What specific infection control measures must be adhered to in order to prevent infection in transplant patients – liver transplant?

Specific infection control measures to prevent infection after liver transplantation are not significantly different from those measures employed for patients undergoing other types of solid organ transplantation (SOT).

  • Appropriate perioperative antimicrobial prophylaxis (reviewed elsewhere).

  • Pre-operative screening of the recipient (Table I) for infections that may complicate the post-transplant period.

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    Screening tests for liver transplantation

    Pathogen Method of testing
    Common tests for both recipients and donors
    HIV Serology
    Hepatitis B virus (HBV) Serology (sAb, cAb), antigen (sAg)
    Hepatitis C virus (HCV) Serology
    Hepatitis A virus (HAV) Serology
    Epstein-Barr virus (EBV) Serology
    Herpes simplex virus (HSV) I/II Serology
    Cytomegalovirus (CMV) Serology
    Toxoplasma gondii Serology
    Treponema pallidum Serology
    Human T-cell lymphotropic virus I/II (HTLV I/II) Serology
    Tests that may be indicated, based on specific risk factors or time constraints
    HIV, HCV, HBV Nucleic acid amplification testing (NAAT)
    Mycobacterium tuberculosis PPD or IGRA (interferon gamma release assay)
    Trypanosoma cruzi Serology
    Strongyloides Serology
    Coccidioides Serology
    Donor testing (center-specific)
    Bacteria Blood and urine cultures, bronchoalveolar lavage (BAL) culture

  • Pre-operative screening of the donor (Table I) for infections that may be transmitted to the recipient.

  • Post-transplant prophylaxis and/or pre-emption for specific pathogens (Table II), based on pre-operative screening results.

    Specific pathogens with available prophylaxis after liver transplantation

    Pathogen Most common agents used for prophylaxis
    Viruses
    Varicella-zoster virus (VZV) Ganciclovir, valganciclovir, acyclovir, valacyclovir, famciclovir
    CMV Ganciclovir, valganciclovir
    HSV I/II Acyclovir, valacyclovir, famciclovir
    Fungi
    Pneumocystis jiroveci Trimethoprim-sulfamethoxazole
    Candida spp. Fluconazole

What are the key conclusions from available clinicaltrials or meta-analyses related to transplant patients – liver transplant that guide infection control practices and policies?

Few clinical trials or meta-analyses are available that directly address infection control measures related to liver transplantation. Relevant clinical trials are summarized here.

Cytomegalovirus disease prevention

The following are key principles that guide care related to CMV disease prevention among liver transplant recipients.

  • The risk of developing CMV disease after liver transplantation is directly related to the serological status of the donor and recipient, with serodiscordance (i.e., donor CMV IgG-positive/recipient CMV IgG-negative, or D+/R-) carrying the greatest risk.

  • Two general prevention strategies, prophylaxis and pre-emption, have been used for CMV disease prevention in SOT. Prophylaxis involves administration of antiviral drug therapy to all patients, regardless of their relative risk of disease. Pre-emption involves monitoring patients for evidence of CMV reactivation using virus-specific markers such as pp65 antigenemia or nucleic acid testing (NAT); patients with CMV reactivation are given antiviral therapy until these markers resolve. A hybrid approach is used by many transplant centers that involves an initial period of universal prophylaxis followed by monitoring and pre-emption.

  • Currently these strategies, prophylaxis and pre-emption, appear to be equally effective at preventing CMV disease in SOT, including liver transplant recipients.

  • Ganciclovir (5mg/kg IV daily, adjusted for renal clearance) and valganciclovir (900mg per os daily, adjusted for renal clearance) are currently the most effective antiviral drugs used for CMV disease prevention in SOT.

  • When used for prophylaxis, the duration of antiviral administration most commonly used is 100 days. However, the IMPACT trial demonstrated that extending prophylaxis to 200 days for serodiscordant (CMV D+/R-) kidney transplants reduced the risk of CMV disease for as long as 2 years post-transplant. Thus, most experts now recommend extending CMV antiviral prophylaxis to 200 days in this patient population (i.e. CMV D+/R-) if this strategy is used. It is not known if the same benefits apply to liver transplant recipients.

Herpes simplex virus I/II disease prevention

The period of greatest risk for reactivation and disease from HSV in liver transplant recipients occurs in the first month following transplantation. All HSV-seropositive recipients, or seronegative recipients receiving an organ from a seropositive donor, should receive prophylaxis for HSV disease for at least 1 month post-transplant.

  • CMV prophylaxis will also prevent HSV disease.

  • If CMV prophylaxis is not administered, liver transplant recipients should receive one of the following agents for HSV prophylaxis:

    Acyclovir 400-800mg per os, twice a day.

    Valacyclovir 500mg per os, twice a day.

    Famciclovir 500mg per os, twice a day.

Varicella zoster virus disease prevention

Regimens used for CMV and HSV prophylaxis also provide protection for VZV reactivation. These regimens are typically not used for long durations, while the risk for VZV reactivation persists for the lifetime of the patient. No current recommendations exist for the routine prophylaxis of VZV in SOT recipients beyond the use of antivirals for CMV and HSV.

Pneumocystis jiroveci pneumonia prophylaxis

Routine administration of Pneumocystis jiroveci prophylaxis (PJP) is recommended for transplant centers with a PJP incidence of 3-5%. The following regimens are recommended by experts, with most clinical trial experience from trials in HIV/AIDS patients:

  • Trimethoprim-sulfamethoxazole (TMP-SMX): 160mg TMP/800mg SMX (DS tablet) per os three times weekly. Some centers use one DS tablet twice weekly, while others use single strength (SS, 80mg TMP/400mg SMX) 2-3 times weekly. TMP-SMX should be considered the first-line agent for PJP prophylaxis.

  • Dapsone 100mg per os daily.

  • Atovaquone 1500mg per os daily.

  • Pentamidine 300mg aerosol via nebulizer once every 28 days.

  • Clindamycin 300mg per os daily/pyrimethamine 15mg per os daily.

The duration of PJP prophylaxis should be 6-12 months, depending on the net state of immune suppression.

Prevention of specific bacterial infections after liver transplantation

Infection control and practices related to the prevention of infections caused by pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Clostridium difficile, or drug-resistant gram-negative bacteria are currently not different from other populations of hospitalized or surgical patients.

What are the consequences of ignoring the concepts related to transplant patients – liver transplant?

Implementation of specific infection control practices as they relate to liver transplantation is critical for the survival and well being of the transplanted patient. As an example, the incidence of CMV disease one year after liver transplantation in patients without prophylaxis was 31% in a randomized, placebo-controlled trial of CMV immune globulin.

What other information supports the key conclusions of studies of or advice from transplant patients – liver transplant (e.g., case control studies and case series)?

TRANSNET (Transplant-Associated Infection Surveillance Network) prospectively collected data regarding invasive fungal infections (IFI) from 15 U.S. transplant centers over a 5-year period (2001-2006). Data from TRANSNET relevant to liver transplant recipients is displayed in Table III. The 12-month cumulative incidence of an IFI among liver transplant recipients was 4.7%.

Table III.
IFI (N=378) Percentile
Candidiasis 68
Aspergillosis 11
Zygomycosis 2
Pneumocystosis 0
Cryptococcosis 6
Endemic mycoses 5
Other/Unspecified Mold 4.5
Other/Unspecified Yeast 3.7

Summary of current controversies.

  • Prophylactic versus pre-emptive strategy for CMV disease prevention.

  • Prevention of IFI after liver transplantation – which antifungal agent is best?

What is the impact of controlling infections in transplant patients – liver transplant relative to the control of infections in other patient populations?

The major difference between the impact of infection control among liver transplant patients and infection control among other patient populations is the magnitude of benefit reaped by preventing infections related to or worsened by the immune suppression necessary to successfully transplant allogeneic organs.

Patients requiring liver transplantation are already at a higher risk for a variety of infections because of the immunological defects associated with acute or chronic liver disease. Although many of these immune deficits are corrected by transplantation of a healthy donor liver (e.g., restoration of complement component synthesis), the immunosuppression required to prevent host rejection of the new liver introduces new immune challenges.

Adherence to good infection control practices as they relate to liver transplant patients offset the infectious burden imposed by this immunosuppression.

Overview of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and transplant patients – liver transplant.

See Table IV, Table V, and Table VI.

Table IV.
Study Number of patients (N)/number of liver transplants Intervention Outcome on Cytomegalovirus disease
Rayes et al. 1999 N=31/31; monitoring via pp65 antigenemia (inclusion criterion for randomization). GCV plus CMV hyperimmune globulin versus no therapy. 2 of 15 patients given no therapy for pp65 antigenemia developed clinical disease, both responded to therapy after symptom onset.
Singh et al. 2000 N=72/72; monitoring via pp65 antigenemia detection (22 of 72, or 31%). Oral GCV (2gm three times a day for 2 weeks then 1gm three times a day for 4 weeks) versus IV GCV for 7 days (control). 0% oral GCV (0 of 11); 11% (1 of 11) IV GCV; median follow up 36 months (3 weeks-58 months).
Rayes et al. 2001 N=60/60; monitoring via pp65 antigenemia (inclusion criterion for randomization). Oral GCV (1gm three times a day for 2 weeks) versus no therapy. 10% oral GCV (3 of 30); 20% no therapy (6 of 30).
Paya et al. 2002 N=69/69; monitoring via blood CMV PCR. Oral GCV (1gm three times a day) versus placebo for 8 weeks. 0% oral GCV; 12% placebo.
Mattes et al. 2004 N=48/17; monitoring via blood CMV PCR. GCV (5mg/kg IV twice a day) versus GCV (5mg/kg IV daily) + FOS (90mg/kg IV daily); therapy given for 14 days. Primary outcome was viremia resolution by PCR; 71% (17 of 24) in GCV group; 50% (12 of 24) in GCV + FOS group.

(* Monitoring for CMV activation before initiating intervention)

GCV: ganciclovir; VGCV: valganciclovir; FOS: foscarnet; PCR: polymerase chain reaction.

Table V.
Study Number of patients (N)/number of liver transplants Intervention Primary outcome Outcome
Winston and Busuttil 2003 N=229 (all CMV R+)/229. Oral GCV versus oral ACV until d+100 post-transplant; after induction iv GCV (14 days). Incidence of CMV disease 1st year post-transplant 0.9% GCV (1 of 110); 7.3% ACV (8 of 109), P=0.019.
Paya, et al. 2004 N=372/177, all CMV D+/R-. VGCV versus oral GCV until d+100 post-transplant. Incidence of CMV disease 6 months post-transplant. 12.1% VGCV (29 of 239); 15.2% GCV (19 of 125), P=NS.
Winston and Busuttil 2004 N=64/64, all CMV D+/R-. Oral GCV versus IV GCV until d+100 post-transplant; after induction IV GCV (14 days). Incidence of CMV disease 1st year post-transplant. 9.3% oral GCV (3 of 32); 12.5% IV GCV (4 of 32); P>0.2.
Gavaldà et al. 1997 N=73/73, all CMV R+. Oral ACV for 16 weeks versus no prophylaxis. Incidence of CMV disease 120 days post-transplant. 5% ACV (2 of 37); 27% no prophylaxis (10 of 36); P=0.009.
King et al. 1997 N=56/56; pediatric (age range 3-197 months); all CMV D+/R-. IVIG (16 weeks) versus IV GCV (30 days) + IVIG (16 wks). Incidence of CMV disease 180 days post-transplant. 26% IVIG (7 of 27); 17% GCV + IVIG (5 of 29); P=NS.
Barkholt et al. 1999 N=55/55; only 5 (9%) CMV D+/R-. ACV or placebo for 12 weeks post-transplant. Incidence of CMV infection and disease up to 3 months post-transplant. 25% ACV with CMV disease (7 of 28); 52% placebo (14 of 27); P=0.013.
Badley et al. 1997 N=167/167. ACV (120 days post-transplant) versus GCV (IV 14 days) followed by ACV (to 120 days post-transplant). Incidence of CMV infection and disease during 1st year post-transplant. Infection: 57% ACV versus 37% GCV + ACV.Disease: 23% ACV versus 11% GCV + ACV.

(*Initiating intervention regardless of evidence for CMV activation)

GCV: ganciclovir; VGCV: valganciclovir; ACV: acyclovir; IVIG: intravenous immune globulin; D: donor; R: recipient.

Table VI.
trial Number of Patients Intervention Outcome
Pneumocystis jirovecii
Torre-Cisneros et al. 1999 N=120 SDX/PYR weekly versus TMP/SMX SS daily, each for 6 months post-transplant. PJP incidence during prophylaxis: 0% SDX/PYR group; 3% TMP/SMX group (P=NS).
Invasive fungal infections (mainly Candida spp. and Aspergillus spp.)
Tollemar et al. 1995 N=77 LAmB (1mg/kg IV daily) for 5 days versus placebo. First month after transplant: 0% (0 of 40) LAmB group; 16% (6 of 37) in placebo group (P<0.01).
Lumbreras et al. 1996 N=143 FLU versus NYS (both oral) for 28 days post-transplant. 28 days post-transplant: 12% FLU group (9 of 76); 27% NYS group (18 of 67), P=0.022.
Winston et al. 1999 N=212 FLU versus placebo for 10 weeks post-transplant. 10 weeks post-transplant: 9% FLU group (10 of 108); 43% placebo (45 of 104), P<0.00.

SDX: sulfadoxine; PYR: pyrimethamine; TMP: trimethoprim; SMX: sulfamethoxazole; SS: single strength; NS: not significant; LAmB: liposomal amphotericin B; FLU: fluconazole; NYS: nystatin; CAS: caspofungin.

Controversies in detail.

1. Prophylaxis versus pre-emption as strategies to prevent CMV disease after liver transplantation.

  • Prophylaxis: all patients at risk of CMV disease are given preventive therapy.

    Arguments for this strategy: Efficacy of prophylaxis at preventing CMV disease, especially among CMV D+/R- recipients, the potential efficacy to prevent bacterial and fungal infections (in addition to CMV disease), the lack of need to perform surveillance testing during prophylaxis, and a theoretical reduction in the risk of selecting for drug-resistant CMV.

    Problems: The cost and toxicities associated with exposure of all at-risk patients to drug therapy, suppression of low-level viral replication that may engender an effective host immune response, risk for late-onset CMV disease after prophylaxis is discontinued.

  • Pre-emption: monitoring patients for evidence of asymptomatic CMV replication, with initiation of therapy only when CMV replication is detected.

    Arguments for this strategy: Efficacy of pre-emption at preventing CMV disease, reduced drug exposure (with associated reductions in cost and toxicities), potential for better “priming” of the host immune response against CMV, reduction in late CMV disease incidence.

    Problems: False negative testing, leading to missed early CMV disease, logistically more difficult due to need for intermittent testing, lack of standardized threshold for initiation of drug therapy, potential for selection of drug-resistant CMV.

2. Prevention of IFIs after liver transplantation – which antifungal agent is best and who should receive antifungal prophylaxis?

  • Several new antifungal agents have become available in the past decade, including the echinocandins (caspofungin, micafungin, and anidulafungin), newer azoles (voriconazole and posaconazole), and lipid formulations of amphotericin B. Fluconazole has become the most commonly used antifungal agent post-liver transplant, but this agent lacks activity against molds and many non-albicans Candida species, especially C. glabrata.

    As a consequence of the “holes” in the spectrum of antifungal activity for fluconazole, and the toxicities associated with using amphotericin B deoxycholate, many transplant clinicians have changed from these agents to newer antifungals for use as post-transplant prophylaxis for IFIs. Some centers only provide antifungal prophylaxis for patients at high-risk for IFIs post-transplant (ex: kidney failure, large blood product requirement), while others provide prophylaxis to all liver transplant recipients.

    Table VII summarizes select studies that have focused on the use of these newer agents for prophylaxis or address “targeted prophylaxis” to high-risk populations.

    Newer agents for prophylaxis/targeted prophylaxis

    Authors/year of publication Study design Results/conclusions Comments
    Tollemar et al. 1995 RCT LAmB (1mg/kg/d) for 5 days post-transplant protected from IFI during 1st month compared to placebo. LAmB=liposomal amphotericin B; 6 IFIs occurred among 37 placebo-exposed patients (5 Candida, 1 Aspergillus).
    Biancofiore et al. 2002 RCT No difference in IFI between three groups: LAmB 7 days – > itraconazole 3 weeks, fluconazole 7 days – > itraconazole 3 weeks, or placebo. Higher rate of fungal colonization among placebo recipients.
    Winston D and Busuttil R 2002. RCT Oral itraconazole (ITRA) solution versus iv/oral fluconazole (FLUC) for 10 weeks post-transplant: proven IFI 9% ITRA versus 4% FLUC (P=0.25). Both ITRA and FLUC well tolerated, but higher rate of GI side effects with ITRA.
    Sharpe et al. 2003 RCT ITRA versus placebo (until fungal endpoint, discharge, or 56 days of therapy): 4% ITRA versus 24% placebo (P=0.04). Fungal endpoints: proven IFI, suspected deep IFI, superficial IFIs requiring systemic therapy, fever of unknown origin requiring empiric antifungal therapy.
    Castroagudin et al. 2005 Prospective interventional (no comparator group) High-risk post-transplant patients received LAmB (1mg/kg/d) for 7-10 days: one year mortality 80%; prevalence of IFI 9.5%. High-risk criteria: acute liver failure, ventilator >7 days, retransplant, relaparotomy, antibiotic >14 days, transfusion >20 RBC units, biliary leak.
    Shah et al. 2005 Open randomized trial High-risk liver transplant patients received either AmB deoxycholate 15mg IV daily or LAmB 50mg IV daily until ICU discharge, death, or increased dose for therapy of IFI: AmB group 2 IFIs among 44 patients. LAmB group 3 IFIs among 48 patients. LAmB group more likely to survive to ICU discharge (79.6% LAmB group versus 59.5% AmB, P=0.038).
    Pappas et al. 2006 (25) Prospective observational study 193 liver transplant patients defined as low risk for IFI, followed for 100 days post-transplant with no prophylaxis: 4% developed IFI (7 of 193) – 3 Candida spp., 3 Aspergillus, 1 Cryptococcus. Conclusion: low risk liver transplant patients may not need antifungal prophylaxis. Low risk defined as having < or =1 of following: choledochojejunostomy, retransplant, intra-operative use of >40 units of blood products, re-operation for bleeding/leak/vascular insufficiency, preoperative creatinine >2mg/dL, perioperative Candida colonization.
    Hadley et al. 2009 Prospective double-blind randomized trial 71 high-risk liver transplant patients randomized to 14 days of either LAmB 2mg/kg IV daily or fluconazole 400mg IV daily, followed 100 days post-transplant: 6 IFIs in LAmB group, 4 IFIs in fluconazole group. Trial designed to enroll 300 patients, closed early due to insufficient enrollment. High-risk defined as > or =2 of following: choledochojejunostomy, retransplant, intraoperative use of >40 units of blood products, re-operation within 5 days for bleeding/leak/vascular insufficiency/graft failure, preoperative creatinine >2mg/dL or dialysis +/- 2 days of transplant, Candida colonization.
    Fortun et al. 2009 Prospective, multicenter, non-comparative, open-label trial High-risk (as above) liver transplant patients received > or =21 days of caspofungin (max 90 days) and followed to day +100 post-transplant: 71 patients enrolled, 2 developed IFI (one Mucor wound infection, one Candida albicans wound infection) No comparator limits conclusions about the efficacy of caspofungin as antifungal prophylaxis.
    San-Juan et al. 2011 Retrospective analysis of prospective cohorts (low-risk patients from centers using universal prophylaxis versus those at centers that do not use this strategy) 12 Spanish hospitals (3 using universal prophylaxis with fluconazole) with a total of 799 low-risk liver transplant patients (206 with universal prophylaxis, 593 no prophylaxis): IFIs in 1st 90 days post-transplant occurred in 1.9% of patients in universal prophylaxis cohort versus 1% in “no prophylaxis” cohort, P=0.36. This study supports withholding antifungal prophylaxis in low-risk liver transplant patients.

What national and international guidelines exist related to transplant patients – liver transplant?

  • American Society of Transplantation Infectious Diseases Guidelines, 2nd edition. American Journal of Transplantation 2009. Volume 9 (Supplement s4): S1-S281.

  • Organ Procurement and Transplantation Network (OPTN) Policy on Minimum Procurement Standards for an Organ Procurement Organization.

  • Organ Procurement and Transplantation Network (OPTN) Policy on Identification of Transmissible Diseases in Organ Recipients.

References

Humar A, Limaye AP, Blumberg EA, et al. Extended valganciclovir prophylaxis in D+/Rkidney transplant recipients is associated with long-term reduction in cytomegalovirus disease: two-year results of the IMPACT study. Transplantation 2010;90:1427-31.

Snydman DR, Werner BG, Dougherty NN, et al. Cytomegalovirus immune globulin prophylaxis in liver transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1993;119:984-91.

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 2010;50:1101-11.

Rayes N, Oettle H, Schmidt CA, et al. Pre-emptive therapy in CMV-antigen positive patients after liver transplantation–a prospective trial. Ann Transplant 1999;4:12-7.

Singh N, Paterson DL, Gayowski T, et al. Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, controlled trial. Transplantation 2000;15:717-22.

Rayes N, Seehofer D, Schmidt CA, et al. Prospective randomized trial to assess the value of pre-emptive oral therapy for CMV infection following liver transplantation. Transplantation 2001;15:881-5.

Paya CV, Wilson JA, Espy MJ, et al. Pre-emptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant infections: a randomized, placebo-controlled trial. J Infect Dis 2002;185:854-60.

Mattes FM, Hainsworth EG, Geretti AM, et al. A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet (each at half dose) for pre-emptive therapy of cytomegalovirus infection in transplant recipients. J Infect Dis 2004;189:1355-61.

Winston DJ, Busuttil RW. Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients. Transplantation 2003;75:229-33.

Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004;4:611-20.

Winston DJ, Busuttil RW. Randomized controlled trial of sequential intravenous and oral ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with cytomegalovirus-seropositive donors. Transplantation 2004;77:305-8.

Gavaldà J, de Otero J, Murio E, et al. Two grams daily of oral acyclovir reduces the incidence of cytomegalovirus disease in CMV-seropositive liver transplant recipients. Transpl Int 1997;10:462-5.

King SM, Superina R, Andrews W, et al. Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with IVIG alone for prevention of primary cytomegalovirus disease in children receiving liver transplants. Clin Infect Dis 1997;25:1173-9.

Barkholt L, Lewensohn-Fuchs I, Ericzon BG, et al. High-dose acyclovir prophylaxis reduces cytomegalovirus disease in liver transplant patients. Transpl Infect Dis 1999;1:89-97.

Badley AD, Seaberg EC, Porayko MK, et al. Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK liver transplantation database. Transplantation 1997;64:66-73.

Torre-Cisneros J, De la Mata M, Pozo JC, et al. Randomized trial of weekly sulfadoxine/pyrimethamine vs. daily low-dose trimethoprim-sulfamethoxazole for the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation. Clin Infect Dis 1999;29:771-4.

Tollemar J, Höckerstedt K, Ericzon BG, et al. Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. A randomized, placebo-controlled study. Transplantation 1995;59:45-50.

Lumbreras C, Cuervas-Mons V, Jara P, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis 1996;174:583-8.

Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999;131:729-37.

Biancofiore G, Bindi ML, Baldassarri R, et al. Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study. Transpl Int 2002;15:341-7.

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 2002;74:688-95.

Sharpe MD, Ghent C, Grant D, et al. Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study. Transplantation 2003;76:977-83.

Castroagudin JF, Pontón 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 2005;37:3965-7.

Shah T, Lai WK, Gow P, et al. Low-dose amphotericin for prevention of serious fungal infection following liver transplantation. Transpl Infect Dis 2005;7:126-32.

Pappas PG, Andes D, Schuster M, et al. Invasive fungal infections in low-risk liver transplant recipients: a multicenter prospective observational study. Am J Transplant 2006;6:386-91.

Hadley S, Huckabee C, Pappas PG, et al. Outcomes of antifungal prophylaxis in high-risk liver transplant recipients. Transpl Infect Dis 2009;11:40-8.

Fortún J, Martín-Dávila P, Montejo M, et al. Prophylaxis with caspofungin for invasive fungal infections in high-risk liver transplant recipients. Transplantation 2009;87:424-35.

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 2011;92:346-50.

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