It’s Here, It’s There, There’s Fungi Everywhere: A Case Series Utilizing Rezafungin for Invasive Candidiasis

Abstract

Rezafungin is a long-acting echinocandin with broad coverage against Candida. Rezafungin has primarily been indicated for candidemia, with limited literature available on its use for infections outside of the bloodstream. Herein, three patient cases are presented from an academic medical center. Infectious processes presented include drug-resistant mucosal candidiasis, prosthetic joint infection, and candidemia involving Candida auris. In all three cases, patients received rezafungin. Clinical response was demonstrated in all patients as was tolerability of rezafungin. Together these cases provide further evidence for the use of rezafungin, including its use for treatment of invasive infections other than candidemia.

Key Summary Points

The treatment of invasive candidiasis is becoming increasingly complicated as infections involving non-Candida albicans species have risen over the last decade.

A new antifungal treatment, rezafungin, is a long-acting echinocandin with broad Candida activity.

Indications for the usage of rezafungin have predominantly involved candidemia, and limited literature is available for infections outside of the bloodstream.

This case series presents three patients with different infectious foci who were successfully treated with rezafungin.

All the patients had resolution in terms of signs and symptoms of infection, and all tolerated the therapy without major incident.

Introduction

Invasive candidiasis (IC) is a life-threatening fungal infection caused by Candida species, most commonly Candida albicans and increasingly Candida auris [1–6]. Empiric antifungal therapy, usually with echinocandins, is recommended while waiting for a diagnosis; however, mortality rates remain high despite these treatment efforts [1, 4, 5, 7] Additionally, the rising incidence of antifungal resistance further complicates treatment [8–10]. Specifically, the emergence of C. auris, a multidrug-resistant pathogen, has heightened concerns, making effective treatment options even more crucial [11, 12]. As a result, there is an urgent need for new antifungal agents that can address these diagnostic and therapeutic challenges, improve patient outcomes, and combat rising resistance [9, 13, 14].

Rezafungin is a novel long-acting echinocandin that has gained attention primarily for its efficacy in treating IC. Its unique pharmacokinetic profile, which allows for once-weekly dosing, positions it as a promising treatment option for difficult-to-treat infections, including those caused by resistant Candida species [15–17]. While clinical studies have demonstrated its noninferiority to caspofungin for the treatment of candidemia, evidence for potential broader applications outside of candidemia is limited [18–24]. As antifungal resistance continues to rise and new therapeutic strategies are urgently needed, the use of rezafungin for IC, including infectious outside candidemia, requires further exploration.

In this case series, three patient cases will be presented, each with a unique source of infection. All patients presented were treated with rezafungin. Institutional ethics committee approval, along with patient consent, was not required as patient identifiers (age, sex, etc.), along with patient specific media (wound images, radiographic images, etc.), were not included in this case series. Additionally, this article does not contain any new studies with human participants or animals performed by any of the authors.

Patient Case 1

A patient with relapsed mantle cell lymphoma with central nervous system involvement who was receiving chemotherapy was found to have candidemia after complaining of increased fatigue. On admission, the patient was afebrile with normal vital signs other than tachycardia (107 beats per minute). Notable labs on admission included a low white blood cell (WBC) count (3.76 K/μL), a low absolute neutrophil count (ANC) (2.7 K/μL), low potassium (2.5 mmol/L), and a mildly elevated serum creatine (1.1 mg/dL). All other labs were within normal range.

Upon admission, identification of the Candida isolate was not yet available. The patient had been on prophylactic fluconazole before admission, so micafungin was initiated. The patient’s central venous access port was removed on hospital day 2 and repeat blood cultures were obtained on hospital day 3. Initial blood cultures identified C. auris. Given the resistant nature of this isolate, susceptibilities to numerous antifungal agents were requested (Table 1) and micafungin was continued as monotherapy on the basis of susceptibility data found in previous literature [25]. The patient was appropriately isolated according to infection prevention protocols, was hemodynamically stable, and repeat blood cultures remained negative. Upon discharge, the patient was initially instructed to come to the infusion clinic to receive micafungin infusions daily for 14 days from the last negative blood culture. However, given the burden of daily micafungin infusions, along with the need for strict infection prevention protocols in the infusion clinic, the patient was transitioned to rezafungin to complete the treatment course. After 7 days of micafungin treatment from cleared cultures, a 400-mg dose of rezafungin was given without complications. The patient remained stable at 30 days post positive blood cultures and was able to resume chemotherapy via a new peripherally inserted central catheter line.

Table 1.

Centers for Diseases Control and Prevention/Clinical & Laboratory Standards Institute minimum inhibitory concentration breakpoints and interpretations for C. auris

Drug	Results (μg/mL)	MIC breakpoints (μg/mL)	Interpretation
Amphotericin B	0.5	≤ 2 (CDC)	Susceptible
Micafungin	0.25	≤ 4 (CDC)	Susceptible
Voriconazole	1	≤ 32 (CDC)	Susceptible
Ibrexafungerp	0.5	No formal recommendation	N/A
Rezafungin	0.5	≤ 0.5 (CLSI)	Susceptible

CDC Centers for Diseases Control and Prevention, CLSI Clinical & Laboratory Standards Institute, MIC minimum inhibitory concentration, N/A not applicable

Patient Case 2

A patient with recent total hip arthroplasty revision due to hardware loosening had Candida parapsilosis isolated from intraoperative cultures and was referred to the infectious diseases clinic for treatment recommendations. The patient had a history of coronary artery disease and previously had a one-vessel coronary artery bypass graft. Additionally, the patient had a history of atrial fibrillation for which he had a pacemaker and was taking both sotalol and warfarin. The patient presented to the clinic with a complaint of left hip pain. Upon admission, the patient was afebrile and the surgical incision was intact without erythema, swelling, or drainage. All labs were within normal limits including WBC (5.98 μg/dL) and C-reactive protein (< 5 μg/dL). This particular C. parapsilosis isolate was susceptible to fluconazole (MIC of 0.5 µg/mL) and no additional antifungal susceptibility testing was performed.

The patient was treated with rezafungin for 12 weeks (400 mg during week 1, and 200 mg weekly during weeks 2–12) to avoid both drug–drug interactions as well as adverse effects associated with fluconazole and central line placement. Treatment was completed without any complications, and the patient noted significant improvement, including the ability to ambulate with the assistance of a walking stick around week 6 of therapy. Chronic suppressive therapy was not initiated after the 12-week rezafungin course because of the limited treatment options and financial barriers in acquiring isavuconazole. No signs or symptoms of therapy failure were seen during the 12 weeks of therapy. To date, the patient continues to do well without recurrence.

Patient Case 3

A patient was referred to the infectious diseases clinic for a history of chronic mucocutaneous candidiasis (CMC) and vaginal candidiasis. The patient had a past medical history of STAT3 deficiency, autosomal dominant hyper IgE syndrome requiring monthly IVIG infusions, and end-stage renal diseases (ESRD) requiring kidney transplant. The patient was taking daily prednisone, belatacept, and mycophenolate for antirejection. On arrival, a history of infections with fluconazole and itraconazole-resistant Candida spp. was reported, and the patient was now presenting for recurrent mouth and tongue ulcers that had persisted for 6 weeks despite chronic posaconazole therapy and recent addition of clotrimazole troches.

On exam, the patient had thrush, glossitis at right lip of mouth, and a shaggy small ulcer on the right buccal mucosa. Otherwise, the patient was hemodynamically stable with normal vitals. An oral swab of the ulcers was sent for fungal culture which revealed C. albicans (Table 2). Symptoms progressed to difficulty eating and drinking, and the patient was instructed to continue posaconazole and start nystatin swish and swallow. Additional treatment options were explored because of the extent of resistance and the lack of improvement, but insurance barriers prevented the acquisition of rezafungin. The patient received gentian violet from an outside clinic with reported improvement; however, symptoms progressed at the tip of the tongue. The patient was treated with 2 weeks of anidulafungin followed by resumption of posaconazole and gentian violet for chronic suppressive therapy.

Table 2.

Susceptibilities of C. albicans

Drug	Results (μg/mL)	MIC breakpoints (μg/mL)	Interpretation
Fluconazole	> 64	≤ 2 (CLSI)	Resistant
Isavuconazole	8	≤ 4b	Resistant
Posaconazole	1	≤ 1a	Susceptible
Micafungin	Not reported	≤ 0.25 (CLSI)	Susceptible (reported by microbiology lab)
Caspofungin	0.25	≤ 0.25 (CLSI)	Susceptible

CLSI Clinical & Laboratory Standards Institute, MIC minimum inhibitory concentration

^aYenisehirli G, Bulut N, Yenisehirli A, Bulut Y. In Vitro Susceptibilities of Candida albicans Isolates to Antifungal Agents in Tokat, Turkey. Jundishapur J Microbiol. 2015;8(9):e28057. https://doi.org/10.5812/jjm.28057

^bPfaller MA, Messer SA, Rhomberg PR, Jones RN, Castanheira M. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol. 2013;51(8):2608–16. https://doi.org/10.1128/JCM.00863-13

Two months later the patient returned to clinic reporting increased tongue lesions along with lesions on the face. Additionally, the patient started having vulvovaginal lesions and discharge. At this time, gentian violet was restarted, posaconazole was continued, and high dose intravaginal terconazole was prescribed. The patient began to report weight loss due to poor oral intake secondary to pain and discomfort and continued to deteriorate. With limited options, rezafungin was initiated for salvage therapy. The patient received six doses of rezafungin (400 mg during week 1 and 200 mg during weeks 2–6). The patient tolerated the treatments well with no reported adverse effects. At the end of the fourth treatment dose, the patient had gained almost 15 lb, reported no longer needing the terconazole due to resolution of vaginal candidiasis, and expressed improvement in her skin lesion with no additional spreading. After completion of the rezafungin, posaconazole was restarted. As of 3 months following treatment, the patient has continued to do well without reoccurrence of CMC or vaginal candidiasis. Of note, safety labs, including liver function enzymes and serum creatine, were routinely monitored given chronic azole therapy, and the patient did not require discontinuation of any antifungal agent deployed due to adverse effects, including rezafungin.

Discussion

Growing antifungal therapy resistance remains a global focal point; however, treatment of deep-seated IC with antifungal therapy has remained largely unchanged over the last decade [6, 9]. Rezafungin offers a unique treatment alternative with benefits mirroring those seen in other long-acting antimicrobial agents [26, 27]. In addition, rezafungin has demonstrated in vitro susceptibility to azole-resistant Candida spp., including C. auris [15, 28, 29]. With growing evidence that rezafungin is an effective therapy for a variety of IC infections, the expanded usage of rezafungin in clinical practice is likely inevitable [18–24].

In this case series, three patients with different infectious foci were treated with rezafungin. All three patients had resolution in terms of signs and symptoms of infection and all tolerated the therapy without major incident. To our knowledge, this is the first patient case describing a drug-resistant, recurrent mucocutaneous candidiasis that was successfully treated with rezafungin. It should be noted that our patient not only had genetic factors that predisposed them to infection but also was a kidney transplant recipient. The patient had received extensive amounts of antifungal therapy spanning over almost an entire decade but continued to experience reoccurrence of candidiasis. After the completion of 6 weeks of rezafungin, the patient reported complete resolution of the candidiasis with no reoccurrence to date. Additionally, we add to the growing evidence in support of rezafungin usage as a long-term treatment for other deep-seated infections (including a prosthetic joint infection), as well as using rezafungin for candidemia involving C. auris in a patient with relapsed lymphoma on chemotherapy.

As previously mentioned, long-acting antimicrobials such as rezafungin, offer unique treatment avenues for patients who are not candidates for traditional therapies that often require central access. Our case series highlights the clinical difficulties associated with managing IC infections, particularly in patients with underlying conditions such as cancer and solid organ transplantation. As global awareness increases on both the emergence of drug-resistant fungal pathogens and the challenges associated with these infections, new approaches for the treatment of IC will be imperative. Despite these advances, the fungal resistance landscape continues to evolve. The need for innovative drug development has never been more pressing, not only to address resistance but also to improve patient outcomes in the face of increasingly complex fungal infections [13, 14].

Limitations

This case series was based on a retrospective chart review of three patients seen by the Department of Infectious Diseases at our institution and may not be applicable to other clinical settings or patient populations because of variations in clinical practice, demographics, and healthcare systems. All data was retrospectively collected, and all data was verified by the attending Infectious Diseases physician who oversaw the primary care for each patient.

Conclusion

Rezafungin is a unique echinocandin that offers activity against a host of Candida species for numerous infectious foci. With its distinctive once-weekly dosing strategy, rezafungin is an attractive option for both patients who central access and/or clinical follow-up is not applicable and those who have failed traditional therapies including azoles and potentially other echinocandins.

Author Contributions

Conceptualization, Jacob M. Keck; writing—original draft preparation, Jacob M. Keck.; writing—review and editing, Jacob M. Keck, Ryan K. Dare, Mitchell B. Jenkins., Juan C. Rico., Luke Grisham., Jennifer McDonald., Alina Viteri, Robert W. Bradsher.; visualization, Jacob M. Keck.; supervision, Mitchell B. Jenkins., Juan C. Rico., Robert W. Bradsher; project administration, Jacob M. Keck; All authors have read and agreed to the published version of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflicts of Interest

Jacob Myles Keck is a consultant and speaker representative of AbbVie. Ryan Keith Dare has nothing to disclose. Mitchell Bruce Jenkins has nothing to disclose. Juan Carlos Rico has nothing to disclose. Luke Grisham has nothing to disclose. Jennifer McDonald has nothing to disclose. Alina Viteri has nothing to disclose. Robert Wilder Bradsher has nothing to disclose.

Ethical Approval

This article does not contain any new studies with human participants or animals performed by any of the authors.