Prophylaxis of fungal infections in transplant patients

Abdala, Edson; Costa, Sílvia Figueiredo; Strabelli, Tania Mara Varejão; Pierrotti, Lígia Camera; Caramori, Marlova Luzzi; Azevedo, Luis Sérgio Fonseca de; Ibrahim, Karim Y.; Dulley, Frederico Luiz; Varkulja, Glaucia Fernanda; Castro Junior, Gilberto de; Almeida, Gisele Madeira Duboc de; Marques, Heloisa Helena de Souza; Shikanai-Yasuda, Maria Aparecida

doi:10.6061/clinics/2012(06)23

TECHNICAL NOTE

Prophylaxis of fungal infections in transplant patients

Edson Abdala^I; SÃlvia Figueiredo Costa^II; Tania Mara Varejão Strabelli^III; LÃgia Camera Pierrotti^IV; Marlova Luzzi Caramori^V; Luis Sérgio Fonseca de Azevedo^VI; Karim Y. Ibrahim^IV; Frederico Luiz Dulley^VII; Glaucia Fernanda Varkulja^VIII; Gilberto de Castro Junior^IX; Gisele Madeira Duboc de Almeida^X; Heloisa Helena de Souza Marques^XI; Maria Aparecida Shikanai-Yasuda^II; Comissão de Infecção em Imunodeprimidos, Hospital das Clínicas da Faculdade de Medicina da USP

^IHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Liver Transplant Service, São Paulo/SP, Brazil

^IIFaculdade de Medicina da Universidade de São Paulo (FMUSP), Department of Infectious and Parasitic Diseases, São Paulo/SP, Brazil

^IIIInstituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR-HCFMUSP), Heart Transplant Area, São Paulo/SP, Brazil

^IVHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Clinical Division of Infectious Diseases, São Paulo/SP, Brazil

^VInstituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR- HCFMUSP), Lung Transplant Unit, São Paulo/SP, Brazil

^VIHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Kidney Transplant Unit, Urology Division, São Paulo/SP, Brazil

^VIIHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Disciplina de Hematologia, Serviço deTransplante de Medula Ossea, São Paulo/SP, Brazil

^VIIIHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (ICHC-HCFMUSP), Infection Control Committee of the Instituto Central, São Paulo/SP, Brazil

^IXInstituto do Cancer do Estado de São Paulo (ICESP), Sao Paulo/SP, Brazil

^XHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Division of Central Laboratory, (HCFMUSP), São Paulo/SP, Brazil

^XIHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (ICr-HCFMUSP), Instituto da Crianca, São Paulo/SP, Brazil

Fungi are an important cause of infection in patients undergoing solid organ transplantation and bone marrow or hematopoietic stem cell transplantation (BMT/HSCT). The incidence and mortality of fungal infections differ according to the organ and the time since transplantation. In the first 30 days after transplantation, yeast (primarily Candida spp.) predominate. After the first month, filamentous fungi, such as Aspergillus spp., are the most frequent agents of infection (1-6).

In BMT/HSCT patients, however, invasive aspergillosis has two peaks of incidence: one at one month post-transplantation and another approximately 90 days after the transplant if the patient develops chronic graft versus host disease (7,8).

Among solid organ transplantation, liver and lung transplant have the highest risk for fungal infection due to underlying diseases, surgical techniques and the graft itself (4,9).

Antifungal prophylaxis use is well established following some transplant types, such as BMT/HSCT and liver (10,11). However, few studies have evaluated heart and pancreas transplants. One of the major challenges is the prevention of filamentous fungal infections, especially by Aspergillus spp., in high-risk patients, such as those who have undergone an allogeneic BMT and developed chronic graft versus host disease or undergone a lung transplantation (12,13).

To standardize the use of primary prophylaxis in transplant patients, we analyzed the literature related to the following transplants: liver, kidney, heart, lung, and HSCT. The IDSA (Infectious Diseases Society of America) system was used to determine the levels of evidence.

Recommendations

1. Liver transplantation (11,14-20)

Universal prophylaxis: no (CII) Targeted prophylaxis: yes (AI)

- Fluconazole 400 mg/day for 21 days

Criterion 1 - at least one of the following risk factors: fulminant hepatitis, re-transplant requirement, post-tx hemodialysis, or the use of antibodies for rejection treatment.
Criterion 2 - at least two of the following risk factors: antibiotic prophylaxis for spontaneous bacterial peritonitis (SBP) pre-tx, reoperation, ICU admission in the 30 days before the tx, or antibiotic use in the 30 days before the tx.

2. Kidney transplantation

There are no studies on prophylaxis. Prophylaxis is not recommended (DII).

3. Lung transplantation (12,21-24) Universal prophylaxis: yes (AI)

- Inhaled amphotericin B deoxycholate for 3 months (50 mg + 50 ml of distilled water; 10 ml inhalation twice a day)

Targeted prophylaxis: yes, if the recipient or donor has airway colonization by Aspergillus spp. pre-tx or post-tx (associated with amphotericin B inhalation).

First choice*: 400 mg itraconazole orally for 3 months (BIII)

Second choice: IV voriconazole (6 mg/kg/day) or oral voriconazole (400 mg/day) for 3 months (CIII) * Advised serum concentration.

4. Heart transplantation (22) Prophylaxis not indicated (DII).

5. Hematopoietic stem cell transplant (HSCT)(10,25-28)

Universal prophylaxis: yes (AI) Fluconazole 400 mg/day IV or oral for 100 days Targeted prophylaxis: yes, for patients under treatment for GVHD

First option: amphotericin B deoxycholate 1 mg/kg/day (or equivalent doses of a lipidic formulation) for 100 days (CIII)

Second option: itraconazole* 400 mg/day, oral for 100 days (CIII)

Third option: EV voriconazole (6 mg/kg/day) or oral voriconazole (400 mg/day) for 100 days (CIII) ** Advised serum concentration.

Controlled and randomized studies have been registered with other azoles, but they were not standardized in the institution or perhaps they are not available in Brazil.

6. Pancreas transplant (29) Universal prophylaxis: yes (CII)

Fluconazole 400 mg/day IV or VO for 7 days (surgical prophylaxis)

Targeted prophylaxis: no (DII)

Conflicts of interest: Edson Abdala - speaker for Bago, performs clinical research with Bristol. Silvia Figueiredo Costa - speaker for Pfizer. Tania Mara Varejao Strabelli -speaker for Novartis, works with Novartis, performs clinical research with Merck.

ACKNOWLEDGMENTS

We thank the Clinical Directors from the Hospital das Clínicas da Faculdade de Medicina da USP for their support: Prof. Jose Otávio Costa Auler Junior, Prof. Tarcisio Eloi Pessoa de Barros Filho and Prof. Eloisa Bonfa.

AUTHOR CONTRIBUTIONS

Abdala E wrote the manuscript (Portuguese), participated of the discussion of the final recommendations and of the revision of the manuscript. Costa SF presented the recommendation for bone marrow transplantation, helped to write the manuscript, wrote part of English version and revised the literature and the final text. Strabelli TMV presented the recommendation for heart transplantantion, wrote part of English version and revised the final text. Caramori ML presented the recommendation for lung transplantation and discussed the final recommendation. Pierrotti LC, Azevedo LSF, Ibrahim KY, Dulley FL, Varkulja GF, Castro Jr C, Almeida GMD, Souza Marques HH participated of the discussion of the text and of the final recommendations. Shikanai-Yasuda MA coordinated the presentations and discussion of the recommendations, helped to revise the final recommendations and to prepare the manuscript for submission.

Email: shikanaiyasuda@gmail.com

Tel.: 55 11 3061 7048

APPENDIX

PROFILAXIA DAS INFECçÕES FUNGICAS EM PACIENTES TRANSPLANTADOS

Os fungos são uma importante causa de infecção nos pacientes submetidos a transplante de órgão sólido e medula óssea ou transplante de células tronco hematopoiéticas (TMO/TCTH). A incidência e a letalidade das infecções fúngicas variam, entretanto, de acordo com o tipo de transplante e do período após o transplante. Nos primeiros 30 dias ocorre o predomínio das leveduras particurlamente Candida spp. Após o primeiro mês predominam os fungos filamentosos como Aspergillus spp (16). Nos pacientes submetidos a TMO/TCTH, entretanto, a Aspergilose invasiva apresenta dois picos de incidência um no final do primeiro mês e outro aproximadamente 90 dias depois do transplante caso o paciente desenvolva doenca do enxerto versus o hospedeiro (7-8). Dentre os trans-plantes de órgão sólidos os que apresentam maior risco para o desenvolvimento de infecções fúngicas são o transplante de fígado e de pulmão, por questões ligadas às próprias doenças de base, técnica cirúrgica e enxerto(4,9).

O uso de profilaxia antifúngica já esta bem consolidada para alguns grupos de transplantes como TMO/TCTH e transplantes hepáticos (10,11). Contudo, ainda há uma escassez de estudo em transplante de coração e pâncreas. O grande dilema, entretanto, é a prevenção de infecções por fungos filamentosos em especial Aspergillus spp nos pacientes de alto risco como transplante de medula óssea alogênico com doença do enxerto contra o hospedeiro (DECH) e transplantados de pulmão (12,13).

Com intuito6 de padronizar o uso de profilaxia primária em pacientes transplantados, foi analisada a literatura referente aos seguintes transplantes: fígado, rim, coração, pulmão e TCTH. Para a determinação dos níveis de evidência foi utilizado o sistema da IDSA (Infectious Diseases Society of America).

Recomendações:

1. Transplante de Fígado (11,14-20)

Profilaxia universal: não (CII)

Profilaxia dirigida: sim (AI)

- Fluconazol 400 mg/dia por 21 dias

Critéirio 1 - pelo menos um dos seguintes fatores de risco: hepatite fulminante, re-transplante, hemodiáilise poós-transplante, uso de anticorpos para tratamento de rejeição.
Critério 2 - pelo menos dois dos seguintes fatores de risco: uso de antibiótico profilático para peritonite bacteriana espontânea pré-transplante, reoperação, admissão em unidade de terapia intensiva nos últimos 30 dias antes do transplante, antibióticos nos últimos 30 dias antes do transplante.

2. Transplante de Rim

Não há estudos sobre profilaxia Profilaxia não indicada (DII)

3. Transplante de Pulmão (12,21-24) Profilaxia universal: sim (AI)

Anfotericina B deoxicolato via inalatória, por 3 meses (50 mg + 50 ml de água destilada - inalação com 10 ml, 2 vezes por dia)

Profilaxia dirigida: sim, se receptor ou doador com colonizacao das vias aereas por Aspergillus spp pré-tx ou pos-tx (associada à anfotericina B inalatória)

Primeira opção: Itraconazol* 400 mg oral por 3 meses (BIII)

Segunda opção: Voriconazol EV (6 mg/kg/dia)/Oral (400 mg/dia) por 3 meses (CIII) *Aconselhável dosagem sérica.

4. Transplante de Coração (22) Profilaxia não indicada (DII)

5. Transplante de Células Tronco Hematopoéticas (10,25-28)

Profilaxia universal: sim (AI) Fluconazol 400 mg/dia EV/Oral por 100 dias Profilaxia dirigida: sim, para pacientes sob tratamento para DECH.

Primeira opção: Anfotericina B deoxicolato 1 mg/kg/dia (ou doses equivalentes de formulacoes lipidicas) por 100 dias (CIII)

Segunda opção: Itraconazol* oral 400 mg/dia por 100 dias (CIII)

Terceira opção Voriconazol: EV (6 mg/kg/dia)/Oral (400 mg/dia) por 100 dias (CIII) *Aconselhavel dosagem serica

Obs. Hai estudos controlados e randomizados com outros azólicos, porém não são medicamentos padronizados na instituiçãa ou talvez não disponíveis no Brasil.

6. Transplante de Pâncreas (29) Profilaxia universal: sim (CII)

Fluconazol 400 mg/dia EV/VO por 7 dias (profilaxia cirúgica)

Profilaxia dirigida: não (DII)

1. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18(1):44-69, http://dx.doi.org/10.1128/CMR.18.1.44-69.2005
2. Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: Analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48(3):265-73, http://dx.doi.org/10.1086/595846
3. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopietic stem cell transplant recipients, 2001-2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) database. Clin Infect Dis. 2010;50(8):1091-100, http://dx.doi.org/10.1086/651263
4. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12(3):220-9, http://dx.doi.org/10.1111/j.1399-3062.2010.00492.x
5. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101-11, http://dx.doi.org/10.1086/651262
6. Person AK, Kontoyiannis DP, Alexander BD. Fungal infections in transplant and oncology patients. Infect Dis Clin North Am. 2010;24(2):439-59, http://dx.doi.org/10.1016/j.idc.2010.01.002
7. Wald A, Leisenring W, vanBurik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175(6):1459-66, http://dx.doi.org/10.1086/516480
8. Pagano L, Caira M, Nosari A, Van Lint MT, Candoni A, Offidani M, et al. Fungal infections in recipients of hematopietic stem cell transplants: Results of the SEIFEM B-2004 studySorveglianza epidemiologica infezioni fungine nelle emopatie maligne. Clin Infet Dis. 2007;45(9):1161-70, http://dx.doi.org/10.1086/522189
9. Pappas PG, Silveira FP. The AST Infectious Diseases Community of Practice. Am J Transplant. 2009;9(Suppl 4):S173-9.
10. MacMillan ML, Goodman JL, DeFor TE, Weisdorf DJ. Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy. Am J Med. 2002;112(5):369-79, http://dx.doi.org/10.1016/S0002-9343(01)01127-5
11. Cruciani M, Mengoli C, Malena M, Bosco O, Serpelloni G, Grossi P. Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis. Liver Transpl. 2006;12(5):850-8, http://dx.doi.org/10.1002/lt.20690
12. Husain S, Zaldonis D, Kusne S, Kwak EJ, Paterson DL, McCurry KR. Variation in antifungal prophylaxis strategies in lung transplantation. Transpl Infect Dis. 2006;8(4):213-8, http://dx.doi.org/10.1111/j.1399-3062.2006.00156.x
13. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335-47, http://dx.doi.org/10.1056/NEJMoa061098
14. Lumbreras C, Cuervas-Mons V, Jara P, del Palacio A, Turrioi n VS, Barrios C, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis. 1996;174(3):583-8, http://dx.doi.org/10.1093/infdis/174.3.583
15. Patel R. Prophylactic fluconazole in liver transplant recipients: a randomized, double-blind, placebo-controlled trial. Liver Transpl. 2000;6(3):376-9, http://dx.doi.org/10.1016/S1527-6465(05)80022-X
16. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients - A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(10):729-37.
17. Biancofiore G, Bindi ML, Baldassarri R, Romanelli AM, Catalano G, Filipponi F, et al. Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study. Transpl Int. 2002;15(7):341-7, http://dx.doi.org/10.1111/j.1432-2277.2002.tb00176.x
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. 2002;74(5):688-95, http://dx.doi.org/10.1097/00007890-200209150-00017
19. Husain S, Tollemar J, Dominguez EA, Baumgarten K, Humar A, Paterson DL, et al. Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients: prospective, multicenter, case-controlled study. Transplantation. 2003;75(12):2023-9, http://dx.doi.org/10.1097/01.TP.0000065178.93741.72
20. Pappas PG, Andes D, Schuster M, Hadley S, Rabkin J, Merion RM, et al. Invasive fungal infections in low-risk liver transplant recipients: a multi-center prospective observational study. Am J Transplant. 2006;6 2):386-91, http://dx.doi.org/10.1111/j.1600-6143.2005.01176.x
21. Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, et al. Systemic availability of itraconazole in lung transplantation. Antimicrob Agents Chemother. 1996;40 9):2217-20.
22. Reichenspurner H, Gamberg P, Nitschke M, Valantine H, Hunt S, Oyer PE, et al. Significant reduction in the number of fungal infections after lung, heart-lung, and heart transplantation using aerosolized amphoter-icin B prophylaxis. Transplant Proc. 1997;29(1-2):627-8, http://dx.doi.org/10.1016/S0041-1345(96)00363-6
23. Hamacher J, Spiliopoulos A, Kurt AM, Nicod LP, Grp GLT. Pre-emptive therapy with azoles in lung transplant patients. Eur Respir J. 1999;13(1):180-6, http://dx.doi.org/10.1034/j.1399-3003.1999.13a33.x
24. Shitrit D, Ollech JE, Ollech A, Bakal I, Saute M, Sahar G, et al. Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction. J Heart Lung Transplant. 2005;24(12):2148-52, http://dx.doi.org/10.1016/j.healun.2005.05.003
25. GoodmanJL,WinstonDJ,GreenfieldRA,ChandrasekarPH,FoxB,Kaizer H, et al. A controlled trial of fluconazole to prevent fungal-infections in patients undergoing bone-marrow transplantation. N Engl J Med. 1992;326(13):845-51, http://dx.doi.org/10.1056/NEJM199203263261301
26. Foot ABM, Veys PA, Gibson BES. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant. 1999;24(10):1089-93, http://dx.doi.org/10.1038/sj.bmt.1702023
27. Nucci M, Biasoli I, Akiti T, Silveira F, Solza C, Barreiros G, et al. A double-blind, randomized, placebo-controlled trial of itraconazole capsules as antifungal prophylaxis for neutropenic patients. Clin Infect Dis. 2000;30(2):300-5, http://dx.doi.org/10.1086/313654
28. Hiemenz J, Cagnoni P, Simpson D, Devine S, Chao N, Keirns J, et al. Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant. Antimicrob Agents Chemother. 2005;49(4):1331-6, http://dx.doi.org/10.1128/AAC.49.4.1331-1336.2005
29. Benedetti E, Gruessner AC, Troppmann C, Papalois BE, Sutherland DE, Dunn DL, et al. Intra-abdominal fungal infections after pancreatic transplantation: incidence, treatment and outcome. J Am Coll Surg.1996;183(4):307-316.

Publication Dates

Publication in this collection
29 June 2012
Date of issue
2012

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18(1):44-69, http://dx.doi.org/10.1128/CMR.18.1.44-69.2005

[2] 2. Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: Analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48(3):265-73, http://dx.doi.org/10.1086/595846

[3] 3. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopietic stem cell transplant recipients, 2001-2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) database. Clin Infect Dis. 2010;50(8):1091-100, http://dx.doi.org/10.1086/651263

[4] 4. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12(3):220-9, http://dx.doi.org/10.1111/j.1399-3062.2010.00492.x

[5] 5. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101-11, http://dx.doi.org/10.1086/651262

[6] 6. Person AK, Kontoyiannis DP, Alexander BD. Fungal infections in transplant and oncology patients. Infect Dis Clin North Am. 2010;24(2):439-59, http://dx.doi.org/10.1016/j.idc.2010.01.002

[7] 7. Wald A, Leisenring W, vanBurik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175(6):1459-66, http://dx.doi.org/10.1086/516480

[8] 8. Pagano L, Caira M, Nosari A, Van Lint MT, Candoni A, Offidani M, et al. Fungal infections in recipients of hematopietic stem cell transplants: Results of the SEIFEM B-2004 studySorveglianza epidemiologica infezioni fungine nelle emopatie maligne. Clin Infet Dis. 2007;45(9):1161-70, http://dx.doi.org/10.1086/522189

[9] 9. Pappas PG, Silveira FP. The AST Infectious Diseases Community of Practice. Am J Transplant. 2009;9(Suppl 4):S173-9.

[10] 10. MacMillan ML, Goodman JL, DeFor TE, Weisdorf DJ. Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy. Am J Med. 2002;112(5):369-79, http://dx.doi.org/10.1016/S0002-9343(01)01127-5

[11] 11. Cruciani M, Mengoli C, Malena M, Bosco O, Serpelloni G, Grossi P. Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis. Liver Transpl. 2006;12(5):850-8, http://dx.doi.org/10.1002/lt.20690

[12] 12. Husain S, Zaldonis D, Kusne S, Kwak EJ, Paterson DL, McCurry KR. Variation in antifungal prophylaxis strategies in lung transplantation. Transpl Infect Dis. 2006;8(4):213-8, http://dx.doi.org/10.1111/j.1399-3062.2006.00156.x

[13] 13. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335-47, http://dx.doi.org/10.1056/NEJMoa061098

[14] 14. Lumbreras C, Cuervas-Mons V, Jara P, del Palacio A, Turrioi n VS, Barrios C, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis. 1996;174(3):583-8, http://dx.doi.org/10.1093/infdis/174.3.583

[15] 15. Patel R. Prophylactic fluconazole in liver transplant recipients: a randomized, double-blind, placebo-controlled trial. Liver Transpl. 2000;6(3):376-9, http://dx.doi.org/10.1016/S1527-6465(05)80022-X

[16] 16. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients - A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(10):729-37.

[17] 17. Biancofiore G, Bindi ML, Baldassarri R, Romanelli AM, Catalano G, Filipponi F, et al. Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study. Transpl Int. 2002;15(7):341-7, http://dx.doi.org/10.1111/j.1432-2277.2002.tb00176.x

[18] 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. 2002;74(5):688-95, http://dx.doi.org/10.1097/00007890-200209150-00017

[19] 19. Husain S, Tollemar J, Dominguez EA, Baumgarten K, Humar A, Paterson DL, et al. Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients: prospective, multicenter, case-controlled study. Transplantation. 2003;75(12):2023-9, http://dx.doi.org/10.1097/01.TP.0000065178.93741.72

[20] 20. Pappas PG, Andes D, Schuster M, Hadley S, Rabkin J, Merion RM, et al. Invasive fungal infections in low-risk liver transplant recipients: a multi-center prospective observational study. Am J Transplant. 2006;6 2):386-91, http://dx.doi.org/10.1111/j.1600-6143.2005.01176.x

[21] 21. Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, et al. Systemic availability of itraconazole in lung transplantation. Antimicrob Agents Chemother. 1996;40 9):2217-20.

[22] 22. Reichenspurner H, Gamberg P, Nitschke M, Valantine H, Hunt S, Oyer PE, et al. Significant reduction in the number of fungal infections after lung, heart-lung, and heart transplantation using aerosolized amphoter-icin B prophylaxis. Transplant Proc. 1997;29(1-2):627-8, http://dx.doi.org/10.1016/S0041-1345(96)00363-6

[23] 23. Hamacher J, Spiliopoulos A, Kurt AM, Nicod LP, Grp GLT. Pre-emptive therapy with azoles in lung transplant patients. Eur Respir J. 1999;13(1):180-6, http://dx.doi.org/10.1034/j.1399-3003.1999.13a33.x

[24] 24. Shitrit D, Ollech JE, Ollech A, Bakal I, Saute M, Sahar G, et al. Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction. J Heart Lung Transplant. 2005;24(12):2148-52, http://dx.doi.org/10.1016/j.healun.2005.05.003

[25] 25. GoodmanJL,WinstonDJ,GreenfieldRA,ChandrasekarPH,FoxB,Kaizer H, et al. A controlled trial of fluconazole to prevent fungal-infections in patients undergoing bone-marrow transplantation. N Engl J Med. 1992;326(13):845-51, http://dx.doi.org/10.1056/NEJM199203263261301

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