Amphotericin drugs

Amphotericin B This second line drug has moved into the first line in India. 

Liposomal Amphotericin B This is a highly effective drug against visceral leishmaniasis with remarkably few side effects. There is, however, only one producer and the price per treatment (US 1,500) is beyond the reaches for most communities affected by the disease. 

An additive nephrotoxicity develops when pentamidine isethionate is administered with other nephrotoxic drugs (eg, aminoglycosides, vancomycin, or amphotericin B). An additive bone marrow depression occurs when the drug is administered with antineoplastic drugs or when the patient lias received radiation therapy recently. 

Antifungal drugs are used to treat superficial and deep fungal infections. The antifungal drugs specifically discussed in this chapter are amphotericin B (Fungizone), flucona-... 

Amphotericin B is the most effective drug available for die treatment of most systemic fungal infections. Administration often results in serious reactions,... 

Flucytosine is contraindicated in patients with known hypersensitivity to the drug. Flucytosine is used cautiously in patients with bone marrow depression and with extreme caution in those with renal impairment. The drug is also used cautiously during pregnancy (Category C) and lactation. When flucytosine and amphotericin B are administered concurrently, the risk of flucytosine toxicity is increased. 

A nurse is preparing to administer amphotericin B to a patient with a systemic mycotic infection. This is the first time the nurse has administered amphotericin B. Determine what information the nurse should be aware of concerning the administration of this drug. Explain your answer. 

Prolonged presence of the drug at the site of injection is the aim of liposome encapsulation of drugs, which are injected in the vitreous body. Both amphotericin and gentamicin in liposome formulations were cleared from the injection site significantly more slowly than the free drug residence times depended on liposome size and, in some cases, on bilayer composition (Tremblay et al., 1985 Barza et al., 1985, 1987 Fishman et al., 1986). 

Altered tissue distribution of amphotericin B by liposomal encapsulation Comparison of normal mice and mice infected with Candida albicans. Cancer Drug Deliv., 1, 199-205. 

Lopez-Berestein, G. (1988). Liposomal amphotericin B in antimicrobial therapy, in Liposomes as Drug Carriers Recent Trends and Progress (G. Gregoriadis, ed.), John Wiley and Sons, Chichester, pp, 345-352. 

Amphotericin B-induced ARF occurs in as many as 40% to 65% of patients treated with the conventional desoxycholate formulation.30 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high doses, treatment for at least 7 days, preexisting kidney dysfunction, and concomitant use of other nephrotoxic drugs.31 Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease the incidence of ARF amphotericin B lipid complex, amphotericin colloidal dispersion, and liposomal amphotericin B. The range of... 

Determine if drug therapy may be contributing to ARF. Consider not only drugs that can directly cause ARF (e.g., aminoglycosides, amphotericin B, NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal ARF (i.e., diuretics and anti hypertensive agents). 

However, it is important to note that the addition of nephrotoxic agents, such as amphotericin B, aminoglysides (e.g., gentamicin, tobramidn, or amikacin), and non-steroidal anti-inflammatory drugs (NSAIDs e.g., naproxen, ibuprofen, or ketorolac) may potentiate the nephrotoxic effects of the calcineurin inhibitors. 

Treatment fluconazole, itraconazole, ketoconazole, Amphotericin B Consider liposomal products decrease or stop CSA or TAC to minimize nephrotoxicity Remember to adjust doses of renally eliminated drugs (e.g., acyclovir, ganciclovir, TMP-SMX)... 

Amphotericin B is the mainstay of treatment of patients with severe endemic fungal infections. The conventional deoxycholate formulation of the drug can be associated with substantial infusion-related adverse effects (e.g., chills, fever, nausea, rigors, and in rare cases hypotension, flushing, respiratory difficulty, and arrhythmias). Pre-medication with low doses of hydrocortisone, acetaminophen, nonsteroidal anti-inflammatory agents, and meperidine is common to reduce acute infusion-related reactions. Venous irritation associated with the drug can also lead to thrombophlebitis, hence central venous catheters are the preferred route of administration in patients receiving more than a week of therapy. 

Hoeprich and Huston [117] assessed the stability of miconazole and three other antifungal agents under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with other drugs, tests should be reliable with all four drugs in view of the rapid action of the polyenes and the relatively slow action of miconazole and 5-fluorocytosines. 

Certain compounds are known to achieve higher absorption rates from the GI tract if they are taken with food, and this observation has been linked to their solubilization by bile salts [74], Bile salts, especially those of cholic and deoxycholic acids, have been used to solubilize steroid hormones [75], antibiotics [76], and nonsteroidal antiinflammatory drugs [77]. For example, amphotericin B (an antifungal agent) has been solubilized for parenteral use in micelles composed of sodium desoxycholate [78], As illustrated in Fig. 11, the degree of solubilization of carbamazepine by sodium desoxycholate is minimal below the critical micelle concentration but increases rapidly above this value [79]. At sufficiently high concentrations, when the micelles become saturated in carb-amezepine, the apparent solubility reaches a limiting value approximately seven times the true aqueous solubility in the absence of desoxycholate. 

I. M. Asher and S. Schwartzman, Amphotericin B, in Analytical Profiles of Drug Substances, Volume 6 (K. Florey, ed.), Academic Press, New York, 1977. 

Amphotericin B is the drug of choice for treatment of acute C. neoformans meningitis. Amphotericin B, 0.5 to 1 mg/kg/day, combined with flucytosine, 100 mg/kg/day, is more effective than amphotericin alone. In the acquired immune deficiency syndrome (AIDS) population, flucytosine is often poorly tolerated, causing bone marrow suppression and GI distress. 

Itraconazole and ketoconazole (200-800 mg/day orally for 1 year) are effective in 74% to 86% of cases, but relapses are common fluconazole 200-400 mg daily is less effective (64%) than ketoconazole or itraconazole, and relapses are seen in 29% of responders Severe disease Amphotericin B 0.7 mg/kg/day for a minimum total dose of 35 mj kg is effective in 59% to 100% of cases and should be used in patients who require hospitalization or are unable to take itraconazole because of drug interactions, allergies, failure to absorb drug or failure to improve clinically after a minimum of 12 weeks of itiaconazole therapy... 

HIV-infected patients should receive induction therapy with amphotericin B and chronic suppressive therapy with an oral azole antifungal. Itraconazole is the drug of choice for non-life-threatening histoplasmosis. 

Amphotericin B is generally preferred as initial therapy in patients with rapidly progressive disease, whereas azoles are generally preferred in patients with subacute or chronic presentations. Lipid formulations of amphotericin B have not been extensively studied for coccidioidomycosis but can offer a means of giving more drug with less toxicity. Treatments for primary respiratory disease (mainly symptomatic patients) are 3- to 6-month courses of therapy. 

Isolated pulmonary disease (without evidence of CNS infection) Asymptomatic disease Drug therapy generally not required observe carefully or fluconazole 400 mg orally daily x 3-6 months Mild to moderate symptoms Fluconazole 200-400 mg orally daily x 3-6 months severe disease or inability to take azoles amphotericin B 0.4-0.7 mg/kg/day (total dose of 1-2 g)... 

In patients who cannot tolerate voriconazole, amphotericin B can be used. Full doses (1 to 1.5 mg/kg/day) are generally recommended, with response measured by defervescence and radiographic clearing. The lipid-based formulations may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. The optimal duration of treatment is unknown. 

Acute tubular necrosis Ischemic Hypotension Vasoconstriction Exogenous toxins Contrast dye Heavy metals Drugs (amphotericin B, aminoglycosides, etc.) (continued)... 

Hypomagnesemia is usually associated with disorders of the intestinal tract or kidneys. Drugs (e.g., aminoglycosides, amphotericin B, cyclosporine, diuretics, digitalis, cisplatin) or conditions that interfere with intestinal absorption or increase renal excretion of magnesium can cause hypomagnesemia. 

Agrawal AK, et al. Superior chemotherapeutic efficacy of amphotericin B in tuftsin-bearing liposomes against Leishmania donovani infection in hamsters. J Drug Target 2002 10 41. 

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