Use of echinocandin prophylaxis in solid organ transplantation

Use of echinocandin prophylaxis in solid organ transplantation Abstract Invasive fungal infections (IFIs) are a major threat to patients undergoing solid organ transplantation (SOT). Owing to improvements in surgical techniques, immunosuppression therapy and antifungal prophylaxis, the incidence of IFIs has been decreasing in recent years. However, IFI-associated morbidity and mortality remain significant. Invasive candidiasis (IC) and aspergillosis (IA) are the main IFIs after SOT. Risk factors for IC and IA continue to evolve, and thus strategies for their prevention should be constantly updated and targeted to both individual patient risk factors and local epidemiology. In this review, we discuss the current epidemiology and risk factors for IFIs in SOT recipients in the context of actual approaches to antifungal prophylaxis, including experience with the use of echinocandins, after SOT. Epidemiology Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among solid organ transplant (SOT) recipients. IFIs occur in 2%–40% of SOT patients depending on the organ transplanted and the use of antifungal prophylaxis.1–7 In addition, the reported burden of IFIs, even within transplant types, varies across centres owing to several probable factors, such as geographically restricted exposure, methods used for case identification (surveillance, diagnostic techniques) and differences in types of patients, immunosuppressive regimens and follow-up.8 Nevertheless, the incidence of IFIs among SOT recipients has declined over the past two decades, which is due in large part to improvements in surgical techniques, immunosuppression and preventive strategies9,10 (Table 1). Table 1. Incidence of invasive fungal infection according to type of transplant in historical cohorts and in the TRANSNET study Type of transplant  Historical cohorts (1990s)  TRANSNET study (12 month cumulative incidence)  Small bowel  40%–59%  12%  Lung and heart–lung  10%–44%  9%  Liver  6%–47%  5%  Pancreas  6%–38%  4%  Heart  3%–21%  3%  Renal  1%–14%  1.3%  Type of transplant  Historical cohorts (1990s)  TRANSNET study (12 month cumulative incidence)  Small bowel  40%–59%  12%  Lung and heart–lung  10%–44%  9%  Liver  6%–47%  5%  Pancreas  6%–38%  4%  Heart  3%–21%  3%  Renal  1%–14%  1.3%  The largest study published to date on the burden of IFIs in SOT recipients is the report of the Transplant Associated Infection Surveillance Network (TRANSNET), consisting of 15 SOT centres in the USA reporting IFI surveillance data over a 5 year period (2001–06).4 The incidence cohort included 16 808 SOT recipients who underwent transplantation between 2002 and 2005, 5% of whom were paediatric patients. The most common types of SOT were kidney and liver, which accounted for 32.8% and 26.6% of transplants, respectively. The estimated cumulative incidence of any IFI 1 year after transplantation was 3.1%. It varied by type of SOT, with the highest being for bowel (11.6%), lung/heart–lung (8.6%) and liver (4.7%) transplantation, and the lowest for kidney recipients (1.3%) (Table 1). The 1 year incidence of each specific IFI was also investigated. Invasive candidiasis (IC) had the highest estimate (1.9%), followed by invasive aspergillosis (IA) (0.7%). Cryptococcosis, mould infections other than aspergillosis or zygomycosis, and endemic fungal infections had estimates of ∼0.2%. All other IFI types had estimates of <0.1%.4 Exposure to antifungal prophylaxis in the TRANSNET study was not reported; however, the authors did note its potential impact on the observed incidences.4 For example, the infection type with lowest cumulative 12 month incidence was Pneumocystis pneumonia (PCP), for which prophylaxis is effective and commonly used. Assessing the burden of PCP in SOT recipients must also consider late-onset infections occurring after the typical period of PCP prophylaxis ∼6–12 month post-transplantation.11–14 The mortality associated with IFIs varies with the causative agent, the organ transplanted and the site of infection. In the TRANSNET study, the 12 month survival after infection was 59% for patients with IA, 61% for infections due to non-Aspergillus moulds, 66% for IC and 73% for cryptococcosis.4 In heart transplant (HT) recipients, the crude mortality associated with fungal infections ranges from 29% to 36%, with a marked decrease observed in recent years.1,7,15 In lung transplant recipients, the mortality rate of bronchial infections, which is roughly 20%, is lower than that of invasive pulmonary mycoses, which approaches 80%.16 In liver transplant (LT) recipients, the mortality rate ranges from 20% to 30%,5,6,17 and is higher (40%–50%) for mould infections, especially those occurring late after transplantation.18,19 In kidney transplant (KT) recipients with IFI, mortality ranges from 39% to 54%20,21 and, in contrast with other organ types, early disease is associated with higher mortality risk.22 A general picture of the current epidemiology of IFI in SOT recipients has been described in the above-mentioned TRANSNET report4 and in the report of the Prospective Antifungal Therapy (PATH) Alliance.23 PATH is a multicentre, observational registry that prospectively collected data on proven and probable IFIs in 17 transplant centres in the USA from 2004 through 2007. A total of 429 adult SOT recipients with 515 IFIs were identified; most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%) and other moulds (5.8%).23 In both reports, IC was the most frequently observed IFI in all transplant types, except for lung recipients, where IA was the most common IFI.4,23 IC occurs earlier than other invasive mycoses, generally within the first 3 months following transplantation, and is viewed as a classic nosocomial infection.24 However, in a recent study, 54% of ICs occurred >6 months after transplantation, and kidney recipients were more likely to develop late IC when compared with liver, lung and heart recipients.25 The most common type of IC in this setting is candidaemia, frequently secondary to infection of vascular devices, followed by abdominal infection.23,25 A peculiar type of IC in transplant recipients is graft-transmitted candidiasis, due to an unexpected transmission from the donor or by the contamination of preservation fluid.26,27 This severe complication generally occurs within 2–3 weeks after transplantation as an arteritis of the graft, which evolves into aneurysm with following rupture if not promptly recognized and treated; graft loss and death are frequent.26 Unfortunately, clinical manifestations are vague, such as fever and pain at the graft. Regarding distribution of Candida species, C. albicans accounts for slightly more than half of the IC seen in SOT recipients. Among non-albicans spp. the most commonly encountered is C. glabrata, especially among patients previously exposed to antifungal therapy.23,28,29 IA is the leading cause of IFI after lung transplantation and the second most common IFI in non-lung recipients. The median time to occurrence of IA ranges between 100 and 200 days after SOT, with approximately half being early-onset (≤90 days) and half late-onset (>90–180 days) episodes.15,21,22,30 In a study of lung transplant recipients, the time of onset was related to the clinical form of IA.16 Tracheobronchitis and bronchial anastomotic infections occurred within 3 months of transplantation; in contrast, invasive or disseminated aspergillosis occurred significantly later (33.7 ± 19.6 months post-transplantation).16 The most common clinical manifestation of IA in SOT recipients is a pulmonary syndrome. Compared with neutropenic patients, SOT recipients are more likely to show peri-bronchial consolidation or ground-glass opacity and less likely to have fever, macro-nodules, mass-like consolidation, halo sign or air-crescent sign.31 The lack of classical angio-invasive signs of invasive pulmonary aspergillosis may contribute to a more protracted clinical presentation, later diagnosis and higher mortality rate, as shown in a study of HT recipients.32 Disseminated IA (two or more non-contiguous organs), with or without involvement of the CNS, was commonly reported in previous series.30,33 In a recent series, CNS involvement and extra-pulmonary localization seem to be more common in late IA cases.15 Regarding distribution of Aspergillus species and susceptibility to antifungals, Baddley et al.34 analysed 274 clinical Aspergillus isolated from transplant recipients with proven or probable IA collected as part of the TRANSNET study. The isolate collection included 181 A. fumigatus, 28 A. niger, 27 A. flavus, 22 A. terreus, 7 A. versicolor, 5 A. calidoustus and 2 A. nidulans isolates and 2 isolates identified as Aspergillus spp. Triazole susceptibilities were ≤4 mg/L for most isolates (posaconazole 97.6%; itraconazole 96.3%; voriconazole 95.9%; ravuconazole 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were ≥4 mg/L. Amphotericin B inhibited 93.3% of isolates with an MIC of ≤1 mg/L. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 mg/L. One of 181 isolates of A. fumigatus showed resistance (MIC ≥4 mg/L) to two of three azoles tested.34 The echinocandin minimum effective concentration (MEC) values were investigated on the same isolate collection and found to be at or below the epidemiological cut-off values for all three echinocandins (caspofungin, micafungin and anidulafungin) against the majority of isolates, including those from patients who had previously received caspofungin.35 Risk factors The occurrence of fungal infection in SOT recipients primarily depends on two factors: the intensity of exposure and the patient's susceptibility to infection.36,37 Intensity of exposure varies according to the type of organ transplanted and the geographical environment.2,8,38 With regard to patient factors, underlying disease that led to the need for transplantation in the first place, surgical complications (e.g. prolonged surgery, need for re-operation, fluid collections), neutropenia and thrombocytopenia, metabolic alterations (e.g. diabetes), infections with immunomodulatory viruses (e.g. cytomegalovirus, HCV), increased immunosuppressive therapy for rejection, and renal failure, especially with the need for renal replacement therapy (RRT), are cited as factors contributing to fungal infections.24,39 Risk factors have been recently updated and are summarized in Table 2.40 Table 2. Risk factors for invasive candidiasis and invasive aspergillosis by transplant type Transplant type  Risk factors   invasive candidiasis  invasive aspergillosis  Liver  pre-operative ICU hospitalization in the prior 90 days multifocal Candida spp. colonization/infection MELD score (>30 or between 20 and 30) fulminant hepatic failurea split, living donor  pre-operative fulminant hepatic failure  intra-operative choledochojejunostomy transfusion of ≥ 40 units of blood products prolonged operation  intra-operative multi-visceral transplantation complicated surgery  post-operative acute renal failure renal failure requiring RRTa any rejection within 2 weeks after transplant CMV-DNaemia >100 000 copies/mL re-operation re-transplantationa  post-operative renal failure RRT rejection requiring treatment with ATG, OKT3 or alemtuzumab >6 g of accumulative prednisone in month 3 post-transplant re-transplantation re-operation leucopenia (<500/mm3) chronic graft dysfunction  Heart  acute rejection RRT re-exploration after transplantation  Aspergillus spp. colonization of respiratory tract ECMO before transplantation re-operation/re-transplantation post-transplant RRT CMV disease another recent IA episode in the HT programme hypogammaglobulinaemia (IgG <400 mg/dL) ICU readmission kidney transplantation >2 acute rejection episodes  Pancreas  post-perfusion pancreatitis acute rejection, poor initial allograft function vascular thrombosis, enteric drainage, anastomotic problems RRT laparotomy after transplantation    Intestinal  acute rejection, poor initial allograft function anastomotic problems RRT laparotomy after transplantation over-immunosuppression    Lung    bronchial anastomotic ischaemia or bronchial stent placement CMV infection acute rejection single-lung transplant Aspergillus spp. colonization before/during first year post-transplant  Kidney    graft lost and RRT longer RRT pre-transplant neutropenia prolonged high corticosteroid doses  Transplant type  Risk factors   invasive candidiasis  invasive aspergillosis  Liver  pre-operative ICU hospitalization in the prior 90 days multifocal Candida spp. colonization/infection MELD score (>30 or between 20 and 30) fulminant hepatic failurea split, living donor  pre-operative fulminant hepatic failure  intra-operative choledochojejunostomy transfusion of ≥ 40 units of blood products prolonged operation  intra-operative multi-visceral transplantation complicated surgery  post-operative acute renal failure renal failure requiring RRTa any rejection within 2 weeks after transplant CMV-DNaemia >100 000 copies/mL re-operation re-transplantationa  post-operative renal failure RRT rejection requiring treatment with ATG, OKT3 or alemtuzumab >6 g of accumulative prednisone in month 3 post-transplant re-transplantation re-operation leucopenia (<500/mm3) chronic graft dysfunction  Heart  acute rejection RRT re-exploration after transplantation  Aspergillus spp. colonization of respiratory tract ECMO before transplantation re-operation/re-transplantation post-transplant RRT CMV disease another recent IA episode in the HT programme hypogammaglobulinaemia (IgG <400 mg/dL) ICU readmission kidney transplantation >2 acute rejection episodes  Pancreas  post-perfusion pancreatitis acute rejection, poor initial allograft function vascular thrombosis, enteric drainage, anastomotic problems RRT laparotomy after transplantation    Intestinal  acute rejection, poor initial allograft function anastomotic problems RRT laparotomy after transplantation over-immunosuppression    Lung    bronchial anastomotic ischaemia or bronchial stent placement CMV infection acute rejection single-lung transplant Aspergillus spp. colonization before/during first year post-transplant  Kidney    graft lost and RRT longer RRT pre-transplant neutropenia prolonged high corticosteroid doses  ATG, anti-thymocyte globulin; OKT-3, anti-CD3 monoclonal antibody. a Major risk factor. In lung and heart–lung transplant recipients, the respiratory tract is an obvious portal of entry for moulds. The treatment of end-stage lung disease favours pre-operative colonization of the recipient with fungi. Lung transplantation surgery itself abolishes important host defences as a result of airway ischaemia, graft ischaemia and bronchial anastomotic irregularities and denervation (i.e. impairment of cough reflexes and mucociliary clearance). In the post-transplantation period, specific risk factors for IFI include reperfusion injury, anastomotic leaks, bronchial alterations, fungal colonization and CMV infection. Poor allograft function and repeated episodes of rejection or bronchiolitis are other risk factors for IFI.9,39 In single-lung transplant patients, IA more commonly affects the native lung than the transplanted lung.41 A seminal study on risk factors for IA in HT recipients showed that re-operation, CMV disease, post-transplant haemodialysis and the existence of an episode of IA in the HT programme 2 months before or after the transplantation date were independent risk factors for IA. In contrast, antifungal prophylaxis showed an independent protective effect against developing IA.2 Tissot et al.7 recently reported that the use of post-transplant extracorporeal membrane oxygenation (ECMO) was the strongest predictor for fungal infection after HT, whereas RRT and Aspergillus colonization were significant predictors only by univariate analysis. Risk factors for fungal infection in LT recipients may be distinguished in predictors for IC and those for IA. In addition, they can be classified as (i) those related to underlying disease and pre-transplant status (e.g. colonization with Candida as a risk factor for IC, or fulminant hepatitis as a risk factor for IA); (ii) those related to surgery (e.g. high transfusion requirements, choledochojejunostomy anastomosis, prolonged operation); and (iii) post-transplant complications (re-operation, RRT, re-transplantation) (Table 2).24,38,39,42,43 In addition, since the introduction of the model for end-stage liver disease (MELD) for prioritizing and standardizing organ allocation, some authors have observed that LT recipients with higher MELD value at transplantation have an increased risk of developing IFI after transplantation.5,6,17,44 In a recent single-centre cohort of 330 LT recipients, graft dysfunction, RRT and prophylaxis with fluconazole were identified as independent risk factors for IFI.43 The latter factor was explained by the fact that most IFI episodes were IA occurring in patients with risk factors for aspergillosis but who were receiving fluconazole as antifungal prophylaxis.43 Kidney transplant recipients are considered to be at low risk of IFI, mainly of those caused by moulds. Recently, two studies have focused on risk factors for IA in KT recipients. Heylen et al.21 carried out a single-centre case–control study showing that leucopenia after KT increased the risk of IA among all patients. In addition, for early-onset infection (i.e. occurring during the first 3 months after transplant), a longer duration of RRT pre-transplant and the occurrence of leucopenia were risk factors, whereas donor CMV seropositivity increased the risk of late-onset IA (i.e. that occurring >3 months after transplant).21 In a multicentre case–control study, Lopez-Medrano et al.45 observed that pre-transplant chronic obstructive pulmonary disease impaired graft function, and that the occurrence of serious post-transplant infections identified KT recipients at the highest risk of early (≤6 months) invasive pulmonary aspergillosis. The data on prevalence of fungal infection in intestinal (small bowel) transplantation are not robust. In one multicentre study, the incidence rate of fungal infections was highest in small bowel transplant recipients, and the most common fungal organism was Candida.46 The data on the risk factors of fungal infections in pancreas and kidney transplantation are limited. In an older study, the risk factors for candidiasis among pancreas transplant recipients included enteric drainage, vascular thrombosis and postperfusion pancreatitis.46 Approach to prophylaxis Since the early 1990s, several studies have evaluated risk factors for developing IFI after transplantation, in order to identify high-risk recipients. In the example of liver transplantation, not all transplant recipients develop an IFI. In the absence of risk factors and without postoperative antifungal prophylaxis, the frequency of IFI is low at <4%.42 Assessment of individual patient risk factors is essential for appropriate antifungal prophylaxis, as is awareness of current practice guidelines. Overview of guidelines Three meta-analyses and a Cochrane review have examined whether antifungal prophylaxis decreases infectious morbidity and mortality in LT patients.28,47–49 Six to seven studies, mostly from the late 1990s, were analysed in order to determine the benefit of fluconazole, itraconazole or amphotericin B lipid formulations as prophylactic drugs in LT recipients. All of them demonstrated that prophylaxis reduced fungal colonization, total proven fungal infections (including both superficial and invasive infections) and mortality attributable to IFI, but prophylaxis did not affect overall mortality. The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection but no beneficial effect on invasive Aspergillus infection was observed. Amphotericin B lipid formulations and fluconazole were therefore, in relation to these studies, recommended for antifungal prophylaxis after liver transplantation by the IDSA and the American Society of Transplantation (AST) Infectious Disease Community of Practice.24,50 The duration of prophylaxis is not clearly determined, but treatment for 3 or 4 weeks or until resolution of risk factors has been recommended by the US and European guidelines.24,40,50 Organ-specific comments/considerations As reported above, an important aspect outlined mainly in kidney and LT recipients is the risk of acquired mycotic aneurysm of the hepatic and renal artery owing to transmission of Candida spp. from the donor, leading to bleeding from arterial rupture in the early post-operative period, loss of the graft and, in a few cases, recipient death. Presence of Candida in the preservation fluid of the organ would require aggressive monitoring by imaging and treatment of the recipient. Echinocandins at therapeutic doses should probably be carefully considered in this setting.26 Pre- and post-transplant Aspergillus colonization in lung transplant recipients is a risk factor for subsequent IA. Pre-transplant colonization, commonly observed in cystic fibrosis patients, increases the risk of airway disease caused by Aspergillus.51 In contrast, post-transplant Aspergillus colonization is observed in lung transplant recipients irrespective of the underlying disease52 and occurs in almost half of lung transplant recipients. Post-transplant colonization is transient in >60% of the cases, but this should not distract from its importance; post-transplant colonization in the first 6 months increases the risk of IA by 11-fold. Pulmonary IA is the most common manifestation in these patients. IA can also occur in the absence of prior known colonization. In addition, Aspergillus airway colonization may increase the risk of subsequent bronchiolitis obliterans. Therefore, either universal or targeted anti-Aspergillus prophylactic strategies in lung transplant recipients appear reasonable. A systematic review of literature until the year 2000 by Singh and Husain (2003)53 revealed that the risk of developing IA was highest in the first year after lung transplantation. The median time to development of tracheobronchitis or bronchial anastomotic infection was 2.7 months, in contrast to 5.5 months for invasive pulmonary disease. Of all IA, 72% and 88% occurred in the first 6 months and 1 year after transplantation, respectively.53 Therefore, one could argue for a 6–12 month duration of anti-Aspergillus prophylaxis. However, recent data suggest a delay in the onset of IA, raising the question of optimum duration of prophylaxis; the PATH Alliance data published in 2010 reported the median time to diagnosis as 504 days in lung transplant recipients, the majority (61.3%) of whom had received prior antifungal therapy (prophylaxis, pre-emptive or empirical) within 30 days of IFI diagnosis.23 Taking into consideration the results of a recent survey by Pavan et al.,54 which revealed that 93% of the responding lung transplant centres have adopted anti-Aspergillus prophylaxis, it is not clear whether delayed onset of IA is due to widespread adoption of prophylaxis or some other unknown factor. A meta-analysis of 22 studies was conducted in order to assess the development of IA and Aspergillus colonization with and without prophylaxis. Nineteen of 235 (8.1%) and 28 of 196 (14.3%) patients developed IA in the universal prophylaxis and no-prophylaxis arms, respectively [relative risk (RR) 0.36, 95% CI 0.05–2.62]. The use of universal prophylaxis did not decrease the rate of fungal colonization.55 However, another meta-analysis suggested that universal prophylaxis may decrease the rate of IA in lung transplant recipients.56 One recent study has suggested the effectiveness of a pre-emptive approach to antifungal treatment in lung transplant recipients.57 In the recently published International Society for Heart and Lung Transplantation guidelines for fungal infections for lung transplant recipients,58 the decision of any transplant centre to use universal prophylaxis or pre-emptive therapy was left for the centre to make based on the local epidemiology, time post-transplant and availability of fungal diagnostics and therapeutic drug monitoring. Universal prophylaxis with agents that have systemic activity against Candida species was suggested in the immediate post-transplant period (i.e. the first 2–4 weeks). While the optimal duration is uncertain, 3–6 months of prophylaxis is common in current practice.54 Immediately after the transplant, mould-active universal prophylaxis or pre-emptive therapy is recommended. In case of implementation of pre-emptive therapy, it was suggested that bronchoalveolar lavage surveillance and therapeutic drug monitoring should be incorporated. In the guidelines, nebulized amphotericin B, fluconazole or an echinocandin (depending on local epidemiology) were recommended during the first 2–4 weeks. No routine antifungal prophylaxis was recommended for HT recipients. However, heightened surveillance of fungi was recommended.58 Despite an absence of antifungal clinical trials in small bowel adult transplant recipients, antifungal prophylaxis in this patient population is routinely practised.4 Higher-risk small bowel transplant recipients include patients with graft rejection, enhanced immunosuppression, anastomotic disruption, abdominal reoperation or multivisceral transplantation. Fluconazole has been recommended as the agent of choice. However, in cases of non-albicans Candida spp., liposomal amphotericin B (LAmB) or an echinocandin is also acceptable. Prophylaxis is usually continued for a minimum of 4 weeks, until anastomosis has completely healed, and rejection is not present.59 Routine antifungal prophylaxis for pancreas transplant recipients is not recommended. Targeted prophylaxis with fluconazole in the presence of the risk factors outlined above is recommended by the American Society of Transplantation. LAmB is recommended in centres with a high prevalence of non-albicans species. Duration of prophylaxis is poorly defined.59 The risk of fungal infection in KT recipients is very low, and the risk factors are not well defined. Routine antifungal prophylaxis is not recommended in KT recipients. Selection of prophylactic agent Echinocandins (caspofungin, micafungin or anidulafungin) are currently recommended as first-line treatment in the therapeutic management of invasive candidiasis and commonly used in the transplant population in relation to their efficacy and safety profile and the absence of drug interactions. Two recent randomized controlled trials and one matched multicentre trial analysed echinocandins in prophylaxis in high-risk LT recipients, and are discussed in the following paragraphs. The TENPIN trial (Liver Transplant EuropeaN Study Into the Prevention of Fungal INfection) was an open-label, randomized non-inferiority study.60 It included 344 LT patients at high risk of fungal infection, who were randomized to 100 mg of micafungin (2 mg/kg in patients ≤40 kg) once daily (n = 172) or centre-specific standard of care (fluconazole 200–400 mg/day; LAmB at 1–3 mg/kg; or caspofungin in a loading dose of 70 mg and 50 mg maintenance) once daily (n = 172). The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at the end of prophylaxis (EOP). At EOP (mean treatment duration: 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care [Δ standard care–micafungin 0.7% (95% CI −2.7% to 4.4%)]. In addition, micafungin had similar efficacy to standard care across all secondary efficacy outcomes assessed. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in the micafungin arm.60 The authors concluded that micafungin proved to be at least as effective as the standard of care (fluconazole/LAmB/caspofungin) in the prevention of IFIs in LT patients at high risk of developing IFI. The Winston et al.44 trial was a randomized controlled trial designed and powered to show superiority of anidulafungin to fluconazole. The study comprised 200 high-risk LT recipients (100 patients per group) who received either anidulafungin or fluconazole for antifungal prophylaxis, with a primary endpoint of IFI (modified ITT analysis). Patients were stratified for MELD score ≥30 and receipt of a pre-transplant antifungal agent. The overall incidences of IFI in the anidulafungin (5.1%) and fluconazole groups (8.0%) were similar (OR 0.61, 95% CI 0.19–1.94; P = 0.40), and the study therefore did not meet the primary endpoint.44 The authors noted differences observed between the anidulafungin and fluconazole prophylaxis groups, such as in rates of Aspergillus colonization or infection (3% and 9%, P = 0.08), breakthrough IFIs (0% versus 27%, P = 0.07) and antifungal resistance (no cases versus five cases); however, these were not statistically significant. 44 The observed rate of IA was lower in this study than that observed in other studies. In such centres with a higher incidence of IA, concerns may arise about the use of fluconazole in high-risk LT patients as an independent risk factor for developing IA.43 More recently, Fortun et al.61 reported a multicentre retrospective trial and used a propensity score approach to compare prophylaxis given to high-risk LT recipients with caspofungin (n = 97) given to a historical group treated with fluconazole (n = 98). Caspofungin and fluconazole had similar efficacy for the prevention of IFIs overall. In total, among 17 (8.7%) patients who developed an IFI, 11 patients had a breakthrough infection (5.6%) and 6 patients developed invasive aspergillosis (3.1%). In patients requiring dialysis (n = 62), caspofungin significantly reduced the frequency of breakthrough IFIs (P = 0.03). The propensity score analysis confirmed a significant reduction in the frequency of invasive aspergillosis in patients receiving caspofungin (absolute risk reduction 0.06; 95% CI 0.001–0.11; P = 0.044). A significant increase in bilirubin levels was noted after administration of caspofungin.61 Data on the use of echinocandins in prophylaxis for thoracic organ transplant recipients are lacking. In a recent survey regarding echinocandin use in lung transplant recipients, the most common agents used were voriconazole (43%) and inhaled amphotericin B (29%), followed by posaconazole (13%) and itraconazole (11%). Caspofungin was a first-line agent at only one centre. Half (25/50) of the survey respondents saw the need to switch 10%–30% of their patients to second-line antifungal agents owing to adverse events. Of centres using universal prophylaxis and inhaled amphotericin B as a first-line agent, 36% (4/11) cited echinocandins as their preferred second-line agents (Figure 1). Fifty-seven percent (32/56) of respondents considered echinocandins suitable for antifungal prophylaxis in lung transplant recipients. If a novel echinocandin became available as a once-weekly intravenous infusion approved for lung transplant antifungal prophylaxis, respondents believed it would significantly increase the use of echinocandins as first-line (55%; 31/56) and second-line (75%; 42/56) prophylaxis. Seventy percent (39/56) of respondents believed that a subcutaneous formulation would significantly increase its use over an intravenous infusion.54 In a retrospective study of 777 lung transplant recipients, antifungals were used in 272 lung transplant recipients. Azoles were used as first-line agents in 80% (216/271) of recipients. Caspofungin was used as a first-line agent in 11% (31/271), followed by micafungin in 7% (19/271) and amphotericin B in 1.5% (4/271). Ninety percent (46/51) of the patients who were started on echinocandins had abnormal liver enzymes at the time of echinocandin initiation. Overall, 23% (50/216) of the patients who were started on azoles were eventually switched to another antifungal; 54% (27/50) were switched to an echinocandin. For 63% of these patients, the reason for switching from an azole to an echinocandin was abnormal liver enzymes. In contrast, after 6 weeks of echinocandin treatment, no recipients had been switched because of adverse effects.62 Figure 1. View largeDownload slide Survey results: preferred first- and second line antifungal prophylaxis. Figure 1. View largeDownload slide Survey results: preferred first- and second line antifungal prophylaxis. Data on the use of echinocandins for antifungal prophylaxis in HT are lacking.7 Kabbani and colleagues63 added micafungin to the usual amphotericin B prophylaxis given to all HT recipients post-HT after a high number of IA cases were observed during an 8 month period. No episodes of IA were observed after institution of this prophylaxis regimen (personal communication, S. Husain, University of Toronto). Echinocandins inhibit 1,3-β-d-glucan, a component of fungal cell walls common to Candida and Aspergillus, as well as Pneumocystis. Current echinocandins have not been considered for monotherapy against PCP owing to in vivo studies that demonstrated efficacy against the cyst form of Pneumocystis but the persistence of significant numbers of the trophic form.64,65 However, treatment-limiting adverse events and development of resistance to sulpha drugs have led to a search for alternatives to the current standard, trimethoprim/sulfamethoxazole. Cases of combination therapy with caspofungin and trimethoprim/sulfamethoxazole in SOT recipients have been reported66,67 and rezafungin (previously CD101), a novel echinocandin in development, has shown promise against PCP in vivo by eradicating both the cyst and trophic forms of Pneumocystis.64,66–68 Risks and benefits of echinocandins versus other antifungal agents/classes The ideal prophylactic agent should have high efficacy against the two most common fungal infections in SOT patients, Candida spp. and Aspergillus spp. Other known fungal pathogens (such as Cryptococcus, endemic or emerging pathogens or those that could be acquired from the donor) are very rare, occurring in ≤1% of recipients, and are less likely to be covered. The drug of choice remains controversial. Only a selected group of transplant recipients at high risk of developing IFI should receive antifungal prevention active against Candida spp. and Aspergillus spp. Echinocandins are strong alternatives to fluconazole and LAmB, the previous recommended options for antifungal prophylaxis in LT recipients. The efficacy of echinocandins for treatment of IFI has been shown in randomized controlled trials that comprised low numbers of SOTs and they are currently recommended as first-line therapy. Efficacy of the three echinocandins as prophylactic agents has recently been shown in randomized trials in high-risk LT patients. The current European guidelines recommend echinocandins as first-line prophylaxis for high-risk LT patients. The risk with the azoles is mainly related to drug–drug interactions with the immunosuppressive regimen in relation to the use of calcineurin (cyclosporin, tacrolimus) and mTOR (sirolimus and everolimus) inhibitors, thereby enhancing their toxicities. This often occurs at the time of introduction and of stopping the azole, in patients with graft dysfunction and when adjusting immunosuppression for treatment of acute rejection. The interactions are enhanced when using itraconazole and voriconazole, which are rarely used for prophylaxis (except in lung transplantation), mostly in relation to liver toxicities. Renal impairment or failure associated with treatment with lipid formulations of amphotericin B is another major concern and might be a limitation of their use. Echinocandins have a well-demonstrated safety profile; liver and renal safety has also been proved in RCTs in transplant recipients. C. glabrata and C. krusei may represent 24% and 6% of Candida spp., respectively.6,69 Fluconazole has some major limitations as it is less effective or lacks activity in certain Candida spp., which include C. glabrata and C. krusei and is not active against Aspergillus spp. LAmB and fluconazole also have limitations in patients with renal dysfunction. Acute kidney injury and chronic kidney disease in the period post-transplantation are associated with worse long-term outcome. The proportion of patients undergoing liver transplantation that have renal dysfunction has markedly increased since the introduction of prioritization based on MELD score. The dosing of fluconazole requires adjustment in patients receiving RRT, as the procedure results in a significant clearance of fluconazole, which varies depending on the technique used.70 Resistance to echinocandins in some Candida species, possibly due to acquired FKS mutations, has been reported in 2%–3% of patients under treatment with an echinocandin and this could rise to 13% for Candida glabrata. Resistance has not been reported in the prophylactic setting.44,60,61,71 Conclusions Although the overall incidence of fungal infections in transplant recipients has declined thanks to advances in surgery, immunosuppression, infection prevention and antifungal prophylaxis, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Despite the fact that there is no consensus about optimal approaches, prophylactic strategies targeted to high-risk patients are of great importance in combination with a routine microbial surveillance programme. Echinocandins might be an attractive alternative for prophylaxis of IFI in high-risk patients because of their coverage of Candida, Aspergillus and PCP, their safety and very low nephrotoxicity and hepatotoxicity, few drug–drug interactions and low risk of drug resistance. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. Transparency declarations F. S. has received speaker honoraria and/or research grants from Novartis, Astellas, Genzyme, Gilead, Merck Sharp & Dohme, Gambro and Baxter. S. H. has received grants from Pfizer, Astellas, and Merck. P. V. has received grants for research projects from Gilead and has served as a speaker for Pfizer, Merck Sharp & Dohme, and Gilead. M. G. has none to declare.  The authors received no compensation for their contribution to the Supplement. This article was co-developed and published based on all authors’ approval. References 1 Grossi P, Farina C, Fiocchi R et al.   Prevalence and outcome of invasive fungal infections in 1,963 thoracic organ transplant recipients: a multicenter retrospective study. Italian Study Group of Fungal Infections in Thoracic Organ Transplant Recipients. Transplantation  2000; 70: 112– 6. Google Scholar PubMed  2 Munoz P, Rodriguez C, Bouza E et al.   Risk factors of invasive aspergillosis after heart transplantation: protective role of oral itraconazole prophylaxis. Am J Transplant  2004; 4: 636– 43. http://dx.doi.org/10.1111/j.1600-6143.2004.00390.x Google Scholar CrossRef Search ADS PubMed  3 Husain S, Paterson DL, Studer S et al.   Voriconazole prophylaxis in lung transplant recipients. Am J Transplant  2006; 6: 3008– 16. http://dx.doi.org/10.1111/j.1600-6143.2006.01548.x Google Scholar CrossRef Search ADS PubMed  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  2010; 50: 1101– 11. http://dx.doi.org/10.1086/651262 Google Scholar CrossRef Search ADS PubMed  5 Lichtenstern C, Hochreiter M, Zehnter VD et al.   Pretransplant model for end stage liver disease score predicts posttransplant incidence of fungal infections after liver transplantation. 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Transpl Infect Dis  2010; 12: 220– 9. http://dx.doi.org/10.1111/j.1399-3062.2010.00492.x Google Scholar CrossRef Search ADS PubMed  24 Pappas PG, Silveira FP, Practice ASTIDCo. Candida in solid organ transplant recipients. Am J Transplant  2009; 9 Suppl 4: S173– 9. Google Scholar CrossRef Search ADS PubMed  25 van Hal SJ, Marriott DJ, Chen SC et al.   Candidemia following solid organ transplantation in the era of antifungal prophylaxis: the Australian experience. Transpl Infect Dis  2009; 11: 122– 7. http://dx.doi.org/10.1111/j.1399-3062.2009.00371.x Google Scholar CrossRef Search ADS PubMed  26 Albano L, Bretagne S, Mamzer-Bruneel MF et al.   Evidence that graft-site candidiasis after kidney transplantation is acquired during organ recovery: a multicenter study in France. Clin Infect Dis  2009; 48: 194– 202. http://dx.doi.org/10.1086/595688 Google Scholar CrossRef Search ADS PubMed  27 Singh N, Huprikar S, Burdette SD et al.   Donor-derived fungal infections in organ transplant recipients: guidelines of the American Society of Transplantation, infectious diseases community of practice. Am J Transplant  2012; 12: 2414– 28. http://dx.doi.org/10.1111/j.1600-6143.2012.04100.x Google Scholar CrossRef Search ADS PubMed  28 Cruciani M, Mengoli C, Malena M et al.   Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis. Liver Transpl  2006; 12: 850– 8. http://dx.doi.org/10.1002/lt.20690 Google Scholar CrossRef Search ADS PubMed  29 Pfaller MA, Andes DR, Diekema DJ et al.   Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008. PLoS One  2014; 9: e101510. 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J Heart Lung Transplant  2014; 33: 1034– 40. http://dx.doi.org/10.1016/j.healun.2014.05.003 Google Scholar CrossRef Search ADS PubMed  33 Singh N, Avery RK, Munoz P et al.   Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients. Clin Infect Dis  2003; 36: 46– 52. http://dx.doi.org/10.1086/345441 Google Scholar CrossRef Search ADS PubMed  34 Baddley JW, Marr KA, Andes DR et al.   Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network. J Clin Microbiol  2009; 47: 3271– 5. http://dx.doi.org/10.1128/JCM.00854-09 Google Scholar CrossRef Search ADS PubMed  35 Lockhart SR, Zimbeck AJ, Baddley JW et al.   In vitro echinocandin susceptibility of Aspergillus isolates from patients enrolled in the Transplant-Associated Infection Surveillance Network. Antimicrob Agents Chemother  2011; 55: 3944– 6. http://dx.doi.org/10.1128/AAC.00428-11 Google Scholar CrossRef Search ADS PubMed  36 Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med  2007; 357: 2601– 14. http://dx.doi.org/10.1056/NEJMra064928 Google Scholar CrossRef Search ADS PubMed  37 Fishman JA. From the classic concepts to modern practice. Clin Microbiol Infect  2014; 20 Suppl 7: 4– 9. Google Scholar CrossRef Search ADS PubMed  38 Eschenauer GA, Kwak EJ, Humar A et al.   Targeted versus universal antifungal prophylaxis among liver transplant recipients. Am J Transplant  2015; 15: 180– 9. http://dx.doi.org/10.1111/ajt.12993 Google Scholar CrossRef Search ADS PubMed  39 Singh N, Husain S. Aspergillosis in solid organ transplantation. Am J Transplant  2013; 13 Suppl 4: 228– 41. Google Scholar CrossRef Search ADS PubMed  40 Gavalda J, Meije Y, Fortun J et al.   Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect  2014; 20 Suppl 7: 27– 48. Google Scholar CrossRef Search ADS PubMed  41 Aldebert D, Pinel C, Brion JP et al.   [Role of local immunity in invasive pulmonary aspergillosis]. Presse Med  2001; 30: 1258– 64. Google Scholar PubMed  42 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  2006; 6: 386– 91. http://dx.doi.org/10.1111/j.1600-6143.2005.01176.x Google Scholar CrossRef Search ADS PubMed  43 Giannella M, Bartoletti M, Morelli M et al.   Antifungal prophylaxis in liver transplant recipients: one size does not fit all. Transpl Infect Dis  2016; 18: 538– 44. http://dx.doi.org/10.1111/tid.12560 Google Scholar CrossRef Search ADS PubMed  44 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  2014; 14: 2758– 64. http://dx.doi.org/10.1111/ajt.12963 Google Scholar CrossRef Search ADS PubMed  45 Lopez-Medrano F, Silva JT, Fernandez-Ruiz M et al.   Risk factors associated with early invasive pulmonary aspergillosis in kidney transplant recipients: results from a multinational matched case-control study. Am J Transplant  2016; 16: 2148– 57. Google Scholar CrossRef Search ADS PubMed  46 Benedetti E, Gruessner AC, Troppmann C et al.   Intra-abdominal fungal infections after pancreatic transplantation: incidence, treatment, and outcome. J Am Coll Surg  1996; 183: 307– 16. Google Scholar PubMed  47 Evans JD, Morris PJ, Knight SR. Antifungal prophylaxis in liver transplantation: a systematic review and network meta-analysis. Am J Transplant  2014; 14: 2765– 76. http://dx.doi.org/10.1111/ajt.12925 Google Scholar CrossRef Search ADS PubMed  48 Playford EG, Webster AC, Sorell TC et al.   Antifungal agents for preventing fungal infections in solid organ transplant recipients. Cochrane Database Syst Rev  2004; issue 3: CD004291. 49 Playford EG, Webster AC, Sorrell TC et al.   Systematic review and meta-analysis of antifungal agents for preventing fungal infections in liver transplant recipients. Eur J Clin Microbiol Infect Dis  2006; 25: 549– 61. http://dx.doi.org/10.1007/s10096-006-0182-3 Google Scholar CrossRef Search ADS PubMed  50 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  2009; 48: 503– 35. http://dx.doi.org/10.1086/596757 Google Scholar CrossRef Search ADS PubMed  51 Helmi M, Love RB, Welter D et al.   Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients. Chest  2003; 123: 800– 8. http://dx.doi.org/10.1378/chest.123.3.800 Google Scholar CrossRef Search ADS PubMed  52 Cahill BC, Hibbs JR, Savik K et al.   Aspergillus airway colonization and invasive disease after lung transplantation. Chest  1997; 112: 1160– 4. http://dx.doi.org/10.1378/chest.112.5.1160 Google Scholar CrossRef Search ADS PubMed  53 Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transplant  2003; 22: 258– 66. http://dx.doi.org/10.1016/S1053-2498(02)00477-1 Google Scholar CrossRef Search ADS PubMed  54 Pavan R, Husain S. Role of echinocandins as antifungal prophylaxis agents in lung transplant recipients. The International Society for Heart & Lung Transplantation . San Diego, CA: The Journal of Heart and Lung Transplantation, 2017; 36: S239– S40. 55 Bhaskaran A, Mumtaz K, Husain S. Anti-Aspergillus prophylaxis in lung transplantation: a systematic review and meta-analysis. Curr Infect Dis Rep  2013; 15: 514– 25. http://dx.doi.org/10.1007/s11908-013-0380-y Google Scholar CrossRef Search ADS PubMed  56 Pilarczyk K, Haake N, Heckmann J et al.   Is universal antifungal prophylaxis mandatory in adults after lung transplantation? A review and meta-analysis of observational studies. Clin Transplant  2016; 30: 1522– 31. http://dx.doi.org/10.1111/ctr.12854 Google Scholar CrossRef Search ADS PubMed  57 Hosseini-Moghaddam SM, Chaparro C, Luong ML et al.   The effectiveness of culture-directed preemptive anti-Aspergillus treatment in lung transplant recipients at one year after transplant. Transplantation  2015; 99: 2387– 93. Google Scholar CrossRef Search ADS PubMed  58 Husain S, Sole A, Alexander BD et al.   The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: executive summary. J Heart Lung Transplant  2016; 35: 261– 82. http://dx.doi.org/10.1016/j.healun.2016.01.007 Google Scholar CrossRef Search ADS PubMed  59 Silveira FP, Kusne S. Practice ASTIDCo. Candida infections in solid organ transplantation. Am J Transplant  2013; 13 Suppl 4: 220– 7. Google Scholar CrossRef Search ADS PubMed  60 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  2015; 60: 997– 1006. 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Blood  2016; 128: 3396. 65 Linke MJ, Ashbaugh A, Collins MS et al.   Characterization of a distinct host response profile to Pneumocystis murina asci during clearance of pneumocystis pneumonia. Infect Immun  2013; 81: 984– 95. http://dx.doi.org/10.1128/IAI.01181-12 Google Scholar CrossRef Search ADS PubMed  66 Tu GW, Ju MJ, Xu M et al.   Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients. Nephrology (Carlton)  2013; 18: 736– 42. http://dx.doi.org/10.1111/nep.12133 Google Scholar CrossRef Search ADS PubMed  67 Utili R, Durante-Mangoni E, Basilico C et al.   Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients. Transplantation  2007; 84: 685– 8. http://dx.doi.org/10.1097/01.tp.0000280546.91617.6c Google Scholar CrossRef Search ADS PubMed  68 Ong V, Bartizal K, Cushion M, Miesel L et al.   Antifungal prophylaxis with CD101 in immunosuppressed mouse models of candidiasis, aspergillosis, and Pneumocystis pneumonia (PCP ). In: 22nd Congress of the European Hematology Association, Madrid, 2017. Abstract P465. 69 Andes DR, Safdar N, Baddley JW et al.   The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis  2016; 18: 921– 31. http://dx.doi.org/10.1111/tid.12613 Google Scholar CrossRef Search ADS PubMed  70 Muhl E, Martens T, Iven H et al.   Influence of continuous veno-venous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole. Eur J Clin Pharmacol  2000; 56: 671– 8. http://dx.doi.org/10.1007/s002280000216 Google Scholar CrossRef Search ADS PubMed  71 Perlin DS. Echinocandin resistance, susceptibility testing and prophylaxis: implications for patient management. Drugs  2014; 74: 1573– 85. http://dx.doi.org/10.1007/s40265-014-0286-5 Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Use of echinocandin prophylaxis in solid organ transplantation

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Abstract

Abstract Invasive fungal infections (IFIs) are a major threat to patients undergoing solid organ transplantation (SOT). Owing to improvements in surgical techniques, immunosuppression therapy and antifungal prophylaxis, the incidence of IFIs has been decreasing in recent years. However, IFI-associated morbidity and mortality remain significant. Invasive candidiasis (IC) and aspergillosis (IA) are the main IFIs after SOT. Risk factors for IC and IA continue to evolve, and thus strategies for their prevention should be constantly updated and targeted to both individual patient risk factors and local epidemiology. In this review, we discuss the current epidemiology and risk factors for IFIs in SOT recipients in the context of actual approaches to antifungal prophylaxis, including experience with the use of echinocandins, after SOT. Epidemiology Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among solid organ transplant (SOT) recipients. IFIs occur in 2%–40% of SOT patients depending on the organ transplanted and the use of antifungal prophylaxis.1–7 In addition, the reported burden of IFIs, even within transplant types, varies across centres owing to several probable factors, such as geographically restricted exposure, methods used for case identification (surveillance, diagnostic techniques) and differences in types of patients, immunosuppressive regimens and follow-up.8 Nevertheless, the incidence of IFIs among SOT recipients has declined over the past two decades, which is due in large part to improvements in surgical techniques, immunosuppression and preventive strategies9,10 (Table 1). Table 1. Incidence of invasive fungal infection according to type of transplant in historical cohorts and in the TRANSNET study Type of transplant  Historical cohorts (1990s)  TRANSNET study (12 month cumulative incidence)  Small bowel  40%–59%  12%  Lung and heart–lung  10%–44%  9%  Liver  6%–47%  5%  Pancreas  6%–38%  4%  Heart  3%–21%  3%  Renal  1%–14%  1.3%  Type of transplant  Historical cohorts (1990s)  TRANSNET study (12 month cumulative incidence)  Small bowel  40%–59%  12%  Lung and heart–lung  10%–44%  9%  Liver  6%–47%  5%  Pancreas  6%–38%  4%  Heart  3%–21%  3%  Renal  1%–14%  1.3%  The largest study published to date on the burden of IFIs in SOT recipients is the report of the Transplant Associated Infection Surveillance Network (TRANSNET), consisting of 15 SOT centres in the USA reporting IFI surveillance data over a 5 year period (2001–06).4 The incidence cohort included 16 808 SOT recipients who underwent transplantation between 2002 and 2005, 5% of whom were paediatric patients. The most common types of SOT were kidney and liver, which accounted for 32.8% and 26.6% of transplants, respectively. The estimated cumulative incidence of any IFI 1 year after transplantation was 3.1%. It varied by type of SOT, with the highest being for bowel (11.6%), lung/heart–lung (8.6%) and liver (4.7%) transplantation, and the lowest for kidney recipients (1.3%) (Table 1). The 1 year incidence of each specific IFI was also investigated. Invasive candidiasis (IC) had the highest estimate (1.9%), followed by invasive aspergillosis (IA) (0.7%). Cryptococcosis, mould infections other than aspergillosis or zygomycosis, and endemic fungal infections had estimates of ∼0.2%. All other IFI types had estimates of <0.1%.4 Exposure to antifungal prophylaxis in the TRANSNET study was not reported; however, the authors did note its potential impact on the observed incidences.4 For example, the infection type with lowest cumulative 12 month incidence was Pneumocystis pneumonia (PCP), for which prophylaxis is effective and commonly used. Assessing the burden of PCP in SOT recipients must also consider late-onset infections occurring after the typical period of PCP prophylaxis ∼6–12 month post-transplantation.11–14 The mortality associated with IFIs varies with the causative agent, the organ transplanted and the site of infection. In the TRANSNET study, the 12 month survival after infection was 59% for patients with IA, 61% for infections due to non-Aspergillus moulds, 66% for IC and 73% for cryptococcosis.4 In heart transplant (HT) recipients, the crude mortality associated with fungal infections ranges from 29% to 36%, with a marked decrease observed in recent years.1,7,15 In lung transplant recipients, the mortality rate of bronchial infections, which is roughly 20%, is lower than that of invasive pulmonary mycoses, which approaches 80%.16 In liver transplant (LT) recipients, the mortality rate ranges from 20% to 30%,5,6,17 and is higher (40%–50%) for mould infections, especially those occurring late after transplantation.18,19 In kidney transplant (KT) recipients with IFI, mortality ranges from 39% to 54%20,21 and, in contrast with other organ types, early disease is associated with higher mortality risk.22 A general picture of the current epidemiology of IFI in SOT recipients has been described in the above-mentioned TRANSNET report4 and in the report of the Prospective Antifungal Therapy (PATH) Alliance.23 PATH is a multicentre, observational registry that prospectively collected data on proven and probable IFIs in 17 transplant centres in the USA from 2004 through 2007. A total of 429 adult SOT recipients with 515 IFIs were identified; most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%) and other moulds (5.8%).23 In both reports, IC was the most frequently observed IFI in all transplant types, except for lung recipients, where IA was the most common IFI.4,23 IC occurs earlier than other invasive mycoses, generally within the first 3 months following transplantation, and is viewed as a classic nosocomial infection.24 However, in a recent study, 54% of ICs occurred >6 months after transplantation, and kidney recipients were more likely to develop late IC when compared with liver, lung and heart recipients.25 The most common type of IC in this setting is candidaemia, frequently secondary to infection of vascular devices, followed by abdominal infection.23,25 A peculiar type of IC in transplant recipients is graft-transmitted candidiasis, due to an unexpected transmission from the donor or by the contamination of preservation fluid.26,27 This severe complication generally occurs within 2–3 weeks after transplantation as an arteritis of the graft, which evolves into aneurysm with following rupture if not promptly recognized and treated; graft loss and death are frequent.26 Unfortunately, clinical manifestations are vague, such as fever and pain at the graft. Regarding distribution of Candida species, C. albicans accounts for slightly more than half of the IC seen in SOT recipients. Among non-albicans spp. the most commonly encountered is C. glabrata, especially among patients previously exposed to antifungal therapy.23,28,29 IA is the leading cause of IFI after lung transplantation and the second most common IFI in non-lung recipients. The median time to occurrence of IA ranges between 100 and 200 days after SOT, with approximately half being early-onset (≤90 days) and half late-onset (>90–180 days) episodes.15,21,22,30 In a study of lung transplant recipients, the time of onset was related to the clinical form of IA.16 Tracheobronchitis and bronchial anastomotic infections occurred within 3 months of transplantation; in contrast, invasive or disseminated aspergillosis occurred significantly later (33.7 ± 19.6 months post-transplantation).16 The most common clinical manifestation of IA in SOT recipients is a pulmonary syndrome. Compared with neutropenic patients, SOT recipients are more likely to show peri-bronchial consolidation or ground-glass opacity and less likely to have fever, macro-nodules, mass-like consolidation, halo sign or air-crescent sign.31 The lack of classical angio-invasive signs of invasive pulmonary aspergillosis may contribute to a more protracted clinical presentation, later diagnosis and higher mortality rate, as shown in a study of HT recipients.32 Disseminated IA (two or more non-contiguous organs), with or without involvement of the CNS, was commonly reported in previous series.30,33 In a recent series, CNS involvement and extra-pulmonary localization seem to be more common in late IA cases.15 Regarding distribution of Aspergillus species and susceptibility to antifungals, Baddley et al.34 analysed 274 clinical Aspergillus isolated from transplant recipients with proven or probable IA collected as part of the TRANSNET study. The isolate collection included 181 A. fumigatus, 28 A. niger, 27 A. flavus, 22 A. terreus, 7 A. versicolor, 5 A. calidoustus and 2 A. nidulans isolates and 2 isolates identified as Aspergillus spp. Triazole susceptibilities were ≤4 mg/L for most isolates (posaconazole 97.6%; itraconazole 96.3%; voriconazole 95.9%; ravuconazole 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were ≥4 mg/L. Amphotericin B inhibited 93.3% of isolates with an MIC of ≤1 mg/L. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 mg/L. One of 181 isolates of A. fumigatus showed resistance (MIC ≥4 mg/L) to two of three azoles tested.34 The echinocandin minimum effective concentration (MEC) values were investigated on the same isolate collection and found to be at or below the epidemiological cut-off values for all three echinocandins (caspofungin, micafungin and anidulafungin) against the majority of isolates, including those from patients who had previously received caspofungin.35 Risk factors The occurrence of fungal infection in SOT recipients primarily depends on two factors: the intensity of exposure and the patient's susceptibility to infection.36,37 Intensity of exposure varies according to the type of organ transplanted and the geographical environment.2,8,38 With regard to patient factors, underlying disease that led to the need for transplantation in the first place, surgical complications (e.g. prolonged surgery, need for re-operation, fluid collections), neutropenia and thrombocytopenia, metabolic alterations (e.g. diabetes), infections with immunomodulatory viruses (e.g. cytomegalovirus, HCV), increased immunosuppressive therapy for rejection, and renal failure, especially with the need for renal replacement therapy (RRT), are cited as factors contributing to fungal infections.24,39 Risk factors have been recently updated and are summarized in Table 2.40 Table 2. Risk factors for invasive candidiasis and invasive aspergillosis by transplant type Transplant type  Risk factors   invasive candidiasis  invasive aspergillosis  Liver  pre-operative ICU hospitalization in the prior 90 days multifocal Candida spp. colonization/infection MELD score (>30 or between 20 and 30) fulminant hepatic failurea split, living donor  pre-operative fulminant hepatic failure  intra-operative choledochojejunostomy transfusion of ≥ 40 units of blood products prolonged operation  intra-operative multi-visceral transplantation complicated surgery  post-operative acute renal failure renal failure requiring RRTa any rejection within 2 weeks after transplant CMV-DNaemia >100 000 copies/mL re-operation re-transplantationa  post-operative renal failure RRT rejection requiring treatment with ATG, OKT3 or alemtuzumab >6 g of accumulative prednisone in month 3 post-transplant re-transplantation re-operation leucopenia (<500/mm3) chronic graft dysfunction  Heart  acute rejection RRT re-exploration after transplantation  Aspergillus spp. colonization of respiratory tract ECMO before transplantation re-operation/re-transplantation post-transplant RRT CMV disease another recent IA episode in the HT programme hypogammaglobulinaemia (IgG <400 mg/dL) ICU readmission kidney transplantation >2 acute rejection episodes  Pancreas  post-perfusion pancreatitis acute rejection, poor initial allograft function vascular thrombosis, enteric drainage, anastomotic problems RRT laparotomy after transplantation    Intestinal  acute rejection, poor initial allograft function anastomotic problems RRT laparotomy after transplantation over-immunosuppression    Lung    bronchial anastomotic ischaemia or bronchial stent placement CMV infection acute rejection single-lung transplant Aspergillus spp. colonization before/during first year post-transplant  Kidney    graft lost and RRT longer RRT pre-transplant neutropenia prolonged high corticosteroid doses  Transplant type  Risk factors   invasive candidiasis  invasive aspergillosis  Liver  pre-operative ICU hospitalization in the prior 90 days multifocal Candida spp. colonization/infection MELD score (>30 or between 20 and 30) fulminant hepatic failurea split, living donor  pre-operative fulminant hepatic failure  intra-operative choledochojejunostomy transfusion of ≥ 40 units of blood products prolonged operation  intra-operative multi-visceral transplantation complicated surgery  post-operative acute renal failure renal failure requiring RRTa any rejection within 2 weeks after transplant CMV-DNaemia >100 000 copies/mL re-operation re-transplantationa  post-operative renal failure RRT rejection requiring treatment with ATG, OKT3 or alemtuzumab >6 g of accumulative prednisone in month 3 post-transplant re-transplantation re-operation leucopenia (<500/mm3) chronic graft dysfunction  Heart  acute rejection RRT re-exploration after transplantation  Aspergillus spp. colonization of respiratory tract ECMO before transplantation re-operation/re-transplantation post-transplant RRT CMV disease another recent IA episode in the HT programme hypogammaglobulinaemia (IgG <400 mg/dL) ICU readmission kidney transplantation >2 acute rejection episodes  Pancreas  post-perfusion pancreatitis acute rejection, poor initial allograft function vascular thrombosis, enteric drainage, anastomotic problems RRT laparotomy after transplantation    Intestinal  acute rejection, poor initial allograft function anastomotic problems RRT laparotomy after transplantation over-immunosuppression    Lung    bronchial anastomotic ischaemia or bronchial stent placement CMV infection acute rejection single-lung transplant Aspergillus spp. colonization before/during first year post-transplant  Kidney    graft lost and RRT longer RRT pre-transplant neutropenia prolonged high corticosteroid doses  ATG, anti-thymocyte globulin; OKT-3, anti-CD3 monoclonal antibody. a Major risk factor. In lung and heart–lung transplant recipients, the respiratory tract is an obvious portal of entry for moulds. The treatment of end-stage lung disease favours pre-operative colonization of the recipient with fungi. Lung transplantation surgery itself abolishes important host defences as a result of airway ischaemia, graft ischaemia and bronchial anastomotic irregularities and denervation (i.e. impairment of cough reflexes and mucociliary clearance). In the post-transplantation period, specific risk factors for IFI include reperfusion injury, anastomotic leaks, bronchial alterations, fungal colonization and CMV infection. Poor allograft function and repeated episodes of rejection or bronchiolitis are other risk factors for IFI.9,39 In single-lung transplant patients, IA more commonly affects the native lung than the transplanted lung.41 A seminal study on risk factors for IA in HT recipients showed that re-operation, CMV disease, post-transplant haemodialysis and the existence of an episode of IA in the HT programme 2 months before or after the transplantation date were independent risk factors for IA. In contrast, antifungal prophylaxis showed an independent protective effect against developing IA.2 Tissot et al.7 recently reported that the use of post-transplant extracorporeal membrane oxygenation (ECMO) was the strongest predictor for fungal infection after HT, whereas RRT and Aspergillus colonization were significant predictors only by univariate analysis. Risk factors for fungal infection in LT recipients may be distinguished in predictors for IC and those for IA. In addition, they can be classified as (i) those related to underlying disease and pre-transplant status (e.g. colonization with Candida as a risk factor for IC, or fulminant hepatitis as a risk factor for IA); (ii) those related to surgery (e.g. high transfusion requirements, choledochojejunostomy anastomosis, prolonged operation); and (iii) post-transplant complications (re-operation, RRT, re-transplantation) (Table 2).24,38,39,42,43 In addition, since the introduction of the model for end-stage liver disease (MELD) for prioritizing and standardizing organ allocation, some authors have observed that LT recipients with higher MELD value at transplantation have an increased risk of developing IFI after transplantation.5,6,17,44 In a recent single-centre cohort of 330 LT recipients, graft dysfunction, RRT and prophylaxis with fluconazole were identified as independent risk factors for IFI.43 The latter factor was explained by the fact that most IFI episodes were IA occurring in patients with risk factors for aspergillosis but who were receiving fluconazole as antifungal prophylaxis.43 Kidney transplant recipients are considered to be at low risk of IFI, mainly of those caused by moulds. Recently, two studies have focused on risk factors for IA in KT recipients. Heylen et al.21 carried out a single-centre case–control study showing that leucopenia after KT increased the risk of IA among all patients. In addition, for early-onset infection (i.e. occurring during the first 3 months after transplant), a longer duration of RRT pre-transplant and the occurrence of leucopenia were risk factors, whereas donor CMV seropositivity increased the risk of late-onset IA (i.e. that occurring >3 months after transplant).21 In a multicentre case–control study, Lopez-Medrano et al.45 observed that pre-transplant chronic obstructive pulmonary disease impaired graft function, and that the occurrence of serious post-transplant infections identified KT recipients at the highest risk of early (≤6 months) invasive pulmonary aspergillosis. The data on prevalence of fungal infection in intestinal (small bowel) transplantation are not robust. In one multicentre study, the incidence rate of fungal infections was highest in small bowel transplant recipients, and the most common fungal organism was Candida.46 The data on the risk factors of fungal infections in pancreas and kidney transplantation are limited. In an older study, the risk factors for candidiasis among pancreas transplant recipients included enteric drainage, vascular thrombosis and postperfusion pancreatitis.46 Approach to prophylaxis Since the early 1990s, several studies have evaluated risk factors for developing IFI after transplantation, in order to identify high-risk recipients. In the example of liver transplantation, not all transplant recipients develop an IFI. In the absence of risk factors and without postoperative antifungal prophylaxis, the frequency of IFI is low at <4%.42 Assessment of individual patient risk factors is essential for appropriate antifungal prophylaxis, as is awareness of current practice guidelines. Overview of guidelines Three meta-analyses and a Cochrane review have examined whether antifungal prophylaxis decreases infectious morbidity and mortality in LT patients.28,47–49 Six to seven studies, mostly from the late 1990s, were analysed in order to determine the benefit of fluconazole, itraconazole or amphotericin B lipid formulations as prophylactic drugs in LT recipients. All of them demonstrated that prophylaxis reduced fungal colonization, total proven fungal infections (including both superficial and invasive infections) and mortality attributable to IFI, but prophylaxis did not affect overall mortality. The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection but no beneficial effect on invasive Aspergillus infection was observed. Amphotericin B lipid formulations and fluconazole were therefore, in relation to these studies, recommended for antifungal prophylaxis after liver transplantation by the IDSA and the American Society of Transplantation (AST) Infectious Disease Community of Practice.24,50 The duration of prophylaxis is not clearly determined, but treatment for 3 or 4 weeks or until resolution of risk factors has been recommended by the US and European guidelines.24,40,50 Organ-specific comments/considerations As reported above, an important aspect outlined mainly in kidney and LT recipients is the risk of acquired mycotic aneurysm of the hepatic and renal artery owing to transmission of Candida spp. from the donor, leading to bleeding from arterial rupture in the early post-operative period, loss of the graft and, in a few cases, recipient death. Presence of Candida in the preservation fluid of the organ would require aggressive monitoring by imaging and treatment of the recipient. Echinocandins at therapeutic doses should probably be carefully considered in this setting.26 Pre- and post-transplant Aspergillus colonization in lung transplant recipients is a risk factor for subsequent IA. Pre-transplant colonization, commonly observed in cystic fibrosis patients, increases the risk of airway disease caused by Aspergillus.51 In contrast, post-transplant Aspergillus colonization is observed in lung transplant recipients irrespective of the underlying disease52 and occurs in almost half of lung transplant recipients. Post-transplant colonization is transient in >60% of the cases, but this should not distract from its importance; post-transplant colonization in the first 6 months increases the risk of IA by 11-fold. Pulmonary IA is the most common manifestation in these patients. IA can also occur in the absence of prior known colonization. In addition, Aspergillus airway colonization may increase the risk of subsequent bronchiolitis obliterans. Therefore, either universal or targeted anti-Aspergillus prophylactic strategies in lung transplant recipients appear reasonable. A systematic review of literature until the year 2000 by Singh and Husain (2003)53 revealed that the risk of developing IA was highest in the first year after lung transplantation. The median time to development of tracheobronchitis or bronchial anastomotic infection was 2.7 months, in contrast to 5.5 months for invasive pulmonary disease. Of all IA, 72% and 88% occurred in the first 6 months and 1 year after transplantation, respectively.53 Therefore, one could argue for a 6–12 month duration of anti-Aspergillus prophylaxis. However, recent data suggest a delay in the onset of IA, raising the question of optimum duration of prophylaxis; the PATH Alliance data published in 2010 reported the median time to diagnosis as 504 days in lung transplant recipients, the majority (61.3%) of whom had received prior antifungal therapy (prophylaxis, pre-emptive or empirical) within 30 days of IFI diagnosis.23 Taking into consideration the results of a recent survey by Pavan et al.,54 which revealed that 93% of the responding lung transplant centres have adopted anti-Aspergillus prophylaxis, it is not clear whether delayed onset of IA is due to widespread adoption of prophylaxis or some other unknown factor. A meta-analysis of 22 studies was conducted in order to assess the development of IA and Aspergillus colonization with and without prophylaxis. Nineteen of 235 (8.1%) and 28 of 196 (14.3%) patients developed IA in the universal prophylaxis and no-prophylaxis arms, respectively [relative risk (RR) 0.36, 95% CI 0.05–2.62]. The use of universal prophylaxis did not decrease the rate of fungal colonization.55 However, another meta-analysis suggested that universal prophylaxis may decrease the rate of IA in lung transplant recipients.56 One recent study has suggested the effectiveness of a pre-emptive approach to antifungal treatment in lung transplant recipients.57 In the recently published International Society for Heart and Lung Transplantation guidelines for fungal infections for lung transplant recipients,58 the decision of any transplant centre to use universal prophylaxis or pre-emptive therapy was left for the centre to make based on the local epidemiology, time post-transplant and availability of fungal diagnostics and therapeutic drug monitoring. Universal prophylaxis with agents that have systemic activity against Candida species was suggested in the immediate post-transplant period (i.e. the first 2–4 weeks). While the optimal duration is uncertain, 3–6 months of prophylaxis is common in current practice.54 Immediately after the transplant, mould-active universal prophylaxis or pre-emptive therapy is recommended. In case of implementation of pre-emptive therapy, it was suggested that bronchoalveolar lavage surveillance and therapeutic drug monitoring should be incorporated. In the guidelines, nebulized amphotericin B, fluconazole or an echinocandin (depending on local epidemiology) were recommended during the first 2–4 weeks. No routine antifungal prophylaxis was recommended for HT recipients. However, heightened surveillance of fungi was recommended.58 Despite an absence of antifungal clinical trials in small bowel adult transplant recipients, antifungal prophylaxis in this patient population is routinely practised.4 Higher-risk small bowel transplant recipients include patients with graft rejection, enhanced immunosuppression, anastomotic disruption, abdominal reoperation or multivisceral transplantation. Fluconazole has been recommended as the agent of choice. However, in cases of non-albicans Candida spp., liposomal amphotericin B (LAmB) or an echinocandin is also acceptable. Prophylaxis is usually continued for a minimum of 4 weeks, until anastomosis has completely healed, and rejection is not present.59 Routine antifungal prophylaxis for pancreas transplant recipients is not recommended. Targeted prophylaxis with fluconazole in the presence of the risk factors outlined above is recommended by the American Society of Transplantation. LAmB is recommended in centres with a high prevalence of non-albicans species. Duration of prophylaxis is poorly defined.59 The risk of fungal infection in KT recipients is very low, and the risk factors are not well defined. Routine antifungal prophylaxis is not recommended in KT recipients. Selection of prophylactic agent Echinocandins (caspofungin, micafungin or anidulafungin) are currently recommended as first-line treatment in the therapeutic management of invasive candidiasis and commonly used in the transplant population in relation to their efficacy and safety profile and the absence of drug interactions. Two recent randomized controlled trials and one matched multicentre trial analysed echinocandins in prophylaxis in high-risk LT recipients, and are discussed in the following paragraphs. The TENPIN trial (Liver Transplant EuropeaN Study Into the Prevention of Fungal INfection) was an open-label, randomized non-inferiority study.60 It included 344 LT patients at high risk of fungal infection, who were randomized to 100 mg of micafungin (2 mg/kg in patients ≤40 kg) once daily (n = 172) or centre-specific standard of care (fluconazole 200–400 mg/day; LAmB at 1–3 mg/kg; or caspofungin in a loading dose of 70 mg and 50 mg maintenance) once daily (n = 172). The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at the end of prophylaxis (EOP). At EOP (mean treatment duration: 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care [Δ standard care–micafungin 0.7% (95% CI −2.7% to 4.4%)]. In addition, micafungin had similar efficacy to standard care across all secondary efficacy outcomes assessed. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in the micafungin arm.60 The authors concluded that micafungin proved to be at least as effective as the standard of care (fluconazole/LAmB/caspofungin) in the prevention of IFIs in LT patients at high risk of developing IFI. The Winston et al.44 trial was a randomized controlled trial designed and powered to show superiority of anidulafungin to fluconazole. The study comprised 200 high-risk LT recipients (100 patients per group) who received either anidulafungin or fluconazole for antifungal prophylaxis, with a primary endpoint of IFI (modified ITT analysis). Patients were stratified for MELD score ≥30 and receipt of a pre-transplant antifungal agent. The overall incidences of IFI in the anidulafungin (5.1%) and fluconazole groups (8.0%) were similar (OR 0.61, 95% CI 0.19–1.94; P = 0.40), and the study therefore did not meet the primary endpoint.44 The authors noted differences observed between the anidulafungin and fluconazole prophylaxis groups, such as in rates of Aspergillus colonization or infection (3% and 9%, P = 0.08), breakthrough IFIs (0% versus 27%, P = 0.07) and antifungal resistance (no cases versus five cases); however, these were not statistically significant. 44 The observed rate of IA was lower in this study than that observed in other studies. In such centres with a higher incidence of IA, concerns may arise about the use of fluconazole in high-risk LT patients as an independent risk factor for developing IA.43 More recently, Fortun et al.61 reported a multicentre retrospective trial and used a propensity score approach to compare prophylaxis given to high-risk LT recipients with caspofungin (n = 97) given to a historical group treated with fluconazole (n = 98). Caspofungin and fluconazole had similar efficacy for the prevention of IFIs overall. In total, among 17 (8.7%) patients who developed an IFI, 11 patients had a breakthrough infection (5.6%) and 6 patients developed invasive aspergillosis (3.1%). In patients requiring dialysis (n = 62), caspofungin significantly reduced the frequency of breakthrough IFIs (P = 0.03). The propensity score analysis confirmed a significant reduction in the frequency of invasive aspergillosis in patients receiving caspofungin (absolute risk reduction 0.06; 95% CI 0.001–0.11; P = 0.044). A significant increase in bilirubin levels was noted after administration of caspofungin.61 Data on the use of echinocandins in prophylaxis for thoracic organ transplant recipients are lacking. In a recent survey regarding echinocandin use in lung transplant recipients, the most common agents used were voriconazole (43%) and inhaled amphotericin B (29%), followed by posaconazole (13%) and itraconazole (11%). Caspofungin was a first-line agent at only one centre. Half (25/50) of the survey respondents saw the need to switch 10%–30% of their patients to second-line antifungal agents owing to adverse events. Of centres using universal prophylaxis and inhaled amphotericin B as a first-line agent, 36% (4/11) cited echinocandins as their preferred second-line agents (Figure 1). Fifty-seven percent (32/56) of respondents considered echinocandins suitable for antifungal prophylaxis in lung transplant recipients. If a novel echinocandin became available as a once-weekly intravenous infusion approved for lung transplant antifungal prophylaxis, respondents believed it would significantly increase the use of echinocandins as first-line (55%; 31/56) and second-line (75%; 42/56) prophylaxis. Seventy percent (39/56) of respondents believed that a subcutaneous formulation would significantly increase its use over an intravenous infusion.54 In a retrospective study of 777 lung transplant recipients, antifungals were used in 272 lung transplant recipients. Azoles were used as first-line agents in 80% (216/271) of recipients. Caspofungin was used as a first-line agent in 11% (31/271), followed by micafungin in 7% (19/271) and amphotericin B in 1.5% (4/271). Ninety percent (46/51) of the patients who were started on echinocandins had abnormal liver enzymes at the time of echinocandin initiation. Overall, 23% (50/216) of the patients who were started on azoles were eventually switched to another antifungal; 54% (27/50) were switched to an echinocandin. For 63% of these patients, the reason for switching from an azole to an echinocandin was abnormal liver enzymes. In contrast, after 6 weeks of echinocandin treatment, no recipients had been switched because of adverse effects.62 Figure 1. View largeDownload slide Survey results: preferred first- and second line antifungal prophylaxis. Figure 1. View largeDownload slide Survey results: preferred first- and second line antifungal prophylaxis. Data on the use of echinocandins for antifungal prophylaxis in HT are lacking.7 Kabbani and colleagues63 added micafungin to the usual amphotericin B prophylaxis given to all HT recipients post-HT after a high number of IA cases were observed during an 8 month period. No episodes of IA were observed after institution of this prophylaxis regimen (personal communication, S. Husain, University of Toronto). Echinocandins inhibit 1,3-β-d-glucan, a component of fungal cell walls common to Candida and Aspergillus, as well as Pneumocystis. Current echinocandins have not been considered for monotherapy against PCP owing to in vivo studies that demonstrated efficacy against the cyst form of Pneumocystis but the persistence of significant numbers of the trophic form.64,65 However, treatment-limiting adverse events and development of resistance to sulpha drugs have led to a search for alternatives to the current standard, trimethoprim/sulfamethoxazole. Cases of combination therapy with caspofungin and trimethoprim/sulfamethoxazole in SOT recipients have been reported66,67 and rezafungin (previously CD101), a novel echinocandin in development, has shown promise against PCP in vivo by eradicating both the cyst and trophic forms of Pneumocystis.64,66–68 Risks and benefits of echinocandins versus other antifungal agents/classes The ideal prophylactic agent should have high efficacy against the two most common fungal infections in SOT patients, Candida spp. and Aspergillus spp. Other known fungal pathogens (such as Cryptococcus, endemic or emerging pathogens or those that could be acquired from the donor) are very rare, occurring in ≤1% of recipients, and are less likely to be covered. The drug of choice remains controversial. Only a selected group of transplant recipients at high risk of developing IFI should receive antifungal prevention active against Candida spp. and Aspergillus spp. Echinocandins are strong alternatives to fluconazole and LAmB, the previous recommended options for antifungal prophylaxis in LT recipients. The efficacy of echinocandins for treatment of IFI has been shown in randomized controlled trials that comprised low numbers of SOTs and they are currently recommended as first-line therapy. Efficacy of the three echinocandins as prophylactic agents has recently been shown in randomized trials in high-risk LT patients. The current European guidelines recommend echinocandins as first-line prophylaxis for high-risk LT patients. The risk with the azoles is mainly related to drug–drug interactions with the immunosuppressive regimen in relation to the use of calcineurin (cyclosporin, tacrolimus) and mTOR (sirolimus and everolimus) inhibitors, thereby enhancing their toxicities. This often occurs at the time of introduction and of stopping the azole, in patients with graft dysfunction and when adjusting immunosuppression for treatment of acute rejection. The interactions are enhanced when using itraconazole and voriconazole, which are rarely used for prophylaxis (except in lung transplantation), mostly in relation to liver toxicities. Renal impairment or failure associated with treatment with lipid formulations of amphotericin B is another major concern and might be a limitation of their use. Echinocandins have a well-demonstrated safety profile; liver and renal safety has also been proved in RCTs in transplant recipients. C. glabrata and C. krusei may represent 24% and 6% of Candida spp., respectively.6,69 Fluconazole has some major limitations as it is less effective or lacks activity in certain Candida spp., which include C. glabrata and C. krusei and is not active against Aspergillus spp. LAmB and fluconazole also have limitations in patients with renal dysfunction. Acute kidney injury and chronic kidney disease in the period post-transplantation are associated with worse long-term outcome. The proportion of patients undergoing liver transplantation that have renal dysfunction has markedly increased since the introduction of prioritization based on MELD score. The dosing of fluconazole requires adjustment in patients receiving RRT, as the procedure results in a significant clearance of fluconazole, which varies depending on the technique used.70 Resistance to echinocandins in some Candida species, possibly due to acquired FKS mutations, has been reported in 2%–3% of patients under treatment with an echinocandin and this could rise to 13% for Candida glabrata. Resistance has not been reported in the prophylactic setting.44,60,61,71 Conclusions Although the overall incidence of fungal infections in transplant recipients has declined thanks to advances in surgery, immunosuppression, infection prevention and antifungal prophylaxis, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Despite the fact that there is no consensus about optimal approaches, prophylactic strategies targeted to high-risk patients are of great importance in combination with a routine microbial surveillance programme. Echinocandins might be an attractive alternative for prophylaxis of IFI in high-risk patients because of their coverage of Candida, Aspergillus and PCP, their safety and very low nephrotoxicity and hepatotoxicity, few drug–drug interactions and low risk of drug resistance. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. Transparency declarations F. S. has received speaker honoraria and/or research grants from Novartis, Astellas, Genzyme, Gilead, Merck Sharp & Dohme, Gambro and Baxter. S. H. has received grants from Pfizer, Astellas, and Merck. P. V. has received grants for research projects from Gilead and has served as a speaker for Pfizer, Merck Sharp & Dohme, and Gilead. M. G. has none to declare.  The authors received no compensation for their contribution to the Supplement. This article was co-developed and published based on all authors’ approval. References 1 Grossi P, Farina C, Fiocchi R et al.   Prevalence and outcome of invasive fungal infections in 1,963 thoracic organ transplant recipients: a multicenter retrospective study. Italian Study Group of Fungal Infections in Thoracic Organ Transplant Recipients. Transplantation  2000; 70: 112– 6. Google Scholar PubMed  2 Munoz P, Rodriguez C, Bouza E et al.   Risk factors of invasive aspergillosis after heart transplantation: protective role of oral itraconazole prophylaxis. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Jan 1, 2018

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