EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Extension of invasive aspergillosis to the central nervous system is associated with high mortality, in part because of poor central nervous system penetration of antifungal drugs. Voriconazole yields fungicidal drug concentrations within the central nervous system, but use of this drug is limited in liver transplant recipients because of hepatotoxicity and drug interactions.

Materials and Methods: We reviewed medical records and antifungal treatment for all liver transplant recipients from 2007 to 2009 who had cerebral aspergillosis (Proven [2]; Probable [1]; Possible [1]) at week 3, 4, 6, and 12 after transplant.

Case report: A 33-year-old white man underwent orthotopic liver transplant for acute liver failure that was caused by acetaminophen overdosage. Risk factors for fungal infection included major blood loss (8 L), prolonged surgery (9 h), and emergency revision transplant that was done because of nonfunctioning of the primary transplant at 48 hours. He developed postoperative aspergillus pneumonia and invasive aspergillosis of the kidneys, brain, and eye. Treatment with voriconazole and amphotericin B was successful, with moderate residual renal impairment.

Conclusions: Voriconazole was effective and safe in the treatment of cerebral aspergillosis in this liver transplant recipient.

Key words : Infection, Fungal, Central, Nervous, System

Despite a 42% incidence of fungal infection in liver transplant recipients, invasive aspergillosis remains uncommon (1% to 8%).^1-3 The most frequent clinical form is pulmonary aspergillosis but 10% to 25% of all cases of invasive aspergillosis have central nervous system involvement, presumably from hematogenous spread.¹ Despite a 60% overall case-fatality frequency in invasive aspergillosis, central nervous system involvement is associated with a mortality of almost 100%.⁴ Poor central nervous system penetration of antifungal drugs traditionally used in invasive aspergillosis, such as amphotericin B, may be responsible for the high mortality.^{1,
5-7}

Voriconazole is a triazole that is superior to other antifungal drugs in treating cerebral aspergillosis because it penetrates the blood-brain barrier and yields fungicidal drug concentrations within the central nervous system that exceed inhibitory concentrations required for Aspergillus species.^8-11 However, there is reluctance within liver transplant units to use voriconazole in liver transplant recipients because of reported drug interactions with calcineurin inhibitors, immune reconstitution syndromes, and hepatotoxicity in 34% patients that frequently necessitates discontinuation of therapy.^12-15 Evidence for the safety and efficacy of voriconazole in the treatment of refractory cerebral aspergillosis in liver transplant recipients is sparse.^{16, 17} This report details the experience of a high volume liver transplant unit in the use of voriconazole in liver transplant recipients with cerebral aspergillosis > 3 years.

Materials and Methods

In total, 458 adults underwent liver transplant at the study center from 2007 to 2009, including 71 adults who had acute liver failure. In these 458 liver transplant recipients, there were 4 patients diagnosed with cerebral aspergillosis. Standardized definitions of invasive fungal infections for clinical research European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (consensus committee) were used to categorize these 4 patients into 3 levels of probability.¹⁸ In 2 patients, invasive fungal infection was confirmed with cytopathology of targeted transcranial needle aspirates that showed classic fungal hyphae, cellular debris, and tissue damage. Four patients each had 1 major clinical criterion used for categorization of possible or probable invasive fungal infection and 1 host factor, and 3 patients each had 1 microbiological criterion; therefore, there was 1 patient with “probable” and 1 with “possible” invasive fungal infection. In this report, only the patient with proven invasive aspergillosis who was treated with voriconazole is presented.

A literature review of all reports on the use of voriconazole in liver transplant recipients with cerebral aspergillosis was done with PubMed/Medline using key words and titles (“invasive aspergillosis,” “aspergillosis,” and “cerebral aspergillosis”), followed by a manual review of all relevant full text manuscripts (Table 1); search limits included English language, human studies, and publications after 1990.

A 33-year-old white man underwent orthotopic liver transplant for acute liver failure that was caused by acetaminophen overdose. Risk factors for fungal infection included major blood loss (8 L), prolonged surgery (9 h), and emergency revision transplant that was done because of nonfunctioning of the primary transplant at 48 hours. He was started on prophylactic amphotericin B (3 mg/kg/d). On postoperative day 17, a positive culture of Aspergillus fumigatus from a bronchoalveolar lavage aspirate confirmed the clinical suspicion of aspergillus pneumonia, and voriconazole was started (500 mg IV twice daily, 1 week later reduced to 300 mg twice daily). However, invasive aspergillosis progressed, involving the kidneys and brain, confirmed with computed tomography (Figure 1). On postoperative day 25, he developed aspergillus endophthalmitis, chorioretinitis, and orbital edema (Figure 1). On postoperative day 30, he had severe hemoptysis caused by a right pulmonary artery pseudoaneurysm and he was treated with emergency embolization.

On postoperative day 44, he was discharged from the liver intensive care unit. Both voriconazole and amphotericin B were continued until postoperative day 119, when he was converted to single drug therapy with oral voriconazole (200 mg/d) and discharged from the hospital. Voriconazole was continued for an additional 6 months, and he developed a transient episode of acute confusion requiring no treatment during this time. At the most-recent examination 2 years after transplant, he was well with moderate renal impairment, possibly caused by calcineurin inhibitors based on experience that transplant centers have.

Immunocompromised patients including liver transplant recipients are at risk for fungal infections despite evidence that inhibitors of calcineurin (tacrolimus) and mammalian target of rapamycin (mTOR) (sirolimus) increase the activity of antifungal agents in vitro.¹ This risk is highest in the immediate postoperative period, and 72% infections occur within the first 30 days (median time to infection,13-17 d).¹⁹ Aspergillosis most commonly affects the respiratory tract, but in these immunocompromised patients, invasive forms can involve the brain, heart, eyes, and skin.^{2, 3} Renal dysfunction and revision transplant are major risk factors for invasive aspergillosis.¹ Other risk factors for invasive fungal infection in liver transplant recipients include surgical technical complexity, primary allograft dysfunction, acute cellular rejection, net state of immunosuppression, renal replacement therapy, postoperative bile leak, substantial blood transfusion, cytomegalovirus infection, and transplant for acute liver failure.^19-21

Voriconazole in invasive aspergillosis
Despite renal toxicity and poor central nervous system penetration, intravenous polyene antifungal drugs such as amphotericin have been used for the treatment of invasive fungal infections, including invasive aspergillosis.^{7, 8} Echinocandins such as caspofungin have fungistatic activity against Aspergillus species, but the use of these drugs in central nervous system infections is not clear because of poor cerebrospinal fluid penetration. Caspofungin has been approved for empiric therapy in presumed invasive fungal infections in febrile and neutropenic adults.^{1, 5, 22} Of the first generation azole antifungal drugs, fluconazole has good oral absorption and central nervous system penetration but is not effective against Aspergillus species.^{3, 7}

In comparison, many reports since 1997 have noted the efficacy of voriconazole in invasive aspergillosis.^{17, 23} Two convincing studies were published in 2002 (including a randomized trial that compared amphotericin with voriconazole), which collectively showed improved survival rates and a lower frequency of adverse events with voriconazole compared with amphotericin B, establishing voriconazole as the treatment of choice for invasive aspergillosis.^{11, 24} Voriconazole is a second-generation triazole, which targets ergosterol biosynthesis, altering cell membrane integrity. The targeted enzyme in the respiratory cycle of the fungi is dependent on cytochrome P450.^{2, 3, 7} Voriconazole is metabolized by the liver, excreted through the kidneys, and has good oral bioavailability, which enables long-term out-patient treatment.²⁵ An excellent tissue penetration profile enables its use as first-line therapy in treatment of invasive aspergillosis of the lung and bone in addition to cerebral aspergillosis.^26-29

Voriconazole for invasive aspergillosis in liver transplant recipients
Three issues arise when using voriconazole in liver transplant recipients. There is a potential interaction between voriconazole and immunosuppressive drugs (cyclosporine, tacrolimus, or sirolimus). In human liver microsomes, voriconazole (4 g/mL) inhibits cytochrome P450 isoenzymes by 50%, demonstrating its potential to increase plasma drug levels at equal dosage, but the pharmacokinetics are nonlinear.^{1, 10} Moreover, large variation between individuals may occur, despite a fixed dosing regimen of voriconazole, in liver transplant recipients, especially in the presence of liver dysfunction.³⁰

The carrier of intravenous voriconazole, which is excreted by the kidneys, may accumulate in patients with impaired creatinine clearance (< 50 mL/min). However, oral administration of voriconazole in patients with moderate to severe renal dysfunction appears safe.¹

Hepatoxicity is a potential adverse event with voriconazole. In 1 study, the frequency of hepatotoxicity was 34% in patients on voriconazole, but it was mild and reversible, and there were no cases of liver failure.¹² However, serious adverse events including liver failure and death have been reported.^{31, 32} This unpredictable adverse event profile, that includes life-threatening toxicity, has caused reluctance in many liver transplant units to use voriconazole in liver transplant recipients, despite its efficacy.^{10, 33}

Voriconazole for invasive aspergillosis in liver transplant recipients with central nervous system involvement
Central nervous system aspergillosis is a unique circumstance in patients with invasive aspergillosis and is associated with a significantly higher mortality rate. Penetration of drugs across the blood-brain barrier is limited by molecular size, physicochemical properties, and drug interaction with transporter systems such as permeability glycoproteins (P-glycoproteins). Most antifungal agents are large molecules (> 700 Da), which makes sufficient central nervous system penetration difficult, confirmed by low levels of most antifungal agents in cerebrospinal fluid and brain tissue in available studies.⁷ In contrast, voriconazole displays central nervous system concentrations that exceed the inhibitory concentrations of Aspergillus species, causing improved response and survival rates.^{7, 26} Voriconazole achieves cerebrospinal fluid levels that exceed trough plasma levels.³⁴ Previous studies about the use of voriconazole for cerebral aspergillosis in liver transplant recipients are limited mainly to case reports, despite the potential for clinical efficacy. In the review of the literature, we identified 8 publications (including 5 case reports), all reporting successful outcomes without major adverse effects except for reversible liver dysfunction in 2 reports, not requiring discontinuation of therapy.^{21, 35-38}

Three larger studies are available about the use of voriconazole in solid-organ transplant recipients with cerebral aspergillosis, primarily hematopoietic stem cell recipients or patients with hematologic malignancies who require immunosuppression. Information about outcomes and adverse events in liver transplant recipients was difficult to isolate from these studies.^{8, 26, 39}

In patients with renal impairment, strict therapeutic drug monitoring is essential to minimize renal injury.¹⁵ We have decreased voriconazole dosage in half in the presence of major renal impairment, but we have made no changes to the immunosuppressive regimen despite the shared drug metabolism pathways of voriconazole and immunosuppressive drugs. It may be beneficial to maintain specific treatment doses of voriconazole and modulate immunosuppression.

In conclusion, this report shows that invasive aspergillosis is not uncommon despite therapeutic doses of amphotericin and caspofungin in liver transplant recipients. Voriconazole was safe and effective in the treatment of cerebral aspergillosis in this liver transplant recipient, with no evidence of major hepatotoxicity. The limited literature to date reveals no contraindications and similar outcomes. However, continued surveillance for adverse events and careful drug assays are mandatory in this selected patient cohort. Early neurosurgical biopsies or bronchial aspiration may be advisable in patients who present diagnostic difficulties, to prevent treatment delay.

Volume: 10 Issue: 5 October 2012

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