Professional Documents
Culture Documents
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 factors
improves its accuracy.
Understanding local candida infection prevalence and resistance patterns is useful in
clinical decision-making.
INTRODUCTION
RISK FACTORS
Patients are at greater risk for Candida infection if they have been exposed to
broad-spectrum antibiotics; have diabetes, central lines, extensive (particularly
Table 1
Septic shock pathogens in the Cooperative Antimicrobial Therapy of Septic Shock (CATSS)
Database (1996–2008)
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 increasing
delays. (Adapted from Morrel M, Fraser VJ, Kollef MH. Delaying the empiric treatment of
Candida bloodstream infection until positive blood culture results are obtained: a potential
risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49:3640–5; with
permission.)
DIAGNOSIS
INFECTION CONTROL
The 2 following principles govern controlling Candida infection: source control and use
of 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 catheter
from an ICU patient with candidiasis, obtained by scanning electronic microscopy, is
shown in Fig. 2; Candida albicans hyphae and coagulase-negative staphylococci are
seen 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 central
line is unjustified. On occasions when venous access catheters removal is impossible
or 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 of Candida 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 intervention
involving disruption of the gastrointestinal tract are at high risk for Candida peritonitis
and 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 This
peritoneal contamination is associated with ICU patient mortality; only appendicular
perforations confer a lower risk of such contamination (4%). However, nosocomial
perforations seem to be associated with mortality attributable to Candida sepsis,
whereas intestinal perforations originating in the community do not.24 Surgical
patients with candidiasis seem to have a better prognosis,25 perhaps because of
the higher prevalence of neutropenia, corticosteroid use, and high colonization indices
noted in the comparative medical population. Patient and health care workers’ skin
Candida in ICU Patients 857
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-negative
staphylococci are seen embedded in the biofilm.
and hand colonization as a source of infection have been described, and epidemio-
logic linked transmission has also been reported.4
THERAPY
surveys however suggest that most patients with candidemia with or without shock
receive antifungals on average 35 hours30 after the positive blood culture has been
drawn 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 by
geographic region,31 over time,32 and in association with factors such as exposure
to 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 glabrata
or Candida parapsilosis, which are more likely to be resistant or less sensitive to
certain antifungal antibiotics, should be considered. Of the 5 most common Candida
species (albicans, glabrata, parapsilosis, krusei, and tropicalis) collected from candi-
demic patients with 779 positive blood cultures from ICUs in 79 medical centers
around 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 to
be resistant overall (0.3% to echinocandins, 0 to azoles). Echinocandins were less
associated 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% to
4.9%. Finally, both C krusei and C parapsilosis isolates were sensitive to all antifungals
save one (Caspofungin and Fluconazole at 6.3% and 6.8%, respectively).34
Although the overall probability of resistance remains low, the narrow physiologic
reserve inherent to most critically ill admissions suggests prudence and a comprehen-
sive spectrum. The caveat about an IC caused by a less susceptible Candida species
must 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 and
azoles are static. Pivotal studies on Candida bloodstream infection treatment suggest
faster (albeit not statistically significant) fungal bloodstream clearance and more rapid
symptom resolution with echinocandins, as well as higher overall success and survival
rates compared with polyenes and azoles.36 Adverse events and toxicities were also
lesser with echinocandins. Newer triazoles, such as voriconazole, show enhanced ac-
tivity against Candida species resistant to fluconazole. However, CYP2C19 genetic
polymorphisms can have substantial impact on its pharmacokinetics. Asians inherit
a 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 levels
of voriconazole have been documented with similar doses39; serum level monitoring
has now been implemented to temper this drug characteristic in some bone marrow
transplant 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 susceptibility
seems warranted in documented IC. How long antifungals should be administered in
the critically ill has not been weighed with methodologically sound outcome studies;
current Canadian recommendations suggest in neutropenic patients at least 48 hours
after resolution of all infectious symptoms and resolution of the absolute neutrophil
count to greater than 0.5 109/L. At least 14 days of antifungal therapy beyond
clearance of organisms from bloodstream must also be completed. In nonneutropenic
patients, at least 14 days after clearance of the Candida from the bloodstream and
resolution of all signs and symptoms of infection is recommended.11
Candida in ICU Patients 859
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 drugs
such as fluconazole metabolized by the CYP3A4/5 isoenzyme46 increases serum
drug levels by competitive inhibition; in addition, the metabolism and excretion of
these drugs decrease with age.47 FEN and MDZ levels are increased when these
drugs are administered simultaneously48,49; both increase independently with the
co-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 relatively
narrow range.51,52 Critical illness influences the pharmacokinetics and pharmacody-
namics of midazolam. Plasma levels, half-life, and terminal half-life varied within a
considerably 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. These
characteristics are also true of the pediatric critical care population54 and thought to
be 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 is
understood, in the context of multiple drug administration, to be more attributable
to drug-drug interactions than to the administration of sedative doses.56
The limited clinical descriptions of drug interactions involving azole family drugs in
the ICU, and their impact in day-to-day clinical practice, are nevertheless compelling.
One example of potentially significant interactions is depicted in Fig. 3 (prototypical
individual patient; unpublished data). Mathematical modeling to project expected
FEN levels based on administered doses and infusion rates failed to predict the
measured 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 doses
once fluconazole was discontinued (>100 hours, Fig. 3). How constant this effect is
across 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 has
been shown to improve detection and adjustment of medication based on identified
interactions 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 which
more than 70% involved CYP3A4. Medication adjustments and follow-up were
deemed to be required in more than 50% of the patients based on the information
860 Skrobik & Laverdiere
Fig. 3. Mathematical modeling to project expected FEN levels based on administered doses
and 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 than
predicted during hours 0 to 60, while fluconazole was being co-administered. These higher
FEN 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 same
as predicted or a little less) when FEN doses continued to be administered once fluconazole
was 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 continuous
infusion in patients admitted to the intensive care unit. American Society for Clinical
Pharmacology and Therapeutics Meeting. Atlanta, March, 2010; with permission.)
provided by the software. Similar smart alert or detection systems have not been
tested 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 progression
and Candida species profiling and sensitivities, heightened awareness and education
among critical care caregivers may help reduce the significant burden associated with
these infections, particularly in patients with septic shock in whom rapid administra-
tion of echinocandins appears warranted.
REFERENCES
37. Chen L, Qin S, Xie J, et al. Genetic polymorphism analysis of CYP2C19 in Chi-
nese Han populations from different geographic areas of mainland China. Phar-
macogenomics 2008;9(6):691–702.
38. Kimura M, Ieiri I, Mamiya K, et al. Genetic polymorphism of cytochrome P450s,
CYP2C19, and CYP2C9 in a Japanese population. Ther Drug Monit 1998;20(3):
243–7.
39. Scholz I, Oberwittler H, Riedel KD, et al. Pharmacokinetics, metabolism and
bioavailability of the triazole antifungal agent voriconazole in relation to
CYP2C19 genotype. Br J Clin Pharmacol 2009;68(6):906–15.
40. Trifilio SM, Yarnold PR, Scheetz MH, et al. Serial plasma voriconazole concentra-
tions after allogeneic hematopoietic stem cell transplantation. Antimicrob
Agents Chemother 2009;53(5):1793–6.
41. Mikus G, Scholz IM, Weiss J. Pharmacogenomics of the triazole antifungal agent
voriconazole. Pharmacogenomics 2011;12(6):861–72.
42. Abele-Horn M, Kopp A, Sternberg U, et al. A randomized study comparing flu-
conazole with amphotericin B/5-flucytosine for the treatment of systemic
Candida infections in intensive care patients. Infection 1996;24(6):426–32.
43. Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, an-
algesics, and neuromuscular blocking agents in critically ill patients. Crit Care
Med 2006;34(2):374–80.
44. Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic,
by human liver microsomes. Role of CYP3A4. Drug Metab Dispos 1996;24(9):
932–9.
45. Gorski JC, Hall SD, Jones DR, et al. Regioselective biotransformation of mida-
zolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Bio-
chem Pharmacol 1994;47(9):1643–53.
46. Saari TI, Laine K, Neuvonen M, et al. Effect of voriconazole and fluconazole on the
pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol 2008;64(1):25–30.
47. Greenblatt DJ, Abernethy DR, Locniskar A, et al. Effect of age, gender, and
obesity on midazolam kinetics. Anesthesiology 1984;61(1):27–35.
48. Hamaoka N, Oda Y, Hase I, et al. Propofol decreases the clearance of midazo-
lam by inhibiting CYP3A4: an in vivo and in vitro study. Clin Pharmacol Ther
1999;66(2):110–7.
49. McKillop D, Wild MJ, Butters CJ, et al. Effects of propofol on human hepatic
microsomal cytochrome P450 activities. Xenobiotica 1998;28(9):845–53.
50. Albrecht S, Ihmsen H, Hering W, et al. The effect of age on the pharmacokinetics
and pharmacodynamics of midazolam. Clin Pharmacol Ther 1999;65(6):630–9.
51. Malacrida R, Fritz ME, Suter PM, et al. Pharmacokinetics of midazolam admin-
istered by continuous intravenous infusion to intensive care unit patients. Crit
Care Med 1992;20:1123–6.
52. Dresser GK. Coordinate induction of both cytochrome P4503A and MDR1 by
St John’s wort in healthy subjects. Clin Pharmacol Ther 2003;73:41–50.
53. Ovakim D, Bosma KJ, Young GB. Effect of critical illness on the pharmacoki-
netics and dose-response relationship of midazolam. Crit Care Med 2012;
16(Suppl 1):330.
54. de Wildt SN, de Hoog M, Vinks AA, et al. Population pharmacokinetics and
metabolism of midazolam in pediatric intensive care patients. Crit Care Med
2003;31(7):1952–8.
55. Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts
long-term mortality in ventilated critically ill patients. Am J Respir Crit Care
Med 2012;186(8):724–31.
864 Skrobik & Laverdiere