Medical

Communication

Biosci. Biotech. Res. Comm. 9(3): 371-381 (2016)

Invasive fungal infections in critically-ill patients: A

literature review and position statement from the

IFI-clinical forum, Shiraz, Iran

Farid Zand

, Mohsen Moghaddami

, Mohammad Ali Davarpanah

, Mansoor Masjedi

, Reza

Nikandish

, Ali Amanati

, Mohammad Afarid

, Leila Nafarieh

and Mohammad Nami

5,6

Shiraz Anesthesiology and Critical Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Non-Communicable Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

HIV/AIDS Research Center, Shiraz University of Medical Sciences,Shiraz, Iran

Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran

Behestan Medical Scienti c Committee, Behestan Group, Tehran, Iran

Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of

Medical Sciences, Shiraz, Iran

The list of collaborators and consultants at IFI-CF, Shiraz, can be found in the appendix at the end of this report.

ABSTRACT

Invasive fungal infections (IFIs) have increasingly been recognized as a serious clinical concern in critically-ill

patients admitted to the intensive care units (ICUs). The most abundant pathogens in this population are Candida

species. As such, a clear understanding on the epidemiology of this infection seems to be a key step in providing

appropriate treatment. Expert input forums are among the practical approaches to de ne locally-adapted clinical-

pathways with regard to debated medical perspectives. To agree upon a shared approach towards IFI management

in ICU, an interdisciplinary panel of experts from infectious diseases and intensive care  elds met up in Shiraz on

28 November 2015 within the IFI-Clinical Forum (IFI-CF).This clinical forum aimed to view the available evidence,

taking into consideration the recent practice guidelines on IFIs management in the ICU to arrive at an agreed posi-

tion in current clinical practice. The aim of this summary is to discuss IFIs in ICU from epidemiology, the range of

pathophysiology from colonization to the invasive infections, risk prediction, diagnosis and treatment perspectives.

KEY WORDS: INVASIVE CANDIDIASIS; INVASIVE FUNGAL INFECTIONS; CRITICAL CARE; CLINICAL PATHWAY

371

ARTICLE INFORMATION:

*Corresponding Author: torabinami@sums.ac.ir

Received 20

July, 2016

Accepted after revision 31

Aug, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

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reserved.

Online Contents Available at: http//www.bbrc.in/

372 IFIS IN CRITICAL CARE SETTING BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Farid Zand et al.

INTRODUCTION

With all the advancing medical care over the past

decade, an increasing number immune-compromised

patients have received in-hospital care and critically-

ill patients have often experienced prolonged hospital

stays. This might have potentially contributed to the

development of invasive fungal infections (IFIs) result-

ing in a nearly  ve-fold increase in the incidence of

such a clinical challenge in the past 10 years mainly in

critical care setting(Elhou et al., 2014; Lepak & Andes,

2011; Montagna et al., 2013). Despite all improved diag-

nostic methods, timely and speci c diagnosis of IFIs

in the ICUhas remained an uphillchallenge (Ahmadi et

al., 2014; Avcu et al., 2016; He et al., 2015; Liu et al.,

2015; Shi et al., 2015; Solmaz et al., 2016; Ullmann et

al., 2012; Wu et al., 2016).

The reason for high mortality and morbidity of IFIs

is at least two-fold. Firstly, the clinicians defer early

empirical interventions as they may fail to consider IFIs

and their possible outcome, and secondly, the etiology

of infection is almost never adequately-established in

time (Kollef, Micek, Hampton, Doherty, & Kumar, 2012;

Pfaller & Diekema, 2007). To lessen such a burden, a

clinical guidance on how to suspect, diagnose and treat

IFIs and mainly invasive candidiasis (IC), which is the

most frequent case in critical care setting need to be

drawn and adapted for local practice.Toward the above,

 eld experts from infectious diseases and intensive

care disciplines in Shiraz, Iran, attended a round-table

discussion on 28 November 2015 to review and dis-

cuss updated epidemiologic insights on IC in ICU, the

related diagnostic challenges, therapeutic approaches

and proper antifungal options in ICU-admitted patients

suspected for or diagnosed with IC.

EPIDEMIOLOGY, INCIDENCE AND MORTALITY

Nosocomial fungal infections comprise around 15% of

healthcare related infections among which Candida fol-

lowed by Aspergillus species are found to be key culprits

in invasive fungal infections (Montagna et al., 2013;

Pfaller & Diekema, 2007). On the other hand, resist-

ance to antifungal agents is an alarming sign for the

emerging common nosocomial fungal infections (Badiee

& Alborzi, 2011). According to an elegant prospective

point-prevalence investigation, Candida was regarded

as the third most common cause accounting for nearly

2% of all infections (Leon et al., 2016; Timsit, Chemam,

& Bailly, 2015; Vincent et al., 2009). Moreover, a Euro-

pean cross-sectional survey revealed thatup to 30%

of all candidemias take place in ICUs(Marchetti et al.,

2004). ICU-admitted patients are shown to be  ve to ten

times more endangered for IC thanpatients in medical

or surgical wards. Based on recent reports from North

America, candida species are among the most common

documented pathogens in blood cultures responsible

forup to 10% of all bloodstream infections. Other studies

from European ICUs have also con rmed candida to be

among top tenestablished pathogens giving rise to3-5%

of bloodstream infections( Mean, et al., 2008, Chen et

al., 2015; Kautzky, Staudinger, & Presterl, 2015) .

Based on the available evidence, IC subjects to high

mortality rate ranging between 40 to 60% (Falagas, Apos-

tolou, & Pappas, 2006; Guery et al., 2009; Leroy et al.,

2009), and the mortality may reach 100% under certain

conditions (Kollef et al., 2012). The face of candida epi-

demiology has transformed over the past two decades.

Though candida albicans used to be known as the domi-

nant pathogen resulting in up to 60% of the infections,

the prevalence of non-albicans species (including include

C. glabrata, C. krusei, C. tropicalis and C. parapsilosis)

has been on the rise lately to comprise over 50% of the

infections (Arendrup, 2010; Deorukhkar & Saini, 2016).

In an Iranian study in which 107 clinical isolates

(each from one high-risk patient) were evaluated non-

albicans candida species were isolated from almost 70%

of IC cases. The most frequently isolated species was C.

glabrata (47.7%), followed by C. tropicalis (15%) and C.

krusei (6.5%) (Zaini, Kordbacheh, Mahmoudi, Safara, &

Shekari, 2012). In another investigation on 855 yeast

strains from different clinical specimen in Iran, over

40% of all isolated turned to be non-albicans species

(Mohammadi et al., 2013). These  ndings are of sig-

ni cant clinical relevance since non-albicans candida

species are generally found to be  uconazole-resistant.

Taking into consideration that  uconazole is the most

widely used antifungal agent against candida infection,

evidence-based decision-making on choosing the proper

treatment option in IC among ICU patients needs to be

refocused.

In a local epidemiological study of fungal infections

from Shiraz, followed by C. albicans; C. kruzei (16.1%),

C. glabrata (13.5%), C. kefyr (7.4%), C. parapsilosis

(4.8%), C. tropicalis (1.7%) and other species (8.5%) were

found to collectively be responsible for over 50% of can-

dida infections. Resistance varied based of the isolates

and the corresponding antifungal agent among which

the lowest MIC90 (mean inhibitory concentration-90)

for non-albicans candida isolates was observed with

caspofungin (0.5 μg/ml)(Badiee & Alborzi, 2011).

POTENTIAL RISK CRITERIA FOR INVASIVE

FUNGAL INFECTIONS

Colonization with various candida species which are

among normal  ora is not risky among healthy sub-

jects, whereas candida species subject to dissemination

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS IFIS IN CRITICAL CARE SETTING 373

Farid Zand et al.

and over growth up on extended-spectrum prolonged

antibiotic therapy, burn injury, diabetes mellitus, neu-

tropenia and immuno supression. Such a context may

progressively result in disseminated candida infection/

candidemia known as IC. The condition, though not nec-

essarily, tends to progress in cases with severe sepsis or

septic shock, those who have undergone major surgeries,

receiving total parenteral nutrition (TPN) and are found

to have multifocal candida colonization. A fundamental

clinical issue is to identify which category of patients

are at increased risk for IC (Ahmadi et al., 2014; Gong

et al., 2016; Hawkshead, Van Dyke, Hassig, Webber, &

Begue, 2016; Lau et al., 2015; Liao et al., 2015; Pu et al.,

2015; Rajendran et al., 2016; Sun et al., 2016).

Candida colonization may consequently turn into

IC following critical illness. In the case of ICU-admit-

ted patients, while only around 10% of cases tend to

be colonized with candida, this would be documented

in up to 80% of the cases during their prolonged ICU

stay, among which as many as 30% of such patients

may develop IC (Leon, Ostrosky-Zeichner, & Schuster,

2014). In patients who stay more than seven days in

the ICU, the incidence of multifocal colonization (which

is reported as an independent risk factor of IC) is dra-

matically increased (Kautzky et al., 2015). Research has

referred to stomach (45.6%), oropharyngeal samples

(34.3%), the trachea (23.4%), perirectal region (21.2%)

and the urinary tract (18.7%) as the most frequent foci

for candida colonization among ICU-admitted patients.

In addition, the relative risk of ICis shown to be notably

increasedonce fecal (7.5% vs. 3.2%, p=0.019) or urine

samples (9.2% vs. 5.2%, p=0.032) turn to be positive

for candida. ICU-admitted patients are then suggestedto

be biweekly screened (feces, urine, tracheal aspirate) to

identify their potential risk for IC (Leon, Alvarez-Lerma,

et al., 2009; Magill et al., 2006; Mardani et al., 2011).In

the event of at least three consecutive positive samples

in two or more occasions; multifocal colonization, as an

independent risk of IC, needs to be considered (Gong et

al., 2016; Hawkshead et al., 2016; Pittet, Monod, Suter,

Frenk, & Auckenthaler, 1994; Rajendran et al., 2016;

Sun et al., 2016).

Due to the higher rate of mortality, catheter-related

candidemia needs to be differentiated from primer or

intra-abdominal candidiasis-related candidemia. Cath-

eter-related candidemia is con rmed once the same

candida species are detected both in the catheter and

peripheral blood samples.Such infection is known to

predominantly occur through the exogenous path related

tocolonization in patient’s skin and the healthcare work-

ers’ hands (Leon et al., 2014).

Depending on cultures, clinical picture and the

patient’s risk pro le, the diagnosis of IFI is generally

categorized into proven, probable or possible(De Pauw

et al., 2008; Moghadami et al., 2013). Proven IFI refers

to positive culture result oronce histologycon rmsthe

presence of proliferous fungiin blood or other infected

specimens. On the other hand, probable or possible IFIs

are considered incritically-ill, neutropenic or non- neu-

tropenic patients with extended ICU stay, multifocal

colonization, sepsis or septic shock who are either posi-

tive (probable) or negative (possible) for known serum

biomarkersincluding (1,3)-b-D-Glucan (BDG) or mannan

antigen and anti-mannan antibody or polymerase chain

reaction (PCR) (Elhou et al., 2014).

DIAGNOSTICS MEASURES

Though many optionsare suggested for diagnosis, none

seems to be  awlesson its own. The diagnostic tools

ranging from different scoring or risk-predictionmodels,

to advanced laboratory measures need to be combined

since IC often tend to occur with no candidemia. As

such, the empirical antifungal therapy adapted based on

patients’ risk pro le is now believed to playa key part in

treating IC (Elhou et al., 2014; Hsu, Nguyen, Nguyen,

Law, & Wong-Beringer, 2010; Martinez-Jimenez et al.,

2016).

RISK PREDICTION MODELS

Multiple colonization, broad spectrum antibiotic therapy,

total parenteral nutrition, dialysis, APACHE II (Acute

Physiology and Chronic Health Evaluation II) score of

> 20 points, central venous catheters (CVC), candiduria>

105cfu/ml and multiple transfusion are considered as

some key risk factors for IC. On the other hand, some

non-speci c risk factors for IC include age>65 years,

diabetes mellitus, renal failure, surgical intervention,

Foley catheters, catheters inserted to vessels and long

ICU stay i.e. > 7 days (Elhou et al., 2014).

COLONIZATION INDEX

Colonization index is known to play a prominent role in

the development of IC. According to Pittet et al (Pittet et

al., 1994), over one third of severely-colonized patients

were found to develop documented candidiasis (p<0.01).

The cut-off of>0.5 could then predictIC one weekprior

tofungal cultures. Severalfuture investigation con rmed

the above  ndings (Caggiano et al., 2011; Calandra,

Roberts, Antonelli, Bassetti, & Vincent, 2016; Eggimann,

Bille, & Marchetti, 2011). Based on the validation studies

the positive predictive value (PPV), negative predictive

value (NPV), sensitivity and speci city of the coloni-

zation index are reported 66%, 100%, 64% and 69.7%,

respectively(Eggimann, Que, Revelly, & Pagani, 2015;

374 IFIS IN CRITICAL CARE SETTING BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Farid Zand et al.

Kautzky et al., 2015; Leon et al., 2014; Posteraro et al.,

2011)

The extent of colonizationcan be determined through-

periodic samples obtained from various site including,

cutaneous  exure regions, nose, throat, endotracheal

tube aspirate,feces and urine. Patients endangeredfor

IC are advised to be biweekly screened for coloniza-

tion. Colonization index is a ratio of non-sterile region

samples to total number of samples.When colonization

index is above 0.5 empiric antifungal therapy needs to

be considered (Figure 1).

CANDIDA SCORE

Candida Score which was proposed 10 years ago by Leon

et al,is in fact an upgraded form of the Colonization

Index(Leon et al., 2006). This risk prediction model was

validated through alarge prospective cohort in which

6%developed IC. According to the  ndings of Leon et

al, surgery, multifocal colonization and severe sepsis

acquired the odd ratios (OR) of 2.71 [95% con dence

interval (Cl): 1.45-5.06], 3.04 [95% CI: 1.45-6.39] and

7.68 [95% CI: 4.14-14.22] to predictIC. As such, each

predictive factor received one point in candida score,

except for severe sepsis which received 2 points. A

Candida score of 2.5 points and more could thenpre-

dict IC with a sensitivity, speci city, NPV and PPV of

81%, 74%, 98% and 16%, respectively. The clinical rel-

evance and adaptability of Candida score was validated

in several subsequent reports (Leon, Ruiz-Santana, et al.,

2009; Tissot et al., 2013) (Figure 1).

THE OSTROSKY-ZEICHNER MODEL

This risk-prediction model was designed to distin-

guishICU admitted patients who potentially require anti-

fungal prophylaxis. The extended ICU stay was found to

strongly predict the risk for ICU in a study on surgical

ICU admitted patients (Paphitou, Ostrosky-Zeichner, &

Rex, 2005). This study similarly indicated that diabe-

tes mellitus, required acute haemodialysis, total paren-

teral nutrition or broad spectrum antibiotic therapy are

other de ning risk factors for the development of IC. IC

was signi cantly higher in high-risk group compared to

those without the aforementioned risk factors (16.6% vs.

5.5%, p=0.001). In fact, over three quarters of patients

who went todevelop candidemia or IC were recognized

by this method. Subsequent studies con rmed these

results(Ahmed, et al., 2014; Yapar, 2014, Aitken et al.,

2014; Lau et al., 2015; Liao et al., 2015; Gong et al.,

2016;).

FIGURE 1. The concurred approach for optimal antifungal therapy against IC in non-neutropenic adult

patients. When culture results become available, based on the reported isolates and sensitivity tests, the

treatment is either continued to complete 14 days from the  rst negative culture or de-escalated/switched

to another agent from a different antifungal class. A more comprehensive clinical pathway for the same

can be followed in (Ahmadi et al., 2014; Elhou et al., 2014). ICU: Intensive Care Unit, CVC: Central

Venous Catheter, TPN: Total Parenteral Nutrition.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS IFIS IN CRITICAL CARE SETTING 375

Farid Zand et al.

NON-CULTURE-BASED METHODS

Fungal cultures become positive relatively late (Morris,

Byrne, Madden, & Reller, 1996) and are often inadequate

to diagnose deep-seated candida infections. On the other

hand, performing tissue biopsies and obtaining body  u-

ids are invasive and/or clinically impractical making them

not readily accessible in routine practice (Eggimann et

al., 2011). This necessitates development of other sensitive

and practical diagnostic methods with high sensitivity

to possibly enable timely recognition of IC. Examples of

such methods include identifying cell-wall components,

circulating fungal DNA, antigens and antibodies.

(1,3)-b-D-Glucan

Studies have substantiated that 1,3-b-D-Glucan (BDG) is

an early biomarker of many fungal infections including

candidiasis and aspergillosis (Ellis et al., 2008, Azoulay

et al., 2016; Nucci et al., 2016; Posteraro et al., 2016).

Based on multicenter investigations, the cut-off value

of 80 pg/ml is con rmed tosuggestIC with good sen-

sitivity and speci city except for candida parapsilosis

(Pickering, Sant, Bowles, Roberts, & Woods, 2005). This

auxiliary biomarker test reveals positive results 7-10

days prior to the established clinical diagnosis of fungal

infections. Cumulative evidence has proposed BDG as an

acceptable indicator of fungal infections and a reliable

biomarker to start preemptive anti-fungal therapy based

upon. While evidence has con rmed the correlation

between BDG levels, clinical outcome and the treatment

response (Takesue et al., 2004), complexity of the test

and the applied cost hinder its wide availability. Some

other downsides of this test include false positive results,

mainly upon early days of ICU admission, and particu-

larlyfollowing surgical interventions, immunglobulin

or extended-spectrum antibiotic therapy. Though data

on the kinetics of BDG are relatively scant,some reports

have related the decreased BDG serum levels to thera-

peutic success (Ahmadi et al., 2014; Takesue et al., 2004;

Tissot et al., 2013).

In case this correlation is further con rmed by clini-

cal investigations, BDG may possibly be considered as a

tool in assessing response to antifungal therapy. While

the test is shown to trace BDG levels even in other body

 uids including cerebro-spinal and peritoneal uids as

well as bronchoalveolar secretions (Lyons et al., 2015;

Mutschlechner et al., 2015), it needs to be validated for

extended clinical use. Lately, the European Society of

Clinical Microbiology and Infectious Diseases (ESCMD),

the Society of Critical Care Medicine (SCCM), and the

European Society of Intensive Care Medicine (ESICM),

have included BDG testing in their recommendations

based on the existing level-II evidence (Elhou et al.,

2014; Hope et al., 2012; Ullmann et al., 2012).

Mannan antigen and anti-mannan antibody

In case of invasive candidiasis, mannan, as a component

of candida cell wall, circulates in the bloodstream. In

practice, a range of immunoassay-based and latex agglu-

tination methods are usedto detect mannan (Schuetz,

2013). The combined detection of mannan antigen and

anti-mannan antibody is known to yield a better sen-

sitivity. Based on a recent meta-analysis, the sensitiv-

ity and speci city ofmannan antigen and anti-mannan

antibody tests were (58%, 93%) and (59%, 83%), respec-

tively. Furthermore, the sensitivity and speci city of the

combined test is shown to be improved (83% and 86%,

respectively) for C. albicans, C. glabrata and C. tropica-

lis infections, when these investigations were combined

(Mikulska et al., 2010). Despite the existing body of evi-

dence, further investigations (examining homogeneous

patient groups with IFIs) are deemed necessary to sub-

stantiate the positive and negative predictive values of

the test and de ne the its role in routine practice.

Detection of Candida nucleic acids by PCR

Despite the potentially informative nature of fungal

DNA detection in the practice of clinical mycology, the

DNA disengagement secondary to human cell-lysis as

well as the contamination from other saprophytic or

pathogen fungi may lead to its false positive results.

This makes the test challenging. Nevertheless, studies

have demonstrated that PCR is appropriate for timely

detection of candidemia and the detection of organic

fragments of the multicopy gene. The test is also shown

to detect non-viable organisms quicker than the culture

where different platforms and target genes (other than

blood samples) are investigated during the test (Avni,

Leibovici, & Paul, 2011).

A recent meta-analysis has reported favorable over-

all sensitivity and speci city (95% and 92%) of PCR in

detecting IC. This elegant report included 54 studies and

4894 patients among which 963 had proven, probable

or possible IC (Avni et al., 2011).Despite the above, direct

molecular detection of candida is not yet considered as

a standard method and until validation for routine clini-

cal use, the position of pan-fungal PCR test or further

molecular methods in early detection of ICremainsin-

de nite.

CULTURE-BASED DIAGNOSTICS

The culture-base diagnosis of IFIs are recognized as

the gold standard(Ahmadi et al., 2014). Based on the

evidence, the sensitivity of blood cultures for invasive

candisiasisranges between 50-70%. This may even be

decreased in neutropenic patients andthose receiving

antifungal therapy (Ahmadi et al., 2014; Ullmann et al.,

2012). When catheter-related infections are suspected,

376 IFIS IN CRITICAL CARE SETTING BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Farid Zand et al.

to establish a source control, samples should also be

obtained from the catheters(Ullmann et al., 2012).

When culture results turn positive for candida species,

in addition to performing resistance tests, it is impor-

tant to note that minimal inhibitory concentration (MIC)

values may also affect the therapy. The documentation

of the candida species is time-consuming may require

several days following positive results. Meanwhile, this

may be fast-tracked through some novel techniques

including PNA-FISH (Peptide Nucleic Acid Fluorescence

In Situ Hybridization) and MALDI-TOF MS (Matrix

Assisted Laser Desorption Ionization Time-of-Flight

Mass Spectrometry) which are not necessarily available

and/or validated in everyday practice (Heil et al., 2012;

Saracli, Fothergill, Sutton, & Wiederhold, 2015).

Despite the fact that the de nite diagnosis of IFI relies

on blood cultures, they certainly cannot be classi ed

among the early diagnostic strategies. Culture results

are typically available after several days while as-early-

as-possible clinical decision is often necessary to save

patient’s life. Based on the above, cultures may largely

be used as con rmatory tests to continue an already

commenced empirical antifungal regimen to de-escalate

it to other options (Elhou et al., 2014).

THERAPEUTIC APPROACHES TOWARDS

INVASIVE CANDIDIASIS

The clinical outcome in patients with invasive can-

didiasis largely depends on the timeliness in antifungal

therapy (Hope et al., 2012; Ullmann et al., 2012). Many

clinical investigations have clearly shown that delayed

approach in antifungal therapy has a negative impact on

survival (Ahmadi et al., 2014; Ahmed et al., 2014; Blot,

Vandewoude, Hoste, & Colardyn, 2002; Corona, Cislaghi,

& Singer, 2008; Elhou et al., 2014; Garey et al., 2006;

Mardani et al., 2011; Morrell, Fraser, & Kollef, 2005;

Skrobik & Laverdiere, 2013; Viaggi, Tascini, & Meni-

chetti, 2014; Yildirmak, Gedik, Simsek, Iris, & Gucuy-

ener, 2013). Based upon the diagnostic possibility of IFIs,

various strategies including prophylaxis, empirical, pre-

emptive, or targeted therapy may be pursued.

PROPHYLAXIS

Prophylactic antifungal therapy is used to prevent IFIs,

namely invasive candida infection in patients who are

asymptomatic yet at high-risk (Moghadami et al., 2013).

Though  uconazole is the mostly used prophylactic

option in general, echinocandins have also been suc-

cessfully used (Senn et al., 2009). Unlike the signi cant

position of prophylaxis in immunocompromised hosts

(Fortun et al., 2016; Mardani et al., 2011; Moghadami et

al., 2013), this approach is not commonly recommended

in non-neutropenic ICU-admitted patients (Ullmann et

al., 2012).

EMPIRICAL THERAPY

As de ned by ESCMID (Arendrup et al., 2014; Ullmann

et al., 2012), empirical approach is warranted in patients

withpersistent fever despite adequate antibiotic therapy

who are found to be at high risk forinvasive candidiasis

based on their increased risk scores.

PRE-EMPTIVE THERAPY

In case of microbiological evidence of IFIs (1-3 BDG

biomarker, mannan/anti-mannan double test or detec-

tion of fungal nucleic acid by PCR) in clinically-sus-

pected cases, pre-emptive approach become warranted

as de ned by ESCMID (Ullmann et al., 2012). Such IFIs

are typically categorized into “possible” or “probable”.

TARGETED THERAPY

The antifungal therapy can be adapted to achieve favora-

ble results as targeted therapy, once the sensitivity of

anti-candidaoptions as well as their MIC from the blood

culture or other specimen is identi ed. Though this is

considered as gold-standard, availability of cultures

results is not timely (Badiee & Alborzi, 2011; Eggimann

et al., 2011; Mean et al., 2008; Ullmann et al., 2012).

CHOICE OF THE ANTIFUNGAL AGENT AND

LENGTH OF THERAPY

A number of international guidelines and national con-

sensus statements (from the IFI-CF forums across Iran)

are available to optimize our practice upon choosing

the appropriate agents in IFI management in critically-

ill patients (Ahmadi et al., 2014; Elhou et al., 2014;

Kontoyiannis, 2001; Mardani et al., 2011; Moghadami

et al., 2013; Pappas et al., 2016; Patterson et al., 2016;

Ullmann et al., 2012). Meanwhile, local epidemiology

and resistance pro les need to be established and taken

into account when considering an antifungal option in a

given clinical scenario.

Considering the available guidelines, local epidemiol-

ogy (Badiee & Alborzi, 2011; Mohammadi et al., 2013;

Zaini et al., 2012), and expert panels’ inputs from the

IFI-CF, Shiraz, the concurred approachto antifungal

therapy against IC in non-neutropenic adult patients is

summarized in Figure 1.

With regard to the initiation and duration of therapy,

in case of a positive blood culture for candida, empiric

antifungal therapy should immediately be commenced

followed by daily blood cultures. The patient needs to

be treated for a minimum of 14 days following the  rst

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS IFIS IN CRITICAL CARE SETTING 377

Farid Zand et al.

negative culture. If candidemia is present, fundoscopic

examination becomes crucial to exclude intraocular

candidiasis (Pappas et al., 2016; Ullmann et al., 2012).

SUMMARY AND CONCLUSIVE REMARKS/

RECOMMENDATIONS FROM THE IFI-CF,

SHIRAZ

The burden of IFIs needs to receive a more focused clini-

cal attentionespecially in our high-risk, critically-ill,

ICU-admitted patients. Despite the recent progress indi-

agnosis and treatment of IFIs, this clinically-signi cant

issue continues to often be overlooked. Timely diagno-

sis and properantifungal therapy is the only chance for

improved survival in critically-ill patients with IFIs. As

far as concernedby the practice guidelines, empirical

and pre-emptive approaches tend to the most promis-

ing strategies (Ahmadi et al., 2014; Elhou et al., 2014;

He et al., 2015; Liu et al., 2015; Pappas et al., 2016;

Patterson et al., 2016; Shi et al., 2015; Ullmann et al.,

2012). Validation and inclusion of fungalbiomarker

assays and DNA tests in our practicewould potentially

improve diagnostic accuracy and enable earlier treat-

ment approaches. Nonetheless, several concerns need

to be resolved not only on availability and validity of

such tests in routine practice, but also the remaining key

issues in diagnostics and therapy as well as determina-

tion of the treatment duration.

The present IFI-CF (Invasive Fungal Infections-Clin-

ical Forum) brought together an interdisciplinary panel

of experts from infectious diseases and intensive care

 elds in Shiraz to view the available evidence, taking

into consideration recent practice guidelines on IFIs

management in the ICU. The panelaimed to arrive at an

agreed position in current clinical practice of IFIs in ICU.

The following remarks emerged from the IFI-CF’s dis-

cussions on epidemiology, the range of pathophysiology

from colonization to the invasive infections, risk predic-

tion, diagnosis and treatment perspectives:

1. The necessity of extending local epidemiology

studies on candida isolates and antifungals’ sensi-

tivity in patients admitted to ICUs

2. Identifying the impact of adherence to the current

local consensus as well as other local and interna-

tional practice guidelines on the clinical outcome

of ICU-admitted patients at risk for IFIs

3. Considering the use of risk prediction models,

namely the ‘Candida Score’, to identify critical-

ly-ill patients eligible for the empirical antifungal

approach

4. Designing clinical studies in the ICU to consider

invasive infections rather than colonization and to

identify the role of fungal biomarkers (1-3 BDG

biomarker, mannan/anti-mannan double test or

detection of fungal nucleic acid by PCR) in opti-

mizing our clinical approaches.

5. Capitalizing on a ‘working-team concept’, with the

medical microbiologists involved, to further ad-

dress key questions including ‘when to start treat-

ment?’, ‘what strategy to pursue?’and ‘which op-

tion to take?’ in IFIs among ICU-admitted patients.

APPENDIX

The IFI-CF received contribution from the following col-

laborators and consultants from Shiraz University of

Medical Sciences, Shiraz, Iran (sorted alphabetically):

Asadpour, Elham (Pharmacology); Badiee, Parisa

(Medical Mycology); Dabiri, Gholamreza (Intensive

Care); Fallahi, Mohammad-Javad (Pulmonology); Ghay-

umi, Seyed Mohammad-Ali (Pulmonology); Haddad-

Bakhodaei, Hosein (Intensive Care); Haghbin, Saeedeh

(Pediatrics, Intensive Care); Khaloo, Vahid (Intensive

Care); Mackie, Mandana (Intensive Care); Momeni,

Behrooz (Pulmonology); Mortazavi, Shahram (Infectious

Diseases); Pouladfar, Gholamreza (Pediatrics, Infectious

Diseases); Sabetian, Golnar (Intensive Care); Savaie,

Mohsen (Intensive Care); Vazin, Afsaneh (Clinical Phar-

macy); Zomorodian, Kamiar (Medical Mycology).

ACKNOWLEDGMENTS

Authors would like to thank Dr. Dindoust P, Salarian

A, Hejazi-Farahmand SAR, for supporting this clini-

cal forum. The ‘IFI-CF, Shiraz’ received scienti c and

administrative support from Shiraz Anesthesiology and

Critical Care Research Center, Shiraz University of Medi-

cal Sciences, Shiraz, Iran, as well as the MSD Medical

team at Behstan Darou PJS, Tehran, Iran.

COMPETING INTEREST

The present report outlined the communications andex-

perts’ opinions during the IFI-CF held on 28 Novem-

ber 2015, Shiraz, Iran. The authors declare no compet-

ing interest upondata review, talk delivery during the

meeting, interactivediscussions and preparation of the

present report. MN provided medical consultancy to

Behestan Medical Scienti c Committee, Behestan Group,

Tehran, Iran.

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