International Journal of Antimicrobial Agents 44 (2014) 194–202

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Review

Antifungal prophylaxis in lung transplantation Chin Fen Neoh a,b , Greg Snell c , Bronwyn Levvey c , C. Orla Morrissey d , Kay Stewart b , David C.M. Kong b,∗ a

Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, Malaysia Centre for Medicine Use and Safety, Monash University (Parkville Campus), Melbourne, VIC, Australia Lung Transplant Service, The Alfred Hospital, Monash University, Melbourne, VIC, Australia d Department of Infectious Diseases, The Alfred Hospital, Monash University, Melbourne, VIC, Australia b c

a r t i c l e

i n f o

Article history: Received 9 May 2014 Accepted 12 May 2014 Keywords: Fungal infections Aspergillosis Prevention

a b s t r a c t Lung transplant (LTx) patients have an increased risk of developing invasive fungal infections (IFIs), particularly invasive aspergillosis. Rapid identification of the causative fungal pathogen, to allow for early administration of appropriate initial antifungal therapy, in LTx patients has been challenging due to the limited sensitivity and specificity of the diagnostic tools. Hence, there is increasing emphasis on antifungal prophylaxis in the LTx setting, given the high mortality rates and substantial cost of treating IFIs. Evidence for the optimal antifungal prophylactic approach in this setting, however, remains scant and inconsistent. This review will briefly discuss the epidemiology, risk factors, timing and clinical manifestations of fungal infections in LTx patients and will focus primarily on the available evidence related to the efficacy, safety and practicality of current prophylactic strategies in LTx recipients as well as challenges and gaps for future research. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Infectious complications following lung transplantation are common, partly due to the immunosuppressive therapy used to prevent graft rejection. According to the International Society for Heart and Lung Transplantation (ISHLT), infections are the leading cause of death, responsible for 38.4% of all deaths in the first year post-lung transplantation [1]. Although fungal infections are less common than bacterial or viral infections in lung transplant (LTx) recipients, they are associated with higher morbidity and mortality [2–4]. Approximately 15–35% of patients develop fungal infections post-LTx, with an overall mortality of nearly 60% [4]. It is vital, therefore, that LTx patients who are at risk of fungal infections should be identified early and managed appropriately. Whilst diagnostic tools for early detection of invasive fungal infections (IFIs) among LTx patients are evolving, they are not without their shortcomings. Hence, antifungal prophylactic therapy appears to be an attractive strategy for reducing the incidence of IFIs and IFIrelated mortality in this patient population. A uniform approach, however, has not been established as no randomised controlled trials (RCTs) have been conducted to investigate the optimal agent,

∗ Corresponding author. Tel.: +61 3 9903 9035; fax: +61 3 9903 9629. E-mail address: [email protected] (D.C.M. Kong).

route of administration or duration of prophylaxis in LTx recipients [5]. Accordingly, this review will provide a brief overview of the epidemiology, risk factors, timing and clinical manifestations of fungal infections in LTx patients. It will then focus on current evidence associated with antifungal prophylaxis in LTx setting, including the challenges and gaps for future research. 2. Fungal infections in lung transplant patients 2.1. Epidemiology of fungal infections At present, aspergillosis is the most common IFI (44–63%) among LTx patients [5–8], with Aspergillus fumigatus being the most common causative pathogen [6,8]. Candida infections remain the second most common causative pathogen (23–23.9%) in the LTx setting, whilst mould infections caused by Scedosporium spp. and Fusarium spp. are increasing (9.7–19.8%) [6,8]. 2.2. Risk factors for fungal infections A good understanding of the risk factors for developing fungal infection can help to identify high-risk candidates for prophylaxis during their most at-risk period. Direct exposure of the transplanted lungs to the environment, along with impaired defences due to decreased cough reflex and mucociliary clearance, increases

http://dx.doi.org/10.1016/j.ijantimicag.2014.05.013 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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the risk of invasive aspergillosis (IA) in LTx recipients [9]. Single lung transplantation [10], pre- or post-LTx airway fungal colonisation [11–14], chronic rejection [3] and cytomegalovirus (CMV) infection [15,16] are common predisposing factors for IA in LTx patients. The risk is further enhanced by hypogammaglobulinaemia [17], relative ischaemia at the anastomosis site [18] and bronchial stent placement [19]. Other risk factors include the use of high-dose corticosteroids, anti-lymphocyte therapy, renal impairment, older donor age, longer ischaemic time and use of daclizumab induction [5,20–22]. In contrast, predisposing factors for Candida infections or emerging mould infections have not been well described in the LTx setting.

outcomes. Despite recent advances in diagnostic tools, early and accurate diagnosis of fungal infections in LTx patients remains challenging given the limited sensitivity and specificity of these tools [34,44,45]. Given that fungal infections are associated with high mortality, and the treatment of IFI is often related with a significant cost burden [46], use of antifungal prophylaxis in LTx recipients is now common practice in most LTx centres. Apart from understanding the epidemiology of IFI post-LTx and identifying LTx patients who are at risk of developing IFI, it is also important to evaluate the efficacy and safety of the antifungal agent(s) prescribed for prophylaxis.

2.3. Timing of fungal infections post-lung transplant

3. Antifungal prophylaxis in lung transplant patients

Apart from the assessment of individual risk factors for each LTx patient, the relative chronology of fungal infections plays an important role in determining the use and duration of prophylactic and pre-emptive strategies. The timeline for fungal infections in LTx patients is similar to that in other solid-organ transplant recipients [23–26]. Candida spp. are responsible for most infections that occur within the first month post-transplant, due to technical and surgical complications, donor-derived infections and nosocomial risk factors [24,25]. Aspergillus infections are uncommon during this period, even in the setting of pre-transplant colonisation [27]. Fungal infection between 1 month and 6 months post-LTx is usually dominated by Aspergillus spp. [24], primarily due to intensive immunosuppression [24,25,28]. The time period beyond 6 months post-LTx is complicated by chronic rejection (i.e. bronchiolitis obliterans syndrome) resulting in the need to augment immunosuppression; thus, fungal infections due to endemic fungi [23,29] are reported. In addition, late-onset aspergillosis has been noted in elderly patients with single lung transplantation [30].

3.1. Definition of antifungal prophylactic strategies Antifungal prophylactic therapy is defined as the administration of an antifungal agent in order to prevent infection to patients who are neither infected with nor manifesting symptoms of fungal infection [47]. In the LTx setting, various terminologies (e.g. universal, pre-emptive/targeted) have been used in studies involving antifungal prophylaxis (Table 1). If antifungal prophylaxis is given to all recipients regardless of the presence of risk factors or immediately after LTx [48,49], it is known as universal prophylaxis. Alternatively, some authors advocate pre-emptive/targeted prophylaxis in LTx patients whom are at very high risk for developing IFI [50]. These high-risk LTx recipients include those with airway fungal colonisation [48,49,51], underlying cystic fibrosis [49], hyperacute rejection/acute graft failure [24], CMV infection [24] and bronchial ischaemia [24].

3.2. Evidence for and types of antifungal prophylaxis 2.4. Definitions and clinical manifestations of fungal infections The European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) updated the diagnostic criteria for IFI in 2008 [31]. The updated definitions, however, do not take into consideration the unique clinical syndromes (e.g. colonisation, tracheobronchitis/bronchial anastomotic infection) that are commonly observed in LTx patients. Furthermore, the category of possible IFI appears not to be applicable in the LTx setting [32]. As a result, a working group of the ISHLT has standardised the definitions for fungal infections related to cardiothoracic transplant recipients [32], which will allow for comparisons between studies conducted in LTx recipients. Of all Aspergillus infections, tracheobronchitis or bronchial anastomotic infections are the most common clinical syndromes (33–58%) [30,33,34], with a median time to onset of 2.7 months post-LTx [30]. The mortality rate of LTx recipients with Aspergillus tracheobronchitis or Aspergillus bronchial anastomotic infections ranges from 23.7% to 29% [7]. Approximately 5–32% of the Aspergillus infections in LTx recipients are related to invasion of the lung parenchyma [30,35,36], which then may become disseminated [30]. The median time to onset of IA in LTx recipients has increased from 5.5 months (reported in 2005) [7] to 16.1 months post-LTx (reported in 2009) [5] owing to the widespread use of antifungal prophylaxis [37]. The occurrence of invasive candidiasis remains low, with candidaemia being more common in heart–lung transplant patients, occurring within 18–36 days post-transplant [38]. The incidence of Scedosporium infections is higher in LTx recipients compared with other organ transplant patients [39] and these are mostly invasive or disseminated in nature [22,40–43]. Early diagnosis of fungal infections is important to ensure timely and appropriate antifungal treatment for improving patient

The evidence for antifungal prophylaxis in reducing the incidence and risk of IA in LTx recipients has been conflicting [4,52,53]. At present, there is no consensus among LTx centres with respect to the choice of antifungal agent, dose and duration owing to the paucity of data from multicentre RCTs evaluating the various prophylactic strategies [24]. The dearth of data has been identified as one of the possible reasons for high mortality in LTx patients [4]. As LTx recipients show significant and sustained rates of infection, antifungal prophylaxis is often thought to be desirable [54]. Consequently, well-controlled trials with clinically relevant endpoints to demonstrate the efficacy and safety of antifungal agents used prophylactically in the LTx setting are warranted. To date, 27 studies have investigated the efficacy and/or safety of antifungal prophylaxis in the LTx setting (Table 1). Most were retrospective reviews, case series, uncontrolled trials or comparisons with historical controls, with a limited number of prospective, single-centre, non-comparative studies [16,35,48,55–78]. Of the studies listed in Table 1, most were related to universal prophylaxis; only five evaluated pre-emptive/targeted antifungal prophylactic use [35,57,63,74,78] and another three compared universal prophylaxis with pre-emptive/targeted prophylaxis [48,73,76]. There have been debates regarding the most suitable type of antifungal prophylactic strategy to use in the LTx setting. Extensive use of universal prophylaxis may increase exposure to potential toxicities of the antifungal drug, the risk of drug–drug interactions, the risk of developing antifungal drug resistance and costs [79]. Conversely, pre-emptive/targeted prophylaxis may not be feasible as high-risk LTx recipients are not readily identifiable, the diagnostic tests to be used in the strategy are not well defined, and the period of vulnerability to Aspergillus infections in these patients always extends over several months [50].

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Table 1 Studies on antifungal prophylaxis in lung transplant (LTx) patients. Study (year)

Study design

Universal prophylaxis Patterson et al. Prospective, (1996) [68] single centre

Type of prophylactic strategy

Comparator 1

Comparator 2

Incidence of fungal infectiona

Incidence (type) of ADRs

Universal

Oral ITC 200–400 mg/day for 3–32 weeks (n = 12) Inhaled CAmB 5 mg t.i.d., increased to 20 mg t.i.d. within 5 days post-Tx (n = 124)c , d Oral ITC 100 mg b.d. for 3 months (n = 10)c Aerosolised CAmB 0.2 mg/kg q8h+ oral FLC 200 mg b.d. for 1–3 months (n = 52) Aerosolised ABLC 50 mg OD for 4 days, then once weekly for a total of 2 months (n = 51)c Inhaled CAmB 6 mg q8 h for 4 months, then OD for life (n = 44)

No comparator

0%b

No ADR was noted

No prophylaxis (n = 101)c , d

0.08/patient vs. 0.20/patient (P < 0.05) after the first 3 months post-Tx

7.9% (mild nausea) of patients receiving prophylaxis

No comparator

0% within the first 3 months post-Tx 0% vs. 23% (unknown P-value) within the first 3 months post-LTx 11.8% within the first 12 months post-Tx

No information

Reichenspurner et al. (1997) [69]

Retrospective, single centre

Universal

Kramer et al. (1997) [71] Calvo et al. (1999) [61]

Retrospective, single centre Prospective, single centre

Universal

Palmer et al. (2001) [67]

Prospective, single centre

Universal

Monforte et al. (2001) [16]

Retrospective, single centre

Universal

Minari et al. 2002 [65]

Retrospective, single centre

Universal

Drew et al. (2004) [62]

Prospective, randomised, double-blinded, single centre

Universal

Shitrit et al. (2005) [72] Lowry et al. (2007) [64]

Retrospective, single centre Retrospective, single centre

Universal

Borro et al. (2008) [59]

Retrospective, single centre

Universal

Hopkins et al. (2008) [56] e Cadena et al. (2009) [60]

Retrospective, single centre Retrospective, single centre

Universal

Monforte et al. (2010) [66]

Prospective, two centres

Universal

Eriksson et al. (2010) [70]

Retrospective, single centre

Universal

Universal

Universal

Universal

Aerosolised CAmB 5–10 mg b.d., then oral ITC 200 mg OD for up to 1 year (n = 81) Aerosolised CAmB 25 mg OD for 4 days, then once weekly for 7 weeks (n = 49) Oral ITC 200 mg b.d. for 6 months (n = 40)c Nebulised CAmB 10 mg b.d. for 20 days (n = 27)

No prophylaxis (n = 13)

No comparator

No prophylaxis (n = 11)

22.7% vs. 72.7% (P < 0.05) within 0.3–41.0 months post-Tx

No prophylaxis (n = 88)

4.9% vs. 18.2% (P < 0.05) within 19.2–44.4 months post-Tx 14.3% vs. 11.8% (unknown P-value) within 2 months of prophylaxis

Aerosolised ABLC 50 mg OD for 4 days, then once weekly for 7 weeks (n = 51)c No comparator Nebulised L-AmB 20 mg b.d. for 24 days (n = 20)

5% within 6 months after prophylaxis 3.7% vs. 0% (unknown P-value) within the first 2 months post-LTx 1.7% within the first 6 months post-Tx

No ADR was noted in patients receiving prophylaxis 1.6% (taste alteration, nausea, vomiting)

32% (cough), 9% (bronchospasm) and 7% (nausea) of the patients receiving prophylaxis No information

42% vs. 28% (P = 0.02) (cough, shortness of breath, taste perversion, nausea, vomiting) No ADR was noted 29.6% vs. 30% (P = 1.0) (cough, shortness of breath, bronchospasm) 6.8% (nausea, vomiting)

Aerosolised ABLC 50 mg EOD for 2 weeks, then once weekly for 13 weeks + i.v. FLC 200 mg for one dose, then oral FLC 200 mg b.d. for 3 weeks (n = 60)c Oral VRCf (n = 35)

No comparator

No comparator

37.1%b

No information

Oral VRC 200 mg b.d. for 3 months + inhaled CAmB 10 mg b.d. for first 2 weeks post-LTx (n = 35) Nebulised L-AmB 25 mg thrice weekly on the first post-Tx day and to 60 days, 25 mg once weekly from 60–180 days, and 25 mg once every 2 weeks thereafter (n = 104)c Nebulised CAmB 25 mg b.d. (n = 15) or nebulised ABLC 50 mg OD (n = 61) for 4 days, then once weekly ± i.v.CAS 50 mg OD

Oral ITC 200 mg b.d. for 3 months (n = 32)

2.9% vs. 12.5% (unknown P-value) within the first 3 months post-Tx

34% vs. 0% (P < 0.001) (drug-related hepatotoxicity)

Nebulised CAmB 6 mg q8hon the first day post-Tx and to 120 days, and then 6 mg OD for life (n = 49)

1.9% vs. 4.1% (P = 0.43) within the first 12 months post-Tx

20.2% vs. 24.5%, (cough), 7.7% vs. 8.2% (difficulty in breathing), 7.7% vs. 6.1% (nausea) (all P > 0.05)

No comparator

2.6% within the first 24 months post-Tx

3% (elevated liver enzymes) of patients receiving CAS

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Table 1 (Continued) Study (year)

Study design

Type of prophylactic strategy

Comparator 1

Comparator 2

Incidence of fungal infectiona

Incidence (type) of ADRs

Clancy et al. (2011) [58] e

Retrospective, single centre

Universal

No comparator

16%b

11% (hepatotoxicity), 14% (nausea, vomiting)

Hayes et al. (2011) [75] Tofte et al. (2012) [77]

Retrospective, single centre Retrospective, single centre

Universal

I.v. VRC 6 mg/kg/dose for two doses, then oral VRC 200 mg b.d. for 6 months (n = 304) Oral ITC 200 mg OD for 12 months (n = 41) Oral VRC 200 mg b.d. for 3 months (n = 57)c

No comparator

22% within 1–22 months post-LTx 49% vs. 45% (P = 0.73) within 0 to > 24 months post-LTxg

No ADR was noted No information

Pre-emptive/targeted prophylaxis Hamacher et al. Prospective, (1999) [63] uncontrolled, single centre

Universal

Pre-emptive

No prophylaxis (n = 82)d

Oral FLC 200–400 mg OD until cultures were negative (ca. 4 months) (n = 17) Oral ITC 200 mg b.d. for 6 months (n = 23) VRCf (n = 14)

Oral ITC 200 mg b.d. until cultures were negative (ca. 4 months) (n = 21) No comparator

0% vs. 9.5% (unknown P-value) within the first 3 months post-LTx 0%b

9.5% (seizure, temporary erectile dysfunction) of patients receiving ITC No information

No comparator

7.1%b

No information

14.3% vs. 0% (unknown P-value) (post-LTx colonisation)b 1.6% at 6 months after prophylaxis

No information

1.5% vs. 23% (P < 0.05) at 12 months post-Tx

37–60% vs. 15–41% (P = 0.005–0.07) (LFT abnormality)

8% vs. 2% (P = 0.05) within the first 2 months post-Tx 35.4% vs. 12.1% (unknown P-value) within the first 12 months post-Tx

No information

8% had Aspergillus-positive cultureb,h

100% (LFT abnormality)

Mehrad et al. (2001) [35] Wearmouth et al. (2009) [74] e Hosseini et al. (2010) [57] e

Retrospective, single centre Retrospective, single centre

Pre-emptive

Retrospective, single centre

Targeted

Oral VRC 200 mg b.d. for 96 days (n = 7)

Inhaled CAmB 20 mg b.d. for 14 days (n = 9)

Neoh et al. (2013) [78]

Retrospective, single centre

Pre-emptive

Oral VRC 200 mg b.d. for 85 days (n = 62)

No comparator

I.v. VRC 6 mg/kg/dose for two doses, then oral VRC 200 mg b.d. for a minimum of 4 months (n = 65)c ITCf (n = 176)

Oral FLC 200 mg OD for 3 months or oral ITC 200 mg b.d. ± inhaled CAmB for 4–6 months (n = 30) VRCf (n = 32)

Pre-emptive

Universal versus pre-emptive/targeted prophylaxis Universal vs. Retrospective, Husain et al. (2006) [48] single centre targeted

Mattner et al. (2006) [73] e

Prospective, single centre

Universal vs. pre-emptive

Koo et al. (2012) [76]

Retrospective, single centre

Universal vs. pre-emptive

Inhaled CAmB 25 mg b.d. or inhaled L-AmB 20 mg b.d. during initial LTx hospitalisation (n = 82)

Inhaled CAmB 25 mg b.d. or inhaled L-AmB 20 mg b.d. during initial LTx hospitalisation + i.v. MFG 100 mg OD from anaesthesia to 7–10 days post-bilateral LTx + oral FLCf or VRCf (n = 83)

No information

VRCf (n = 37)

No comparator

Unknown prophylactic strategy Retrospective, Lehneman et al. (2005) [55] e single centre

16.1% (hepatotoxicity)

No ADR was noted

ADR, adverse drug reaction; ITC, itraconazole; CAmB, conventional amphotericin B; t.i.d., three time daily; Tx, transplant; q8h, every 8 h; FLC, fluconazole; b.d., twice daily; ABLC, amphotericin B lipid complex; OD, once daily; L-AmB, liposomal amphotericin B; EOD, every other day; i.v., intravenous; VRC, voriconazole; CAS, caspofungin; LFT, liver function test; MFG, micafungin. a Including fungal tracheobronchitis, bronchial anastomotic infections and invasive fungal infections. b Timepoint for evaluating incidence of fungal infection was not specified. c Included heart–lung Tx patients: Reichenspurner et al. [69] (n = 27 for inhaled CAmB prophylaxis and n = 12 for controls); Kramer et al. [71] (n = 1); Palmer et al. [67] (n = 4); Drew et al. [62] (n = 1 for aerosolised ABLC prophylaxis); Shitrit et al. [72] (n = 5); Borro et al. [59] (n = 1); Monforte et al. [66] (n = 4 for nebulised L-AmB prophylaxis); Tofte et al. [77] (n = 1 for VRC prophylaxis);and Husain et al. [48] (n = 2 for VRC prophylaxis). d Included heart Tx patients: Reichenspurner et al. [69] (n = 75 for inhaled CAmB prophylaxis and n = 77 for controls); and Tofte et al. [77] (n = 2 for controls). e Abstracts from international conferences. f Dose, frequency, route of administration and duration of antifungal agent not specified. g Aspergillus infection including colonisation, anastomotic infection and invasive aspergillosis. h Unspecified for Aspergillus colonisation or infection.

Of those studies that compared universal prophylaxis with pre-emptive/targeted prophylaxis, universal voriconazole prophylaxis was associated with a significantly lower incidence of IFI at 1 year post-LTx than pre-emptive/targeted prophylaxis using itraconazole, with or without inhaled amphotericin B (AmB); however, higher rates of Candida colonisation and hepatotoxicity were also noted [48]. Mattner et al. [73] demonstrated that the incidence of IA decreased from 8% to 2% (P = 0.05)

with a switch from a universal prophylactic strategy with itraconazole to pre-emptive voriconazole prophylaxis in high-risk patients. Likewise, Koo et al. [76] noted a dramatic decline in IFI rates when antifungal prophylaxis targeting high-risk LTx patients was implemented, with no reported adverse drug reactions (ADRs). The difference in drug comparators, rather than the antifungal prophylactic strategies, might explain these observations.

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4. Efficacy of antifungal agents used prophylactically As noted earlier (Table 1), there is a wide variability in the choice of antifungal prophylactic agents in the LTx setting. Most studies performed in the 1990s and early 2000s evaluated the efficacy and safety of inhaled conventional amphotericin B (CAmB) alone [16,69] or in combination with fluconazole or itraconazole [61,65], and monotherapy with fluconazole or itraconazole [35,63,68,71,72,75]. Recent studies have focused on the prophylactic use of the newer agents or formulations, such as aerosolised liposomal amphotericin B (L-AmB) [64,66], aerosolised amphotericin B lipid complex (ABLC) [59,62,67], voriconazole [48,55–58,60,73,74,77,78], caspofungin [70] and micafungin [76]. 4.1. Agents used in universal prophylaxis The universal prophylactic use of aerosolised CAmB alone [16,69] or in combination with fluconazole/itraconazole [61,65] has been shown to significantly reduce the rate of fungal infections in the LTx setting compared with historical controls who did not receive any prophylaxis. Whilst the incidence of fungal infections was reported at 11.8% in two LTx centres using inhaled ABLC alone [62,67], a much lower rate (1.7%) was documented with the combination of inhaled ABLC and oral fluconazole [59]. This could be due to the synergistic effect of combination therapy, but this remains to be confirmed in prospective multicentre studies. The fact that AmB was undetected (limit of detection of analytical assay = 50 ng/mL) in all plasma samples obtained from LTx patients following administration of inhaled ABLC [67] suggests that combination therapy of an inhaled AmB formulation and a systemic antifungal agent (e.g. azole, echinocandin) may be required to provide additional protection against extrapulmonary fungal infections [67,80]. In comparison with inhaled CAmB, universal prophylaxis with aerosolised lipid formulations of AmB (e.g. L-AmB [64], ABLC [62]) was reported to be more efficacious in reducing the incidence of IFI. Neither of these studies, however, demonstrated whether or not the difference in efficacy was statistically significant. In contrast, the efficacy of nebulised L-AmB and nebulised CAmB was reported to be similar in a recent study by Monforte et al. [66]. These conflicting findings could be due to the different dosing regimens used (Table 1). The dose, frequency and duration of inhaled AmB formulations, inhaled CAmB and L-AmB in particular, vary considerably among LTx centres [16,61,62,64–66,69]. As such, the optimal dosing regimen of inhaled AmB formulations remains to be determined in a RCT, prior to comparing inhaled AmB formulations with other antifungal agents [81]. LTx patients are at high risk of acquiring Aspergillus infections; thus, azoles, which have excellent activity against mould species, are potentially the most appropriate antifungal prophylactic agents. A survey published in 2004 revealed that itraconazole was commonly prescribed both for pre- and post-LTx Aspergillus colonisation [51]. Fluconazole, which lacks anti-mould activity, was the preferred agent for post-LTx Candida colonisation [51]. In studies investigating the prophylactic use of itraconazole immediately post-LTx [68,71,72,75], the rates of fungal infection varied from 0% to 22%, with Aspergillus spp. being the common causative pathogen [63,75]. In recent years, use of voriconazole prophylaxis has been increasing (Table 1), given its superior effectiveness against Aspergillus and its demonstrated effectiveness against the emerging fungi (e.g. Scedosporium apiospermum and Scedosporium aurantiacum) that are normally resistant to AmB [82]. Husain et al. reported that universal prophylaxis with voriconazole was more efficacious in decreasing the rate of IA than pre-emptive prophylaxis with fluconazole or itraconazole, with or without inhaled CAmB, in LTx patients [48]. Cadena et al. [60] reported that universal prophylaxis

with voriconazole and inhaled CAmB afforded similar clinical effectiveness to itraconazole. In contrast, universal prophylaxis with voriconazole failed to prevent IA in one centre, with 37.1% of LTx patients subsequently developing IA despite achieving therapeutic levels [56]. Likewise, work by Tofte et al. [77] demonstrated that universal voriconazole prophylaxis did not reduce the rate of Aspergillus infections at their centre. A non-comparative study by Clancy et al. [58] reported a higher rate of IFI (16%) among 304 LTx patients receiving voriconazole prophylaxis with the same dosing regimen used by Husain et al. [48]. It is unknown whether these LTx patients had subtherapeutic plasma or tissue concentrations that might explain the observed clinical failures or higher rate of IFI. Use of intravenous (i.v.) caspofungin as a short-term prophylactic agent has also been recently reported (Table 1) [70]. Two LTx patients developed invasive pulmonary aspergillosis (one probable, one possible); however, given that inhaled CAmB or ABLC was administered prior to caspofungin prophylaxis in this study, the actual efficacy of caspofungin cannot be determined. As caspofungin is available only as an i.v. formulation, its use in the outpatient setting is limited. 4.2. Agents used in pre-emptive/targeted prophylaxis Itraconazole, fluconazole, inhaled CAmB, voriconazole and micafungin have each been administered as a pre-emptive/targeted prophylactic agent in the LTx setting (Table 1). Hamacher et al. [63] reported two cases of Aspergillus tracheobronchitis in 21 LTx patients receiving pre-emptive/targeted prophylaxis with itraconazole (200 mg twice daily), whilst no incident of fungal infection was documented in a study by Mehrad et al. [35] using the same dose of itraconazole but for a longer duration. In 2006, Mattner et al. [73] suggested that pre-emptive/targeted prophylaxis with voriconazole appeared to be superior to universal prophylaxis with itraconazole, particularly in patients with a history of preLTx Aspergillus colonisation. The efficacy of voriconazole was also highlighted in a recent study by Neoh et al. [78], suggesting that voriconazole pre-emptive prophylaxis was associated with a low rate of IFI, with only one patient (1.6%) having autopsy-confirmed IA at 6 months after initiation of prophylaxis, and the majority of LTx patients (75.8%) were cleared of their colonising isolate. Two studies, however, have reported higher rates of fungal infection (7.1–14.3%) in patients receiving pre-emptive/targeted prophylaxis with voriconazole [57,74]. Likewise, the reported higher rate of IFI could be due to the subtherapeutic plasma voriconazole levels in these LTx patients. Whilst voriconazole therapeutic drug monitoring (TDM) has a role in eradication of airway fungal colonisation and prevention of IFI in the LTx setting, this remains to be confirmed in a larger multicentre RCT [83]. Evidence related to the efficacy of pre-emptive/targeted use of voriconazole in LTx remains mixed and warrants further investigation. Use of i.v. micafungin [76] as part of a pre-emptive/targeted prophylactic strategy has also been recently reported and was associated with a lower rate of IFI. However, as inhaled CAmB or L-AmB was administered prior to, and oral fluconazole or voriconazole was given after, micafungin prophylaxis in this study, the actual efficacy of micafungin was uncertain. Its efficacy when used as the only antifungal agent still requires elucidation. 5. Safety profiles of antifungal agents used prophylactically 5.1. Inhaled amphotericin B formulations Although nebulised antifungal agents are delivered directly to the site of infection (i.e. the lung), the tolerability of these inhaled agents is a major drawback. Nausea, vomiting,

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cough, bronchospasm, shortness of breath and taste alteration are commonly reported ADRs, ranging between 1.6% and 42% [16,59,62,64,66,67,69]. No significant difference in the incidence of adverse events was reported between inhaled L-AmB and inhaled CAmB [64,66], whilst fewer ADRs were observed in LTx patients receiving aerosolised ABLC in comparison with aerosolised CAmB (P = 0.02) [62]. All three formulations were shown to be generally safe and well tolerated. The risk of nephrotoxicity is also diminished compared with the i.v. route of administration, given that insignificant plasma levels of AmB were detected in LTx patients receiving nebulised formulations [64,84]. Drug–drug interactions between these inhaled AmB formulations and other concomitant agents were not reported [66]. 5.2. Fluconazole and itraconazole No ADRs were documented in patients receiving fluconazole prophylaxis [63]. Two possibly related adverse events (i.e. seizure and temporary erectile dysfunction) were reported in patients receiving pre-emptive itraconazole prophylaxis in one study [63], whilst no ADRs were reported in other studies employing universal prophylaxis with itraconazole [68,72]. Concomitant use of itraconazole has been found to increase plasma concentrations of calcineurin inhibitors (e.g. cyclosporine, tacrolimus), leading to renal toxicity [85,86]. 5.3. Voriconazole Despite its clinical efficacy, several ADRs are associated with voriconazole, of which visual abnormality (21%) is the most frequently reported, followed by elevation in hepatic enzyme levels (15.6%) and skin rash, including photosensitivity (7%) [87]. In studies that employed voriconazole prophylaxis, the reported incidence of drug-related hepatotoxicity among LTx recipients ranged between 11% and 100% [48,55,58,60,78] and was significantly higher than in those receiving itraconazole (P < 0.001) [60]. In one study, up to 32.4% of patients discontinued voriconazole prophylaxis owing to liver function test abnormality [55]. In a recent study by Luong et al. [88], initiation of voriconazole therapy within the first 30 days of LTx was an independent predictor for developing hepatotoxicity. Drug–drug interactions between voriconazole and calcineurin inhibitors (e.g. tacrolimus) have been documented in LTx patients [89]. Emerging reports of skin squamous cell carcinoma (SCC) and melanoma associated with prolonged voriconazole therapy are also of concern. To date, three cases series [90–92] and five case reports [93–97] have reported a causal association between voriconazole exposure and SCC among immunocompromised patients, including LTx patients [91,92,97]. Miller et al. [98] reported two cases of skin melanoma associated with prolonged voriconazole use in patients with coccidioidomycosis meningitis and long-standing granulomatous disease. Long-term use of voriconazole has also been reported to increase the incidence of skin cancer and was associated with more aggressive clinical presentations of skin carcinoma in LTx patients [99]. Recent case–control and cohort studies have also reported prolonged voriconazole exposure, high cumulative voriconazole dose, and residence in locations with high levels of sun exposure to be independent risk factors for LTx patients to develop SCC [99–102]. 5.4. Caspofungin and micafungin Short-term (7–10 days) caspofungin [70] or micafungin [76] prophylaxis appears to have a favourable safety profile in the LTx setting, with only 1 of 63 LTx patients experiencing a moderate increase in liver enzymes that required discontinuation of

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caspofungin therapy [70]. In comparison with other antifungal agents, the echinocandins have fewer significant drug–drug interactions [103], and dose adjustment is not often required. Co-administration of cyclosporine has been shown to increase caspofungin concentrations [104] but the clinical relevance is uncertain [105–107]. 6. Antifungal therapeutic drug monitoring Recent reviews by Lewis [108] and Andes et al. [109] have recommended TDM for itraconazole, voriconazole and posaconazole, with relatively well-defined therapeutic and safety ranges, for antifungal prophylaxis or treatment. Whilst the correlation between plasma azole concentrations and patient outcome or toxicity remains uncertain in LTx patients, a recent survey has shown an increased trend towards the application of antifungal TDM in this setting [110]. This observation was in stark contrast to an earlier study in which only one centre reported routine monitoring of itraconazole plasma levels [49]. Voriconazole was most frequently monitored, followed by itraconazole and posaconazole [110]. This could be due to concern with the highly variable interindividual pharmacokinetic profile of voriconazole, especially in cystic fibrosis LTx patients [111], and that voriconazole is the most commonly prescribed antifungal agent in current practice [110]. Some LTx centres have reported the routine use of antifungal TDM during the prophylaxis period [110]. The role of antifungal TDM remains controversial, with limited data to support target levels in patients receiving voriconazole prophylaxis post-LTx [83,112,113]. 7. Duration of antifungal prophylaxis There is great disparity in the duration of antifungal prophylaxis among the studies reported in Table 1. The American Society of Transplantation has suggested that the duration of antifungal prophylaxis in the LTx setting should be guided by regular bronchoscopy surveillance, fungal cultures of respiratory specimens, and clinical risk factors [5]. A period of 4 months may be sufficient in the majority of patients with satisfactory airway modelling and without graft dysfunction or alveolar damage, CMV infection, enhanced immunosuppression or respiratory Aspergillus culture [22]. In elderly single LTx patients with underlying chronic obstructive pulmonary disease, a period of more than 6–8 months continuous treatment may be warranted given the reported incidence of late-onset IA [24]. In general, most LTx centres employ universal prophylaxis during the first 3 months post-LTx, after which they may use targeted prophylaxis [21]. 8. Surveys of antifungal prophylaxis in lung transplantation Current clinical practice with antifungal prophylaxis in the LTx setting has evolved primarily from case series, individual anecdotal experience and single-centre trials [24], leading to a wide diversity in antifungal prophylactic strategies among LTx centres. Four surveys have been conducted to determine practice among LTx centres [49,51,110,114]. One of these investigated clinical practice in LTx centres in North America [114]. It focused mainly on transplant patient selection issues and post-transplant management and included only three questions related to antifungal prophylaxis. Husain et al. [49] reported considerable variation in antifungal prophylactic strategies among 50 LTx centres worldwide; 69% of the centres used universal prophylaxis post-LTx, whereas 31% used pre-emptive prophylaxis for patients with pre- and/or post-transplant airway fungal colonisation. Almost all of the centres (91%) used a single agent, and the remaining centres used multiple agents. Similar results were obtained from a survey by

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Dummer et al. [51] involving 69 LTx centres in the USA. The antifungal agent(s) used and the duration of prophylaxis varied substantially from centre to centre. From the work by Dummer et al. [51] and Husain et al. [49], it is clear that clinicians believe in the value of antifungal prophylaxis in LTx patients despite the lack of rigorous clinical studies [79]. However, neither Husain et al. [49] nor Dummer et al. [51] clearly defined the terminology used in their surveys. The investigators did not explore the types of prophylaxis used at different time points (e.g. within the first 6 months and beyond 6 months posttransplantation). Husain et al. did not include some centres from Europe (e.g. France, Finland, The Netherlands and Spain), South America (e.g. Argentina), Asia (e.g. Japan) and Oceania (e.g. New Zealand) [49]; whilst Dummer et al. [51] included only centres in the USA. As such, antifungal prophylactic practice of LTx centres in many parts of the world remains unknown. As these surveys were conducted before 2003, it is likely that voriconazole and caspofungin were not available on hospital formularies during the survey period and, most certainly, posaconazole, micafungin and anidulafungin were not commercially available. Consequently, data from these surveys are unlikely to be applicable today. A recent web-based survey conducted by Neoh et al. [110] among LTx centres worldwide has provided several important insights into contemporary changes in antifungal prophylactic practice. Within the first 6 months post-LTx, the majority of sites used universal prophylaxis, with voriconazole as monotherapy or in combination with inhaled AmB being the preferred agent(s) [110]. Likewise, voriconazole was most commonly used in those centres that employed pre-emptive/targeted prophylaxis beyond 6 months post-LTx [110]. The survey showed increased use of echinocandins, posaconazole and inhaled L-AmB and a tendency towards routine TDM of antifungal drugs [110]. Most respondents indicated a desire for establishing international guidelines on antifungal prophylactic use in the LTx setting to guide prescribing [110]. These findings highlighted the need for clinical and economic data to support the use of these newer and more costly antifungal agents.

hepatotoxicity, skin SCC) associated with voriconazole therapy in LTx patients. The clinical evidence for employing posaconazole as a first-line prophylactic antifungal agent, however, remains limited; therefore, further studies to determine the efficacy and safety of posaconazole prophylaxis in LTx setting are warranted. In addition, future studies should consider investigating the clinical outcomes and cost–benefit of employing different antifungal prophylactic strategies in the LTx setting. Efforts to enhance early and accurate diagnosis of IFI are crucial for pre-emptive/targeted prophylaxis to be a practical modality, suggesting the need for future investigations to explore the benefit of combining the use of advanced diagnostic testing techniques (e.g. galactomannan and PCR) in LTx recipients. The impact of immunosuppressive agents on the risk of IFI in the LTx setting also needs to be elucidated in future studies in order to improve the clinical and survival outcomes of these patients.

9. Challenges and gaps for future research

References

The limitations associated with clinical studies (Table 1) to date have hindered interpretation of the data. A major drawback of existing studies is study design, being primarily retrospective and observational in nature [16,35,48,55–60,64,65,69–72,74–78]. Confounding factors (e.g. degree of immunosuppression, rejection, use of advanced diagnostic testing for IFI, clinical characteristics of LTx patients), which can impact on the rate of fungal infection, have been difficult to exclude in the analysis. Because these studies were conducted over long time periods and were compared with historical controls from different chronological periods [16,61,65,69,77], it is difficult to estimate the true benefits of antifungal prophylaxis. It is noteworthy that the risk of IFI varies with the time point postLTx; however, most studies did not take into account the different time-dependent risks of IFI following LTx. All except three studies [58,69,73] have a relatively small sample size. Wide variations in dosing regimens, different time points used to determine efficacy, and different definitions for IFI have yielded conflicting results and limited direct comparisons. Therefore, well-designed RCTs that address these considerations are needed to facilitate informed decisions with respect to the use of these antifungal prophylactic agents in LTx settings. With a view to optimising the use of voriconazole in prophylaxis, antifungal TDM would be beneficial in exploring the relationship between drug levels and clinical outcomes or adverse events in LTx recipients. A recent survey [110] has noted the increasing use of posaconazole, mainly due to the significant ADR (i.e.

10. Conclusions Increasing emphasis has been placed on antifungal prophylaxis given the high mortality from IFI among LTx patients. A uniform approach on the optimal agent, dose, frequency, route of administration, type and duration of antifungal prophylaxis in LTx recipients, however, has not been established. Despite the lack of RCTs, the majority of existing studies suggested that antifungal prophylaxis can reduce the incidence and risk of IA among LTx recipients, with tolerable ADRs. Larger multicentre RCTs in this setting are anticipated. Funding: No funding sources. Competing interests: COM has sat on advisory boards for, received investigator-initiated grant support from and given lectures for Gilead Sciences, Pfizer, Merck, Schering-Plough and Orphan Australia; DCMK has sat on advisory boards for Pfizer and receives financial support from Pfizer, Roche, Novartis, Merck and Gilead Sciences. All other authors declare no competing interests. Ethical approval: Not required.

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