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Abstract

Candida species is the most common cause of invasive fungal infection in the critically ill population admitted to the intensive care unit (ICU). Numerous risk factors for developing invasive candidiasis (IC) have been identified, and some, like the breach of protective barriers, abound within the ICU. Given that IC carries a significant mortality, morbidity, and healthcare cost burden, early diagnosis and treatment have become an essential topic of discussion. Several expert panels and task forces have been established to provide clear guidance on the management of IC. Unfortunately, IC remains a diagnostic and therapeutic challenge attributable to the changing fungal ecology of Candida species and the emergence of multidrug-resistant strains. This narrative review will focus on the following: (1) the incidence, outcomes, and changing epidemiology of IC globally; (2) the risk factors for developing IC; (3) IC risk stratification tools and their appropriate use; (4) diagnosis of IC; and (5) therapeutic agents and regimens.

Plain Language Summary Title

A review of severe Candida infection in patients admitted to the Intensive Care Unit Plain Language Summary:

Candida infections are the most common type of serious fungal infections that affect patients in Intensive Care Units (ICUs). There are many known risk factors for developing these infections, especially in ICU patients who often experience situations like damage to protective barriers in the body. Since these infections can lead to death, serious illness, and higher healthcare costs, itâ€™s important to diagnose and treat them as early as possible. However, diagnosing and treating invasive Candida infections is still very difficult. This is because the types of Candida fungi are changing, and some strains are becoming resistant to multiple antifungal medications. The goal of this review is to help improve understanding and management of these serious infections in ICU settings.

Keywords

Intensive care unit invasive candidiasis antifungal therapy critical care medicine infection sepsis

Introduction

Candida is a normal part of human flora, most frequently isolated from the gut.¹ Invasive candidiasis (IC) develops when disruptions in immune barriers allow Candida to translocate into the bloodstream (candidemia) or result in deep-seated localized infections.² IC is particularly prevalent in intensive care units (ICUs), where its incidence is 10 times greater than in medical and surgical wards, accounting for between 70% and 90% of all ICU fungal infections.¹ This is partly due to an ageing patient population, severe acute illness, invasive procedures, use of immunosuppressants, and broad-spectrum antimicrobials.¹ IC encompasses both candidemia and deep-seated Candida infection with or without the associated bloodstream infection, with intra-abdominal candidiasis (IAC) being the most common deep-seated infection.¹ We completed a MEDLINE search for English articles published between 1998 and 2024 using the terms “Invasive Candidiasis,” “Candidaemia,” “Epidemiology,” “Diagnosis,” “Biomarkers,” and “Treatment” and also reviewed the reference lists of articles identified in this search. We aim to produce an up-to-date and concise overview of IC in the ICU.

Epidemiology

The epidemiology of Candida infections in the ICU involves a complex interplay of patient risk factors and antifungal resistance. The observed rise in the prevalence of yeast infections in ICUs and the associated mortality rate from candidemia could be influenced by several factors.^3,4 Therefore, a comprehensive analysis of IC incidence over several years and across various countries is necessary to discern whether the observed increase is due to changes in diagnostic practices or a bona fide increase in prevalence and mortality rates. In this context, epidemiological surveillance remains essential.

While numerous registries exist for ICUs, their global representation is limited. Additionally, regions with a low to lower-middle income per capita need to be more represented. It's crucial to note that an isolate does not necessarily equate to an infection, as Candida species are a frequent commensal fungus that colonize the oropharyngeal cavity, gastrointestinal and vaginal tract without causing disease.⁵ In Europe, the incidence of IC was 7.0 cases per 1000 ICU admissions, with a crude mortality rate of approximately 40%.⁶ The incidence and distribution of Candida species varies within different regions with a reported higher incidence for IC in Southern Europe than in Northern or Western Europe.^3,6,7 C. albicans remains the leading cause of IC in Europe, the United States, and Australia, followed by C. glabrata.^7–9 Interestingly, In Asia and South America, non-albicans Candida (naC) is dominant, with C. parapsilosis and C. tropicalis being the most frequently isolated, respectively.¹⁰ Despite its vast population and geographic diversity, data on IC in Africa remain limited. A comprehensive review of IC cases across Africa reported only 18 293 cases over 45 years. Of these, C. albicans was the most common species (32.6%), followed by C. parapsilosis (30.4%) and the emerging C. auris (7.8%).¹¹

There is a trend of increasing naC prevalence in Europe and America, but not in Asia and South America (which already have a higher prevalence of naC).¹⁰ The shift towards naC is concerning as many of these Candida species have intrinsic azole resistance (C. glabrata and C. krusei), are adept at forming biofilms (C. parapsilosis), and easily develop resistance (C. glabrata).^12,13

A microcosm of epidemiological shift can be seen with C. parapsilosis. Although initially considered fully susceptible to fluconazole, the emergence of fluconazole-resistant C. parapsilosis has been reported in a growing number of countries.¹³ In Africa, the emergence of azole resistance has propelled C. parapsilosis to the second most common cause of IC.¹¹ Since 2018, these resistant strains have expanded and outcompeted fluconazole-sensitive strains in Southern Europe, leading to major outbreaks in Spain, Greece, Italy, and Turkey.¹³

The growing concern of azole resistance in naC and reported echinocandin resistance is further complicated by the emergence of C. auris.⁴ This multidrug-resistant yeast has appeared almost simultaneously in various locations worldwide. It poses an additional challenge in the diagnosis and management of IC, and has been linked with outbreaks globally, particularly in ICUs.^3,4,14 Identifying this species requires molecular methods and is often misidentified. A retrospective review of the SENTRY isolate collection found no C. auris isolates before 2009, indicating that the pathogen was genuinely rare and not merely misidentified in the past.¹⁵ The rapid emergence may partly be due to the increased availability of antifungal agents and the resulting selection pressure. C. auris appears to be inherently resistant to azoles, with variable susceptibility to amphotericin B and echinocandins. This is evident in South Africa, where a unique clade of C. auris has emerged in hospitals.¹⁶ This is believed to have occurred due to the indiscriminate use of fluconazole as prophylaxis and treatment as well as suboptimal adherence to infection control practices.

Current evidence indicates that major risk factors for IC, such as intestinal mucosal barrier damage, abdominal surgery, pancreatitis, and dysbiosis of resident microbiota, are more common in surgical ICUs.^1,2 In contrast, patients in medical ICUs are also at risk for IC due to factors such as the growing use of antineoplastic and immunosuppressive therapies, an increased number of hematopoietic stem cell transplants, and the widespread use of broad-spectrum antibiotics.¹⁷

The limitations identified in the studies on the prevalence of IC in ICUs include challenges in ascertaining the true incidence of candidemia due to the use of different denominators such as indwelling catheter duration, bed days, admissions, discharges, and patient days.

Risk Factors and Stratification

Given the time-sensitive nature of initiating treatment for IC to prevent significant morbidity and mortality, early suspicion and diagnosis are essential. Thomas-Rüddel et al¹⁸ conducted a meta-analysis which identified broad-spectrum antimicrobials, blood transfusion, Candida colonization, the presence of a central venous catheter, and total parenteral nutrition (TPN) as the factors associated with the highest risk of developing IC. It is thus not surprising that these factors are often included in risk stratification tools, the most widely known being the Candida Colonization Index, the Candida Score, and the Ostrosky-Zeichner Clinical Prediction Rule. Additionally, mechanical ventilation, renal replacement therapy, and other breaches of protective barriers such as extracorporeal membrane oxygenation also played a major role. Finally, there are risk factors that are more difficult to define such as “prolonged” ICU stay and genetic polymorphisms that have also come to light.^7,18 The development of IC is ultimately dependent on the incidence and distribution of Candida species in each unit, as well as the summation and interplay of these risk factors.^7,18,19

The utility of risk stratification tools for guiding the diagnosis and initiation of antifungal therapy remains contentious. Numerous scoring systems have been developed to identify patients who may benefit from early empiric antifungal treatment; however, these tools generally demonstrate low to moderate positive predictive values (PPVs) of 10% to 66% and high negative predictive values (NPVs), above 90% (Table 1).^20–25,26 A 2022 systematic review by Giacobbe et al²⁴ evaluated the diagnostic accuracy of these tools, including modified versions, across 16 studies and corroborates this, even among symptomatic patients. Consequently, expert recommendation is to use these tools primarily to rule out patients at low risk of IC and for who empiric antifungal therapy should not be a consideration, while identifying those who require further diagnostic evaluation.²⁵

Table 1.

Risk stratification tools for IC.

Risk stratification tool	Performance	Additional information	References
Colonization Index
Candida Colonization Index	PPV 66% NPV 100%	Requires surveillance cultures	^{22, 23}
Clinical prediction scores
Candida Score	Sensitivity 81% Specificity 74% PPV 16% NPV 98%	Improved specificity and PPV in combination with BDG	^{23, 24, 25}
Ostrosky-Zeichner Clinical Prediction Rule	Sensitivity 50% Specificity 83% PPV 10% NPV 97%		²⁶

Diagnosis

Given that the risk stratification tools have more value as a “rule out” than a “rule in” predictor, it stands to reason that the development of rapid turnover, sensitive, and specific laboratory tests are of paramount importance in patients where IC cannot be ruled out. Unfortunately, no such test yet exists. Conventional culture-based methods remain the gold standard for diagnosing IC, despite limitations such as delayed results, low sensitivity (∼75% in bloodstream infections, ∼5%-20% in IAC), and challenges with sterile site sampling for deep-seated infections.^7,25 These limitations underscore the importance of culture adjuncts. Mass spectrometry, especially matrix-assisted laser desorption/ionization time-of-flight, is cost-effective and has the ability to rapidly identify Candida, including the often misdiagnosed C. auris. It also holds promise for detecting antifungal resistance.^25,27,28 The Peptide Nucleic Acid in Situ Hybridisation Yeast Traffic Light (PNA-FISH YTL) system provides species identification and azole sensitivity grouping within an hour, but its high cost and inability to distinguish between C. albicans and C. parapsilosis, or between the azole-resistant C. glabrata and C. krusei, limit its use.^26,29–31

Given the delay in turnaround time for culture-based diagnosis and that cultures are negative in approximately 50% of IC, non-culture-based tests (NCBT) are important IC diagnostic tools.³² NCBT have a rapid turnover time, which may aid in decreasing time to treatment initiation, thus guiding empiric and pre-emptive antifungal treatment, and could possibly be useful in advising treatment duration and monitoring clinical improvement, given that NCBT remains positive for longer than cultures.^7,25 However, clinician interpretation is crucial, as pretest probability and diagnostic thresholds affect their interpretation.^7,25,33 Most NCBT display a low PPV, but have high NPV (see Table 2).^7,25,33 Of the NCBT, the serological test 1,3-β-D-Glucan (BDG) is widely used and validated, and is included in the European Organization for Research and Treatment of Cancer/Mycosis Study Group diagnostic criteria for invasive fungal infection. It is a cell wall constituent of most pathogenic fungi (ie, Candida, Aspergillus, and Pneumocystis), and thus inherently lacks specificity. Its performance is improved when 2 positive results are obtained or used in conjunction with Candida risk prediction models, PCT or other fungal biomarkers.^7,25,33,34 Importantly, the CandiSep trial found no 28-day mortality benefit with the use of BDG for antifungal treatment guidance in ICU patients with risk factors for IC.³⁵ Additional considerations include the high false positive rate associated with BDG due a range of factors including (but not limited to) hemodialysis, certain B-lactam antibiotics, human blood products, and TPN, all of which are frequently present in the ICU population.³³

Table 2.

Overview of non-culture-based tests.

Non-culture-based tests	Description	Performance	Additional information	References
Polymerase chain reaction
Multiplex Candida real time PCR panel	DNA segment detection and amplification	Sensitivity: 73% to 95% Specificity: 92% to 95%	Not FDA approved Still requires validation in large multi-center studies Performance in IC without candidemia uncertain Performance heterogeneity depending on assay, sample type and study design	^{25, 36, 40}
Miniaturized magnetic resonance-based technology
T2 Candida	DNA amplified by PCR, the amplified product is then identified by agglomeration of supermagnetic particles and T2 magnetic resonance	Sensitivity: ∼91% Specificity: ∼94%	Capable of identifying 5 most common Candida spp: Candida: albicans, glabrata, parapsilosis, tropicalis, and krusei FDA approved	^{29, 36, 41}
Serological tests
Mannan antigen detection	Mannan is a fungal cell wall constituent	Sensitivity: 58% Specificity: 93%	Combined mannan and anti-mannan sensitivity: 83% and specificity: 86% Not FDA approved	⁴²
Anti-mannan IgG antibody detection	Mannan is a fungal cell wall constituent	Sensitivity: 59% Specificity: 83%	Combined mannan and anti-mannan sensitivity: 83% and specificity: 86% Not FDA approved	⁴³
CAGTA	Detects antibodies against a hyphal protein expressed by Candida spp	Sensitivity: 59% to 73% Specificity: 58% to 88%	Not FDA approved	^{36, 43}
BDG	Cell wall constituent of most fungal cell walls	Sensitivity: 77%-81% Specificity: 60% to 85%	See text body for additional information	^{44, 45, 46}

Polymerase chain reaction (PCR)-based tests, despite lacking FDA approval, are widely available and can quickly identify common IC-associated Candida species.^25,33 The T2 Magnetic Resonance Candida assay (T2 Candida) is an FDA approved, fully automated, novel detection technique that offers rapid (3-5 h) and highly sensitive (>90%) detection of Candida species in patients with low fungal burdens.^33,36 Other serological biomarkers that are widely used across Europe for the early detection of IC include mannan antigens, anti-mannan IgG antibodies, and Candida species germ tube antibodies (CAGTA), all of which exhibit low sensitivity and specificity^33,37,38 (Table 2). Presepsin is a new and accurate sepsis biomarker, with a turnaround time of 15 min.³⁹ Its use in combination with BDG holds promise for distinguishing between IC and colonization.⁴⁰

IAC diagnosis is especially challenging, as candidemia occurs in only 4% to 14% of patients.⁴¹ Confirming IAC without candidemia requires a culture from a specimen obtained from a normally sterile site via sterile procedure, and does not differentiate between Candida colonization and infection. NCBT may help provide clarity in these cases.^10,42 A recent study suggests that low BDG concentrations in peritoneal fluid could potentially rule out IAC.⁴³ Given the challenges in diagnosing IAC, including the aforementioned limitations of blood cultures and its nonspecific clinical presentation, clinicians must remain mindful of the low sensitivity of traditional tests and by extension, the underreporting in surveillance studies.

As alluded to, the NPV and PPV of both NCBT and risk stratification scores may be improved through combinations of 2 different laboratory tests or by pairing one laboratory test with a clinical score.^7,24,25 Preliminary data from several studies suggest that these combinations may enhance diagnostic accuracy for IC, particularly by improving PPV when both tests indicate IC and NPV when neither test does.²⁴

Treatment

Antifungal stewardship represents a coordinated, strategic effort to optimize the use of antifungal medications. This includes implementing guidelines for appropriate antifungal therapy, utilizing diagnostic tools to tailor treatment, promoting de-escalation from broad-spectrum to targeted therapy when possible, and monitoring the use of antifungal agents to ensure their judicious and effective utilization. The goal is 4-fold: to reduce unnecessary usage, minimize adverse effects, maximize cure rates, and reduce resistance emergence.

Currently, 4 classes of antifungals are available for systemic treatment of Candida species infections in clinical practice.

Azoles (fluconazole, itraconazole, isavuconazole, posaconazole, and voriconazole)

Polyenes (conventional amphotericin B and its lipid formulations)

Echinocandins (anidulafungin, caspofungin, and micafungin)

Pyrimidine analog (flucytosine)

Azoles work by inhibiting the synthesis of ergosterol, an essential component of the fungal cell membrane. This disruption leads to cell death. Azoles are fungistatic against Candida species.⁴⁴ The effectiveness of azoles is concentration- and time-dependent, with a prolonged post-antifungal effect.²⁵ Azoles have variable activity against biofilms, with some studies suggesting that they may have only limited effectiveness in eradicating fungal biofilms due to altered metabolic states and reduced susceptibility of biofilm-encased organisms.²⁷ Echinocandins target the fungal cell wall by inhibiting glucan synthesis, showing fungicidal activity against most Candida species, including biofilm-forming and azole-resistant strains.^7,27 Historically, Amphotericin B was used for severe fungal infections due to its broad spectrum of activity and fungicidal properties against most Candida species. However, its association with nephrotoxicity has led to a decrease in its use. More recently, better-tolerated formulations of amphotericin B, such as liposomal amphotericin B (L-AmB), amphotericin B lipid complex, and amphotericin B colloidal dispersion, have been developed, providing alternatives with reduced toxicity profiles but similar clinical efficacy.⁴⁵ In cases of multidrug-resistant Candida infections or for better tissue penetration, amphotericin B may still be considered.²⁵ Flucytosine, a synthetic compound, is converted into 5-fluorouracil after being taken up by susceptible fungal cells. This conversion inhibits fungal nucleic acid synthesis. Flucytosine is fungistatic and resistance frequently develops, so it should not be used as monotherapy. It should be used only as an adjunct to other drugs to enhance efficacy and prevent the development of resistance.^46,47

Pharmacokinetic variability is prevalent in critically ill patients due to factors such as capillary leak, altered protein binding, augmented renal clearance, extracorporeal circuits, and end-organ dysfunction. Consequently, standard dosing regimens may be inadequate, necessitating dosage adjustments, and lead to unpredictable clinical outcomes. In such cases, therapeutic drug monitoring (TDM)-guided dosing is a safe and effective way to ensure that all critically ill patients achieve therapeutic antimicrobial exposures. TDM is most helpful for mold-active azoles (eg, voriconazole) and flucytosine as echinocandins and polyenes appear to be less affected by pharmacokinetic changes in critical illness.^48,49 While TDM may be used in selected cases, its routine use is not recommended in current guidelines and its precise role in the treatment of IC remains to be defined.

It is essential to acknowledge that the majority of clinical trials and therefore treatment guidelines are biased toward patients with candidemia. This stems from the relative ease of identifying candidemia compared to other forms of IC. Therefore, these patients are more likely to be enrolled in clinical studies than patients with deep-seated candidiasis. Other IC conditions for which higher doses of echinocandins are suggested are endocarditis, IAC, and esophageal candidiasis.^50,51

Echinocandins demonstrate limited peritoneal penetration, which is further reduced in critically ill patients. For instance, anidulafungin concentrations in these patients have been reported to be approximately 30% of those observed in healthy individuals, increasing the risk of insufficient drug exposure at the site of infection. Therefore, it has been suggested that L-AmB be used for IAC.^50,52,53 L-AmB is less affected by pharmacokinetic disturbances and has powerful action against biofilm formation, although strong evidence about its peritoneal penetration is lacking.⁵² The use of L-AmB is supported in cases involving hard-to-reach sites such as the central nervous system, and the eyes but, notably, not the urinary tract.^27,50 Unfortunately cost considerations present a significant barrier to the use of L-AmB.

Furthermore, combining antifungal therapy with adequate source control measures such as removing indwelling catheters, appropriate drainage, and surgical control is essential.²⁵ Removal of indwelling catheters is nuanced, but recommendations advocate for the removal of indwelling catheters as early as possible when the source is presumed to be the catheter and the catheter can be removed safely, but this decision should be individualized for each patient.⁵⁴

Prophylactic therapy: Patients with no evidence of current infection, clinical or biomarker, but who are at high risk of developing IC due to risk factors. Despite reductions in IC, the mortality benefit remains to be proven. The current European Society of Intensive Care Medicine and European Society of Clinical Microbiology and Infectious Diseases (ESICM/ESCMID) recommendation is against the use of antifungal prophylaxis in any critically ill non-neutropenic patients.^25,55 The Infectious Diseases Society of America (IDSA) guidelines do allow for antifungal prophylaxis in adult ICUs with a high rate of IC (>5%) in “high-risk” patients.⁵⁰ However, the guidelines do not explicitly define “high-risk” patients, and institutional protocols will differ regarding eligibility for prophylactic therapy. In alignment with the current ESICM/ESCMID recommendations, this author group advocates for prophylactic antifungal treatment exclusively in neutropenic patients.²⁵

Empiric therapy: Is the use of antifungal therapies in patients with signs and symptoms of infection, plus risk factors for IC, without proof of fungal infection. Echinocandins are the preferred choice for initial empiric antifungal treatment in critically ill patients. This preference is due to their wide range of activity, which includes naC, as well as a safety profile and a drug interaction profile that is more favorable than other antifungal agents.^{27,55,56–59}

The key to the successful use of empiric therapy is selecting the appropriate target patient population as highlighted by the EMPIRICUS trial. They demonstrated a reduced incidence of invasive fungal infections in the empiric treatment group, which did not translate into a survival benefit. Empiric therapy should be initiated for patients with septic shock and multi-organ failure, who have more than 1 extra-digestive site colonized by Candida species—this is in accord with both IDSA and ESICM/ESCMID guidelines.^25,50,58 Figure 1 summarizes the ESICM/ESCMID and IDSA empiric antifungal guidelines, highlighting their subtle differences.

Figure 1.

Summary of IDSA and ESICM/ESCMID approach to empiric antifungal therapy.

Directed/targeted therapies: Are based on microbiological confirmation of an invasive infection due to Candida. Prompt and appropriate treatment to prevent complications and improve patient outcomes should be initiated in patients with proven candidemia. ESICM/ESCMID suggests that fluconazole be considered in selected stable patients with IC, without prior azole exposure.²⁵ Further, those patients treated with fluconazole should receive a loading dose and a weight-based dosing regimen. However, due to its limited spectrum of activity and lack of fungicidal activity, current IDSA guidelines recommend echinocandins as first-line therapy.⁵⁰ IDSA considers fluconazole an alternative to echinocandins if fluconazole-resistant species are unlikely, irrespective of prior exposure. ESICM/ESCMID recommends echinocandins as the first treatment option in patients with septic shock and IC. For cases involving foreign bodies, echinocandins are preferred due to their enhanced activity against biofilm.^25,50

In cases of suspected echinocandin resistance, both guidelines suggest using liposomal amphotericin B (L-AmB). For patients unable to remove indwelling catheters, ESICM/ESCMID supports using L-AmB or echinocandins, while IDSA specifically recommends L-AmB for non-removable intracardiac devices. Both guidelines advocate de-escalation to fluconazole, with IDSA suggesting de-escalation within 5 to 7 days, while ESICM/ESCMID does not specify an exact timeframe. The duration of therapy is consistent between guidelines, requiring 2 weeks of treatment after negative blood cultures. For IAC without positive blood cultures, ESICM/ESCMID recommends 10 to 14 days of treatment, whereas IDSA advises a 2-week course, depending on source control and clinical response.^25,50 There is no consensus on whether blood cultures should be taken daily or every other day until negative growth, but current guidelines accept both approaches.^25,50 The authors have provided a summary of the ESICM/ESCMID and IDSA guidelines for treating IC in non-neutropenic patients, as outlined in Figure 2 .

Figure 2.

Summary of the treatment of IAC and candidemia in non-neutropenic ICU patients.

In cases where blood cultures are negative and disseminated disease has been excluded, a treatment period of 10 to 14 days is deemed acceptable. This recommendation is based on clinical evidence suggesting that shorter durations within this range are effective for resolving the infection when blood cultures are negative from the outset.²⁵

De-escalation has been proposed with a transition from an echinocandin (or amphotericin B) to an azole in clinically stable patients, with isolates that are susceptible to the azole and have negative repeat blood cultures (in the case of candidemia) following initiation of antifungal therapy. This transition may be safely performed within 5 days after initiation of antifungal therapy.⁶⁰

Conclusion

Despite ongoing research and expert advisory committees, IC remains a diagnostic and therapeutic challenge in the ICU, with significant morbidity, mortality, and healthcare cost consequences. The incidence and mortality rate of IC continue to rise, reflecting the changing epidemiology of the disease. However, the lack of consistent terminology and denominators complicates accurately determining the incidence and prevalence of IC, impacting research and the development and implementation of guidelines. Risk prediction models are valuable tools for identifying patients needing further IC evaluation, and many models require additional validation. No perfect NCBT exists yet; these tests should be used alongside risk stratification and culture-based testing to inform clinical decisions about initiating and discontinuing antifungal therapy. Although no survival benefit has been conclusively demonstrated with empiric or prophylactic antifungal therapy, empiric therapy remains recommended for select groups of critically ill patients. In the writing of this manuscript, the authors have identified the following areas that necessitate further research and development:

Consistent terminology and denominators in order to accurately describe IC and determine its incidence in ICU.

Antifungal stewardship programs that work in parallel with existing antibiotic stewardship programs.

Risk stratification tools with high PPV to identify which patients would benefit from empiric antifungal therapy.

Risk stratification tools that take into consideration factors like patient population diversity, regional fungal epidemiology, and healthcare resource availability to ensure universal applicability across diverse regions and patient demographics.

A cheap and rapid turnover diagnostic test with a sensitivity and specificity that can be used for the rapid diagnosis of IC, detect drug-resistant strains, and guide discontinuation of therapy.

The development of antifungal drugs and regimens that do not require dose adjustment in patients with altered pharmacokinetics, such as those patients encountered within the ICU.

Footnotes

Author Contribution(s)

Julian Robert Paul Eloff: Conceptualization; Writing – original draft; Writing – review & editing.

Sean Keane: Conceptualization; Writing – original draft; Writing – review & editing.

Ignacio Martin-Loeches: Conceptualization; Supervision; Writing – original draft; Writing – review & editing.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: IM-L has received speaking and advisory board fees from Merck and Gilead Sciences.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Sean Keane

Ignacio Martin-Loeches

Elnè Noppè

References

Soulountsi

Schizodimos

Kotoulas

. Deciphering the epidemiology of invasive candidiasis in the intensive care unit: Is it possible? Infection 2021; 49: 1107–1131. doi: https://doi.org/10.1007/s15010-021-01640-7

Kullberg

Arendrup

. Invasive candidiasis. N Engl J Med 2015; 373: 1445–1456. doi: https://doi.org/10.1056/NEJMra1315399

Koehler

Stecher

Cornely

, et al. Morbidity and mortality of candidaemia in Europe: An epidemiologic meta-analysis. Clin Microbiol Infect 2019; 25: 1200–1212. doi: https://doi.org/10.1016/j.cmi.2019.04.024

Poissy

Rouzé

Cornu

, et al. The changing landscape of invasive fungal infections in ICUs: A need for risk stratification to better target antifungal drugs and the threat of resistance. J Fungi (Basel) 2022; 8: 946. doi: https://doi.org/10.3390/jof8090946

Talapko

Juzbašić

Matijević

, et al. Candida albicans—The virulence factors and clinical manifestations of infection. J Fungi (Basel) 2021; 7: 79. doi: https://doi.org/10.3390/jof7020079

Bassetti

Giacobbe

Vena

, et al. Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: Results of the EUCANDICU project. Crit Care. 2019; 23: 219. doi: https://doi.org/10.1186/s13054-019-2497-3

Logan

Martin-Loeches

Bicanic

. Invasive candidiasis in critical care: Challenges and future directions. Intensive Care Med. 2020; 46: 2001–2014. https://doi.org/10.1007/s00134-020-06240-x

Chapman

Slavin

Marriott

, et al.; Australian and New Zealand Mycoses Interest Group. Changing epidemiology of candidaemia in Australia. J Antimicrob Chemother 2017; 72: 1103–1108. doi: https://doi.org/10.1093/jac/dkw422

Ricotta

Lai

Babiker

, et al. Invasive candidiasis species distribution and trends, United States, 2009–2017. J Infect Dis. 2021; 223: 1295–1302. doi: https://doi.org/10.1093/infdis/jiaa502

10.

Giacobbe

Maraolo

Simeon

, et al. Changes in the relative prevalence of candidaemia due to non-albicans Candida species in adult in-patients: A systematic review, meta-analysis and meta-regression. Mycoses 2020; 63: 334–342. doi: https://doi.org/10.1111/myc.13054

11.

Okoye

Nweze

Ibe

. Invasive candidiasis in Africa, what is the current picture? Pathog Dis 2022; 80: ftac012. doi: https://doi.org/10.1093/femspd/ftac012

12.

Whaley

Berkow

Rybak

, et al. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front Microbiol 2017; 7: 2173. doi: https://doi.org/10.3389/fmicb.2016.02173

13.

Daneshnia

de Almeida Júnior

Ilkit

, et al. Worldwide emergence of fluconazole-resistant Candida parapsilosis: Current framework and future research roadmap. Lancet Microbe 2023; 4: e470–e480. doi: https://doi.org/10.1016/S2666-5247(23)00067-8

14.

Eyre

Sheppard

Madder

, et al. A Candida auris outbreak and its control in an intensive care setting. N Engl J Med 2018; 379: 1322–1331. doi: https://doi.org/10.1056/NEJMoa1714373

15.

Lockhart

Etienne

Vallabhaneni

, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 2017; 64: 134–140. doi: https://doi.org/10.1093/cid/ciw691

16.

Govender

Magobo

Mpembe

, et al. Candida auris in South Africa, 2012–2016. Emerg Infect Dis. 2018; 24: 2036–2040. doi:https://doi.org/10.3201/eid2411.180368

17.

Basmaciyan

Bon

Paradis

, et al. Candida albicans interactions with the host: Crossing the intestinal epithelial barrier. Tissue Barriers 2019; 7: 1612661. doi: https://doi.org/10.1080/21688370.2019.1612661

18.

Thomas-Rüddel

Schlattmann

Pletz

, et al. Risk factors for invasive Candida infection in critically ill patients. Chest 2022; 161: 345–355. doi: https://doi.org/10.1016/j.chest.2021.08.081

19.

Ostrosky-Zeichner

Al-Obaidi

. Invasive fungal infections in the intensive care unit. Infect Dis Clin North Am 2017; 31: 475–487. doi: https://doi.org/10.1016/j.idc.2017.05.005

20.

Alenazy

Alghamdi

Pinto

Daneman

. Candida colonization as a predictor of invasive candidiasis in non-neutropenic ICU patients with sepsis: A systematic review and meta-analysis. Int J Infect Dis 2021; 102: 357–362. doi: https://doi.org/10.1016/j.ijid.2020.10.092

21.

Eggimann

Pittet

. Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later. Intensive Care Med 2014; 40: 1429–1448. doi: https://doi.org/10.1007/s00134-014-3355-z

22.

León

Ruiz-Santana

Saavedra

, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006; 34: 730–737. doi: https://doi.org/10.1097/01.CCM.0000202208.37364.7D

23.

Pemán

Zaragoza

. Current diagnostic approaches to invasive candidiasis in critical care settings. Mycoses 2010; 53: 424–433. doi: https://doi.org/10.1111/j.1439-0507.2009.01732.x

24.

Giacobbe

Asperges

Cortegiani

, et al. Performance of existing clinical scores and laboratory tests for the diagnosis of invasive candidiasis in critically ill, nonnneutropenic, adult patients. A systematic review with qualitative evidence synthesis. Mycoses 2022; 65: 1073–1111. 10.1111/myc.13515

25.

Martin-Loeches

Antonelli

Cuenca-Estrella

, et al. ESICM/ESCMID Task Force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019; 45: 789–805. doi:https://doi.org/10.1007/s00134-019-05599-w

26.

Ostrosky-Zeichner

Pappas

Shoham

, et al. Improvement of a clinical prediction rule for clinical trials on prophylaxis for invasive candidiasis in the intensive care unit. Mycoses 2011; 54: 46–51. doi: https://doi.org/10.1111/j.1439-0507.2009.01756.x

27.

Bassetti

Giacobbe

Vena

Wolff

. Diagnosis and treatment of candidemia in the intensive care unit. Semin in Resp and Crit Care 2019; 40: 524–539. doi:https://doi.org/10.1055/s-0039-1693704

28.

Abdolrasouli

Fraser

. Candida auris identification and profiling by MALDI-ToF mass spectrometry. Methods Mol Biol 2022; 2517: 21–32. doi: https://doi.org/10.1007/978-1-0716-2417-3_2

29.

Maenchantrarath

Khumdee

Samosornsuk

, et al. Investigation of fluconazole susceptibility to Candida albicans by MALDI-TOF MS and real-time PCR for CDR1, CDR2, MDR1 and ERG11. BMC Microbiol. 2022; 22: 153. doi: https://doi.org/10.1186/s12866-022-02564-4

30.

Alves

Alonso-Tarrés

Rello

. How to identify invasive candidemia in ICU—A narrative review. Antibiotics (Basel) 2022; 11: 1804. doi: https://doi.org/10.3390/antibiotics11121804

31.

Klingspor

Lindbäck

Ullberg

Özenci

. Seven years of clinical experience with the yeast traffic light PNA fish: Assay performance and possible implications on antifungal therapy. Mycoses 2018; 61: 179–185. doi:https://doi.org/10.1111/myc.12722

32.

Stone

Gorton

Barker

, et al. Evaluation of PNA-FISH yeast traffic light for rapid identification of yeast directly from positive blood cultures and assessment of clinical impact. J Clin Microbiol 2013; 51: 1301–1302. doi: https://doi.org/10.1128/JCM.00028-13

33.

Clancy

Nguyen

. Diagnosing invasive candidiasis. J Clin Microbiol 2018; 56: e01909–17. doi: https://doi.org/10.1128/JCM.01909-17

34.

Karageorgopoulos

Vouloumanou

Ntziora

, et al. β-D-glucan assay for the diagnosis of invasive fungal infections: A meta-analysis. Clin Infect Dis 2011; 52: 750–770. doi: https://doi.org/10.1093/cid/ciq206

35.

Bloos

Held

Kluge

, et al. (1 → 3)-β-D-glucan-guided antifungal therapy in adults with sepsis: The CandiSep randomized clinical trial. Intensive Care Med 2022; 48: 865–875. doi: https://doi.org/10.1007/s00134-022-06733-x

36.

Tang

Chen

Zhu

, et al. Pooled analysis of T2 Candida for rapid diagnosis of candidiasis. BMC Infect Dis. 2019; 19. https://doi.org/10.1186/s12879-019-4419-z

37.

Mikulska

Calandra

Sanguinetti

, et al. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: Recommendations from the Third European Conference on Infections in Leukemia. Crit Care 2010; 14: R222. doi: https://doi.org/10.1186/cc9365

38.

Wei

, et al. Diagnostic accuracy of Candida albicans germ tube antibody for invasive candidiasis: Systematic review and meta-analysis. Diagn Microbiol Infect Dis 2019; 93: 339–345. doi: https://doi.org/10.1016/j.diagmicrobio.2018.10.017

39.

Azim

. Presepsin: A promising biomarker for sepsis. Indian J Crit Care Med 2021; 25: 117–118. doi: https://doi.org/10.5005/jp-journals-10071-23741

40.

Dobiáš

Káňová

Petejová

, et al. Combined use of presepsin and (1,3)-β-D-glucan as biomarkers for diagnosing Candida sepsis and monitoring the effectiveness of treatment in critically ill patients. J Fungi (Basel) 2022; 8: 308. doi: https://doi.org/10.3390/jof8030308

41.

Bassetti

Righi

Ansaldi

, et al. A multicenter multinational study of abdominal candidiasis: Epidemiology, outcomes and predictors of mortality. Intensive Care Med 2015; 41: 1601–1610. doi: https://doi.org/10.1007/s00134-015-3866-2

42.

Clancy

Nguyen

. Finding the “missing 50%” of invasive candidiasis: How nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 2013; 56: 1284–1292. doi: https://doi.org/10.1093/cid/cit006

43.

Nourry

Wallet

Darien

, et al. Use of 1,3-beta-D-glucan concentration in peritoneal fluid for the diagnosis of intra-abdominal candidiasis in critically ill patients. Med Mycol. 2023; 61: myad029. https://doi.org/10.1093/mmy/myad029

44.

Manavathu

Cutright

Chandrasekar

. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother 1998; 42: 3018–3021. doi: https://doi.org/10.1128/AAC.42.11.3018

45.

Johansen

Gøtzsche

. Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev 2014; 2014: CD000969. doi: https://doi.org/10.1002/14651858.CD000969.pub2

46.

Nivoix

Ledoux

Herbrecht

. Antifungal therapy: New and evolving therapies. Semin Respir Crit Care Med 2020; 41: 158–174. doi: https://doi.org/10.1055/s-0039-3400291

47.

Arendrup

Patterson

. Multidrug-resistant Candida: Epidemiology, molecular mechanisms, and treatment. J Infect Dis 2017; 216: S445–S451. doi: https://doi.org/10.1093/infdis/jix131

48.

Calandra

Roberts

Antonelli

, et al. Diagnosis and management of invasive candidiasis in the ICU: An updated approach to an old enemy. Crit Care 2016; 20: 125. doi: https://doi.org/10.1186/s13054-016-1313-6

49.

Ashbee

Barnes

Johnson

, et al. Therapeutic drug monitoring (TDM) of antifungal agents: Guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–1176. doi: https://doi.org/10.1093/jac/dkt508

50.

Pappas

Kauffman

Andes

, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62: e1–e50. doi: https://doi.org/10.1093/cid/civ933

51.

Novy

Roger

Roberts

, et al. Pharmacokinetic and pharmacodynamic considerations for antifungal therapy optimisation in the treatment of intra-abdominal candidiasis. Crit Care 2023; 27: 449. https://doi.org/10.1186/s13054-023-04742-w

52.

Maseda

Martín-Loeches

Zaragoza

, et al. Critical appraisal beyond clinical guidelines for intraabdominal candidiasis. Crit Care 2023; 27: 382. doi: https://doi.org/10.1186/s13054-023-04673-6

53.

Shields

Nguyen

Press

Clancy

. Abdominal candidiasis is a hidden reservoir of echinocandin resistance. Antimicrob Agents Chemother 2014; 58: 7601–7605. doi: https://doi.org/10.1128/AAC.04134-14

54.

Mermel

Allon

Bouza

, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49: 1–45. doi: https://doi.org/10.1086/599376

55.

Cuenca-Estrella

Kett

Wauters

. Defining standards of CARE for invasive fungal diseases in the ICU. J Antimicrob Chemother 2019; 74: ii9–ii15. doi: https://doi.org/10.1093/jac/dkz038

56.

Tagliaferri

Menichetti

. Treatment of invasive candidiasis: Between guidelines and daily clinical practice. Expert Rev Anti Infect Ther 2015; 13: 685–689. doi: https://doi.org/10.1586/14787210.2015.1029916

57.

Peçanha-Pietrobom

Colombo

. Mind the gaps: Challenges in the clinical management of invasive candidiasis in critically ill patients. Curr Opin Infect Dis 2020; 33: 441–448. doi: https://doi.org/10.1097/QCO.0000000000000684

58.

Timsit

Azoulay

Schwebel

, et al.; EMPIRICUS Trial Group. Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: The EMPIRICUS randomized clinical trial. JAMA 2016; 316: 1555–1564. doi: https://doi.org/10.1001/jama.2016.14655

59.

Bartalucci

Giacobbe

Vena

Bassetti

. Empirical therapy for invasive candidiasis in critically ill patients. Curr Fungal Infect Rep. 2024; 18: 136–145. doi:https://doi.org/10.1007/s12281-024-00489-1

60.

Tabah

Bassetti

Kollef

, et al. Antimicrobial de-escalation in critically ill patients: A position statement from a task force of the European Society of Intensive Care Medicine (ESICM) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Critically Ill Patients Study Group (ESGCIP). Intensive Care Med. 2020;46:245–265. doi: https://doi.org/10.1007/s00134-019-05866-w.

A Narrative Review of Invasive Candidiasis in the Intensive Care Unit

Abstract

Plain Language Summary Title

Keywords

Introduction

Epidemiology

Risk Factors and Stratification

Diagnosis

Treatment

Conclusion

Footnotes

Author Contribution(s)

Declaration of Conflicting Interests

Funding

ORCID iDs

References