Safety of rezafungin as a long-term treatment option in two patients with complicated fungal infections: two cases from Lecco Hospital (Italy)

ABSTRACT

Rezafungin is an echinocandin characterized by a long elimination half-life which allows for weekly administration. It has been recently approved for the treatment of candidemia. Few data are available about the long-term use of rezafungin and its use for deep infections like endocarditis and osteomyelitis. We describe our experience with its prolonged use in two azole-resistant Candida infections: a case of sacral osteomyelitis and a prosthetic valve endocarditis also involving a thoracic endovascular aneurysm repair.

INTRODUCTION

Rezafungin is a second-generation echinocandin with potent activity against Pneumocystis spp., Aspergillus spp., and Candida spp., including azole-resistant Candida spp. (1, 2).

Rezafungin demonstrated non-inferiority to caspofungin in the treatment of candidemia and invasive candidiasis in phase 2 (STRIVE) and phase 3 (ReSTORE) multinational clinical trials (3, 4). A subsequent analysis of ReSTORE showed rezafungin seems to be effective regardless of Candida species (5). Currently, it has been approved for the treatment of candidemia and invasive candidiasis in the USA since December 2023 and January 2024 in the EU and UK, respectively (6).

Due to a chemical modification that reduces drug degradation, compared to other echinocandins, rezafungin has high tissue penetration and a prolonged half-life (133 hours) allowing once-weekly dosing (6–8). The rezafungin weekly dosing regimen is shown to achieve high plasma concentrations, which might also be able to overcome some mutations associated with echinocandin-resistance like mutations in FKS genes (9); it also appears to maintain activity in some echinocandin-resistant Candida strains in mouse models (10). It shows a potent anti-biofilm activity compared to fluconazole, both in preventing its formation and in eradication of mature biofilm (7).

The efficacy of rezafungin has not been evaluated in patients with endocarditis, osteomyelitis, and meningitis due to Candida spp., and its safety beyond four weekly doses has not been determined (6). However, due to its unique pharmacokinetics and pharmacologic features, rezafungin may be an interesting option for difficult-to-treat Candida infections that require long duration of treatment.

Here we describe our experience with the use of rezafungin in two different Candida tropicalis infections, both with azole resistance: a case of sacral osteomyelitis and a prosthetic valve endocarditis also involving a thoracic endovascular aneurysm repair (TEVAR).

CASE PRESENTATIONS

Case 1

A 79-year-old female patient with a medical history of breast cancer, hypertension, and pulmonary thromboembolism underwent an abdominoperitoneal resection due to rectal carcinoma. Subsequently, she received chemotherapy and radiation therapy. Three years later, she developed a sacral pressure ulcer. After 3 months of multiple unsuccessful attempts with medical therapy only, she underwent surgical debridement. Deep tissue biopsies tested positive for Proteus mirabilis, Escherichia coli extended spectrum beta-lactamase (ESBL) positive, and methicillin-sensitive Staphylococcus aureus; antimicrobial therapy with ertapenem, daptomycin, and negative pressure wound therapy (NPWT) was started. Three months later (after 8 weeks of antibiotic therapy), the patient underwent plastic surgery of the gluteal flap with an initial good response.

Her recent medical history began after 2 months when she came to the attention of the Infectious Diseases Unit of Manzoni Hospital with a sacro-coccygeal ulcer with purulent discharge. Upon admission, both magnetic resonance imaging (MRI) and positron emission tomography (PET) using 18F-FDG revealed osteomyelitis affecting S4-S5 and inflammation of the nearby soft tissues. Ulcer biopsy tested positive for Candida tropicalis (azole resistant; see Table 1 for susceptibility test), and treatment with caspofungin was initiated (70 mg intravenous—iv—loading dose, followed by 50 mg iv every 24 hours). After 2 weeks of iv therapy, the patient was discharged and continued caspofungin iv treatment as an outpatient. At 1 month of treatment, a computed tomography (CT) scan showed the presence of a cutaneous fistula starting from the presacral soft tissues. Multiple wound swabs (taken under caspofungin treatment) yielded C. tropicalis (with the same susceptibility test) and C. glabrata (fluconazole-resistant; see Table 1 for complete susceptibility test).

TABLE 1.

Minimum inhibitory concentration (MIC) values for different antifungal agents for the Candida tropicalis and Candida glabrata strains isolated from biopsies in Case 1^a

Drug	Susceptibility (MIC, µg/mL) and clinical interpretation
	Case 1, strain 1 (C. tropicalis)		Case 1, strain 2 (C. glabrata)
	MIC	Int.	MIC	Int.
Caspofungin	0.06	S	0.25	S
Fluconazole	256	R	128	R
Voriconazole	8	R	0.06	R
Anidulafungin	0.13	S	0.25	S
Rezafungin	NAb	NA	NA	NA
Micafungin	0.03	S	0.06	S
5-Flucytosine	0.13	S	≤0.06	S
Posaconazole	8	R	0.5	R
Itraconazole	16	R	0.5	SDD
Amphotericin B	0.5	S	1	S
Isavuconazole	NA	NA	NA	NA

^a S = susceptible; R = resistant; SDD = susceptible dose-depending. Susceptibility interpretations are made using CLSI (Clinical and Laboratory Standards Institute) antifungal breakpoint tables (11).

^b NA, not applicable.

To improve the patient’s quality of life, after 3 months of therapy, caspofungin treatment was discontinued, and rezafungin was initiated (400 mg loading dose, followed by 200 mg intravenously weekly). In the following weeks, the size of the ulcer decreased. Finally, plastic surgeons reassessed the patient and decided to perform a wide cutaneous and subcutaneous debridement, with excision of the malacic coccygeal tissue, and reconstruct the defect with a fasciocutaneous flap. After 8 weeks of therapy with rezafungin, an antifungal holiday was scheduled prior to the surgery, performed 2 weeks after stopping antifungals. Intraoperative culture of the biopsy material showed negative results.

After surgery, the patient received 2 weeks of antimicrobial therapy with levofloxacin. She was medicated three times a week with local antiseptics, sterile dressings, and wound cleaning by nursing staff for 3 months until complete healing of the flap. Nowadays, the patient is clinically in good condition and was able to reprise her daily life activities.

No adverse events were reported during the administration of rezafungin, which was well tolerated by the patient. Blood tests did not reveal any renal, hepatic, or hematopoietic toxicities (see Fig. 1). Timeline of this case is described in Fig. 2.

Fig 1.

Weekly blood exams monitoring hemoglobin, transaminases, creatinine, and C-reactive protein since the start of rezafungin in Case 1.

Fig 2.

Timeline of the main events of Case 1.

Case 2

A 69-year-old male patient with a history of atrial fibrillation, heart failure (NYHA III), blood hypertension, and iron deficiency anemia underwent an aortic valve replacement for Staphylococcus epidermidis endocarditis. After 4 months, he suffered from a Candida tropicalis CVC-related candidemia that resulted in a prosthetic valve endocarditis (susceptibility test is shown in Table 2). High-dose caspofungin (150 mg iv daily) was started and the patient underwent a second cardiosurgical intervention with both valve replacement and TEVAR. Two weeks after valve replacement, caspofungin was switched to oral fluconazole (400 mg po daily) for chronic suppression. Unfortunately, due to a misunderstanding, at one point fluconazole dosing was reduced to 100 mg daily. Almost 1 year after the second surgery, the patient was admitted to our hospital because of worsening abdominal pain. On admission, the abdominal CT showed a superior mesenteric artery thrombosis with ileal and jejunal involvement, plus multiple splenic and renal emboli. The patient underwent multiple open abdominal surgeries, with thrombectomy and partial removal of jejunum and ileum and the creation of both a duodeno-jejunal and ileo-ileal anastomosis.

TABLE 2.

Minimum inhibitory concentration (MIC) values for different antifungal agents for the Candida tropicalis strains isolated in Case 2^a

Drug	Susceptibility (MIC, µg/mL) and clinical interpretation
	Case 2, strain 1		Case 2, strain 2
	MIC	Int.	MIC	Int.
Caspofungin	0.03	S	0.016	S
Fluconazole	1	S	>256	R
Voriconazole	0.03	S	>8	R
Anidulafungin	0.06	S	0.03	S
Rezafungin	NA	NAb	NA	NA
Micafungin	0.03	S	0.03	S
5-Flucytosine	<0.06	S	<0.06	S
Posaconazole	0.06	S	>8	R
Itraconazole	0.125	S	>16	R
Amphotericin B	1	S	0.5	S
Isavuconazole	NA	NA	0.06	S

^a Strain 1 was isolated from blood cultures in January 2022. strain 2 was isolated from intestinal thrombus, blood cultures, and bile. One year later, isavuconazole susceptibility was tested in another laboratory (Microbiology Unit of Policlinico Hospital, Milan). S = susceptible; R = resistant. Susceptibility interpretations are made using CLSI (Clinical and Laboratory Standards Institute) antifungal breakpoint tables (11).

^b NA, not applicable.

An azole-resistant Candida tropicalis (only isavuconazole retained some activity; see Table 2 for complete susceptibility testing) was isolated from intestinal thrombus, blood cultures, and bile. Fluconazole was thus transitioned to caspofungin. Three days later, an aortic valve vegetation was discovered on transesophageal echocardiogram (TEE). At the same time, the inflammatory index increased and the clinical conditions deteriorated. For these reasons, caspofungin was stopped and B-liposomal amphotericin (L-AMB, 5 mg/kg/day iv) was started. Blood cultures were negative 5 days from the first positive blood cultures. PET at 1 month of therapy showed pathological uptake of the aortic valve, the posterior wall of the ascending thoracic aorta, and multiple hepato-splenic septic foci. A multidisciplinary meeting was held, and surgical intervention for both a splenectomy and aortic valve substitution was ruled out due to a high-risk intervention for the patient. Meanwhile, clinical conditions improved. Therefore, antimycotic therapy was simplified to high-dose caspofungin (150 mg iv daily) from week 6 of therapy, with isavuconazole (100 mg po every 12 hours) added 10 days later. A repeated PET at 2 months of therapy showed metabolic stability around the aortic valve and the thoracic aorta, with new multiple emboli in the liver and the spleen (see Fig. S2). Due to its stable conditions, the patient was discharged on week 10 of therapy and immediately admitted to an outpatient setting to continue daily caspofungin, with oral isavuconazole. At 3 months of therapy, a TEE was executed, describing an unchanged filamentous structure on the biological valve. To continue a long-term suppressive therapy and to increase tissue penetration, rezafungin was started at 4 months of therapy with standard dosing (400 mg loading dose, then 200 mg weekly) in combination with isavuconazole. A PET 2 weeks later showed remission of metabolic activity around the prostheses, with weak metabolic activity in the hepatic emboli (see Fig. S2 and S3). At 11 months of therapy, a new PET (see Fig. S4) was performed showing complete metabolic remission of the uptake around the aortic prosthetic valve and of hepato-splenic lesions. Isavuconazole was thus discontinued, while rezafungin is still ongoing. No adverse events were reported during the administration of rezafungin, which was until now well tolerated by the patient. Blood tests did not reveal any renal, hepatic, or hematopoietic toxicities in a patient who already suffered partial hepatic impairment (see Fig. 3). The trend of B-d-glucan values over time is described in Fig. S1.

Fig 3.

Weekly blood exams monitoring hemoglobin, transaminases, creatinine, and C-reactive protein since the start of rezafungin in Case 2.

Timeline of this case is described in Fig. 4.

Fig 4.

Timeline of the main events of Case 2.

TREATMENT AND OUTCOME

Rezafungin is a novel echinocandin approved for the treatment of patients affected by invasive candidiasis with limited treatment options (6). The peculiarity of this drug is the long half-life that determines a weekly iv dosing, potentially allowing patients affected by complicated or chronic Candida spp. infections to access the hospital only once weekly instead of a more protracted stay.

Case 1 describes a 79-year-old female patient who developed a chronic fungal sacral osteomyelitis with a skin ulcer after being treated with radiotherapy for rectal cancer. Taken into consideration the overall good condition of the woman and her active lifestyle, rezafungin was started to improve her quality of life. She was successfully treated with this drug for 7 weeks and monitored with weekly blood exams which did not show any signs of toxicity (Fig. 1). No adverse events were recorded.

Due to the scarce available literature, treatment recommendations for Candida osteoarticular infections are based on case reports and case series. Current guidelines recommend prolonged treatment (up to 12 months) with an azole or an echinocandin, together with surgical debridement in selected cases (12). While issues with azole class include possible side effects, drug-drug interactions, and possible azole resistance, currently available echinocandins need daily intravenous administration (13); so, due to its pharmacokinetics, rezafungin could be an interesting option in the complex scenario of fungal osteoarticular infections.

Case 2 describes a 69-year-old male affected by complicated C. tropicalis prosthetic valve endocarditis and TEVAR without the possibility of further surgical interventions. Due to the presence of infected and non-removable prosthetic material, a long-term suppression therapy was started. At this time, the patient has been treated with rezafungin for 6 months. Similarly to Case 1, no adverse events were reported. Moreover, weekly blood examinations did not show a worsening of his hepatic parameters that were already partially elevated at the baseline (AST/ALT 25/34 mU/mL, γGT 299 U/L). Blood cell population and renal function were not affected either (see Fig. 2).

Fungal endocarditis, especially when involving prosthetic material, shows a high mortality rate. A recent review performed by Meena et al. showed an overall mortality rate of fungal endocarditis of 40%, with better survival in patients treated with surgery along with antifungals compared to those treated with antifungals alone (14). Valve replacement is mandatory in Candida endocarditis involving a prosthetic valve; patients who cannot undergo surgery must continue chronic suppressive therapy lifelong. Current guidelines for oral suppressive therapies are based mainly on experience with fluconazole (12, 15). Treatment options are very limited in case of fluconazole resistance and include mainly voriconazole and posaconazole. Isavuconazole has been used in some cases (16, 17). Like in osteoarticular infections, suppressive therapy with first-generation echinocandins is not feasible due to the need for daily hospital access; rezafungin could overcome this issue becoming an option for azole-resistant strains and for patients who cannot take triazoles for other reasons.

Few data are available about the use of rezafungin for periods of time longer than 4 weeks. To the best of our knowledge, two other cases reporting prolonged use of rezafungin have been published so far. Adeel et al. reported the compassionate use of rezafungin for over 1 year in a patient with a multidrug-resistant Candida glabrata mediastinal vascular graft infection with retained foreign material. In this case, the isolated Candida strain developed resistance to azoles and other echinocandins and the patient had shown intolerance to liposomal amphotericin B and oral flucytosine, while rezafungin was well tolerated (18). More recently, another Italian group described the case of a 70-year-old patient with native aortic valve endocarditis due to a Candida glabrata strain with a fluconazole MIC of 8, who was put on suppressive therapy with rezafungin after 8 weeks of treatment with anidulafungin. The patient has received rezafungin for 8 weeks and later died due to Klebsiella pneumoniae CTX-M + urosepsis (19).

In addition to these case descriptions, our case reports provide further experience in long-term treatment with rezafungin. First, we report two different Candida species (C. tropicalis vs C. glabrata). Second, Case 1 is, to the best of our knowledge, the first published report of rezafungin use in chronic osteomyelitis. Finally, in Case 2, we describe the tolerability of extended use of rezafungin (approximately 6 months), taken together with isavuconazole, for suppressive therapy of a complex chronic infection involving both a TEVAR and an aortic prosthetic valve. In both cases, therapy was well tolerated, no adverse events were reported, and no toxicities on the renal, hepatic, and hematopoietic side were observed in the weekly blood exams. Thanks to the weekly administration of rezafungin, both patients were discharged from the hospital reducing costs and securing a good quality of life.

Conclusion

To the best of our knowledge, these are the first cases of difficult-to-treat azole-resistant Candida tropicalis infections treated with long-term (>4 weeks) rezafungin described in the literature. According to our small experience, rezafungin constitutes a safe and well-tolerated option for long-term therapies in chronic and complicated fungal infections, allowing a good quality of life for patients who should otherwise be hospitalized or access the hospital setting with a daily schedule to receive an equivalent effective therapy. More data are urgently needed to obtain conclusions about the efficacy of rezafungin in these difficult-to-treat infections.

SUPPLEMENTAL MATERIAL

The following material is available online at https://doi.org/10.1128/aac.00750-24.

Supplemental material. aac.00750-24-s0001.doc.

Figures S1 to S4, associated with Case 2.

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