Salon a 15 kasim 10.45 12.00 volkan i̇nal

1. Candida;
treat, or not treat...that is the
question
Dr. Volkan İnal

2. WHY?

3. Impact of candidiasis
• 9-12% of all BSI
• 4th nosocomial BSI in US
• 6th in European
• Incidence rised 50 % between 2000 to 2005
• Mortality 35–75 %

4. Impact of candidiasis
• Candida colonisation - hospital admission;
– 22 days (SCOPE)
– 14 days (Paris)
– 19 days (EPIC II)
• 5-15% colonized at ICU admission
• increases with time to 50-80%
• 5-30% of colonized develop invasive candidiasis
• Accounts for up to 17 % of all ICU-acquired infections

5. Impact of candidiasis
• The overall mortality:
– 42.6% (EPIC II)
– 35.2% (PATH)
– 37.9% (ECMM)
– 85.9% (SCOPE)

8. ....inappropriate / late therapy....
• Mortality
– receive appropriate antifungal therapy (< 5%)
– without appropriate therapy (25-40%)
– delayed beyond 12 h after sampling of blood has
been associated with an increase of in-hospital
mortality from < 20% to 40%

11. SOME DEFINITIONS

12. Prophylactic
• Treatment with no evidence of infection
• in selected high risk patients
• in patients with persistent neutropenia
• only for ICUs with a high rate of invasive
candidiasis

13. Empric
• Treatment in the presence of persistent and
refractory fever
• no other known cause of fever
• who are at high risk for fungal infection
• but no microbiological confirmation

14. Pre-emptive
• Treatment initiated in response to one or more biological
markers of infection
• Candida spp. isolated from at least 2 non-contiguous skin and
mucosal sites of high risk patients starting antifungals when
the following conditions are satisfied:
– the presence of long ICU stay (>96 hours)
– broad-spectrum antibiotic therapy
– the presence of any other risk factors
• severe sepsis
• gastrointestinal surgery
• TPN
• microbiological evidence of Candida infection
• multifocal colonisation
• a positive result for serum β-d-glucan

15. • multifocal
• > 7 days
Colonisation
– Gastric aspirates (45.6 %)
– Oropharyngeal (34.3 %)
– Tracheal aspirates (23.4 %)
– Perirectal swabs (21.2 %)
– Urine (18.7 %)
• surveillance cultures
– rectal, urinary, and respiratory cultures; twice a week
– gastric / pharyngeal aspirates / skin rare

16. Colonisation
• Candida colonization
– low grade
– high grade
colonization of at least three body sites
on two or more consecutive occasions

17. Risk Factors

18. • Increasing age
• APACHE score II > 20
• Immunosuppressive therapy, Neoplasia
• Corticosteroids, Neutropenia
• Inadequate / late antifungal therapy

19. • Concomitant bacterial infection, Broad-spectrum
antibiotics
• Diabetes, Renal failure, Hemodialysis
• Recent abdominal surgical procedure
• Parenteral nutrition
• Pancreatitis

20. • Colonization of several body sites
• Burns (> 50%)
• Major trauma (ISS > 20)
• Disruption of physiological barriers in digestive tract
• Surgery of the urinary tract in presence of candiduria

21. • Urinary catheter, Candiduria > 105 cfu/ml
• Central venous catheter
• Prolonged ICU stay (> 7 days)
• Multiple transfusions
• Hands of healthcare workers
• Contaminated IV fluids, hospital food, medical devices

24. Mortality rates and risk factors associated with nosocomial
Candida infection in a respiratory intensive care unit.
Adigüzel N1, Karakurt Z, Güngör G, Yazicioğlu Moçin O, et al. Tuberk
Toraks. 2010;58(1):35-43.
• Nosocomial Candida infections; 163 RICU patients
– Age 65 +/- 15
– Female / Male: 8/18
– Longer ICU stay 48.2 +/- 7.5 days vs. 10.3 +/- 0.8
– Invasive mechanical ventilations
– Central catheters and related infections
– TPN
– Multiple antibiotics
– Ventilator associated tracheobronchitis
– Ventilator associated pneumonia
– Sepsis

25. Evaluation of risk factors in patients with candiduria.
Nayman Alpat S, Özguneş I, Ertem OT, Erben N, et al.
Mikrobiyol Bul. 2011 Apr;45(2):318-24.
• 93 hospitalized patients
– Longer stay in ICU 9.56 ± 9.09
– Nosocomial origin n= 45, 90%
– Higher rate of antibiotic prior to candiduria 86%
– Presence of urinary system intervention
– Catheter use
– Immunosuppression

26. • Surgical
• Longer ICU LOS
• Invasive applications/instrumentations
• Sepsis
• Broad spectrum antibiotics

27. diagnosis

28. • Blood cultures 50% sensitivity, takes 1-3 days
• Beta-D-Glucan
– sensitivity 51 - 100%
– specificity 59 - 98.4%
– false positive due to dialysis, TPN, cardio-pulmonary bypass,
intravenous immunoglobulins, other fungi like Aspergillus, fusarium,
trichosporon etc

29. beta-d-glucan
• adjunct to culture for the diagnosis of IC and is currently
recommended in several guidelines:
– European Organization for Research and Treatment of Cancer/Invasive
Fungal Infections Cooperative Group
– National Institute of Allergy and Infectious Diseases
– Mycoses Study Group (EORTC/MSG)
– European Society of Clinical Microbiology and Infectious Diseases (ESCMDI)
– Society of Critical Care Medicine (SCCM)
– European Society of Intensive Care Medicine (ESICM)

30. • Mannan
– sensitivity 58 - 60%
– specificity 59%
• Anti-mannan
– sensitivity 93 %
– specificity 83 %
• Mannan combined to Anti-mannan
– sensitivity 83%
– specificity 86 %

31. • Antimycelial antibodies (Candida albicans germ
tubespecific antibody CAGTA)
– sensitivity 77–89 %
– specificity 91–100 %

32. • Fungal PCR - Detection of Candida DNA
– provenIC;
• sensitivity 95%
• specificity 92 %,
– probable IC
• sensitivity 85%
• Genetic risk testing mutations, such as the
CARD9 and DECTIN-1 genes

33. ... combinations??
• BG + CAGTA
– sensitivity 90.3 %
– specificity 54.8 %
• Blood culture + BG / PCR
– sensitivity 79 %
– specificity 98 %
• Mn-Anti-Mn
– sensitivity 89.3 %
– specificity 63.0 %
• BDG + mannan antigen
– sensitivity 89.3
– specificity 85.0 %

34. PREDICTION RULES

37. Colonosation Index
CI = non blood cultures/total sites cultured
«blood cultures are not considered»
cCI = cultures with heavy growth/total culture
«+++ / 100.000»
Colonization may turn into invasion
if CI 0.5 or cCI 0.4

38. Leon Score
Clinical Features Score
Sepsis 2
Surgery 1
TPN 1
Multifocal colonization 1
A score of > 2.5 associated with 7x candidemia

39. Ostrosky Zeichner Score
• ICU stay for at least 4 days
• + Antibiotic use
• + Central Venous Catheter
• + any 2 of the following:
Surgery
Total parenteral nutrition(TPN)
Hemodialysis
Pancreatitis
Steroids
Immunosuppression

43. GUIDELINES

44. IDSA 2009

45. IDSA 2009
• Documented Candidemia – Tx
• Empirical Tx critically ill patients with risk factors for invasive
candidiasis and no other known cause of fever, risk factors,
serologic markers, culture data from nonsterile sites
• Empirical Tx suspected invasive candidiasis in neutropenic patients
• Prophylaxis solid-organ transplant recipients, neutropenic patients
receiving chemotherapy, stem cell transplant recipients

46. IDSA 2009
• asymptomatic candiduria NO Tx if low risk group
• symptomatic candiduria with suspected
disseminated candidiasis Tx
• Growth of Candida from respiratory secretions rarely
indicates invasive candidiasis and NO Tx

48. • it is difficult to universally recommend antifungal prophylaxis
• apart from patient groups with a known very high risk
• Antifungal prophylaxis may also be reasonable where local
incidence rates and epidemiology are compelling
• Among stable patients with multifocal Candida colonization
and/or a multitude of clinical-risk factors, preemptive therapy is
currently not indicated
• Among patients with refractory fever despite broad-spectrum
antibacterial therapy, empiric antifungal therapy may be
reasonable where local incidence rates are high (e.g. >10%)

50. ESCMID 2012
European Society for Clinical Microbiology and Infectious Diseases

53. ESCMID 2012 - Diagnosis-driven
approach (pre-emptive)
• Candida isolation from respiratory secretions should
never trigger Tx
• (1,3)-b-D-glucan detection in serum or plasma
prompting antifungal treatment is marginally
supported
• Asymptomatic candiduria should not Tx
• Symptomatic cystitis should be Tx

54. IRANIAN 2013

55. IRANIAN 2013

56. IRANIAN 2013

57. IAC 2013

58. IAC 2013
• Direct microscopy examination for yeast detection from purulent
and necrotic intra-abdominal specimens obtained during surgery or
by percutaneous aspiration is recommended in all patients with
nonappendicular abdominal infections including secondary and
tertiary peritonitis
• Samples obtained from drainage tubes are not valuable except for
study of colonization
• Blood cultures should be taken through peripheral vein punctures
upon diagnosis or suspicion of intraabdominal infections and
tertiary peritonitis, and specific media for fungi are recommended
• Antifungal susceptibility test should be performed on yeast isolates
from blood, sterile sites, and other appropriate specimens

59. IAC 2013
• Systemic antifungal treatment should be considered
when adequate intra-abdominal specimens (obtained
surgically or within 24 h from external drainage) are
positive for Candida, irrespective of the fungal
concentration and the associated bacterial growth
• Positive cultures from drains should not be treated,
especially if the drains are in place for more than 24h

60. IAC 2013
• mannan / antimannan / BDG test should be
performed in patients with secondary or tertiary
peritonitis and at least one specific risk factor for IAC
• Patients with recent abdominal surgery and
recurrent gastrointestinal perforation or
anastomotic leakage should receive Tx

61. IAC 2013
• Empirical antifungal treatment may be considered
in patients with a diagnosis of intra-abdominal
infection and at least one specific risk factor
• In patients with intra-abdominal infection with or
without specific risk factor for Candida infection,
empirical Tx should be administered if a positive
mannan / antimannan or BDG or PCR test result is
present

62. EPICO 2013
Rev Esp Quimioter 2013;26(2):131-150

63. EPICO 2013
• blood cultures at the time of suspected
• use direct vision (microscopy)
• Initiate early Tx
• Echinocandin the first-line
• At least one ophthalmological evaluation

64. EPICO 2.0 2014
Rev Esp Quimioter 2014;27(3): 196-212

65. EPICO 2.0 2014
• Empirical Tx is recommended in secondary
nosocomial peritonitis with risk factors and in
tertiary peritonitis
• Early and appropriate Tx
• Echinocandins
• Neutropenic patients

66. ITALIC 2014

67. ITALIC 2014
• In the asymptomatic patient, the isolation of a
Candida strain from a non-sterile body site (bronchial
aspirate, tracheal aspirate, bronchoalveolar lavage fluid or
sputum) should not prompt any Tx and should be
merely considered as colonisation
• Antifungal prophylaxis should not be administered in
non-immunocompromised

68. ITALIC 2014
• However, in a patient with signs and symptoms of
infection, multiple Candida colonisation, including
isolation from urine in a patient fitted with a bladder
catheter, might be suggestive of a Candida infection
and might prompt Tx

69. ITALIC 2014
• The repeated isolation of Candida from fluids
obtained from a surgical drainage should not be
underestimated and should prompt additional
investigations, even in the absence of clinical signs
and symptoms
• The same applies to Candida isolation from
peritoneal fluids in a patient undergoing peritoneal
dialysis

70. ITALIC 2014
• BDG is diagnostic
• results should be interpreted in the presence of
other risk factors and the patient’s clinical
conditions
• There is insufficient evidence to recommend the use
of the BDG test as a screening tool in patients
without symptoms

71. ITALIC 2014
• The mannan/antimannan detection test may be
useful for the diagnosis of IC
• The separate detection of either mannan or
antimannan cannot be recommended

72. ITALIC 2014
• Echocardiography persistent candidaemia to rule out
Candida endocarditis
• Fundoscopic examination should be performed and
possibly repeated in every patient with IC to rule out
chorioretinitis and endophthalmitis

76. NOT support the use of antifungal treatment in patients
with VAP and Candida in the endotracheal secretions

78. What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Cristo´bal Leo´n, Luis
Ostrosky-Zeichner, Mindy Schuster. Intensive Care Med (2014) 40:808–819.

79. Antifungal agents
for preventing fungal infections
in non-neutropenic critically ill patients
• included 12 unique trials (eight comparing fluconazole and
four ketoconazole with no antifungal or a nonabsorbable
agent) involving 1606 randomized patients
• Prophylaxis with fluconazole or ketoconazole in critically ill
patients reduces invasive fungal infections by one half and
total mortality by one quarter
• In patients at increased risk of invasive fungal infections,
antifungal prophylaxis with fluconazole should be considered
Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients (Review)
Copyright © 2012 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

80. Routine / selective antifungal administration
for control of fungal infections
in patients with cancer
• 32 trials, 4287 patients were included
• Intravenous Amphotericin-B was the only antifungal agent
that reduced total mortality
• It should therefore be preferred when prophylactic or
empirical antifungal therapy is introduced in cancer patients
with neutropenia
Routine versus selective antifungal administration for control of fungal infections in patients with cancer (Review)
Copyright © 2014 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

81. Nystatin prophylaxis and treatment
in severely immunodepressed patients
• 14 trials (1569 patients)
• People on chemotherapy for cancer, receiving a transplant or
with AIDS are at risk of fungal infections (lifethreatening)
• The review found that nystatin was no better than placebo
(no treatment)
Nystatin prophylaxis and treatment in severely immunodepressed patients (Review)
Copyright © 2014 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

82. Antifungal agents
for preventing fungal infections
in solid organ transplant recipients
• 14 unique trials with 1497 randomised participants were
included
• antifungal prophylaxis with fluconazole significantly reduces
the incidence of IFIs with no definite mortality benefit
• In transplant centres where the incidence of IFIs is high, or in
situations where the individual risk is great, antifungal
prophylaxis should be considered
Antifungal agents for preventing fungal infections in solid organ transplant recipients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

83. To takeaway

85. Thanks