Antifungals and Antiprotozoals

Antifungals and Antiprotazoals

Antifungals

General: multiply in the host (can lead to resistance, inoculum does not represent extent of infection)

host factors are very important in infection, host is usually compromised somehow (immuno-compromised,
secondary to antibiotic therapy, prolonged angiocatheterization, etc)
fungal membranes use ergosterol, so that is the major therapeutic target (except pneumocystis - cholesterol)

Polyene Marcolides: bind to ergosterol and forms pores in the membrane

amphotericin B: broad spectrum: good for everything but Candida lusitaniae, Pseudalleschria boydii, Fusarium, pneumocystis carinii (no ergosterol)

does not penetrate the blood-brain barrier, but can be given intrathecally
side effects: fever, chills, rigors, hypotension; long-term renal toxicity (due to afferent constriction)

nystatin: too toxic for parenteral use; topical or oral (not absorbed at all)

great for superficial candida infections

Azoles: inhibits ergosterol synthesis at the 14a -demethylase step (a P-450 dependant system)

ketoconazole (diazole): the prototype of this class

use has declined with advents of less toxic triazoles; still used for superficial candida

also inhibits testosterone and cortisol synthesis, so hormonal side effects

fluconazole (triazole): no hormonal side effects

penetrates the BBB, so drug of choice in cryptococcal meningitis; also candida, coccidiomycosis

itraconazole (triazole): no hormonal side effects, no BBB penetration

used for Candida (except C. krusei), Histoplasma, Cryptococcus and Coccidioides, Aspergillis blastomycosis

flucytosine: is incorporated into RNA and disrupts protein synthesis

enters cells through pores, so only used as an adjunct with amphotericin B for cryptococcus and candida

griseofulvin: binds to microtubules; fungistatic

a systemic drug (given orally) for superficial infections that are unresponsive to other treatment

Trimethoprim-sulfamethoxazole: folate antagonist used against Pneumocystis carinii

Antiprotazoals

protazoa are unicellular; multiply in the host

for aerobes:

malaria: quinolines: mechanism unknown, but could involve alkalization of food vacules, inhibition of heme metabolism leading to a toxin, or DNA inhibition

primaquine: only effective against the tissue stages of malaria; used in radical cure of vivax to kill the liver phase and prevent relapse

causes hemolytic anemia in G-6-Pase deficient patients

chloroquine: resistant except in central America, Turkey, and Arabian Peninsula

used as prophylaxis in these areas
can have retinal toxicity

quinine: quinidine (oral form): more toxic, but used to treat severe forms

arrhythmias may result from quinidine
quinine can cause chinchonism (N/V, tinnitus, vertigo)

mefloquine: used against P. falciparum (most severe form of malaria)

used in prophylaxis
toxic when combined with quinine

toxoplasmosis

pyrimethamine-sulfadiazine: folate antagonist

for anaerobes:

E. histolytica (ameobiasis), Trichomonas vaginalis, Giardia lamblia

metronidazole: forms free radicals in anaerobes (bacteria and protozoa; can act like anabuse and raise acetaldehyde levels

Antihelminths

helminths are multicellular; don’t multiply in host; inoculum determines severity; resistance development is usually not a problem, so single broad-spectrum drugs can often be used

nematodes (roundworms)

benzimidizoles (albendazole, mebendazole, thiobendazole): inhibit microtubules

used in tissue and luminal infections; albendazole also used for tapeworms

ivermectin: activates glutamate-sensitive Cl^- channels; used in systemic infections

cestodes and trematodes (flukes)

praziquantel: increases Ca⁺⁺ permiability; drug of choice for shisto and other flatworms

Important Parasitic Drugs

Drug Class	Target parasite(s) and stage	Mechanism of action	Routes of Admin.	Toxic effects and drug interations
quinolines chloroquine quinine (quinidine) mefloquine primaquine	malaria asexual blood stages tissue stages and gametes	Probable: concentrate in parasite; raise vacuolar pH, interfere with heme metabolism; toxic complexes with heme, DNA, etc. unknown- ? similar to above	oral and i.v. oral	chloroquine-retinal degeneration quinine-cinchonism quinidine-arrhythmias mefloquine-arrhythmias/CNS motor hemolysis in G6PD individuals
Tetracyclines Tetracycline doxycycline	malaria asexual blood stages	Prevents protein synthesis; binds the small rRNA subunit.	oral and i.v. (tet only)	incorporated in teeth and bone. not given to young children or pregnant women
antifolates	malaria - asexual blood stages and Toxoplasma	Interfere with folate biosynthesis and metabolism (see antibacterials)	oral and i.v.	allergy bone marrow suppression
metronidazole	amebiasis-liver, intestinal forms; Giardia; Trichomonas	Interferes with redox of anaerobic organisms generating free radicals	oral and i.v.	abdominal cramping and Antabuse-like effects
benzimidazoles mebendazole albendazole thiabendazole	round worms intestinal and tissue. Note: albendazole is also used for tissue tapeworms	Binds selectively to parasite beta tubulin	oral	nausea and vomiting side effects most common with thiabendazole
praziquantel	adult and immature tapeworms and trematodes, e.g. Schistosoma.sp.i	induces calcium-dependent tetany and tegumental damage	oral	nausea and vomiting CNS toxicity at high doses

Antifungal Drugs

Drug Class	Target parasite(s) and stage	Mechanism of action	Routes of Administration	Toxic effects and drug interactions
Polyene macrolides
Amphotericin B	All invasive fungal infections except: Pneumocystis, Candida lusitaniae, Pseudalleschria boydii, Fusarium	Probable: disrupts fungal cytoplasmic membranes rich in ergosterol	intravenous or intrathecal	Acute: fever, chills, rigors and hypotension. Chronic: nephrotoxicity
Nystatin	Topical candidiasis	as Amphotericin	topical and oral (not absorbed)	virtually none
Azoles
Fluconazole	Candida (except C. krusei) Cryptococcus and Coccidiodes	Inhibits 14-b -demethylase used in ergosterol synthesis	oral and i.v.	Rare: hepatitis Drug interaction by P-450 activation
Itraconazole	Candida (except C. krusei), Histoplasma, Cryptococcus and Coccidioides	Inhibits 14-b -demethylase used in ergosterol synthesis	oral (requires increased gastric acid for absorption)	Rare: hepatitis Drug interaction by P-450 activation
Other
Trimethoprim- sulfamethoxazole	Pneumocystis carinii	Inhibits folate metabolism	Oral	Allergy, Bone marrow suppression

Antiprotozoal Drugs

*PROTOZOAL INFECTION*			Drug(s) for Treatment
Malaria
Chemoprophylaxis Central America, Mexico, Caribbean, Arabian Peninsula, Turkey			chloroquine
Everywhere else (note: P. falciparum resistance may be found in isolated areas of SE Asia to any of these)			mefloquine tetracycline proquanil§/chloroquine
Acute Attack When possible, 1 or 2 other drugs should be combined with quinine or chloroquine to avoid unsuspected resistances. Mefloquine and quinine should never be combined, however. Glucose infusion or consumption is important, especially in children.			quinine/quinidine (isoschizimers) chloroquine doxycycline pyrimethamine-sulfadoxine (controversial) mefloquine halofantrine§ artemether©§ (Wow! Watch this space)
Dormant Stage Parasites (for suspected P. vivax or P. ovale)			primaquine (P. vivax and P. ovale ; G6PD status?)
Amebiasis and Giardia
Entamoeba histolytica			metronidazole (intestinal and hepatic) iodoquinol or diloxanide‡ (intestinal carrier state)
Giardia Lamblia			chloroquine (hepatic only) metronidazole or quinacrine (Giardia in children and pregnancy)
Trichomoniasis
Trichomonas vaginalis			metronidazole
Toxoplasmosis
Toxoplama gondii			pyrimethamine-sulfadiazine trimethoprim-sulfamethoxazole pentamidine
Leishmaniasis
Visceral Cutaneous Leishmani donovani, L. major L. chagasi, L. mexicana, braziliensis			sodium stibogluconate amphotericin B pentamidine (visceral disease)
Trypanosomal infection
Trypanosoma brucei Trypanosoma cruzi (none is very effective)			African - suramin‡ (acute), pentamidine (acute) melarsoprol‡ (CNS) American - nifurtimox‡ (acute), primaquine (chronic)

Antihelminth Drugs

HELMINTH				Drug(s) for Treatment
Intestinal Roundworms
Ascaris lumbricoides (Ascariasis) Whipworm (Trichuris trichiura) Pinworm* (Enterobius vermicularis) Hookworm (Ankylostoma duodenale, Necator americanus)				mebendazole albendazole§ pyrantel
Intestinal Flatworms
Tapeworms-pork, beef, fish, rat (Taenia solium , T. saginata, Diphylabothrium latum, Hymenolepis nana)				niclosamide praziquantel
Invasive Roundworms
Stongyloidiasis (Strongyloides stercoralis) Cutaneous larva migrans (Ankylostoma caninum) Visceral larva migrans (Toxocara canis) Trichiniasis (Trichinella spiralis)				thiabendazole albendazole§
Onchocerciasis (Onchocerca volvulus) Lymphatic filariasis (Wuchereria bancrofti) Loa loa				ivermectin‡ diethylcarbamazine ivermectin‡
Guinea-worm† (Dracunculus medinensis)				thiabendazole metronidazole
Invasive Flatworms
Schistosomiasis (S. mansoni, S, haematobium, S. japonicum) Other flukes (Fasciola, Clonorchis, Paragonimus)				Praziquantel
Hydatid disease†† (Echinococcus granulosus)				Albendazole§
Cysticercosis (infection with larval T. solium)				albendazole§ praziquantel