Abstract
Background
Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients.
Methods
A single-center, retrospective study of patients who received isavuconazole (September 2015–February 2018) or voriconazole (September 2013–September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria.
Results
Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005).
Conclusions
Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.
Keywords: lung transplantation, invasive fungal infection, antifungal prophylaxis, voriconazole, isavuconazole
Isavuconazole was as effective as and better tolerated than voriconazole in preventing invasive fungal infections (IFIs) after lung transplantation. Breakthrough IFIs occurred in 3% of patients receiving isavuconazole or voriconazole prophylaxis. IFIs were associated with increased mortality and longer hospitalizations.
Lung transplant recipients are at high risk of invasive fungal infection (IFI), especially early after transplant [1–4]. In the Transplant-Associated Infection Surveillance Network (TRANSNET) of 11 US transplant centers, the cumulative incidence of IFI in the first year following lung transplant was 8.6% [5]. Invasive aspergillosis, non-Aspergillus invasive mold infections, and invasive candidiasis accounted for 44%, 23%, and 23% of post–lung transplant IFIs in TRANSNET, respectively. Mortality rates among lung transplant recipients with IFI ranged from 40% to 82% [3, 4, 6–8].
Guidelines recommend a variety of antifungal prophylaxis strategies for lung transplant recipients [9–11]. A survey of 44 US centers found that 97.5% of lung transplant programs used posttransplant antifungal prophylaxis, including universal (ie, administered to all patients) or targeted/preemptive strategies at 90% and 7.5% of centers, respectively [12]. The most common universal regimens were systemic antifungals (usually azole derivatives) combined with inhaled amphotericin B (iAmB). A recent meta-analysis concluded that universal antifungal prophylaxis reduces the incidence of invasive aspergillosis after lung transplant [13]. There have not been any randomized comparative trials of different antifungal prophylaxis regimens in lung transplant recipients.
Universal voriconazole prophylaxis was established as the standard following lung transplant at our center in 2005. Inhaled amphotericin B was used as adjunctive prophylaxis at clinicians’ discretion. In September 2015, we experienced a cluster of mucormycosis cases among solid-organ transplant recipients. Isavuconazole, which demonstrates in vitro activity against several Mucorales species, was initiated as universal prophylaxis in organ transplant recipients instead of voriconazole, which lacks Mucorales activity. Adjunctive iAmB was recommended for all patients. The objective of this study was to compare the effectiveness, safety, and tolerability of isavuconazole and voriconazole in preventing IFIs in lung transplant recipients.
METHODS
We conducted a retrospective study at a single center. Inclusion criteria included all adults (≥18 years old) who underwent lung transplantation between 1 September 2013 and 28 February 2018 and received either isavuconazole or voriconazole for prophylaxis for 5 days or more. Voriconazole and isavuconazole groups comprised patients who underwent transplantation between September 2013 and September 2015 and between September 2015 and February 2018, respectively. We reviewed patients’ electronic medical records and the transplant database for pretransplant and up to 1 year posttransplant data (Supplementary Material 1). The study was reviewed and approved by the University of Pittsburgh Institutional Review Board.
Standard immunosuppression consisted of preoperative methylprednisolone, intraoperative alemtuzumab or basiliximab, and postoperative tacrolimus, mycophenolate, and prednisone (Supplementary Material 2). Alemtuzumab induction was part of our “steroid-sparing” immunosuppression regimen, with which patients were maintained on prednisone 5 mg and mycophenolate 1.5 g daily. Basiliximab induction was followed by tapering doses of methylprednisolone and then prednisone 20 mg daily, along with mycophenolate 2 g daily. The standard duration of antifungal prophylaxis was 3 and 4 months for patients receiving basiliximab and alemtuzumab induction, respectively. Other standard institutional transplant protocols are summarized in Supplementary Material 2.
Definitions
Invasive fungal infection was defined as proven or probable according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and Mycoses Study Group (EORTC/MSG) criteria [14, 15]. No patients had possible IFI by these criteria. Breakthrough infection was defined as IFI occurring while on isavuconazole or voriconazole prophylaxis or within 7 days following discontinuation of prophylaxis. Premature discontinuation of an antifungal was defined as stopping an agent within 90 days of transplant.
Statistical Analysis
Effectiveness in preventing IFI was determined using an intention-to-treat approach, including data from all patients fulfilling the inclusion criteria. The primary outcome was development of breakthrough IFI (bIFI) while on isavuconazole or voriconazole. Secondary outcomes were IFI at 6 and 12 months and adverse events requiring premature discontinuation of prophylaxis. Data analyses were conducted using Stata, version 15 (StataCorp), and GraphPad Prism, version 8.0 (GraphPad Software). For the assessment of risk factors for IFI, patients with proven or probable IFI were compared with those with no IFI. Comparisons between 2 groups were performed by Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Variables significant by univariate analysis (P ≤ .05) were entered into a multivariate logistic regression model with bootstrapping to determine independent risk factors for IFI. Kaplan-Meier curves were used to estimate IFI-free and overall survival, and log-rank test was used to compare curves between groups. Significance was defined as P ≤ .05 (2-tailed).
RESULTS
Demographics
During the study period, 320 patients underwent lung transplantation. Twenty patients were excluded (Figure 1). Among the remaining 300 patients, 49% (144/300) and 51% (156/300) received isavuconazole and voriconazole, respectively (Table 1), for median durations of 3.4 and 3.1 months, respectively. There were no significant differences in demographic or clinical characteristics between the groups, except that more patients treated with isavuconazole received extracorporeal membrane oxygenation (ECMO; P = .01) posttransplant. All patients treated with isavuconazole and 44% (69/156) of patients treated with voriconazole received adjunctive iAmB. There were no significant differences in demographics or clinical data among patients who received voriconazole with or without iAmB.
Figure 1.
Description of patients included and excluded in this study. Inclusion criteria included all adults (≥18 years) who underwent lung transplantation between 1 September 2013 and 28 February 2018 and received either isavuconazole or voriconazole for prophylaxis for ≥5 days. Exclusion criteria included those (1) receiving no or another antifungal (outside of isavuconazole and voriconazole) for prophylaxis, (2) receiving <5 days of prophylaxis, (3) death within 1 month of transplant due to a non-IFI-related cause, and (4) evidence of IFI in the lung allograft at the time of transplant. Abbreviation: IFI, invasive fungal infection.
Table 1.
Demographic and Baseline Characteristics of Lung Transplant Recipients Receiving Isavuconazole or Voriconazole Prophylaxis
| Isavuconazole (n = 144) | Voriconazole (n = 156) | P | |
|---|---|---|---|
| Recipient demographics | |||
| Age at transplant, median (IQR), years | 58 (20–72) | 60 (24–76) | .22 |
| Male sex, % (n) | 57 (82) | 58 (90) | .91 |
| African-American,a % (n/N) | 6 (8/142) | 6 (10/155) | .81 |
| Malignancy pretransplant, % (n) | 15 (2) | 11 (13) | .10 |
| Diabetes mellitus, % (n) | 5 (7) | 5 (8) | 1.0 |
| Underlying lung diseases, % (n) | |||
| Cystic fibrosis | 13 (19) | 15 (24) | |
| COPD/emphysema | 28 (41) | 28 (44) | |
| IPF | 33 (48) | 22 (34) | |
| Rheumatologic disorders | 20 (29) | 13 (20) | |
| Others | 12 (17) | 15 (24) | |
| Pretransplant conditions | |||
| BMI, median (IQR), in kg/m2 | 24 (15–35) | 25 (16–36) | .06 |
| Lung allocation score, median (IQR) | 46 (32–91) | 50 (32–95) | .29 |
| Requirement for mechanical ventilation pretransplant, % (n) | 12 (18) | 12 (18) | .86 |
| Requirement for ECMO, % (n) | 10 (14) | 8 (12) | .55 |
| Mold colonization of the respiratory tract, % (n) | 6 (19) | 3 (5) | .28 |
| Donor factors | |||
| Donor age, median (IQR), years | 36 (13–64) | 33 (8–62) | .09 |
| Male donor, % (n) | 48 (69) | 52 (81) | .56 |
| Donor weight, median (range), kg | 73 (43–126) | 74 (35–135) | .72 |
| PHS increased risk donor, % (n) | 27 (39) | 26 (40) | .79 |
| Transplant factors, % (n) | |||
| Re-transplantation | 2 (3) | 2 (3) | 1.0 |
| CMV mismatch | 27 (39) | 28 (43) | 1.0 |
| Alemtuzumab induction | 83 (120) | 81 (126) | .30 |
| Double lung transplant | 83 (120) | 81 (126) | .65 |
| Mold-positive respiratory culture at transplant (recipient or donor) | 3 (4) | 3 (4) | 1.0 |
| Posttransplant factors, % (n) | |||
| Requirement for ECMO | 20 (29) | 10 (15) | .014 |
| Renal replacement therapy | 10 (15) | 11 (18) | .85 |
| Bronchial necrosis extending > 2cm from anastomosis | 5 (7) | 4 (6) | .78 |
Abbreviations: BMI, body mass index; CMV, cytomegalovirus; CMV serology mismatch (donor-positive/recipient-negative); COPD, chronic obstructive pulmonary disease; CRRT, chronic renal replacement therapy; ECMO, extracorporeal membrane oxygenation; IPF, idiopathic pulmonary fibrosis; IQR, interquartile range; PHS, US Public Health Service.
aRace of 3 patients was not stated.
Invasive Fungal Infections
The IFI rate was 6% (17/300) at 6 months and 8% (23/300) at 1 year. The incidence of mold and yeast infection was 5% (16/300) and 2% (7/300), respectively (Figure 2 and Table 2). Yeast infections were exclusively observed within the first 6 months after transplant. Mucormycosis was diagnosed in a single patient, who received voriconazole.
Figure 2.
Cumulative incidence of IFIs and receipt of antifungal prophylaxis. The figure depicts the 1-year cumulative incidence rate of IFI, stratified by invasive yeast and invasive mold infections. The cumulative incidence of mold infections was higher than that of yeast infections at all time points. Abbreviation: IFI, invasive fungal infection.
Table 2.
Pathogens Recovered From Lung Transplant Recipients With Invasive Fungal Infections
| Breakthrough IFI | Non–breakthrough IFI | |||
|---|---|---|---|---|
| Isavuconazole (n = 5) | Voriconazole (n = 5) | Isavuconazole (n = 5) | Voriconazole (n = 8) | |
| Yeasts (n = 7) | Candida glabrata candidemia (n = 2, proven); one also had chest-wall infection | Candida glabrata and C. parapsilosis chest-wall infection (n = 1, proven) | Candida glabrata and C. dubliniensis pyelonephritis (n = 1, proven) | Candida glabrata and C. albicans chest-wall infection (n = 1, proven) |
| Candida tropicalis fungemia (n = 1, proven) | ||||
| Saccharomyces cerevisiae intra-abdominal infection (n = 1, proven) | ||||
| Molds (n = 16) | Aspergillus fumigatus invasive endobronchial infection and pneumonia (n = 1, proven) | Aspergillus fumigatus chest-wall infection (n = 1, proven) | Fusarium endobronchial infection (n = 1, proven) and disseminated infection (n = 1, probable) | Aspergillus fumigatus pneumonia (n = 2, both probable) |
| Cladophialophora endobronchial infection (n = 1, probable) | Aspergillus niger chest-wall infection (n = 1, proven) | Aspergillus fumigatus pneumonia (n = 2, 1 proven, 1 probable) | Aspergillus terreus invasive endobronchial infection (n = 1, proven) and pneumonia (n = 1, probable) | |
| Biopsy-proven, culture-negative invasive endobronchial infection (n = 1, proven) | Rhizopus microsporus empyema (n = 1, proven) | Aspergillus lentulus pneumonia (n = 1, proven) | ||
| Cladosporium pneumonia (n = 1, probable) | ||||
Abbreviation: IFI, invasive fungal infection.
There were no differences in IFI rates between isavuconazole and voriconazole groups (7% [10/144] and 8% [13/156], respectively; P = .7) or in time to IFI between the groups (P = .99) (Figure 3).
Figure 3.
IFI-free survival for patients receiving isavuconazole or voriconazole prophylaxis. There was no significant difference in IFI-free survival between the isavuconazole and voriconazole groups (P = .99, log-rank test). Abbreviation: IFI, invasive fungal infection.
Breakthrough Invasive Fungal Infection
Three percent (10/300) of patients developed bIFIs, which were evenly distributed in isavuconazole (5/144) and voriconazole (5/156) groups (P = 1.0) (Table 3). Seventy percent (7/10) of bIFIs were due to molds and 30% (3/10) were due to yeasts. There were no significant differences in rates of bIFIs or breakthrough invasive mold infections (bIMIs) among patients receiving voriconazole with or without iAmB (P = .63 and .26, respectively) or among those receiving iAmB with either isavuconazole or voriconazole (P = .43 and .31, respectively) (Table 4, footnote f).
Table 3.
Breakthrough Invasive Fungal Infections During Isavuconazole or Voriconazole Prophylaxis
| Patient | Age (years); Sex; Underlying Disease; Induction Agent | Presumed Risk Factors for IFIa | Onset of IFI (days posttransplant) | Type of Breakthrough IFI | Breakthrough Fungal Organism | MIC, µg/mL | Trough Level, µg/mL | Outcome at 1 Year; Days to Death From Transplant; Cause of Death |
|---|---|---|---|---|---|---|---|---|
| Isavuconazole | ||||||||
| I1 | 43; woman; scleroderma; alemtuzumab | Prolonged ICU stay with indwelling vascular catheters; multiple antibiotics; steroid pulse for ACR 6 days prior to IFI diagnosis | 172b | Candidemia (proven) | Candida glabrata | 4 | 1.6 | Died; 182 days; fungal infection |
| I2 | 65; woman; COPD; basiliximab | Steroid pulse for ACR 44 days prior to IFI diagnosis | 65 | Chest-wall infection and candidemia (proven) | C. glabrata | 4 | 1.6 | Alive |
| I3 | 52; man; chronic GvHD; basiliximab | Extensive bronchial necrosis; steroid pulse for ACR 29 days prior to IFI diagnosis | 176c | Endobronchial infection (probable)d | Cladophialophora boppi | 1 | 1.7 | Alive |
| I4 | 55; woman; cystic fibrosis; basiliximab | Positive culture pretransplant; extensive bronchial wall necrosis | 16 | Invasive tracheobronchitis and pneumonia (proven) | Aspergillus fumigatus | 1 | 0.7 | Died; 219 days; thoracic graft failure due to fungal infection |
| I5 | 52; man; IPF; basiliximab | Positive donor culture for mold | 15 | Tracheobronchitis (proven) | Culture negative | Not applicable | Not done | Alive |
| Voriconazole | ||||||||
| V1 | 24; woman; cystic fibrosis; alemtuzumab | Hemodialysis | 36 | Chest-wall infection and surrounding soft tissue (proven) | C. glabrata C. parapsilosis | 4 0.03 | Not done | Alive |
| V2 | 36; woman; mixed CTD; basiliximab | Positive recipient’s culture for A. fumigatus during transplant | 12 | Chest-wall infection (proven) | A. fumigatus | 0.5 | 0.7 | Alive |
| V3 | 67; man; IPF; basiliximab | Steroid pulse for ACR 26 days prior to IFI diagnosis | 47 | Pneumoniae (probable) | Cladosporium | 1 | 0.7 | Died; 175 days; bacterial superinfection after prolonged hospitalization stay |
| V4 | 65; woman; pulmonary fibrosis and hypersensitivity pneumonitis; basiliximab | Steroid pulse for ACR 9 days before IFI diagnosis | 36 | Chest-wall infection (proven) | Aspergillus niger | Not done | 0.4 | Alive |
| V5 | 70; man; COPD; alemtuzumab | Hemodialysis | 31 | Empyema (proven) | Rhizopus microsporus | >16 | Not done | Died; 189 days; allograft failure due to mucormycosis, disseminated varicella zoster infection |
Abbreviations: ACR, acute cellular rejection; BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; GvHD, graft-versus-host disease; ICU, intensive care unit; IFI, invasive fungal infection; IPF, idiopathic pulmonary fibrosis; MIC, minimum inhibitory concentration.
aRisk factors for yeasts or molds were based on known risk factors for IFI and those identified in this study (Table 4).
bAntifungal prophylaxis (isavuconazole) was continued past 4 months because patient continued to be critically ill in the ICU.
cAntifungal prophylaxis (isavuconazole) was continued past 3 months because of recurrent neutropenia.
dProbable endobronchial infection was based on plaque observed on tracheobronchial tree at the time of bronchoscopy and the BAL culture grew Cladophialophora boppi.
eProbable pneumonia was based on chest computed tomography scan criteria (nodular lesion surrounding by halo sign) and the BAL culture grew Cladosporium sp.
Table 4.
Risk Factors for Breakthrough Invasive Fungal and Invasive Mold Infections
| Breakthrough IFI | No Breakthrough IFI | P | Breakthrough Mold Infection | No Breakthrough Mold Infectiona | P | |
|---|---|---|---|---|---|---|
| Recipient demographics | ||||||
| Age at transplant, median (IQR), years | 54 (43–65) | 59 (47–65) | .71 | 55 (52–67) | 59 (47–65) | .80 |
| Recipient male sex, % (n/N) | 40 (4/10) | 58 (168/290) | .33 | 57 (4/7) | 58 (168/290) | 1.0 |
| Recipient African-American, % (n/N) | 30 (3/10) | 5 (15/287)b | .02 | 29 (2/7) | 5 (25/287) | .13 |
| Cystic fibrosis, % (n/N) | 20 (2/10) | 13 (39/290) | .63 | 14 (1/7) | 13 (39/290) | 1.0 |
| Malignancy pretransplant, % (n/N) | 0 (0/10) | 12 (34/290) | .61 | 0 (0/7) | 12 (34/290) | 1.0 |
| Diabetes mellitus, % (n/N) | 0 (0/10) | 5 (15/290) | 1.0 | 0 (0/7) | 5 (15/290) | 1.0 |
| Recipient pretransplant conditions | ||||||
| BMI, median (IQR), kg/m2 | 20 (20–24) | 24 (21–28) | .08 | 20 (19–24) | 25 (21–28) | .053 |
| Lung allocation score, median (IQR) | 60 (38–64) | 48 (35–70) | .39 | 62 (38–64) | 48 (35–70) | .65 |
| Requirement for ventilation pretransplant, % (n/N) | 20 (2/10) | 12 (34/290) | .34 | 14 (1/7) | 12 (34/290) | .59 |
| Requirement for ECMO pretransplant, % (n/N) | 0 (0/7) | 9 (26/290) | 1.0 | 0 (0/7) | 9 (26/294) | 1.0 |
| Mold colonization in the respiratory tract, % (n/N) | 10 (1/10) | 4 (13/290) | .39 | 14 (1/7) | 4 (13/289) | .29 |
| Donor factors | ||||||
| Donor age, median (IQR), years | 27 (22–49) | 33 (24–54) | .53 | 25 (20–54) | 33 (24–47) | .84 |
| Male donor, % (n/N) | 30 (3/10) | 51 (147/290) | .36 | 43 (3/7) | 51 (147/290) | .72 |
| Donor weight, median (IQR), kg | 66 (59–85) | 74 (64–86) | .29 | 68 (60–85) | 74 (64–86) | .49 |
| PHS increased risk, % (n/N) | 40 (4/10) | 26 (75/290) | .30 | 28 (2/7) | 26 (75/290) | 1.0 |
| Transplant factors | ||||||
| Re-transplantation, % (n/N) | 0 (0/10) | 2 (6/290) | 1.0 | 0 (0/7) | 2 (6/290) | 1.0 |
| CMV serology mismatch,c % (n/N) | 50 (5/10) | 26 (77/290) | .14 | 57 (4/7) | 27 (77/290) | .09a |
| Alemtuzumab induction, % (n/N) | 30 (3/10) | 55 (160/289)d | .19 | 14 (1/7) | 55 (160/289) | .05 |
| Double-lung transplant, % (n/N) | 100 (10/10) | 81 (236/290) | .22 | 100 (7/7) | 81 (236/290) | .36 |
| Number of RBC units, median (IQR) | 12 (9–25) | 4 (0–64) | .02 | 11 (9–33) | 4 (1–8) | .013 |
| Receipt of >7 RBC units transfusion,e % (n/N) | 80 (8/10) | 295 (83/290) | .001 | 86 (6/7) | 29 (85/293) | .004 |
| Mold-positive respiratory culture at transplant (recipient or donor), % (n/N) | 20 (2/10) | 2 (6/290) | .025 | 29 (2/7) | 2 (6/290) | .02 |
| Posttransplant factors, % (n/N) | ||||||
| Requirement for ECMO | 10 (1/10) | 15 (43/290) | 1.0 | 14 (1/7) | 15 (43/290) | 1.0 |
| CRRT posttransplant | 20 (2/10) | 11 (31/290) | .30 | 14 (1/7) | 11 (31/290) | .55 |
| Isavuconazole prophylaxis | 40 (4/10) | 52 (152/290) | .53 | 43 (3/7) | 52 (152/290) | .71 |
| Inhaled amphotericin Bf | 70 (7/10) | 71 (206/290) | 1.0 | 57 (4/7) | 71 (206/290) | .42 |
| Bronchial necrosis extending >2 cm from anastomosis | 20 (2/10) | 3 (10/290) | .055 | 29 (2/7) | 3 (10/290) | .028 |
| Immuno-augmentation for treatment of rejection | 50 (5/10) | 57 (164/290) | .70 | 43 (3/7) | 57 (164/290) | .70 |
Abbreviations: BMI, body mass index; CMV, cytomegalovirus; CMV serology mismatch (donor-positive/recipient), COPD, chronic obstructive pulmonary disease; CRRT, chronic renal replacement therapy; ECMO, extracorporeal membrane oxygenation; IFI, invasive fungal infection; IPF, idiopathic pulmonary fibrosis; IQR, interquartile range; PCR, polymerase chain reaction; PHS, US Public Health Service; RBC, red blood cell.
aThe 3 patients with yeast infection were not included in this analysis.
bRace was not known in 3 recipients.
cUse of basiliximab induction was linked to CMV serology mismatch (donor-positive/recipient-negative [D+/R−]) status (94% [77/82] of CMV D+/R− received basiliximab induction versus only 27% (59/217) of CMV–non-mismatch; P < .0001). However, there was no association between CMV viremia or disease and development of breakthrough mold infection among D+/R− patients. In reviewing CMV infection among patients with CMV D+/R− within the first year, there was no difference in CMV PCR or disease between patients with breakthrough mold infection and those without. All CMV D+/R− patients received at least 1 year of valganciclovir.
dOne patient received thymoglobulin induction rather than alemtuzumab or basiliximab.
eUsing a receiver operating curve, we determined that the cutoff of 7 units of RBC transfusion differentiated breakthrough IFI from no-breakthrough IFI groups.
fThere was no difference in the rates of breakthrough IFI or breakthrough mold infection among patients receiving isavuconazole or voriconazole prophylaxis with or without inhaled amphotericin B. In the isavuconazole group, all patients with IFI received adjunctive inhaled amphotericin B. In the voriconazole group, 0% (0/68) of patients receiving adjunctive inhaled amphotericin B and 3% (3/87) of those not receiving inhaled amphotericin B developed breakthrough mold infections (P = .26); note that 1 patient in the voriconazole and inhaled amphotericin B had breakthrough yeast infection and was not included in the breakthrough mold infection analysis. There was no difference in the rates of breakthrough mold infections among patients receiving inhaled amphotericin B in conjunction with isavuconazole (3%; 4/142) or with voriconazole (0%; 0/68) (P = .31).
Risk factors for bIFIs and bIMIs are presented in Table 4. Neither receipt of isavuconazole or voriconazole nor administration of iAmB was associated with bIFI or bIMI. Mold-positive respiratory culture at transplant and more than 7 units of red blood cell (RBC) transfusions during transplant were risk factors for both bIFI and bIMI (Table 4). African-American (AA) race was associated with bIFI (but not bIMI), whereas basiliximab (rather than alemtuzumab) induction and bronchial necrosis extending more than 2 cm from anastomosis were associated with bIMI (Table 4). By multivariate analysis, receipt of 7 or more units of RBCs and mold-positive respiratory culture at transplant were independent risk factors for bIFI and bIMI. Bronchial necrosis extending more than 2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI (Table 5). Numbers were insufficient to determine risk factors for yeast infections.
Table 5.
Independent Risk Factors for Breakthrough Invasive Fungal and Invasive Mold Infections Identified by Multivariate Logistic Regression
| Univariate, P | Multivariate | ||
|---|---|---|---|
| P | Odds Ratio (95% CI) | ||
| Breakthrough IFI | |||
| African-American race | .02 | .18 | |
| Receipt of >7 RBC units transfusion | .001 | .01 | 7.5 (1.5–36.6) |
| Mold-positive respiratory culture at transplant (recipient or donor) | .025 | .04 | 7.1 (1.1–44.4) |
| Breakthrough IMI | |||
| Receipt of >7 RBC units transfusion | .004 | <.0001 | 8.6 (2.7–26.9) |
| Mold-positive respiratory culture at transplant (recipient or donor) | .02 | <.0001 | 18.5 (3.7–91.7) |
| Bronchial necrosis extending >2 cm from the anastomosis | .03 | .008 | 7.05 (1.7–29.7) |
| Alemtuzumab induction | .05 | .01 | 0.17 (.04–.68) |
An exact logistic regression model, which produces more accurate inference in small numbers of breakthrough IFI and breakthrough IMI, was used to compute P values and odds ratios with 95% CIs. A Bayesian regression simulation using 1000 iterative samples was also used to estimate the odds ratio, and similar results were obtained.
Abbreviations: CI, confidence interval; IFI, invasive fungal infection; IMI, invasive mold infection; RBC, red blood cell.
Isavuconazole serum trough levels were available for 4 patients with bIFI. Troughs were 1.6–1.7 µg/mL in 3 patients and 0.7 µg/ml in the fourth patient. Isavuconazole minimum inhibitory concentrations (MICs) were 1 µg/mL against 2 mold isolates and 4 µg/mL against 2 Candida glabrata isolates. Voriconazole serum troughs were less than 1 µg/mL for all 3 patients with bIFI in whom levels were measured. Voriconazole MICs were 0.03 µg/mL and 4 µg/mL against Candida parapsilosis and C. glabrata isolates, respectively; 1 µg/mL against Aspergillus niger; and more than 16 µg/mL against Rhizopus microsporus (Table 3).
Non–Breakthrough Invasive Fungal Infection
Four percent (13/300) of patients developed IFI off antifungal prophylaxis, including 3% (5/144) and 5% (8/156) of patients in the isavuconazole and voriconazole groups, respectively (Tables 2 and 4).
Compliance and Toxicities
Isavuconazole and voriconazole prophylaxis was discontinued prematurely in 30% (42/138) and 41% (63/152) of patients who did not develop bIFI, respectively (P = .066) (Table 6). Sixty-six percent (69/105) of premature azole discontinuation in these cases was due to adverse events. Adverse events were responsible for early discontinuation of prophylaxis in 11% (15/138) and 36% (54/152) of patients in the isavuconazole and voriconazole groups, respectively (P = .0001) (Table 6). Patients receiving voriconazole had significantly higher rates of liver toxicity and central nervous system side effects than those receiving isavuconazole (Table 6). In contrast, significantly more patients discontinued isavuconazole (20%, 27/138) than voriconazole (6%, 9/152) for reasons other than adverse events (P = .0006). In 36% (15/42) of instances, isavuconazole was discontinued because patients were made nil per os (NPO) due to oropharyngeal dysphagia-related aspiration. In 12% (5/42) of instances, isavuconazole was discontinued in favor of voriconazole or posaconazole, in an effort to boost calcineurin inhibitor levels (Table 6).
Table 6.
Causes of Premature Discontinuation of Antifungal Prophylaxis
| Isavuconazolea (n = 139) | Voriconazolea (n = 151) | P | Notes | |
|---|---|---|---|---|
| Premature discontinuation of antifungal prophylaxis | 30 (42) | 41 (63) | .066 | … |
| Discontinuation due to side effects | 11 (15) | 36 (54)b | .0001 | … |
| Hepatotoxicity | 5 (7) | 18 (28) | <.0001 | … |
| Gastro-intestinal complaints | 5 (7) | 5 (8) | 1.0 | … |
| Neurotoxicity | 0 | 9 (13) | <.0001 | … |
| Skin | 0 | 1 (2) | .50 | … |
| Others | 0.7 (1) | 4 (6) | .12 | Isavuconazole: edema (1); voriconazole: edema (3), arthralgia (2), pancreatitis (1) |
| Discontinuation due to causes other than adverse events | 20 (27) | 6 (9) | .0006 | … |
| Nil per os | 11 (15) | 0 | <.0001 | … |
| To boost calcineurin inhibitor levels | 4 (5) | 0 | .023 | … |
| Recipient histopathology of explanted lungs with IFI or recipient/donor culture positive for histoplasma or mold at the time of transplant | 2 (3) | 1 (2) | .67 | … |
| Physician’s choice | 1 (2) | 3 (5) | .45 | Isavuconazole: BAL galactomannan positive, but fungal culture negative and no evidence of pulmonary infection while on isavuconazole (1); airway colonization with Aspergillus fumigatus (1); voriconazole: history of skin cancer (1), concerns for skin cancer (2), concern of liver toxicity due to HCV infection (1); QTc prolongation (1); in response to cluster of mucormycosis cases (1) |
| Others | 1 (2) | 1 (2) | 1.0 | Isavuconazole: patient not able to swallow due to large pill (1); superficial skin culture for Candida glabrata (without evidence of infection; voriconazole: insurance issue at discharge (2) |
Data are presented as % (n) unless otherwise indicated.
Abbreviations: BAL, bronchoalveolar lavage; HCV, hepatitis C virus; IFI, invasive fungal infection; QTc, corrected QT interval.
aNote that antifungal prophylaxis discontinued due to clinical failure is not included in the table (isavuconazole and voriconazole, n = 5 each). One patient was in the isavuconazole prophylaxis group by intention-to-treat.
bThree patients had >1 side effect.
Forty-nine percent (51/105) of patients without bIFI who discontinued isavuconazole or voriconazole prematurely were switched to another mold-active azole. In 42% (44/105) of patients, a full course (≥90 days) of antifungal prophylaxis was administered after the initial azole was discontinued. Altogether, 78% (225/290) of patients without bIFI received a full course of mold-active azole prophylaxis. Within 1 year of transplant, non-bIFIs were diagnosed in 3% (7/225) and 9% (7/65) of patients who received and did not receive full mold-active prophylaxis courses, respectively (P = .02). The median time from premature prophylaxis discontinuation to IFI was 42 days; the median time from transplant to IFI in these patients was 82 days.
Mortality
All-cause mortality within 1 year of transplant was 10% (14/144) and 12% (18/156) in isavuconazole and voriconazole groups, respectively (P = .54). Mortality rates at 1 year among patients with and without IFI were 39% (9/23) and 8% (23/277), respectively (P < .001) (Figure 4A). Mortality among patients with IFI was comparable for patients receiving isavuconazole or voriconazole (Figure 4). Patients diagnosed with IFI during the index transplant hospitalization had significantly longer lengths of stay than those without IFI (93 days vs 28 days, respectively; P = .0005)
Figure 4.
Mortality rate of patients with and without IFIs. Panel A shows that the survival rate of patients without IFI was significantly higher than that of patients with IFI (P < .0001, log-rank test). Panel B further stratifies survival rates according to isavuconazole and voriconazole groups. Again, survival was significantly higher among patients without IFI, regardless of prophylactic agent (P < .0001, log-rank test). Differences in survival among patients with IFI who received isavuconazole or voriconazole were not significant. Abbreviation: IFI, invasive fungal infection.
DISCUSSION
To our knowledge, this is the first study comparing the effectiveness and tolerability of isavuconazole and voriconazole as antifungal prophylaxis in lung transplant recipients. Isavuconazole was as effective as voriconazole in preventing IFIs and resulted in significantly fewer drug-related adverse events that prompted premature drug discontinuation. The use of iAmB in combination with an azole had no significant impact on IFIs or other outcomes. Our findings therefore indicate that isavuconazole was a useful antifungal agent for IFI prophylaxis following lung transplantation.
Our 1-year IFI rate was lower than the 6-month rate of 19.1% published recently for lung transplant recipients at another academic center, at which standard prophylaxis consisted of iAmB [16]. In that study, patients who had delayed chest closure or mold colonization pretransplant, or required ECMO posttransplant, also received micafungin or a mold-active azole [16]. It is unclear if our use of universal, systemic mold-active azole prophylaxis accounted for the lower IFI rate, or if differences between the centers reflected candidate selection criteria, immunosuppressive regimens, or other factors. The 1-year IFI rate in our program was similar to the rate of 8.6% reported for lung transplant recipients by US TRANSNET [5]. No cases of mucormycosis were diagnosed among patients receiving isavuconazole in the present study, which is notable since a case cluster in our transplant programs led to the change in prophylaxis regimens. Furthermore, isavuconazole was effective in preventing Candida and other yeast infections in our patients, an important finding given the inferior performance of isavuconazole compared with caspofungin in a clinical trial of treatment for invasive candidiasis [17].
Only 3% of patients who received either isavuconazole or voriconazole developed bIFI. This breakthrough rate was lower than the 6% rate among lung transplant recipients in the single-center study cited above [16]. In studies of patients with active leukemia or undergoing hematopoietic stem cell transplant (HSCT), isavuconazole prophylaxis bIFI rates ranged from 3% to 18% [18–20]. Of note, bIFIs in these studies were associated with prolonged neutropenia, which has been linked to poor outcomes among patients with invasive aspergillosis treated with isavuconazole or voriconazole [21]. Prolonged neutropenia is uncommon in lung transplant recipients, and it was not observed among our patients.
We identified several independent factors that predisposed patients to bIMI, including mold-positive respiratory cultures from recipients or donors at time of transplant, extensive bronchial wall necrosis extending more than 2 cm from anastomosis, and transfusion of more than 7 units of RBCs during transplant. Previous studies have shown that Aspergillus colonization prior to lung transplant is a risk factor for anastomotic aspergillosis [22–25]. Airway ischemia is a common complication of lung transplant due to transection of the bronchial artery during donor lung harvest [26]. For the first 4 to 6 weeks after transplant, the donor’s bronchus and the anastomotic site rely on collateral blood supply until revascularization is established; these areas are vulnerable to ischemic insult. It is likely that bronchial wall necrosis creates a favorable environment for fungal proliferation, adherence, and airway tissue invasion. Furthermore, disrupted bronchial arteries can lead to transiently devascularized tissues, which might impede antifungal agents from reaching airways. The need for significant RBC transfusions often reflects profound bleeding during transplant, which may further decrease blood supply and worsen ischemia and bronchial necrosis. Interestingly, lung transplant recipients who received alemtuzumab induction were less likely to develop bIMI than those who received basiliximab, an association that was not linked to the development of cytomegalovirus (CMV) infection or other clinical factors. Alemtuzumab, a potent antilymphocyte antibody that produces long-lasting lymphopenia, has been associated with severe infections [27] but its impact on IFIs in lung transplant recipients is unknown. We hypothesize that alemtuzumab mitigated the risk of mold infections compared with basiliximab by enabling lower doses of steroid and/or mycophenolate for maintenance immunosuppression.
Three of four patients with isavuconazole bIFIs in whom therapeutic drug monitoring (TDM) was performed had serum troughs of 1.6 µg/mL or greater. In a previous study, we demonstrated that isavuconazole troughs were ≥1, ≥1.5, and ≥2 µg/mL in 94%, 81%, and 63% of solid-organ-transplant recipients, respectively [28]. To date, an association between isavuconazole exposure and efficacy has not been established [29]. Using population pharmacokinetic analysis, we showed that standard intravenous isavuconazole dosing was unlikely to attain pharmacokinetic-pharmacodynamic targets for effective treatment against A. fumigatus and C. glabrata exhibiting MICs more than 0.5 µg/mL and more than 0.125 µg/mL, respectively [2]. Isavuconazole MICs against breakthrough C. glabrata (n = 2) and A. fumigatus (n = 1) in this study were 4 µg/mL and 1 µg/mL, respectively. In contrast to the isavuconazole data, all 3 patients with voriconazole bIFIs in whom TDM was performed had serum troughs less than 1 µg/mL. Voriconazole exhibits highly variable interindividual pharmacokinetics [30]. We previously showed that 23% of lung transplant recipients had serum voriconazole troughs that were consistently less than 1 µg/mL [31], and that bIFIs or colonization during voriconazole prophylaxis were more likely with troughs of 1.5 µg/mL or less [31]. Furthermore, clinical studies and meta-analyses have supported troughs greater than 1 µg/mL as predictive of treatment successes [32–34]. Taken together, the data suggest that isavuconazole bIFIs may often be caused by fungi with reduced antifungal susceptibility, while voriconazole bIFIs may be associated with subtherapeutic troughs. These hypotheses and the potential value of TDM merit investigation in future studies.
The more favorable side-effects profile we found with isavuconazole compared with voriconazole was consistent with published literature [20, 35, 36]. Interestingly, isavuconazole was discontinued most often for reasons other than side effects, in particular due to NPO status. Oropharyngeal dysphagia is a common complication following lung transplant that is associated with long-term graft dysfunction [37]. At our center and many others, swallowing assessments are routinely performed posttransplant. Patients with aspiration are kept NPO, and nutrition is maintained via enteral feeding until dysphagia resolves, a process that might take weeks to months. Current Food and Drug Administration labeling that isavuconazole capsules cannot be administered through enteric feeding tubes [38] presents challenges since intravenous drug administration is inconvenient for prophylaxis over weeks to months. For this reason, isavuconazole was commonly changed to voriconazole upon hospital discharge, since voriconazole can be administered through enteral feeding tubes. A recent case report suggested that administering contents of isavuconazole capsules through a gastrostomy-jejunostomy tube resulted in desired serum concentrations [39]. Preliminary data from 7 NPO organ-transplant recipients at our center who received isavuconazole via feeding tubes indicated that troughs were comparable to those of patients treated via oral or intravenous routes [40]. More studies are needed on isavuconazole pharmacokinetics and the effectiveness of prophylaxis and treatment following enteral feeding administration.
This study has several limitations. Patients received isavuconazole or voriconazole in different time periods, and it is possible that ongoing advances in transplantation medicine and surgery influenced our results. The small number of IFIs also limited our analytic capabilities. As always with single-center studies, results and conclusions here should be interpreted and extrapolated cautiously to other programs. Since lung transplant recipients at our center received universal antifungal prophylaxis, we cannot address the relative value of this or other prophylaxis strategies. Findings supporting the value of our prophylaxis regimens include IFI rates that were higher among patients who did not receive a full prophylaxis course of 90 days or longer and 1-year mortality that was significantly higher among patients who developed an IFI. The positive impact of prophylaxis must be balanced against side effects and drug interactions of antifungal agents, the risk of selecting for antifungal resistance, and costs associated with long courses of antifungal therapy. Experience in leukemia and HSCT transplant populations suggests that universal antifungal prophylaxis might be most useful during the period of profound immunosuppression early after lung transplant at centers with IFI rates of 6% or higher [10, 41, 42], an hypothesis that could be tested in an IFI prophylaxis trial.
In conclusion, isavuconazole was as effective as voriconazole in preventing IFI after lung transplantation, and it was better tolerated. Antifungal prophylaxis is routinely administered to lung transplant recipients, but the best approach, optimal duration, and cost-effectiveness of different antifungal prophylaxis strategies are unknown. It is long past time for the lung transplant community to organize at least 1 multicenter, randomized clinical trial to rigorously define best practices for preventing IFIs. Our data indicate that either isavuconazole or voriconazole would be reasonable mold-active azoles to include in such a trial.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Financial support. This work was supported by investigator-initiated grants from Astellas and Pfizer. The following authors are supported by the National Institutes of Health: C. J. C (grant numbers R21AI126157, R21AI142049, R21AI144390); M. H. N. (grant number R21AI128338); R. K. S. (grant numbers K08AI114883, R03AI144636).
Potential conflicts of interest. C. J. C. has been awarded investigator-initiated research grants from Astellas, Merck, Melinta, and Cidara for projects unrelated to this study; has served on advisory boards or consulted for Astellas, Entasis, Merck, Melinta, The Medicines Company, Cidara, Scynexis, Shionogi, Qpex, and Needham & Company; and has spoken at symposia sponsored by Merck and T2Biosystems. R. K. S. has received grant support from Accelerate Diagnostics, Achaogen, Allergan, Merck, Melinta, Roche, Shionogi, Tetraphase, VenatoRx, and the National Institutes of Health; has served on advisory boards for Accelerate Diagnostics, Achaogen, Astellas, Allergan, Entasis, Menarini, Merck, Pfizer, Nabriva, Shionogi, and VenatoRx; and has received speaking honoraria from Allergan, Menarini, Pfizer, and T2Biosystems. M. H. N. has been awarded investigator-initiated research grants from Astellas and Pfizer related to this study, and from Merck, Astellas, and Cidara for projects unrelated to this study. F. S. reports grants from Shire, Ansun, and Whiscon, outside the submitted work. R. V. M. reports grants for retrospective review research from Merck, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
- 1. Samanta P, Singh N. Complications of invasive mycoses in organ transplant recipients. Expert Rev Anti Infect Ther 2016; 14:1195–202. [DOI] [PubMed] [Google Scholar]
- 2. Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis 2010; 12:220–9. [DOI] [PubMed] [Google Scholar]
- 3. Husain S, Camargo JF. Invasive aspergillosis in solid-organ transplant recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13544. [DOI] [PubMed] [Google Scholar]
- 4. Hosseini-Moghaddam SM, Ouédraogo A, Naylor KL, et al. Incidence and outcomes of invasive fungal infection among solid organ transplant recipients: a population-based cohort study. Transpl Infect Dis 2020; 22:e13250. [DOI] [PubMed] [Google Scholar]
- 5. 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. [DOI] [PubMed] [Google Scholar]
- 6. Silveira FP, Husain S. Fungal infections in solid organ transplantation. Med Mycol 2007; 45:305–20. [DOI] [PubMed] [Google Scholar]
- 7. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005; 18:44–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Patel TS, Eschenauer GA, Stuckey LJ, Carver PL. Antifungal prophylaxis in lung transplant recipients. Transplantation 2016; 100:1815–26. [DOI] [PubMed] [Google Scholar]
- 9. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63:e1–e60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 2018;24Suppl 1:e1–e38. [DOI] [PubMed] [Google Scholar]
- 11. 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. [DOI] [PubMed] [Google Scholar]
- 12. Pennington KM, Yost KJ, Escalante P, Razonable RR, Kennedy CC. Antifungal prophylaxis in lung transplant: a survey of United States’ transplant centers. Clin Transplant 2019; 33:e13630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. 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. [DOI] [PubMed] [Google Scholar]
- 14. De Pauw B, Walsh TJ, Donnelly JP, et al. ; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group ; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis 2020; 71:1367–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Baker AW, Maziarz EK, Arnold CJ, et al. Invasive fungal infection after lung transplantation: epidemiology in the setting of antifungal prophylaxis. Clin Infect Dis 2020; 70:30–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Kullberg BJ, Viscoli C, Pappas PG, et al. Isavuconazole versus caspofungin in the treatment of candidemia and other invasive Candida infections: the ACTIVE trial. Clin Infect Dis 2019; 68:1981–9. [DOI] [PubMed] [Google Scholar]
- 18. Abbott JD, Fernando HV, Gurling K, Meade BW. Pulmonary aspergillosis following post-influenzal bronchopneumonia treated with antibiotics. Br Med J 1952; 1:523–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Fontana L, Perlin DS, Zhao Y, et al. Isavuconazole prophylaxis in patients with hematologic malignancies and hematopoietic cell transplant recipients. Clin Infect Dis 2020; 70:723–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Bose P, McCue D, Wurster S, et al. Isavuconazole as primary anti-fungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective, phase II stud y. Clin Infect Dis 2020. doi: 10.1093/cid/ciaa358 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Kontoyiannis DP, Selleslag D, Mullane K, et al. Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial. J Antimicrob Chemother 2018; 73:757–63. [DOI] [PubMed] [Google Scholar]
- 22. Nunley DR, Ohori P, Grgurich WF, et al. Pulmonary aspergillosis in cystic fibrosis lung transplant recipients. Chest 1998; 114:1321–9. [DOI] [PubMed] [Google Scholar]
- 23. Helmi M, Love RB, Welter D, Cornwell RD, Meyer KC. 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. [DOI] [PubMed] [Google Scholar]
- 24. Paradowski LJ. Saprophytic fungal infections and lung transplantation—revisited. J Heart Lung Transplant 1997; 16:524–31. [PubMed] [Google Scholar]
- 25. Luong ML, Chaparro C, Stephenson A, et al. Pretransplant aspergillus colonization of cystic fibrosis patients and the incidence of post-lung transplant invasive aspergillosis. Transplantation 2014; 97:351–7. [DOI] [PubMed] [Google Scholar]
- 26. Della Rocca G, Pierconti F, Costa MG, et al. Severe reperfusion lung injury after double lung transplantation. Crit Care 2002; 6:240–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Farley JJ. Full prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf. Accessed 10 March 2020.
- 28. Wu X, Venkataramanan R, Rivosecchi RM, et al. Population pharmacokinetics of intravenous isavuconazole in solid-organ transplant recipients. Antimicrob Agents Chemother 2020; 64:e01728–19. doi: 10.1128/AAC.01728-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Desai AV, Kovanda LL, Hope WW, et al. Exposure-response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi. Antimicrob Agents Chemother 2017; 61:e01034–17. doi: 10.1128/AAC.01034-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Hope WW. Population pharmacokinetics of voriconazole in adults. Antimicrob Agents Chemother 2012; 56:526–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Mitsani D, Nguyen MH, Shields RK, et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother 2012; 56:2371–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Luong ML, Al-Dabbagh M, Groll AH, et al. Utility of voriconazole therapeutic drug monitoring: a meta-analysis. J Antimicrob Chemother 2016; 71:1786–99. [DOI] [PubMed] [Google Scholar]
- 33. Hamada Y, Seto Y, Yago K, Kuroyama M. Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis. J Infect Chemother 2012; 18:501–7. [DOI] [PubMed] [Google Scholar]
- 34. Stott KE, Hope WW. Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations. J Antimicrob Chemother 2017; 72:i12–8. [DOI] [PubMed] [Google Scholar]
- 35. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387:760–9. [DOI] [PubMed] [Google Scholar]
- 36. Maertens J, Selleslag D, Heinz WJ, et al. Treatment outcomes in patients with proven/probable vs possible invasive mould disease in a phase III trial comparing isavuconazole vs voriconazole. Mycoses 2018; 61:868–76. [DOI] [PubMed] [Google Scholar]
- 37. Baumann B, Byers S, Wasserman-Wincko T, et al. Postoperative swallowing assessment after lung transplantation. Ann Thorac Surg 2017; 104:308–12. [DOI] [PubMed] [Google Scholar]
- 38.Available at: https://www.cresemba.com/?msclkid=6ddd93079a5b16acf368cd69e812eadd&utm_source=bing&utm_medium=cpc&utm_campaign=Cresemba%20HCP_Branded_Exact&utm_term=isavuconazole%20package%20insert&utm_content=Branded_PI. Accessed 10 March 2020.
- 39. Adamsick ML, Elshaboury RH, Gift T, Mansour MK, Kotton CN, Gandhi RG. Therapeutic drug concentrations of isavuconazole following the administration of isavuconazonium sulfate capsules via gastro-jejunum tube: a case report. Transpl Infect Dis 2019; 21:e13048. [DOI] [PubMed] [Google Scholar]
- 40. McCreary EK, Nguyen M, SachaLM, et al. Achievement of clinical isavuconazole serum and plasma trough concentrations in seven patients with isavuconazonium capsules administered via ente ral feeding tube. European Congress of Clinical Microbiology and Infectious Diseases Amsterdam, Netherlands, April 2019. Available at: https://webcache.googleusercontent.com/search?q=cache:4GxyYY2xCLcJ:https://www.escmid.org/escmid_publications/escmid_elibrary/material/%3Fmid%3D68689+&cd=3&hl=en&ct=clnk&gl=us
- 41. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348–59. [DOI] [PubMed] [Google Scholar]
- 42. De Pauw BE, Donnelly JP. Prophylaxis and aspergillosis–has the principle been proven? N Engl J Med 2007; 356:409–11. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.