Invasive candidiasis in critical care setting, updated recommendations from “Invasive Fungal Infections-Clinical Forum”, Iran

Abstract

Invasive candidiasis (IC) bears a high risk of morbidity and mortality in the intensive care units (ICU). With the current advances in critical care and the use of wide-spectrum antibiotics, invasive fungal infections (IFIs) and IC in particular, have turned into a growing concern in the ICU. Further to blood cultures, some auxiliary laboratory tests and biomarkers are developed to enable an earlier detection of infection, however these test are neither consistently available nor validated in our setting. On the other hand, patients’ clinical status and local epidemiology data may justify the empiric antifungal approach using the proper antifungal option. The clinical approach to the management of IC in febrile, non-neutropenic critically ill patients has been defined in available international guidelines; nevertheless such recommendations need to be customized when applied to our local practice. Over the past three years, Iranian experts from intensive care and infectious diseases disciplines have tried to draw a consensus on the management of IFI with a particular focus on IC in the ICU. The established IFI-clinical forum (IFI-CF), comprising the scientific leaders in the field, has recently come up with and updated recommendation on the same (June 2014). The purpose of this review is to put together literature insights and Iranian experts’ opinion at the IFI-CF, to propose an updated practical overview on recommended approaches for the management of IC in the ICU.

Key Words: Invasive candidiasis, Intensive care unit, IFI-clinical forum, Recommendations, Iran

Core tip: The present consensus statement has attempted to summarize the practical highlights regarding the management of Invasive Candidiasis (IC) in critical care setting. This easy-to-follow clinical pathway is expected to be not only of interest but also of clinical use for those who deal with the management of invasive fungal infections in hospital setting and especially the intensive care units. The focus of this paper is the concept of timely management of IC in critically ill patients.

INTRODUCTION

Despite the remarkable progress in the diagnostic and therapeutic approaches, infections continue to be a critical challenge in the intensive care units (ICUs) worldwide[1]. The use of wide-spectrum antibiotics, advanced care in the ICU and improved knowledge on fungal infections have potentially led to an increased incidence of invasive fungal infections (IFIs) especially in critically ill and immunosuppressed patients[2-4]. IFIs are shown to be often hard to diagnose and treat in critical care setting[4]. Timely management of IFIs based on risk stratification and empirical approach is shown to be of meaningful clinical benefit, meanwhile dependence on the culture results and relying on fungal biomarkers may delay clinical decisions and lead to potential complications, morbidity and mortality in such patients[5,6]. There are risk prediction models which suggest empirical approach for patients who are supposed to significantly benefit from empirical antifungal therapy[7,8]. Despite the validated clinical impact of applying IFIs’ predictive tools such as Candida Score[9,10], many clinicians seem not to be consistently using them in routine practice[11]. This report is based on the communicated insights and position statements within the IFI-clinical forum comprising an Iranian panel of intensive care experts. The present article summarizes a literature review on the role of IFIs in mortality and morbidity in critical care setting, experts’ panel inputs as well as updates on the local consensus and international guidelines with regard to the management of invasive candidiasis (IC) in ICU patients.

THE UNMET NEED WHICH PROMPTED AN “IFI-CLINICAL FORUM” ESTABLISHMENT

In compliance with the international guidelines on the management of IC in ICU, a group of Iranian experts in the fields of intensive care and infectious disease consolidated a consensus as a simple algorithmic approach in the management of IC in critical care setting in 2013[12]. This was primarily rooting in an earlier local consensus on the same, published in 2011; while the first report was predominantly based upon the infectious disease experts’ opinion[13]. Pursuant to the above publications, an IFI-Clinical Forum (IFI-CF) comprising Iranian critical care experts and infectious disease specialists was established in 2014. The IFI-CF was formed to pursue clinical research, idea exchange and regular updates and recommendations with regard to optimal management of IFIs. The forum attempts to improve the current situation in the diagnosis and management of IC in critical care units by means of continued education, research and promoting evidence-based practice.

To reach the above, field experts from different universities across Iran attended a round table discussion on 26-27 June 2014. Discussions in this clinical forum revolved around updated epidemiologic insights on IC in ICU, the related diagnostic challenges, therapeutic approaches and proper antifungal options in ICU-admitted patients afflicted with IC.

The meeting objectives, established as part of the planning process, were used to guide development of meeting content and activities. Following two days of scientific debates, reviewing evidence and case discussions, the panel could unanimously draw an updated recommendation for the management of IC in the ICU. This meeting and similar future ones will hopefully allow optimizing models of patient care with regard to IFIs in ICU through an inter-professional influence.

Materializing the above perspective is believed to depend upon five tenets including: 1-classifying the critically ill patients’ risk for IFIs, 2-defining a timely and reasonable approach for treating IFIs in ICU-admitted patients, 3-developing center-based algorithms for diagnosis, treatment and surveillance of ICU patients with high risk of IFIs, as epidemiology may differ center by center, 4-determining advantages and disadvantages of antifungal options when used in the ICU and 5-optimizing antifungal treatment paradigm in our local setting for ICU patients who are at increased risk or clinical suspicion for IFIs.

LITERATURE REVIEW, PARTICIPANTS AND GROUP CONSENSUS

A systematic literature search in PubMed, Scopus, Cochrane and Google Scholar databases (1990-2014) was conducted using the combination of our keywords including invasive fungal infections, ICU, diagnosis, treatment approach, antifungal therapy and recommendations. Following the cross-check, documents describing the significance of IFIs in ICU and recommendations for diagnosis and treatment approaches were isolated for review and discussions. Most recent guidelines[12,14-17] and relevant papers were circulated among all IFI-CF attendees one month prior to the meeting.

The IFI-CF delegates discussed the available evidence, shortcomings and clinical challenges in the management of IFIs and particularly IC in ICU-admitted patients. Each delegate was invited based on his/her expertise in the management of IC and other fungal infections in critical care setting. All experts actively participated during the plenary talks, problem-based round table discussions and case studies over a 2-d interactive discussion forum. Through a point-to-point systematic approach and discussions on key issues such as: 1-local epidemiology of IFIs, 2-preferred diagnostic and therapeutic approaches, 3-implication of risk prediction tools and 4-optimized antifungal therapy, the available evidence as well as participants’ inputs/responses were compiled to draw a clinical pathway.

EPIDEMIOLOGIC INSIGHTS ON INVASIVE CANDIDIASIS; A GLOBAL AND LOCAL PROBLEM ON THE RISE

The current advances in critical care and the advent of broad-spectrum antibiotics not only have resulted in patients’ longer survival but also in increasing the incidence of opportunistic infections such as IFIs over the past decade[18]. Currently, IFIs constitute a clinical issue on the rise in the ICUs both in the developing and developed world[19,20]. Predisposing factors such as patients’ complicated medical or surgical status, invasive bedside procedure and wide administration of antibiotics have contributed to increased rate of IFIs, mainly IC and invasive aspergillosis (IA), in the ICU[21-23]. Candidemia is thus far known to be the most prevalent fungal infection afflicting ICU patients[23]. According to an elegant survey which was carried out in over 1000 ICUs in more than 70 countries, almost one fifth of the isolated pathogens in ICU patients were found to be fungi[24]. Based on the same report, Candida species (spp.) were almost 10 times more isolated than aspergillosis and known to be linked with a high mortality and increased hospital length of stay (LoS) as well as medical care cost[24]. Since most of the diagnostic tests lack proper specificity and the culture result normally requires a long time, diagnosis of IFIs and IC in particular remains a challenge. Cumulating evidence suggest that institution of appropriate antifungal therapy upon initial clinical suspicion of IFIs is crucial for a positive outcome[8].

The increasing risk of IFIs in ICU, as well as the criticality of the timely decision making on treatment with the most proper options, have turned IFIs’ management to a difficult task for intensivists. While the incidence of IFIs in immunocompromised hosts such as transplanted patients, those with hematologic malignancies or human immunodeficiency virus is significant, this report focuses on IFIs in non-neutropenic critically ill ICU-admitted patients. Candida spp. are considered the fourth most common blood stream infection (BSI) isolated from ICU-admitted patients in the West[25]. Where Candida albicans (C. albicans) has long been regarded as the most prevalent candida type, the relatively recent emergence of non-albicans species such as fluconazole-resistant Candida krusei (C. krusei) and Candida glabrata (C. glabrata) has turned into a challenge[20,25]. Recent data suggests an increased incidence of non-albicans Candida species. As such, C. glabrata and Candida parapsilosis (C. parapsilosis) are now ranked as second in the Northern Europe and the United States[26,27], and in Latin America and Southern Europe[28,29], respectively. Some predisposing factors including central venous catheters (CVC), total parenteral nutrition (TPN), and prior azole exposure are proposed to result in the emergence of non-albicans Candida species. Previous exposure to azole is particularly linked to isolation of C. krusei and C. glabrata[30].

Based on our practice, the incidence of Candidemia, and other fungal infections in Iran seem to be on a steep rise. A local epidemiological survey on IFIs in ICU and transplant wards in Iran suggested C. albicans, Penicillium spp., Aspergillus niger, and Cladosporium spp. as the most dominant isolates[31]. According to this report, environmental fungal contamination was found to be more prominent in ICU and the length of hospital stay in critical care setting was strongly associated with the colonization of fungi.

Another local epidemiology research on IFIs in pediatric patients with advanced kidney disease undergoing peritoneal dialysis and adults with kidney transplantation showed the significant impact of Candidemia on mortality and morbidity[32]. Furthermore, based on a multi-center analysis on the prevalence of deep-seated mycosis in immunocompromised hosts in Tehran, Iran, Candida spp. were isolated in almost 70% of IFIs cases[33]. Of note, non-albicans spp. comprised almost one third of the Candida infections suggesting a possible clinical challenge with fluconazole-resistant Candida species[31-34]. The current state of our local epidemiologic insights on IFIs are in line with those of international reports[19,20,35-37]. Further research is needed to draw a clearer map about the incidence of IC and IA and the related subspecies in ICUs of different hospitals, cities and provinces all around Iran. There is an urgent need for institutions to set tight nosocomial IFIs surveillance and protective measures including hand hygiene and aseptic techniques especially upon bedside intensive care interventions.

DIAGNOSTIC CHALLENGES OF INVASIVE CANDIDIASIS IN THE INTENSIVE CARE UNIT

The diagnosis of IC can be either definitive or probable. The definitive diagnosis is based upon identification of Candida in the blood or its histological characterization in tissue[12]. However, in almost half of the instances, specimen may reveal false-negative results and the tissue may not be available in critical care setting. Moreover, awaiting culture results requires much time and defers the clinical decision making. Further to culture and tissue examination, some auxiliary testing methods and biomarkers such as 1-3 beta-D-Glucan (BDG) and panfungal polymerase chain reaction (PCR) may suggest probable IC when positive[38-40].

The BDG test detects beta-D-glucan which is an important constituent of the cell wall of pathogenic fungi. This test may however be a subject to a notable false-positive results in patients who receive albumin, immunoglobulins and beta lactams as well as those who are on hemodialysis with cellulose membrane[39]. Furthermore, the test is incapable to differentiate between Candida and Aspergillus, and remains inconclusive for Zygomycetes and Cryptococcal infection[39,41]. To indicate the probability of invasive candidiasis based on such a test, a single positive test lacks enough sensitivity thus serial measurements may be required. PCR which detects fungal nucleic acid is found to have a high sensitivity and specificity[42]. Although it is shown to be a highly promising tool in the diagnosis of IFIs, it is neither available nor validated in many settings and its exact use in clinic is questionable[38,43].

Given the time-consuming nature of all the aforementioned laboratory tests, and considering the critical time span for initialization of the therapy, the diagnosis of IC in ICU remains a challenge. Over the past decade some risk prediction models have put forward a pathway to identify patients at increased risk for IFIs. Evidence has suggested clinical benefits of empirical antifungal therapy in non-neutropenic critically-ill patients who remain febrile despite adequate antibiotic therapy and are characterized as high risk[7,8,11].

RISK STRATIFICATION TOOLS AND PREDICTIVE MODELS; PATH TO A TIMELY APPROACH

Prompt diagnosis and management of IC should be sought as it leads to a significant decline in human and cost burden in the ICU[26,27]. Potential risk factors for IC are compiled into risk prediction models. The proper use of these models in clinical practice would help clinicians identify the high-risk patients who significantly benefit from timely treatment against IC[10,11,44]. Meanwhile, the positive auxiliary tests such as BDG and/or PCR may further add to the accuracy of the risk prediction tools for IC[43,45,46]. Some of these validated tools include the Candida Score[9,47] and Ostrosky-Zeichner[23] model. Calculating the candida score assists a risk-factor-based prediction of IC depending on the presence or absence of four independent risk factors in febrile non-neutropenic critically-ill patients. These risk factors are severe sepsis (2 points), TPN (1 point), multifocal colonization (1 point), and surgery (1 point). The candida score of ≥ 3 is shown to predict IC with a sensitivity and a specificity of 81% and 74%, respectively[9]. These “risk factors” which are proposed as Candida Prediction Rules have been reported in many other studies[47-53]. In addition to Leon’s Candida Score[47] and the Ostrosky-Zeichner[23] model, other models such as Agvald-Ohman et al[48], Pittet et al[49], Hermsen et al[51], Paphitou et al[52], and Dupont et al[53] tried to establish similar frameworks putting together risk factors which contribute to IC while assigning separate relative risk scores for each variable. There is a visible overlap in considered risk factors among these models. Several differences in these studies make it difficult to draw a generally applicable conclusion. Figure 1 summarizes these risk prediction models with risk factors in common amongst them. According to these models, the most commonly considered risk factors such as TPN, use of wide-spectrum antibiotics, CVC, recent gastrointestinal (GI) surgery, use of steroids, dialysis and sepsis are regarded as the most significant contributors to IC in critical care units. Although fungal colonization is known to be linked with the development of Candidemia, based on more recent investigations, only a small proportion of colonized patients (3%-25%) are found to develop invasive candidiasis[48,54].

Figure 1 Risk prediction models for invasive candidiasis in critically ill patients with overlapping contributing factors. Factors which are common in several risk-prediction models appear to bear a higher relative risk for IC. Given the heterogeneity in study designs and populations, these models can hardly be merged to represent a single paradigm, however their common contributing factors appear to be of higher predictive value for IC prediction. So far, the most widely applied predictive tool for IC is the Leon’s Candida Score followed by the Ostrosky-Zeichner’s model. ABx: Antibiotic; CCI: Candida colonization index; CVC: Central venous catheter; GI: Gastrointestinal; ICU: Intensive care unit; TPN: Total parenteral nutrition; LoS: Length of stay.

Some of the important differences in IC risk prediction models which are outlined in Figure 1 include the heterogeneity in the examined populations, non-similarity in the underlying disease severity, incidence of IC in centers where the investigations were carried out and the study end-points. It should be noted that most models were defined in surgical ICU populations[23,48,49,51-53].

Intra-abdominal infections secondary to intestinal perforations and anastomotic leakage are also among the risk factors in patients who tend to mostly benefit from timely antifungal therapy for IC[23]. Fluconazole (FCZ) has been the most abundant antifungal regimen used to treat IC. However the critical concern is the imprudent and wide usage of FCZ which has resulted in an increased resistance and the shift to non-albicans species[55]. Considering the emergence of different Candida species rather than C. albicans, a more justified approach should be sought to: 1-ensure the timely treatment of IC and 2-cover fluconazole-resistant Candida species.

APPROACH TO INVASIVE CANDIDIASIS IN INTENSIVE CARE UNIT

Treatment approaches towards IC in the ICU comprise prophylaxis, empirical-, preemptive- and targeted-therapy[56].

Prophylaxis, which is done to prevent IFIs development, is characterized as the use of antifungals in high-risk subjects in whom no sign or symptom of infection is so far documented. While FCZ is the main regimen used for this purpose, echinocandins (ECH) have recently been field tested with successful results[57].

On the other hand, initiation of antifungal agents in the presence of multiple risk factors and positive biomarkers such as BDG or PCR or other paraclinical findings is referred to as the pre-emptive treatment[56].

The time of treatment initiation is a key factor for the favorable outcome of IC[56,58]. According to several investigations[58-60], delayed antimicrobial therapy for more than 24 to 48 h negatively affects mortality. As such, in critically-ill or hemodynamically-unstable patients, late antifungal therapy may potentially predict death. Therefore, upon clinical suspicion for Candidemia, blood cultures need to be obtained and the treatment should to be administered without proof of IC based on the culture result[17]. This is generally referred to as the empirical approach. Prolonged length of stay in the ICU, surgery, multi-focal Candida colonization, sepsis, the use of TPN and/or wide-spectrum antibiotics are the key risk factors which warrant the empirical use of antifungals[14,56]. These are the risk factors considered in the “Candida Score”[47].

According to the latest international guidelines[14-17], the appropriate empirical antifungal choice greatly depends upon the local resistance patterns, likelihood of the presence of non-albicans species, hemodynamic status and criticality of the illness, prior exposure to azoles, pharmacodynamics and pharmacokinetics as well as the potential adverse effects of the selected antifungal, and last but not least, availability and cost of the treatment.

Based on the current guidelines, FCZ, ECH, amphotericin B (AmB) or its lipid formulations [Liposomal Amphotericin B (L-AmB)] and voriconazole (VCZ) are the recommended options while the first two are considered as the preferred choices in many instances. When the patient is hemodynamically unstable or has a prior exposure to FCZ with a high probability of non-albicans candida isolation (i.e., or C. glabrata or C. krusei), echinochandins (e.g., Caspofungin) are the preferred options[14,16]. AmB or L-AmB remain as alternative choices[14,17]. According to the Infectious Disease Society of America guideline, echinocandins should be taken as the first option in hemodynamically-unstable critically-ill patients[14]. Moreover, the most recent Canadian guideline contains similar recommendations about the critically-ill[17]. Caspofungin (CFG) is the only available echinocandin in our practice. De-escalation from CFG to FCZ is warranted in case of favorable clinical response and sterilization of blood cultures[12]. Based on the same guidelines, FCZ is suggested in hemodynamically stable cases without FCZ exposure over the last 30 d[14,15], meanwhile CFG is an equally suggested alternative[14,16,17]. Identification of local and general resistance patterns in our ICUs at different provinces would assist Iranian physicians to take more evidence-based decisions in their daily practice of IFIs management especially in the vulnerable critically-ill patients. In case of catheter-related BSI, an antifungal choice with activity against biofilm (e.g., CFG or AmB) should be considered. CVCs should be removed at earliest. Generally, when the treatment is started, serial blood cultures should be taken to ensure blood sterilization. Treatment duration is 14 d after the negative blood culture[14,17].

Recommendations from the current international guidelines are summarized in Table 1. Table 2 demonstrates the dosing recommendations for the preferred options.

Table 1 Recommended treatment options for invasive candidiasis in adult non-neutropenic critically-ill patients based on the current international and local practice guidelines/consensus statements.

Guideline	First choice	First alternative	Second alternative
ECCMID[15]	ECH	VCZ, L-AMB	FCZ
European experts opinion[16]	FCZ (stable patients and susceptible isolates) ECH (severe sepsis, micafungin last choice)	L-AmB
IDSA[14]	FCZ (stable patients, azole naive) ECH (critically ill, Severe sepsis, recent azole exposure)	AmB or L-AmB	VCZ
Canadian practice guideline for invasive candidiasis in adults[17]	FCZ (stable patients, azole naïve) ECH (stable or unstable patients, recent azole exposure, avoid in C. parapsilosis)	AmB or L-AmB
Consensus statement from the Iranian panel of experts[12]	FCZ (stable, No prior azole exposure, when hospital epidemiology indicates low incidence of NAC Spp.) ECH (hemodynamic instability, Fluconazole resistance)	VCZ, AmB or L-AmB (if available), considering the tolerability and cost vs utility

ECCMID: European Congress of Clinical Microbiology and Infectious Diseases; ECH: Echinocandins; VCZ: Voriconazole; AmB: Amphotericin B; L-AmB: Liposomal Amphotericin B; FCZ: Fluconazole; IDSA: Infectious Disease Society of America; NAC: Non-albicans Candida.

Table 2 Recommended therapy with proper dosing in invasive candidiasis based on the current practice guidelines and consensus statements[12,14-16].

Recommended treatment	Candidemia(non-neutropenic patients, moderate to severe illness)	Candidemia(neutropenic patients)	Candidaglabrata	Candida parapsilosis	Solid organ transplant recipients (prophylaxis)	ICU prophylaxis(high risk patients only)
Caspofungin	70 mg iv loading dose, then 50 mg/d per iv	70 mg iv loading dose, then 50 mg/d per iv	70 mg iv loading dose, then 50 mg/d per iv
Micafungin	100 mg/d per iv	100 mg/d per iv	100 mg/d per iv
Anidulafungin	200 mg/iv loading dose; then 100 mg/d per iv	200 mg/iv loading dose; then 100 mg/d per iv	200 mg/iv loading dose; then 100 mg/d per iv
Fluconazole				800 mg iv loading, then 400 mg/d per iv or PO	200-400 mg/d iv or PO for 7-14 d	400 mg/d per iv or PO
(Alternative regimen) Fluconazole	800 mg iv loading, then 400 mg/d per iv or PO	800 mg iv loading, then 400 mg/d per iv or PO
(Alternative regimen) Voriconazole if mold coverage is desired		6 mg/kg per iv q12h for 2 doses; then 4 mg/kg iv q12h or 200 mg PO q12h
(Alternative regimen) Fluconazole or Voriconazole			With susceptibility testing
(Alternative regimen) Echinocandins				If already responding to therapy
(Alternative regimen) Liposomal Amphotericin B					1-2 mg/kg iv/d for 7-14 d

ICU: Intensive care unit; PO: Per Os (Oral administration); iv: Intravenous.

THE PANEL’S POSITION ON THE MANAGEMENT OF IC IN CRITICALLY-ILL PATIENTS

The current consensus roots in the earlier position statement from the Iranian experts in IFI-CF[12]. This report is considered as an updated recommendation for local practitioners who are involved in the management of IC critically-ill patients. Considering the limitations such as lack of availability or validity of fungal biomarker tests, narrow antifungal options and cost utility issue in our local practice, a customized format of international guidelines clinical pathway was drawn and agreed by the experts’ panel. There is less focus on fungal biomarkers in this algorithm compared to the earlier consensus from the Iranian experts. Furthermore; prophylaxis, empirical, pre-emptive and targeted approaches are separately highlighted. The suggested clinical pathway is illustrated in Figure 2.

Figure 2 Management of invasive candidiasis in critical care setting. An updated consensus from the Iranian experts at invasive fungal infection-clinical forum. For justification and referencing see “diagnostic challenges of invasive candidiasis in the intensive care unit” and “approach to invasive candidiasis in intensive care unit” in the present report. IC: Invasive candidiasis; ICU: Invasive fungal infection; AmB: Amphotericin B; L-AmB: Liposomal Amphotericin B; IFIs: Invasive fungal infections.

Some other issues including the importance of catheter removal, fundoscopic examination, frequency of blood cultures after the initiation of antifungal therapy, the possibility to draw a pathway for the patients without clinical response, and the subtype-specific antifungal therapy were also addressed by the panel. Below are some recommendations with regard to the above issues: (1) With respect to the clinical manifestations of suspected IFIs in the ICU and routine clinical evaluations, fundoscopic examination needs to be done by an intensivist. However, this examination has a low negative predictive value against IFIs and treatment should be based on a wider risk stratification and assessment; (2) In case of a documented IFI, catheter removal becomes mandatory since eradicating the infection without removing the device looks unlikely. The challenge will arise in the context of suspected IFIs in the presence of permanent catheters, pace makers, implantable cardioverter defibrillator or cardiac resynchronization therapy, etc. where some expert recommend a “device salvage trial” for successful outcome. Taken together, the general recommendation is to remove catheters the soonest possible; (3) The duration of antifungal therapy depends mainly on both response to treatment and status of blood culture at the beginning of IFI therapy. Normally, 72 to 96 h of treatment duration is adopted with a repeated blood culture after IFI therapy was started. The treatment will usually be stopped after 14 d since the first negative blood culture. If the therapy was started empirically (no positive blood culture), the duration of therapy is 14 d provided the patient’s condition is improving on treatment. Repeated blood culture will prove whether the fungal infection is resolved; (4) Drawing a clinical pathway for non-responding patients may be difficult but still possible. Lack of response may be due to an alternative diagnosis, either non-fungal or additional microbial infections which have not been properly covered in the current therapy. Either way, a review has to be done to detect the possible source of infection and necessary investigations including standard blood cultures, non-culture based assessments, if available, and possible imaging studies such as high-resolution computed tomography and advanced ultrasound should be considered to diagnose a possibly-disseminated IFIs or resistant organisms not fully sensitive to the current therapy. In challenging, non-responding IFI cases, the treatment should be adjusted with the possibility of combination antifungal therapy. Finally, lack of response may be due to inappropriate source control including devices, foreign bodies, and surgically-accessible factors like collections which require appropriate interventions. One should always bear in mind that the lack of response may be due to non-infectious causes which also need to be well-explored; and (5) Based on the risk and severity assessment, empirical approach allows the timely management of IFIs. According to the evidence highlighted in this report, moderate- to high-risk patients for severe infections require echinocandins. Streamlining depends on response and the culture results. Meanwhile, mild infections in stable patients can still be treated with FCZ. Suspected Aspergillus requires VCZ, whereas the emerging and rare fungal infections would still require AmB. Furthermore, the possibility of combination antifungal therapy should be considered.

CONCLUSION

IC is a serious clinical condition with a notable risk of death in critically-ill patients when not treated properly. Increased awareness and practical insights through share of experience as well as adherence to international and local guidelines are key elements of success in the management of IC in the ICU.

According to the panel’s opinion, LoS in the ICU and total days on mechanical ventilation, the presence of CVC/TPN, dialysis catheters, use of broad spectrum antibiotics, sepsis, presence of GI surgery, burn and high Acute Physiology and Chronic Health Evaluation II Score (> 16)[61] were considered as main risk factors justifying the empirical antifungal therapy against IC in febrile, non-neutropenic critically-ill patients admitted to the ICU.

The entire panel admitted that lack of experience and insufficient awareness is the main cause for delayed initiation of antifungal therapy in critically-ill patients. Meanwhile half of the participants believed that the paucity of diagnostic tools and inconsistent availability of the therapeutic options are crucial obstacles in parallel. All experts agreed that holding well-planned educational programs and fostering scientific activities within our IFI-CF will be a road to increase awareness and better practice with regard to the management of IFIs in critical care setting.

Upon conclusion, experts at the IFI-CF decided to continue holding regular meetings at institutional level in order to educate junior ICU staff and increase their awareness on the management of IC in the ICU.

The IFI-CF became determined to conduct biannual meetings to share experience and update local guidelines on IFIs management as required. In addition, utilizing the already established consensus, the experts agreed to pursue preparing printed protocols in each ICU in order to make it easier for the juniors to follow and implement.

ACKNOWLEDGMENTS

Authors would like to thank Dr. Dindoust P, Fahim R, Nabil Y, Nafarieh L and Salarian A for supporting this clinical forum. Appreciation is extended to Ms. Ranjbar E and Liaghi A for their invaluable assistance. This meeting received scientific and administrative support from Behestan Darou PJS and Behphar scientific Committee, Tehran, Iran.