caspofungin
Regulatory sources consulted
Approved indications
- Invasive candidiasis, invasive aspergillosis refractory to or intolerant of other therapies, and empirical treatment of fungal infection in febrile neutropenia.
Contraindications
Absolute
- Hypersensitivity to caspofungin or its components.
Clinical warnings
- It may cause anaphylaxis and histamine-mediated reactions; stop the infusion and treat if they occur. — CIMA/AEMPS, ficha técnica 01196001
- Major warning · Monitor hepatotoxicity and severe skin reactions, including SJS/TEN. — CIMA/AEMPS, ficha técnica 01196001
Drug interactions
- HighCyclosporine
Mechanism: It may increase exposure and transaminases.
Recommendation: It may be used if benefit outweighs risk; monitor liver enzymes.
CIMA/AEMPS, ficha técnica 01196001
- HighRifampin or other enzyme inducers
Mechanism: They may reduce caspofungin exposure.
Recommendation: Consider 70 mg/day maintenance in adults according to the label.
CIMA/AEMPS, ficha técnica 01196001
- HighTacrolimus
Mechanism: Caspofungin reduces tacrolimus trough concentration by approximately 26%.
Recommendation: Use standard trough-concentration monitoring and adjust tacrolimus as needed.
CIMA/AEMPS, ficha técnica 01196001
Adverse events
Common (≥1%)
Fever, nausea, diarrhea, headache, and liver-test abnormalities
Rare but serious
Anaphylaxis, hepatotoxicity, and SJS/TEN
Pregnancy and lactation
Use during pregnancy only if clearly necessary. Do not breastfeed during caspofungin treatment.
Recent literature (PubMed)
Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.
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. 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. 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
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 in vitro 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.
Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades have seen a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications. The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies. Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.
At the 10th European Conference on Infections in Leukaemia (ECIL), the guidelines for antifungal prophylaxis in pediatric and adult patients with hematological malignancies (HM) were updated and some changes introduced. Regarding acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients undergoing remission induction chemotherapy, a B-II grading has been assigned to isavuconazole, micafungin, and caspofungin, based on non-randomized studies that have shown efficacy in preventing invasive fungal diseases (IFD). Regarding high-risk MDS patients treated with azacytidine, prophylaxis with posaconazole during the first four cycles of treatment is supported in the literature. Prophylaxis is not indicated in patients treated for myeloproliferative neoplasms (NPM), acute lymphoid leukemia (ALL), and Hodgkin lymphoma (HL). For patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), prophylaxis is not generally indicated. For patients with multiple myeloma (MM), prophylaxis is not indicated and the limited epidemiological data available do not support the use of prophylaxis in subjects treated with bispecific antibodies. For patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), no substantial changes were made, apart from the addition of isavuconazole with grading B-II in the post-engraftment period. In patients undergoing auto-HSCT, antifungal prophylaxis is not indicated. Previous ECIL guidelines did not include CAR-T cells. The expert panel proposes to endorse the use of anti-mold prophylaxis in high-risk patients during pre-infusion and post-infusion, while in low-risk patients, anti-yeast prophylaxis can be recommended (B-II). For pediatric hematology patients, based on newly published data, caspofungin received a B-I grading as mold-active prophylaxis. Moreover, patients with ALL with insufficient treatment response during induction therapy, and children older than 12 y.o are now considered at high risk f