Amphotericin B

Publication Details

OVERVIEW

Introduction

Amphotericin B is an antifungal agent with a broad spectrum of activity against many fungal species. Amphotericin B commonly causes mild to moderate serum aminotransferase elevations and can cause hyperbilirubinemia, but acute, clinically apparent drug induced liver injury from amphotericin B therapy is exceedingly rare.

Background

Amphotericin (am" foe ter' i sin) B is a polyene macrolide antibiotic that acts by binding to sterols in the plasma membranes of fungi causing the cells to leak, eventually leading to fungal cell death. Amphotericin B is indicated for the treatment of a several fungal and other infections including leishmaniasis, invasive aspergillosis, blastomycosis, candidiasis, coccidiomycosis, cryptococcal meningitis, cryptococcosis, histoplasmosis, mucormycosis, sporotrichosis, and others. Amphotericin B was approved by the FDA in 1971 and is currently widely used in the treatment of serious fungal infections. Amphotericin B is insoluble in water and is formulated for intravenous use by complexing it with lipotrophic molecules such as deoxycholate, liposomes or lipid complexes. Amphotericin is available in multiple forms and concentrations generically and under the brand names Amphocin and Fungizone (deoxycholate), Ambisome (liposome), Abelcet (lipid complex), and Amphotec (cholesteryl sulfate complex). The recommended dose varies by drug form and by disease entity; amphotericin B is given intravenously and the usually dosage is up 0.5 to 1.0 mg/kg daily. Many fungal infections require prolonged therapy (for 1 month to as many as 9 months). Common side effects include fever and chills, nausea, weight loss, headache, malaise, azotemia, hypokalemia, anemia, renal tubular acidosis and phlebitis at peripheral vein infusion sites.

Hepatotoxicity

Mild and transient elevations in liver enzymes occur in up to 20% of patients receiving amphotericin. Clinically apparent hepatotoxicity is rare, but several convincing cases have been published. The liver injury arises as early as 4 to 14 days after starting therapy, typically with a hepatocellular or mixed pattern of enzyme elevation. Most patients have no symptoms or jaundice. Recovery occurs promptly upon stopping therapy. In addition, isolated but dramatic instances of hyperbilirubinemia arising within days of starting amphotericin have been reported with elevations largely in the direct (conjugated) bilirubin fraction. These patients become visually jaundiced but have no constitutional symptoms, minimal if any elevations in serum ALT or alkaline phosphatase levels, and no evidence of frank hepatic injury. Finally, rare instances of acute cholestatic hepatitis with jaundice have been reported in patients receiving amphotericin, but these patients have generally been critically ill and exposed to multiple potentially hepatotoxic agents, so that the attribution to amphotericin has been weak.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The cause of serum aminotransferase elevations during amphotericin B therapy is unknown, but may be a direct hepatotoxicity from the polyene based upon its effects on cell membranes. There is little evidence of hypersensitivity, although the injury is idiosyncratic and usually recurs with reexposure and, thus, may be due to a genetic predisposition based upon the metabolism of amphotericin B which is largely hepatic. The hyperbilirubinemia of amphotericin therapy is likely due to inhibition of bilirubin transport mechanisms and is likely to occur in patients with genetic variations in the major hepatic bilirubin transporter (MRP2).

Outcome and Management

The severity of the liver injury due to amphotericin is usually mild, most patients being asymptomatic and anicteric. Recovery is rapid with stopping amphotericin but can recur with rechallenge. No instances of acute liver failure or chronic liver injury have been convincingly linked to amphotericin therapy. There appears to be no cross sensitivity of the hepatotoxicity of amphotericin to other antifungal agents.

Drug Class: Antifungal Agents

CASE REPORT

Case 1. Serum aminotransferase elevations during amphotericin B therapy.

[Modified from: Gill J, Sprenger H, Ralph E, Sharpe M. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother 1999; 33: 683-5. PubMed Citation]

A 26 year old man developed elevations in serum aminotransferase levels 3 days after starting intravenous amphotericin B for pulmonary blastomycosis. He had received oral itraconazole for 7 days without much improvement before starting amphotericin B. When serum enzymes continued to rise (Table), amphotericin B was stopped while itraconazole was maintained. He was asymptomatic of liver disease, and tests for viral hepatitis and autoantibodies were negative. An abdominal ultrasound showed no evidence of biliary obstruction. A percutaneous liver biopsy showed mild focal fatty change and little evidence of inflammation or hepatocellular necrosis. Stains for fungal elements were negative. Within 4 days of stopping amphotericin B, serum enzymes had returned to baseline.

Key Points

Laboratory Values

Comment

The evidence that amphotericin was the cause of the liver test abnormalities was the timing of onset within a few days of starting amphotericin B, and the timing of recovery which was immediate upon stopping. The injury was mild and the decision to stop treatment was based entirely on the fact that the serum ALT level had risen to more than 10 times the upper limit of the normal range. While itraconazole was another possible cause of the abnormalities, the serum enzymes decreased immediately upon stopping amphotericin despite continuing itraconazole.

Case 2. Cholestatic serum enzyme elevations induced by Amphotericin B.

[Modified from: Mohan U, Bush A. Amphotericin B-induced hepatorenal failure in cystic fibrosis. Ped Pulmonol 2002; 33: 497-500. PubMed Citation]

A nine year old girl with cystic fibrosis developed nausea and vomiting on the third day of amphotericin B therapy for suspected pulmonary aspergillosis. Her symptoms worsened and the amphotericin was switched to a liposomal formulation. Serum enzymes, which had been normal, were found to be elevated by day 8 of therapy. Because of severe vomiting, dehydration and hematemesis, all antibiotic and antifungal therapy was stopped. There were moderate elevations in ALT and alkaline phosphatase levels, but serum bilirubin remained normal. All abnormalities resolved within 7 days of stopping amphotericin.

Key Points

Laboratory Values

Comment

While the authors described this case as demonstrating hepatorenal failure, most evidence suggests that the hepatic injury was mild. There was no jaundice and laboratory tests returned to baseline rapidly with the patient’s clinical improvement. The elevations in prothrombin time may have been due to the antibiotic therapy and the nutritional status of the patient, rather than hepatic failure. This case demonstrates the difficulty of attributing hepatic enzyme elevations and liver damage to a medication in a critically ill patient with multiple medical problems who is receiving several potent medications, several of which can also cause hepatic injury (clavulanic acid, ceftazidime).

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Amphotericin B – Generic, Amphocin®, Fungizone®

DRUG CLASS

Antifungal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 08 April 2016

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    (Expert review of hepatotoxicity of antifungal agents published in 1999; “Amphotericin B has rarely been incriminated in hepatic injury”; “The rarity of cases despite widespread use of the drug demonstrates its minimal hepatotoxic threat”).
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    (Review of hepatotoxicity of antifungal agents mentions that amphotericin B rarely causes clinically apparent liver injury but several case reports have been published).
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    : amphotericin B is insoluble in water and is formulated for iv use by complexing with bile salts or lipids; binds ergosterol in fungal membrane and increases permeability).
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    (32 year old man with cryptococcal meningitis and complicated course developed nausea and low grade fever with renal insufficiency and severe phlebitis with each of 4 courses of iv amphotericin [60 to 80 mg/day] developing high fever, large tender liver and pneumonia [bilirubin 1.4 mg/dL, Alk P normal], autopsy showing centrolobular fat, but no inflammation and “some degree of hepatic failure”).
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    (51 year old man with acute leukemia developed abnormal ALT [950 U/L], Alk P [150 U/L] and bilirubin [1.6 mg/dL] levels 18 days after starting amphotericin B for pulmonary aspergillosis; asymptomatic and improved on stopping with rapid increase in ALT [100→300 U/L] after 2 day rechallenge).
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    (29 year old man with HIV infection developed rising Alk P [1000 U/L] and GGT [133 U/L, normal <65] after 10 days of amphotericin B, with improvement on lowering dose; no symptoms and no mention of ALT).
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    (26 year old man with blastomycosis developed elevations in ALT [518 U/L], Alk P [205 U/L] but not bilirubin [0.8 mg/dL] after 10 days of amphotericin B; liver biopsy showed mild fatty change only; enzyme elevations fell to normal within a few days of stopping amphotericin despite continuing itraconazole: Case 1).
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    (9 year old girl with cystic fibrosis became critically ill while on amphotericin B [bilirubin 0.6 mg/dL, ALT 364 U/L, Alk P 1254 or ~3 times baseline, prothrombin time 27.5 sec], with rapid reversal on stopping amphotericin B, but with other possible causes of liver injury present: Case 2).
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    (53 year old with lung cancer developed marked increases in direct and total bilirubin [5.5 and 6.1 mg/dL] within 2 days of starting amphotericin with minimal increase in ALT or Alk P, resolving with stopping and recurring with rechallenge using a different formulation).
  • Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther 2007; 29: 1980-6. [PubMed: 18035197]
    (Among 64 patients undergoing autopsy after death from cancer and fungal infections, 92% had abnormal liver tests, but histological features of hepatotoxicity were infrequent and mild, consisting of focal fatty change and necrosis).
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    (Systematic review of 39 controlled trials in more than 8000 patients, found liver enzyme elevations in 14.5% of patients on amphotericin, but only 0.2-1.2% stopped therapy for this reason [pooled estimates]).
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    (28 year old man with chronic granulomatous disease developed hepatosplenomegaly having been treated with liposomal amphotericin for 8 years [bilirubin 0.9 mg/dL, ALT 26 U/L, Alk P 698 U/L], liver biopsy showing nodular regenerative hyperplasia and sea-blue foamy macrophages [also found in the bone marrow], suggestive of lysosomal accumulation of lipid from the amphotericin liposomes).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
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  • Giannella M, Ercolani G, Cristini F, Morelli M, Bartoletti M, Bertuzzo V, Tedeschi S, et al. High-dose weekly liposomal amphotericin b antifungal prophylaxis in patients undergoing liver transplantation: a prospective phase II trial. Transplantation 2015; 99: 848-54. [PubMed: 25531982]
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 14 were attributed to antifungal agents, but none to amphotericin).