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Antifungal Prophylaxis in Liver Transplant Recipients – Adult – Inpatient

Antifungal Prophylaxis in Liver Transplant Recipients – Adult – Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Infection and Isolation


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Antifungal Prophylaxis in
Liver Transplant Recipients –
Adult – Inpatient
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 3
METHODOLOGY ...................................................................................................................... 4
DEFINITIONS ............................................................................................................................ 5
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS .............................................................................................................. 5
UW HEALTH IMPLEMENTATION ............................................................................................. 6
REFERENCES .......................................................................................................................... 7
CPG Contact for Changes:
Philip Trapskin, PharmD, BCPS; Drug Policy Program Manager
Phone Number: 608-265-0341
Email Address: PTrapskin@uwhealth.org
CPG Contact for Content:
Lucas Schulz, PharmD, BCPS AQ-ID
Phone Number: 608-890-8617
Email Address: LSchulz2@uwhealth.org
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2016CCKM@uwhealth.org

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Guideline Authors:
Sara Koth, PharmD; Lucas Schulz, PharmD, BCPS AQ-ID; Margaret Jorgenson, PharmD,
BCPS; Dave Hager, PharmD, BCPS
Coordinating Team Members
Joshua Vanderloo, PharmD, Drug Policy Program
Lucas Schulz, PharmD, BCPS AQ-ID
Review Individuals/Bodies:
David Andes, MD
Luis Fernandez, MD
Barry Fox, MD
Alex Lepak, MD
Jeannina Smith, MD
Jaime Myers, Liver Transplant Manager
Committee Approvals/Dates:
Antimicrobial Use Subcommittee, July 2015; November 2015, July 2016
UWHealth P&T Committee, September 2015; November 2015, July 2016
Release Date: September 2015; Minor revisions: November 2015, July 2016
Next Review Date: September 2018
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2016CCKM@uwhealth.org

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Executive Summary
Guideline Overview
This document is intended to guide clinicians in the screening of liver transplant recipients to
determine their risk for invasive fungal infections and initiating antifungal prophylaxis when
appropriate.
Key Practice Recommendations
1. Liver transplant patients should be evaluated for risk of postoperative invasive fungal
infection. (Class I, Level C)
2. Liver transplant patients at high risk of invasive fungal infection should receive antifungal
prophylaxis with either fluconazole or micafungin. (Fluconazole Class I, Level B; Micafungin
Class IIb, Level C)
3. Antifungal selection based on patient and microbiological factors may be reasonable.
(Class IIb, Level C)
Companion Documents
ξ Liver Transplant Antifungal Prophylaxis Delegation Protocol [123]
Pertinent UW Health Policies & Procedures
None
Scope
Disease/Condition: Patients undergoing liver transplantation.
Clinical Specialty: Transplant, Pharmacy
Intended Users: Transplant surgeons, physicians, physician assistants, advanced practice
nurse practitioners, pharmacists
CPG Objectives:
ξ To guide clinicians in identifying liver transplant recipients at high risk for invasive fungal
infections based on recipient risk factors.
ξ Selection and initiation of antifungal prophylaxis when appropriate based on these risk
factors.
Target Population: Adult patients who have received a liver transplant
Interventions and Practices Considered:
This guideline provides recommendations for the identification of liver transplant recipients at
high risk of developing an invasive fungal infection. It also provides recommendations on the
use, dosing, and duration of antifungal prophylaxis in patients at high risk for developing an
invasive fungal infection after transplant.
Major Outcomes Considered:
ξ Rates of invasive fungal infections after transplant
ξ Rates of adverse effects with antifungal medications
ξ Antifungal resistance rates
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
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Guideline Metrics:
ξ Identification of high-risk liver transplant recipients
ξ Initiation of antifungal prophylaxis in high-risk patients
ξ Incidence of invasive fungal infections after transplant
Methodology
1. PUBMED was searched using the terms antifungal prophylaxis AND liver transplant.
References from identified articles were further evaluated. Internal expert opinion was
also incorporated into guideline development in cases of a lack of evidence or conflicting
evidence.
2. A modified Grading of Recommendations Assessment, Development, and Evaluation
(GRADE) developed by the American Heart Association and American College of
Cardiology Foundation has been used to assess the Quality and Strength of the
Evidence in this Clinical Practice Guideline (Figure1).1




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Definitions
ξ IFI: Invasive fungal infection

Introduction
Invasive fungal infections (IFIs) have been associated with increased mortality, length of hospital stay and
overall cost.2,3 Liver transplant recipients are at high risk for IFIs because of the immunosuppression
required and risk factors associated with surgery.3,4 In June 2013, the United Network of Organ Sharing
(UNOS) instituted the Share 35 Regional Policy, which shares organs not only with local but regional
candidates with MELD scores of 35 and higher. With the advent of this policy, UWHC providers have
been transplanting patients with higher MELD scores more frequently. Although these patients generally
have more risk factors for IFIs, IFI prophylaxis has been non-standardized. The aim of this guideline is to
standardize the process for identifying high-risk patients and prescribing appropriate antifungal
prophylaxis with the goals of reducing the incidence of IFIs after transplant and minimizing the use and
consequences of long-term antifungal medications used to treat IFIs.
Recommendations
1. Screening for liver transplant recipients at high risk for invasive fungal infections
1.1. It is recommended that high-risk patients be defined as those with any of the following risk
factors: (Class I, Level B)
ξ Operation time greater than 10 hours in duration5-9
ξ Any repeat operation within 30 days of transplant5,7,9-17
ξ Retransplantation5-17
ξ Dialysis requirement prior to transplant5-7,9,11-14
ξ High intra-operative transfusion requirement during transplant surgery5-14
o Greater than or equal to 40 units of cellular blood products (platelets, pRBCs,
plasma, cryoprecipitate)
ξ History of choledocho-jejunostomy5-8,11-16
ξ Candida colonization in the peri-operative period5-9,11-15
o One or more cultures positive for Candida within one month of prior to transplant
o Active treatment for Candida infection at the time of transplant
ξ Physiologic MELD equal to or greater than 35 (Class IIb, Level C)
ξ Hospital admission seven days or longer prior to liver transplant (Class IIb, Level C)
ξ ICU admission within seven prior to transplant (Class IIb, Level C)

2. Ordering of prophylaxis for high-risk liver transplant recipients
2.1. All high-risk patients should receive antifungal prophylaxis post-transplant. (Class I, Level C)
2.2. Fluconazole at a dose of 400 mg by mouth daily is recommended prophylaxis.5-7,9,12,14,15,18,19
(Class I, Level B)
2.2.1. Fluconazole dose adjustment for renal dysfunction is not indicated due to low risk of
toxicity and wide therapeutic index. (Class IIb, Level C)
2.2.2. An alternative regimen is probably indicated for patients with prior isolation of a
fluconazole-resistant Candida isolate. (Class IIb, Level C)
2.2.3. An alternative regimen is probably indicated for patients who have received triazole
treatment dosing (fluconazole 400 mg daily for at least seven days or equivalent) within
the previous 90 days. (Class IIb, Level C)
2.2.4. If micafungin is used for this indication, it should not be considered for outpatient
antibiotic therapy (OPAT) if the patient has improved rapidly and is ready for discharge
before fourteen days.3,6,7,9,12,14-16,20,21 (Class III, Level C)
2.3. Fourteen days of prophylaxis duration of therapy may be reasonable. (Class IIb, Level C)
2.3.1. Extension of antifungal prophylaxis beyond fourteen days may be considered if risk
factors persist (e.g. ongoing biliary leak). (Class IIb, Level C)
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2.3.2. If the patient is discharged from the transplant encounter prior to fourteen days of
systemic prophylaxis, discontinuation of antifungal prophylaxis may be considered at
discharge. (Class IIb, Level C)
2.4. While fluconazole resistance is rising in Candida species, the rate of fluconazole-resistant
Candida albicans at UWHC is low (below 5%).20

3. Alternative to fluconazole
3.1. The risk of hepatic injury is low with fluconazole, with approximately 1% of fluconazole-treated
patients experiencing a significant elevation in serum transaminase levels in clinical trials. Hepatic
metabolism is generally not clinically significantly altered until the patient has a Child Pugh Score
of C. In a patient with a Child Pugh Score of C, micafungin can be recommended.9,11,14,20,21 (Class
IIa, Level B).
3.2. In the case of a fluconazole allergy or intolerance, micafungin 100 mg IV daily is probably
recommended.9,14,20 (Class IIa, Level B).
3.3. Liposomal amphotericin B has been studied for the prevention of IFIs after liver transplantation.22
Given alternatives with comparable outcomes and the higher risk of nephrotoxicity with liposomal
amphotericin B, this agent is not currently preferred for routine use as antifungal prophylaxis in
liver transplant recipients.17 (Class III, Level B).
UW Health Implementation

Potential Benefits:
The primary benefit of implementation of this guideline is the standardization of screening for patients at
high risk for developing invasive fungal infections after liver transplant and ensuring that they receive
antifungal prophylaxis.

Potential Harms:
The risk of implementing this guideline and administering antifungal prophylaxis is an increase in side
effects such as nausea, vomiting and headache as well as a need for close monitoring of drug
interactions with immunosuppressive medications.

Qualifying Statements
There is a lack of consensus regarding various risk factors for IFIs in liver transplant recipients and
various levels of evidence; therefore, these guidelines are based on current evidence and local expert
opinion. The recommendations included in this guideline are subject to change with publication of
additional evidence.

Implementation Plan/Tools
1. Document will be housed on U-Connect on the Guideline webpage.
2. Education on this guideline will be distributed to liver transplant surgeons and clinical pharmacists
through service line meetings
3. A pharmacist delegation protocol will be created
4. Reference links to the guideline will be added to fluconazole and micafungin medication records

Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
LQWHQGHG�WR�UHSODFH�D�FOLQLFLDQ¶V�MXGJPHQW�RU�WR�HVWablish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.
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References
1. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC, Jr. Scientific evidence underlying the ACC/AHA clinical
practice guidelines. JAMA. Feb 25 2009;301(8):831-841.
2. Menzin J, Meyers JL, Friedman M, et al. Mortality, length of hospitalization, and costs associated with
invasive fungal infections in high-risk patients. Am J Health Syst Pharm. Oct 1 2009;66(19):1711-1717.
3. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis:
2009 update by the Infectious Diseases Society of America. Clin Infect Dis. Mar 1 2009;48(5):503-535.
4. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients:
results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. Apr 15
2010;50(8):1101-1111.
5. Eschenauer GA, Kwak EJ, Humar A, et al. Targeted versus universal antifungal prophylaxis among liver
transplant recipients. Am J Transplant. Jan 2015;15(1):180-189.
6. Perrella A, Esposito C, Pisaniello D, et al. Role of liposomal amphotericin B prophylaxis after liver
transplantation compared with fluconazole for high-risk patients. impact on infections and mortality within
one year. Transplant Proc. Sep 2012;44(7):1977-1981.
7. Silveira FP, Kusne S. Candida infections in solid organ transplantation. Am J Transplant. Mar 2013;13 Suppl
4:220-227.
8. Trudeau RE, Bowman LJ, Wills AR, Crippin JS, Chapman WC, Anderson C. Once weekly fluconazole for
antifungal prophylaxis post-liver transplantation. HPB (Oxford). Jul 2013;15(7):541-547.
9. Winston DJ, Limaye AP, Pelletier S, et al. Randomized, double-blind trial of anidulafungin versus
fluconazole for prophylaxis of invasive fungal infections in high-risk liver transplant recipients. Am J
Transplant. Dec 2014;14(12):2758-2764.
10. Castroagudin JF, Ponton C, Bustamante M, et al. Prospective interventional study to evaluate the efficacy
and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant
recipients. Transplant Proc. Nov 2005;37(9):3965-3967.
11. Fortun J, Martin-Davila P, Montejo M, et al. Prophylaxis with caspofungin for invasive fungal infections in
high-risk liver transplant recipients. Transplantation. Feb 15 2009;87(3):424-435.
12. Hadley S, Huckabee C, Pappas PG, et al. Outcomes of antifungal prophylaxis in high-risk liver transplant
recipients. Transpl Infect Dis. Feb 2009;11(1):40-48.
13. Pappas PG, Andes D, Schuster M, et al. Invasive fungal infections in low-risk liver transplant recipients: a
multi-center prospective observational study. Am J Transplant. Feb 2006;6(2):386-391.
14. Saliba F, Pascher A, Cointault O, et al. Randomized trial of micafungin for the prevention of invasive fungal
infection in high-risk liver transplant recipients. Clin Infect Dis. Apr 1 2015;60(7):997-1006.
15. Saliba F, Delvart V, Ichai P, et al. Fungal infections after liver transplantation: outcomes and risk factors
revisited in the MELD era. Clin Transplant. Jul-Aug 2013;27(4):E454-461.
16. San-Juan R, Aguado JM, Lumbreras C, et al. Universal prophylaxis with fluconazole for the prevention of
early invasive fungal infection in low-risk liver transplant recipients. Transplantation. Aug 15 2011;92(3):346-
350.
17. Sun HY, Cacciarelli TV, Singh N. Micafungin versus amphotericin B lipid complex for the prevention of
invasive fungal infections in high-risk liver transplant recipients. Transplantation. Sep 2013;96(6):573-578.
18. Winston DJ, Busuttil RW. Randomized controlled trial of oral itraconazole solution versus intravenous/oral
fluconazole for prevention of fungal infections in liver transplant recipients. Transplantation. Sep 15
2002;74(5):688-695.
19. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients. A randomized,
double-blind, placebo-controlled trial. Ann Intern Med. Nov 16 1999;131(10):729-737.
20. Evans JD, Morris PJ, Knight SR. Antifungal prophylaxis in liver transplantation: a systematic review and
network meta-analysis. Am J Transplant. Dec 2014;14(12):2765-2776.
21. DIFLUCAN (fluconazole) [package insert]. New York, New York; Pfizer; Revised March 2014.
22. Tollemar J, Hockerstedt K, Ericzon BG, Jalanko H, Ringden O. Liposomal amphotericin B prevents invasive
fungal infections in liver transplant recipients. A randomized, placebo-controlled study. Transplantation. Jan
15 1995;59(1):45-50.


Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2016CCKM@uwhealth.org