Keywords

Critically ill patient, Invasive candidiasis, Antifungal susceptibility testing, Antifungal resistance, b-D-glucan, Echinocandins

Abbreviations

AKI: Acute Kidney Injury; BDG: β-D-Glucan Detection Assays; CKD: Chronic Kidney Disease; CNS: Central Nervous System; CRP: C-Reactive Protein; CRRT: Continuous Renal Replacement Therapy; ECMO: Extracorporeal Membrane Oxygenation; EORTC/MSGERC: European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; EUCANDICU: Candidemia/Intra-Abdominal Candidiasis in European ICU Project; FDA: Food and Drug Administration; HSCT: Hematopoietic Stem Cell Transplant; IC: Invasive Candidiasis; ICUs: Intensive Care Units; IDSA: Infectious Diseases Society of America; NAC: Non-Albicans Candida; PCR: Polymerase Chain Reaction; TPN: Total Parenteral Nutrition

Introduction

Candidiasis is a broad term that encompasses cutaneous, mucosal, and deep-seated organ infections caused by various species of the Candida genus [1]. Invasive candidiasis (IC) is a serious candida infection, which might involve candidemia (bloodstream infections with Candida spp.), deep-seated candidiasis, or deep-seated candidiasis with associated candidemia [2]. The incidence of IC has increased over the past few decades and, on an average, ~700,000 people across the world are affected every year [3]. It is often associated with high rates of morbidity and mortality, as well as prolonged hospitalization. Patients who develop IC are typically those being treated for serious medical conditions; hence, it is difficult to estimate the mortality directly due to IC [4]. Despite improved access to antifungal drugs, an estimated mortality of 40%-55% due to IC has been reported in studies among patients in the intensive care units (ICUs) over the past decade [2]. Risk factors for IC include exposure to broad-spectrum antibiotics, cancer chemotherapy, premature neonates requiring advanced care, major abdominal surgery, organ transplantation, prolonged ICU stay, implanted medical devices such as vascular catheters and prosthetic heart valves, and total parenteral nutrition (TPN) [5]. The timely initiation of appropriate antifungal therapy and controlling the source of infection are associated with decrease in mortality. Further, there is considerable geographic, center-to-center, and even unit-to-unit variability in the prevalence of pathogenic Candida species [6]. Although there is sufficient evidence on the burden of candidiasis and its impact on Indian patients, knowledge about management protocols is limited. This could be due to the lack of a national surveillance system and the absence of a law for obligatory reporting of fungal diseases. Knowledge about local epidemiology, rates of antifungal resistance, the organism and susceptibility profile, and treatment outcomes with existing therapies is important for prompt and appropriate therapeutic decisions while awaiting culture and susceptibility data.

Hence, a group of intensive care specialists, infectious disease specialists and hemato-oncologists from across India discussed the epidemiology and challenges of treating IC in India, best practices for early diagnosis of IC, and appropriate treatment to reduce mortality.

Burden of IC in India

There are very few recent or large-scale population-based studies on the burden of IC in India, and most studies conducted over the last 2 decades have reported data from individual centers (Table 1). Only one multicenter study involving 27 centers across India has been conducted, which reported a low incidence of 0.65% with wide regional variations, and a highest reported incidence of 0.9% [7]. The reported incidence of IC varied from 5% to 7% in 3 other single-center studies [8-10] to as low as 0.65% in 2 studies [7,11] and 4.2% in the pediatric population [12]. Findings from a study conducted over 20 years at a tertiary care center from North India revealed a rising trend of candidemia over 20 years from 1999 to 2018 with the majority of cases being reported from pediatric units [13].

In a recent study conducted at 23 ICUs from 9 European countries as part of the candidemia/intra-abdominal candidiasis in European ICU (EUCANDICU) project, the cumulative incidence of IC was 7.07 episodes per 1000 ICU admissions [14]. Similarly, the overall incidence of IC in another long-term follow-up study from the United States was 90/100,000 patients from 2009 to 2017, which did not change significantly over time [15]. Comparing various studies in terms of the incidence of IC might not be meaningful because denominators used to calculate incidence vary among different studies. Population-based studies report incidence as cases per 100,000 persons, while hospital-based studies often report it as cases per 10,000 patient days or 1000 admissions. Moreover, some diagnostic methods are not standardized across healthcare settings. Furthermore, many studies look at a single disease spectrum, e.g., bloodstream candidemia, and deep-seated candidiasis often gets overlooked [16].

According to the Indian experts, the incidence of IC is 4-5% among patients admitted to the ICU. Among tertiary-care hospitals, the incidence in public hospitals may be higher. The incidence is about 10% to 15% among hospitalized pediatric patients, and it is more commonly seen in those receiving TPN. The incidence of IC is 2% among the hospitalized neonates and 5%-10% among children with malignancy undergoing transplant and chemotherapy. In the opinion of the experts, no major regional variations have been observed in the incidence rates of IC across India.

Risk Factors for IC in ICUs in India

It has been reported that among all admitted patients, those in the ICU have the highest rate of Candida infections [17]. A recently published systematic review and meta-analysis of 34 studies reported that the factors associated with the highest risk for IC among critically ill patients were broad-spectrum antibiotics, blood transfusion, Candida colonization, central venous catheter, and TPN. Moreover, length of ICU stay was associated with extremely high risk. Results from a meta-analysis also identified renal replacement therapy, mechanical ventilation, blood transfusion, and diabetes as important risk factors [18].

Common medical devices that have been associated with Candida infections include central venous catheters, cardiovascular devices, and urinary catheter [19]. C. albicans is the predominant fungal species isolated from medical device infections and is known to form biofilms on surfaces of catheters. A C. albicans biofilm on an implanted medical device is highly resistant to antimicrobials and the host immune system and can subsequently lead to disseminated bloodstream infections (candidemia) and invasive systemic infections of tissues and organs [20] although echinocandins have a good penetration through biofilms. Epidemiological studies from India corroborate these findings. In fact, in most Indian studies, ICU admission and use of broad-spectrum antibiotics were associated with the highest risk of IC, followed by catheterization (Table 1).

According to the experts, common risk factors for IC include chronic kidney disease (CKD), TPN, administration of broad-spectrum antibiotics for more than 7 to 10 days, abdominal surgery, underlying respiratory illness, and acute kidney injury (AKI). Other risk factors include pancreatitis, malnutrition, chronic neutropenia, solid organ transplants, immunosuppressant therapy, and malignancy. Heart disease and history of septic shock were not considered as risk factors for IC by the experts.

Predominant Candida Species Associated with IC in India

More than 15 Candida species have been described as etiologic agents of IC; however, > 90% of cases were reportedly caused by five species: C. albicans , C. glabrata , C. parapsilosis , C. tropicalis , and C. Krusei [16]. Candida albicans has been the predominant species for a long time; however, in the last 2 decades, there has been a global shift towards non-albicans Candida (NAC) species [21]. Among the other species of Candida , an emerging strain is C. auris , which is multidrug resistant. The incidence of C. auris candidemia was reported to be significantly higher in patients who had previous exposure to fluconazole or echinocandin [22]. Results of the global SENTRY Antifungal Surveillance Program conducted from 1997 to 2016 showed a decrease in the isolation of C. albicans and an increase in the isolation of C. glabrata and C. parapsilosis over time. C. glabrata was the most common NAC species detected in all geographical regions, except for Latin America, where C. parapsilosis and C. tropicalis were more common. Data from 2006 to 2016 showed that in Asia, C. albicans , C. glabrata , C. parapsilosis , and C. tropicalis were detected in 46.0%, 17.9%, 12.9%, and 14.1% of isolates, respectively [23]. However, most studies from India show a dominance of C. tropicalis , followed by C. albicans (Table 1).

The experts agreed that the most common species in recent times is C. tropicalis followed by C. albicans and the non-albicans species. The 5 most dominant species are C. tropicalis , C. albicans , C. parapsilosis , C. glabrata , and C. krusei . In children, C. tropicalis , C. parapsilosis , C. albicans , C. auris , C. glabarata , and C. krusei are the dominant species. The incidence of C. auris is largely associated with infection control practices of the hospital. There was an increase in the cases of C. auris when COVID-19 was at its peak. Among patients admitted for pancreatitis and long-term surgery, approximately 7% of the bacterial blood culture isolates are found to be Candida . The order of prevalence is C. tropicalis , C. albicans , C. glabrata , and C. auris .

Signs and Symptoms of IC

No clinical signs or symptoms are specific for IC. IC should be suspected in patients with known risk factors who have unexplained fever that is unresponsive to antibacterial treatment [1]. Other symptoms can develop if the infection spreads to other parts of the body, such as the heart, brain, eyes, bones, or joints. Manifestations range from fever in a hemodynamically stable patient, to sepsis and septic shock [19].

The experts concurred that there are no specific signs and symptoms of fungal infection; however, in the presence of risk factors, when a patient is not responding to antibacterial treatment, IC should be suspected. In children, hypothermia due to IC is more common than fever. Hypotension, hypoglycemia, hyperglycemia, and necrotizing enterocolitis are the other clinical manifestations. Additionally, when vegetation can be seen on intravascular devices and the patient shows no clinical improvement despite antibiotic treatment, IC should be suspected. Sudden hypoglycemia or hyperglycemia in a patient who has been hospitalized for some days indicates clinical deterioration and should raise suspicion for IC. Hypoglycemia in patients on prolonged TPN (for graft vs. host disease or mucositis) might also be an indicator of IC.

Diagnosis of IC and Challenges in Diagnosis

Blood cultures or culture of samples from other sites have been considered the gold standard for diagnosing IC. Additionally, nonculture diagnostic tests, such as antigen-antibody tests (galactomannan) or β-D-glucan (BDG) detection assays, and polymerase chain reaction (PCR) are used [6]. The 2019 consensus guidelines by the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC) suggested four options for the diagnosis of IC [24]: (1) Histopathologic, cytopathologic, or direct microscopic detection of Candida in specimens from normally sterile sites; (2) Positive culture from a sample from a normally sterile site with clinical or radiological abnormality indicative of infection; these include samples from drains placed in the last 24 hours; (3) Detection of Candida by PCR with subsequent DNA sequencing; and (4) Positive blood culture for Candida species.

Culture-based tests

The sensitivity of blood culture is limited; moreover, the turnaround time is very high. Usually, the incubation time until detection of growth is 24-72 h, followed by an additional 24-48 h for species identification. Further, there is no universally agreed gold standard reference test; hence, its sensitivity remains uncertain and varies with the type of IC (i.e., intravascular or deep-seated with or without secondary candidemia) and the type of Candida species (e.g., lower for C. glabrata ) [25]. The overall sensitivity of blood cultures for diagnosing IC is approximately 50% [6]. The sensitivity can be improved with larger sample volumes and higher testing frequency [26]. However, cultures might be negative in cases of extremely low-level candidemia, deep-seated candidiasis that persists after sterilization of the bloodstream, or direct deep-seated candidiasis without candidemia. Cultures of tissues or fluid recovered from infected sites during deep-seated candidiasis also show poor sensitivity (often < 50%) and have long turnaround times. Moreover, invasive sampling procedures might be required, which could be dangerous or contraindicated due to underlying medical conditions [6,26].

Non-culture-based tests

Challenges with culture-based tests led to the development of non-culture-based and non-histopathological tests for diagnosing IC. Among the antigen-antibody tests, the best-studied test is a combined mannan/anti-mannan antibody assay [6]. However, in a meta-analysis of 14 studies, the sensitivity/specificity of mannan and anti-mannan IgGs individually for the diagnosis of IC were 58%/93% and 59%/83%, respectively. Sensitivity and specificity for the combined assay were 83% and 86%, with best performances for C. albicans , C. glabrata , and C. tropicalis infections [27]. The increase in antibody concentration might be more helpful in the diagnosis of candidiasis. However, the diagnosis might be delayed as a result. Moreover, it is not discriminative in the diagnosis of IC. Currently, neither mannan nor anti-mannan antibody detection has been approved for the diagnosis of IC by the United States Food and Drug Administration (FDA) [26]. The biomarker most commonly used for detecting fungi in critically ill patients is the BDG test [25]. It has been approved by the FDA as an adjunct to cultures for the diagnosis of invasive fungal infections. Nevertheless, results are not specific for IC, but suggest the possibility of an invasive fungal infection [6]. BDG assay has a sensitivity of 92% and specificity of 81% for the diagnosis of IC. The high negative predictive value helps in the exclusion of IC [26]. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) also recommends the BDG test for ruling out candidemia or IC in adult patients at risk of infection. The specificity of this test can be further increased by using higher cut-off values (≥ 200 pg/mL instead of 80 pg/mL) or by considering two consecutive positive tests as a definitive diagnosis [25].

PCR-based tests are also used for rapid diagnosis of IC. The pooled sensitivity and specificity of PCR for suspected IC in a recent meta-analysis were 95% and 92%, respectively [28]. PCR provides Candida spp. identification in 2-4 h and is also useful for monitoring the persistence or resolution of infection [26]. PCR can also detect molecular markers for drug resistance [6]. However, the lack of standardization is a major limitation of this method [25].

The combination of various non-culture tests has a higher negative predictive value than single tests. This strategy is also used to decide discontinuation of unnecessary therapy in cases with suspected IC. The combination of Candida antigen detection and procalcitonin is useful in clinical practice for the early differential diagnosis of infection in severely ill patients. Procalcitonin levels in IC do not exceed 2 ng/mL unlike the very high levels in bacterial sepsis. The combination of procalcitonin level < 2 ng/mL and a positive BDG test has a sensitivity of 66% and specificity of 98% for IC [26].

According to the experts, the major challenges in the diagnosis of IC include low sensitivity of the diagnostic tests, high turnaround time of the test results, and lack of adequate laboratories that can conduct specific tests. Nevertheless, the role of biomarkers was considered important by the experts. In a patient with grade III sepsis, low procalcitonin and high C-reactive protein (CRP) can be considered to start pre-emptive treatment instead of empirical treatment while BDG test results are awaited. All the experts agreed that biomarkers and cultures are reliable indicators of IC, while PCR needs to be standardized further. Blood culture remains the gold standard in the diagnosis of IC in children, and the yield is better in newborns than in older children. Among other tests, mannan antigen and anti-mannan antibody detection have limitations because of the challenge of contamination and variations in rates of sensitivity. Sensitivity varies with different Candida species; it is better for C. albicans , C. glabrata , and C. tropicalis . Moreover, specificity decreases in the presence of Candida colonization. Further, it has a low positive predictive value, which is further limited by low serum concentrations and rapid bloodstream clearance. Because mannan antigen and anti-mannan antibody detection tests are not species-specific, further tests are required to identify the causative fungal species [29]. Most experts solely depend on the BDG assay. All the experts agreed that combining culture and non-culture-based tests is a useful strategy for early detection of IC in ICU patients. There was a consensus on the following diagnostic tests: Blood culture, histopathology, 1,3-BDG assay (a very high value of BDG is a very good indicator of IC), Candida mannan and anti-mannan (serum biomarker), and PCR.

What can be done for early diagnosis of IC?

Timely diagnosis of IC is key to ensure a favorable outcome. In fact, a 1-2-day delay in initiation of effective antifungal therapy has been associated with a doubling of mortality [1].

Goals of early diagnosis: The experts opined that the primary goals of early diagnosis are reducing antifungal toxicity, avoiding the emergence of resistance, and avoiding selection pressure. They suggested that it is important to avoid the inappropriate use of antifungal therapy (especially empirical treatment) to achieve these goals. There was concurrence that point-of-care diagnosis is the need of the hour. Further, increasing biochemical testing for 1-3 BDG and galactomannan, fungal staining and culture/sensitivity is necessary. Apart from clinical suspicion, sending samples for 2 sets of blood cultures obtained within a few hours of each other via peripheral venipuncture, biomarkers, and procalcitonin levels can help in early diagnosis of IC. Additionally, ultrasound screening can help in locating unexplained hepatic lesions in the absence of fever.

Risk prediction models: Several studies have looked at prediction models to identify patients at highest risk of IC. These studies are characterized by high specificity, but low sensitivity; therefore, many patients with candidiasis are missed [6]. The commonly known risk prediction models for IC are scores based on clinical risk factors, i.e., clinical prediction rules e.g., Ostrosky-Zeichner clinical prediction rule, scores based on microbiological parameters ( Candida colonization), and combined clinical and microbiological Candida scores [30]. The components of Candida score are severe sepsis, TPN, multifocal colonization, and surgery. Each component is assigned 1 point, except for severe sepsis, which is assigned 2 points [31]. Candida colonization index is calculated as non-blood distinct body sites colonized by Candida divided by total number of sites tested [32]. The Ostrosky‑Zeichner clinical prediction score includes intensive care admission for 72 h with mechanical ventilation for at least 48 h, antibiotic use for 3 days, central line use for 3 days with at least any one of the following criteria: Any surgery (day -7 to day 0), immunosuppressive use (day -7 to day 0), pancreatitis (day -7 to day 0), TPN (day 1 to day 3), any dialysis (day 1 to day 3), and steroid use (day -7 to day 0) [33]. A recent systematic review of major risk prediction models for IC reported that due to major limitations, including lack of model generalizability, inconvenience of use, and inadequate validation, risk prediction models are currently impractical for clinical use. Moreover, when they were created, they had several inclusion and exclusion criteria, which can significantly restrict the patient population in which they can be reliably used [34].

However, none of the experts believed in using risk prediction models for IC in daily clinical practice. According to them, the risk prediction scores are not practical or significantly beneficial in terms of positive patient outcomes. Some experts suggested that risk prediction models can be used for research purposes but not for initiation of therapy.

Management of IC

There are three main groups of antifungal agents: the azoles, the polyenes, and the echinocandins. The selection of an antifungal regimen is based on multiple factors, including patient characteristics, epidemiological data, hospital setting, fungal strain, patient comorbidities, site of infection, and safety profiles of the antifungal agents [35]. International guidelines for the treatment of IC published by ESICM/ESCMID and by the Infectious Diseases Society of America (IDSA) are widely known and followed [6,25]. The four widely understood treatment strategies for IC are (1) Prophylactic therapies, which are administered to critically ill patients with a high risk of developing IC because of intrinsic or patient-specific risk factors (such as immunosuppression); (2) Pre-emptive therapies, which are administered to patients at risk of IC with a diagnosis based on fungal biomarkers. (The ESCMID guidelines define pre-emptive therapy as therapy triggered by microbiological evidence without proof of invasive infection due to Candida species [25]. However, the IDSA guidelines no longer use this term nor have any recommendations related to it [6]); (3) Empirical therapy, which refers to the administration of antifungal agents in patients with signs and symptoms of infection along with specific risk factors for IC, irrespective of biomarkers; and (4) Directed/targeted therapies, which are treatments based on microbiological confirmation of an invasive infection due to Candida species (e.g., a positive blood culture for Candida species) [25].

The key recommendations of IDSA and ESICM/ESCMID guidelines are shown in Table 2. The IDSA guidelines are more detailed [6]. Echinocandins (micafungin, anidulafungin, caspofungin) are usually the recommended first-line drugs with transition from an echinocandin to fluconazole (usually within 5-7 days) in patients who are clinically stable, have isolates that are susceptible to fluconazole, and have negative repeat blood cultures. In various clinical trials, micafungin has shown favorable efficacy against IC with response rates ranging from 71% to 90% [36-39]. Micafungin has also been shown to be useful as a preventive measure (prophylaxis) against fungal infections in patients with neutropenia [40].

The experts in the panel follow the IDSA guidelines in general [6]. Though the ESCMID guidelines do not recommend amphotericin B for IC, experts agreed that the drug may have to be considered in Indian practice for patients with limited economic resources [25].

Prophylaxis

According to the experts, colonization scores cannot be used to guide prophylactic treatment and infection control. Further, prophylaxis should not be used routinely and universally to prevent IC. Appropriate candidates for prophylactic antifungal therapy in India are high-risk patients, such as those undergoing solid organ or bone marrow transplants and immunocompromised patients. Among unstable patients with multifocal Candida colonization and/or clinical risk factors for infection, pre-emptive therapy may also be considered.

Empirical therapy

According to the experts, in hospitalized patients with refractory fever despite 4/5 days of broad-spectrum antibacterial therapy, empiric antifungal therapy is reasonable where local incidence rates are high. In such cases, antifungals are started empirically, and samples are sent to assess biomarker levels. This helps in early detection of candidiasis, especially if the BDG level is very high. Empirical antifungal therapy may also be administered to an ICU patient who exhibits signs of new-onset sepsis of unknown origin or persisting signs of infection following 4 to 7 days in the ICU with adequate antibiotic therapy. The first-line antifungal drug in such cases should be echinocandin, except in cases of central nervous system (CNS) candidiasis and urinary tract infections. For urinary tract infections, fluconazole is the first drug of choice. Echinocandins are not used for treating CNS infections as they cannot pass through the blood-brain barrier. Hence, amphotericin B alone or combined with voriconazole is preferred. Treatment discontinuation should be based on clinical judgment, negative biomarkers, and negative cultures.

Some experts suggested that fluconazole can be a good drug of choice for patients in a low-resource setting like public sector setups, who have not been exposed to an azole. However, some experts disagreed with this strategy considering that public sector setups have high rates of resistance.

Duration of treatment and dose adjustment

All experts agreed to switching to fluconazole from echinocandin once the patient is clinically stable, repeat blood cultures are negative, and the Candida isolate is found to be sensitive to fluconazole. If a patient has no clinical response to empirical antifungal therapy by 4 to 5 days with no subsequent evidence of IC after the initiation of empirical therapy, investigations should be repeated to confirm the diagnosis of IC. Some experts recommended looking for seeding while others suggested 2 to 3 cultures to rule out the absence of candidiasis. Furthermore, close monitoring for any complications like endocarditis is necessary. The recommended duration of antifungal treatment in patients with uncomplicated candidemia and IC depends on the extent of infection, organ involvement, and source control. It should be continued for at least 14 days after a negative culture and then de-escalated based on clinical judgment. For deep-seated candidemia, at least 6 weeks of treatment is necessary. Blood cultures should be performed on alternate days till 3 negative cultures. De-escalation from echinocandins is not recommended in cases where intravascular catheter or any other foreign device cannot be removed. Among echinocandins, both caspofungin and anidulafungin require a loading dose, while micafungin does not [41].

Resistance

The ESICM/ESCMID and the IDSA guidelines have not discussed resistance in detail [6,25]. Azole and multidrug resistance were seen in 11.8% and 1.9% of isolates in a multicenter Indian study [7]. Among two recent studies from India, Candida species showed good sensitivity to voriconazole (80%), fluconazole (67.78%), and amphotericin B (62.22%) in a tertiary care center from North India [42]. In the other study from North-West India, resistance to fluconazole, voriconazole, 5-flucytosine, and amphotericin-B was 36%, 20%, 4%, and 7%, respectively. There was no resistance to echinocandins [43]. However, various studies from different centers in India have reported varying rates of resistance (Table 1). Nevertheless, all experts agreed that Candida species are highly susceptible to echinocandins. According to them, C. tropicalis , C. albicans , and C. parapsilosis are sensitive to echinocandins. Some experts opined that high minimum inhibitory concentration (MIC) for some echinocandins like anidulafungin has been observed in cases of C. parapsilosis . Micafungin and caspofungin can also be administered for C. parapsilosis infections. C. auris has a high MIC for echinocandins, but it is sensitive to all 3 types of echinocandins, namely, caspofungin, micafungin, and anidulafungin. However, some experts contended that C. auris is sensitive to both echinocandins and amphotericin B though most isolates of C. auris are resistant to azoles. Hence, they recommended starting with echinocandins and then switching to amphotericin B if required in cases with C. auris infection.

Managing IC in specific settings

According to the experts, fluconazole should be the first choice for urinary tract infections due to Candida . Because echinocandins do not penetrate CNS, amphotericin B should be the drug of choice for Candida infection in the CNS. In such cases, voriconazole must be administered in combination with amphotericin B because posaconazole cannot penetrate the blood brain barrier.

For patients with AKI, those on extracorporeal membrane oxygenation (ECMO), or those with acute/chronic liver failure, echinocandins are the preferred antifungal therapy for IC. There is insufficient literature on the dosage of echinocandins in patients on ECMO [44]. Some experts suggested that ECMO should be treated as continuous renal replacement therapy and the initial dose should be high as there is a possibility of hemodilution. For C. auris infection in the urinary tract, some studies suggest one and a half times the usual dose of micafungin [45]. The preferred choice of therapy for IC in critically ill pediatric patients is echinocandins because of azole resistance and higher presence of non-albicans species. For patients undergoing hematopoietic stem cell transplant, echinocandins should be mainly used. Micafungin probably has the lowest drug interactions with tacrolimus, cyclosporine or any other drugs, among the antifungals [46]. In IC due to non-albicans species, a combination of echinocandins + azole (voriconazole) as targeted therapy should be used. Voriconazole probably has an erratic absorption profile, and its use is challenging without therapeutic drug monitoring. The dose should be 8 to 10 mg/kg in neonates and 2 mg/kg in the pediatric population. In case there is persistent C. auris and the culture is positive despite antifungal therapy, the micafungin dose can be increased to 15 mg/kg. Flucytosine can be used for resistant C. auris ; however, it is nephrotoxic and not easily available. In the pediatric population, micafungin and caspofungin are A-I recommendation for therapy while anidulafungin is B-II [25].

Conclusion

Prolonged ICU stay with use of broad-spectrum antibiotics and catheterization are associated with the highest risk of IC. The 5 most dominant Candida species associated with IC are C. tropicalis , C. albicans , C. parapsilosis , C. glabrata , and C. krusei . Combining culture and non-culture-based tests such as BDG, Candida antigen, procalcitonin, and CRP is a useful strategy for early detection of IC. It is important to avoid unnecessary use of empirical antifungal therapy to prevent the emergence of resistance. Appropriate candidates for prophylactic antifungal therapy in India are high-risk patients, while empirical therapy can be initiated in patients with refractory fever or persisting signs of infection despite 4-5 days of broad-spectrum antibacterial therapy. Echinocandins can be considered as first-line therapy for IC except in cases of CNS candidiasis and urinary tract infections. The efficacy of micafungin for the treatment of candidemia and other forms of invasive candidiasis is well-supported by published literature and standard practice guidelines. Treatment de-escalation and discontinuation should be based on clinical judgment, negative biomarkers, and negative cultures in concordance with the guidelines.

Disclosures

The author received speaker’s honorarium from Abbott for participation in the focus group discussion.

Funding Support

The expert group discussion was conducted in association with Abbott India Ltd. This article is based on the views expressed during the expert group discussion. The views expressed and discussed in the meetings and stated in this article are the independent views of the authors and not of Abbott.

Acknowledgement

We are grateful to the following doctors for participating in the advisory board meeting and contributing to the concept and recommendations of the present document: Dr. Rajesh Chawla, Dr. Shririsha Rani, Dr. Haripriya Reddy Challa, Dr. Chandrashish Chakravarty, Dr. Rajkumar, Dr. Vishnu Rao, Dr. Asif Iqbal, Dr. Nitin Shinde, Dr. Ashutosh Bhardwaj, Dr. B K Malpani, and Dr. Punit Jain. Medical writing assistance was provided by Dr. Sangeeta Dhanuka and Dr. Sujatha Vijayakumar from Hashtag Medical Writing Solutions Pvt. Ltd., Chennai.

Statement of Authors' Contribution

YM has contributed to the concept, design, critical review, and revision of this document. The author has read and approved the final draft of the manuscript for publication.

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