Caspofungin Versus Fluconazole as Prophylaxis of Invasive Fungal Infection in High-Risk Liver Transplantation Recipients: A Propensity Score Analysis

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1 ORIGINAL ARTICLE Caspofungin Versus Fluconazole as Prophylaxis of Invasive Fungal Infection in High-Risk Liver Transplantation Recipients: A Propensity Score Analysis Jesus Fortun, 1 Alfonso Muriel, 2 Pilar Martın-Davila, 1 Miguel Montejo, 3 Oscar Len, 4 Julian Torre-Cisneros, 6 Jordi Carratala, 7 Patricia Mu~noz, 8 Maria Carmen Fari~nas, 9 Asuncion Moreno, 5 Gema Fresco, 1 Josune Goikoetxea, 3 Joan Gavalda, 4 Juan Carlos Pozo, 6 Marta Bodro, 7 Antonio Vena, 8 Fernando Casafont, 10 Carlos Cervera, 5 Jose Tiago Silva, 11 and Jose M. Aguado, 11 and for the Grupo de Estudio de Infeccion en Pacientes Trasplantados Grupo de Estudio de Micologıa Medica (Sociedad Espa~nola de Enfermedades Infecciosas y Microbiologıa Clınica), and Red Espa~nola de Investigacion en Patologıa Infecciosa 1 Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Ramon y Cajal, Universidad de Alcala, Madrid, Spain; 2 Unit of Biostatistics, Ramon y Cajal Hospital, Centro de Investigacion Biomedica en Red Epidemiologıa y Salud Publica, Madrid, Spain; 3 Unit of Infectious Diseases, Hospital Universitario Cruces, Barakaldo-Bilbao, Spain; 4 Department of Infectious Diseases, Hospital Universitari Vall dhebron and 5 Department of Infectious Diseases, Hospital Universitari Clinic, Barcelona, Universidad Autonoma, Barcelona, Spain; 6 Department of Infectious Diseases, Hospital Universitario Reina Sofıa-IMIBIC (Instituto Maimonides de Investigacion Biomedica de Cordoba)-Universidad de Cordoba, Cordoba, Spain; 7 Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, Barcelona, Spain; 8 Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Mara~non, Madrid, Spain; 9 Unit of Infectious Diseases, Hospital Universitario Marques de Valdecilla, Universidad de Cantabria, Santander, Spain; 10 Department of Digestive Diseases, Hospital Universitario Marques de Valdecilla, Santander, Spain; and 11 Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Instituto de Investigacion Hospital 12 de Octubre, Madrid, Spain Targeted prophylaxis has proven to be an efficient strategy in liver transplantation recipients (LTRs). The aim of this study was to compare the effectiveness and safety of caspofungin with that of fluconazole in high-risk (HR) LTRs. Caspofungin and fluconazole were compared in a multicenter, retrospective, cohort study in HR-LTRs in Spain. Outcomes were assessed at 180 days after transplantation. A propensity score approach was applied. During the study period ( ), we analyzed 195 HR-LTRs from 9 hospitals. By type of prophylaxis, 97 patients received caspofungin and 98 received fluconazole. Of a total of 17 (8.7%) global invasive fungal infections (IFIs), breakthrough IFIs accounted for 11 (5.6%) and invasive aspergillosis (IA) accounted for 6 (3.1%). By univariate analysis, no differences were observed in the prevention of global IFIs. However, caspofungin was associated with a significant reduction in the rate of breakthrough IFIs (2.1% versus 9.2%, P ). In patients requiring dialysis (n 5 62), caspofungin significantly reduced the frequency of breakthrough IFIs (P ). The propensity score analysis confirmed a significant reduction in the frequency of IA in patients receiving caspofungin (absolute risk reduction, 0.06; 95% confidence interval [CI], ; P ). Linear regression analysis revealed a significant decrease in blood alanine aminotransferase levels and a significant increase in bilirubin levels after administration of caspofungin. Cas- Abbreviations: ALT, alanine aminotransferase; AmB, amphotericin B; AST, aspartate aminotransferase; BALF, bronchoalveolar lavage fluid; CC, Candida colonization; CI, confidence interval; CJ, choledochojejunostomy; D, donor; FHF, fulminant hepatic failure; GESITRA, Grupo de Estudio de Infeccion en Pacientes Trasplantados; HR, high-risk; IA, invasive aspergillosis; ICU, intensive care unit; IFI, invasive fungal infection; INR, international normalized ratio; IPTW-PS, inverse probability of treatment weighting using the propensity score; IQR, interquartile range; LTR, liver transplantation recipient; MELD, Model for End-Stage Liver Disease; MIC, minimum inhibitory concentration; NS, not significant; PLT, previous liver transplantation; R, recipient; RR, renal replacement; RS, repeat surgery; SD, standard deviation; TR, transfusion; UCBP, units of cellular blood products. Address reprint requests to Jesus Fortun, Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Carretera Colmenar km 9,1, Madrid, Spain. Telephone: ; FAX: ; fortunabete@gmail.com 427

2 LIVER TRANSPLANTATION, APRIL 2016 pofungin and fluconazole have similar efficacy for the prevention of global IFIs in HR-LTRs in this observational, multicenter cohort study. However, caspofungin was associated with a significant reduction of breakthrough IFIs and, after adjusting for confounders, caspofungin was associated with a lower rate of IA. This benefit is probably more favorable in patients on dialysis. Caspofungin is safe in HR-LTRs, although bilirubin levels may be increased. Liver Transplantation AASLD Received October 17, 2015; accepted November 28, SEE EDITORIAL ON PAGE 396 Invasive fungal infections (IFIs) are associated with high mortality in liver transplantation recipients (LTRs). (1-5) Although most IFIs are due to Candida spp., the risk and severity of invasive aspergillosis (IA) in LTRs is well known. (6,7) Universal prophylaxis, mainly with fluconazole, is controversial in patients with a low risk of IFIs. It has been associated with an increased risk of toxicity and interactions and may have an ecological impact through the selection of resistant strains. (8,9) The administration of prophylaxis according to the presence of high-risk (HR) factors for IFIs is a more efficient strategy. (8) The benefit of voriconazole or itraconazole, both of which are active against Aspergillus spp., is limited because of potential liver toxicity. (10) Prophylaxis with a lipid preparation of amphotericin B (AmB) significantly reduced the frequency of IFI in HR-LTRs. (11,12) However, prophylaxis with a lipid formulation of AmB may be limited by infusion-related toxicity and nephrotoxicity, particularly in patients with renal failure, a major risk factor for the development of IFI in LTRs. (13) Echinocandins are an attractive alternative for prophylaxis of IFI in HR-LTRs because of their specific mechanism of action, minimal nephrotoxicity, and activity against both Candida and Aspergillus species. Winston et al. (14) recently published the results of a clinical trial comparing anidulafungin and fluconazole in HR-LTRs. For most patients at high risk of IFI, anidulafungin and fluconazole have similar prophylactic efficacy. In the case of patients who are at high risk of IA or have received fluconazole before transplantation, anidulafungin could prove beneficial. (14) The TENPIN study is a recent, international, multicenter trial comparing micafungin with the standard of care (fluconazole, caspofungin, or liposomal AmB) in 344 HR-LTRs. (15) The per protocol analysis showed that micafungin was successful (98.6% free of IFI) and not inferior to standard of care (99.3%), although kidney function was better preserved with micafungin. (15) A prospective study performed by our group with 81 LTRs in Spain demonstrated that caspofungin was effective in reducing the frequency of IFI. (16) Consequently, caspofungin began to be widely used as prophylaxis of IFI in LTRs in Spain. However, the real impact of this measure has not been analyzed in a large cohort of patients. The members of the investigation group are listed in the supporting material. This study was cofunded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (cofinanced by the European Development Regional Fund A Way to Achieve Europe ), and by the Spanish Network for Research in Infectious Diseases (REIPI RD12/0015). The funding bodies had no involvement in the preparation of the manuscript. Jesus Fortun has received grant support from Astellas Pharma, Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness). Jesus Fortun has also been an advisor/consultant to Astellas Pharma, Gilead Sciences, Merck Sharp and Dohme, and Pfizer. Jesus Fortun, Pilar Martın-Davila, Miguel Montejo, Oscar Len, Julian Torre-Cisneros, Jordi Carratala, Patricia Mu~noz, Carmen Fari~nas, Asuncion Moreno, Josune Goikoetxea, Carlos Cervera, and Jose Ma Aguado have received honoraria for talks on behalf of Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Astellas Pharma. The remaining authors report no potential conflicts. Presented in part at the 24th European Congress of Clinical Microbiology and Infectious Diseases; May 10-13, 2014, Barcelona, Spain, as an oral presentation. Additional supporting information may be found in the online version of this article. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt Potential conflict of interest: Nothing to report. 428

3 LIVER TRANSPLANTATION, Vol. 22, No. 4, 2016 We performed a multicenter, retrospective study in 9 Spanish hospitals to evaluate the effectiveness of targeted prophylaxis for the prevention of IFI in HR- LTRs. We compared 2 strategies: caspofungin (group 1) and fluconazole (group 2). Patients and Methods STUDY SETTING The study was approved by the institutional review board of Ramon y Cajal Hospital and by the Spanish Agency of Medicines and Medical Devices. It was sponsored by Grupo de Estudio de Infeccion en Pacientes Trasplantados (GESITRA) and Group of Study of Fungal Infections of the Spanish Society of Infectious Diseases and Clinical Microbiology and was cofinanced by the European Development Regional Fund (A Way to Achieve Europe program; Spanish Network for Research in Infectious Diseases). Our study was an observational retrospective cohort study performed in LTRs at 9 centers in Spain from January 2005 to December DEFINITIONS AND DATA COLLECTION IFI was defined as proven or probable according to the criteria proposed by the European Organization for Research and Treatment in Cancer and the Mycoses Study Group. (17) INCLUSION CRITERIA We included patients based on the criteria of the prospective GESITRA-01 protocol. (16) The study population comprised LTRs at high risk of IFI and with no previous IFI. The factors that led patients to be considered as having a high risk of IFI are set out below. One of the following: 1. Retransplantation because of severe dysfunction of a previous graft. 2. Need for renal replacement (RR) therapy, including dialysis or venous hemofiltration, within a maximum period of 30 days. 3. Prior history of fulminant hepatitis leading to liver transplantation. Or 2 or more of the following: 1. Intraoperative or perioperative transfusion (TR) of 20 units of cellular blood products (UCBP). 2. Need for choledochojejunostomy. 3. Two or more positive clinical site surveillance cultures (nasal, pharyngeal, or rectal) for Candida spp. from 48 hours before to 48 hours after LT. 4. Repeat abdominal surgery within 7 days of LT. EXCLUSION CRITERIA Prophylaxis with lipid AmB, micafungin, anidulafungin, or other antifungals were not prescribed in the study groups (see next paragraph). STUDY DESIGN We analyzed 2 groups of patients: group 1, LTRs receiving prophylaxis with caspofungin; and group 2, LTRs receiving prophylaxis with fluconazole. Day 0 was the first day of antifungal prophylaxis. Clinical, microbiological, and analytical data were obtained for all patients immediately before and immediately after surgery. Data were obtained in the 2 groups at days 0, 1 3, 1 7, 1 14, 1 28, and 190. All patients underwent a final evaluation at day An electronic case report form was used to record data at all participating centers. The primary outcome measure was the development of global IFI or IA and was assessed 180 days after the onset of prophylaxis in both groups. The secondary study outcomes were breakthrough IFI (development of IFI during the administration of antifungal prophylaxis), candidiasis, other fungal infections, empirical antifungal therapy during the study period (until 180 days), and overall mortality (until 180 days). Safety was assessed at day 0 (preprophylaxis) and at day 1 14 (while on prophylaxis or after prophylaxis) on the basis of the following blood parameters: bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, international normalized ratio (INR), creatinine, and creatinine clearance. STATISTICAL ANALYSIS We expressed continuous variables as the mean and standard deviation (SD) or as the median and interquartile range (IQR) if their distribution was skewed. Discrete variables were expressed as relative and absolute frequencies. We used the t test for independent samples to compare normally distributed continuous variables and the Mann-Whitney U test to compare nonnormally distributed continuous variables. The 429

4 LIVER TRANSPLANTATION, APRIL 2016 association between categorical variables was evaluated using the chi-square test when samples were of sufficient size, or the Fisher s exact test when they were not. Patients who died without evidence of IFI were censored at the date of death (risk competitive). All remaining patients were censored at day 180 after starting prophylaxis. Because clinicians did not randomly allocate the type of prophylaxis, the influence of confounding variables was addressed by means of inverse probability of treatment weighting using the propensity score (IPTW-PS). (18-20) A propensity score for type of prophylaxis chosen was created using baseline clinical variables that were previously shown to be associated with fungal infections in HR-LTRs, many of which were considered inclusion criteria for receiving antifungal prophylaxis. The variables present at initiation of prophylaxis included RR therapy, fulminant hepatic failure (FHF), previous liver transplantation (PLT), repeat abdominal surgery, multiple Candida colonization (CC), TR (>20 UCBP), corticosteroids before transplant, other antifungals before transplant, and need for sedative drugs. A multivariate logistic regression model was generated using factors that differed between the groups, as was a model predicting the likelihood, or propensity, of the type of prophylaxis. Inverse propensity scores were then used to weight a logistic regression model, with global IFI, breakthrough IFI, and IA as the dependent variables. The safety analysis was based on a comparison of the means of the values of the aforementioned parameters at day 0 and day 1 14 in both groups. A linear regression analysis adjusted for the variables included in the propensity score analysis was performed. All P values were 2-tailed. P values of 0.05 or less were considered to indicate statistical significance. Stata version 13.1 for Windows (StataCorp, College Station, TX) was used for the propensity score analysis (effect command). SPSS, version 15.0 (IBM SPSS, Chicago, IL) was used for all other analyses. Results During the study period ( ), a total of 3784 patients received liver transplantations at the 9 participating institutions; our analysis was based on 195 (5.2%) of these patients. The distribution was as follows: group 1 (caspofungin), 97 patients; group 2 (fluconazole), 98 patients. The median time to initiation of antifungal prophylaxis after transplantation was 3.2 days (1 to 18 days) in group 1 and 2.6 days (1 to 14 days) in TABLE 1. Demographic and Baseline Characteristics of Patients Group 1 (n 5 97) Group 2 (n 5 98) P Value Time to prophylaxis, median (IQR), days 3.2 (2-18) 2.6 (1-14) NS Days on prophylaxis, median (IQR), days 22 (14-26) 24 (17-28) NS Age, median (range), years 55 (19-75) 58 (20-74) NS Sex, male 67 (69.1) 76 (77.6) NS Primary liver disease Hepatitis C virus 45 (46.4) 47 (48.0) NS Alcoholic cirrhosis 35 (36.1) 31 (31.6) NS Other 17 (17.5) 15 (15.3) NS Hepatocellular carcinoma 24 (24.7) 18 (18.4) NS Cytomegalovirus mismatch (R /D1) 4 (4.1) 4 (4.1) NS Baseline immunosuppression Tacrolimus 90 (92.7) 87 (88.8) NS Cyclosporine 7 (7.2) 11 (11.2) NS Risk factors for IFI (on day 0) RR therapy (n 5 80) 42 (43.3) 20 (20.4).01 FHF (n 5 27) 11 (11.3) 16 (16.3) NS PLT (n 5 32) 9 (9.3) 18 (18.4) NS Repeat abdominal surgery (n 5 50) 19 (19.6) 18 (18.4) NS CC, 2 sites (n 5 10) 4 (4.1) 4 (4.1) NS CJ (n 5 26) 9 (9.3) 13 (13.3) NS TR, > 20 UCBP (n 5 81) 34 (35.1) 35 (35.7) NS Other factors MELD > 25 (on transplant) 55 (56.7) 48 (49.0) NS Steroids before transplant (4 weeks) 11 (11.3) 19 (19.4) NS Antifungals before transplant (4 weeks) 8 (8.2) 8 (8.2) NS ICU stay before transplant (4 weeks) 13 (13.4) 15 (15.3) NS Sedative drugs (on day 0) 72 (74.2) 71 (72.4) NS Acute rejection (4 weeks) 10 (10.3) 9 (9.2) NS 430

5 LIVER TRANSPLANTATION, Vol. 22, No. 4, 2016 Number IFI Cases (n 5 17) TABLE 2. Description of IFI and Outcome Risk Factors Time to Starting Prophylaxis (days) Time to IFI (days) Prophylaxis Groups Overall Mortality, 5/17 (29.4%) Invasive Candidiasis (n 5 9) Candidemia (n 5 5) 62 Candidemia (catheter-related FHF 1 25 Group 2 No and phlebitis; C. albicans) 128 Candidemia (unknown RS 4 18 Group 2 No origin; C. parapsilosis) 161 Candidemia (Intra-abdominal TR, RS 3 26 Group 2 Yes origin; C. albicans) 171 Candidemia (catheter-related PLT, TR 1 18 Group 1 No and phlebitis; C. albicans) 199 Candidemia (catheter-related TR 4 37 Group 1 No and phlebitis; C. parapsilosis) Intra-abdominal infection (n 5 4) 116 Intra-abdominal infection (C. albicans) TR 2 8 Group 2 No 125 Intra-abdominal infection (C. glabrata) TR 3 14 Group 2 No 130 Intra-abdominal infection RR, RS 4 17 Group 2 No (C. parapsilosis) 188 Intra-abdominal infection TR 3 30 Group 1 No (C. parapsilosis) IA (n 5 6) 37 Pulmonary IA (A. fumigatus) FHF 1 9 Group 2 Yes 38 Pulmonary IA (A. fumigatus) FHF 1 5 Group 2 No 44 Pulmonary IA (A. fumigatus) RR 5 16 Group 2 No 115 Pulmonary invasive (A. fumigatus) FHF, RR, TR, CC 1 7 Group 2 Yes 216 Pulmonary IA (A. fumigatus) RR Group 1 Yes 230 Cerebral aspergillosis (A. fumigatus) PLT, TR 1 25 Group 2 Yes Other (n 5 2) 225 Necrotizing wound infection FHF, RR, TR, RS 1 20 Group 2 Yes (Rhizopus spp.) 248 Necrotizing wound infection (Rhizopus spp.) FHF, RR, PLT, TR 1 90 Group 1 No group 2. The median duration of prophylaxis in groups 1 and 2 was 22 and 24 days, respectively. Fluconazole was administered at a median dose of 200 mg/day ( mg) and caspofungin at 50 mg/day. Table 1 shows the baseline characteristics of patients included in the 2 groups. The most frequent risk factors for antifungal prophylaxis were multiple TR (>20 UCBP) in 69 (35.4%) patients, RR therapy in 62 (31.8%) patients, and repeat abdominal surgery in 37 (18.9%) patients. Many patients had more than 1 condition. Allocation to the prophylaxis group was according to the physician s criteria at each center. No differences were observed between the 2 groups for risk factors or type of prophylaxis administered, except for RR therapy, which was more frequent in group 1 (44.7% versus 20.4%; P ). Fluconazole and caspofungin were administered homogeneously throughout the study period ( ). Table 2 describes the fungi documented in all cases of IFI, the risk factors, the time to starting prophylaxis, the time to IFI (from day 0), the type of prophylaxis, and overall mortality during follow-up. Three of 5 cases of Candidemia were catheter-related. Intraabdominal infection was the source of invasive candidiasis in 5 patients (1 with Candidemia). Five out of 6 cases of IA were pulmonary and the other cerebral. In pulmonary aspergillosis (n 5 5), bronchoscopy and bronchoalveolar lavage fluid (BALF) confirmed A. fumigatus in culture in all cases, and BALF galactomannan was positive in all. According to European Organization for Research and Treatment of Cancer criteria, (17) IA was probable in all pulmonary aspergillosis cases. The patient with cerebral aspergillosis was confirmed by culture (A. fumigatus) of cerebral biopsy ( proven IA). Finally, 2 cases of cutaneous zygomycosis (necrotizing wound infection) were documented in 1 patient during prophylaxis with fluconazole and in a retransplanted patient 70 days after stopping prophylaxis with caspofungin. Table 3 shows the risk of global IFI (until day 180), breakthrough IFI (during prophylaxis administration), IA, need for antifungal therapy, and death. IFI was 431

6 LIVER TRANSPLANTATION, APRIL 2016 documented in 17 (8.7%) patients, 11 (5.6%) of whom became infected during administration of prophylaxis (breakthrough IFI). Although the frequency of global IFI and IA was lower in patients receiving caspofungin, the differences were not significant in the univariate analysis (5.2% versus 12.2%; P ; and 1% versus 5.1%; P , respectively). However, the difference was significant in the case of breakthrough IFI (2.1% versus 9.2%; P ). Overall mortality was 19.5%, with no differences between the groups (23.7% versus 16.3%, P ). Mortality attributed to IFI was estimated at 7.5%, with no differences between prophylaxis with caspofungin and prophylaxis with fluconazole. An analysis focused on patients receiving dialysis (the only baseline condition for which significant differences were detected between both types of prophylaxis) revealed similar results (Table 3). A lower rate of all infections was demonstrated in patients receiving TABLE 3. Outcome According to the Type of Prophylaxis in All Patients (n 5 195) and in Patients Receiving Dialysis (n 5 62) for Univariate Analysis Global IFI (Until Day 180) Breakthrough IFI IA (Until Day 180) Antifungal Therapy (Until Day 180) Death (Until Day 180) n (%) P Value n (%) P Value n (%) P Value n (%) P Value n (%) P Value All patients (n 5 195) 17 (8.7) (5.6) (3.1) (21.5) (19.5) 0.21 Caspofungin (n 5 97) Fluconazole (n 5 98) Patients in 6 (9.7) (4.8) (4.8) (27.4) (30.6) 0.37 dialysis (n 5 62) Caspofungin (n 5 42) Fluconazole (n 5 20) TABLE 4. Absolute Risk Reduction for IA, Breakthrough IFI, and Global IFI According to the Type of Prophylaxis for Adjusted Clinical Outcome Nonadjusted Adjusted for IPTW-PS Outcome Caspofungin (97) Fluconazole (98) Absolute Risk Reduction (95% CI) P Value Absolute Risk Reduction (95% CI) P Value IA 1 (0.010) 5 (0.06) ( to 0.088) ( ) Breakthrough IFI 2 (0.020) 9 (0.091) ( ) ( to 0.165) Global IFI 5 (0.06) 12 (0.122) ( to 0.149) ( to 0.178) TABLE 5. Safety Analysis and Means of Differences of Blood Parameters (Values at Day 0 of Prophylaxis Minus Values at Day 114 of Prophylaxis) Unadjusted Adjusted* Difference Between Values (Day 0 Day 14) for Group 1 (Caspofungin) Difference Between Values (Day 0 Day 14) for Group 2 (Fluconazole) P Value Effect 95% CI P Value Creatinine, mg/dl to Creatinine clearance, to ml/minute INR to Bilirubin, mg/dl to AST, IU/L to ALT, IU/L to Gamma-glutamyl to transpeptidase, IU/L Alkaline phosphatase, IU/L to *Linear regression adjusted for RR therapy, FHF, PLT, repeat abdominal surgery, multiple CC, TR (>20 UCBP), corticosteroids before transplant, other antifungals before transplant, and need for sedative drugs. 432

7 LIVER TRANSPLANTATION, Vol. 22, No. 4, 2016 caspofungin, and in the case of breakthrough IFI, this difference was statically significant (0% versus 15%; P ). In these patients, a significantly higher number of patients receiving prophylaxis with fluconazole required empirical antifungal therapy (47.4% versus 19.0%; P ). A propensity score was used to evaluate the impact of the type of prophylaxis on the development of global IFI, breakthrough IFI, and IA in the absence of the influence of confounding variables (Table 4). The propensity score analysis revealed a significant reduction in the absolute risk of IA in patients receiving caspofungin (risk reduction, 0.06; 95% confidence interval [CI], ; P ). With respect to the other 2 objectives, the propensity score analysis did not confirm a significant result, although a trend toward reduced frequency of breakthrough IFI was observed (P ). To evaluate the safety of the different types of prophylaxis, we compared the means of blood parameters at day 0 and day 1 14 of prophylaxis (Table 5). Significant variations were found according to the type of prophylaxis and baseline conditions. A linear regression analysis adjusted for the variables included in the propensity score confirmed a significantly higher decrease in blood levels of ALT in patients receiving caspofungin (group 1; IU/mL; 95% CI, ; P ). Similarly, a trend was observed in levels of AST (537.9 IU/mL; 95% CI, 71.5 to ; P ). However, a significantly higher increase in blood levels of bilirubin was confirmed in patients receiving caspofungin (group 1; 4.2 mg/dl; 95% CI, 6.8 to 1.5; P ; Table 5). No other significant differences indicative of hepatic or renal toxicity were observed for the remaining parameters. No significant differences were observed in the mean values of blood parameters at day 1 90 and day Discussion In the absence of antifungal prophylaxis, invasive mycosis typically affects 36%-50% of HR- LTRs. (6,7,11,12,21) The meta-analysis by Cruciani et al. (22) confirmed that universal prophylaxis (mainly fluconazole) reduced colonization, total proven fungal infections, and mortality attributable to fungal infection. In addition, clinical practice guidelines recommend fluconazole for prevention of IFI in LTRs. (23,24) However, this strategy raises several doubts. In the absence of risk factors, the frequency of IFI is <4%. (8,25) Universal antifungal prophylaxis with fluconazole for LTRs has been associated with increased hepatotoxicity and interactions with immunosuppressive drugs. (8,9) Additionally, the emergence of nonalbicans Candida spp. and increasing rates of resistance have limited the use of fluconazole. (4) A recent retrospective study at the University of Pittsburgh confirmed that, compared with universal prophylaxis, targeted prophylaxis is effective, feasible, and safe. (26) Therefore, in many transplant groups, prophylaxis targeting Candida spp. and Aspergillus spp. is based on lipid formulations of AmB or echinocandins. The use of lipid formulations of AmB for targeted prophylaxis has been widely evaluated. (11,12,27,28) One potential concern with AmB is impaired recovery of renal function, because renal failure, especially that requiring dialysis, is a relevant risk factor for IFI in LTRs. A recent meta-analysis that evaluated randomized controlled trials echinocandins were not included and compared regimens for antifungal prophylaxis in liver recipients confirmed that fluconazole or L-AmB reduces the incidence of IFI. (29) The evidence provided by the meta-analysis suggests that the 2 are equally efficacious when compared with placebo. Echinocandins are active against both Aspergillus spp. and Candida spp., including fluconazole-resistant strains. A recent review of clinical practice in the United States confirmed that 72% of centers apply a targeted strategy in LTRs, and the leading choice of mold-active agents for targeted prophylaxis was echinocandins. (9) Winston et al. (14) recently reported the results of a clinical trial comparing anidulafungin and fluconazole. Although the rate of IFI was similar in both groups, a lower risk of breakthrough IFI, including IA, was observed in patients receiving prophylaxis with anidulafungin who had a Model for End-Stage Liver Disease (MELD) score of > 30, required RR therapy, were given >15 units of packed red blood cells during transplant surgery, or had received fluconazole before transplantation. In the present study, no significant differences were observed in these subgroups, with the exception of patients requiring dialysis who presented a significant reduction of breakthrough IFI and antifungal therapy and a trend in IA in patients receiving caspofungin in comparison to fluconazole (Table 3). In the international, multicenter TENPIN study, which compared micafungin with the standard of care in HR-LTRs (fluconazole, caspofungin, or liposomal AmB), the per protocol analysis did not confirm differences in the incidence of IFI or IA, although kidney function was better with micafungin. (15) Unlike the aforementioned studies, which were performed in a 433

8 LIVER TRANSPLANTATION, APRIL 2016 clinical trial setting, the present study analyzes the efficacy of 2 different antifungal prophylaxis regimens in clinical practice. We detected higher rates of IFI and overall mortality (8.7% and 19.5%, respectively) than Winston et al. (14) and Saliba et al. (15) Consistent with the results of other studies, we found no differences between caspofungin and fluconazole in the prevention of global IFI in HR-LTRs. Nevertheless, the propensity score analysis showed a significantly reduced frequency of IA in patients receiving caspofungin and, consistent with the findings of Winston et al., (14) a trend toward reduced frequency of breakthrough IFI. This benefit is probably more evident in patients on dialysis, although the low number of events and patients on dialysis precluded a more intensive analysis. The superiority of echinocandins over fluconazole in breakthrough infections stems mainly from their ability to control premature fungal infection rather than from the risk of resistance to azoles. In the present study, only 8.2% of transplant recipients had received prior antifungal therapy, including fluconazole. Only 1 of the 9 Candida spp. infections was produced by C. glabrata (minimum inhibitory concentration [MIC] fluconazole: 16 mg/ml, European Committee on Antimicrobial Susceptibility Testing (EUCAST)); the remaining infections were produced by fluconazolesensitive strains. The increased activity of echinocandins with respect to fluconazole against IA and the rate of early IA in this series (5 of 6 IA occurred before day 36) may also have contributed to these results. Finally, clearance of echinocandins by dialysis is poor. Fluconazole, on the other hand, is easily eliminated by dialysis and is therefore not a good option for prophylaxis in these patients. The large number of confounders makes it difficult to perform a safety analysis in such a complicated setting as the immediate posttransplant period. Nevertheless, our safety analysis showed a significant decrease in transaminase levels (ALT and AST) but a significant increase in bilirubin levels in patients who received prophylaxis with caspofungin. Increased bilirubin levels have been observed in other studies with caspofungin, even in healthy volunteers. (30) Despite the initial recommendation to avoid caspofungin in advanced liver disease, the findings of the present study show a significant decrease in transaminase levels in patients receiving caspofungin. Other studies performed in patients with liver disease confirm the hepatic safety of caspofungin. (10,16,31-33) The present study is subject to a number of limitations. First, it is not a clinical trial, and selection of prophylaxis regimens could be conditioned by various circumstances in a specific case or center. In this sense, the propensity score analysis may help to calibrate the impact of other variables on the selection of a specific prophylaxis regimen. We used a propensity score analysis because the number of events per confounder was very low. Other authors have confirmed that the propensity score produces estimates that are less biased, more robust, and more precise than the logistic regression estimates in the presence of 7 events per confounder. (34) Second, in order to simplify the analysis, we did not evaluate the role of anidulafungin and micafungin, which are widely used echinocandins. Third, the study period was 8 years, during which time protocols changed and therapeutic innovations were incorporated at the centers. Finally, although the number of LTRs included represents only 5.1% of all liver transplantations performed in the 9 centers during the study period, the estimated number of HR-LTRs would probably be close to 10%-20%. (8) This difference could be explained by the exclusion of other prophylactic drugs (eg, lipid AmB, anidulafungin, and micafungin) or the lack of prophylaxis in some HR-LTRs. In summary, despite the limitations cited above, the results of our observational study show caspofungin and fluconazole to be equally efficacious in the prevention of global IFI in HR-LTRs. However, caspofungin could be associated with a lower rate of IA and breakthrough IFI. This benefit is confirmed even after adjusting for confounders and is probably more favorable in patients on dialysis. Caspofungin is safe in HR- LTRs, although bilirubin levels may be increased. Acknowledgment: We thank Thomas O Boyle for his assistance in writing the manuscript. REFERENCES 1) Gavalda J, Meije Y, Fortun J, Roilides E, Saliba F, Lortholary O, et al.; for ESCMID Study Group for Infections in Compromised Hosts. Invasive fungal infections in solid organ transplant recipients. 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