Resistance to amphotericin

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... 

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. 

Although frank resistance to amphotericin B Is not observed In all Isolates, It Is well described for Isolates of C. lusitanlae. S = susceptible S-DD = susceptible-dose dependent (see text) I = Intermediate R = resistant. 

A series of papers [305—310,323] examined the genetics of polyene resistance in S. cerevisiae and suggested that nystatin resistance was controlled by three recessive genes and two dominant modifiers. Thf genes that gave rise to the s-l, nys-2 and nys-3 mutants differed markedly in their ability to give crossresistance to filipin and amphotericin B, nys-l confered resistance to amphotericin B and nystatin but not to filipin, while nys-2 and nys-3 confered resistance to nystatin and filipin but made the yeasts hypersensitive to amphotericin... 

Polyene Resistance - Two of 51 in vitro induced nystatin resistant strains of Cryptococcus neoformans showed cross resistance to amphotericin B.l >121 Studies using three in vitro induced nystatin resistant mutants of Saccharomyces cerevisiae indicated that cross resistance correlated with polyene size.122 variants of Candida albicans resistant to... 

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. 

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. 

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. 

One compound that has been associated with distal tubular injury is amphotericin B, a polyene antifungal agent used in the treatment of systemic mycoses caused by opportunistic fungi. Clinical utility of amphotericin B is limited by its nephrotoxicity, characterized functionally by polyuria resistant to antidiuretic hormone administration, hyposthenuria, hypokalemia, and mild renal tubular acidosis. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Nephrogenic diabetes insipidus, resistant to vasopressin, following damage to the distal renal tubule, may be more common than reported (103,104). Careful monitoring of electroljhes is therefore recommended in aU instances of amphotericin therapy. 

Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections who were treated for 40 (17-73) days by 24-hour continuous infusions of amphotericin 1 mg/kg (113). They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, five patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43-73) ml/minute to a nadir of 35 (28-39) and recovered to 52 (33-60) after the end of therapy. One patient needed temporary hemofiltration for 7 days. Besides three episodes of mild hypokalemia there were no adverse effects attributable to amphotericin. Asymptomatic colonization with Candida persisted for 10 months in one case, but the other five patients were cured. 

Flucytosine is a fluorinated pyrimidine that is transported across the fungal cell wall by a permease, where it is deaminated to the cytotoxic principal fluorouracil. Some fungi may lack the permease and are resistant to the drug and its clinical use is usually restricted to treating Candida spp. infection, although even here resistance may arise. It is synergistic with amphotericin B and... 

High cerbiden activity against Candida albicans, Candida tropicalis, Candida krusei, Candida parapsitosis and Candida guilliermondii sensitive and resistant to nystatin, amphotericin C and clotrimazole was detected. 

Resistance to other antifungal agents such as amphotericin B has been observed less frequently in clinical fungal isolates however, the molecular basis of this resistance is not currently well understood. To solve the problems associated with antifungal resistance a number of novel azole drugs (e.g. voriconazole) and novel classes of drug (e.g echinocandins) have been developed (see Chapter 12). 

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