Once-Weekly Echinocandin Could Facilitate Continuity of Echinocandin Treatment and Outpatient Administration

Background

Invasive candidiasis encompasses a group of deep infections caused by yeasts of the genus Candida that can involve the bloodstream (ie, candidemia), intra-abdominal cavity, peritoneum, heart, kidney, bones, or other internal organs.^1,2 Candida yeasts are found in the skin and gut microbiota of approximately 60% of healthy individuals; however, invasive infection can occur from increased colonization and impaired host defenses. Factors contributing to invasive infection include heavy use of broad-spectrum antibiotics; breakdown of the gastrointestinal (GI) tract or cutaneous barriers caused by chemotherapy, surgery, GI damage, or placement of central venous catheters; and immunosuppression secondary to a medical intervention (eg, chemotherapy or corticosteroid use). Other risk factors associated with the development of invasive candidiasis include a long stay in the intensive care unit (ICU), necrotizing pancreatitis, and use of dialysis or total parenteral nutrition.¹

Mortality attributable to invasive candidiasis may range from 30% to 60%, and average cost per hospitalization ranges from approximately $65,000 to $153,000 (2017 US$).³ Factors associated with an increased risk for mortality include older age, higher Acute Physiology and Chronic Health Evaluation II scores, identification of highly virulent Candida, use of immunosuppressants, presence of comorbidities (particularly renal dysfunction), and retention of a venous catheter.¹

Epidemiology and Trends in Causative Pathogens

Invasive candidiasis is associated with technological advances in medicine, and Candida is among the 3 or 4 most common pathogens implicated in bloodstream infections acquired in a health care setting.¹ Candidemia is the most common form of invasive candidiasis; from 2013 to 2017, the annual incidence of candidemia in the United States was approximately 9 per 100,000 people, or approximately 25,000 cases per year.² Approximately 50% of candidemia cases occur in the ICU, and large national surveys estimate that candidemia occurs in 1% to 2% of patients admitted to the medical and surgical ICU.¹

Clinical investigators have related human candidiasis to some 15 Candida species, but the 5 most common types—Candida albicans, C glabrata, C tropicalis, C parapsilosis, and C krusei—account for more than 90% of invasive cases. Considerable variability exists in the distribution and presence of these Candida species across geographic locations, centers, and units within centers.⁴ C albicans is the most common species contributing to disease in adult and pediatric populations. The prevalence of candidemia not related to C albicans infection has increased among adults and children in recent years; it is affected by regional patterns of antifungal therapy use, patient factors, and clonal outbreaks in a specific health care setting. In the settings not related to outbreaks, C glabrata is generally the second most commonly detected species in the United States and northwestern Europe, whereas C parapsilosis and C tropicalis tend to be more prevalent in Latin America, Southern Europe, India, and Pakistan.¹ Candidiasis is highly heterogeneous, as each Candida species has a different ability to invade the host, be virulent, and respond to antifungal therapies.⁴

Current Diagnosis and Management for Invasive Candidiasis

Making a prompt diagnosis, controlling the source of infection, and initiating the appropriate therapy early are essential for effective treatment of invasive candidiasis, as inadequate source control, delays in diagnosis or treatment, or suboptimal treatment (ie, choosing the wrong drug, administering an inadequate dose) are associated with higher mortality. However, the wide variability among pathogens, limited sensitivity of diagnostic blood cultures, and increasing rates of resistance to echinocandins and azoles challenge the effective management of invasive candidiasis. The proportion of cases caused by the more treatment-responsive C albicans has decreased, whereas the prevalence of cases caused by the more treatment‑resistant C glabrata and C parapsilosis species has increased. Additionally, multidrug-resistant C auris has increasingly been implicated in health care facility outbreaks; this pathogen remains a threat worldwide due to its propensity to rapidly spread, develop resistance mechanisms, and be misidentified by current methods used for diagnosis.¹

Diagnostic Strategies

Fungal cultures with blood or tissue/typically sterile body fluid specimens are the gold standard for diagnosis of invasive candidiasis; their use can be advantageous for species identification and susceptibility testing. However, results typically take 2 to 3 days to obtain, with 3 days of incubation believed to be ideal for culturing tissue/sterile body fluids. Additionally, test sensitivity is relatively low and further reduced when small volumes of samples are used, the blood culture bottle is not specific for fungal specimens, selective media are not employed, and the sample does not spread properly on the growth medium. Antigen detection tests, including Candida mannan antigen/antimannan antibody (primarily available in Europe) and b-D-glucan testing, may be used with blood cultures; however, false-positive results can occur in immunocompromised patients who have had a previous candidemia or heavy colonization in the absence of infection. Additionally, b-D-glucan testing is unable to differentiate between candidiasis and infections caused by other fungal species. Many polymerase chain reaction (PCR) assays can detect Candida; they can be added to blood cultures if invasive candidiasis is suspected.PCR tests have the advantage of producing rapid results, but tests are expensive, and they may not detect all Candida species.¹

Standard Therapy Recommendations

The turnaround time for blood cultures is slow; if invasive candidiasis is suspected, systemic antifungal therapy is typically initiated before the results of a diagnostic blood culture test are available. Factors to consider when choosing an antifungal therapy include history of exposure to and adverse events (AEs) from use of antifungal drugs, severity of infection, comorbidities, and organ systems involved.¹ The Infectious Diseases Society of America 2016 clinical practice guideline for the management of candidiasisstates that echinocandins, azoles, amphotericin B, and flucytosine have activity in the treatment of invasive candidiasis.⁴ Echinocandins and azoles are most commonly used as initial therapy, whereas use of amphotericin B is typically reserved for patients with infections caused by Candida and who are known or suspected to be multidrug resistant, who are intolerant to echinocandins and azoles, or who have infections located in the heart valves, central nervous system (CNS), or eye.¹ Flucytosine is often used with another antifungal agent (commonly, amphotericin B for treatment-refractory infections of the endocardium, CNS, or eye), because it is associated with high rates of resistance when used alone.⁴

Echinocandins

Echinocandins (eg, micafungin, caspofungin, and anidulafungin) are inhibitors of b-D-glucan synthase, an enzyme involved in building the fungal cell wall. Their use is recommended as first-line therapy for most cases of candidemia, because they have strong antifungal activity against the majority of Candida.¹ Use of echinocandins is generally considered to be safe, with few associated drug-drug interactions and survival rates that are significantly greater than are those of other antifungal classes.^1,5 However, echinocandin therapy is not recommended to treat infections involving the eye, CNS, or urinary tract, because drugs in this class offer minimal penetration via the blood-brain barrier and do not pass through the urine. These agents are given intravenously (IV) on a daily basis and are generally considered to be interchangeable in terms of efficacy and safety.^1,4

Fluconazole

Fluconazole and other members of the azole class of antifungals inhibit lanosterol 14a-demethylase; this enzyme is involved in the creation of ergosterol, a key element of the fungal cell membrane.¹ Fluconazole can be given as an alternative to an echinocandin in the frontline setting to some patients (eg, those without critical illness or who are unlikely to have a fluconazole-resistant infection), and its use is strongly recommended as stepdown therapy within 5 to 7 days for patients who are stable, known to harbor a fluconazole-sensitive pathogen (eg, C albicans), and have negative repeat blood cultures after starting antifungal treatment. Fluconazole is commonly used for Candida infections in the CNS and eye, because it has relatively high penetrance into the cerebrospinal fluid and vitreous. Its use also is favored in cases of symptomatic cystitis, because the urinary concentration of the drug is up to 20 times higher than that noted in serum.⁴

Fluconazole can also be given orally, which may be more convenient than the daily IV administration required with echinocandins. Additionally, acquired resistance to azoles generally is less common than is resistance to echinocandins, although it tends to be more complex and involve multiple mechanisms, including ERG11 mutations, increases in production of the target protein, and alterations in efflux pumps.¹ However, multiple drug-drug interactions have been reported with fluconazole and other azole drugs (eg, statins, benzodiazepines, warfarin, calcineurin inhibitors, corticosteroids, and phenytoin), because azoles inhibit multiple isoenzymes of the cytochrome P450 family.⁶ Additionally, toxicity and drug-induced injury of the liver have been reported with use of fluconazole and other azole drugs, and elevations in liver function test (LFT) values may occur in up to 10% of patients taking fluconazole. Most cases of hepatotoxicity occur during the first month of treatment, and liver injury usually reverses within 2 weeks of dose reduction or therapy discontinuation. Therefore, regular monitoring with LFTs should be performed before starting, and periodically during, treatment with azoles.⁷

Challenges With Standard Treatment

Use of first-generation echinocandins is considered to be highly efficacious against Candida infection, yet treatment failure occurs in around 40% of cases.⁵ The use of these antifungal therapies also has led to an increase in prevalence of Candida species that have lower sensitivity to first-generation therapies than does C albicans; these species include C glabrata in areas of high fluconazole use and C parapsilosis in areas of high echinocandin use. Further, an overall increase in acquired drug resistance has been noted among all subspecies.¹ Resistance to echinocandins apparently is increasing particularly rapidly in the C glabrata species, which already is highly resistant to fluconazole. Furthermore, treatment options are limited for Candida infections that are resistant to echinocandins and azoles. Amphotericin B is typically given in this scenario; it is often highly toxic for these patients, who tend to be critically ill. Patients with treatment‑resistant candidemia have a higher risk for mortality compared with those who have treatment-responsive candidemia.⁸ Coupled with the increase in treatment-resistant pathogens, the dose-response relationship to echinocandins is unpredictable in certain groups of patients (eg, critically ill or obese individuals), and it may contribute to their high therapeutic failure rates and their need for additional antifungal agents.^5,9

Even if treatment results in a response, outpatient administration of systemic antifungal therapy has several challenges, including inconvenience, need for administration at least once daily, possible drug-related AEs and toxicities (eg, nausea, vomiting, renal impairment, altered liver function, and rash), and drug-drug interactions (eg, voriconazole and fluconazole may interact with rifampin, cyclosporine, and tacrolimus).¹ These challenges stress the need for novel antifungal therapies that are effective against a wide range of Candida pathogens and adequate for continuity of treatment from the inpatient to outpatient setting.^1,10

Rezafungin: A Next-Generation Echinocandin

Rezafungin [REZZAYOTM (rezafungin for injection); Melinta Therapeutics] is a novel, semisynthetic echinocandin that was approved by the FDA in 2023 for patients 18 years or older who have limited or no alternative options for treatment of candidemia and invasive candidiasis. Similar to other echinocandins, rezafungin interacts with the 1,3-b-D-glucan synthase enzyme complex to prevent formation of 1,3-b-D-glucan.¹¹ Rezafungin has broad-spectrum activity and a long half-life (133 hours), which enables an IV infusion to be given weekly and yields high plasma concentration of the drug in the early stages of treatment; in turn, this may promote continuity of care from the inpatient to outpatient setting when stepdown therapy with an azole is not indicated.^9,11 The results of preclinical and clinical studies demonstrated that rezafungin has activity against most Candida species, including C albicans, C glabrata, C parapsilosis, and C tropicalis.¹¹

Safety and efficacy were investigated in the randomized, double-blind, phase 3 ReSTORE trial (NCT03667690), which included 199 adults with candidemia and/or invasive candidiasis; approximately 70% of these individuals had only candidemia.⁹ In all, 100 patients were randomly assigned 1:1 to receive rezafungin, 400 mg IV on day 1 and 200 mg on day 8 (200-mg doses could be given on days 15 and 22 if the investigator determined it necessary); 99 patients were given a loading dose of caspofungin, 70 mg IV on day 1, followed by 50-mg IV doses daily for a total of 3 to 28 days of antifungal therapy. Both groups could receive optional oral stepdown therapy with placebo (rezafungin group) or 200 to 800 mg of fluconazole (caspofungin group) after 3 days if criteria for stepdown therapy were met (ie, detection of a fluconazole-susceptible isolate, resolution of baseline signs and symptoms of candidemia or invasive candidiasis, and recent blood culture found to be negative for Candida).⁹ An IV placebo infusion was given on other study days to patients in the rezafungin group to ensure that the study staff and they were unaware of the treatment received.⁹

The ReSTORE investigators found that the all-cause mortality rate at 30 days for rezafungin was noninferior to that of caspofungin, with death or unknown survival status reported in 22 of 93 evaluable patients (24%) given rezafungin and 20 of 94 evaluable patients (21%) given caspofungin (treatment difference, 2.4%; 95% CI, –9.7% to 14.4% [the upper limit of the 95% CI did not exceed the prespecified upper CI bound of 20%]). At 14 days, the rate of global cure (sum of clinical cure, radiologic cure, and mycologic eradication) was non-inferior in the rezafungin and caspofungin groups (59% vs 61%; weighted treatment difference, –1.1%; 95% CI, –14.9% to 12.7% [the lower limit of the 95% CI was above the prespecified lower bound of 20%]). In a prespecified exploratory analysis, among patients with a positive blood culture, the median time to a negative blood culture was shorter in the rezafungin group (23.9 hours; IQR, 15.4-48.3 hours) than in the caspofungin group (27.0 hours; interquartile range [IQR], 16.4-111.3 hours) (P = .18). IV treatment beyond 14 days was needed by 17% of the rezafungin group and 28% of the caspofungin group. The study authors also noted that extended treatment with rezafungin only required 1 or 2 additional doses, whereas up to 14 additional doses of caspofungin was needed (on days 15-28 of treatment). In practice, the authors theorized that, in addition to the convenience offered by weekly dosing of rezafungin, lower‑frequency dosing may reduce the risk for opportunistic infection inherent in all interactions with the health care system, eliminate the need for placement of a peripherally inserted central catheter (and in turn, costs and AEs related to catheter placement), and shorten the length of hospital stay in some cases.⁹

Treatment-emergent AEs (TEAEs) were reported in 91% and 85% of patients in the rezafungin and caspofungin groups, respectively. The most common TEAEs were pyrexia (14%), hypokalemia (13%), pneumonia and septic shock (10% each), and anemia (9%) in the rezafungin group. In the caspofungin group, they were hypokalemia, septic shock, and anemia (9% each); diarrhea (7%); and hypotension, urinary tract infection, and hyperkalemia (6% each). Serious AEs were reported in 56% and 53% of the rezafungin and caspofungin groups, respectively. The authors concluded that the results offered comparable safety and tolerability profiles for the drugs that accurately reflected safety information previously found for agents in the echinocandin class.⁹

The phase 2 dose-finding STRIVE trial (NCT02734862), which provided safety and supportive efficacy data, included patients with candidemia and invasive candidiasis. Overall cure rates (after exclusion of indeterminate results) were similar among the groups that received rezafungin, 400 mg weekly; rezafungin, 400 mg on week 1 followed by 200 mg weekly; or caspofungin (69.7%, 81.4%, and 70.7%, respectively).⁵ A post hoc analysis also found that median time to a negative blood culture was 19.5 hours in patients treated with rezafungin and 22.8 hours in those given caspofungin.⁵

Conclusions

Use of novel antifungal therapies, such as the next-generation echinocandin rezafungin, offers pharmacokinetics to prolong drug half-life, and it may enable appropriate patients to be transitioned to an outpatient setting while maintaining continuity of echinocandin treatment.^9,11 This may be helpful for reducing hospital length of stay, as the results of a retrospective, multicenter, observational study found that 38% of hospitalized patients with candidemia and invasive candidiasis who were receiving an echinocandin within 2 days of their hospital discharge were potentially eligible for earlier discharge.¹⁰ The ability to give rezafungin in the outpatient setting may be helpful for decreasing the duration of hospital stay, which could benefit patients and reduce their health care burden.^10,12

INDICATION AND USAGE

REZZAYO^™ (rezafungin for injection) is an echinocandin antifungal indicated in patients 18 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis. Approval of this indication is based on limited clinical safety and efficacy data.

Limitations of Use

REZZAYO^™ has not been studied in patients with endocarditis, osteomyelitis, and meningitis due to Candida.

IMPORTANT SAFETY INFORMATION

Contraindications

REZZAYO^™ is contraindicated in patients with known hypersensitivity to rezafungin or other echinocandins.

Warnings and Precautions

• Infusion-related Reactions: REZZAYO^™ may cause infusion-related reactions, including flushing, sensation of warmth, urticaria, nausea, or chest tightness. If these reactions occur, slow or pause the infusion.
• Photosensitivity: REZZAYO^™ may cause photosensitivity. Advise patients to use protection from sun exposure and other sources of UV radiation.
• Hepatic Adverse Reactions: Abnormalities in liver tests have been seen in clinical trial patients treated with REZZAYO^™. Monitor patients who develop abnormal liver tests and evaluate patients for their risk/benefit of continuing REZZAYO^™ therapy.

Adverse Reactions

Most common adverse reactions (incidence ≥ 5%) are hypokalemia, pyrexia, diarrhea, anemia, vomiting, nausea, hypomagnesemia, abdominal pain, constipation, and hypophosphatemia.

Please see full Prescribing Information for REZZAYO™ (rezafungin for injection).

References

1. Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Primers. 2018;4:18026. doi:10.1038/nrdp.2018.26
2. Invasive candidiasis statistics. Centers for Disease Control and Prevention. Updated January 13, 2023. Accessed May 28, 2023. https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html
3. Benedict K, Jackson BR, Chiller T, Beer KD. Estimation of direct healthcare costs of fungal diseases in the United States. Clin Infect Dis. 2019;68(11):1791-1797. doi:10.1093/cid/ciy776
4. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50. doi:10.1093/cid/civ933
5. Thompson GR, Soriano A, Skoutelis A, et al. Rezafungin versus caspofungin in a phase 2, randomized, double-blind study for the treatment of candidemia and invasive candidiasis: the STRIVE trial. Clin Infect Dis. 2021;73(11):e3647-e3655. doi:10.1093/cid/ciaa1380
6. Sahadevan NV. Drug interactions of azole antifungals. J Skin Sex Transm Dis. 2023;5(1):50-54. doi:10.25259/JSSTD_61_2021
7. Benitez LL, Carver PL. Adverse effects associated with long-term administration of azole antifungal agents. Drugs. 2019;79(8):833-853. doi:10.1007/s40265-019-01127-8
8. Antimicrobial resistance in Candida. Centers for Disease Control and Prevention. Updated May 18, 2020. Accessed May 28, 2023. https://www.cdc.gov/fungal/diseases/candidiasis/antifungal-resistant.html#print
9. Thompson GR 3rd, Soriano A, Cornely OA, et al; ReSTORE trial Investigators. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet. 2023;401(10370):49-59. doi:10.1016/S0140-6736(22)02324-8
10. Lodise T Jr, Garey KW, Nathanson BH. 468. Assessment of the proportion of hospitalized patients (pts) with candidemia (C) and invasive candidiasis without candidemia (IC) who received an echinocandin (EC) and were potentially eligible for an earlier hospital discharge (HD). Open Forum Infect Dis. 2022;9(suppl 2):ofac492.526. doi:10.1093/ofid/ofac492.526
11. Rezzayo. Prescribing information. Melinta Therapeutics; 2023. Accessed May 28, 2023. https://rezzayo.com/pdfs/REZZAYO%20(rezafungin%20for%20injection)%20Package%20Insert.pdf
12. Norris AH, Shrestha NK, Allison GM, et al. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clin Infect Dis. 2019;68(1):e1-e35. doi:10.1093/cid/ciy745

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