Antiprotozoal drugs Dr Kirtan Bhatt KIMS Bangalore
Jun 09, 2015
Antiprotozoal drugs
Dr Kirtan BhattKIMS
Bangalore
Protocol
• Trypanosomiasis• Giardiasis• Trichomoniasis• Toxoplasmosis• Cryptosporidiosis• Others – Babesiosis, Balantidiasis, Isospora, Cyclospora, P. jiroveci
Trypanosomiasis
• Two main types1. T. brucei (African trypanosomiasis/African sleeping sickness)
T. brucei gambiense (west Africa) T. brucei rhodesiense (east Africa)
2. T. cruzi (Chagas disease/south american trypanosomiasis)
Drugs for trypanosomiasis
• African trypanosomiasis
• South american trypanosomiasisNifurtimoxBenznidazole
Disease Stage 1st line drugs Alternative drugs
West African EarlyCNS involvement
PentamidineEnflornithine
Suramine,enflornithineMelarsoprol, NECT
East African EarlyCNS involvement
SuraminMelarsoprol
Pentamidine
Suramin
• Sulfated naphthylamine• Introduced in 1920• 1st line drug for the early, hemolymphatic stage of East African
Trypanosomiasis (T. brucei rhodesiense)• Also effective against T. brucei gambiense• No role in American Trypanosomiasis
Mechanism of action
• Exact mechanism not known• Parasites take up the protein bound drug by receptor mediated
endocytosis• Damage to intracellular structures• Also inhibits:
Trypanosomal cytosolic serine oligopeptidaseDihydrofolate reductaseThymidine kinaseGlycolytic enzymes
Pharmacokinetics
• Not absorbed orally• Can cause local inflammation if given SC/IM, hence given only IV• Complex pharmacokinetics & marked inter-individual variability• 99.7% protein bound• Terminal elimination t ½ is 41-78 days• Not appreciably metabolised; renal clearance is responsible for 80%
of the elimination. • Penetration into the CSF is poor
Therapeutic uses
• 1st line drug for T. brucei rhodesiense in early stage• Also useful in late stages• Given before melarsoprol to avoid reactive encephalopathy• No treatment until 24 hours of active disease; rule out CNS
involvement• Cautious use in patients with Oncocerciasis (River blindness) for fear
of Mazotti reaction.
Dose
• Given IV as 10% aqueous solution after a 200mg test dose1g IV is given on days 1, 3, 7, 14 and 21.
• In children 20mg/day on same days
• Combination with pentamidine may improve efficacy.
Toxicity & side effects• Most serious immediate reaction : nausea, vomiting, shock and loss of
consciousness is rare (1 in 2000)• Hypersensitivity due to parasite destruction• Malaise, nausea, fatigue are common• Most common problems after several doses:
Nephrotoxicity (albuminuria)Delayed neurological complications
• Less common – vomiting, diarrhoea, chills, stomatistis, abdominal pain, edema• In AIDS patients – leukopenia, occasional agranulocytosis,
thrombocytopenia, ↑creatinine, ↑bilirubin, ↑liver enzymes
Precautions and contraindications
• Renal insufficiency
Pentamidine
• Positively charged aromatic diamine• Accidentally discovered in 1937• Broad spectrum agent with activity against many protozoa and fungi
Mechanism of action
• Exact mechanism not known• Multiple effects on a single parasite and different mechanisms in
different parasites• Transporter systems (energy dependent high affinity uptake – P2
purine transporter best characterized)• Reacts with negatively charged intracellular organelles and leads to;
Ribosomal aggregationInhibition of DNA and protein synthesisEnzyme inhibitionLoss of kinetoplast (topoisomerase II inhibition)
• Also inhibits S-adenosyl-L-methionine decarboxylase in vitro and plasma Ca2+-Mg2+-ATPase
Pharmacokinetics
• PK data more extensively studied in AIDS patients• Well absorbed parenteral sites• Following IV injection, it disappears from plasma very fast with t ½ of a few
minutes to a few hours• Elimination t ½ is weeks to months• Maximum plasma concentration after IM injection in 1 hour• Protein binding 70%• Poorly absorbed orally• Doesn’t cross BBB• Inhalational route – less systemic absorption and less toxicity
Therapeutic uses1. T. brucei gambiense
Useful in early stagesGiven IM 4mg/kg/day for 7 daysIneffective in late stages
2. Leishmaniasis4mg/kg IM on alternate days for 15-20 doses (VL) and 2-7 doses for (CL)
3. P. jiroveciPatients not tolerating or not responding to co-trimoxazole300mg dose in a 5-10% as nebulization over 30-45 mins monthlyWhen to give?
I. CD4 count < 200II. Persistent oro-pharangeal candidiasisIII. Secondary prophylaxis
Toxicity and side effects
• Very toxic drug (50% show adverse effects)• On IV injection – hypotension, tachycardia• Hypoglycemia• Paradoxical hyperglycemia due to pancreatitis• Nephrotoxicity• IM injection – sterile abcess at the injection site• Others – rashes, anemia, neutropenia, thrombophlebitis, increased
liver enzymes
Melarsoprol • Dimercaptopropanol derivative of Melarsen oxide• Found in 1949 for late stages of Trypanosomiasis• Still the only drug for late stage East African Trypanosomiasis
Mechanism of action
• Prodrug (Melarsoprol --> Melarsen Oxide)• Not well understood• Earlier it was thought to be inhibition of glycolytic enzymes• Reacts with trypanothione and forms Melarsen-Oxide-Trypanothione
compound which competitively inhibits trypanothione reductase (the enzyme responsible for keeping trypanothione in reduced form)
Pharmacokinetics
• Always given IV• T ½ is 30 minutes• Small but therapeutically significant levels reach CNS• Excreted rapidly, 70-80% arsenic seen in faeces
Therapeutic uses
• Only drug available for late stages of east African trypanosomisis (100% fatal if left untreated)• Also effective in early disease but reserved for late stages because of
toxicities• On relapse, patients often respond to a second course
Dose • Earlier very long schedules were used• Now, • For T. brucei gambiense: continuous 10 day course of 2.2mg/kg/day is
equivalent to earlier long courses• For T. brucei rhodesiense:
trials are on for 10 day course, till then old schedule is to be followedthree series of 3 daily doses with a 7 day rest period in between1st series – 1.8 2.7 3.6 mg/kg
D1 D2 D3
subsequent series 3.6mg/kg/day
• Prednisolone given concurrently to reduce hypersensitivity (mostly during 2nd or subsequent doses)
Toxicities and side effects
• Significant toxicity and morbidity• Febrile reaction after injection• Reactive encephalopathy• Peripheral neropathy (10%)• Vomiting and abdominal pain are common• Uncommonly, hypertension and myocardial damage• Albuminuria
Precautions and contraindications
• Given only under hospital supervision• During febrile illness, chances of reactive encephalopathy are more• Contraindications
1. G6PD deficiency2. Leprosy3. During influenza epidemics
Enflornithine
• α-D,L difluromethylornithine
Mechanism of action
• Irreversible inhibitor ornithine decarboxylase by covalent binding (rate limiting step in polyamine biosynthesis)• Polyamines (Putrescine, Spermidine and Spermine) are needed for
cell division and normal cell differentiation• In trypanosomes, spermidine is additionally needed for trypanothione
synthesis• Can also inhibit human enzymes• T. brucei rhodesiense less sensitive than T. brucei gambiense (effective
dose is 10-20 times more)
Pharmacokinetics
• Given by IV infusion• Doesn’t bind to plasma proteins, well distributed and also penetrates
the BBB• Suramin enhances this penetration• CSF concentration must reach 50 μM to clear parasites• Rapid renal clearance after IV injection (2mL/min/kg) and more than
80% excreted unchanged
Therapeutic uses
• Used in late stage of west African trypanosomiasis 100mg/kg given IV every 6 hours as a 2 hour infusion for 14 days
• Children need higher doses150mg/kg given IV every 6 hours for 14 days
• Less effective in AIDS patients with trypanosomiasis• Combination Nifurtimox shown to reduce the treatment duration
400mg/kg/day IV every 12 hours by a 2 hour infusion for 7 days+
Nifurtimox orally 15mg/kg/day in 3 divided doses for 10 days
• Advantages of the combination
Toxicity and side effects
• Adverse effects are common but reversible• Abdominal pain, headache, injection site reaction• Tissue infections and pneumonia• Reversible hearing loss after prolonged therapy with oral doses
(observed when it was given as an anticancer drug)• Fluid overload
Nifurtimox
• A nitrofuran analog• Effective against trypomastigote and amastigote forms of T. cruzi• Also effective against T. brucei, both in early and late stages
Mechanism of action
• Activated by NADH dependent mitochondrial nitroreductase which leads to generation of nitro radical anions trypanocidal effects (by covalent attachment with cellular macromolecules) • Further, transfer of electrons from this activated drug leads to
formation of the native compound and in the process forms free radicals• Parasites do not have catalase
Pharmacokinetics
• Well absorbed after oral administration• Peak plasma concentration in 3.5 hours, despite this very low
concentration found in plasma• <0.5% excreted in urine• Elimination t ½ is 3 hours• High concentration of several unidentified metabolites is found
Therapeutic uses
• In Chagas disease – markedly reduces parasitemia, morbidity and mortality• Parasitological cure is achieved in 80% cases of acute cases and 50%
of chronic cases• Current recommendations:
Patients < 50 years with acute or chronic disease without cardiomyopathy – treatPatients > 50 years optional treatment due less tolerability
• Also used in combination with Enflornithine for T. b. gambiense
Dose
• Adults (>17 years) with acute infection8-10mg/kg/day in 3-4 divided doses for 90 days
• Children (11-16 years)12.5-15mg/kg/day in 3-4 divided doses for 90 days
• Children (1-10 years)15-20mg/kg/day in 3-4 divided doses for 90 days
Toxicity and adverse effects
• Immediate hypersensitivity • Delayed hypersensitivity (dermatitis, icterus, fever)• GI problems and anorexia can lead to weight loss• Peripheral neuropathy
Benznidazole • Nitroimidazole analog• Better tolerated than nifurtimox• Mechanism of action is same as that of nifurtimox• Half life is 12 hours• Dosing:
Adults (>13years) 5-7mg/kg/day in 2 divided doses for 60 daysChildren (upto 12 years) 10mg/kg/day in 2 divided doses for 60 days
• Gastric upset and weight loss can occur• Avoid alcohol during treatment as it increases the chances of side
effects
Giardiasis
• Giardia lamblia is a flagellate protozoan• Infection by oro-faecal route• Can invade the mucosa and cause acute watery short duration
diarrhea with foul smelling stools, gas and abdominal cramps• Untreated, it can progress to chronic diarrhea with greasy/frothy
stools
G. lamblia
Treatment
1. MetronidazoleDrug of choice : 200mg TDS for 5-7 days OR 2 g daily for 3 daysChildren – 15mg/kg/dayAlternatively, tinidazole 600mg daily for 7 days (or 2g single dose) OR secnidazole 2g single dose
Treatment (cont.)
2. Nitazoxanideprodrug and gets converted to tizoxanidegiven 500mg (children 7.5mg/kg) BD for 3 daysused in patients not responding to imidazoles
3. Quiniodochlor (250mg TDS for 7 days)4. Paromomycin
500mg TDS for 5-7 days (can be used during pregnancy)5. Furazolidone
nitrofuran compound100mg TDS for 5-7 daysalso effective against salmonella, shigella and trichomonaspartly absorbed from intestine, excreted in urine which can turn orangeS/E – nausea, headache, dizziness
Trichomoniasis
• Microaerophilic flagellate protozoan which causes vulvovaginitis• Sexually transmitted disease which affects 10% of sexually active
women• Typical presentation:• Intense vaginitis with purulent, greenish yellow, profuse, frothy, offensive
discharge• There is pruritus, burning, edema, dyspareunia and urinary frequency
T. vaginalis
Management
• Drugs used orallyOral metronidazole is the DOCGiven 400mg TDS for 7 days OR 2g single dose
ORTinidazole 600mg OD for 7 days OR 2g single dose
ORSecnidazole 2g single dose
A repeat course after 6 monthsTreat the partner also to prevent recurrences
• Intravaginal Additional intravaginal treatment may be needed in refractory casesDihydroxyquin 200mg inserted intravaginally at bed time for 1-2 weeks
ORQuiniodochlor 200mg inserted at bed time for 1-3 weeks
ORPovidone iodine 400mg HS for 2 weeks
Toxoplasmosis
• Toxoplasma gondii is an obligate intracellular coccidian parasite, first described in 1908• Word toxoplasma is derived from Greek word Toxon which means arc
or bow, which refers to the shape of the parasite• Now recognized as the most common protozoan parasite globally,
with widest range of hosts spreas over 200 species including birds, reptiles and mammals
T. gondii
Clinical featutres
• Largely asymptomatic and self-limiting, nut a small percentage of patients have fever, malaise and lymphadenopathy• Retinochoroiditis in children (25-35%). Rare in adults• Myocarditis and pneumonitis• Repeated abortions in infected women
Management • Directed towards trophozoites mainly• In pregnancy, 1g orally TID spiramycin is continued throughout
pregnancy and monthly USG to check for fetal abnormality• Congenitally infected neonates:
Aggressive treatment with pyrimethamine (0.5-1mg/kg/day) and sulfadiazine (100mg/kg/day) and folic acid for 1 yearSpiramycin (100mg/kg/day) may also be used
Drug of choice Alternative drugsPyrimethamine + clindamycin + folinic acid
Spiramycin in pregnancy
Pyrimethamine + sulfadiazine + folinic acid ORAzithromycin ORClarithromycin ORAtovaquone
• Pyrimethamine dose for adults:75mg daily followed by 25-50mg daily
• Sulfadiazine 2g followed by 0.5-1g orally every 6 hours• Combination treatment for 6 weeks
Cryptosporidiosis
• Coccidian protozoa found in intestinal tract• Causes watery diarrhea
Drug of choice Alternative drugs
Paromomycin 500mg TID or QID for 10 days ORNitazoxanide 500mg OD for 3 days(children 100-200mg BD for 3 days)
Azithromycin 500mg OD for 21 days
P. jiroveci
• Found in lungs of many healthy individuals but clinical disease usually occurs when the resistance is low• Spreads by respiratory droplets
• Drug of choice: Co-trimoxazole• Alternatively:
PentamidineTrimethoprim-DapsoneClindamycin+primaquineAtovaquone
Babesiosis
• Named after Babes who described the intra-erythrocytic parasite in the blood of cattle• Causative agents: B. microti, B. divergens• Tick borne zoonosis, resembles malaria• Usually mild and self limiting bit can be severe and even fatal in
asplenic and immunocompromised.• Management:
Clindamycin + quinine for severe diseaseAzithromycin + atovaquone for mild to moderate disease
Balantidiasis
• Only ciliate protozoan known to infect humans• Zoonosis caused by B. coli• Infection of large intestine that resembles amoebiasis• Tetracycline
Isospora belli
• Coccidian parasite that can cause diarrhea mainly in AIDS patients• Co-triomoxazole
Cyclosopora
• Another coccidian parasite• Self limiting diarrhea in normal individuals and chronic diarrhea in
AIDS patients• Co-trimoxazole
Microsporidia
• Spore forming unicellular eukaryotic fungal parasites responsible for many disease syndromes in humans• Infection with microspora of genus Encephalitozoon are treated by
Albendazole• In the immunocompromised, infection is treated with fumagillin
(doesn’t repond to albendazole)
Fumagillin
• Acyclic polyene macrolide produced by Aspergillus fumigatus• Both fumagillin and its metabolite TNP-470 are toxic to microsporidia• Also inhibits angiogenesis and tumour growth (TNP-470 is under trials
as an anticancer agent)Human methionine-aminopeptidase 2 (MetAP2) is the target for its antitumour activity
• Uses:1. Microsporidiosis (E. binensi) 20mg TDS for 2 weeks2. Keratoconjuctivitis caused by E. hellem
C. parvum