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Antifungal Prophylaxis in Lung Transplant Recipients

Patel, Twisha S. PharmD; Eschenauer, Gregory A. PharmD; Stuckey, Linda J. PharmD; Carver, Peggy L. PharmD

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doi: 10.1097/TP.0000000000001050
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Invasive fungal infections (IFIs), which manifest as invasive pulmonary disease, disseminated disease, tracheobronchitis, or fungemia, are a major postlung transplantation complication and are associated with poor clinical outcomes, with mortality historically ranging from 23% to 29% in patients with tracheobronchitis and up to 82% in patients with invasive pulmonary disease.1-4 More recent evidence suggests 3-month mortality of 21.7% in lung transplant recipients who developed invasive mold infections.5 Lung transplant recipients are at exceptionally high risk for developing fungal infections, with a reported cumulative incidence of IFIs of 8.6% in the first year after lung or heart-lung transplantation, despite the use of prophylactic regimens at most institutions.3,6 The most common cause of infection is Aspergillus spp, with an incidence as high as 40.5 cases per 1 000 patient-years.7 Recent analysis of surveillance data confirms the predominance of Aspergillus spp. as the most common pathogen with a reported 4.13% 12-month cumulative incidence of invasive Aspergillosis (IA).5

Given the negative impact of IFIs on survival and clinical outcomes, preventing their development is increasingly important. However, consensus on the choice of antifungal agent(s), route of administration, and duration of prophylaxis has not been established.8,9 This review will provide an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluate the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offer recommendations and opportunities for future research.

EPIDEMIOLOGY AND RISK FACTORS

Common Pathogens

In lung transplant recipients, the majority of IFIs are due to Aspergillus (44%), Candida (23%), other molds (19.8%), Mucorales (3%), Cryptococcus (2%), and endemic mycoses (1%), such as Histoplasma, Blastomyces, and Coccidioides.3,10-12 Of the 12.2% of lung transplant recipients that developed invasive mold infections in a recent 5-year surveillance study, 72.7% had Aspergillus infections whereas 3.5% had Scedosporium and 2.1% had Mucorales.5 Of Aspergillus spp., A. fumigatus and A. flavus are the most commonly isolated.5,13 Rarely, donor-derived endemic fungal infections have been described.14

Invasive Aspergillus infections occur most commonly within 1 year posttransplantation, but can occur (infrequently) up to 3 years posttransplantation.3,10,15,16Aspergillus ulcerative tracheobronchitis or bronchial anastomotic infections generally occur within the first 3 months posttransplantation, whereas invasive pulmonary disease and disseminated Aspergillosis, which are observed in up to 20% of patients, generally present longer than 3 months posttransplantation.15 The time to onset of IA is shortest (0.7 months) after heart-lung transplantation and is significantly longer (5 and 3 months, respectively) for individuals undergoing bilateral versus single lung transplantation.10 In recent years, the time to onset of IA appears to have shifted, perhaps due to more widespread use of routine antifungal prophylaxis or changes in the agents used. In 2 recent large, multicenter studies of lung transplant patients followed during 2001 to 2006 and 2004 to 2007, the time to diagnosis of IA after transplantation was a median of 184 versus 504 days, respectively.3,16

Risk Factors

Table 1 describes independent risk factors that have been evaluated for the development of early-onset (≤1 year) IA postlung transplantation in adult patients; these include airway ischemia,19 posttransplantation colonization with Aspergillus spp,17,18,20,21 the use of daclizumab versus polyclonal induction,19 and increased donor age.19 Several risk factors remain controversial: for example, 2 groups21,22 identified the presence of cytomegalovirus infection or viremia as a risk factor, whereas another group20 did not. Similarly, Cahill et al17 identified the use of a single (versus double) lung transplantation as an independent risk factor for Aspergillus colonization posttransplantation, whereas 2 other groups19,20 did not. Although additional risk factors have been suggested, including the development of intraoperative anastomotic complications, acquired hypogammaglobulinemia (IgG < 400), the presence of bronchiolitis obliterans, stenting, and environmental exposures, such as construction work, gardening, or camping, many of these studies used inadequate controls or inappropriate statistical methodology to identify at-risk populations.18,23-29 Additional risk factors have yet to be identified, particularly for patients at risk for late-onset infections.18

TABLE 1
TABLE 1:
Evaluation of independent risk factors for the development of Aspergillosis in adult lung transplant recipients

In patients with cystic fibrosis (CF), infections often involve the bronchial anastomosis and occur early (<60 days) postoperatively. The risk of postoperative Aspergillosis is higher in CF patients colonized pretransplantation, in those with positive intraoperative cultures for Aspergillus (odds ratio, 4.36; 95% confidence interval [95% CI], 1.35-14.05; P = 0.01), and in those undergoing treatment for acute cellular rejection within 90 days postoperatively (odds ratio, 3.53; 95% CI, 1.03-12.15; P = 0.05).23,30

EFFICACY OF ANTIFUNGAL PROPHYLAXIS REGIMENS

Limitations of currently available data evaluating the efficacy of antifungal prophylaxis strategies include lack of prospective, randomized clinical trial data, and the variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. Of the available studies, all are single center, with the exception of Monforte et al,31 which included 2 centers. Most are retrospective7,20,22,32-45 and noncomparative.22,33,34,36,38,39,42-48 Of comparative trials,7,20,31-33,35,37,40,41,45,49,50 all used a nonrandomized, sequential design, with the exception of Drew et al.51 Although the majority of studies evaluated inhaled formulations of amphotericin B alone,7,22,31,35,47,51 in combination with,20,40,43 or as compared with other antifungals,22,36,37,40,51 universal or targeted20,50 prophylaxis with oral administration of fluconazole,20,36,40,49 itraconazole,20,33,34,37,38,44-46,50 voriconazole,20,37,40-42,48,50 echinocandin,40,43 or no prophylaxis7,31,32,39,41,49 have also been assessed. Key published studies evaluating the efficacy of antifungal prophylaxis in lung transplant recipients are summarized in Table 2.7,15,20,22,31,33-49,51

TABLE 2
TABLE 2:
Studies evaluating the efficacy of antifungal prophylaxis in lung transplant recipients

Although inhaled formulations of amphotericin B remain the most widely studied agent for antifungal prophylaxis, their optimal dosages, formulations, and durations of therapy remain unknown.52-54 In pharmacokinetic studies performed in lung transplant recipients, inhaled deoxycholate amphotericin B achieves high concentrations in the lower airways of transplanted lungs, but concentrations at the bronchial anastomosis and in native lungs (in the case of single-lung transplant) are lower.55 Most available studies have used daily administration of inhaled amphotericin B.22,31,32,35,37,40,47,49,51 Daily administration for short periods of time (4-14 days) followed by once weekly or every other week administration for 1 to 3 months has also proved successful.36,43,47,51 The concentrations of inhaled amphotericin B lipid complex (measured in epithelial lining fluid) and inhaled liposomal amphotericin B (in bronchoalveolar lavage aliquots) remain above typical minimum inhibitory concentrations of Aspergillus for at least 7 days, enabling once-weekly administration.56,57 However, this route of administration does not protect against extrapulmonary infections, in particular, early postoperative pleural space infection due to Candida.58 In several early studies, administration of inhaled deoxycholate amphotericin B resulted in a decreased incidence of IA as compared with no prophylaxis.7,32 The results of several comparative studies of inhaled formulations of amphotericin B suggest a lack of significant differences between the deoxycholate and lipid formulations in reducing the incidence of IA, when used as single agents.31,35,51,52

Although the role of fluconazole appears limited, due to its lack of activity against Aspergillus, the role of several newer azoles with activity against Aspergillus has been explored. Although itraconazole20,33,34,37,38,44-46,50 and voriconazole,20,37,40,41,48,50 have proved effective in comparative trials, neither has achieved superiority against comparator agents in the reduction of IFIs.37,40,48,50,52 In addition, long-term use of itraconazole and voriconazole is not optimal due to unpredictable pharmacokinetics,33,48 drug-drug interactions via cytochrome P450 enzyme system inhibition,59 and adverse effects (described below).20,37

Current data suggest that flaws exist with all currently studied prophylactic strategies. Universal prophylaxis is less optimal because it could result in patients receiving toxic therapy that are not at significant risk of infection, in addition to the collateral damage of potentially unnecessary antifungal use.39 Targeted prophylactic approaches, aimed at patients with significant risk factors for infection, are limited by the paucity of studies identifying specific risk factors other than Aspergillus colonization.17,18,20,21 A preemptive approach, defined as the institution of therapy when colonization with Aspergillus is noted, assumes that colonization is the only significant risk factor for infection.15,40,42,46

A recent meta-analysis pooled the available data regarding the efficacy of antifungal prophylaxis to prevent the development of IA. Overall, there was no significant difference in the rate of IA when pooling 3 studies that compared universal and no-prophylaxis strategies: 19 of 235 patients (8.1 %) and 28 of 196 patients (14.3 %) developed IA in the universal and no-prophylaxis arms, respectively (relative risk, 0.36; 95% CI, 0.05-2.62). On indirect analysis of studies which assessed universal prophylaxis strategies, the rates of IA in each arm were 12% (no prophylaxis), 5.3% (inhaled amphotericin B deoxycholate), 2.2% (inhaled lipid formulation of amphotericin B), 10% (itraconazole), and 4.4% (voriconazole). The use of inhaled lipid formulations of amphotericin B was as advantageous in reducing the incidence of IA as compared with no prophylaxis (P = 0.02). The heterogeneity of the studies included in this meta-analysis limited the conclusions that could be made.52

Despite the lack of a clearly defined optimal prophylactic agent, most adult lung transplantation centers use antifungal prophylaxis and treat Aspergillus airway colonization, although not in all patients, and there are substantial variations in clinical practice between centers. Based on data from surveys published in 2004, 2011, and 2015 of centers using prophylaxis, the preferred agent has shifted from itraconazole to inhaled amphotericin B and most recently, to voriconazole, alone or in combination with inhaled amphotericin B.9 Prophylactic regimens are used for widely variable periods of time; with 30% to 40% of centers using prophylaxis for up to 6 months, and 30% to 40% for 12 months or longer. Many centers use preemptive or targeted (to high risk) therapy, usually based on preoperative (for CF patients) or postoperative colonization with Aspergillus spp.6,9 Therapeutic drug monitoring of itraconazole and voriconazole is currently used in 26% of adult and 86% of adult and pediatric centers, respectively.9,60 In pediatric lung transplant centers, the most commonly used regimens are monotherapy with either voriconazole or inhaled amphotericin, with alternative antifungals generally reserved for patients who are intolerant, or who experience toxicity or positive surveillance cultures.60

TOXICITIES OF ANTIFUNGAL AGENTS STUDIED FOR PROPHYLAXIS

Inhaled formulations of amphotericin B are associated with cough, shortness of breath, bronchospasm, wheezing, and nausea, which may result in poor adherence or early discontinuation of therapy. Systemic absorption of inhaled amphotericin B is minimal.57,61 A recent meta-analysis of available studies was unable to compare adverse events of the inhaled deoxycholate and lipid formulations of amphotericin, due to nonuniform reporting of data; however, discontinuation rates due to adverse effects were similar between formulations.31,35,51,52

Regarding the azole antifungals, fluconazole is very well tolerated. All azoles can cause hepatotoxicity,62 but the risk is greatest with itraconazole and voriconazole,63 and hepatotoxicity is more common with voriconazole than itraconazole in lung transplant recipients.52,64 Voriconazole is uniquely associated with visual disturbances62 and hallucinations, both of which are associated with high doses.65 Itraconazole oral solution is associated with significant gastrointestinal disturbances.62 Long-term use of triazoles has been associated with the development of peripheral neuropathies (itraconazole, voriconazole, and posaconazole) and alopecia (fluconazole and voriconazole).64 In addition, voriconazole has been associated with the development of periostitis and exostoses, as well as phototoxicity with an associated development of squamous cell carcinomas (SCC).66-72 The time to development of periostitis in lung transplant patients treated with voriconazole ranges from 9 months to 3 years.70-72 Unfortunately, neither plasma voriconazole or fluoride concentrations nor serum creatinine serve as good markers for the development of this adverse effect, which appears to be related to the duration of exposure versus the plasma drug concentrations of fluoride or voriconazole.

The development of SCC is related to the duration of exposure to voriconazole and the development of skin lesions with continued sun exposure.66-68 However, transplant patients appear to have a higher frequency and shorter time to development of SCC than nontransplant recipients.73 In lung transplant patients, additional risk factors for the development of SCC have been identified, including the presence of Fitzpatrick skin type V/VI, time since transplantation, a longer duration of voriconazole therapy, older age at transplant, a history of skin cancer before transplantation, and residence in geographic regions with higher sun exposure.68,73 Fortunately, in the majority of patients, discontinuation of voriconazole generally results in rapid improvement of lesions; thus, prospective monitoring of patients is advised.

FUTURE DIRECTIONS

Data regarding the use of various antifungal agents for prophylaxis in lung transplant recipients are limited, and thus, an ideal agent has yet to be identified. Posaconazole is an extended-spectrum triazole that has activity against Candida, Aspergillus, endemic mycoses, and the Mucorales. A prospective study conducted in lung transplant recipients evaluated the plasma and intrapulmonary concentrations of the immediate-release formulation of posaconazole. The mean concentrations of posaconazole in the plasma, pulmonary epithelial lining fluid, and alveolar cells were maintained above the MIC90 for Aspergillus spp.74 Because posaconazole can achieve adequate concentrations at the most common site of infection, it may be an effective prophylactic agent in lung transplant recipients. Although the broad antifungal spectrum and improved bioavailability of the newer extended-release tablet formulation of posaconazole (allowing once daily dosing) make this agent an appealing (but costly) potential option for prophylaxis in lung transplant recipients, there are currently no studies evaluating its efficacy in this setting. Nevertheless, 2 recent surveys noted that some centers are using posaconazole (as monotherapy or in combination with inhaled lipid amphotericin B), both within and after the first 6 months posttransplantation, in patients intolerant to voriconazole.6,9,40,75

Limited data are available to evaluate the prophylactic use of echinocandins in lung transplant recipients, although 2 recent surveys note its use as first-line prophylaxis in some centers, as monotherapy or in combination with intravenous lipid amphotericin B.6,9 A prospective study evaluated the pharmacokinetics and pharmacodynamics of intravenous micafungin in this patient population. Mean drug concentrations were maintained above the MIC90 for A. fumigatus in plasma, pulmonary epithelial lining fluid, and alveolar cells.76 Despite their favorable spectrum of activity and drug interaction and adverse effect profile, the lack of oral bioavailability of echinocandins is likely to limit their use to bridging therapy in patients unable to tolerate oral medications, or in those intolerant to other agents. Nonetheless, these agents may be useful as part of a combination regimen for initial antifungal prophylaxis and in patients who cannot tolerate azole therapy.

Isavuconazole is a new broad-spectrum triazole antifungal agent with a spectrum of activity similar to that of posaconazole, and a drug interaction profile similar to that of fluconazole or itraconazole. Because it is well tolerated, available in both oral and intravenous formulations, further investigation is warranted to determine the possible role of isavuconazole in prophylaxis.77

The potential role of alternative routes of administration of antifungal agents continues to be investigated. An in vitro study evaluated the properties of aerosolized micafungin using various nebulization systems. Results from this study are promising and illustrate that nebulizers can be used to effectively deliver micafungin to the lungs.78 However, clinical data supporting inhaled micafungin are lacking. In a murine model of invasive pulmonary Aspergillosis, prophylaxis with nebulized voriconazole appeared to be an effective form of drug delivery directly to the lungs. Although the results of this study postulate an intriguing new alternative to traditional routes of voriconazole administration, additional studies are necessary to determine the effectiveness of this strategy as a means for prophylaxis and tolerability.79

RECOMMENDATIONS AND CONCLUSIONS

Invasive Aspergillosis is a significant contributor to morbidity and mortality within the first year after lung transplantation. Thus, antifungal prophylaxis is a potentially lifesaving intervention and should be considered in all lung transplant recipients. Unfortunately, data evaluating the efficacy of the various antifungal agents for prophylaxis against invasive infections are limited.

Ideally, large prospective, randomized clinical trials are needed to determine the optimal antifungal agent, dose, and duration for prophylaxis in lung transplant recipients. If such funding is not available, alternative study designs should be explored. One suggestion would be to compare outcomes between centers with different prophylactic strategies in a prospective, observational design, using propensity scoring or logistic regression to control for confounders.

Until more data are available, it is impossible to develop an evidence-based, comprehensive set of recommendations for all centers and patients. As such, the following recommendation is an attempt to interpret the data in the context of our own experience. Because the meta-analysis by Bhaskaran et al52 suggests that universal prophylaxis may be optimal, we endorse this approach until more rigorous data are available to demonstrate the efficacy and feasibility of targeted and preemptive approaches. The optimal duration of prophylaxis is unknown and may need to be individualized by center or even by individual by considering induction and maintenance immunosuppression strategies and the need for augmented immunosuppression.

Given the concern for extrapulmonary Candida infections in the early postoperative period, perhaps a combination of strategies, with universal systemic prophylaxis with itraconazole or voriconazole in the early postoperative period (until the anastomosis is healed, and there are no further surgical complications) followed by inhaled lipid amphotericin B once weekly, is reasonable. Use of an inhaled lipid formulation of amphotericin B, which enables weekly administration as an outpatient and spares the toxicity and interaction concerns with prolonged azole prophylaxis, should be considered for the remaining period of prophylaxis.

Once prophylaxis is complete, a preemptive strategy of reinitiation of inhaled therapy in patients who are colonized with Aspergillus or in whom risk factors for infection (eg, enhanced immunosuppression) present in the first year posttransplant is likely warranted, as posttransplantation Aspergillus colonization has been consistently found to be an independent risk factor for invasive infection.17,18,20,21 The availability of new agents and new delivery mechanisms may enable the funding of systematic comparative trials.

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