Antimicrobial 5: Other Antiprotozoals Flashcards
Protozoa
What are the 4 major groupings (Phylums)?
i. Flagellates
ii. Amoebas
iii. Sporozoans
iv. Ciliates
Protozoa
• ____: any stage in a protozoan’s life cycle which can
ingest food. In practice also refers to the motile
form
• ____: the non motile form which is protected by a
distinct membrane or cyst wall. This is an
infective stage of the parasite
• ____: the process of emergence of the trophozoite
from the cyst (vs. encystation)
TROPHOZOITE
CYST
EXCYSTATION
Protozoa
Name 8 infections:
- Amoebiasis: organisms Infection caused by
Entamoeba
– Entamoeba hystolytica is the main organism of
concern - Trypanosomiasis: Trypanosomes belong to
pathogenic flagellate protozoa
– Trypanosoma brucei infection causes African
sleeping sickness
– Trypanosoma cruzi infection causes Chagas
disease - Leishmaniasis : Leishmania are protozoa spread by
the sandfly - Trichomoniasis: The principle organism infecting
humans is Trichomonas vaginalis - Giardiasis: Ingestion of food/water contaminated with
fecal matter containing cysts from Giardia
lamblia
– Giardia lamblia colonizes the upper GI tract
(trophozoite) - Cryptosporidiosis: Caused by the coccidian protozoal
species Cryptosporidium parvum
and Cryptosporidium hominis - Toxoplasmosis: Cat is the definitive host and its
infective cysts are found in the feces
– Toxoplasma gondii is a pathogenic member that can
infect humans (disease is usually self-limiting) - Pneumocystis: Caused by Pneumocystis jirovecii
(previously known as P. carinii ) and
causes pneumonia
– Shares structural features with both protozoa and
fungi
Protozoa
Drugs
See slide 8 picture
Metronidazole
Characteristics
• Clinically effective in trichomoniasis, amebiasis and
giardiasis
• Nitroimidazole antibiotic
Metronidazole
MOA
• Metronidazole is a prodrug: it requires reductive
activation of the nitro group to a reactive radical anion
by susceptible anaerobic organisms.
• The radical anion and other generated radicals target
DNA and other biomolecules of the parasite.
Metronidazole
AE
• * Rare neurotoxicity (encephalopathy, ataxia)
- Headache
- Nausea & vomiting
- Diarrhea
- Urticaria, flushing & pruritus
- Stevenson-Johnson syndrome
Metronidazole
Contraindications & Precautions
• Can interact with alcohol and disulfiram, resulting in
side effects such as headache, confusion, psychotic
states
• Not indicated in patients with active disease of the
CNS
• Not indicated in the first trimester of pregnancy
(teratogenic)
Tinidazole
Characteristics
MOA
- can be used during pregnancy
- same MOA as Metronidazole
Iodoquinol
Characteristics
MOA
• Orally administered to eliminate intestinal E.
histolytica
• Not effective on tissue trophozoites
• Halogenated 8-hydroxyquinoline
• Potent metal-binding agent. MOA unknown
Iodoquinol
AE
- Optic atrophy
- Permanent loss of vision
• Neuropathy
Iodoquinol
Contraindications & Precautions
• Use with caution in patients with neuropathies or
thyroid diseases
Paromomycin
Characteristics
• Aminoglycoside of the neomycin/kanamycin family
• Used to treat cryptosporidiosis, giardiasis and
trichomoniasis. It is also the drug of choice (in
combination with metronidazole) for treating intestinal
colonization with E. histolytica
Paromomycin
MOA
• Bind irreversibly to the 30S ribosomal subunit and
inhibit protein synthesis (trap ribosomes at the AUG
start codon)
Paromomycin
AE
- Nephrotoxicity
- Ototoxicity
- Abdominal pain
- Nausea & vomiting
- Diarrhea
Nitazoxanide
Characteristics
• Nitazoxanide is an oral antiparasitic and antiviral gent,
its metabolite tizoxanide is active and this agent is
approved for the treatment of giardiasis and
cryptosporidiosis
Nitazoxanide
MOA
• Proposed mechanism of action is due to inhibiting
pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-
dependent electron transfer, which is important for
parasite anaerobic energy metabolism
Nitazoxanide
AE
- Headache
- GI upset (abdominal pain, vomiting, diarrhea)
- Teratogenic in animal studies
Co-Trimoxazole
Characteristics
• Combination therapy of sulfamethoxazole (sulfa
antibiotics) and trimethoprim (folic acid antagonist)
that is the treatment of choice for toxoplasmosis and
pneumocystis pneumonia
Co-Trimoxazole
MOA
- Sulfamethoxazole inhibits dihydropteroate synthetase
* Trimethoprim inhibits dihydrofolate reductase
Co-Trimoxazole
AE
• Similar to those discussed sulfadoxine + pyrimethamine
African Sleeping Sickness
What are 2 subtypes of Trypanosoma brucei that
can cause African sleeping sickness?
Trypanosoma brucei gambiense
Trypanosoma brucei rhodesiense
African Sleeping Sickness
Transmission?
When bitten by an infected tsetse fly, the protozoa is injected into the human skin. From there, it then move into the lymphatic system and bloodstream, where it is
able to travel throughout the body and reach the brain.
African Sleeping Sickness
Symptoms
Skin:
A bump on the skin within a few days from
tsetse fly bite
Blood/lymph nodes:
fevers, chills, headache, muscle/joint pain
Brain/cerebrospinal fluid:
persistent headaches, drowsiness that worsens,
loss of concentration, troubles with
balance/walking
See slide 18 for more details :-)
Chagas Disease
Also called the Kissing Bug Disease.
What infection causes Chagas disease?
Trypanosoma cruzi infection
Chagas Disease
Transmission
• When a kissing bug (Triatromine) bites a human or
animal, the infected bug deposits feces that contains
the protozoa. The protozoa then enters the body
through the bite wound.
• The protozoan can also enter through tissues around
the eye
Chagas Disease
Symptoms
1st stage:
- swollen red bump at bite wound or swelling at area
around the eye
2nd stage:
- Latent period. No symptoms. ECG and imaging tests
are normal, despite protozoa still present in body
- Many people remain in this stage for the rest of their
lives
3rd stage:
- Mainly affects heart and digestive system
African Sleeping Sickness
Drugs (4)
- Suramin
- Pentamidine
- Melarsoprol
- Eflornithine
Chagas Disease
Drugs (2)
- Nifurtimox
- Benznidazole
Suramin
MOA
Binds to plasma proteins and enters the parasite via endocytosis, where it inhibits key enzymes (e.g. glycolysis enzymes, thymidine kinase, dihydrofolate reductase) inducing gradual destruction of organelles
Suramin
AE
- Renal toxicity
- Leukopenia (in people with AIDS)
- Optical atrophy
- Adrenal insufficiency
- Skin rashes
- Hemolytic anemia
Pentamidine
MOA
Taken up into parasite via an energy-dependent carrier and thought to interact with DNA (may inhibit both DNA and protein synthesis)
Pentamidine
AE
- Hypoglycemia
- Decreased blood pressure
- Tachycardia
- Headache
- Breathlessness
- Vomiting
- Kidney damage
- Hepatic impairment
- Blood dyscrasias
Melarsoprol
MOA
• Organic arsenic compound used when CNS infection
at play as it enters the CNS in high concentrations
(prodrug that gets converted to melarsen oxide)
• Interacts with protein sulfhydryl groups (enzyme
inactivation)
Melarsoprol
AE
Highly toxic, can cause encephalopathy and sometimes immediate fatality (administered only under strict supervision)
Eflornithine
MOA
Inhibits parasite ornithine decarboxylase (ODC) enzyme
irreversibly (decreases formation of polyamines needed for cell replication)
Eflornithine
AE
- Abdominal pain
- Headache
- Fever
- Seizures
- Hearing loss
Nifurtimox/Benznidazole
MOA
• Nifurtimox is a nitrofuran analog and benznidazole a
nitroimidazole analog
• Both are activated by NADH dependent
nitroreductases in mitochondria, leading to
generation of nitro free radicals that are believed to
kill the parasite
Nifurtimox/Benznidazole
AE
- Hypersensitivity (dermatitis, fever, anaphylaxis)
- GI upset (nausea, vomiting)
- Peripheral neuropathy
- Neurotoxicities (less frequent)
- Leukopenia
Summary
____ which is a prodrug that is converted into a free radical that can interact with DNA, and is used for the treatment of trichomoniasis, amebiasis and giardiasis
Metronidazole
Summary
____ and ____ (aminoglycoside antibiotic) are used to treat intestinal colonization with E. histolytica as they are not absorbed by the GI tract
Iodoquinol
paromomycin
Summary
____ is a prodrug metabolized to tizoxanide, which
inhibits pyruvate:ferredoxin oxidoreductase and thereby
impairs anaerobic energy metabolism
Nitazoxanide
Summary
____ or ____ are used for early stage infection
Sleeping Sickness
Suramin
pentamidine
Summary
____ or ____ are used for late stage infection
Sleeping Sickness
Melarsolprol
eflornithine
Summary
____ and ____ are used for Chagas disease
Nifurtimox
benznidazole
