Drugs for Leishmaniasis

DRUGS FOR LEISHMANIASIS

Visceral leishmaniasis (kalaazar) caused by Leishmania donovani occurs in several tropical and subtropical regions of the world. According to current estimates, ~15 lakh people worldwide suffer from the disease, of which nearly 2 lakh die every year. In India, it is estimated that 2 lakh new infections occur annually, of which 90% are in Bihar, but the disease is also present in eastern UP, West Bengal, Aasam and Tamil Nadu. In north Bihar it is a serious health problem because many cases are resistant to the first choice drug sodium stibogluconate (SSG).

Leishmaniasis is transmitted by the bite of the female sand-fly phlebotomus. In the fly the parasite exists in the flagellate extracellular (promastigote) form, while in man it is found only intracellularly within macrophages in the nonflagellate (amastigote) form. Mucocutaneous and dermal leishmaniasis are caused respectively by L. braziliensis and L. tropica (also other species).

Drugs used in the treatment of leishmaniasis are:

Antimonial    Sodium stibogluconate (SSG)

Diamidine     Pentamidine

Antifungal Drugs  Amphotericin B (AMB), Ketoconazole (KTZ)

Others           Miltefosine,, Paromomycin, Allopurinol

Sodium Stibogluconate

It is the drug of choice for kalaazar, but no longer useful in Bihar because of extensive resistance. It is a water-soluble pentavalent antimonial containing 1/3 antimony by weight. The mechanism of action and the basis of selective toxicity to the leishmania amastigotes is unclear; probably SH dependent enzymes are inhibited and bioenergetics of the parasite is interfered with. It is thought to be acting by blocking glycolytic and fatty acid oxidation pathways. Recent evidence indicates that a specific enzyme, present in leishmania amastigots, reduces pentavalent-Sb of SSG to the toxic trivalent form, which then promotes efflux of glutathione and other reduced thiols from the parasite exposing it to oxidative damage. Resistance to SSG may involve reduced capacity of the parasite to convert it to the trivalent form, and/or alteration in thiol metabolism of the parasite.

Sod. stibogluconate is rapidly absorbed from the site of i.m. injection and excreted unchanged in urine within 6–12 hrs. A small fraction enters tissues and remains stored for long periods. Repeated doses are cumulative.

It is available as aqueous solution: ABANTE, STIBO 100 mg (antimony)/ml in 30 ml vials. Dose: 20 mg/kg (max. 850 mg) daily by i.m. (in buttocks) or i.v. injection for 20–30 days or more. The duration of treatment is adjusted according to clinical response. Patients are considered cured when no parasites are detected in splenic or bone marrow aspirates.

Patients who relapse after responding initially should be retreated immediately using the same doses. In poor health patients and those who experience adverse effects, the injections may be given on alternate days. In India, SSG failure rate now is high (>60% in Bihar); it has been largely replaced by AMB and other drugs.

Adverse Effects

In general, antimonials are toxic drugs, but the pentavalent compounds (particularly SSG) are better tolerated. Nausea, vomiting, metallic taste, cough, pain abdomen, pain and stiffness of injected muscle, sterile abscesses, and mental symptoms often occur. Pancreatitis, liver and kidney damage, myelosuppression, ECG changes are possible, but are seldom severe. Few cases of shock and death are on record.

Sod. stibogluconate, nevertheless, is less toxic than amphotericin B or pentamidine.

Pentamidine

The diamidines are active against L. donovani, Trypanosomes, Pneumocystis jiroveci, some bacteria and fungi (Blastomyces). Their mechanism of action is not properly understood. Pentamidine probably interacts with kinetoplast DNA and inhibits topoisomerase II, or interferes with aerobic glycolysis and/or utilization of polyamines.

Dose: 4 mg/kg deep i.m. or slow i.v. injection (over 1 hr) on alternate days for 5–15 weeks till no parasites are demonstrated in two splenic aspirates taken 2 weeks apart. Now, upto 40 injections are needed. It is supplied in 200 mg and 300 mg vials, only through Government agencies. The dry powder in vials should be dissolved to yield 10% solution just before injection.

After absorption from the site of injection it is rapidly taken up by tissues, especially liver and kidney and stored for months, during which time it is slowly excreted in urine, mostly in the unchanged form. Penetration into brain is poor.

Toxicity of pentamidine is high. Because of its strong basic nature, it causes histamine release

which is responsible for much of the acute reaction.

Acute Reaction: sharp fall in BP, cardiovascular collapse, dyspnoea, palpitation, fainting, vomiting, rigor and fever occur frequently after i.v. injection; these are less severe with i.m. route, but i.m. route may cause local tissue necrosis. Patients must remain supine for ½ to 1 hr after injection. Other adverse effects are rashes, mental confusion, kidney and liver damage, ECG changes, rarely cardiac arrhythmias.

Pentamidine causes cytolysis of pancreatic cells: insulin is released initially causing hypoglycaemia. Later on, permanent insulindependent diabetes mellitus can result in some cases.

Use

Kalaazar: Pentamidine should be used only for salvage therapy of antimonial failure cases. Amphotericin B is generally preferred over pentamidine, because of still higher toxicity of the latter. Though, proper use of pentamidine has achieved up to 98% cure rate in antimonial unresponsive or relapse cases, it is often used irregularly so that up to 25% pentamidine resistance is reported from Bihar. It is no longer the 2nd line drug in kalaazar.

Pneumocystis jiroveci pneumonia in AIDS patients: Pentamidine 3 mg/kg/day i.m. or slow i.v. injection for 3 weeks is an alternative drug to cotrimoxazole. It can also be given by inhalation (of nebulized solution) for treatment of established infection in AIDS patients.

Trypanosomiasis: May be used before CNS is involved.

Amphotericin B (AMB)

Like fungi, leishmania has high percentage of ergosterol and is susceptible to this antifungal antibiotic. Presently, AMB is the drug with highest cure rate in kalaazar: up to 98% clinical and parasitological cure has been reported in SSG-resistant cases. However, high toxicity and need for prolonged hospitalization, monitoring and repeated slow i.v. infusions limit its application. Currently, it is indicated in resistant kalaazar, and is being increasingly employed. In Bihar, it has become almost the standard treatment due to high incidence of SSG resistance.

Liposomal AMB is particularly suitable for kalaazar because it delivers the drug inside the reticuloendothelial cells in spleen and liver where the amastigotes live, but high cost is prohibitive. AMB is also useful in mucocutaneous leishmaniasis.

Dose: 0.5–1.0 mg/kg/day slow i.v. infusion till 15–20 mg/kg is administered.

Ketoconazole

Another antifungal drug found to kill leishmania by inhibiting conversion of lanosterol to ergosterol: membrane function is impaired due to lowered ergosterol content. It is quite effective in dermal leishmaniasis. Limited trials with 600 mg/day for 4 weeks have found lower efficacy in kalaazar: it may be useful as add on drug.

Miltefosine

It is the first oral anti-leishmania drug that has been under clinical study in India for the last 15 years, but has not yet been marketed commercially. A 4 week course of 100 mg/day has achieved >95% cure in kalaazar as well as cutaneous leishmaniasis. Stibogluconate-resistant leishmania are susceptible to miltefosine. Though vomiting and diarrhoea occur in over ½ of the patients, its toxicity is low. Reversible derangement of liver and kidney function has been observed.

Paromomycin

This aminoglycoside antibiotic was introduced in the 1960s as a luminal amoebicide by oral route, but was soon withdrawn. Over the past decade it has been widely tried in India and Africa for kalaazar by i.m. injection and found to be effective in SSG-resistant cases.

In a recent phase III trial on 667 kalaazar patients in Bihar,* paromomycin 11 mg/kg/day × 21 days has yielded 95% cure rate, which was not inferior to 99% cure rate obtained with AMB 1 mg/kg × 15 injections over 30 days. Mortality was <1% with both the drugs. In Sudan, a 17 day course of SSG + paromomycin has become the 1st choice treatment of kalaazar, because it yielded higher initial cure rate and better survival than monotherapy with 30 day course of SSG. However, in India, combination of SSG + paromomycin has not been encouraging.

Though paromomycin produces ototoxicity, elevated serum transaminase and injection site pain, it may prove to be an effective and easier to use alternative to AMB in resistant kalaazar. The Drugs Controller General of India has recently approved it for use in kalaazar.

Dose: 10–15 mg/kg/day i.m. × 21 days.

Allopurinol

This hypoxanthine analogue and uric acid synthesis inhibitor exerts selective toxic effect on amastigotes. The unique purine salvage pathway present in Leishmania metabolizes allopurinol into the corresponding nucleotides which are incorporated in RNA—resulting in interference with protein synthesis. These allopurinol derived analogues may also compete with ATP.

Allopurinol has been tried in kalaazar in India and Africa at a dose of 4–12 mg/kg TDS for 3–4 weeks. Failure rate has been high and it may be used only as a companion drug to antimonials in cases which do not respond to the latter alone.

Drugs Used Locally For Dermal Leishmaniasis (Oriental Sore)

1. Sodium stibogluconate: Infiltrate 2 ml of the solution (100 mg antimony/ml) round the sore.

2. Paromomycin ointment: applied topically on the sore.

Small and mild lesion may heal by itself in a few months. Multiple sores and severe cases should be treated by systemic drugs as for kalaazar. Ketoconazole is quite effective.

Antibiotics may be needed for secondary infection of the sore.