Caspofungin pre-emptive therapy failed to prevent susceptible Candida auris breakthrough infection or colonization: An in-depth clinical survey of four cases

To the Editor, We read with interest the article by Balázsi et al., which reported that caspofungin improved survival rates against four Candida auris (C. auris) clades in a neutropenic mouse bloodstream infection model.[1] Indeed, echinocandin regimens are the first-line recommendation for treating C. auris infections in clinical settings.[2] However, an increasing number of studies have reported failures of caspofungin therapy against C. auris.[3] Notably, our study observed that even pre-emptive treatment with caspofungin in high-risk patients in intensive care units (ICUs) failed to prevent infection or colonization by caspofungin-susceptible C. auris. C. auris, a multidrug-resistant yeast, poses a significant threat in healthcare settings, particularly among critically ill ICU patients. Invasive medical devices—such as ventilators, central lines, and urinary catheters—are often essential for patient care but can serve as conduits for C. auris to enter the body.[4] Once invasive, C. auris can lead to severe, life-threatening infections, including bloodstream infections. In addition, patients infected or colonized with C. auris can contaminate surfaces and medical equipment, facilitating transmission. Since the fungus can persist on surfaces for extended periods, environmental decontamination is challenging.[5] Treatment options are often hard to make as many C. auris strains are resistant to multiple antifungal agents. Echinocandins, such as caspofungin, anidulafungin, micafungin, and rezafungin, are effective against C. auris infections. However, reports of treatment failures with echinocandins have been increasingly documented,[3] emphasizing the need for vigilant surveillance and judicious antifungal prescribing. This retrospective study assessed the use of caspofungin in treating C. auris infections. A thorough evaluation was conducted on 16 patients infected with C. auris between April 2024 and June 2025. All data were anonymized and ethical approval of this retrospective study was exempt by the ethics committee of Shenzhen Third People’s Hospital. Written informed consent was secured from all patients at the time of admission for the publication of their diagnosis and treatment data in peer-reviewed journals. From this cohort, we selected four patients for in-depth analysis because they had received caspofungin before C. auris infection was confirmed, having been treated for other fungal infections, such as Pneumocystis jirovecii, Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida glabrata. All patients were admitted to the ICU due to severe infections or chronic organ failure resulting from underlying conditions (Table 1). Consequently, these patients were inherently at high risk for C. auris infections or colonization.[4]C. auris was confirmed by culture in three patients and by metagenomic next-generation sequencing (mNGS) in one patient, all from bronchoalveolar lavage fluid (BALF). Susceptibility testing indicated that three of the isolated C. auris strains were sensitive to caspofungin. All patients received prolonged courses of broad-spectrum antibiotics such as beta-lactam antibiotics, carbapenem antibiotics, and underwent invasive procedures, such as central venous catheter (CVC) placement. Those features are common among ICU patients. Table 1 - Clinical characteristics of four ICU patients. Case No. Sex/Age (years) Underlying Diseases Diagnosis on Admission Albumin (g/L) Initial Prescription of Caspofungin (Days*) First Detection of Candida auris (Daysa) Usage Length of Caspofungin (Days) Dosage and Administration of Caspofungin 1 M/85 T2DM, Hypertension, Cerebral infarction Infectious shock, Severe pneumonia, Influenza A infection 27.9 35 43 8 Load: 70 mg/day IVMaintain: 50 mg/day, IV 2 M/71 T2DM, Coronary heart disease Septic shock, Severe pneumonia, Acute respiratory distress syndrome 25.4 5 17 12 Load: 70 mg/day IVMaintain: 50 mg/day, IV 3 M/68 T2DM, Hypertension, Cerebral infarction, Cancer Septic shock, Severe pneumonia 28.4 1 43 42 Load: 70 mg/day IVMaintain: 50 mg/day, IV 4 M/59 T2DM, Hypertension, Cerebral infarction, Cancer, Coronary heart disease Severe pneumonia, Acute-on-chronic liver failure 26.3 20 29 9 Load: 70 mg/day IVMaintain: 35 mg/day, IV Case No. Clinical Samples Test Methods Susceptible Test of Caspofungin Hemopurification Long-term Use of Broad-Spectrum Antibiotics ICUs Admission Invasive Procedures e.g. CVC Date of Hospitalizaiton 1 BALF Culture S Y Y Y Y 2024.05 2 BALF mNGS NA Y Y Y Y 2024.07 3 BALF Culture S Y Y Y Y 2024.08 4 BALF Culture S Y Y Y Y 2025.05 aDays since hospital admission.ICUs: Intensive care units; CVC: Central venous catheter; T2DM: Type 2 diabetes mellitus; M: Male; S: Susceptible; NA: Not available; Y: Yes; BALF: Bronchoalveolar lavage fluid; mNGS: metagenomic next-generation sequencing; IV: Intravenous drip. An in-depth clinical survey revealed that pre-emptive caspofungin therapy failed to prevent infection or colonization by caspofungin-susceptible C. auris. The four patients had received caspofungin for 8−42 days (Table 1). Prior cultures or mNGS of the same samples were negative for C. auris. This suggests that C. auris was not present at the time of initial testing, ruling out undetected colonization or infection. Several factors may explain this observation: 1. Hemopurification effects: Procedures such as continuous renal replacement therapy (CRRT) and inflammatory factor removal can significantly alter patients’ hemodynamic distribution and affect the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs.[6] Furthermore, certain biomaterials, such as polyacrylonitrile (PAN)-derived filters used in CRRT, can absorb caspofungin.[7] These changes may lead to insufficient drug distribution and inadequate tissue concentrations, potentially resulting in treatment failure. In our study, all patients received blood purification therapy due to septic shock or organ failure (Table 1). 2. Impact of hypoalbuminemia: Critically ill patients often exhibit hypoalbuminemia (Table 1), which increases the unbound fraction of highly protein-bound drugs, such as caspofungin. This elevation may accelerate drug clearance and lead to suboptimal drug exposure and reduced efficacy.[8] 3. Underlying drug−drug interactions (DDIs): ICU patients often receive complex medication regimens, increasing DDI risk. In our study, all four patients were on long-term courses of multiple broad-spectrum antibiotics and supportive drugs (Table 1), which can lead to significant DDIs. Caspofungin, primarily metabolized in the liver, is susceptible to interactions due to P450 enzyme induction.[9] Consequently, its PK and PD can be altered, reducing therapeutic effect. Vigilant assessment and management of potential DDIs are essential in ICU settings to optimize outcomes. 4. Effects of drug-dosing adjustment: Patient 4, diagnosed with acute-on-chronic liver failure due to HBV infection, had a Child-Pugh score of class C, indicating advanced liver damage. Consequently, the caspofungin dose was adjusted (35 mg/day) according to the manufacturer’s instructions, leading to suboptimal drug exposure, as previously reported.[10] C. auris infections are frequently associated with treatment failures due to antimicrobial resistance.[4] However, our study indicates that even when the isolate is susceptible in vitro, pre-emptive therapy may fail to prevent colonization or infection if the patient has conditions such as hemopurification, hypoalbuminemia, prolonged and complex medication histories, or dose adjustments due to organ dysfunction. Clinicians should be aware that the risk of treatment failure increases with the number of these concurrent factors. Thus, caution is advised when administering antifungal agents, and clinicians should consider adjusting dosing regimens, routes of administration, or implementing therapeutic drug monitoring (e.g., measuring blood drug concentrations). Nevertheless, this study has limitations, including the small number of cases and a single-center retrospective design. Given the super-resistant nature of C. auris and the limited therapeutic options, further research in diverse treatment scenarios is imperative to promote rational antimicrobial use and improve patient outcomes. Funding This work was supported by Shenzhen Clinical Research Center for Emerging Infectious Diseases (No. LCYSSQ20220823091203007) & Shenzhen High-level Hospital Construction Fund, Sanming Project of Medicine in Shenzhen (SZSM202311033). Author Contributions Qiuping Li and Zhi Wang made literature review and drafted the initial manuscript. Weipeng Cao, Haihui Song, and Weiming Yao collected and organized the clinical data and assisted in revising the manuscript. Ting Wu, Yuanlong Lin, Shiyan Feng, Jinhong Luo, and Xijie Huang performed the data analysis and contributed to subsequent manuscript revisions. Qiqi Miao, Xiaochun Chen, Lihua Hu, Jinkai Qu, and Xueshan Chen assisted with data interpretation and polished the manuscript. Ming Tang and Fuxiang Wang designed the study and provided significant revisions to the manuscript. All authors have read and approved the final version. Conflicts of Interest None. Data Availability Statement The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.