Amphotericin, liposomal nephrotoxicity

Amphotericin B nephrotoxicity can be reduced by slowing the infusion rate to 24 hours or, in at-risk patients, substituting liposomal amphotericin B. 

Amphotericin-B is highly toxic as ergosterol is very similar to cholesterol and amphotericin has thus cross-reactivity to cholesterol in human cell membranes. Adverse effects include chills, fever, dyspnea, hepatotoxicity and anemia. However, nephrotoxicity is the most common complication, although adequate hydration can reduce the risk for this toxicity to some extend. Amphotericin induced nephrotoxicity may be irreversible. Liposomal preparations have shown to be therapeutically effective with little or no renal damage. 

Liposomal amphotericin (3 mg/kg/day) has been compared with conventional amphotericin (0.7 mg/kg/day) for induction therapy of moderate to severe disseminated histoplasmosis in a randomized, double-blind, multicenter trial in 81 patients with AIDS (119). The duration of induction was 2 weeks, to be followed by 10 weeks of itraconazole in the case of a response. Clinical success was achieved in 14 of 22 patients treated with conventional amphotericin compared with 45 of 51 patients who received liposomal amphotericin (difference, 24% 95% Cl = 1%, 52%). Culture conversion rates were similar. Three patients treated with conventional amphotericin and one treated with liposomal amphotericin died during induction. Infusion-related adverse effects were more common with conventional amphotericin (63%) than with liposomal amphotericin (25%). Nephrotoxicity occurred in 37% of patients treated with conventional amphotericin and 9% of patients treated with liposomal amphotericin. The results of this study suggest that liposomal amphotericin is less toxic than conventional amphotericin and is associated with improved survival. 

Sabra R, Zeinoun N, Sharaf LH, et al. Role of humoral mediators in, and influence of a liposomal formulation on, acute amphotericin B nephrotoxicity. PharmacoiToxicoi 2001 88 168-75. 

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... 

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)... 

Liposomal amphotericin B 3 mg/kg IV daily Lower incidence of nephrotoxicity and infusion reactions more expensive. 

Amphotericin B, a polyene, is discussed more fully in Chapter 52. It has produced healing of the mucocutaneous lesions of American leishmaniasis, but its potential for nephrotoxicity makes it a drug of second choice. On the other hand, liposomal amphotericin B, approved by the U. S. Food and Drug Administration (FDA) for treatment of visceral leishmaniasis, is considered the drug of choice for that indication and is much less toxic than pentavalent antimonials or amphotericin B. 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

All patients receiving amphotericin intravenously suffer from nephrotoxicity. In nonconventional dosage forms, such as liposomal formulations, the adverse effects are similar but less toxic when compared with conventional dosage. 

Amphotericin can cause both glomerular and tubular damage. Lipid-based formulations (colloidal dispersion, lipid complex, and liposomal amphotericin) are less nephrotoxic than conventional amphotericin deoxy-cholate (97). However, several caveats have to be kept in mind in making such comparisons. For example, there are no defined equivalent doses for amphotericin deoxycholate and its lipid-based counterparts. 

Weitkamp JH, Poets CF, Sievers R, Musswessels E, Groneck P, Thomas P, Bartmann P. Candida infection in very low birth-weight infants outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome). Infection 1998 26(1) II-I5. 

Joly V, Dromer F, Barge J, et ai. Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits. J Pharmacol Exp Ther 1989 251 311-6. 

Cesaro S, Zignol M, Burlina AB, et al. Assessment of nephrotoxicity of high-cumulative dose of liposomal amphotericin B in a pediatric patient who underwent allogenic bone marrow transplantation. Pediatric Transplantation 2006 10 255-8. 

Amphotericin B remains the antifungal drug of choice for most systemic infections, but dose-dependent nephrotoxicity occurs to varying degrees in many patients. Toxicity is seen initially with cumulative doses as low as 300 to 400 mg, and reaches an incidence of 80% when cumulative doses approach 4 g. Several liposomal amphotericin B formulations are now available. Although numerous studies demonstrate lower rates of nephrotoxicity with hposomal formulations compared to conventional amphotericin B, it is difficult to compare rates of toxicity between products and studies due to varying study populations eiuoUed, different doses administered, and inconsistent definitions of nephrotoxicity and methods of assessment. ... 

Nephrotoxicity is best minimized by limiting the cumulative dose and avoiding concomitant administration of other nephrotoxins, particularly cyclosporine. Additionally, providing hydration with a high sodium diet and 1 L intravenous 0.9% sodium chloride daily appears to reduce toxicity. Mannitol infusion to induce an osmotic diuresis has not been protective. Lastly, several liposomal amphotericin B formulations are now available and have been reported to reduce nephrotoxicity by enhancing drug delivery to sites of infection and thereby reducing exposure of mammalian cell membranes. ... 

Many clinicians recommend using liposomal formulations of amphotericin B in all patients with pre-existing kidney disease and those at risk for developing nephrotoxicity, while others maintain thatthe safety and efficacy of liposomal formulations remains to be unequivocally established and their judicious use is warranted. 

A large, randomized, multicenter trial that compared voriconazole with hposomal amphotericin B for empirical antifungal therapy showed comparable composite success rates however, voriconazole did not fulfill the protocol-defined criteria for noninferiority to liposomal amphotericin. Voriconazole was superior in reducing documented breakthrough infections, infusion-related toxicity, and nephrotoxicity. However, patients who received voriconazole had more frequent... 

The use of deoxycholate amphotericin B frequently is associated with the development of induced nephrotoxicity. In an attempt to decrease the incidence of nephrotoxicity, three lipid formulations of amphotericin B have been developed and approved for use in humans amphotericin B lipid complex (ABLC, Abelcet Enzon Pharmaceuticals), amphotericin B colloidal dispersion (ABCD, Amphotec Inter-mune Pharmaceuticals), and liposomal amphotericin B (AmBisome Gilead Pharmaceuticals). In these preparations, amphotericin B is incorporated into the phospholipid bilayer membrane rather than in the enclosed aqueous phase. 

All of the three lipid formulations of amphotericin B available in North America and Western Europe, in controlled trials, have demonstrated significantly lower nephrotoxicity than amphotericin B [145]. Differences in biochemical, pharmacokinetic and pharmacodynamic properties among the lipid products have been documented (Table 2). The clinical significance, however, of pharmacokinetic differences between the liposomal preparations is unknown because of the lack of comparative trials. 

Despite early enthusiasm, more recent studies have yielded more equivocal information. In a randomized, double blind study, Wingard et al [146] have compared the safety of two Upid formulations of amphotericin B in febrile neutropenic patients. Subjects were randomized to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L-Amph) at a dose of 3 mg/kg/ d (n=85), or L-Amph at a dose of 5 mg/kg/d (n=81). They found that the incidence of nephrotoxicity (doubhng of the base-... 

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