-
Lancet (London, England) Jan 2023Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis.
METHODS
ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete.
FINDINGS
Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events.
INTERPRETATION
Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development.
FUNDING
Cidara Therapeutics and Mundipharma.
Topics: Adult; Male; Humans; Female; Middle Aged; Caspofungin; Administration, Intravenous; Candidiasis, Invasive; Double-Blind Method; Treatment Outcome
PubMed: 36442484
DOI: 10.1016/S0140-6736(22)02324-8 -
Antimicrobial Agents and Chemotherapy Sep 2022Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi.... (Review)
Review
Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.
Topics: Antifungal Agents; Candidiasis, Invasive; Caspofungin; Fungi; Humans; Invasive Fungal Infections; Nitriles; Pyridines; Triazoles; Voriconazole
PubMed: 35969068
DOI: 10.1128/aac.00177-22 -
Medicina Oral, Patologia Oral Y Cirugia... Mar 2019Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and... (Review)
Review
BACKGROUND
Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation.
MATERIAL AND METHODS
Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library.
RESULTS
Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides.
CONCLUSIONS
Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.
Topics: Administration, Intravenous; Administration, Oral; Administration, Topical; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candidiasis, Oral; Caspofungin; Clotrimazole; Databases, Factual; Drug Interactions; Echinocandins; Fluconazole; Humans; Miconazole; Nitriles; Nystatin; Pyridines; Triazoles
PubMed: 30818309
DOI: 10.4317/medoral.22978 -
Clinical Infectious Diseases : An... Dec 2021Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC).
METHODS
Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up.
RESULTS
Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS.
CONCLUSIONS
RZF was safe and efficacious in the treatment of candidemia and/or IC.
CLINICAL TRIALS REGISTRATION
NCT02734862.
Topics: Adult; Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Double-Blind Method; Echinocandins; Humans; Treatment Outcome
PubMed: 32955088
DOI: 10.1093/cid/ciaa1380 -
Nature Communications Apr 2023Fungal infections cause more than 1.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening...
Fungal infections cause more than 1.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, we identify the host defense peptide mimetic, brilacidin (BRI) as a synergizer with caspofungin (CAS) against CAS-sensitive and CAS-resistant isolates of Aspergillus fumigatus, Candida albicans, C. auris, and CAS-intrinsically resistant Cryptococcus neoformans. BRI also potentiates azoles against A. fumigatus and several Mucorales fungi. BRI acts in A. fumigatus by affecting cell wall integrity pathway and cell membrane potential. BRI combined with CAS significantly clears A. fumigatus lung infection in an immunosuppressed murine model of invasive pulmonary aspergillosis. BRI alone also decreases A. fumigatus fungal burden and ablates disease development in a murine model of fungal keratitis. Our results indicate that combinations of BRI and antifungal drugs in clinical use are likely to improve the treatment outcome of aspergillosis and other fungal infections.
Topics: Humans; Mice; Animals; Antifungal Agents; Caspofungin; Antimicrobial Cationic Peptides; Disease Models, Animal; Aspergillosis; Mycoses; Aspergillus fumigatus; Candida albicans; Drug Resistance, Fungal
PubMed: 37045836
DOI: 10.1038/s41467-023-37573-y -
Revista Chilena de Infectologia :... Dec 2011The echinocandins, caspofugin, micafungin, and anidulafungin, are lipopeptides that inhibit fungal growth by binding to β - (1.3) d glucan synthase. This enzyme is... (Review)
Review
The echinocandins, caspofugin, micafungin, and anidulafungin, are lipopeptides that inhibit fungal growth by binding to β - (1.3) d glucan synthase. This enzyme is responsible for the formation of the peptidoglycan cell wall, and it is essential in fungi such as Candida spp, but less important in the case of Aspergillus and Fusarium species. We review the history, pharmacology and clinical trials that have showed clinical efficacy similar to amphotericin B for the management of fungal infections such as candidemia, invasive candidiasis and aspergillosis, even in cases refractory to initial treatment. These drugs have less toxicity and discontinuation is uncommonly required. Despite similar spectrum and tolerability, there are several pharmacological differences. Only a few clinical trials compare the clinical efficacy between them and their clinical application cannot be generalized. However, the echinocandins have demonstrated clinical efficacy in patients with invasive candidiasis and in others forms of systemic mycoses.
Topics: Anidulafungin; Antifungal Agents; Aspergillus; Candida; Caspofungin; Clinical Trials as Topic; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests
PubMed: 22286675
DOI: No ID Found -
BMC Infectious Diseases Jun 2022To observe the changes of hepatic function and efficacy of conventional dosage of caspofungin in the treatment of patients with different Child-Pugh scores.
BACKGROUND
To observe the changes of hepatic function and efficacy of conventional dosage of caspofungin in the treatment of patients with different Child-Pugh scores.
METHODS
In total, 200 patients (Child-Pugh A group: 66 patients, Child-Pugh B group: 83 patients, Child-Pugh C group: 51 patients) treated with caspofungin from May 2018 to March 2021 in the Second Affiliated Hospital of Chongqing Medical University were enrolled. Main investigation items were as follows: sex, age, weight, duration of treatment, dosage, department, underlying diseases, risk factors for fungal infection, albumin, liver enzyme, total bilirubin, serum creatinine, estimated glomerular filtration rate. To investigate the changes of liver, kidney function tests and efficacy during the treatments of caspofungin. Patients were divided into three groups according to the duration of treatment of caspofungin:1-week group, 2-week group and 3-week group, respectively.
RESULTS
In the three groups, albumin, liver enzyme levels, total bilirubin and serum creatinine, estimated glomerular filtration rate had no significant difference (P > 0.05). The efficacy of different Child-Pugh scores and different duration of treatment was also significantly different (P > 0.05).
CONCLUSIONS
Caspofungin is well tolerated and highly effective. And it will not exacerbate the hepatic and renal function when administered with the not-reducing dose, which indicate the clinical application value of caspofungin. Besides, extending the treatment duration has little effect on improving the efficacy of caspofungin. The drug should be withdrawn timely according to the patients' clinical condition in order to reduce the adverse reactions and economic burden.
Topics: Albumins; Bilirubin; Caspofungin; Creatinine; Hepatic Insufficiency; Humans; Liver Failure
PubMed: 35725403
DOI: 10.1186/s12879-022-07527-8 -
Archivos Argentinos de Pediatria Aug 2016Invasive fungal infections are a significant cause of morbidity and mortality in children. Caspofungin is an echinocandin used as an alternative treatment in the... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Invasive fungal infections are a significant cause of morbidity and mortality in children. Caspofungin is an echinocandin used as an alternative treatment in the prevention and/or treatment of certain invasive fungal infections in children, although compared to the standard treatment there is little evidence on its efficacy and safety.
OBJECTIVE
To evaluate the efficacy and safety of caspofungin compared with other antifungal drugs for the prevention and/or treatment of invasive fungal infections in children.
MATERIALS AND METHODS
The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old.
RESULTS
The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old.
CONCLUSIONS
This systematic review suggests that caspofungin could be considered as an alternative drug in children for the prevention and treatment of invasive fungal infections. However, given the small number of existing publications, more studies are required to reach definite conclusions.
Topics: Antifungal Agents; Caspofungin; Child; Echinocandins; Humans; Lipopeptides; Mycoses; Treatment Outcome
PubMed: 27399007
DOI: 10.5546/aap.2016.eng.305 -
Clinical Infectious Diseases : An... Feb 2023Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven... (Randomized Controlled Trial)
Randomized Controlled Trial
Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.
BACKGROUND
Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown.
METHODS
Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization.
RESULTS
Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001).
CONCLUSIONS
The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.
Topics: Humans; Antifungal Agents; Fluconazole; Caspofungin; Mycoses; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 35906831
DOI: 10.1093/cid/ciac623 -
Brazilian Journal of Microbiology :... Sep 2022Caspofungin and other echinocandins have been used for the treatment of human infections by the opportunistic yeast pathogen, Candida albicans. There has been an... (Review)
Review
Caspofungin and other echinocandins have been used for the treatment of human infections by the opportunistic yeast pathogen, Candida albicans. There has been an increase in infections by non-albicans Candida species such as Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, and Candida auris in clinical or hospital settings. This is problematic to public health due to the increasing prevalence of echinocandin resistant species/strains. This review will present a summary on various studies that investigated the inhibitory action of caspofungin on 1,3-β-D-glucan synthesis, on cell wall structure, and biofilm formation of C. albicans. It will highlight some of the issues linked to caspofungin resistance or reduced caspofungin sensitivity in various Candida species and the potential benefits of antimicrobial peptides and other compounds in synergy with caspofungin.
Topics: Antifungal Agents; Candida; Candida albicans; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests
PubMed: 35352319
DOI: 10.1007/s42770-022-00739-9