Mechanism of action of anti-trypanosomal drugs

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Mechanism of action of anti-trypanosomal drugs
Suramin
Suramin inhibits trypanosome glycolytic enzymes
more effectively that it does those of the host
Melarsoprol Similar to suramin, melarsoprol also
inhibits enzymes of glycolytic pathway
Pentamidine Pentamidine binds mitochondrial DNA
of trypanosomes (kDNA) and disrupts its function
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American trypanosomiasisgeographic distribution
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American trypanosomiasis Etiologic agent (T.
cruzi)
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T. cruzi life cycle
Reservoir
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Associated with poor living conditions
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Triatoma sordida, T. infestans, Panstrongylus
megistus, Rhodnius prolixus, etc.
kissing bugs cone nose bugs
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Spread of infection by defecation of kissing bug
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Chagas disease symptoms
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Chagas disease Symptoms (chagoma)
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Chagas disease mega colon
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Chagas disease mega colon
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Chagas disease megacardium
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Chagas disease T. Cruzi diagnosis
Trypanosoma cruzi parasite in a thin blood smear.
(CDC Photo)
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• Direct Inflammatory response
• damage to infected cells
• Destruction of autonomic nerve ganglions
• Products of humoral and CMI

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• Antibody kills, but not eradicate T. cruzi
• CMI of some protective value
• Activation macrophages kill the organism
• Immunosuppression

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Chagas' diseasediagnosis

• History of travel and sometimes cardiac problems
• Romanas sign or chagoma
• Organisms in the chagoma exudate, lymph node
  aspirate or blood

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• Bioassay in mice or uninfected triatoma

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Use of Polymerase Chain Reaction to Diagnose the
Fifth Reported US Case of Autochthonous
Transmission of Trypanosoma cruzi, in Tennessee,
1998
In July 1998, the mother of an 18-mo.-old boy in
rural Tenn. found a triatomine bug in his crib,
which she saved because it resembled a bug shown
on a TV program about insects that prey on
mammals. The gut contents of the bug were found,
by light microscopy and PCR, to be infected with
T. cruzi. Blood specimens obtained from the
child in July and August were negative by
microscopy and hemoculture but positive by PCR
and DNA hybridization, suggesting a low level
parasitemia. Specimens obtained after
benznidazole treatment were negative. He did not
develop antiT. cruzi antibody 19 relatives and
neighbors also were seronegative. Two of 3
raccoons trapped in the vicinity had positive
hemocultures for T. cruzi. (J. Infect. Dis.
20001813959)
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Trypanosoma cruzi in Transplant recipients
Case 1. In December 2005, a man aged 64 years
received a heart transplant. In February 2006, he
was readmitted to the hospital with anorexia
(eating disorder), fever, and diarrhea of 2
weeks' duration. T. cruzi was seen in both blood
and biopsy from the heart. The patient had no
identifiable risk factors for T. cruzi infection
(e.g., travel to a country endemic for Chagas
disease). He was seronegative for T. cruzi
antibodies but positive for T. cruzi DNA by
polymerase chain reaction (PCR). After
initiation of nifurtimox therapy, his parasitemia
rapidly cleared. However, in April 2006, the
patient died from complications attributed to
acute rejection of the transplanted organ. The
source of infection tracked the organ donor who
tested seropositive for T. cruzi. antibodies by
RIPA (radioimmunoprecipitation assay) and tested
borderline-positive by IFA (immunofluorescent
antibody). He had been born in the US but had
traveled to a T. cruzi-endemic area of Mexico.
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Trypanosoma cruzi in Transplant recipients
Case 2. In January 2006, a man aged 73 years
received a heart transplant. The patient was
readmitted to the hospital in February 2006 with
fever, fatigue, and an abdominal rash. A thin
blood smear revealed T. cruzi trypomastigotes,
and blood cultures were positive for T. cruzi.
The patient had no identifiable risk factors for
T. cruzi infection. He was seronegative but
PCR-positive for T. cruzi, indicating recent
infection. The patient's rash and parasitemia
resolved after 10 days of nifurtimox treatment.
Serial endomyocardial biopsies did not reveal
trypanosomes, and he remained seronegative by IFA
for T. cruzi. The patient died in June 2006 from
a cardiac failure. The source of infection was
the organ donor, who had been born in El Salvador
and was residing in Los Angeles at the time of
his death, tested positive for T. cruzi
antibodies.
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• Nifurtimox effective in acute stage
• Benznidazole may be of value in chronic stage
• Avoid and control the insect population
• No vaccine

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Nifurtimox- generates cytotoxic superoxide
anion (02-) which is toxic to the parasite
Benznidazole- protein- and RNA-synthesis
inhibitor 
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Leishmaniasis
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Leishmaniasis
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Leishmania morphology

• Amastigote (leishmania) seen in the mammalian
  host
• Promastigote (leptomonad) seen in sand fly

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Leishmania life cycle
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Leishmania life cycle
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• 1-4 months fever chills, diarrhea, dysentery
• Progressive hepato-splenomegaly
• Skin hyperpigmentation
• Death, if untreated

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Patient A. Fever (104º F) was first noted by
patient A in late December 2003 and rigors,
flushing, sweats, and mild orthostasis in early
January 2004 and lost 13 pounds of body weight.
Visceral Leishmaniasis was suspected but no
leishmanial parasites were noted on
lightmicroscopic examinations or cultures of
bone-marrow and liver-biopsy specimens, and no
leishmanial DNA was detected by genus-specific
polymerase chain reaction (PCR). The findings
in the splenic enlargement suggested, and
surgical splenectomy was considered briefly. In
February 2004, because of continuing concern that
the patient had VL, the liver-biopsy specimen was
reexamined by light microscopy one definite and
multiple probable leishmanial parasites were
noted.
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Visceral Leishmania recent cases
Patient B. Abrupt onset of fever 104º F, myalgia,
and abdominal pain were noted in mid-December
2003. Symptoms worsened and there was anorexia,
with a loss of 25 pounds of body weight) during
the next 6 weeks. No leishmanial parasites were
found on light microscopic examinations of
bone-marrow and buffy-coat specimens but were
prevalent in a liver-biopsy specimen. During
February 317, 2004, the patient was treated with
a lipid formulation of amphotericin B, resulting
in a transient improvement of symptoms. He was
rehospitalized on March 5, with a temperature of
102º F. Results of PCR analysis indicated
Leishmania donovani. On March 19, a 28-day course
of antileishmanial therapy was begun with
Pentostam (dose 20 mg/kg/d, intravenously
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Cutaneous leishmaniasis
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Muco-cutaneous leishmaniasis
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Leishmania Diagnosis

• History
• Lesions or symptoms
• Organisms in the lesion

• Montenegro test
• (type IV hypersensitivity)

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Leishmania diagnosismacrophage and bone marrow
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LeishmaniasisPathogenesis and immunology

• Damage due to CMI
• Leishmanial proteoglycan
• Leukopenia with monocytosis and lymphocytosis
• Immunosuppression
• Interferon and TNF are protective

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LeishmaniasisPreventions and treatment

• No vaccine
• Control of sand fly and infected animals
• avoidance of sand fly
• Pentosam (antimony gluconate)

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