Amphotericin resistance

The spectrum of action of azole medications is broad, including many Candida species, C neofbrmans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole, even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii. 

Twenty percent of HIV-infected patients develop fluconazole-resistant Candida albicans isolates after repeated exposure to fluconazole.33 To treat fluconazole-resistant oropharyngeal candidiasis, daily itraconazole for 2 to 4 weeks may be used. Oral itraconazole solution exhibits a mycological cure rate of 88% and a clinical cure rate of 97% in immunocompromised patients.34 Fluconazole-resistant esophageal candidiasis should be treated with intravenous amphotericin B or caspofungin. 

Preclinical studies suggest mold-active azoles plus echinocandins have enhanced activity against Aspergillus A. terreus should be considered resistant to amphotericin B Activity of amphotericin B and voriconazole is decreased versus Aspergillus species higher doses or combination therapy may be indicated in more refractory cases... 

Disseminated histoplasmosis Acute (Infantile) Subacute Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS) 0.02-0.05 Disseminated histoplasmosis Untreated mortality 83% to 93% relapse 5% to 23% in non-AIDS patients therapy is recommended tor all patients Nonimmunosuppressedpatients Ketoconazole 400 mj day orally x 6-12 months or amphotericin B 35 mg/kg IV Immunosuppressed patients (non-AIDS) or endocarditis or CNS disease Amphotericin B >35 mg/kg x 3 months followed by fluconazole or itraconazole 200 mg orally twice daily x 12 months Life-threatening disease Amphotericin B 0.7-1 mg/kg/day IV for a total dosage of 35 mj kg over 2-4 months once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support therapy can be changed to itraconazole 200 mg orally twice daily for 6-18 months Non-life-threatening disease Itraconazole 200-400 mg orally daily for 6-18 months fluconazole therapy 400-800 mg daily should be reserved for patients intolerant to itraconazole, and the development of resistance can lead to relapses... 

Mbongo N, et al. Mechanism of amphotericin B resistance in Leishmania donovani promastigotes. Antimicrob Agents Chemother 1998 42 352. 

Resistance Variants with reduced susceptibility to amphotericin B have been isolated from several fungal species after serial passage in cell culture media containing the drug and from some patients receiving prolonged therapy with amphotericin B desoxycholate. The relevance of drug resistance to clinical outcome has not been established. 

Combinations of amphotericin-B with flucytosine are sometimes used to reduce the occurrence of resistance. Amphotericin-B is not absorbed from the gastrointestinal tract which necessitates intravenous administration. It is 90% protein bound and widely distributed, except for the CNS. For the treatment of fungal meningitis therefore only intrathecal drug administrations can be effective. Amphotericin-B is eliminated very slowly in urine, mainly in an inactive form, with an elimination half-life of about 24 hours which can increase to up to 15 days with repeated doses. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

Grim SA, Smith KM, RomaneUi F, Ofotoknn 1. Treatment of azole-resistant oropharyngeal candidiasis with topical amphotericin. Ann Pharmacother 2002 36(9) 1383-6. 

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. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Resistance to amphotericin occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug. 

The spectrum of activity of flucytosine is restricted to C neoformans, some Candida species, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. Clinical use at present is confined to combination therapy, either with amphotericin for... 

Voriconazole is similar to itraconazole in its spectrum of action, having excellent activity against Candida sp (including fluconazole-resistant species such as C krusei) and the dimorphic fungi. Voriconazole is less toxic than amphotericin and is the treatment of choice for invasive aspergillosis. 

This important antifungal drug (see Chapter 48) is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate. Liposomal amphotericin has shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1-5, 14, and 21. Nonliposomal amphotericin (1 mg/kg intravenously every other day for 30 days) is much less expensive, also efficacious, and widely used in India. Amphotericin is also used for cutaneous leishmaniasis in some areas. The use of amphotericin, and especially liposomal preparations, is limited in developing countries by difficulty of administration, cost, and toxicity. 

J.H. Rex, C.R. Cooper, W.G. Merz, J.N. Galgiani, and E.J. Anaissie, Detection of amphotericin B-resistant Candida isolates in a broth-based system, Antimicrob. Agents Chemother., 39, 906,1995. 

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