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ABSTRACT
Introduction
Solid organ transplant (SOT) recipients face an increased susceptibility to invasive fungal infection (IFI) due to filamentous fungi. Post-transplant invasive aspergillosis (IA) and mucormycosis are related to exceedingly high mortality rates and graft loss risk, and its management involve a unique range of clinical challenges.
Areas covered
First, the current treatment recommendations for IA and mucormycosis among SOT recipients are critically reviewed, including the supporting evidence. Next, we discussed particular concerns in this patient population, such as drug-drug interactions (DDIs) between triazoles and post-transplant immunosuppression or treatment-related toxicity. The role for immunomodulatory and host-targeted therapies is also considered, as well as the theoretical impact of the intrinsic antifungal activity of calcineurin inhibitors. Finally, a personal opinion is made on future directions in the pharmacological approach to post-transplant IFI.
Expert opinion
Despite relevant advances in the treatment of mold IFIs in the SOT setting, such as the incorporation of isavuconazole (with lower incidence of DDIs and better tolerability than voriconazole), there remains a large room for improvement in areas such as the position of combination therapy or the optimal strategy for the reduction of baseline immunosuppression. Importantly, future studies should define the specific contribution of newer antifungal agents and classes.
Article highlights
Invasive fungal infection (IFI) due to filamentous fungi is one of the most serious complications in solid organ transplant (SOT) recipients, with high rates of mortality and graft loss among survivors.
Second-generation expanded-spectrum triazoles (voriconazole and isavuconazole) are the agents of choice for post-transplant invasive aspergillosis (IA). Voriconazole requires therapeutic drug monitoring and involves a high risk of clinically relevant interactions with immunosuppressive drugsin particular, calcineurin and mTOR inhibitors.
As compared to voriconazole, isavuconazole exhibits predictable pharmacokinetics, more easily manageable drug-drug interactions and better tolerability, although both triazoles have not been head-to-head compared in the SOT population.
The use of lipid-based formulations of amphotericin B (AmB) is recommended as the first-line therapy for post-transplant mucormycosis. Mortality and treatment-related nephrotoxicity rates are still high. Clinical experience with frontline posaconazole and isavuconazole is limited.
Due to the lack of supporting evidence, no clear recommendations can be made on the role of combination antifungal therapy in the management of post-transplant IA (e.g. voriconazole plus an echinocandin) or mucormycosis (e.g. AmB plus isavuconazole).
As compared to the non-transplant population, SOT recipients face an increased risk of treatment-related adverse events and premature discontinuation of therapy.
Various host-targeted approaches have been proposed to improve the outcomes of post-transplant IFI, including the adjuvant use of recombinant interferon-γ or immune checkpoint inhibitors. The potential for increased alloreactivity and graft rejection remains a concern.
Abbreviations
| ABLC | = | amphotericin B lipid complex |
| allo-HSCT | = | allogeneic hematopoietic stem-cell transplantation |
| AmB | = | amphotericin B |
| AST-IDCoP | = | American Society of Transplantation Infectious Diseases Community of Practice |
| AUC0–24 | = | area under the concentration-time curve |
| C/D | = | concentration/dose |
| CI | = | confidence interval |
| CNS | = | central nervous system |
| COVID-19 | = | coronavirus disease 2019 |
| CTLA-4 | = | cytotoxic T lymphocyte antigen 4 |
| CYP | = | cytochrome P450 |
| DDI | = | drug-drug interaction |
| EMA | = | European Medicines Agency |
| ESCMID | = | European Society for Clinical Microbiology and Infectious Diseases |
| ECMM | = | European Confederation of Medical Mycology |
| ERS | = | European Respiratory Society |
| FDA | = | Food and Drug Administration |
| NFAT | = | nuclear factor of activated T cells |
| HT | = | heart transplantation |
| IA | = | invasive aspergillosis |
| ICI | = | immune checkpoint inhibitor |
| IFI | = | invasive fungal infection |
| IFN | = | interferon |
| IV | = | intravenous |
| IDSA | = | Infectious Disease Society of America |
| KT | = | kidney transplantation |
| LT | = | liver transplantation |
| LTx | = | lung transplantation |
| MATE1 | = | human multidrug and toxin extrusion |
| MIC | = | minimum inhibitory concentration |
| MSG-RC | = | Mycoses Study Group & Research Consortium |
| mTOR | = | mammalian target of rapamycin |
| OCT | = | organic cation transporter |
| PD-1 | = | programmed cell death 1 |
| PK | = | pharmacokinetics |
| RCT | = | randomized clinical trial |
| SOT | = | solid organ transplantation |
| TDM | = | therapeutic drug monitoring |
Declaration of interest
M Fernández-Ruiz received honoraria for educational activities from Pfizer, MSD and Gilead Sciences. They also hold a contract ‘Miguel Servet’ (CP18/00073) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.
The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.