Why Candida Sepsis ShouldMatter to ICU Physicians

Yoanna Skrobik, MD, FRCP(c)a,b,*, Michel Laverdiere, MD, FRCP(c)c

KEYWORDS

� Candidemia � Invasive candidiasis � Sepsis � Critical care � Intensive care

KEY POINTS

� Severe candida infections are prevalent in the critically ill.

� Prompt treatment with source control and timely antifungal initiation improves mortality.

� Because diagnosis is challenging in many clinical settings, stratification by risk factorsimproves its accuracy.

� Understanding local candida infection prevalence and resistance patterns is useful inclinical decision-making.

INTRODUCTION

Candidemia and/or invasive candidiasis (IC) infection significantly contribute tomortality and morbidity in the critically ill.1,2 IC by definition refers to infection indeep-seated tissue or other normally sterile sites, excluding urine, documented byhistopathology and/or microbiological culture.Candida bloodstream infection (ie, can-didemia) is the most common form of documented IC; this pathologic condition is alsoalmost exclusively the one reported in current epidemiology studies. Infection rateshave increased dramatically (100- to 1000-fold) over the last 2 decades3,4 in mostenvironments, with increments within intensive care units (ICUs) as well as outsidethe ICU environment. Outpatient acquisition of Candida bloodstream infections isnow reported5; it is likely to represent health care–associated infection because ofits frequent association with central vein long-term use of indwelling catheters (periph-erally inserted central catheter line, hemodialysis). True variations in candidemia/ICincidences and profiles between centers, regions, and countries have not been

Disclosures: The authors have nothing to disclose.a Department of Medicine, Universite de Montreal, 5415 Boulevard De l’Assomption,Montreal, Quebec H1T 2M4, Canada; b Respiratory Critical Care Group, Respiratory HealthNetwork of the FRQS, Montreal, Quebec, Canada; c Department of Medicine, Hopital Maison-neuve Rosemont, Universite de Montreal, 5415 Boulevard De l’Assomption, Montreal, Quebec,H1T 2M4, Canada* Corresponding author. Universite de Montreal, 5415 Boulevard De l’Assomption, Montreal,Quebec H1T 2M4, CanadaE-mail address: yoanna.skrobik@umontreal.ca

Crit Care Clin 29 (2013) 853–864http://dx.doi.org/10.1016/j.ccc.2013.06.007 criticalcare.theclinics.com0749-0704/13/$ – see front matter � 2013 Elsevier Inc. All rights reserved.

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garnered from epidemiologically rigorous simultaneously collected data. The impactof Candida sepsis on the sickest of the sick seems considerable, however. Datacollected in multiple sites in a single Canadian geographic region suggest septicshock is purportedly attributable to Candida in more than 7% of cases (Table 1),and in neutropenic patients in greater than 20% of cases (Kumar A, personal commu-nication, 2012). Candida is the fourth leading cause of hematogenous infections inNorth American hospital in the 1990s,4 and 33% of Candida episodes are identifiedin ICUs.5 Among critically ill patients with nosocomial infections surveyed in a WesternEuropean 1-day point prevalence study including 1417 ICUs, 17% of samples yieldedpositive fungal cultures. In November 2004, a Canadian ICU point prevalence studyaimed to identify all colonized or infected patients. Greater than 60% were colonizedor infected with Candida, although patients with positive blood cultures for funguswithin 4 days of the point prevalence sampling constituted less than 1% of the studypopulation, making infection and colonization challenging to differentiate.In addition to the worsening and worrisome prevalence of Candida among the

critically ill, the risk of death is exceptionally high among patients with septic shockattributed to Candida infection. Delayed treatment of candidemia is an importantdeterminant of patient outcome and mortality (Fig. 1).6,7 Timely source control andantifungal treatment are associated with improved clinical outcomes.8 Inappropriateantimicrobial therapy is associated with higher mortality and worsemorbidity.9 Prompttreatment of IC should therefore constitute a priority for critical care physicians.

RISK FACTORS

Patients are at greater risk for Candida infection if they have been exposed tobroad-spectrum antibiotics; have diabetes, central lines, extensive (particularly

Table 1Septic shock pathogens in the Cooperative Antimicrobial Therapy of Septic Shock (CATSS)Database (1996–2008)

IsolatesAll Septic Shock(n 5 5858) (%)

Neutropenic SepticShock (n 5 297) (%)

Pseudomonas 7.2 13.5

Enterobacter 3.3 3.0

Acinetobacter 1.2 0.7

Serratia 1.2 0.0

Citrobacter 0.8 0.3

Potentially resistant gram-negative bacilli 13.7 17.5

C albicans 4.5 13.5

C glabrata 1.0 1.3

C tropicalis 0.2 1.0

C parapsilosis 0.2 0.7

C krusei 0.1 1.0

C neoformans 0.1 0.0

Other yeast 0.4 1.0

Aspergillus/mucor 0.7 3.4

Blastomyces 0.3 0.0

Fungal pathogens 7.6 21.9

Courtesy of Dr Anand Kumar, MD, Winnipeg, Manitoba, Canada.

Fig. 1. Hospital mortality of patients with candidemia in relation to delay in initiating anti-fungal therapy after the index positive blood culture. Mortality risk climbs with increasingdelays. (Adapted from Morrel M, Fraser VJ, Kollef MH. Delaying the empiric treatment ofCandida bloodstream infection until positive blood culture results are obtained: a potentialrisk factor for hospital mortality. Antimicrob Agents Chemother 2005;49:3640–5; withpermission.)

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intra-abdominal) surgery, or burns; receive parenteral nutrition; are immunocompro-mised (whether in the context of chemotherapy, neutropenia, transplantation, orother); have renal failure; and/or are dialyzed. Prematurity and advanced age alsoconsidered risk factors.10 As if these were insufficient to describe critically ill patients,prolonged ICU stay confers further risk.11

DIAGNOSIS

Diagnosis of candidemia or IC is notoriously challenging. The manifestations of IC arenonspecific. An abnormal culture may correspond to Candida infection or to coloniza-tion. Recovery of Candida species (spp) from a single specimen of normally sterilebody fluid (except urine) in the critically ill establishes a diagnosis of IC or candidemiaif recovered from blood cultures.12 The detection of antigens, such as mannan andb-D-glucan, metabolites (arabinitol et enolase), or antibodies (anti-mannan) as wellas fungal DNA amplification by polymerase chain reaction have been variable ordisappointing in clinicians’ and scientists’ quests to diagnose severe Candida infec-tions in a troponin-equivalent. Until now, these assays have generally showed variablediagnostic utility and are not ubiquitously available. The detection of b-D-glucan andpolymerase chain reaction hold the greatest promise.13

Negative cultures of Candida in any site preclude the diagnosis of a Candida infec-tion. How many Candida- positive sites are required to raise concern about the pres-ence of candidemia/IC is unclear and may depend on patient population. Thepresence of Candida in cultures in up to 4 sites were poorly predictive and were asso-ciated with an only 18% probability of deep invasive infection or candidemia14 in onestudy; however, the number of culture positive sites with Candida is associated withinfection rate, as a percentage greater than 50% of sites is associated with a higherprobability of invasive infection.4 Prophylaxis does not improve outcomes normortalityof IC in highly colonized patients.15 Additional clinical challenges lie in the diagnosticvalue and the interpretation of the presence of Candida in sputum or urine. The pres-ence of Candida in these specimens may be a marker of colonization or deep seated

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infection. In the case of candiduria it may reflect Candida bloodstream infection, orcystitis, whereas in the respiratory tract, it is frequently a marker of airway colonizationand rarely documents deep pulmonary infections. Patients with Candida in theirsputum cultures, however, have a worse prognosis in trials addressing ventilator asso-ciated pneumonia.16 Unfortunately, feasibility of a randomized controlled trial testingthe administration of antifungals to patients with suspected pulmonary Candida infec-tion (CANTREAT17) was not demonstrated, and the question of how to best managethese patients (who are at low risk for a verymorbid disease andmay haveworse prog-nosis, if only sputum cultures are positive for Candida) remains unanswered.Predictive rules for the diagnosis of candidemia and IC in critical care patients have

been modeled in 3 publications. In greater than 1100 patients in 3 countries, a scorewas created whereby surgery, total parenteral nutrition, and multiple colonization(meaning sites where Candida growth could be demonstrated, from wounds, drains,and catheters, or in body fluids) conferred one point, and severe sepsis conferred 2points.18 Patients with a score of less than 3 were unlikely to have Candida. Serumlevels of (1–3)-b-D-glucan (a cell wall panfungal constituent) greater than 75 pg/mLpredicted both candidiasis and response to treatment. In the second study, femalesex, exposure to antibiotics for 48 hours or more, and upper gastrointestinal sourceof peritonitis, as well as perioperative cardiovascular failure, predicted peritonealcandidiasis in a surgical population of more than 220 ICU patients.19 The combinationof ICU stay, abdominal surgery, antibiotic exposure, dialysis, and central lines pre-dicted Candida peritonitis in the third large multicenter study, including more than2800 patients (odds ratio 4.3).20

INFECTION CONTROL

The 2 following principles govern controllingCandida infection: source control and useof antifungals antibiotics.In source control, it is essential to consider central venous catheters as a potential

source of Candida sepsis. The internal lumen of the infected central venous catheterfrom an ICU patient with candidiasis, obtained by scanning electronic microscopy, isshown in Fig. 2; Candida albicans hyphae and coagulase-negative staphylococci areseen embedded in the biofilm.The failure to remove a colonized catheter is strongly associated with mortality in

several studies in the critically ill21,22 and any delay in efforts to do away with a centralline is unjustified. On occasions when venous access catheters removal is impossibleor ill advised, such as in patients with profound thrombocytopenia, administering anti-fungal agents via the catheter lumen daily can be considered a temporary measure.The origin ofCandida can frequently be endogenous from the colonized gastrointes-

tinal tract; 50% of healthy individuals are colonized with Candida species,4 which ex-plains in part why surgical patients with gastrointestinal perforation or interventioninvolving disruption of the gastrointestinal tract are at high risk for Candida peritonitisand Candida sepsis. Gastric, jejunal, and colonic perforations contaminate the perito-neal cavity with Candida 64%, 50%, and 40% to 50% of the time, respectively.23 Thisperitoneal contamination is associated with ICU patient mortality; only appendicularperforations confer a lower risk of such contamination (4%). However, nosocomialperforations seem to be associated with mortality attributable to Candida sepsis,whereas intestinal perforations originating in the community do not.24 Surgicalpatients with candidiasis seem to have a better prognosis,25 perhaps because ofthe higher prevalence of neutropenia, corticosteroid use, and high colonization indicesnoted in the comparative medical population. Patient and health care workers’ skin

Fig. 2. Electron microscope image of the internal lumen of an infected central venous cath-eter from an ICU patient with candidiasis; Candida albicans hyphae and coagulase-negativestaphylococci are seen embedded in the biofilm.

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and hand colonization as a source of infection have been described, and epidemio-logic linked transmission has also been reported.4

THERAPY

The use of antifungal antibiotics in the therapeutic management of IC infections incritically ill patients is based on 3 different strategies of interventions: prophylactic,preemptive, and targeted or definitive treatment.Although azole-based antifungal prophylaxis reduces the event rate of invasive

fungal infections,26 it has not been shown to be useful in the critically ill.27

Preemptive therapy is probably the most commonly used strategy in the ICUsetting. However, the preemptive treatment strategy in the nonneutropenic ICU pa-tient has not been studied adequately. Prospectively most patients do not have a diag-nosis, have a high index of suspicion based on the risk factors described earlier andwarrant catheter removal and early antifungal therapy. Preemptive use of fluconazolemay reduce proven candidiasis in surgical critically ill patients.28 Candida infectionsoccurred more frequently in the historical control cohort (7% vs 3.8%; P 5 .03) andmicrobiologically ICU-acquired proven infections decreased from 2.2% to 0% in theprospective interventional group. However, in the absence of reliable surrogatemarkers, and in the context of the current dearth of efficacy data, preemptive therapyin nonneutropenic patients cannot be advocated at this time in all patients. Despite thedata from patients with Candida-colonized sputum cited earlier, preemptive antifungaltherapy in hemodynamically stable ICU patients does not confer an overall mortalitybenefit when all patients (ie, those with subsequently proven Candida infection andpatients without it [2/3 of the cohort]) are considered in a pooled outcomes analysis.29

Management in the context of shock is less clear; the high probability of havingCandida as a cause for shock (see Table 1) probably warrants early prescriptionand rapid administration of antifungals; when these are given to patients with candi-demia within 2 hours of shock onset, the survival rates exceed 80%.30 Practice

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surveys however suggest that most patients with candidemia with or without shockreceive antifungals on average 35 hours30 after the positive blood culture has beendrawn in North America.Targeted therapy refers to the use of antifungal antibiotics in patient with proven

Candida infection; choice of agent is tempered by 3 considerations: efficacy, cost,and risk.Efficacy against Candida infection should partly be guided by local patterns of

resistance in Candida species, as Candida sp distributions and sensitivities vary bygeographic region,31 over time,32 and in association with factors such as exposureto broad spectrum antibiotics.33 Even though C albicans is the most common path-ogen causing IC, the frequency with which other species, such as Candida glabrataor Candida parapsilosis, which are more likely to be resistant or less sensitive tocertain antifungal antibiotics, should be considered. Of the 5 most common Candidaspecies (albicans, glabrata, parapsilosis, krusei, and tropicalis) collected from candi-demic patients with 779 positive blood cultures from ICUs in 79 medical centersaround the world, none were susceptible to all 6 tested therapeutic agents (Anidula-fungin, Caspofungin, Micafungin, Fluconazole, Posaconazole, and Voriconazole).C albicans was the most common species (393/779, or 51%) and was least likely tobe resistant overall (0.3% to echinocandins, 0 to azoles). Echinocandins were lessassociated with resistant C glabrata (2.2%) than were azoles (4.4%–5.9%). No C tro-picalis were resistant to echinocandins, and resistance to azoles ranged from 1.2% to4.9%. Finally, both C krusei and C parapsilosis isolates were sensitive to all antifungalssave one (Caspofungin and Fluconazole at 6.3% and 6.8%, respectively).34

Although the overall probability of resistance remains low, the narrow physiologicreserve inherent to most critically ill admissions suggests prudence and a comprehen-sive spectrum. The caveat about an IC caused by a less susceptible Candida speciesmust be kept in mind, particularly in patients at higher risk for non-albicans species,such as those afflicted with hematologic malignancies, solid organ transplant recipi-ents, or patients previously exposed to azoles.33,35 Echinocandins are fungicidal andazoles are static. Pivotal studies on Candida bloodstream infection treatment suggestfaster (albeit not statistically significant) fungal bloodstream clearance and more rapidsymptom resolution with echinocandins, as well as higher overall success and survivalrates compared with polyenes and azoles.36 Adverse events and toxicities were alsolesser with echinocandins. Newer triazoles, such as voriconazole, show enhanced ac-tivity against Candida species resistant to fluconazole. However, CYP2C19 geneticpolymorphisms can have substantial impact on its pharmacokinetics. Asians inherita larger proportion of CYP2C19 poor metabolizer gene (15%–20%) in relation to Cau-casians (2%–3%).37,38 Depending on phenotype, subtherapeutic or toxic blood levelsof voriconazole have been documented with similar doses39; serum level monitoringhas now been implemented to temper this drug characteristic in some bone marrowtransplant centers.40 Drug interactions,41 a common problem in the ICU, are particu-larly frequent with azole antifungals. Initial treatment with an echinocandin (anidulafun-gin, caspofungin, micafungin) while awaiting species identification and susceptibilityseems warranted in documented IC. How long antifungals should be administered inthe critically ill has not been weighed with methodologically sound outcome studies;current Canadian recommendations suggest in neutropenic patients at least 48 hoursafter resolution of all infectious symptoms and resolution of the absolute neutrophilcount to greater than 0.5 � 109/L. At least 14 days of antifungal therapy beyondclearance of organisms from bloodstreammust also be completed. In nonneutropenicpatients, at least 14 days after clearance of the Candida from the bloodstream andresolution of all signs and symptoms of infection is recommended.11

Candida in ICU Patients 859

Cost needs to be considered in the selection of antifungal antibiotics. Fluconazoleand amphotericin B are less expensive than the more recently marketed triazolesand echinocandins. Pharmacoeconomic analysis of the risk inherent to the surveil-lance and management of amphotericin B renal toxicity imposes the considerationof an alternative to polyene antifungals.42 Despite their lesser intrinsic toxicitieswhen compared with the Amphotericin B parent compound, the use of lipid prepara-tions of amphotericin B remains risky because of significant nephrotoxicity andhepatotoxicity,29 and proof of any benefit is limited in the critically ill population.

DRUG-DRUG INTERACTIONS

Multiple drugs, among them the opiate fentanyl (FEN) and the sedative benzo-diazepine midazolam (MDZ), are commonly administered in the critical care setting43

and are extensively metabolized by the same CYP450 isoenzymes, namely,CYP3A4/5.44,45 Co-administration of FEN and MDZ, or of either, with other drugssuch as fluconazole metabolized by the CYP3A4/5 isoenzyme46 increases serumdrug levels by competitive inhibition; in addition, the metabolism and excretion ofthese drugs decrease with age.47 FEN and MDZ levels are increased when thesedrugs are administered simultaneously48,49; both increase independently with theco-administration of fluconazole or voriconazole in noncritically ill recipients.The pharmacokinetics and pharmacodynamics of MDZ are predictable in healthy

adults.50 Metabolic clearance in healthy populations is preserved over a relativelynarrow range.51,52 Critical illness influences the pharmacokinetics and pharmacody-namics of midazolam. Plasma levels, half-life, and terminal half-life varied within aconsiderably broader range than that reported in healthy or noncritically ill patients,53

with very broad intrasubject and intersubject variability. In addition, terminal half-life,which is determined after drug infusion cessation, is prolonged in all patients. Thesecharacteristics are also true of the pediatric critical care population54 and thought tobe attributable, among others, to covariates such as renal failure, hepatic failure,and concomitant administration of CYP3A inhibitors such as older and recent anti-fungal azoles. These issues take on particular importance given the growing aware-ness of the morbidity and mortality associated with deep sedation,55 which isunderstood, in the context of multiple drug administration, to be more attributableto drug-drug interactions than to the administration of sedative doses.56

The limited clinical descriptions of drug interactions involving azole family drugs inthe ICU, and their impact in day-to-day clinical practice, are nevertheless compelling.One example of potentially significant interactions is depicted in Fig. 3 (prototypicalindividual patient; unpublished data). Mathematical modeling to project expectedFEN levels based on administered doses and infusion rates failed to predict themeasured FEN levels when fluconazole was being co-administered (such as the indi-vidual whose values in hours 0–50 are shown in Fig. 3). The higher FEN levels corre-lated with deep sedation. The effect was no longer present with similar FEN dosesonce fluconazole was discontinued (>100 hours, Fig. 3). How constant this effect isacross cohorts and with different CYP 450 3A4 inhibitors is not known.Computerized cytochromic interaction alerting software exists to identify potential

drug interactions in vulnerable populations receiving multiple medications. It hasbeen shown to improve detection and adjustment of medication based on identifiedinteractions in geriatric patients.57 In 100 elderly patients receiving 5 or more medica-tions, a total of 238 cytochrome P450 drug-drug interactions were identified, of whichmore than 70% involved CYP3A4. Medication adjustments and follow-up weredeemed to be required in more than 50% of the patients based on the information

Fig. 3. Mathematical modeling to project expected FEN levels based on administered dosesand infusion rates. The graph represents concentrations predicted by the ADAPT-V model(lines) and the observed plasma levels (dots); the peak represents a high predicted concen-tration corresponding to a bolus. Measured FEN plasma levels were significantly higher thanpredicted during hours 0 to 60, while fluconazole was being co-administered. These higherFEN levels correlated with deep sedation (Richmond Agitation and Sedation Scale [RASS]levels of �3 and �4). The effect was no longer present (ie, the levels are about the sameas predicted or a little less) when FEN doses continued to be administered once fluconazolewas discontinued (>100 hours, as depicted in the figure). The increase in measured/pre-dicted levels at about 110 hours is due to an increase in dose of FEN. (From Michaud V,Skrobik Y, Tarasevych V, et al. Population pharmacokinetics of fentanyl during continuousinfusion in patients admitted to the intensive care unit. American Society for ClinicalPharmacology and Therapeutics Meeting. Atlanta, March, 2010; with permission.)

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provided by the software. Similar smart alert or detection systems have not beentested to date in critically ill adults or correlated with clinical outcomes.

SUMMARY

Candidemia and IC are significant and morbid clinical issues in the critically ill.Although much remains to be understood about determinants of disease progressionand Candida species profiling and sensitivities, heightened awareness and educationamong critical care caregivers may help reduce the significant burden associated withthese infections, particularly in patients with septic shock in whom rapid administra-tion of echinocandins appears warranted.

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