When should an antifungal be started empirically

in severe community acquired sepsis?

18th Infection and Sepsis Symposium
Porto, 27/2 to 1/3/2013
Pedro Pvoa
Professor of Medicine
Medical Sciences Faculty
New University of Lisbon
Polyvalent Intensive Care Unit
So Francisco Xavier Hospital
Lisbon, Portugal

Disclosures
Potential conflicts of interest:
Honoraries and member of advisory board of
Astra Zeneca, Ely-Lilly, Gilead, Janssen-Cilag,
Merck Sharp & Dohme, Novartis and Pfizer
Research grants (unrestricted) from Gilead,
Brahms/ThermoFisher Scientific and Virogates

When should an antifungal be started

empirically in severe CAS?
Concepts and definitions
CAS:
Community-acquired infection is defined as the onset of
an infection before hospital admission or not present at
admission but becoming evident in the first 48 hrs

Severe CAS:
CAS complicated with organ dysfunction

Garner JS In: APIC Infection Control and Applied Epidemiology: Principles and
Practice. Olmsted RN (ed). St. Louis, Mosby, 1996; pp A1A20
Bone CCM 1992;20:864874

When should an antifungal be started

empirically in severe CAS?

Possible scenarios:
In a general UCI patient population
In a medical UCI patient population
In a surgical UCI patient population
In a onco/hematologic ICU patient population

When should an antifungal be started empirically in severe CAS?

In a general UCI patient population

Additional questions
Why should an antifungal be started empirically in severe
CAS?
Is the incidence of fungal CAS increasing?
Currently, what is the rate of fungal CAS?
Because time is lives!

What diagnostic tests are used in ICU and how helpful are
they for the diagnosis of a fungal infection?

When
shouldan
anantifungal
antifungalbe
be
Why should
started empirically in severe
community acquired sepsis?
Because prevalence of invasive
candidiasis is increasing and it carries
a high morbidity and mortality!

Host factors and

the incidence of invasive mycosis
Last decades marked change in the patient population leading
to an increasing number of patients at risk of invasive mycosis

Longevity (older age group)

More complex surgery
Aggressive chemotherapy
Marked immunosuppressive therapy
Mortality from chronic diseases

Epidemiology of sepsis: 1979-2000

1979 to 2000 - 8.7%/yr

Cost per candidemia episode 90.000 USD
Martin G NEJM 2003;348:1546
Rentz AM CID 1998;27:781
Hermsen Crit Care 2011;15:R198

Nosocomial BSI in US hospitals

analysis of 24,179 cases
Candida 4th most common cause of BSI in ICUs in USA

N=1890 candida BSI

Wisplinghoff CID 2004; 39:30917

EPIC II
1265 ICU
14141 pts (50.9% infected) mortality 12%
Nosocomial infections not analyzed as a subgroup
69.6% of infected pts with positive cultures

JAMA 2009; 302:2323

EPIC II

N=67 (8%)

1.4% of the 4947 documented (nosocomial and community-acquired) infections

In hospital mortality Candida OR 1.1 (95% CI: 0.92-1.32, p=0.308)

JAMA 2009; 302:2323

SAC i UCI

897 CAS - ICU admitted

40% positive cultures (N=364)

Absolute and relative frequency of the

12 most frequently isolated microbes, n (%)
Streptococcus pneumoniae
110
Escherichia coli
95
Staphylicoccus aureus meticilino sensivel
64
Klebsiella pneumoniae
34
Haemophilus influenzae
25
Enterococcus faecalis
17
Staphylococcus aureus meticilino resistente
16
Pseudomonas aeruginosa
15
Candida albicans
12
Legionella pneumophila
12
Proteus mirabilis
11
Mycobacterium tuberculosis
9
Others
102

(21)
(18)
(12)
(7)
(5)
(3)
(3)
(3)
(2)
(2)
(2)
(2)
(20)

>60%

INFAUCI
INFeco na Admisso UCI
15 ICU, May 2009 to May 2010
1556 pts with infection at admission (44%)
Documented infections
N=751 (24% polimicrobial)

Microorganisms, N=963; CAS 29%

From the total 4% fungi mycobacteria
Not only Candida
25 intra-abdominal , 9 BSI and 8 respiratory samples
CAS (7 intra-abdominal, 1 BSI) 2.5% fungi
Cortesy of J. G. Pereira

Invasive Mycosis
UCIP 2008-2012
2008

2009

2010

2011

2012

Patients (N)

299

312

247

285

302

Infections (N)

158

227

191

167

177

Invasive Candidiasis* (% of pts total N)

1.0

0.3

1.2

0.7

1.0

Invasive Candidiasis* (% of infections total N)

1.9

0.4

1.6

1.2

1.7

Invasive Candidiasis
CVC related candidemia

CVC
1
5 infected
year-period,
920 septic patients, N=16 (1.7%)
had an invasive mycosis
primary candidemia

Candida peritonitis with/without candidemia

Majority were not community-acquired!

pneumonia in immunosuppresed pt (BAL)

2
1

Invasive Candidiasis (N)

Candida albicans

Candida non-albicans
Aspergilosis
Aspergillus fumigatus
Aspergullis flavus
Aspergillus candidus

* Respiratory (tracheal aspirates and BAL) and urinary isolates are considered colonization

1
1

Incidence of fungal CAS

Is incidence really increasing? What is the true
significance? No consensus.
Rate of fungal CAS - <2% (tuberculosis and MRSA!)
We should also ask:
when should an antimycobacterial agent be started empirically
in severe CAS?
when should vancomycin be started empirically in severe CAS?

Time is lives!
Retrospective (N=157)
therapy >12h: OR mortality 2.09 (p=0.018)

Morrel AAC 2005;49:3640

Retrospective (N=230)
Mortality (d0, d1, d2, d3) p=0.009

Garey CID 2006;43:25

Pre-emptive or empiric therapy in high risk patients

Empiric Antimicrobial Therapy

Key of Success

HIT THE FIRST MOVE!

early empiric therapy with fluconazole was not shown to be beneficial

in an ICU population with an incidence of invasive candidiasis of 9%!
Pittet Ann Surg 1994, 220:751

Contradiction?
EPIC II
Candidiasis without
significant correlation
with hospital mortality!
JAMA 2009; 302:2323

The later the start of

antifungal therapy the
higher the mortality!
Garey CID 2006;43:25
Morrel AAC 2005;49:3640

Problem colonization vs. infection

Question what is the true rate of fungal infections?
Pretest probability!

When should an antifungal be started empirically in severe CAS?

In a general UCI patient population

Additional questions
Why should an antifungal be started empirically in severe
CAS?
Is the incidence of fungal CAS increasing?
Currently, what is the rate of fungal CAS?
Because time is lives!

What diagnostic tests are used in ICU and how helpful are
they for the diagnosis of a fungal infection?

Invasive Candidiasis
Risk Factors
1. Neutropenia
2. Diabetes mellitus
3. HIV/AIDS
4. Common variable immunodeficiency
5. Myeloperoxidase deficiency
6. Broad spectrum antibiotic therapy
7. Central venous catheters
8. Major Surgery
9. Parenteral nutrition
9. Transplantation
10. Low birth weight newborns
11. Severe disease (medical/surgical)
12. IV drug abuse
13.

And some are also known

risk factors for tuberculosis
and MRSA!

A Candida is documented!
colonization

infection

Diagnosis problems
Cultures
Blood cultures ( sensitivity, specificity; but slow growth)
Limited value of Candida detection in other samples (wound
exudates, urine, trachea and BAL, )
Tissue cultures

Histopathology
Almost always not possible to obtain (slow results)

Radiology
specificity

New methods
Detection of mannan and -glucans ( sensitivity, specificity)
Detection of Candida DNA by real-time PCR (interpretation??)

Diagnosis problems
These () data offer new perspectives for early
diagnosis of Candida infections, but continued
evolution of these assays will be required before they
can be used routinely.
Pappas CID 2009;48:503-35

Patients with mycosis without antifungal therapy

Patients without mycosis with antifungal therapy

Pretest probability!
Pretest probability can also be thought of as the
prevalence of a disease: the proportion of people
with the target disorder in the population at risk at a
specific time.
Present situation:
What is the prevalence of Candida CAS (not colonization) in
the general ICU patient population?

Overestimated
Dependent of the case-mix
(ex. immunosuppression)

Additional diagnostic information given

by the test/score
Bayesian analysis formal way of doing explicitly what most
clinicians do implicitly (how do we interpret the results of a diagnostic test
in light of the clinical situation?).
Basic paradigm: What was thought before the test was done
combined with the test result what is thought after the test
result (probability that the disease is present, given that the test is positive)
This paradigm can be converted as follows:
What was thought before the test was done = pretest probability of
disease (prevalence)
The test result = likelihood ratio (LR)
What is thought after = post test probability (PPV)

Post-test probability positive predictive value (example of candida infection)

Specificity as good as possible for rare events

Sensitivity as good as possible for frequent events

Diagnosis problems
Identify pts that may benefit from early empiric antifungal
therapy
Difficulties in diagnosis; develop of a score!
Is this the final solution?
Whats the best score?

5 Candida scores

Seville score Leon C

Paphitou NI
Ostrosky-Zeichner L
MSG
NMC

Candida Scores
Present low PPVs and high NPVs more useful for
identifying patients who are not likely to develop
invasive candidiasis, potentially preventing
unnecessary antifungal use (Hermsen Crit Care 2011;15:R198)
Not designed and not useful for CAS

Surveillance cultures
TPN
CVC

Key of Success
adapt to each local reality

Yu Chest 2000;117:1496

() the prevailing approach of wait

and see and treat early will probably
continue to be followed ()

NEJM 2007;356:2525

When should an antifungal be started

empirically in severe CAS?

In the great majority of severe CAS

Almost NEVER;
In particular severe CAS patients with several high
risk factors (ex. gastroduodenal perforation with late source control)
Consider empirical antifungal;
Stop early if cultures are negative.

The essence of wisdom is the ability to

make the right decision on the basis of
inadequate evidence.
Alan Gregg