Antifungal Formulations

The Centers for Disease Control and Prevention (CDC) is alerting health care providers of an outbreak of suspected fungal meningitis in US patients.

These patients were hospitalized in Texas after undergoing cosmetic procedures under epidural anesthesia in the city of Matamoros, state of Tamaulipas, Mexico. According to the CDC, it is currently unknown what organism is causing the outbreak; 1 of the 5 patients hospitalized has died.

For patients who present with symptoms consistent with fungal meningitis following a medical or surgical procedure under epidural anesthesia in Matamoros, Mexico (after January 1, 2023), the CDC advisory recommends brain imaging and a diagnostic lumbar puncture (unless contraindicated). If fungal meningitis is suspected, consultation with an infectious disease specialist is recommended.

Treatment with broad-spectrum antifungal medications should be initiated promptly, regardless of diagnostic test results. Dual antifungal therapy has been used in previous fungal meningitis outbreaks and can be considered for these patients.

Suspected fungal meningitis cases should be reported to state or local health departments. The agency has linked 2 clinics to this outbreak, the River Side Surgical Center and Clinica K-3, though more facilities may be identified as the investigation continues.

Additional recommendations for individuals and clinical laboratories can be found here.

HealthDay News — Confirmatory laboratory testing is only used in 1 in 5 cases of suspected tinea capitis (TC), according to a research letter published in the July issue of the Journal of the American Academy of Dermatology.

Jeremy A.W. Gold, MD, from the US Centers for Disease Control and Prevention in Atlanta, and colleagues calculated TC incidence and described testing and treatment practices for 3.9 million commercially insured US children identified from the Merative MarketScan Commercial Database (July 1, 2016, to December 31, 2020).

The researchers found that the one-year TC incidence was 16.3 per 10,000 person-years, with incidence highest among 5-year-olds (31.6 per 10,000 person-years), boys (20.9), and Southern residents (22.5). Pediatricians made the most diagnoses (54.6%), followed by dermatologists (11.7%) and family practitioners (10.4%). Clinicians infrequently used confirmatory testing (21.9%). When used, the most common tests were fungal culture (17.8%) and direct microscopy (9.7%). Testing was significantly more common for diagnoses by dermatologists (51.0%) vs pediatricians (16.4%) or family practitioners (11.0%). Three-quarters of patients were prescribed an antifungal (61.2% an oral antifungal and 14.7% a topical antifungal therapy).

“Most patients diagnosed with TC received no confirmatory laboratory testing, which is concerning because visual inspection alone of suspected cutaneous fungal infections can lead to diagnostic errors and unnecessary antifungal use,” the authors write.

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Cresemba, an azole antifungal, is available for injection in children 1 year of age and older. The capsule formulation is indicated for patients 6 years of age and older weighing at least 16kg. 

The pediatric approval was supported by data from a phase 2, open-label noncomparative study (ClinicalTrials.gov Identifier: NCT03816176) that evaluated the safety, efficacy and pharmacokinetics of Cresemba in pediatric patients aged 1 to 17 years with IA or IM (N=31). Patients received Cresemba 10mg/kg every 8 hours on days 1 and 2, and once daily thereafter for up to 84 days for IA or up to 180 days for IM. 

The median treatment duration was 55 days. All-cause mortality was reported to be 6.5% through day 42 (primary endpoint) and 9.7% through day 84. A successful response was observed in 54.8% of patients at the end of treatment. The most frequent adverse reactions reported in pediatric patients were diarrhea, abdominal pain, vomiting, elevated liver chemistry tests, rash, nausea, pruritus, and headache.

“The recent COVID-19 pandemic drove an uptick in these serious and life-threatening fungal infections, presenting an even greater urgency to address this growing unmet medical need,” said Lynn Fenicchia, senior vice president and Head of US Medical Specialties Business Unit, Astellas. “Patients are waiting, and we know that young IA and IM patients are most at risk. Today’s approval will bring hope to this highly vulnerable patient population with limited treatment options.”

DefenCath is a combination of taurolidine, a thiadiazinane antimicrobial, and heparin, an anticoagulant. Taurolidine has been shown to be active against the following microorganisms: Staphylococcus aureus (including methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus), Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans, and Candida glabrata. The product is indicated for use only in adult patients with kidney failure receiving chronic hemodialysis through a CVC.

The approval of DefenCath was based on data from a double-blind, active-controlled phase 3 trial (ClinicalTrials.gov Identifier: NCT02651428) that enrolled 806 patients with end-stage renal disease undergoing chronic hemodialysis at least 2 times per week. Study participants were randomly assigned to receive either Defencath (n=397) or heparin (n=398) as a catheter lock solution. 

The primary outcome measure was the presence of CRBSI, defined as at least 1 positive blood culture from a peripheral site or bloodline sample, or either the arterial or venous catheter hub, with signs and symptoms of infection and no other apparent source of bloodstream infection. The final assessment was determined by a clinical adjudication committee (CAC).

Results showed that DefenCath reduced the risk of CRBSI by 71% (95% CI, 38-86) compared with heparin (P =.0006). The incidence of CAC-adjudicated CRBSI was 2.3% (n=9) in the DefenCath group (event rate per 1000 catheter-days, 0.13 [95% CI, 0.07-0.26]) and 8% (n=32) in the heparin group (event rate per 1000 catheter-days, 0.46 [95% CI, 0.33-0.66]).

The most frequently reported adverse reactions reported with DefenCath were hemodialysis catheter malfunction, hemorrhage/bleeding, nausea, vomiting, dizziness, musculoskeletal chest pain, and thrombocytopenia. The prescribing information also includes warnings and precautions related to heparin-induced thrombocytopenia and drug hypersensitivity reactions. 

DefenCath is supplied as a sterile catheter lock solution in single-dose vials in the following strengths: 3mL containing taurolidine 40.5mg/3mL (13.5 mg/mL), and heparin 3000 USP Units/3mL (1000 USP Units/mL); and 5mL containing taurolidine 67.5mg/5mL (13.5mg/mL), and heparin 5000 USP Units/5mL (1000 USP Units/mL). It is intended for instillation into CVCs only and should not be used as a catheter lock flush product. Each single-dose vial is designed for use with a single patient as a single instillation in the CVC.

“As the first FDA-approved antimicrobial catheter lock solution designed to prevent CRBSIs, DefenCath offers health care providers an option to reduce the risk of infections in a patient population already vulnerable due to underlying kidney failure,” said Joseph Todisco, Chief Executive Officer of CorMedix.

The product is expected to be available in the first quarter of 2024 in the inpatient setting.

DefenCath is a combination of taurolidine, a thiadiazinane antimicrobial, and heparin, an anticoagulant. The treatment received approval in November 2023 based on data from the phase 3 LOCK-IT-100 trial (ClinicalTrials.gov Identifier: NCT02651428), which included 806 patients with end-stage renal disease undergoing chronic hemodialysis at least 2 times per week. Findings showed patients in the DefenCath treatment arm had a lower incidence of CRBSI events compared with those in the control arm.

The most frequently reported adverse reactions with DefenCath were hemodialysis catheter malfunction, hemorrhage/bleeding, nausea, vomiting, dizziness, musculoskeletal chest pain, and thrombocytopenia. The prescribing information also includes warnings and precautions related to heparin-induced thrombocytopenia and drug hypersensitivity reactions. 

DefenCath is supplied as a sterile catheter lock solution in single-dose vials in the following strengths: 3mL containing taurolidine 40.5mg/3mL (13.5 mg/mL), and heparin 3000 USP Units/3mL (1000 USP Units/mL); and 5mL containing taurolidine 67.5mg/5mL (13.5mg/mL), and heparin 5000 USP Units/5mL (1000 USP Units/mL). 

DefenCath is intended for instillation into CVCs only and should not be used as a catheter lock flush product. Each single-dose vial is designed for use with a single patient as a single instillation in the CVC.

The safety and effectiveness of Defencath have not been established for use in populations other than adult patients with kidney failure receiving chronic hemodialysis through a CVC.

“Today opens a new chapter for health care providers, offering them an opportunity to reduce the risk of CRBSIs in a patient population already vulnerable due to underlying kidney failure,” said Joseph Todisco, CEO of CorMedix. “We are proud to provide an option for adult patients who face the risk of CRBSIs.”

According to the Company, the outpatient commercialization of DefenCath is expected to begin on July 1, 2024.

The Food and Drug Administration (FDA) has approved Rezzayo (rezafungin for injection) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Approval of this indication was based on limited clinical safety and efficacy data for Rezzayo.

Rezafungin is a once-weekly echinocandin antifungal. The approval was based on data from the randomized, double-blind phase 3 ReSTORE study (ClinicalTrials.gov Identifier: NCT03667690), which included 187 adults diagnosed with candidemia and/or invasive candidiasis.

Treatment with rezafungin was found to be noninferior to caspofungin for the primary endpoint of all-cause mortality at day 30, using a 20% noninferiority margin. The trial provided evidence for efficacy to support an indication with a limited use statement, given the wider noninferiority margin. All-cause mortality at day 30 was reported to be 23.7% for the rezafungin group and 21.3% for the caspofungin group (treatment difference, 2.4% [95% CI, -9.7, 14.4]).

The approval was also supported by safety and efficacy data from the double-blind, randomized, phase 2 STRIVE study (ClinicalTrials.gov Identifier: NCT02734862). The primary objectives of this study were to evaluate safety and tolerability of rezafungin and overall success (mycological eradication and resolution of systemic signs attributable to candidemia and/or invasive candidiasis) at day 14.

The most common adverse reactions reported with rezafungin were hypokalemia, pyrexia, diarrhea, anemia, vomiting, nausea, hypomagnesemia, abdominal pain, constipation, and hypophosphatemia.

Rezzayo is supplied as a solid (cake or powder) in a single-dose vial containing 200mg of rezafungin. Treatment is administered once weekly by intravenous infusion after reconstitution.

“The FDA approval of Rezzayo is tremendous news for those of us who have been hoping for a new option to treat our patients with these deadly fungal infections,” said George Thompson, MD, principal investigator in the ReSTORE trial and professor of clinical medicine at the University of California, Davis, School of Medicine. “Based on the totality of clinical data generated, Rezzayo has the potential to simplify the management of invasive candidiasis and enhance the continuity of echinocandin care.”

The product is expected to be available in the summer of 2023.

The Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for olorofim for the treatment of invasive fungal infections in patients who have limited or no treatment options.  

According to the FDA letter, additional data will be needed before a decision on approval can be made. Olorofim is part of a new class of antifungal agents called orotomides, which work by targeting a key enzyme in the de novo pyrimidine biosynthesis pathway.

The NDA included data from the open-label, single-arm, phase 2b FORMULA-OLS study (ClinicalTrials.gov Identifier: NCT03583164). The trial enrolled patients who had limited or no treatment options for either proven invasive fungal disease (including aspergillosis, lomentosporiosis, scedosporiosis, Scopulariopsis infections, and refractory extrapulmonary coccidioidomycosis) or probable pulmonary invasive aspergillosis. 

Findings based on an analysis of the first 100 study participants showed that 44% of patients had a complete or partial response to treatment at day 42 (primary endpoint). All-cause mortality was reported to be 15% and 20% at day 42 and day 84, respectively (secondary endpoint).

“While F2G is disappointed with this outcome, we remain optimistic about olorofim’s potential to address an unmet need for patients with invasive fungal infections who have exhausted their treatment alternatives,” said Francesco Maria Lavino, CEO of F2G. “We are assessing the details of the CRL, and we plan to meet with the FDA to discuss it further, but we are confident that we can identify a regulatory path forward in the US.”

According to the Company, the FORMULA-OLS study is now fully enrolled with a total of 203 patients; the full data set will be submitted as part of the revised NDA application.

The Food and Drug Administration’s (FDA) Antimicrobial Drugs Advisory Committee voted 14 to 1 that the benefits of rezafungin outweigh its potential risks in the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options.

Rezafungin is an investigational echinocandin antifungal that is administered once weekly. The panel’s vote was based on data from the randomized, double-blind phase 3 ReSTORE study (ClinicalTrials.gov Identifier: NCT03667690), which evaluated the efficacy and safety of rezafungin in 187 adults diagnosed with candidemia and/or invasive candidiasis.

Treatment with rezafungin was found to be noninferior to caspofungin for the primary endpoint of all-cause mortality at day 30, using a 20% noninferiority margin. The trial provided evidence for efficacy to support an indication with a limited use statement, given the wider noninferiority margin. Efficacy data from the double-blind, randomized, phase 2 STRIVE study (ClinicalTrials.gov Identifier: NCT02734862) was also included in the application.

The safety profile of rezafungin was observed to be similar to other FDA-approved echinocandins. A neurotoxicity safety signal was identified in nonclinical and clinical studies.

Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act target date of March 22, 2023 has been set for the application.

References

1. Cidara Therapeutics and Melinta Therapeutics announce FDA advisory committee recommends approval of rezafungin for the treatment of candidemia and invasive candidiasis. News release. January 25, 2023. https://www.globenewswire.com/news-release/2023/01/25/2595033/0/en/Cidara-Therapeutics-and-Melinta-Therapeutics-Announce-FDA-Advisory-Committee-Recommends-Approval-of-Rezafungin-for-the-Treatment-of-Candidemia-and-Invasive-Candidiasis.html.
2. US Food and Drug Administration. Rezafungin for Injection. FDA Briefing Document. January 24, 2023. https://www.fda.gov/media/164666/download.

The first authorized generic versions of Noxafil^® (posaconazole) 200mg/5mL oral suspension have been made available in the US. Both Hikma Pharmaceuticals and Par Pharmaceuticals announced they will be supplying the product.

Posaconazole, an azole antifungal, is indicated for:

• Prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy in adult and pediatric patients 13 years of age and older.
• Treatment of oropharyngeal candidiasis (OPC), including OPC refractory to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older.

Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation.

Christina C. Chang, PhD, from Alfred Hospital in Melbourne, Australia, and colleagues updated guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of patients with cryptococcosis.

The authors note that accurate delineation of cryptococcosis clinical syndrome is important as it guides the choice and duration of antifungal treatment. In high-income settings, the most optimal induction therapy option for cryptococcal meningitis, disseminated cryptococcosis, and severe isolated pulmonary cryptococcosis is liposomal amphotericin B 3 to 4mg/kg daily and flucytosine 25mg/kg four times a day. Patients with HIV-associated cryptococcal meningitis in low-income settings are best treated with liposomal amphotericin B 10mg/kg as a single dose, with 14 days of flucytosine 25mg/kg four times a day and fluconazole 1200mg daily as induction therapy. Outcomes should be optimized by providing the most effective antifungal therapy while preventing, monitoring, and managing potential toxicity. Clinical relapse should be expected and monitored for and examined thoroughly for causality.

“More clinical research needs to be done in high-income settings, where host risk profiles are changing and an increasing array of presentations of cryptococcosis are being recognized, necessitating more nuanced and individualized treatment plans,” the authors write.

Several authors disclosed ties to the pharmaceutical industry.

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