Editorial
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Amphotericin B deoxycholate: time to retire our old standard?
Jason C Gallagher Temple University, Assistant Professor, 3307 North Broad Street, Philadelphia, PA 19140, USA Tel.: +1 215 707 2573 Fax: +1 215 707 8326
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10.1586/14787210.3.3.313
‘Recently, several new broad-spectrum antifungal agents have challenged the position of amphotericin B deoxycholate and other amphotericin B products as the drugs of choice for many fungal infections.’ Expert Rev. Anti Infect. Ther. 3(3), 313–316 (2005)
Amphotericin B deoxycholate (AmBd) has intravenous formulation was available. Ketoenjoyed a long lifespan in our antifungal arma- conazole was also shown to be less effective in mentarium. A broad spectrum of activity, rela- immunocompromised patients, and lacks activtively low levels of acquired resistance in fungi, ity against many molds. AmBd continued to be low acquisition cost and most importantly, a used in many clinical situations. The approval of fluconazole in 1990 reprelack of suitable alternatives, has kept AmBd as a drug of choice for the treatment of systemic sented a true advance in antifungal therapy. fungal infections for over 40 years [1]. Unfortu- Fluconazole was the first of the triazoles to nately, AmBd has many well-known and severe reach the market [2]. With its excellent oral toxicities that can only be absorption, intravenous forpartially attenuated through ‘AmBd has many well- mulation, low adverse known and severe saline loading and preeffects and good activity medicating, including dose- toxicities that can only against many yeasts, flucolimiting nephrotoxicity and be partially attenuated nazole has supplanted considerable infusion-related through saline loading AmBd as a drug of choice reactions. Despite this signififor the treatment of many and premedicating...’ fungal infections. Although cant toxicity profile, more clinical experience has been gained with AmBd fluconazole is a very good anti-yeast drug, it than with virtually any other systemic anti- lacks useful activity against most molds, and fungal. Recently, several new broad-spectrum its popularity in prophylactic regimens in antifungal agents have challenged the position some patient populations has caused a shift of AmBd and other amphotericin B products as towards both intrinsically resistant the drugs of choice for many fungal infections. Candida spp. and fluconazole resistance in Alternatives to AmBd for systemic antifungal Candida albicans in some centers [3]. therapy have existed for many years, but are Fluconazole’s introduction provided a wellladen with significant drawbacks. Early azoles tolerated and efficacious oral antiyeast medicasuch as clotrimazole and miconazole were intro- tion, although it did not add to our ability to duced in the 1960s, but their systemic use was treat filamentous fungi. To address this, itracolimited by adverse effects and problematic phar- nazole was introduced to the antifungal marmacokinetics [2]. Ketoconazole was introduced ket in 1992. With much of the anti-yeast in 1981 and became the drug of choice in non- activity of fluconazole and activity against severe endemic mycoses. It was the first orally Aspergillus and other fungi, itraconazole had a available systemic antifungal agent. However, lot of promise. Unfortunately, its use has been the oral formulation had problematic inter- tempered by several of the same issues that patient differences in absorption, and no held back the early azoles. The initially
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introduced oral capsule formulation has highly variable, and The newest agents to enter the antifungal market are the often poor, bioavailability. An intravenous formulation was also echinocandins and voriconazole. Voriconazole is an extendednot initially available. Although both of these issues have since spectrum triazole with activity against most clinical Candida been rectified, use of itraconazole has been limited. The more spp. and many molds. It is indicated in the USA for primary bioavailable liquid oral formulation of itraconazole is poorly therapy of invasive aspergillosis, esophageal candidiasis, canditolerated, and itraconazole has more adverse effects and more demia in non-neutropenic patients and serious infections severe drug interactions than fluconazole. It has also not been caused by Scedosporium apiospermum and Fusarium spp. Voricostudied as a primary therapy in invasive aspergillosis and has nazole was proven to be more effective than AmBd in the treatbeen mostly relegated to a role in consolidation therapy for that ment of invasive aspergillosis by both increased cure rates at invasive fungal infection. Although both fluconazole and itra- 12 weeks and decreased mortality [8]. Significantly, it is only one conazole were shown to be equivalent to AmBd as empiric anti- of two drugs approved for primary therapy of invasive aspergillofungal therapy in persistently febrile neutropenic patients, the sis in the USA, the other being AmBd. Voriconazole was only broader antifungal spectrum of AmBd and its extensive history recently approved in the USA for the treatment of candidemia, in this patient population led to its continued predominant use for but its broad spectrum against Candida including C. glabrata and this indication. C. kruseii, its activity against some fluconazole-resistant C. albiThe need for an alternative well tolerated, broad-spectrum cans, and its oral formulation makes it a good alternative in these antifungal with activity against yeasts and molds continued. infections. The oral formulation of voriconazole is a highly bioaIncreasing numbers of immunocompromised patients, fueled by vailable tablet, giving it an advantage over itraconazole and the increasingly intense oncology regimens, more echinocandins, since preferential use of ‘Increasing numbers of highly bioavailable oral antifungal therapy organ transplant recipients, and the AIDS immunocompromised epidemic, engendered the search for a safer has been shown to decrease institutional alternative to AmBd that maintained its patients...engendered the costs [9]. Voriconazole has been studied as broad spectrum and good activity. Enter the empiric antifungal therapy in persistently search for a safer lipid formulations of amphotericin B alternative to AmBd that febrile neutropenic patients in a controver(LFABs). In the mid- to-late 1990s, three sial trial [10]. In this study, voriconazole did maintained its broad LFABs were introduced: amphotericin B not achieve noninferiority by the investigaspectrum and good lipid complex (ABLC), amphotericin B coltors’ predefined composite end point, but activity.’ loidal dispersion (ABCD) and liposomal did show significantly less breakthrough funamphotericin B (L-AmB). gal infections than L-AmB. These seemingly These compounds were designed to attenuate some of the tra- contradictory findings have caused many to question the design ditional toxicities of AmBd while maintaining its efficacy. They and primary end points of this type of study, and many clinicians have been successful to varying degrees. All have been shown to are using voriconazole for this indication. be less nephrotoxic than AmBd (L-AmB the least of the three), Voriconazole does have a down side, namely a large number and some have been shown to also attenuate infusion-related of significant drug interactions, nonlinear pharmacokinetics reactions [4]. This reduced toxicity has allowed increased amounts and an adverse-effect profile that includes visual effects in a of the drug to be delivered, up to 10 mg/kg/day for L-AmB [5]; a high percentage of patients and liver function abnormalities in consideration that is especially important for fungal infections others. It also has an antifungal spectrum that, while very that are relatively resistant to amphotericin B, such as zygomyco- broad, does not include the zygomycetes, a group of emerging sis. What is the drawback to the LFABs? Cost. Pharmacy costs of fungi that are somewhat covered by amphotericin B formulaLFABs are many times higher than for AmBd [4], and with no tions. However, its high tolerability, highly bioavailable oral obvious efficacy differences, many institutions have been slow to formulation and strong clinical data for several indications have embrace their use. It is the cost difference between AmBd and led to it displacing amphotericin B formulations for many uses. Two echinocandins have been approved for clinical use – the LFABs that has led many institutions to restrict the use of LFABs to patients who have developed, or are likely to develop, caspofungin and micafungin. Caspofungin has been available in intolerable adverse effects to AmBd. Recent data shows that a the USA for several years; micafungin was only recently approved trend towards increased efficacy with LFABs in many invasive by the US Food and Drug Administration (FDA), but has been fungal infections appears to have emerged [6]. However, this available in Japan for some time. These drugs have excellent trend is subtle and many institutions continue to restrict LFABs activity against most clinical Candida spp., as well as activity to AmBd-intolerant patients or patients with pre-existing renal against Aspergillus. They have a low incidence of adverse reacdysfunction. This strategy of waiting for toxicity to develop in tions, and have been studied in refractory therapy for invasive patients with seemingly normal renal function is only cost justifi- aspergillosis, candidiasis, antifungal prophylaxis in cancer able from the perspective of the drug budget, since some patients and as empiric antifungal therapy in persistent febrile pharmacoeconomic analyses have shown that the overall health- neutropenia. Caspofungin has been compared with AmBd in a care costs for LFABs and AmBd are not as disparate when the large, randomized, double-blinded trial for the treatment of invacost of nephrotoxicity and other adverse effects are considered [7]. sive candidiasis and demonstrated at least equivalent efficacy
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Amphotericin B deoxycholate: time to retire our old standard?
with less toxicity [11]. Noninferiority was demonstrated with likely that many of these patients did not have fungal infecless adverse effects when caspofungin was compared with tions. Also, the relatively small sample size makes interpretaL-AmB for empiric therapy in persistently febrile neutropenic tion questionable. A separate noncomparative study demonpatients in another large double-blinded trial [12]. Less robust strated that the reduced toxicity of continuous infusions of data are available for the treatment of invasive aspergillosis, but AmBd allows for increased dosing. This paper demonstrated the novel mechanism of action of echinocandins combined that up to 2.0 mg/kg/day of AmBd was well tolerated. Both with their low toxicity has renewed interest in combination of these studies prove that continuous-infusion AmBd is less toxic than intermittent infusions, but they are unable to prove antifungal therapy for this disease. The echinocandins are unfortunately limited to intravenous greater or even equal efficacy than the 2–6 h intermittent formulations. They also have activity against Aspergillus that is infusions that most patients receive. Amphotericin B is a concentration-dependent drug, suggesting neither classically fungicidal, nor fungistatic. Instead, they inhibit the rapidly ‘AmBd has survived years of that better killing may occur with high challenges from many intermittent dosing. Until studies in dividing tips of growing hyphae, leading patients with proven fungal infections to the production of aberrant hyphal different newer forms [13]. This mechanism has led to antifungals...However, that are conducted, continuous infusion AmBd remains a potentially efficacious concern that they may not be ideal has finally changed.’ therapy, not a proven one. choices of monotherapy for patients AmBd has survived years of challenges from many new with invasive aspergillosis that has been present for some time. This concern has not been proven, but they have taken and different antifungals, but has remained our de facto a back seat to voriconazole for the treatment of this disease default therapy for decades. However, that has finally changed. The introduction of the echinocandins has given due to voriconazole’s wealth of clinical trial data. So where does this leave AmBd? It is still an inexpensive us a class of agents with broad anticandidal activity and few option that is effective for many mycoses. To try to improve adverse reactions. Voriconazole has proven to be more efficaAmBd’s margin of safety, some investigators have studied cious than AmBd in the treatment of invasive aspergillosis, continuous infusions of AmBd [14,15]. One group studied with less serious adverse events and a convenient oral formuAmBd given over 4 h to continuous infusion AmBd in lation. For the indications where AmBd remains a drug of 80 patients with cancer [14]. The patients were randomized, choice, the LFABs are available for the patients who do not and each group received approximately 1 mg/kg/day of or cannot tolerate AmBd. Continuous infusions of AmBd AmBd in an unblinded fashion. Most patients in the study have been shown to considerably reduce toxicity, but the had acute leukemia, although the indications for AmBd efficacy of this method remains unproven in invasive fungal therapy were not listed. The investigators found that the infections. Although there are indications for AmBd where continuous infusion AmBd patients experienced signifi- alternatives have not been well studied, these are few in cantly less nephrotoxicity and infusion-related toxicity than number and represent the minority of patients who require the 4 h infusion patients. The mortality rate in the 4 h infu- systemic antifungal pharmacotherapy. After a long period of few effective antifungal options, we sion arm was also significantly higher, with seven patients dying during treatment (three from proven fungal infec- now find ourselves with many. We need to decide if the cost tions) compared with none in the continuous infusion arm. savings to our drug budget is worth exposing our patients to Although this study introduces an interesting premise, it is the significant and likely toxicity of AmBd therapy. References 1
Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev. Infect. Dis. 12(2), 308–329 (1990).
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Maertens JA. History of the development of azole derivatives. Clin. Microbiol. Infect. 10(Suppl. 1), 1–10 (2004).
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Singh N. Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin. Infect. Dis. 33(10), 1692–1696 (2001).
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Walsh TJ, Goodman JL, Pappas P et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob. Agents Chemother. 45(12), 3487–3496 (2001). Barrett JP, Vardulaki KA, Conlon C et al. A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations. Clin. Ther. 25(5), 1295–1320 (2003). Cagnoni PJ, Walsh TJ, Prendergast MM et al. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the
empirical treatment of persistently febrile neutropenic patients. J. Clin. Oncol. 18(12), 2476–2483 (2000). 8
Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 347(6), 408–415 (2002).
9
Gallagher JC, Lee KB. Program to restrict use of IV fluconazole. Am. J. Health. Syst. Pharm. 61(16), 1695–1698 (2004).
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Walsh TJ, Pappas P, Winston DJ et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N. Engl. J. Med. 346(4), 225–234 (2002).
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11
Mora-Duarte J, Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N. Engl. J. Med. 347(25), 2020–2029 (2002).
12
Walsh TJ, Teppler H, Donowitz GR et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N. Engl. J. Med. 351(14), 1391–1402 (2004).
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Graybill JR. The echinocandins, first novel class of antifungals in two decades: will they live up to their promise? Int. J. Clin. Pract. 55(9), 633–638 (2001).
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Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 h: randomised controlled trial. Br. Med. J. 322(7286), 579–582 (2001).
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Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an openlabel observational study. Clin. Infect. Dis. 36(8), 943–951 (2003).
Affiliation •
Jason C Gallagher, Pharm D, BCPS Assistant Professor of Clinical Pharmacy, Temple University, Clinical Specialist, Infectious Diseases, 3307 North Broad Street Philadelphia, PA 19140, USA Tel.: +1 215 707 2573 Fax: +1 215 707 8326
[email protected]
Expert Rev. Anti Infect. Ther. 3(3), (2005)
