Pentamidine. AIDS

Opravil M, Heald A, Lazzarin A, Hirschel B, Luthy R, and the Swiss Group for Clinical Studies in AIDS.. Combined prophylaxis of Pneumocystis carinii pneumoniae and toxoplasmosis dapsone-i-pyrimethamine vs aerolized pentamidine. AIDS (London, England). 1992 6 S8. 

The answer is d. (Hardman, p 989.) Both trimethoprim-sulfamethoxazole and pentamidine are effective in pneumonia caused by E carinii. This protozoal disease usually occurs in immunodeficient patients, such as those with AIDS. Nifurtimox is effective in trypanosomiasis and metronidazole in amebiasis and leishmaniasis, as well as in anaerobic bacterial infections. Penicillins are not considered drugs of choice for this particular disease state. 

Injection - 244 of 424 (57.5%) patients treated with pentamidine injection developed some adverse reaction. Most of the patients had acquired immunodeficiency syndrome (AIDS). In the following, severe refers to life-threatening reactions or reactions that required immediate corrective measures and led to discontinuation of pentamidine. 

Pentamidine is active against Pneumocystis carinii, trypanosomes, and leishmaniasis unresponsive to pentavalent antimonials. It is an alternative agent for the treatment of P. carinii pneumonia. Although it is more toxic than trimethoprim-sulfamethoxazole, it has been widely used in patients with acquired immunodeficiency syndrome (AIDS), in whom P. carinii infection is common. 

This route presents not only a quick, efficient way to deliver drugs into the bloodstream but a vulnerable route for poisoning. In early 1989 the FDA gave "Treatment IND" status to an aerosol form of pentamidine for the prevention and treatment of Pneumocystis carnii pneumonia which is the most common life-threatening infection seen in AIDS patients. 

Pneumocystosis, caused by Pneumoq/stis carinii (now classified as a fungus), is an important cause of potentially fatal pneumonia in the immimo-suppressed. It is treated with co-trimoxazole in high dose (120 mg/kg daily in 2-4 divided doses for 14 days by mouth or i.v. infusion). Intolerant or resistant cases may benefit from pentamidine or, if mild to moderate, from atovaquone, or trimetrexate (given with calcium folinate). Co-trimoxazole by mouth or intermittent inhaled pentamidine are used for prophylaxis in patients with AIDS. 

Pentamidine is structurally similar to amiloride and can cause severe hyperkalemia if co-prescribed with potassium-sparing diuretics (10). This is a particularly important interaction in patients with AIDS. 

Dohn MN, Weinberg WG, Torres RA, Follansbee SE, Caldwell PT, Scott JD, Gathe JC Jr, Haghighat DP, Sampson JH, Spotkov J, Deresinski SC, Meyer RD, Lancaster DJ. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group. Ann Intern Med 1994 121(3) 174-80. 

In one patient with AIDS with severe but reversible thrombocytopenia after intravenous pentamidine, the serum during the acute phase contained antiplatelet antibodies that reacted with glycoprotein Ilb/IIIa, similar to the reactions observed with quinine-induced thrombocytopenia (SEDA-18, 292). This suggests that even aerosol treatment or environmental exposure will need to be avoided in such patients. 

Episodes of acute pancreatitis and of hemorrhagic pancreatitis have been reported. This may or may not be combined with evidence of damage to pancreatic beta cells (SEDA-13, 825) (SEDA-16, 315) (SEDA-17, 331) (4). However, pancreatitis has also been seen in patients with AIDS who did not receive pentamidine. The risk of pancreatitis seems to be greater in children with CD4 counts under 100 x 10 /1. In a case-control study 12 of 44 patients with AIDS and pancreatitis had used pentamidine (SEDA-20, 264). 

Gabriels G, Stockem E, Greven J. Hyperkaliamie nach Trimethoprim oder Pentamidin. Eine bisher wenig beach-tete Nebenwirkung antimikrobieller Therapiemassnahmen bei AIDS-Patienten. [Hyperkalemia after trimethoprim or pentamidine. Until now, a little noticed side effect of antimicrobial therapeutic measures in AIDS patients.] Dtsch Med Wochenschr 1998 123(45) 1351-5. 

A number of drugs of miscellaneous class are capable of producing various degrees of renal damage and will be reviewed in this Chapter. Some have been used extensively in the past for the treatment of general infections (sulfonamides), others have had specific indications (pentamidine, dapsone), and others such as quinolones are of more recent application. Many of these, however, are of current interest because of their use in treating the complications occurring in patients with acquired immunodeficiency syndrome (AIDS). 

When compared to pentamidine, TMP-SMZ has been associated with a lesser degree of renal impairment in the treatment of opportunistic infections in AIDS. In a prospective, randomized study of patients with AIDS, Wharton et al [102] reported major adverse renal reactions characterized by an increase in serum creatinine of > 3.0 mg/dl in 1 of 32 patients treated with intravenous TMP-SMZ in comparison to 2 of 32 patients receiving pentamidine. Lesser increases in serum creatinine (levels between... 

Pentamidine is a diamidine compound developed more than five decades ago [128]. Initially, it was only used for its antiprotozoal properties against African trypanosomiasis [129], and visceral leishmaniasis [130]. Subsequently, its use was extended to the treatment and prophylaxis of PCP in immunosuppressed patients [131-133]. The use of pentamidine, which was rare in countries without tropical diseases, increased notably because of the high incidence of PCP observed in patients with AIDS [72, 97, 134-136]. Until 1984, pentamidine distribution in the USA was restricted indeed it was only available through the Center for Disease Control. Although TMP-SMZ is regarded as the preferred treatment for PCP [102, 103], pentamidine or less frequently used combinations (trime-trexate/leucovorin, clindamycin/ primaquine [137]) are reasonable alternatives when TMP-SMZ is not tolerated or is without effect [138]. 

Interestingly, it was shown that pentamidine slowly accumulates in and is slowly excreted from the major human organs detectable levels of pentamidine are present in some tissues as late as one year after the last dose. Tissue levels of pentamidine obtained in autopsy specimens from AIDS patients revealed that tissue accumulation was usually greater in liver, kidneys, adrenal glands, and spleen than in the lung. Nevertheless, there is no correlation between tissue levels and renal dysfunction, as measured by serum creatinine levels [149]. 

Table 1. Clinical studies reporting on adverse effects of pentamidine in patients with AIDS (1984-1997).

Antoniskis et al reported four cases of reversible acute kidney injury in patient with AIDS who received both intravenous pentamidine (for PCP) and amphotericin B (for systemic mycoses). Of note, nephrotoxicity did not develop in three AIDS patients treated with both TMP-SMZ and amphotericin B or in two patients who concomitantly received inhaled pentamidine and amphotericin B [160]. Reports of renal damage in patients receiving parenteral pentamidine for the treatment of non-HIV diseases continue. Reversible acute kidney injury and nephrotic syndrome were documented in a young child given pentamidine mesylate and an antimonial salt for the treatment of visceral leishmaniasis [161]. In Africa (Kenya) patients with visceral leishmaniasis have developed renal toxicity during prolonged treatment (1 to 10 months) with pentamidine [162]. 

The exact mechanism of the pentamidine-induced hyperkalemia has not yet been defined. Many different mechanisms can impair the renal handling of potassium and thus favor hyperkalemia in patients with AIDS. These include decreased renal function secondary to volume depletion, presence of under-lying renal disease, including tubular dysfunction with the possibility of hyporeninemic hypoaldos-teronism, hypoadrenalism, and the administration of drugs with potential for impairing renal potassium excretion (nonsteroidal anti-inflammatory agents, ACE inhibitors, potassium-sparing diuretics. 

Symptomatic hj/pocalcenda and hj/pomagnesenda with rend magnesium wasting associated with pentamidine therapy was described in a patient with AIDS [183]. Three other cases have been reporte [184-186]. 

Another previous report [187] described severe hypocalcemia with tetany in patients with AIDS concomitantly receiving pentamidine and foscarnet. The hypocalcemia, however, was attributed to the administration of foscarnet. Despite magnesium replacement, magnesium wasting may persist up to two months after the discontinuation of pentamidine, suggesting that anatomic renal tubular injury may be responsible [183,185]. Both abnormalities developed within 6 to 10 days of pentamidine administration. Because life-threatening arrhythmias can develop, especially at serum magnesium levels less than 1.6 mg/dl, early replacement therapy is clinically warranted. 

Vohringer HF AK. Pharmakokinetik von Pentamidin bei knochenmarktransplantierten und AIDS-patienten. In Gruyter Wd, ed. Pneumocystis-carinii-Pneumonie bei Immunsuppression Berli n. New York 1991 25-32. 

Conte JE, Jr., Upton RA, Phelps RT, Wofsy CB, Zurlinden E, Lin ET. Use of a specific and sensitive assay to determine pentamidine pharmacokinetics in patients with AIDS. The Journal of infectious diseases. 1986 Dec l 54(6) 923-9. 

Donnelly H, Bernard EM, Rothkotter H, Gold JW, Armstrong D. Distribution of pentamidine in patientswith AIDS.The Journal of infectious diseases. 1988 May l 57(5) 985-9. 

Andersen R, Boedicker M, Ma M, Goldstein EJ. Adverse reactions associated with pentamidine isethionate in AIDS patients recommendations for monitoring therapy. Drug intelligences clinical pharmacy. 1986 Nov 20(11) 862-8. 

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