Real-life experience on the use of isavuconazole in solid organ transplantation

Abstract

Solid organ transplant (SOT) recipients have a higher risk of developing invasive fungal infection (IFI). Isavuconazole is a novel broad-spectrum azole active against Aspergillus and Mucor. Isavuconazole is well tolerated, shows an excellent bioavailability and predictable pharmacokinetics, good diffusion to tissues, significantly reduced drug–drug interactions with immunosuppressive drugs in comparison with other broad-spectrum azoles, and few serious adverse effects, including hepatic toxicity. We have performed an extensive literature review concerning the clinical experience on the use of isavuconazole in SOT as prophylaxis and treatment of IFI, which included the SOTIS and the ISASOT studies, and fourteen published case reports. Clinical response, all-cause and invasive aspergillosis-attributable mortality in recipients treated with isavuconazole were similar to those described with voriconazole. Drug–drug interactions with immunosuppressive agents were manageable after the adjustment of tacrolimus and mTOR inhibitors. Isavuconazole showed fewer drug-related side effects and a smaller rate of premature discontinuation than voriconazole. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IFI in SOT, and can be an alternative to voriconazole as antifungal prophylaxis in lung transplantation. Nonetheless, more clinical studies are needed.

Resumen

Los receptores de trasplante de órgano sólido tienen un mayor riesgo de desarrollar una infección fúngica invasiva. El isavuconazol es un nuevo azol de amplio espectro, activo frente a Aspergillus y Mucor. Es bien tolerado, presenta una biodisponibilidad excelente y una farmacocinética predecible, buena difusión a tejidos, interacciones farmacológicas significativamente menores que otros azoles y pocos efectos adversos graves, incluida la toxicidad hepática. Se ha realizado una extensa revisión bibliográfica sobre la experiencia clínica en el uso de isavuconazol en trasplante de órgano sólido como profilaxis y tratamiento de infección fúngica invasiva que incluyó los estudios SOTIS e ISASOT y catorce casos clínicos. La respuesta clínica y la mortalidad atribuible a la aspergilosis invasiva y por todas las causas en los receptores tratados con isavuconazol fueron similares a las descritas con voriconazol. Las interacciones farmacológicas con los agentes inmunosupresores fueron manejables después del ajuste de tacrólimus y los inhibidores de mTOR. El isavuconazol provocó menos efectos secundarios y una tasa de interrupción prematura inferior a aquella para el voriconazol. En conclusión, el isavuconazol parece ser una opción razonable para el tratamiento de la infección fúngica invasiva en trasplante de órgano sólido, y puede ser una alternativa al voriconazol como profilaxis antifúngica en el trasplante de pulmón. No obstante, se necesitan más estudios clínicos.

Solid organ transplant (SOT) recipients have an increased risk of developing invasive fungal infections (IFI) due to the prolonged use of immunosuppressive drugs that diminish the rate of graft rejection.⁴³ The administration of high doses of corticosteroid therapy for acute rejection, renal replacement treatment after transplantation, cytomegalovirus infection, extracorporeal membrane oxygenation (ECMO), and liver re-transplantation or transplantation due to fulminant hepatic failure have been described as risk factors for IFI.^32,36 Among SOT, lung transplantation (LuT) is linked to a greater risk of developing IFI due to ciliary and cough reflex impairment, early airway ischemia, viral infections, rejection and augmented immunosuppression, pre- or post-transplant Aspergillus colonization within a year after transplantation, and hypogammaglobulinemia (IgG < 400 mg/dL).^20,22 Although most infections are caused by species of Candida and Aspergillus, IFI caused by zygomycetes (mucormycosis), Fusarium, Scedosporium, and dematiaceous fungi (dark molds) have also been described in these patients.²⁵ The morbidity and mortality associated with IFI in SOT is extremely high, and the treatment normally requires the combined use of antifungal drugs and surgical resection in the infection site, whenever possible.³⁵

Several antifungal drugs can be prescribed to treat IFI. Recent published guidelines consider voriconazole as the treatment of choice for invasive pulmonary aspergillosis.^13,42 Nonetheless, the potential hepatotoxicity of this azole, and it's frequent interaction with the immunosuppressive drugs, such as calcineurin (tacrolimus, cyclosporine) and mTOR (sirolimus, everolimus) inhibitors, make the use of voriconazole in SOT complicated.¹⁰ Liposomal amphotericin B is considered the treatment of choice for mucormycosis, while posaconazole is recommended as a second-line drug.³ Unfortunately, the increased risk of nephrotoxicity associated with amphotericin B,⁷ and the drug–drug interaction between posaconazole and immunosuppressive drugs,¹⁷ entails that the administration of these antifungals in SOT is complicated.

Isavuconazole (ISA) (Cresemba®; Pfizer, New York City, USA) is a second-generation broad-spectrum triazole with activity against yeasts, dimorphic fungi, and molds. ISA shows excellent oral bioavailability and predictable pharmacokinetics, good tolerance and few adverse effects, mainly gastrointestinal symptoms, headache, peripheral edema, and dose-dependent shortening of the QT interval. The diffusion to tissues, including the central nervous system, is good.²⁶ Moreover, the intravenous formulation of ISA does not contain the excipient sulfobutyl ether β-cyclodextrin sodium (SBECD), which allows its use in patients with moderate or severe kidney failure. Synergistic action between ISA and micafungin in the treatment of invasive pulmonary aspergillosis has also been confirmed.³⁷

We have performed an extensive literature review concerning the use of ISA, in a real-life setting, for the treatment of IFI and as antifungal prophylaxis in SOT.

Methods

We conducted a computer-based PubMed (Medline) search with the MeSH (Medical Subject Headings). “Isavuconazole”, “Solid Organ Transplantation”, “Invasive Fungal Infection” “Invasive Aspergillosis” (IA) and “Invasive Mould Disease” (IMD) were used to find published literature (until August 2024) that describe the clinical use of ISA in SOT. We searched for articles written in English language. Case reports, prospective and retrospective clinical studies that included SOT patients who received ISA as prophylaxis or as treatment for IFI were selected. Articles from which data could not be gathered based on the published results were not included.

Real-life experience on the use of ISA in SOT

Overall, 18 studies met the inclusion criteria, including one multicenter retrospective study which included 81 SOT recipients with proven or probable IMD treated with ISA for ≥24 h as first-line or salvage therapy,⁸ one prospective observational study which described 53 SOT recipients treated with ISA for fungal infections,³³ one post hoc analysis of two retrospective multicenter cohorts of SOT recipients with IFI and treated with voriconazole or ISA,⁹ fourteen case reports describing the use of ISA as treatment in SOT,^{1,5,6,11,12,14,18,19,21,23,24,29,40,41} and a single-center, retrospective study which included LuT recipients who received ISA or voriconazole as antifungal prophylaxis (Fig. 1).³⁹ Case reports are described in Table 1.

Fig. 1.

Flowchart of the study.

Table 1.

Brief description of the 14 cases included in the review.

Authors [ref.], year, country	Gender	Age (years)	Organ transplanted	Type of infection	First line treatment	Length of treatment with isavuconazole	Isavuconazole-induced side effects	Isavuconazole stopped due to side effects?	Outcome
Assaf et al.,^1 2020, France	Male	65	Heart	Aspergillus fumigatus sternal osteomyelitis	Voriconazole, followed by liposomal amphotericin B^a	10 months	No	No	Successful treatment
Kim et al.,^23 2015, United States	Female	30	Lung	Mediastinal Aspergillus fumigatus	Caspofungin and liposomal amphotericin B^b	8 weeks	Possibly, hair thinning	No	Successful management with isavuconazole and tacrolimus TDM
Happaerts et al.,^18 2022, Belgium	Male	38	Lung and liver	Invasive pulmonary aspergillosis	Voriconazole^c	1 day	Azole-induced myositis	Yes	Successful treatment
Hernández et al.,^19 2021, United States	Male	69	Kidney	Disseminated Cladophialophora bantiana infection	Voriconazole and liposomal amphotericin B^d	2 months	No	No	Death
Lango-Maziarz et al.,^24 2022, Poland	Male	67	Heart	Colonic mucormycosis	Isavuconazole and liposomal amphotericin B	–	No	No	Death
Fortuzi et al.,^11 2023, United States	Male	51	Liver	Pleural aspergillosis	Isavuconazole	–	No	No	Pending follow-up
Gani et al.,^12 2019, United States	Male	79	Kidney	Gastric mucormycosis	Isavuconazole	6 months	No	No	Successful treatment
Maisons et al.,^29 2022, France	Male	69	Heart	Subcutaneous nodule by Alternaria infectoria	Isavuconazole	2 months	Tacrolimus overdose, acute renal failure, diarrhea, tachycardia	Yes	Successful treatment
Trujillo et al.,^41 2021, Spain	Female	55	Kidney	IA after a COVID-19 infection	Isavuconazole	–	No	No	Successful treatment
Kabulski et al.,^21 2018, United States	Female	20	Lung	Mucormycosis	Isavuconazole	6 months	Nausea, abdominal discomfort, and diarrhea	No	Successful treatment, using isavuconazole and tacrolimus TDM
Silva et al.,^40 2018, Spain	Male	46	Small bowel	IA	Voriconazole and liposomal amphotericin B^e	6 weeks	No	No	Pending follow-up
Dvořáčková et al.,^6 2023, Czech Republic	Female	70	Lung	Mucormycosis	Isavuconazole and liposomal amphotericin B	12 months	No	No	Successful treatment, using isavuconazole TDM
Dalla Gasperina et al.,^5 2019, Italy	Male	68	Kidney	Subcutaneous IMD	Voriconazole, followed by posaconazole^f	–	No	No	Successful treatment
Giacinta et al.,^14 2024, Spain	Male	65	Heart	Aspergillus granulosus femoral osteomyelitis	Isavuconazole	137 days	No	No	Successful treatment

IA: invasive aspergillosis; IMD: invasive mould disease; TDM: therapeutic drug monitoring.

a

Voriconazole was stopped due to a severe drug-induced cutaneous and neurological toxicity, while liposomal amphotericin B was withdrawn due to acute kidney injury.

b

Liposomal amphotericin B was stopped because of poor tolerance.

c

Voriconazole was stopped due to a drug-induced myositis.

d

Voriconazole was changed to isavuconazole due to the better side-effect profile of the latter.

e

Voriconazole was withdrawn due to drug-related hepatitis.

f

Vorizonazole was stopped due to hallucinations, confusion, dizziness, and burning eyes, whereas posaconazole was withdrawn due to nausea and vomiting.

SOTIS study

SOTIS is a retrospective study that included adult SOT recipients with proven or probable IMD who received ISA for ≥24 h as first-line or salvage therapy at ten Spanish centers between September 2017 and November 2021.⁸ The study focused on the clinical response by weeks 6 and 12, the rates of treatment-emergent adverse events, and premature ISA discontinuation. Transplant types comprised kidney (KT) or sequential pancreas after kidney (29 [35.8%]), LuT (23 [28.4%]), liver (LT) (15 [18.5%]), heart (HT) (11 [13.6%]), and small bowel/multivisceral (3 [3.7%]). Overall, 71 and 10 SOT recipients received ISA for the treatment of invasive aspergillosis and mucormycosis, respectively. ISA was used as first-line treatment in 72.8% of patients, and the median duration of treatment was 58 days (interquartile range [IQR 19–116). Clinical response by weeks 6 and 12 was achieved in 53.1% and 54.3% of the patients, respectively, whereas the IMD-attributable mortality rate by weeks 6 and 12 was 19.8% and 22.2%, respectively. At least 17.3% of the patients developed an adverse event, most frequently liver enzyme elevation (8.6%). A total of five patients (6.2%) required permanent discontinuation of ISA (liver toxicity and gastrointestinal disturbances in two cases each, and neurological adverse event in one patient). Tacrolimus dose reduction was the most common initial drug modification after starting ISA therapy (the daily tacrolimus dose was reduced by a median of 50% within the first day), although tacrolimus concentration remained stable throughout the first month of therapy. The authors concluded that ISA was a safe therapeutic option for IMD in SOT recipients, with a clinical efficacy comparable to that in other patient groups.

ISASOT study

The ISASOT was a non-comparative prospective observational study that included 53 SOT recipients with a median age of 60 years old (IQR 46–65), who were treated with ISA for a fungal infection.³³ Interestingly, the majority of the patients were LuT recipients (83%), received ISA for a fungal tracheobronchitis (25 recipients [47.2%]), and Aspergillus spp. was the most frequent isolated fungal species (81.1%). ISA was used as first-line treatment in 67.9% of patients, and the median duration of treatment was 81 days (IQR 15–197). Clinical cure rate at the end of treatment was 50.9%, and at the end of follow-up IMD-attributable mortality accounted for 12.5% of all deceased patients. Approximately 50% of the recipients developed, at least, one adverse event. The most common adverse events were cholestatic liver enzymes elevation (34%) and myopathy (13.2%). Only six (11.3%) patients required total premature discontinuation of ISA (hepatotoxicity and fatigue in two cases each, digestive intolerance and myopathy in one case each). The dose of tacrolimus was adjusted during the first 14 days of treatment in 85.1% of the recipients who were receiving this immunosuppressive drug. Seven recipients (13.2%) received mTOR inhibitors during ISA treatment (sirolimus in six and everolimus in one patient), which also required dose adjustment within the first 14 days. There were no significant interactions or toxicity related to the simultaneous administration of mTOR inhibitors and ISA. The authors concluded that therapy with ISA was well tolerated, and proved to be an effective treatment for fungal infections in SOT. Drug–drug interaction episodes were correctly managed in the daily clinical practice, including those in patients who were also receiving concomitant mTOR inhibitors.

Post hoc analysis of the SOTIS and the DiasperSOT studies

This study described the result of a post hoc analysis of two retrospective multicenter cohorts of SOT recipients treated for proven/probable IA with ISA (SOTIS) or voriconazole (DiasperSOT) as first-line therapy,¹⁵ for ≥48 h, either in monotherapy or combination regimen.⁹ A total of 57 patients were included in the SOTIS study, and 77 patients were included in the DiasperSOT study (total of 134 recipients included). The primary outcome was the rate of clinical response at week 12 after starting the antifungal therapy, while the secondary outcomes comprised all-cause, IA-attributable mortality, the rates of treatment-emergent adverse events, and premature treatment discontinuation at week 12. Both groups were comparable in their demographics and clinical characteristics. The authors reported that there were no differences in the rate of clinical response between both groups (59.6% vs. 59.7%, respectively; odds ratio [OR], 0.99; 95% confidence interval [CI], 0.49–2.00), which was confirmed after propensity score adjustment (OR, 0.81; 95% CI, 0.32–2.05) and matching (OR, 0.79; 95% CI, 0.31–2.04). All-cause (28.1% [16/57] vs. 29.9% [23/77]; p = 0.821) and IA-attributable mortality (15.8% [9/57] vs. 22.1% [17/77]; p = 0.363) were also similar in the ISA and voriconazole groups, respectively. It is worthy of mention that the recipients treated with ISA were less likely to experience treatment-induced adverse events (17.5% vs. 37.7%; p = 0.011) and premature treatment discontinuation (8.8% vs. 23.4%; p = 0.027). The authors concluded that first-line treatment with ISA for IA after SOT transplantation led to similar clinical outcomes to those treated with voriconazole, but with a better tolerability and a higher rate of treatment completion.

Case reports

Fourteen SOT recipients suffering IFI were treated with ISA (Table 1). Approximately, 71.4% were male, with a mean age of 56 ± 17 years. HT (28.6%) and KT (28.6%) recipients were the most frequent, followed by LuT (21.4%). Species within Aspergillus accounted for almost 50% of the IFI cases treated with ISA. ISA was prescribed as first-line treatment in eight (57.1%) patients, and mostly used as second-line therapy due to drug-induced side effects associated to the antifungal drugs previously prescribed. Switching voriconazole for ISA was safe and well tolerated, with only one patient re-experiencing an azole-related side effect while having ISA (azole-induced myositis). Although four (28.6%) patients developed an ISA-associated side effect, only two (14.3%) required discontinuation of the antifungal drug. Treatment failure was reported in two patients (14.3%).

ISA as antifungal prophylaxis in LuT

A single-center, retrospective study, which included patients who underwent LuT between September 1st 2013 and February 28th 2018, and received ISA (n = 144) or voriconazole (n = 156) as antifungal prophylaxis for a median of 3.4 and 3.1 months, respectively, was carried out.³⁹ There were no differences in the rates of diagnosed IFI (7% [10/144] vs. 8% [13/156]; p = 0.7), elapsed time until IFI onset (p = 0.99) or in the rate of breakthrough IFI (3.5% [5/144]) vs. 3.2% [5/156]; p = 1.0) between ISA and voriconazole groups, respectively. Hepatotoxicity and neurotoxicity were significantly more common in the voriconazole group (p < 0.0001). Moreover, early discontinuation of prophylaxis due to adverse events was significantly more common in patients receiving voriconazole (11% [15/138] vs. 36% [54/152]; p = 0.0001). The authors concluded that ISA was as effective as voriconazole in preventing IFI after LuT, and better tolerated.

Discussion

We have performed an extensive literature review; a total of 4 clinical studies and 14 case reports met the selected criteria. We observed that ISA appeared to be well-tolerated, and drug–drug interaction between ISA and the immunosuppressive drugs were manageable in the daily clinical practice.

ISA was approved for the treatment of IA and mucormycosis based on two pivotal trials.^28,30 The SECURE trial included patients who received ISA or voriconazole for an IMD.²⁸ A total of 258 patients were enrolled in each arm. ISA was non-inferior to voriconazole as primary treatment of suspected invasive mold disease. This trial confirmed that ISA was better tolerated, with fewer overall drug-related adverse events (42% vs. 60%, p < 0.001) and lesser hepatobiliary adverse events (9% vs. 16%, p = 0.016).²⁸ The VITAL trial included 37 patients diagnosed with mucormycosis, who were treated with ISA for a median of 84 days.³⁰ Patients were matched with up to three contemporaneous FungiScope patients who had received a primary amphotericin B-based treatment for proven or probable mucormycosis. By the end-of-treatment, complete and partial response to ISA were similar to those associated with liposomal amphotericin B, and less than 10% of enrolled patients experienced hepatotoxicity.³⁰ ISA proved to be a reasonable primary or secondary treatment (refractory or intolerant to other antifungals). Unfortunately, of the approximately 550 patients included in both clinical trials, only one was a SOT recipient.

There are very few studies comparing the effectiveness of ISA and voriconazole in the treatment of IFI in SOT. Noteworthy, the study by Fernandez-Ruiz et al. in which two groups of SOT recipients treated with ISA or voriconazole were compared, concluded that the clinical response, all-cause mortality and IA-attributable mortality were similar between both groups, but with a significant smaller rate of treatment-induced adverse events and premature treatment discontinuation in patients who received ISA.⁹ The Swiss Transplantation Cohort Study, which included 70 patients diagnosed with probable and proven IA, treated with different antifungal drugs than ISA, reported a mortality rate of 22.9% at the third month of IA diagnosis,³⁴ whereas a multinational study that included 112 KT recipients diagnosed with IPA, who were also treated with antifungal drugs different than ISA, reported that 39.3% of the patients had died in week 12 after the diagnosis.²⁷ The mortality rate of both studies was very similar or even higher than that reported in the SOTIS study (all-cause mortality of 32.1%, and IMD-attributable mortality of 22.2%).⁸

Our review corroborates that the combined use of ISA and immunosuppressive drugs, such as calcineurin and mTOR inhibitors, can be effectively manageable in the daily clinical practice. ISA is associated with a smaller rate of drug-induced toxicity than voriconazole in SOT recipients. ISA is a milder inhibitor of the cytochrome CYP3A4 than other triazole antifungal agents, such as voriconazole or posaconazole, resulting in lesser drug–drug interactions, and a fewer rate of drug-related side effects.¹⁶ The rate of permanent discontinuation due to ISA-related adverse effects was notably lower in the SOTIS and ISASOT studies compared to the DiasperSOT study. For instance, in the DiasperSOT study, 35.3% of SOT recipients treated with voriconazole experienced some degree of drug-related toxicity, whereas this figure was 17.3% in the SOTIS study. Moreover, 15.3% of patients in the DiasperSOT study required premature discontinuation of the antifungal agent, compared to 6.2% and 11.3% in the SOTIS and ISASOT studies, respectively.¹⁵ The same trend was observed when ISA was prescribed as prophylaxis in LuT.³⁹ Nevertheless, we can gather from this review that SOT recipients who required discontinuation of voriconazole due to any adverse event were able to continue treatment with ISA.

Although ISA concentration in serum has shown more stability than voriconazole, significant interpatient variability and between types of SOT has been described. Therapeutic drug monitoring (TDM) helps in guiding the immunosuppressants.⁴ Two retrospective studies that included 55 and 26 SOT recipients treated with ISA as prophylaxis, and being under TDM for both ISA and tacrolimus, concluded that the interaction between these drugs was more significant after liver transplantation, the impact of ISA on tacrolimus concentration varied between individuals, and that there was moderate interpatient variability in ISA pharmacokinetic parameters.^38,44 Although there is still limited data on the routine use of TDM of ISA,^2,31 it could be especially useful in patients who do not respond to treatment, have unexpected toxicity or possible drug–drug interaction, patients suffering an infection caused by a mold with elevated minimum inhibitory concentration values, or patients in whom the infection is located in sanctuary sites, such as the central nervous system.⁴²

Most patients of the SOTIS and the ISASOT studies had their daily dose of tacrolimus lowered at the beginning of therapy, and adjusted according to the serum concentration afterwards. At the end of the treatment, the daily dose of tacrolimus was increased. Interestingly, patients receiving mTOR inhibitors were also able to maintain the immunosuppressive drug during the entire treatment with ISA.

Some limitations in this review must be taken into account. As we have previously mentioned, the ISASOT study, which was retrospective, included a significant high number of LuT recipients (83%), who were treated with ISA for fungal tracheobronchitis (25/53 [47.1%]). The length of the follow-up was also extremely different in the clinical studies and the case reports. Unfortunately, TDM of ISA was not available in most of the studies either; these data would have been extremely valuable in order to optimize treatment in SOT patients. The inclusion of case reports may have introduced a potential bias in our review, given that cases with favorable outcomes are more likely to be published.

Nonetheless, we are confident that we have included almost all of the clinical studies and case reports published to date describing the use of ISA as prophylaxis and treatment of IFI in SOT, and that this review gives a broader, real-life experience on the use of this drug in these difficult-to-treat patients.

Conclusion

According to the accumulated experience in the use of ISA in the SOT setting, it is possible to conclude that ISA is a well-tolerated drug, with mild and reversible side effects. Drug interactions between ISA and calcineurin and mTOR inhibitors are also manageable, although TDM of immunosuppressive drugs is recommended to help adjusting the treatment. TDM of ISA could also be useful in cases of known pharmacokinetic variability and/or refractory/resistant infections where higher concentrations may be desired. The clinical responses, and the rates of all-cause and IA-attributable mortality of SOT recipients treated with ISA are comparable to those in patients receiving voriconazole. There are no clinical trials studying prophylaxis with ISA in LuT. However, there is one study that shows similar outcomes to those with voriconazole, with a better tolerance and drug interaction profile. Nonetheless, further prospective studies are needed.

Funding

The publication of this article has been funded by Pfizer. Pfizer has neither taken part, nor intervened in the content of this article.

Conflict of interest

JMA has received honoraria for speaking at symposia and participating on advisory boards for antifungal agents organised on behalf of Pfizer, Mundipharma, Knight Biotoscana, and Gilead Science. JTS and AS have no conflict of interest to declare.