancroft filariasis. This agent immobilizes immature roundworms (microfilariae) and facilitates the

destruction of these microfilariae by the body’s immune system. Side effects associated with diethylcarbamazine include headache, malaise,

weakness, and loss of appetite.

Ivermectin is the primary treatment for filarial nematode infections (onchocerciasis) that invade

ocular tissues and cause loss ofvision (river blindness). Ivermectin binds to chloride ion channels in parasitic nerve and muscle cells, thereby

increasing membrane permeability to chloride. may cause swollen or tender lymph glands, fever, skin rash, itching, and joint and

muscle pain

Mebendazole is effective against many types of roundworms and a few tapeworms that parasitize

humans. this drug selectively damages intestinal cells in these worms, thus inhibiting the

uptake and intracellular transport of glucose and other nutrients into these parasites. Mebendazole is a relatively safe drug, although some mild, transient gastrointestinal

problems may occur.

Niclosamide This drug inhibits certain mitochondrial enzymes in these parasites, which ultimately

results in the breakdown of the protective integument of the worm, thus allowing the digestive enzymes in the host (human) intestine to attack the parasite.

There are relatively few adverse effects of niclosamide treatment, probably because the drug is not absorbed to any great extent from the human intestine.

Oxamniquine is effective against a genus of parasitic worms known as blood flukes

(schistosomes). Oxamniquine inhibits muscular contraction of the sucker that holds the fluke to the

vessel wall, thus allowing the worm to dislodge and travel to the liver. Common side effects associated with this drug include headache, dizziness, and

drowsiness.

Piperazine Citrate is typically used as a secondary agent in ascariasis (roundworm) and enterobiasis

(pinworm) infections This drug appears to paralyze the worm by blocking the effect of acetylcholine at the

parasite’s neuromuscular junction Side effects such as headache, dizziness, and gastrointestinal disturbance

Praziquantel is one of the most versatile and important anthelmintic agents, and is the drug of

choice in treating all major trematode (fluke) infections and several common types of tapeworm infections

may stimulate muscular contraction of the parasite, resulting in a type of spastic paralysis, which causes the worm to lose its hold on intestinal or vascular tissue.

frequent side effects, including gastrointestinal problems (abdominal pain, nausea, vomiting), CNS effects (headache, dizziness), and mild hepatotoxicity

Pyrantel Pamoate is one of the primary agents used in several types of roundworm and pinworm

infections This drug stimulates acetylcholine release and inhibits acetylcholine breakdown at

the neuromuscular junction, thus producing a prolonged state of excitation and muscular contraction that causes spastic paralysis of the worm

Thiabendazole The anthelmintic mechanism of this drug is not fully understood, but selective

inhibition of certain key metabolic enzymes in susceptible parasites is probable. The most common side effects associated with this drug involve gastrointestinal

distress (nausea, vomiting, loss of appetite).