Treatment of Invasive Fungal Infections
Over ninety percent of invasive fungal infections begin in the inpatient setting. Invasive candidiasis and candidemia comprise the majority of invasive fungal infections in intensive care units, internal medicine and hematology wards within hospitals. High rates of morbidity and mortality are associated with invasive Candida infections. According to a study published in Clinical Infectious Disease (2009), candidemia has a crude mortality rate of 35% within 12 weeks of diagnosis.
Over the past decade, there has been a shift in epidemiology of Candida infections from albicans to non-albicans strains as well as an increase in antifungal resistant strains of both Candida and Aspergillus. The incidence of candidemia caused by non–Candida albicans species (54.4%) was higher than the C. albicans-related incidence (45.6%). These changes vary between institution/city/region/country depending on environment, populations at risk, and antifungal use.
In the U.S., it is estimated that up to 95% of invasive Candida infections are caused by five species of Candida: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei.
In a retrospective, multicenter U.S. study in > 600 ICU’s, the prevalence of invasive aspergillosis (IA) was determined to be 0.017%, with an in hospital mortality of 46%. In another large international multicenter study involving >30 ICU’s in 8 countries, mortality was significantly higher (79%) in patients with proven IA than in those with probable IA (67%).
Trends in Antifungal Resistance
Emerging resistant fungal species are another growing cause of concern for physicians responsible for the care of high risk patients.
Fungi can become resistant to antifungal agents by different modes. Some species like C. Krusei and C. lusitaniae are typically less susceptible (intrinsically resistant) to certain antifungal agents. Acquired resistance is thought to be largely due to the widespread use of antifungal agents for patient care or agricultural use (azoles), which has resulted in some fungal species developing resistance (e.g., azole resistant non- albicans candida and aspergillus species). Mutations in fks1 region of the gene encoding the echinocandin target enzyme 1-3-b-D-glucan synthase result in some Candida isolates having reduced susceptibility to echinocandins.
|Resistance||Microbiological Resistance to All Antifungal Agents||Intrinsic Resistance|
|Aspergillus (azoles)||Lomentospora [formerly Scedosporium] prolificans||C. Krusei (fluconazole)|
|Non-albicans candida (azoles)||Fusarium solani||C. lusitaniae (amphotericin B)|
|C. glabrata (echinocandins)|
|C. auris (multiple antifungal classes)|
In addition to the growing challenge of azole resistant aspergillus and non-albicans Candida species, emerging fungi such as C. auris pose a particularly serious threat. The three main features of C. auris raising the alarm are a) multidrug resistance, b) difficult identification with standard laboratory techniques and c) transmission from one patient to another, particularly in hospitals and nursing homes, often resulting in outbreaks.
Current Treatment Options and Limitations
Treatment options for IFI are increasingly challenging especially in high risk patients who are likely to have severe co-morbidities and underlying conditions that require a complex mix of immunosuppressive and chemotherapeutic agents.
In the last two decades, there have been several major advances in the development of predictive tools/scores, diagnostic tools, new antifungal agents (azoles & echinocandins) as well as guidelines and recommendations. Despite these developments there are still many limitations, including drug toxicities, drug-drug interactions, and development of resistance in the existing armamentarium for treatment of IFI.
Several factors need to be considered when choosing the “appropriate antifungal therapy.” Besides the right antifungal agent for systemic therapy, the timing of administration, the dose and duration of treatment as well as management of adverse events and drug-drug interactions are all associated with a successful outcome. In the 2016 update to Clinical Practice Guideline for Management of Candidiasis, the Infectious Disease Society of America (IDSA) has given a strong recommendation for echinocandins as the agents of choice for initial therapy for the treatment of suspected and confirmed Candida infections. Echinocandins have displaced azole and polyene antifungals in guidelines in both North America and Europe as first line therapy for Candida infections based on superior outcomes in Phase 3 trials as well as growing concerns of resistance to azoles.
Currently available echinocandins (anidulafungin, caspofungin and micafungin) approved for first line treatment of invasive Candida infections leave significant room for improvement:
- Daily IV administration constrains to mainly inpatient use yet many patients would benefit from continued outpatient echinocandin dosing post hospital discharge
- Suboptimal dosing can lead to lack of efficacy and development of resistance in critically ill patients including those with: invasive disease, altered clearance of drugs, altered volume of distribution, infections caused by less susceptible pathogens
- Rising rates of resistance
- Emergence of new multidrug resistant species such as C. auris
Rezafungin: a Novel Echinocandin for the treatment of IFI
Rezafungin is a novel, broad-spectrum, once-weekly echinocandin with excellent activity against both wild-type and azole- and echinocandin-resistant strains of Candida, as well as Aspergillus and Pneumocystis.
The unique front-loaded PK of rezafungin enables concentration dependent fungicidal activity and provides high concentrations that may suppress resistance development. Additionally, nonclinical data have demonstrated that rezafungin penetrates and accumulates at higher levels at the site of infection compared to once-daily echinocandins.
Rezafungin enables convenient, once-weekly treatment with a favorable tolerability profile and offers new hope for treatment of serious fungal infections. Rezafungin has the potential to treat more invasive disease, help clinicians discharge patients earlier from the hospital to benefit health and economic outcomes and provide convenient cost-effective outpatient dosing of an echinocandin antifungal for the first time.
We have announced topline results of our Phase 2 international trial of rezafungin in the treatment of candidemia and invasive candidiasis called STRIVE, and initiated a Phase 3 registration trial (ReSTORE) in 2018.
Key Attributes and Data
- Comparative Potency
- Efficacy in Animal Models
- Tissue Penetration
- Optimized Dosing
Structural modification yields improved chemical and biological properties
Permanent charge and highly stable ring structure:
- Prolongs PK: once weekly dosing in clinical studies
- Allows high exposures: improved efficacy
- Eliminates toxic degradation products: improved safety
- Enables multiple formulations: intravenous and subcutaneous
Comparative potency in vitro, against representative strains of Candida spp., Aspergillus spp.
Rezafungin, anidulafungin and caspofungin tested against international clinical surveillance isolates.
CLSI broth microdilution methodology was employed for MIC/MEC determination (M27-A3, M38-A2)
- Candida spp. MIC data were derived from the 2014 and 2015 JMI SENTRY international surveillance program and the 2014 Micromyx US surveillance program (Pfaller, et al, 2017, AAC; Pfaller, et al, 2017, IJAA; Hall, et al, 2017, DMID)
- Aspergillus spp. isolates were collected internationally by JMI between 2007 and 2011 and were tested as part of a retrospective study (Pfaller, et al, 2016, JAC)
Excellent efficacy compared with standards of care in animal models
CFU in kidneys of mice 24 hours after infection with C. albicans and treatment with anidulafungin or rezafungin.
Significant and sustained tissue penetration in invasive candidiasis model
Rezafungin (CD101) penetrates and accumulates at high levels at the site of infection.
Drug distribution in liver after single dose rezafungin (CD101) at 20 mg/kg determined by MALDI MS Imaging
Multidoses Micafungin vs. single dose rezafungin (CD101)
Unique PK profile that supports 1X weekly dosing
Phase 1 PK Supports 400 or 200 mg weekly IV dosing.
Optimized dosing to address resistance
Exposure is key to improved efficacy, especially when facing less susceptible pathogens.
MIC=0.25 for caspofungin. MIC=0.12 for CD101
Bader et al. Emerging Candida glabrata Resistance and Echinocandin Dosing: A Call to Arms! IDWeek 2016
Bader et al. Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata. Submitted AAC 2018; revised with Phase 2 results.