Pentamidine

Pentamidine is an aromatic diamidine antiprotozoal and antifungal used for Pneumocystis pneumonia when co-trimoxazole cannot be used, as aerosolised prophylaxis, and for first-stage African trypanosomiasis caused by Trypanosoma brucei gambiense. It is also a second-line drug for visceral leishmaniasis. Dysglycaemia, hypotension, pancreatitis, kidney injury and QT prolongation make it a high-risk drug.

Class. Antiprotozoal; diamidine.

Mechanism. Binds nucleic acids and inhibits DNA, RNA, phospholipid and protein synthesis in protozoa and Pneumocystis. Uptake by trypanosomes is mediated by a specific transporter.

Pharmacokinetics. Poorly absorbed orally. After intravenous or intramuscular use, widely distributed and accumulates in tissues. Terminal half life 6 to 9 days. Aerosolised use gives high lung levels and low systemic exposure.

Pneumocystis pneumonia (moderate to severe, alternative to co-trimoxazole). 4 mg/kg intravenously once daily over at least 60 minutes for 21 days, with prednisolone in hypoxic patients.

Prophylaxis of Pneumocystis pneumonia. 300 mg by nebuliser (specific device) every 4 weeks.

First-stage Trypanosoma brucei gambiense infection. 4 mg/kg intramuscularly once daily for 7 days.

Visceral leishmaniasis (second-line). 4 mg/kg intravenously or intramuscularly on alternate days for 15 doses (specialist care).

Dose adjustment for kidney function (Pneumocystis). CrCl 10 to 30 mL/min: 4 mg/kg every 36 hours; CrCl under 10: 4 mg/kg every 48 hours.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 4 mg/kg daily.

Main alternatives. Co-trimoxazole, primaquine with clindamycin, or atovaquone for Pneumocystis; suramin for Trypanosoma brucei rhodesiense; liposomal amphotericin B for leishmaniasis.

Contraindications. Hypersensitivity; with intravenous use, uncorrected hypotension or severe cardiac arrhythmia.

Serious adverse effects. Severe hypoglycaemia and later diabetes mellitus, hypotension and cardiovascular collapse with rapid infusion, pancreatitis, acute kidney injury, QT prolongation and torsades de pointes, hypocalcaemia, hyperkalaemia, neutropenia, thrombocytopenia, and sterile abscess at injection sites.

Common adverse effects. Nausea, vomiting, metallic taste, cough with aerosol, rash and pain at the injection site.

Interactions. - Foscarnet: severe hypocalcaemia and nephrotoxicity. - Aminoglycosides, amphotericin B, cidofovir, ciclosporin and tenofovir disoproxil fumarate add nephrotoxicity. - Didanosine and stavudine add pancreatitis risk. - QT-prolonging drugs (macrolides, fluoroquinolones, antipsychotics) add risk.

Common prescribing errors. Rapid infusion, not checking glucose, and giving to a patient on other nephrotoxins.

Special groups. - Pregnancy: avoid unless essential. - Breastfeeding: avoid. - Children: weight-based dosing. - Older adults: monitor kidney function and glucose. - Kidney impairment: lengthen the interval in Pneumocystis dosing. - Liver impairment: caution.

Regional points. Pentamidine is used for first-stage T. b. gambiense disease in north-west Uganda, but it is not effective against T. b. rhodesiense disease in Uganda, Tanzania and Malawi, where suramin is used for the first stage.

Formulations. Powder for injection 300 mg vial; powder for nebulisation.

Administration. Intravenous: dilute in 50 to 250 mL of 5% glucose and infuse over 60 to 120 minutes with the patient lying down. Intramuscular: deep injection, in divided sites.

Baseline. Glucose, creatinine and electrolytes, calcium, amylase or lipase, ECG, full blood count, blood pressure.

Monitoring. Blood pressure before and during infusion; glucose daily; creatinine and electrolytes every 2 to 3 days; ECG weekly.

Stopping thresholds. Stop for severe hypoglycaemia, symptomatic hypotension, pancreatitis, QTc over 500 ms, or creatinine rise of more than 50%.

Referral and escalation. Admission for all intravenous use; specialist review for Pneumocystis pneumonia, trypanosomiasis and leishmaniasis.