138
Views
4
CrossRef citations to date
0
Altmetric
Review

Management of Multidrug Resistant Infections in Lung Transplant Recipients with Cystic Fibrosis

, ORCID Icon, &
Pages 5293-5301 | Published online: 10 Dec 2021

Abstract

Cystic fibrosis (CF) is an inherited multisystem disease characterised by bronchiectasis and chronic respiratory infections which eventually cause end stage lung disease. Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated lung disease, improving survival and quality of life. Navigating recurrent infections in the setting of LTx is often difficult, where immune suppression must be balanced against the constant threat of infection. Sepsis/infections are one of the major contributors to post-LTx mortality and multiresistant organisms (eg, Burkholderia cepacia complex, Mycobacterium abscessus complex, Scedosporium spp. and Lomentospora spp.) pose a significant threat to survival. This review will summarize current and novel therapies to assist with the management of multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort.

Introduction

Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder of the Caucasian population, causing multisystem failure through defects in a single protein (CF transmembrane conductance regulator, CFTR).Citation1 CFTR is highly expressed in respiratory epithelial cells, and its impaired function leads to airway dehydration, progressive inflammation and reduced mucociliary clearance. A diverse and pathogenic microbiome, repeated pulmonary infection and a large cumulative exposure to antimicrobial agents are the hallmarks of CF.Citation2 Median life expectancy for CF patients in the contemporary age of multidisciplinary management and CFTR directed therapy is 32–46 years.Citation3,Citation4

Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated end-stage lung disease, improving survival and quality of life.Citation5 Globally, from 1995–2016, 8484 CF patients underwent LTx. CF is the third most common indication for adult LTx, and the most common reason for pediatric LTx.Citation6 Survival following LTx is highest for CF compared to other indications (chronic obstructive pulmonary disease, interstitial lung disease, etc), with the latest international registry data demonstrating a median five-year survival of >50%. The leading cause of death amongst adults with CF who have had a LTx is pulmonary infection.Citation7

Improved management and survival amongst pre-LTx CF patients have been reflected in the gradually increasing median age of the CF LTx recipient.Citation7 Although post-LTx survival is thought to improve when recipients are past adolescence at time of LTx,Citation8 an older cohort brings new challenges. Over time, the evolving microbiome within the CF lung acquires increasing resistance, reflecting cumulative exposure to antimicrobial agents.Citation9 There is increasing concern regarding the re-emergence of multiresistant infections following LTx, with a limited antimicrobial armamentarium at hand.

Over the past decade, advances in culture-independent sequence-based analysis of microbial genomes has highlighted the richness and complexity of the CF microbiome, beyond the pathogens classically linked to CF (eg, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia)Citation10 Although LTx replaces both native and heavily infected CF-lungs, many microbiome studies demonstrate preservation of the pre-LTx lower airway microbiome post-LTx.Citation11 This review will summarize the emerging multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort, together with some novel therapies to assist with management of these infections.

Bacterial Infections

Gram-negative Bacteria

Gram-negative bacteria represent the vast majority of pathogens featured in a recent World Health Organization (WHO) list of “priority pathogens” which pose the greatest threat to humans.Citation12 Major adversaries featuring on this list, include Stenotrophomonas maltophilia, Acinetobacter baumannii and Enterobacteriaceae, and are commonly found within the CF microbiome.Citation13,Citation14 Traditionally, post-LTx bacterial infections caused by known pre-LTx colonizers within the host have been considered manageable.Citation15 Particularly, the presence of pre-LTx multiresistant P. aeruginosa which has been linked to increased frequency of post-LTx pneumonia, but importantly is not linked to a decreased survival.Citation16,Citation17 Microbiome studies, specifically examining resistance patterns of gram-negative bacteria amongst CF-LTx patients are scarce; however, treating post-LTx re-emergent gram negatives in the current climate of growing antibacterial resistance is increasingly problematic.

Amongst gram-negative pathogens, resistance to β-lactam antibiotics is largely mediated by β-lactamases. Carbapenems will overcome β-lactamases; however, are themselves neutralized by metallo-β-lactamases (MBL).Citation18 MBL expression by P. aeruginosa represents one of the recent and most challenging resistance patterns clinicians have to manage. MBL-producing P. aeruginosa has been described in a postoperative CF-LTx patient, who ultimately needed a lung lobectomy eight months following LTx due to atelectasis with suppuration.Citation19 Similarly, a further case report of fatal empyema caused by MBL-producing P. aeruginosa in a CF-LTx patient was associated with failure of all antimicrobial therapy and required a right pneumonectomy.Citation20

Ceftolozane-tazobactam was the first amongst the second-generation β-lactams with β-lactamase activity. There is growing experience with using it against extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae, and it has demonstrated activity against multidrug resistant P. aeruginosa.Citation21 The chemical structure of ceftolozane is similar to ceftazidime, with the exception of a modified side chain which potentiates antipseudomonal activity.Citation22 Successful use in LTx recipients with ventilator-acquired pneumonia and complicated intra-abdominal infections have been reported.Citation23,Citation24 Ceftolozane-tazobactam, however, lacks activity against carbapenemase-producing organisms.

Novel agents with activity against carbapenamase-producing gram-negative bacteria (including carbapenamase-resistant Enterobacteriaceae, CRE) such as ceftazidime/avibactam and meropenem/vaborbactam, have changed the management of invasive CRE, with increased cure rates, decreased mortality and decreased acute kidney injury when compared to colistin-based therapies.Citation25 In addition, the use of aztreonam together with ceftazidime/avibactam has been suggested as a strategy against ESBL with MBL expression, to avoid acquired resistance.Citation26

Infections with B. cepacia complex (BCC) in the CF-lower airway have been associated with significantly increased early post-LTx mortality relating to overwhelming chest sepsis (pneumonia, mediastinitis, and empyema).Citation27 Many centers still consider isolation of BCC an absolute contraindication to LTx. Smaller studies attribute the increased mortality seen with BCC to the subspecies B. cenocepacia specifically.Citation28 Newer meta-genomic tools have identified specific strains of B. cenocepacia (eg, those with ET12) which appear to have increased pathogenicity. The treatment of BCC is notoriously difficult, and no standard guidelines for management exists. Prolonged multidrug regimens are usually prescribed using local institution expertise and sensitivity testing. A reasonable combination includes inhaled tobramycin, trimethoprim-sulfamethoxazole, minocycline and a β-lactam (usually meropenem or ceftazidime).Citation29 In addition, some success with ceftazidime/avibactam and meropenam/varobactam has been reported against BCC in the CF-LTx cohort.

New strategies for management of gram-negative infections are under development. High-dose adjunct inhaled nitric oxide has recently been reported as safe, well tolerated and of clinical benefit in an adolescent with CF suffering from B. multivorans infection.Citation30 A Phase II placebo-controlled clinical trial of inhaled nitric oxide amongst CF-LTx patients is currently underway (NCT2498535). Primary outcomes include change in FEV1 and sputum colony forming units after a seven-day course of inhaled nitric oxide. In addition, technology to facilitate phage therapy (ie, the therapeutic application of viruses that infect bacteria) has existed for decades,Citation31 and recent reports confirm success of phage/antibiotic synergy against gram-negative pathogens.Citation32 Clinical trials for phage therapy in CF are currently underway (NCT4684641). Topical disinfectant application at the time of CF-LTx has also been explored and demonstrates some degree of success. A single center recently reported reduced colonization with multidrug resistant pathogens (particularly P. aeruginosa) at one year post-LTx when a 2% taurolidine bronchial lavage was applied intra-op to recipient native bronchi and pleural cavities.Citation33

Nontuberculous Mycobacteria (NTM)

NTM have an estimated annual prevalence of 12% amongst patients with CF. Recent United States CF patient registry data demonstrated 20% had isolated a pathogenic NTM species at least once over a 5-year period.Citation34 The literature on NTM infection in solid organ transplant recipients is very limited, apart from case reports and institutional experiences.Citation35 M. abscessus complex (MABC) is the second most common NTM (following M. avium complex, MAC) and is emerging as one of the most worrisome NTM amongst CF-LTx patients. Infection is often associated with accelerated lung function decline and complicated toxic multidrug therapy which may span years.Citation36 MABC most commonly infects the pleuropulmonary space; however, cutaneous sites, operative sites, and disseminated disease have been reported.Citation35 A recent case report describes prolonged multidrug therapy for recurrent MABC in a CF-LTx recipient with cutaneous and pulmonary infection complicated by drug toxicities causing multi-organ failure and loss in lung allograft function.Citation37

An isolation of NTM does not always confer disease, and recent guidelines highlight the clinical and microbiological features for diagnosis.Citation38 Given the absence of randomized clinical trial data, treatment is based on expert opinion. Macrolides are the cornerstone of NTM treatment; however, treatment is limited by resistance.Citation39 Therapy is guided by local epidemiology and pathogen sensitivity, and usually involves an induction phase with multiple intravenous and oral agents (including macrolide/clofazimine, amikacin and β-lactam) and a suppressive phase with multiple oral/inhaled drugs (macrolide, fluoroquinolone, inhaled aminoglycoside±clofazimine). In addition, surgical intervention may be required, hyperbaric oxygen therapy can be consideredCitation40 and reduction in immune suppression should be considered.Citation37,Citation41

Several novel therapies for treatment of NTM have recently emerged. Amikacin liposome inhalation suspension (ALIS) is a formulation of the aminoglycoside designed to facilitate targeted drug delivery whilst minimizing systemic exposure.Citation42 The molecule is phagocytosed by respiratory macrophages and delivered directly to infected respiratory cells. A recent prospective open-label randomized study revealed that addition of ALIS to guideline-based therapy for treatment refractory MAC lung disease achieved greater culture conversion by six-months.Citation43 Recent studies report success of regimens involving combination clofazimine and amikacin inhalational therapy, with significant synergistic activity and ongoing culture negativity in 43% after 12-months in MABC airway infections.Citation39 Linezolid use against pulmonary MABC has been reported; however, treatment limiting side effects such as cytopenia and peripheral neuropathy are potential complications.Citation44 Tedizolid has reported greater in vitro activity than linezolid against MABC; however, a large single center study reports no significant safety benefit of tedizolid over linezolid for treatment of NTM amongst solid organ transplant recipients.Citation45

Viral Infections

Cytomegalovirus

Cytomegalovirus (CMV) is a β-herpesvirus which is usually acquired via primary infection in childhood or early adulthood and thereafter establishes latency in monocytes, megakaryocytes, dendritic cells and myeloid progenitor cells.Citation46 It is a major cause of morbidity/mortality after LTx when immunosuppression facilitates viral reactivation, manifesting as asymptomatic viremia, viremia with nonspecific symptoms (fever and malaise) or evidence of tissue invasion with end-organ damage (most commonly pneumonitis). Fifty percent of CF-LTx recipients are seronegative pre-LTx for CMV. CMV reactivation is associated with increased rates of acute cellular rejection and chronic lung allograft dysfunction.Citation47 Before universal prophylaxis with valganciclovir, 54–95% of lung transplant recipients developed viraemia and over half developed disease.Citation48 This has significantly improved with prophylaxis, but CMV remains a serious problem especially for the CF-LTx at highest risk, (ie, donor seropositive/recipient seronegative mismatch LTx).Citation49

The development of viral resistance to ganciclovir/valganciclovir is one of the complications of prolonged antiviral exposure, affecting approximately 2% of lung transplant recipients and nearly 5% of serological mismatches with three-year mortality rates as high as 70%.Citation50 CF is also associated with an increased risk of CMV resistance.Citation51 Resistance testing should be performed when CMV does not respond to ganciclovir therapy (eg, CMV viral load increases on therapy or fails to fall by a log within seven days of commencement of therapy). Resistance is most often mediated by mutations in UL97, which encodes a viral enzyme necessary for the activation of ganciclovir. Mutations in UL54 usually arise as a second step and additionally confer resistance to foscarnet.Citation52 Management of ganciclovir-resistant CMV includes a combination of cautious reduction in immunosuppression, CMV-immunoglobulin, and an alternative antiviral strategy such as foscarnet, cidofovir and sometimes high-dose ganciclovir depending on resistance phenotype.Citation53Citation55 Novel agents such as maribavir appear to have efficacy for the treatment of resistant CMV. Letermovir as treatment is poorly studied to date, but appears to have a low barrier to resistance and may have more utility as secondary prophylaxis once the CMV viral load is suppressed and undetectable adoptive T cell immunotherapy is an investigational modality which holds promise.Citation56 Data are limited in this area and there are no specific studies on the management of resistant CMV in post-transplant CF patients. Further studies are required.

Epstein–Barr Virus

Epstein–Barr virus (EBV) is a γ-herpesvirus which is even more prevalent than CMV, with approximately 85% of individuals seropositive by 25 years of age.Citation57 Latent infection persists in B cells. In solid organ and hematologic transplantation, there is strong evidence that immunosuppression permits EBV to exert an oncogenic effect on B cells to precipitate post-transplant lymphoproliferative disorder (PTLD).Citation58 PTLD is the most common non-skin malignancy after SOT and serological mismatch enormously increases this risk.Citation59 EBV-mismatched CF patients have an even higher risk of PTLD, with a registry study of over 30,000 lung transplant recipients demonstrating 31% will be affected.Citation60,Citation61 Although there is a lack of strong data supporting this strategy, many centers attempt to prevent PTLD in serologically mismatched patients via lifelong antiviral prophylaxis.Citation62 Management of PTLD usually involves a stepwise combination of reduction in immunosuppression, rituximab, and chemotherapy/radiotherapy depending on extent and phenotype of disease.Citation63Citation66

Polyomaviruses

Polyomaviruses are nonenveloped double-stranded DNA viruses. The commonest is BK virus (BKV) which persists as a latent infection in renal tubular and uroepithelial cells in approximately 80% of adults and reactivates in 25–30% of renal transplant recipients, with 1–10% developing BKV-associated nephropathy.Citation67 BKV-associated nephropathy and presumed BKV-driven urological malignancies have been reported after LTx, including in CF patients.Citation68,Citation69 The only proven therapy is reduction in immunosuppression (often withholding the cell-cycle inhibitor and temporarily or permanently exchanging the calcineurin inhibitor for a mammalian target of rapamycin inhibitor), but intravenous immunoglobulin, leflunomide and cidofovir have also been employed.Citation70,Citation71

John Cunningham virus (JCV) is a neutrotropic polyomavirus that can cause progressive multifocal leukoencephalopathy in immunocompromised hosts.Citation72 Although it remains very rare after LTx, with only several cases reported and none in CF patients, this demyelinating disease of the central nervous system frequently causes severe morbidity or death and thus, a high index of clinical suspicion should be maintained.Citation73,Citation74

Fungal Infections

Fungal pathogens following CF-LTx are of particular importance, given fungi are commonly found in the native CF-airway.Citation75 Due to the higher strength of initial immune suppression, the first year following LTx represents significant vulnerability to invasive fungal disease, contributing to significant morbidity and mortality. Invasive disease with Aspergillus fumigatus has a significant mortality (41–51%),Citation76 followed by Candida albicans and Cryptococcus spp. (23%).Citation77 In addition, reported mortality from invasive Scedosporium/Lomentospora spp. disease is close to 100%.Citation78 Respiratory manifestations of fungal disease post-LTx include fungal pneumonia, other manifestations of invasive disease or local infection of the anastomosis (ie, tracheobronchitis or bronchial anastomotic infection) or colonization.Citation75

Aspergillus spp

Invasive Aspergillus spp. disease are typically treated with triazoles such as posaconazole or voriconazole, needing close therapeutic drug monitoring and consideration of interactions with calcineurin inhibitors given its moderate inhibition of the CYP3A4 enzyme.Citation75 Isavuconazole is the newest extended spectrum triazole antifungal, approved as an alternative to voriconazole for treatment against invasive aspergillosis and as an alternative treatment to liposomal amphotericin B for mucormycosis. Unlike most other azole-antifungals, isavuconazole has excellent oral bioavailability and predictable linear pharmacokinetics in adults, with reduced impact from genetic polymorphisms, and reduced inter-patient variability. Isavuconazole is a mild inhibitor of CYP3A4, and causes increased serum concentration of calcineurin inhibitors, but much less than with posaconazole and voriconazole; but, dose adjustments are still required. In addition, isavuconazole increases serum concentration of mycophenolate, and monitoring for mycophenolate toxicity is required.Citation79

Candida spp

Retrospective analysis of over 25,000 respiratory samples from a national German registry reports up to 75% of patients with CF isolated yeast (mainly Candida spp.) and around 35% isolated Aspergillus spp.Citation80 Candida albicans is the most common Candida spp. isolated from the CF airway, followed by C. dubliniensis, C. glabrata complex and C. parapsilosis complex. Although the Candida spp. do not commonly cause pulmonary exacerbations in CF patients, a recent retrospective analysis over 16-years revealed that colonization (in particular C. albicans and C. dubliniensis) was associated with a decline in lung function.Citation81 In addition, colonized patients who require central venous access are at risk of Candida spp. fungemia/sepsis and endocarditis. In a survey of bloodstream infections post LTx, Candida spp. were the second most common.Citation82 Randomized trials support the treatment for invasive candidemia typically with echinocandin therapy (anidulafungin or caspofungin) over fluconazole amphotericin B.Citation83,Citation84 Non-neutropenic patients who are not critically unwell and unlikely to have fluconazole resistant organisms (eg, C. glabrata or C. krusei) can be treated with fluconazole, particularly as step-down therapy.

Scedosporium spp. and Lomentospora spp

Filamentous fungi (S. apiospermum/L. prolificans—formerly known as S. prolificans) are reported in up to 4% of CF patients, and multiple single-center studies demonstrate similar rates in CF-LTx patients.Citation80,Citation85 S. apiospermum/L. prolificans are intrinsically multiresistant pathogens that often require complex surgical debridement and prolonged multidrug regimens with significant morbidity/mortality.Citation85,Citation86 Treatments for these fungi are based on expert opinion and retrospective data. S. apiospermum is treated either with voriconazole monotherapy, or in conjunction with terbinafine.Citation87,Citation88 Based on a review of the literature from 2000–2018 and Fungiscope (an international rare invasive fungal registry), patients with voriconazole-based therapy had longer overall survival and reduced 42-day mortality compared to amphotericin-based regimens.Citation89 Infections with L. prolificans are aggressive and often fatal, and treatments must be tailored on a case-by-case basis. Surgical debridement and reduction in immune suppression are often considered. Although L. prolificans has greater intrinsic resistance to voriconazole, multidrug regimens involving either posaconazole/voriconazole and terbinafine have been reported with reduced mortality,Citation90 although limited data is available.

Fungal Prophylaxis

There is significant global discordance in the fungal prophylaxis strategy that should be used post-LTx, and available data are contradictory.Citation91 A review and meta-analysis of 748 LTx recipients suggested that universal prophylaxis (agents included were fluconazole, voriconazole, and inhaled amphotericin B) reduced pulmonary invasive aspergillosis; however, limitations such as single center data and nonrandomized protocols were acknowledged.Citation92 Subsequently, two recent meta-analyses reveal no difference in the odds of fungal infection with universal prophylaxis compared to no prophylaxis following LTx.Citation93,Citation94 Long-term exposure to antifungal medication has been reported as the major risk factor in the emergence of multiresistant fungal infections post-LTxCitation85 and the question remains as to whether universal prophylaxis risks breeding increased resistance to first-line antifungal medication without a mortality benefit.

In place of universal fungal prophylaxis, pre-emptive strategies have been successfully applied by large LTx units. This involves treatment with antimould agents after initial isolation on surveillance bronchoscopy/sputum culture or following positive galactomannan on broncho-alveolar lavage sample. This strategy has been reported to reduce antifungal exposure by 60% compared to universal prophylaxis, without affecting mortality at one year.Citation95 Head-to-head randomized trials are needed to confirm which approach is superior.

Novel Antifungals

Olorofim (formerly F901318) is a novel investigational antifungal agent. This mould-active antifungal targets dihydroorotate dehydrogenase and inhibits pyrimidine biosynthesis. It is the first member of the orotomide class and is currently being evaluated for use against resistant moulds, including species with intrinsic or acquired resistance to azoles and amphotericin B; however, it lacks activity against yeasts and the Mucorales.Citation96 Published experience is currently limited to case reports (abstracts) against resistant moulds causing persistent infections and is quite promising.Citation97Citation99 A Phase II clinical trial for patients with invasive fungal disease (Scedosporium spp., Lomentospora spp. and azole-resistant Aspergillus spp.) is currently recruiting (NCT3583164).

Azole-resistant Aspergillus spp. infections are increasingly prevalent in CF patients, and can reach high prevalence in CF patients who are chronically treated with azoles. A second mould-active antifungal agent, fosmanogepix (formerly APX001A), which blocks glycophosphatidylinositol biosynthesis is currently under development.Citation100

Conclusions

CF the is one of the most common indications for LTx and a diverse airway microbiome with high exposure to antimicrobial agents are hallmarks of this disease state. Improving multidisciplinary care and evolving CFTR-directed therapies are successfully preserving native lung function and delaying LTx. However, this delay may come with further challenges such as increasing multidrug resistance. Although few infections are established contraindications to LTx, immune suppression and pathogen reservoirs encourage re-emergent infections and threaten early and late LTx outcomes. Antimicrobial prophylaxis strategies are varied across virus, bacterial, and fungal pathogens, with a wide variation in global practice. Short-term bacterial prophylaxis against donor-derived infections and extended viral prophylaxis are generally well accepted strategies (depending on individual risk profiles); however, the approach to antifungal prophylaxis is less clear. Resistance to antimicrobial agents is emerging at a rapid rate, and the armamentarium against these pathogens is only slowly growing. Cautious and directed use of antimicrobial agents against multiresistant pathogens as guided by local epidemiology and resistance profiles and for well-defined timeframes are likely to continue to support the increased survival and improved quality of life experienced by CF patients following LTx.

Disclosure

The authors report no conflicts of interest in this work.

References

  • Cutting GR. MODIFIER GENETICS: cystic Fibrosis. Annu Rev Genom Hum Genet. 2005;6(1):237–260. doi:10.1146/annurev.genom.6.080604.162254
  • Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1(1):15010. doi:10.1038/nrdp.2015.1027189798
  • Keogh RH, Szczesniak R, Taylor-Robinson D, Bilton D. Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: a longitudinal study using UK registry data. J Cyst Fibros. 2018;17(2):218–227. doi:10.1016/j.jcf2017.11.01929311001
  • Nettie Burke SA. The Australian cystic fibrosis data registry annual report, 2019. Monash University, Department of Epidemiology and Preventive Medicine; 2021. Available from: https://www.cysticfibrosis.org.au/getmedia/bcab56d9-5bbe-4b19-9486-85a0ad2c2a21/ACFDR-2019-Annual-Report.pdf.aspx. Accessed June 15, 2021.
  • Thabut G, Christie JD, Mal H, et al. Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation. Am J Respir Crit Care Med. 2013;187(12):1335–1340. doi:10.1164/rccm.201303-0429OC23590274
  • Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for heart and lung transplantation: thirty-fourth adult lung and heart-lung transplantation report—2017; focus theme: allograft ischemic time. J Heart Lung Transpl. 2017;36(10):1047–1059. doi:10.1016/j.healun.2017.07.016
  • Benden C, Goldfarb SB, Stehlik J. An aging population of patients with cystic fibrosis undergoes lung transplantation: an analysis of the ISHLT Thoracic Transplant Registry. J Heart Lung Transpl. 2019;38(11):1162–1169. doi:10.1016/j.healun.2019.06.025
  • Paraskeva MA, Edwards LB, Levvey B, et al. Outcomes of adolescent recipients after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transpl. 2018;37(3):323–331. doi:10.1016/j.healun.2017.02.017
  • Thomas O’Neil BM. Cystic fibrosis foundation patient registry 2019 annual data report. Bethesda, Maryland: ©2020 Cystic Fibrosis Foundation; 2020. Available from: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2019-Patient-Registry-Annual-Data-Report.pdf. Accessed June 15, 2021.
  • Huang YJ, LiPuma JJ. The microbiome in cystic fibrosis. Clin Chest Med. 2016;37(1):59–67. doi:10.1016/j.ccm.2015.10.00326857768
  • Aaron SD. Changes in the cystic fibrosis airway microbiome after lung transplant: the more things change, the more they stay the same. Annals ATS. 2016;13(12):2109–2110. doi:10.1513/AnnalsATS.201609-700ED
  • Breijyeh Z, Jubeh B, Karaman R. Resistance of gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules. 2020;25(6):1340. doi:10.3390/molecules25061340
  • Rocha GA, Lima DF, Rodrigues ER, et al. Species distribution, sequence types and antimicrobial resistance of Acinetobacter spp. from cystic fibrosis patients. Epidemiol Infect. 2018;146(4):524–530. doi:10.1017/S095026881700284929283077
  • Vermeulen F, Proesmans M, Vermaelen M, Boon M, De Boeck K. Isolation of Enterobacteriaceae in airway samples is associated with worse outcome in preschool children with cystic fibrosis. J Cystic Fibrosis. 2020;19(3):365–369. doi:10.1016/j.jcf.2019.10.019
  • Egan T. Long term results of lung transplantation for cystic fibrosis. Eur J Cardio Thorac Surg. 2002;22(4):602–609. doi:10.1016/S1010-7940(02)00376-7
  • Dobbin C, Maley M, Harkness J, et al. The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre. J Hosp Infect. 2004;56(4):277–282. doi:10.1016/j.jhin.2004.01.00315066737
  • Bonvillain RW, Valentine VG, Lombard G, LaPlace S, Dhillon G, Wang G. Post-operative infections in cystic fibrosis and non-cystic fibrosis patients after lung transplantation. J Heart Lung Transpl. 2007;26(9):890–897. doi:10.1016/j.healun.2007.07.002
  • Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-β-lactamases: structure, function, epidemiology, treatment options, and the development pipeline. Antimicrob Agents Chemother. 2020;64:10. doi:10.1128/AAC.00397-20
  • Pollini S, Mugnaioli C, Dolce D, et al. Chronic infection sustained by a Pseudomonas aeruginosa high-risk clone producing the VIM-1 metallo-β-lactamase in a cystic fibrosis patient after lung transplantation. J Cystic Fibrosis. 2018;17(4):470–474. doi:10.1016/j.jcf.2018.01.007
  • Carugati M, Piazza A, Peri AM, et al.; IFALT working group. Fatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature. BMC Infect Dis. 2020;20(1):635. doi:10.1186/s12879-020-05338-332847524
  • Pouch SM, Patel G; the AST Infectious Diseases Community of Practice. Multidrug‐resistant gram‐negative bacterial infections in solid organ transplant recipients—guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9). doi:10.1111/ctr.13594
  • Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74(1):31–51. doi:10.1007/s40265-013-0168-224352909
  • Arena F, Marchetti L, Henrici De Angelis L, et al. Ceftolozane-tazobactam pharmacokinetics during extracorporeal membrane oxygenation in a lung transplant recipient. Antimicrob Agents Chemother. 2019;63(3). doi:10.1128/AAC.02131-18
  • Puzniak L, Dillon R, Palmer T, Collings H, Enstone A. Real-world use of ceftolozane/tazobactam: a systematic literature review. Antimicrob Resist Infect Control. 2021;10(1):68. doi:10.1186/s13756-021-00933-833832545
  • Pogue JM, Bonomo RA, Kaye KS. Ceftazidime/avibactam, meropenem/vaborbactam, or both? Clinical and formulary considerations. Clin Infect Dis. 2019;68(3):519–524. doi:10.1093/cid/ciy57630020449
  • Pouch SM. New drugs for difficult bugs: management of multidrug-resistant gram-negative infections in solid organ transplant recipients. Curr Opin Organ Transplant. 2021. doi:10.1097/MOT.0000000000000890
  • Koutsokera A, Varughese RA, Sykes J, et al. Pre-transplant factors associated with mortality after lung transplantation in cystic fibrosis: a systematic review and meta-analysis. J Cystic Fibrosis. 2019;18(3):407–415. doi:10.1016/j.jcf.2018.10.013
  • Courtney JM, Dunbar KEA, McDowell A, et al. Clinical outcome of Burkholderia cepacia complex infection in cystic fibrosis adults. J Cystic Fibrosis. 2004;3(2):93–98. doi:10.1016/j.jcf.2004.01.005
  • Snell G, Smibert O, Tullis E. Burkholderia in transplant: important to speciate and important to treat. In: Morris MI, Kotton CN, Wolfe C, editors. Emerging Transplant Infections. Springer International Publishing; 2020:1–19. doi:10.1007/978-3-030-01751-4_22-1
  • Bartley BL, Gardner KJ, Spina S, et al. High-dose inhaled nitric oxide as adjunct therapy in cystic fibrosis targeting Burkholderia multivorans. Case Rep Pediatr. 2020;2020:1–6. doi:10.1155/2020/1536714
  • McCallin S, Brüssow H. Clinical trials of bacteriophage therapeutics. In: Harper DR, Abedon ST, Burrowes BH, McConville ML, editors. Bacteriophages. Springer International Publishing; 2021:1099–1127. doi:10.1007/978-3-319-41986-2_38
  • Kamal F, Dennis JJ, Elliot MA. Burkholderia cepacia Complex Phage-Antibiotic Synergy (PAS): antibiotics stimulate lytic phage activity. Elliot MA, ed. Appl Environ Microbiol. 2015;81(3):1132–1138. doi:10.1128/AEM.02850-1425452284
  • Zeriouh M, Sabashnikov A, Patil NP, et al. Use of taurolidine in lung transplantation for cystic fibrosis and impact on bacterial colonization†. Eur J Cardio Thorac Surg. 2018;53(3):603–609. doi:10.1093/ejcts/ezx359
  • Adjemian J, Olivier KN, Prevots DR. Erratum: epidemiology of pulmonary nontuberculous mycobacterial sputum positivity in patients with cystic fibrosis in the United States, 2010–2014. Annals ATS. 2018;15(9):1114–1115. doi:10.1513/AnnalsATS.159erratum
  • Piersimoni C. Nontuberculous mycobacteria infection in solid organ transplant recipients. Eur J Clin Microbiol Infect Dis. 2012;31(4):397–403. doi:10.1007/s10096-011-1329-421732201
  • Degiacomi S, Chiarelli R, Makarov P. Mycobacterium abscessus, an emerging and worrisome pathogen among cystic fibrosis patients. IJMS. 2019;20(23):5868. doi:10.3390/ijms20235868
  • Vazirani J, Snell GI, Westall GP. Prolonged survival after lung transplantation in the absence of conventional immunosuppression. J Heart Lung Transpl. 2020;39(10):1159–1162. doi:10.1016/j.healun.2020.06.018
  • Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis. 2020;71(4):e1–e36. doi:10.1093/cid/ciaa24132628747
  • Weng Y-W, Huang C-K, Sy C-L, Wu K-S, Tsai H-C, Lee SS-J. Treatment for Mycobacterium abscessus complex–lung disease. J Formosan Med Assoc. 2020;119:S58–S66. doi:10.1016/j.jfma.2020.05.02832527504
  • Higuchi T, Oto T, Millar IL, Levvey BJ, Williams TJ, Snell GI. Preliminary report of the safety and efficacy of hyperbaric oxygen therapy for specific complications of lung transplantation. J Heart Lung Transpl. 2006;25(11):1302–1309. doi:10.1016/j.healun.2006.08.006
  • Tan S, Kasperbauer S. Nontuberculous mycobacteria. Semin Respir Crit Care Med. 2021;42(04):567–586. doi:10.1055/s-0041-173099734261181
  • Shirley M. Correction to: amikacin liposome inhalation suspension: a review in mycobacterium avium complex lung disease. Drugs. 2019;79(7):791. doi:10.1007/s40265-019-01111-230941606
  • Griffith DE, Eagle G, Thomson R, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium Complex (CONVERT). A prospective, open-label, randomized study. Am J Respir Crit Care Med. 2018;198(12):1559–1569. doi:10.1164/rccm.201807-1318OC30216086
  • Winthrop KL, Ku JH, Marras TK, et al. The tolerability of linezolid in the treatment of nontuberculous mycobacterial disease. Eur Respir J. 2015;45(4):1177–1179. doi:10.1183/09031936.0016911425614169
  • Poon YK, La Hoz RM, Hynan LS, Sanders J, Monogue ML. Tedizolid vs linezolid for the treatment of nontuberculous mycobacteria infections in solid organ transplant recipients. Open Forum Infect Dis. 2021;8(4):ofab093. doi:10.1093/ofid/ofab09333884276
  • Söderberg-Nauclér C, Fish KN, Nelson JA. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997;91(1):119–126. doi:10.1016/S0092-8674(01)80014-39335340
  • Paraskeva M, Bailey M, Levvey BJ, et al. Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome: CMV in the allograft is associated with BOS. Am J Transpl. 2011;11(10):2190–2196. doi:10.1111/j.1600-6143.2011.03663.x
  • Duncan AJ, Dummer JS, Paradis IL, et al. Cytomegalovirus infection and survival in lung transplant recipients. J Heart Lung Transplant. 1991;10(5 Pt 1):638–644; discussion 645–646.
  • van Delden C, Stampf S, Hirsch HH, et al. Burden and timeline of infectious diseases in the first year after solid organ transplantation in the Swiss transplant cohort study. Clin Infect Dis. 2020;71(7):e159–e169. doi:10.1093/cid/ciz111331915816
  • Heliövaara E, Husain S, Martinu T, et al. Drug-resistant cytomegalovirus infection after lung transplantation: incidence, characteristics, and clinical outcomes. J Heart Lung Transplant. 2019;38(12):1268–1274. doi:10.1016/j.healun.2019.09.00531570289
  • Gagermeier JP, Rusinak JD, Lurain NS, et al. Subtherapeutic ganciclovir (GCV) levels and GCV-resistant cytomegalovirus in lung transplant recipients. Transpl Infect Dis. 2014;16(6):941–950. doi:10.1111/tid.1231725491023
  • Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–931. doi:10.1097/TP.000000000000219129596116
  • Wilkens H, Sester M. Treatment of cytomegalovirus infection with cidofovir and CMV immune globulin in a lung transplant recipient. Case Rep Transplant. 2016;2016:4560745. doi:10.1155/2016/456074526885432
  • Schulz U, Solidoro P, Müller V, et al. CMV immunoglobulins for the treatment of CMV infections in thoracic transplant recipients. Transplantation. 2016;100(Suppl 3):S5–10. doi:10.1097/TP.000000000000109726900992
  • Veit T, Munker D, Kauke T, et al. Letermovir for difficult to treat cytomegalovirus infection in lung transplant recipients. Transplantation. 2020;104(2):410–414. doi:10.1097/TP.000000000000288631385924
  • Smith C, Beagley L, Rehan S, et al. Autologous adoptive T-cell therapy for recurrent or drug-resistant cytomegalovirus complications in solid organ transplant recipients: a single-arm open-label phase I clinical trial. Clin Infect Dis. 2019;68(4):632–640. doi:10.1093/cid/ciy54929982441
  • Kuri A, Jacobs BM, Vickaryous N, et al. Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom. BMC Public Health. 2020;20(1):912. doi:10.1186/s12889-020-09049-x32532296
  • Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. N Engl J Med. 1998;338(20):1413–1421. doi:10.1056/NEJM1998051433820039580648
  • Adami J, Gäbel H, Lindelöf B, et al. Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer. 2003;89(7):1221–1227. doi:10.1038/sj.bjc.660121914520450
  • Saueressig MG, Boussaud V, Amrein C, Guillemain R, Souilamas J, Souilamas R. Risk factors for post-transplant lymphoproliferative disease in patients with cystic fibrosis. Clin Transplant. 2011;25(4):E430–436. doi:10.1111/j.1399-0012.2011.01464.x21518001
  • Lowery EM, Adams W, Grim SA, Clark NM, Edwards L, Layden JE. Increased risk of PTLD in lung transplant recipients with cystic fibrosis. J Cyst Fibros. 2017;16(6):727–734. doi:10.1016/j.jcf.2017.03.01328456611
  • AlDabbagh MA, Gitman MR, Kumar D, Humar A, Rotstein C, Husain S. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: a systematic review. Am J Transplant. 2017;17(3):770–781. doi:10.1111/ajt.1402027545492
  • Reshef R, Vardhanabhuti S, Luskin MR, et al. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder(★). Am J Transplant. 2011;11(2):336–347. doi:10.1111/j.1600-6143.2010.03387.x21219573
  • Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines. Br J Haematol. 2010;149(5):693–705. doi:10.1111/j.1365-2141.2010.08160.x20408848
  • Choquet S, Oertel S, LeBlond V, et al. Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Ann Hematol. 2007;86(8):599–607. doi:10.1007/s00277-007-0298-217522862
  • Trappe RU, Dierickx D, Zimmermann H, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol. 2017;35(5):536–543. doi:10.1200/JCO.2016.69.356427992268
  • Viswesh V, Yost SE, Kaplan B. The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: a systematic review. Transplant Rev (Orlando). 2015;29(3):175–180. doi:10.1016/j.trre.2015.02.00425736693
  • Dufek S, Haitel A, Müller-Sacherer T, Aufricht C. Duct Bellini carcinoma in association with BK virus nephropathy after lung transplantation. J Heart Lung Transplant. 2013;32(3):378–379. doi:10.1016/j.healun.2012.11.03323321158
  • Kuppachi S, Holanda D, Eberlein M, et al. An unexpected surge in plasma BKPyV viral load heralds the development of BKPyV-associated metastatic bladder cancer in a lung transplant recipient with BKPyV nephropathy. Am J Transplant. 2017;17(3):813–818. doi:10.1111/ajt.1405727647675
  • Moscarelli L, Caroti L, Antognoli G, et al. Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience. Clin Transplant. 2013;27(4):546–554. doi:10.1111/ctr.1215123758330
  • Wojciechowski D, Chandran S, Webber A, Hirose R, Vincenti F. Mycophenolate mofetil withdrawal with conversion to everolimus to treat BK virus infection in kidney transplant recipients. Transplant Proc. 2017;49(8):1773–1778. doi:10.1016/j.transproceed.2017.06.03028923623
  • Shitrit D, Lev N, Bar-Gil-Shitrit A, Kramer MR. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int. 2005;17(11):658–665. doi:10.1007/s00147-004-0779-315616809
  • Ishii K, Yamamoto F, Homma S, et al. Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review. BMC Neurol. 2019;19(1):263. doi:10.1186/s12883-019-1493-131672142
  • Crowhurst T, Koszyca B, Holmes M, Holmes-Liew C-L. Progressive multifocal leukoencephalopathy in a lung transplant recipient presenting with memory impairment: case report and literature review. Transpl Infect Dis. 2020;22(3):e13293. doi:10.1111/tid.1329332291834
  • Renner S, Nachbaur E, Jaksch P, Dehlink E. Update on respiratory fungal infections in cystic fibrosis lung disease and after lung transplantation. JoF. 2020;6(4):381. doi:10.3390/jof604038133371198
  • Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transpl. 2003;22(3):258–266. doi:10.1016/S1053-2498(02)00477-1
  • 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(8):1101–1111. doi:10.1086/65126220218876
  • Solé A, Salavert M. Fungal infections after lung transplantation. Transplant Rev. 2008;22(2):89–104. doi:10.1016/j.trre.2007.12.007
  • Li J, Nguyen C, Garcia-Diaz J. Role of new antifungal agents in the treatment of invasive fungal infections in transplant recipients: isavuconazole and new posaconazole formulations. JoF. 2015;1(3):345–366. doi:10.3390/jof103034529376915
  • Ziesing S, Suerbaum S, Sedlacek L. Fungal epidemiology and diversity in cystic fibrosis patients over a 5-year period in a national reference center. Med Myco. 2016;54(8):781–786. doi:10.1093/mmy/myw035
  • Al Shakirchi M, Klingspor L, Bergman P, Hjelte L, de Monestrol I. A 16-year retrospective study on fungal prevalence and diversity in patients with cystic fibrosis: candida dubliniensis was associated with a decline in lung function. Int J Infect Dis. 2020;96:663–670. doi:10.1016/j.ijid.2020.05.06332450290
  • Palmer SM, Alexander BD, Sanders LL, et al. Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients1. Transplantation. 2000;69(11):2360–2366. doi:10.1097/00007890-200006150-0002510868641
  • Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020–2029. doi:10.1056/NEJMoa02158512490683
  • Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24):2472–2482. doi:10.1056/NEJMoa06690617568028
  • Vazirani J, Westall GP, Snell GI, Morrissey CO. Scedosporium apiospermum and Lomentospora prolificans in lung transplant patients – a single center experience over 24 years. Transpl Infect Dis. 2021;23(3). doi:10.1111/tid.13546
  • Denton EJ, Smibert O, Gooi J, et al. Invasive Scedosporium sternal osteomyelitis following lung transplant: cured. Med Mycol Case Rep. 2016;12:14–16. doi:10.1016/j.mmcr.2016.07.00127595059
  • Husain S, Muñoz P, Forrest G, et al. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis. 2005;40(1):89–99. doi:10.1086/42644515614697
  • Troke P, Aguirrebengoa K, Arteaga C, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52(5):1743–1750. doi:10.1128/AAC.01388-0718212110
  • Seidel D, Meißner A, Lackner M, et al. Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope®. Crit Rev Microbiol. 2019;45(1):1–21. doi:10.1080/1040841X.2018.151436630628529
  • Jenks JD, Seidel D, Cornely OA, et al. Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: analysis of patients in the FungiScope® registry. Mycoses. 2020;63(5):437–442. doi:10.1111/myc.1306732080902
  • Neoh CF, Snell GI, Kotsimbos T, et al. Antifungal prophylaxis in lung transplantation-a world-wide survey: world-wide survey of antifungal prophylaxis. Am J Transpl. 2011;11(2):361–366. doi:10.1111/j.1600-6143.2010.03375.x
  • 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(12):1522–1531. doi:10.1111/ctr.1285427653443
  • Pennington KM, Baqir M, Erwin PJ, Razonable RR, Murad MH, Kennedy CC. Antifungal prophylaxis in lung transplant recipients: a systematic review and meta‐analysis. Transpl Infect Dis. 2020;22(4). doi:10.1111/tid.13333
  • Bhaskaran A, Mumtaz K, Husain S. Anti-aspergillus prophylaxis in lung transplantation: a systematic review and meta-analysis. Curr Infect Dis Rep. 2013;15(6):514–525. doi:10.1007/s11908-013-0380-y24173585
  • Husain S, Bhaskaran A, Rotstein C, et al. A strategy for prevention of fungal infections in lung transplantation: role of bronchoalveolar lavage fluid galactomannan and fungal culture. J Heart Lung Transpl. 2018;37(7):886–894. doi:10.1016/j.healun.2018.02.006
  • Wiederhold NP. Review of the novel investigational antifungal olorofim. JoF. 2020;6(3):122. doi:10.3390/jof6030122
  • Tio SH, Thursky K, Ng G, Rex JH, Carney D, Slavin M. Olorofim for a case of severe disseminated Lomentospora prolificans infections. In Proceedings of the 30th European Congress of Clinical Microbiology and Infectious Diseases, Paris, France. April 18 2020.
  • Chen S, Rai NJ, Cunneen S, et al. A case of Lomentospora prolificans treated with the novel antifungal olorofim. In Proceedings of the 30th European Congress of Clinical Microbiology and Infectious Diseases, Paris, France. 2020:abstr. 2585.
  • Morrissey CO, Garlick J, Gaffney N, Harvey E, Rex J. Long-term use of olorofim in the treatment of scedosporium apiospermum chest wall infection. In Proceedings of the 31st European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria. 2021:abstr.2641.
  • Zhao M, Lepak AJ, Marchillo K, et al. APX001 pharmacokinetic/pharmacodynamic target determination against aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2019;63:e02372–18. doi:10.1128/AAC.02372-1830670426