2. Protozoal Infections - Introduction
• Amebiasis , Giardiasis , Trichomoniasis , Trypanosomiasis , Leishmaniasis
• Transmitted by insect vectors or directly from other mammalian
• Protozoa multiply rapidly in their hosts
• Effective vaccines are unavailable
• Chemotherapy is only practical way to both:
1. Treat infected individuals
2. Reduce transmission
oImmune system plays a crucial role in protecting of protozoal infections
2
3. Protozoal Infections - Amebiasis
•10% of the world's population
•Ingested E. histolytica cysts from contaminated food or water
survive acid gastric contents and transform into trophozoites that
reside in the large intestine
1. Asymptomatic
2. Colitis and bloody diarrhea (amebic dysentery)
3. amebic liver abscess
3
4. Protozoal Infections - Amebiasis
•The cornerstone of therapy :
•Metronidazole or its analogs Tinidazole
•The drugs of choice
• Less effective against cysts
•Luminal agents
• to eradicate any E. histolytica trophozoites residing within the gut
lumen
• Paromomycin and Iodoquinol
oDiloxanide furoate
4
5. Protozoal Infections - Giardiasis
oGiardia intestinalis
1. asymptomatic carrier state
2. acute self-limited diarrhea
3. chronic diarrhea
•a 5-day course of metronidazole usually is successful
•A single dose of tinidazole probably is superior to metronidazole
oParomomycin
oFurazolidone
5
6. Protozoal Infections -Trichomoniasis
•Trichomonas vaginalis
•the genitourinary tract of the human host
oWomen & Men
•The drug of choice : Metronidazole
•Tinidazole
•Better tolerated than metronidazole
•Successfully at higher doses to treat metronidazole-
resistant T. vaginalis
6
7. Protozoal Infections -Toxoplasmosis
oToxoplasma gondii
•The acute illness
•usually self-limiting
•treatment rarely is required
•Individuals who are immunocompromised
•a risk of developing toxoplasmic encephalitis
oClinical manifestations of congenital toxoplasmosis vary
widely
7
8. Protozoal Infections -Toxoplasmosis
• The primary treatment for toxoplasmic encephalitis
• Pyrimethamine and sulfadiazine (or Clindamycin)
• Clindamycin is the substitution of sulfadiazine without loss of efficacy
• Alternative regimens
• azithromycin, clarithromycin, atovaquone, or dapsone
+
• Trimethoprim-sulfamethoxazole or pyrimethamine and folinic acid
oAcute acquired toxoplasmosis in pregnancy : Spiramycin
• Fetal infection
othe combination of pyrimethamine, sulfadiazine, and folinic acid for the mother
8
9. Protozoal Infections - Cryptosporidiosis
•Cryptosporidium parvum (newly named C. hominis)
•Diarrhea
•self-limited infection in most individuals
oin immunocompromised individuals, the severity of voluminous,
secretory diarrhea
•Nitazoxanide
•the only drug approved for cryptosporidiosis in the U.S.
9
10. Protozoal Infections -Trypanosomiasis
oAfrican trypanosomiasis, or "sleeping sickness"
• Trypanosoma brucei
• The parasite is entirely extracellular
• stage 1 : early human infection
• Pentamidine for T. brucei gambiense and Suramin for T. brucei rhodesiense
• stage 2 : CNS involvement
• Traditionally : Melarsoprol
• a highly toxic agent that causes a fatal reactive encephalopathy in 2-10% of treated
patients
• the only alternative : Eflornithine
• which was developed originally as an anticancer 10
11. Protozoal Infections - Leishmaniasis
• obligate intramacrophage protozoa
• Cutaneous forms of leishmaniasis generally are self-limiting
• with cures occurring in 3-18 months after infection
• can leave disfiguring scars
• The mucocutaneous, diffuse cutaneous, and visceral forms of the disease do not resolve without
therapy
• The classic therapy for all species of Leishmania : pentavalent antimony
• alternative : amphotericin B
• highly effective agent for visceral leishmaniasis
• The drug of choice for antimony-resistant disease
o Paromomycin
• Pentamidine may also be used for cutaneous disease
11
12. Protozoal Infections - Other Protozoal Infections
oBabesiosis
• clindamycin and quinine for severe disease (first line)
• azithromycin and atovaquone for mild or moderate infections
oBalantidiasis
oIsospora belli (Cystoisospora belli)
oMicrosporidia (Albendazole) 12
13. Anti-Protozoal Drugs
oAmphotericin B
• visceral leishmaniasis
• highly effective ( cures >90% )
• the drug of choice for antimonial-resistant cases
• second-line drug for cutaneous or mucosal leishmaniasis
oDiloxanide Furoate
• Emetine and Dehydroemetine
• systemic amebicide
• Dehydroemetine has similar pharmacological properties but less toxic
• have been replaced by metronidazole, which is as effective and far safer
13
14. Anti-Protozoal Drugs - 8-Hydroxyquinolines
• A luminal agent to eliminate intestinal colonization with E. histolytica
• appropriate doses (never to exceed 2 g/day and duration of therapy not greater than 20
days in adults)
oThe most important toxic reaction : Subacute myelo-optic neuropathy
• Peripheral neuropathy
• High doses in children with chronic diarrhea : optic atrophy and loss of vision
• To treat amebiasis
• Paromomycin is preferred as the luminal agent used
• Iodoquinol is a reasonable alternative
• Amebic colitis or amebic liver abscess
• A combination with metronidazole
oAsymptomatic E. histolytica (a single agent for)
14
15. Anti-Protozoal Drugs - Metronidazole
• Active against a wide variety of anaerobic protozoal parasites and anaerobic bacteria
• Directly trichomonacidal
• Potent amebicidal activity against E. histolytica
• Activity against all anaerobic cocci
• Both anaerobic gram-negative bacilli
• Bacteroides spp., anaerobic spore-forming gram-positive bacilli
15
16. Anti-Protozoal Drugs - Metronidazole
•usually is absorbed completely and promptly after oral intake
•With the exception of the placenta, metronidazole penetrates well
into body tissues and fluids
•vaginal secretions, seminal fluid, saliva, breast milk, CSF
•The liver is the main site of metabolism
16
17. Metronidazole -Therapeutic Uses
1. T. vaginalis
• in both females and males in >90% of cases
• 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 than metronidazole
• metronidazole-resistant strains can be treated successfully by giving a second 2-g dose
to both patient and sexual partner
2. Amebiasis (choice)
• Against all symptomatic forms
• amebic colitis and amebic liver abscess
17
18. Metronidazole -Therapeutic Uses
3. Giardiasis
• Tinidazole as a single 2-g dose and is appropriate first-line therapy
4. susceptible anaerobic bacteria
• Bacteroides, Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus,
Eubacterium, Helicobacter
5. polymicrobial infections with aerobic and anaerobic bacteria
6. prophylaxis for colorectal surgery
7. bacterial vaginosis
8. in regimens to treat infection with H. pylori
9. primary therapy for Clostridium difficile infection
10. Crohn's disease with perianal fistulas
18
19. Metronidazole - Side effects
• The most common : headache, nausea, dry mouth, a metallic taste
• Vomiting, diarrhea, abdominal distress
• exacerbation of candidiasis
• Furry tongue, glossitis, and stomatitis
• Neurotoxic effects
• Dizziness, vertigo, and very rarely, encephalopathy, convulsions, incoordination, ataxia
• warrant discontinuation of metronidazole
• caution in patients with active disease of the CNS because of its potential neurotoxicity
• should be withdrawn if numbness or paresthesias of the extremities occur
• Urticaria, flushing, and pruritus are indicative of drug sensitivity that can require withdrawal of
metronidazole
• Stevens-Johnson syndrome (toxic epidermal necrolysis) (rare)
• Dysuria, cystitis, and a sense of pelvic pressure have been reported
• Disulfiram-like effect
• during the first trimester generally is not advised
• Although it has been taken during all stages of pregnancy with no apparent adverse effects 19
20. Paromomycin
• orally to treat cryptosporidiosis and giardiasis
• topical to treat trichomoniasis
• Treating intestinal colonization with E. histolytica (choice)
• amebic colitis and amebic liver abscess
• combination with metronidazole
• asymptomatic E. histolytica intestinal colonization
ocutaneous leishmaniasis
ovisceral leishmaniasis
• Oral adverse effects (rare)
• abdominal pain and cramping, epigastric pain, nausea and vomiting, steatorrhea, diarrhea
20
21. Chemotherapy of Malaria: Introduction
•single-celled protozoan parasites of genus Plasmodium
•Five Plasmodium spp. are known to infect humans:
oP. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi
•P. falciparum accounts for majority of burden of malaria
•the most severe disease
21
26. Three general categories
1. Artemisinins (Artemisinin, artesunate, artemether), chloroquine, mefloquine,
quinine and quinidine, pyrimethamine, sulfadoxine, tetracycline
• that are not reliably effective against primary or latent liver stages
• against the asexual blood stages responsible for disease
• These drugs will treat, or prevent, clinically symptomatic malaria
2. atovaquone and proguanil (Malarone)
• not only the asexual erythrocytic forms but also the primary liver stages of P. falciparum
• This additional activity shortens to several days the required period for postexposure chemoprophylaxis
3. Primaquine
• against primary and latent liver stages as well as gametocytes
• Primaquine is used most commonly to eradicate the intrahepatic hypnozoites of P. vivax and P. ovale that
are responsible for relapsing infections
• Tafenoquine, a long half-life analogue of primaquine
• similar spectrum of action as primaquine, is in advanced clinical trials
27
29. Chloroquine and Hydroxychloroquine
•Hydroxychloroquine
•equivalent to chloroquine against P. falciparum malaria
•preferred over chloroquine for treatment of mild rheumatoid
arthritis and lupus erythematosus
• in the high doses required, it may cause less ocular toxicity
• Care should be taken in G6PD deficiency
30
30. Chloroquine and Hydroxychloroquine -Therapeutic Uses
•Chloroquine
•Erythrocytic forms of Plasmodium
• Highly effective
• Choice For P. ovale and P. malariae
•Nonmalarial conditions (Chloroquine and hydroxychloroquine)
• Hepatic amebiasis
• have anti-inflammatory properties
• Rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis
31
31. Chloroquine and Hydroxychloroquine -Toxicity and Side Effects
• Cardiovascular
• Hypotension, vasodilation, suppressed myocardial function, cardiac
arrhythmias, eventual cardiac arrest
• Hemolysis and blood dyscrasias (rare)
• Discoloration of nail beds and mucous membranes
• High daily doses of chloroquine or hydroxychloroquine
• irreversible retinopathy and ototoxicity
• Prolonged therapy with high doses of chloroquine or hydroxychloroquine
• toxic myopathy, cardiopathy, peripheral neuropathy
32
32. Chloroquine and Hydroxychloroquine -Toxicity and Side Effects
•Precautions and Contraindications
• Chloroquine is not recommended in epilepsy or myasthenia gravis
• Most important, chloroquine opposes the action of anticonvulsants
• Chloroquine can cause hemolysis in patients with G6PD deficiency
• Chloroquine should not be used for patients with psoriasis or other
exfoliative skin conditions
• should not be used to in patients with porphyria cutanea tarda
• the danger of cutaneous reactions
• Ophthalmological and neurological evaluations every 3-6 months in long-
term and high-dose
33
33. QUININE & QUINIDINE
oClinical Uses
1. Parenteral treatment of severe falciparum malaria
2. Oral treatment of falciparum malaria
3. Malarial chemoprophylaxis
•Quinine is not generally used in chemoprophylaxis owing to its
toxicity
4. Babesiosis
•Quinine is first-line therapy, in combination with clindamycin
5. Nocturnal Leg Cramps
34
34. QUININE & QUINIDINE - Side Effects
oCinchonism
oHypoglycemia (common)
oHypotension (rare)
•Severe hemolysis
• can result from hypersensitivity to these cinchona alkaloids
• “Blackwater fever” : massive hemolysis, hemoglobinemia, hemoglobinuria
• leading to anuria, renal failure, and in some instances death
• a rare hypersensitivity reaction to quinine therapy that can occur during treatment of
malaria
• Milder hemolysis, in people with G6PD deficiency
• should be discontinued immediately if evidence of hemolysis appears35
35. Primaquine
•acts on exoerythrocytic tissue stages of Plasmodium spp.
•in the liver to prevent and cure relapsing malaria
•Patients should be screened for G6PD deficiency prior to therapy
with this drug
Therapeutic or higher doses of primaquine may cause acute
hemolysis and hemolytic anemia in humans with G6PD deficiency
36
