Pentamidine resistance

Chapuy B, Koch R, Radunski U et al. (2008) Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22 1576-1586 Coelho AC, Messier N, Ouellette M et al. (2007) Role of the ABC transporter PRPl (ABCC7) in pentamidine resistance in Leishmania amastigotes. Antimicrob Agents Che-mother 51 3030-3032... 

Foscarnet (Foscavir) [Antiviral] Uses CMV retinitis acyclovir-resistant hCTpes Infxns Action -1- Viral DNA polym ase RT Dose CMV retinitis Induction 60 mg/kg IV qSh or 100 mg/kg ql2h X 14—21 d Meant 90-120 mg/kg/dIV (Moo.-Fiti ) Acyclovir-resistant HSV Induction 40 mg/kg IV q8-12h x 14—21 d use central line -1- w/ renal impair Caution [C, —] T Sz potential w/ fluoroquinolones avoid n hrotoxic Rx (cyclosporine, aminoglycosides, ampho B, protease inhibitors) Contra CrCl <0.4 mL/min/kg Disp Inj SE Nephrotox, electrolyte abnormalities Interactions T Risks of Sz W/ quinolones t risks of n hrotox W/ aminoglycosides, amphotCTicin B, didanosine, pentamidine, vancomycin EMS Known to cause electrolyte disturbances (extremity numbness paresthesia indicates electrol5rte unbalance) monitor ECG OD May cause extremity numbing, and Szs hydrate w/ IV fluids... 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Pentamidine is an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis, with similar efficacy, although resistance has been reported. The drug has been successful in some cases that have failed therapy with antimonials. The dosage is 2-4 mg/kg intramuscularly daily or every other day for up to 15 doses, and a second course may be necessary. Pentamidine has also shown success against cutaneous leishmaniasis, but it is not routinely used for this purpose. 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

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. 

There is an increased incidence of spontaneous pneumothorax after the administration of pentamidine by aerosol, which may be connected with the effect on airway resistance. There was a particularly high frequency of spontaneous pneumothorax in people with hemophilia the authors suggested that P. jiroveci infection and treatment resistance had played a role (SEDA-16, 313). 

Pentamidine is an alternative agent for the treatment of antimony-resistant visceral leishmaniasis, although the availability of newer, less toxic agents (e.g., liposomal preparations of amphotericin and miltefosine) may decrease its use. Pentamidine is also used as an alternative agent in the treatment and prophylaxis of pneumocystis pneumonia caused by the ascomycetous fungus Pneumocystis jiroveci (formerly known as Pneumocystis carinii). T. brucei rhodesiense is refractory to treatment by pentamidine for... 

Melarsoprol resistance likely involves transport defects. The P2 adenine-adenosine transporter has activity on melarsoprol as well as pentamidine and berenil point mutations in this transporter are found in melarsoprol-resistant isolates. 

Fig. 3 Organometallic complexes of known organic antiproliferation agents designed to overcome drug resistance a ferrocenyl-penicillin derivatives b ferrocenyl-cephalosporin derivatives c rhodium chloroquine complex d ferrocenjd-chloroquine derivative e iri-dium-COD-pentamidine complex...

Mukherjee A, Padmanabhan PK. Sahani MH. Barrett MP. Madhubala R. Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani, Molecular and Biochemical Parasitology 2006 145, 1-10. Doi 10.1016/j.molbiopara. 2005.08.016. 

Jha TK (1983) Evaluation of diamidine compound (pentamidine isethionate) in the treatment of resistant cases of kala-azar occurring in North Bihar, India. Trans R Soc Trop Med Hyg... 

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