Mechanism Of Action And Resistance

The diamidines display multiple effects on any given parasite and act by disparate mechanisms in different parasites. In T. brucei, for example, the diamidines are concentrated via an energy-dependent uptake system to millimolar concentrations that are essential for efficacy. The best-characterized diamidine transporter is a purine (P2) adenine and adenosine transporter that also is used by the melamine-based arsenicals, which explains the cross-resistance to diamidines exhibited by certain arsenical-resistant strains of T. brucei. Multiple transporters mediate pen-tamidine uptake, which may account for the fact that little resistance to this drug is observed despite years of prophylactic use. The diamidines may exert their trypanocidal effects by reacting with a variety of negatively charged intracellular targets such as membrane phospholipids, enzymes, RNA, and DNA. In Leishmania, pentamidine accumulates within mitochondria and causes early disintegration of the kinetoplast and collapse of the mitochondrial membrane potential. Moreover, pentamidine resistance is linked to decreased drug concentration within mitochondria, again implicating this organelle in drug action.


The pharmacokinetics and biodisposition of pentamidine isethionate have been studied most extensively in AIDS patients with P. jiroveci infections. Pentamidine isethionate is fairly well absorbed from parenteral sites of administration. Following a single intravenous dose, the drug disappears from plasma with an apparent t/2 of several minutes to a few hours and maximum plasma concentrations after intramuscular injection occur at 1 hour. The drug is highly protein bound and has an elimination t122 of weeks to months. This highly charged compound does not cross the blood—brain barrier, explaining why it is ineffective against late-stage trypanosomiasis.

Inhalation of pentamidine aerosols is used for prophylaxis of Pneumocystis pneumonia; delivery of drug by this route results in little systemic absorption and decreased toxicity compared with intravenous administration in both adults and children.

THERAPEUTIC USES For sleeping sickness, pentamidine isethionate usually is given by intramuscular injection in single daily doses of 4 mg/kg/day for a series of 7 days. Because of failure to penetrate the CNS, pentamidine is ineffective against late stage disease and appears to have reduced efficacy against T. brucei rhodesiense. Thus, pentamidine is limited to use in early stage T. brucei gambiense infections.

Pentamidine has been used successfully in courses of 12-15 intramuscular doses of 2-4 mg/kg either daily or every other day to treat visceral leishmaniasis. It provides an alternative to antimo-nials or lipid formulations of amphotericin B for patients who cannot tolerate these agents.

Pentamidine is one of several drugs used to treat or prevent Pneumocystis infection. Pneumocys-tis pneumonia (PCP) is a major cause of mortality in individuals with AIDS and can occur in patients who are immunosuppressed by other mechanisms. Trimethoprim—sulfamethoxazole is the drug of choice for the treatment and prevention of PCP (see Chapter 43). Pentamidine given intravenously as a 4 mg2kg single daily dose for 21 days is used to treat severe PCP in individuals who cannot tolerate trimethoprim—sulfamethoxazole and are not candidates for alternative agents such as atovaquone or the combination of clindamycin and primaquine. Pentamidine has been recommended as a "salvage" agent for individuals with PCP who failed to respond to initial therapy (usually trimethoprim—sulfamethoxazole) but may be less effective than the combination of clin-damycin and primaquine or atovaquone for this indication. Pentamidine administered as an aerosol preparation is used to prevent PCP in at-risk individuals who cannot tolerate trimethoprim—sulfamethoxazole and are not deemed candidates for either dapsone (alone or in combination with pyrimethamine) or atovaquone. Candidates for PCP prophylaxis are individuals with HIV infection and a CD4 count of <200 per mm3 and individuals with HIV infection and persistent unexplained fever or oropharyngeal candidiasis. Secondary prophylaxis is recommended after any documented PCP episode. For prophylaxis, pentamidine isethionate is given monthly as a 300-mg dose in a 5—10% nebulized solution over 30-45 minutes. Although convenient, aerosolized pen-tamidine has several disadvantages, including its failure to treat any extrapulmonary sites of Pneu-mocystis, the lack of efficacy against any other potential opportunistic pathogens, and a slightly increased risk for pneumothorax. For individuals who receive HAART and achieve CD4 counts persistently >200 per mm3 for 3 months, primary or secondary PCP prophylaxis can be stopped.

TOXICITY AND SIDE EFFECTS Approximately 50% of individuals given pentamidine at recommended doses will show some adverse effect. Intravenous administration may be associated with hypotension, tachycardia, and headache, probably secondary to the ability of pentamidine to bind imidazoline receptors, which can be ameliorated by slowing the infusion rate. Hypoglycemia, which can be life threatening, may occur at any time during pentamidine treatment. Careful monitoring of blood glucose is the key. Paradoxically, pancreatitis, hyperglycemia, and insulin-dependent diabetes also may occur. Pentamidine is nephrotoxic (~25% of treated patients will show signs of renal dysfunction), and if the serum creatinine concentration rises significantly, it may be necessary to withhold the drug temporarily or change to an alternative agent. Individuals developing pentamidine-induced renal dysfunction are at higher risk for hypoglycemia. Other adverse effects include rashes, thrombophlebitis, anemia, neutropenia, and elevated hepatic enzymes. Intramuscular administration of pentamidine can cause sterile abscesses at the injection site, and most authorities prefer intravenous administration. Aerosolized pentamidine has few adverse events.

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