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