gestione pratica delle infezioni fungine in terapia intensiva epidemiologia, fattori di rischio e...

Gestione pratica delle infezioni fungine in terapia intensiva

Epidemiologia, fattori di rischio e diagnosi delle infezioni

fungine in terapia intensiva

Nicola Petrosillo

UOC Infezioni Sistemiche e dell’ImmunodepressoIstituto Nazionale per le Malattie Infettive

“Lazzaro Spallanzani

SIMIT 2010

•The bulk of literature about IA involves patients with classic risk factors for IA, such as prolonged neutropenia and hematopoietic stem cell transplantation.

•However, a broad group of patients who are admitted to ICUs may also be susceptible to these infections.

Invasive Aspergillosis (IA) in the ICU

IS IA A PROBLEM IN THE ICU?

•Estimates about the incidence of IA among critically ill patients are sparse and variable.

•For various reasons, figures about the true incidence of IA are difficult to generate: 1. discrimination between colonization and infections remains challening; 2. few istitutions perform autopsies routinely; 3. characteristic radiological signs of IA are usually absent in the nonneutropenic ICU patient. 4. diagnostic utility of non-culture based microbiological tools has not been properly validated in the nonhematology ICU population; 5. EORTC/MSG guidelines were not designed for patient categories other than patients with cancer and patients who have undergone bone marrow transplantation

Retrospective autopsy-controlled studies

•127 (6.9%) of 1850 hospitalized patients had microbiologic or histopathologic evidence of aspergillosis during their ICU stay, including 89 cases (70%) in which there was not an underlying hematological malignancy.

•The observed mortality rate of 80% was much higher than the mortality rate predicted on the basis of the Simplified Acute Physiology Score II (48%).

Meersseman W et al. Am J Respir Crit Care Med 2004;170:621–5

•A study sought unsuspected causes of death in a ICU revealed that, among 100 autopsies, there were 15 cases of IA, of which 5 were missed before death.

Roosen J et al. Mayo Clin Proc 2000; 75:562–7.

•IA prevalence in pts with septic shock 0.3%(Vandewoude KH et al. Crit Care 2006; 10:R31).

• High prevalence of IA (pathologic and/or microbiologicevidence of aspergillosis) in a cohort of patients withsevere hospital-acquired pneumonia who had been admitted to the ICU 13 (19%) of 67 episodes of IA in the ICU(Valles et al. Intensive Care Med 2003; 29:1981–8).

•During a 6-year period, Cornillet et al. found that a mean number of 15 patients per year received a diagnosisof IA; approximately one-half of these patients were in the ICU.(Cornillet A et al. Clin Infect Dis 2006; 43:577–84).

Other epidemiological data on IA in the ICU

WHO IS AT RISK OF DEVELOPING IA

IN THE ICU?

Meersseman W et al. Clin Infect Dis 2007; 45: 205-16

Which diseases are associated to IA in

the ICU?

COPD AND ASPERGILLOSIS

Lin SJ et al. Clin Infect Dis 2001; 32: 358-66

• In a review of 50 studies, COPD was the underlying condition in 26 out of 1,941 (1.3%) patients with aspergillosis

• In one large study, 9% of 595 patients with IA sufferedfrom pulmonary disease Patterson TF et al. Medicine 2000; 79: 250-60

• Steroids are believed to play a role in the emergence of IA, and some authors have investigated the correlation between the daily dose of corticosteroids and the probability of developing IA Leav BA et al. N Engl J Med 2000; 343: 586

Samarakoon P et al. Chronic Resp Dis 2008; 5: 19-27

Tools for diagnosis of invasive aspergillosis

and their applicability in the ICU

CT

Halo sign sign arrives too early (5 days before the onset of disease). Not specific for Aspergillus spp (also other molds)

Crescent sign obscured by atelectasis, ARDS, and/or pleural effusion.

CT often is not feasible in a patient with a high fraction of inspired oxygen

Balloy V et al. Infect Immun 2005; 73: 494-503

Bulpa P et al. Eur Respir J 2007; 30: 782-800

Histopathologic evidence[acutely branching (45°), septated hyphae

mainly in lung tissue]

It is a global standard for ICURoosen J et al. Mayo Clin Proc 2000; 75: 562-7 100 IAMeersseman W et al. Am J Respir Crit Care 2004; 170:621-5 129 IA

However, biopsies often are not feasible inpatients with thrombocytopenia or a high fractionof inspired oxygen

Culture(Sabouraud agar)

•Poor sensitivity and specificity.

•Isolation of the species takes several days.

•50% of cases are missed on the basis of culture•and microscopy findings.

•Discrimination of colonization versus invasive•disease is difficult

•Positive predictive value increases with increasedimmunosuppression.

Direct microscopy

• PAS, Grocott stain, calcofluor visualization of hyphal elements (not only Aspergillus spp), rapid test.

• Same problems of Culture

Galactomannan serum assay(threshold, 0.5-1.5 ng/mL)

• Tested mainly for haematologic non-ICU patients

• False positive (Pip/Taz)

• In the nonneutropenic critically ill patients, BAL may perform better than serum

Meersseman W et al. Am J Respir Crit Care Med 2008; 177:27-34

•Paziente con COPD in terapia cronica steroidea. •Ricovero in ICU per esacerbazione di COPD ed insufficienza respiratoria.

•BAL colturale positivo per Haemophilus influenzae e negativo per funghi.

•Galattomannano serico negativo, ma positivo su BAL.

•Trattato con terapia antiaspergillare, ma deceduto.

•Autopsia aspergillosi limitata al polmoneMeersseman W et al. Clin Infect Dis 2007; 45: 205-16

PCR

• PCR holds promise for patient with haematologic malignancy, but has not been systematically studied for the diagnosis of IA in the ICU

• In the nonneutropenic, critically ill patient, BAL may perform better than blood

• PCR of respiratory secretion specimens as a modality of surveillance is an interesting topic of research

Beta-(1,3)D-glucan

• hampered by false positive results (albumin, wound gauze, hemodialysis, bacterial infection).

• Not specific for Aspergillus spp; also present in yeasts and bacteria

• May be useful as a negative predictor of fungal infection

What is the meaning of Aspergillus colonization?

Khaasawneh F et al. J Crit Care 2006; 21: 322-7

Bouza E et al. J Clin Microbiol 2005; 43:2075-9

Candida in ICU

Suspected invasive candidiasis in the ICU

An invasive Candida infection is typically considered when a febrile nonneutropenic patient in the ICU who has some risk factors for Candida infection

•vascular access, •administration of TPN, •the receipt of corticosteroids, •therapy using broad-spectrum antimicrobial agents,•recent surgery, •a prolonged stay in the ICU, •colonization with Candida

fails to respond to broad-spectrum antibacterial therapy

De Pauw BE et al. Clin Infect Dis 2008; 45: 1813-21

Rapid progression of IC: a reason for suspecting Candida infection in the ICU

Garey KW et al. Clin Infect Dis 2006; 43:25-31

Day to start of fluconazole

Delay in starting antifungal therapy is an independent determinant of hospital mortality in pts with candidemia

Morrell M et al. Antimicrob Agents Chemother 2005; 49:3640-5

Marriot DJE et al. Critical Care 2009; 13: R115

• The past two decades have marked a dramatic rise in the frequency of infections caused by Candida species.

• 1% to 8% of patients residing in the hospital develop invasive candidiasis versus 10% of patients residing in ICUs

(Eggimann P et al. Lancet Infect Dis 2003; 3:685–702).

• Invasive candidiasis accounts for up to 15% or 30% of all nosocomial infections in critically ill patients.

(Eggimann P et al. Lancet Infect Dis 2003; 3:685–702; Magnason S et al. Acta Anaesthesiol Scand 2008;52: 1238–45)

Candida in the ICU- epidemiology-

•About 80% of cases of candidemia arise from or evolve in the presence of a vascular access, including access related to central venous catheters, hemodialysis catheters, peripherally inserted central catheters, and implanted ports.

•An estimated 33% to 55% of all episodes of candidemia occur in patients in the ICU, and the associated mortality rates range from 5% to 71%.

Candida in the ICU- epidemiology-

Ben-Ami R et al. J Clin Microbiol 2008;46:2222–6Bouza E et al. Int J Antimicrob Agents 2008;32(Suppl 2):S87–91.

Candida in the ICURisk factors

•Two main factors predispose to infections with Candida spp.: - colonization of skin and mucous membranes with Candida and - alteration of natural host barriers (wounds, surgery, and insertion of indwelling intravascular and urinary catheters).

•The gastrointestinal tract, the skin and the urogenital tract are the main portals of entry for Candida infections.

•Since 1994, colonization by Candida spp. has been established as a major risk factor for invasive candidiasis [Pittet D et al. Ann Surg 1994; 220:751-758].

Candida in the ICU- Risk factors-

Risk factors for candidemia in patients in the ICU include: •the use of intravascular catheters, •parenteral nutrition, •prior abdominal surgery, •the use of broad-spectrum antibacterial therapy,•the use of corticosteroids, •acute renal failure, •a prolonged stay in the ICU, •and Candida colonization, particularly if it is multifocal.

Bouza E et al. Int J Antimicrob Agents 2008;32(Suppl 2):S87–91.

Leroy O et al. Crit Care Med 2009; 37: 1612-18

Bassetti M et al. BMC Infect Dis 2006; 6: 21

Bassetti M et al. J Antimicrob Chemother 2009; 64: 625-29

Bassetti M et al. BMC Infect Dis 2006; 6: 21

0

5

10

15

20

25

30

1999 2000 2001 2002 2003

C albicansC parapsilosisC glabrataC tropicalisother Cand

#

Epidemiology of Candidaemia in Europe: Results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study

Tortorano AM et al. Eur J Clin Microb Infect Dis 2004; 23: 317-22

Lee I et al. Arch Intern Med 2009; 169: 379-83

• 76 pts with Fl-R C glabrata BSI• 68 pts with Fl-S C glabrata BSI• 512 controls

Leroy O et al. Crit Care Med 2009; 37: 1612-8

In vitro susceptibility to fluconazole of Candida species inpatients naive for azole agents and in previously exposed toazole agents

S= susceptible S-DD= susceptible dose dependantR= resistant

Epidemiology of Candidaemia in Europe: Results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study

Tortorano AM et al. Eur J Clin Microb Infect Dis 2004; 23: 317-22

Mortality rates by etiological agent

05

1015202530354045

C albicans

C glabrata

C parapsilosis

C tropicalis

Leroy et al. Critical Care 2010, 14:R98

Prospective, observational, multicenter, French study conducted from October 2005 to May 2006

•Among the 136 patients analyzed, 78 (57.4%) had candidemia caused by C. albicans.

•These patients had -earlier onset of infection (11.1 ± 14.2 days after ICU admission vs. 17.4 ± 17.7, p = 0.02), -higher severity scores on ICU admission (SOFA: 10.4 ± 4.7 vs. 8.6 ± 4.6, p = 0.03; SAPS II: 57.4 ± 22.8 vs. 48.7 ± 15.5, P = 0.015), and -were less often neutropenic (2.6% vs. 12%, p = 0.04)

than patients with candidemia due to non-albicans Candida species.

Role of Colonization

Candida Colonization of the Respiratory Tract and Subsequent Pseudomonas Ventilator-Associated Pneumonia Azoulay E et al, Chest, 2006

In 803 immunocompetent critically ill patients receiving MV for > 2 days, the incidence of pneumonia in patients with and without respiratory-tract Candida colonization was compared. Patients were matched on study center, admission year, and MV duration.

24,1

9

39,7

17,6

4,88,3

%

VAP PseudomonasVAP

extra pulmonarycandida

colonized no-colonized

OR 2.22

(95% CI 1.00-4.92)

OR 1.58

(95% CI 0.94-2.68)

Troughton JA et al. J Infect 2010;61:403-409

974 patients; 46 patients with candidaemia and 928 with colonisation.


•A higher proportion of blood isolates were Candida glabrata compared with non-sterile isolates (16/46 vs 106/1062; p < 0.001),

•similarly a greater proportion of blood isolates were fcz-resistant compared with non-sterile isolates (15/46 vs 101/1062; p < 0.001).


•C. glabrata candidaemia was more likely to occur in the absence of non-sterile site colonisation compared with non-glabrata candidaemia (12/16 vs 8/30; p < 0.005).

•Of candidaemic patients, 43% had no preceding colonisation by any Candida spp.; in 67% of these patients, candidaemia was due to C. glabrata.

•Pre-emptive therapy based upon colonisation of at least two sites may be inadequate as 43% of candidaemic patients had no evidence of prior colonisation, 67% of whom had candidaemia due to C. glabrata.

Scores and prediction rules

Prediction rules and scores for identification of non-neutropenic critically ill patients at risk for invasive

candidiasis

Candida score

The “Candida score” cut-off value is 2.5 (sensitivity 81%, specificity 74%)

Leon C et al. Crit Care Med 2006; 34:730–737


candidiasis

Prediction rule

Ostrosky-Zeichner L et al. Eur J Clin Microbiol Infect Dis 2007; 26:271-276

•Analysis of risk factors in 2,890 patients who stayed in the ICU for more than 4 days •The best prediction rule used a combination of the following factors: -any systemic antibiotic or presence of central venous catheter and at least two other risk factors, including - total parenteral nutrition, - major surgery, - pancreatitis, - any use of steroids and use of immunosuppressive agents.

•This prediction rule exhibited a sensitivity of 34%, a specificity of 90%, a positive predictive value of 10% and a negative predictive value of 97%.

•This clinical rule may therefore help clinicians to rule out invasive candididiasis.


candidiasis

Leon C et al. Crit Care Med 2009; 37:1624 –1633

Is the CS useful for discriminating between Candida colonization and invasive candidiasis in non-

neutropenic critically ill patients?

•Prospective, cohort, observational study on 1107 pts for >7 d in ICU

•A CS>=3 selected pts at high risk for IC

•IC=2.3% if CS<3

•(1–3)-Beta-D-glucan was also an independent predictor of IC (odds ratio 1.004, 95% CI 1.0 –1.007)


candidiasis

Leon C et al. Crit Care Med 2009; 37:1624 –1633

Diagnosis

Diagnosing invasive fungal infections

•Given that rapid initiation of appropriate antifungal therapy is crucial for reducing mortality, prompt diagnosis of infection is of the utmost importance.

•Unfortunately, diagnosing invasive fungal infections remains difficult and is often delayed.

•Indeed, blood cultures lack sensitivity (reported to be <50%) (Reiss E et al. Clin Microbiol Rev 1993, 6:311-323), and usually become positive late (Morris AJ et al. J Clin Microbiol 1996, 34:1583-1585)

Diagnosing invasive fungal infections

•Invasive tissue sampling is often problematic in critically ill ICU patients.

•Radiological signs appear often late in the course of infection.

•Moreover, the EORTC/MSG criteria for diagnosis of invasive mycoses, which are based on clinical, microbiological and radiological criteria, were developed in immunocompromised patients and may not apply to ICU patients.

•Need for sensitive and specific diagnostic tools non-culture based methods aimed at detecting circulating fungal metabolites, antigens, antibodies and fungal DNA.

Mean M et al Critical Care 2008, 12:204

There are two major antigen-based tests commercially available today:

-the mannan antigen test (Biorad) and -the beta D-glucan test (several suppliers).

Sendid B et al. Medecine/Sciences 2009; 25:473–481.

•The test detects the presence of mannan, a major cell wall component of the most frequently recovered Candida species in blood.It is thus a Candida-specific test. The test is intended to be used in serum or plasma.

•Because the circulation of detectable levels of Candida antigen is of short duration in the blood, it is recommended that frequent tests are carried out, two to three times a week during the period at risk.

Sendid B et al. Medecine/Sciences 2009; 25:473–481.

Mannan antigen test

Verduyn Lunel FM et al. Diagn Microbiol Infect Dis 2009; 64:408–415.Verduyn Lunel FM et al. Clin Microbiol Infect 2009; 15:380–386.Arendrup MC et al. Clin Microbiol Infect 2009. Ellis M et al. J Med Microbiol 2009; 58:606–615.

- mannan -

•Antibodies to mannan usually develop when mannan disappears; it is also recommended that antigen and antibody detection is combined in the serial screening of patients at risk to improve the sensitivity.

•Well designed clinical cohort studies exploring this strategy are still rare, most of them are screening populations of onco-hematologic patients rather than ICU medical or surgical patients.

- mannan -

•The per patient sensitivity value of mannan detection is in the range of 60%, of antimannan antibodies of 60%, and of combined tests (ag+ab) of 89%.

•The specificity of both tests was over 90%.

•A positive antigen test generally precedes positive blood cultures or conventional diagnosis of hepatosplenic candidiasis.

•Additional prospective cohort studies are needed to determine the impact of mannan–antimannan detection on the diagnosis, treatment, and outcome of invasive candidiasis.

- beta-D-glucan -

•The second antigen-based test is intended to detect the presence in plasma or serum of beta-D-glucan (BDG), another important component of the cell wall of the majority of fungi, but in particular of Candida, Aspergillus,and Pneumocystis.

•This test is thus not Candida specific.

•More than 20 studies have been published, half as case– control, half as cohort studies.

- beta-D-glucan -

•Case–control studies have shown a slightly higher sensitivity (50–90%) than cohort studies (45–70%), and an equal specificity (70–100%) for the diagnosis of proven or probable invasive candidiasis.

•Two tests per week were most often performed, and one positive test considered as positive.

•False positive tests may occur (through various contaminated material), and the assay is technically demanding.

Bille J et al. Curr Opin Crit Care 2010 16:460–464

β- (1,3)-D-glucan

•Given these excellent negative predictive values β-(1,3)-D-glucan tests can help to rule out invasive candidiasis.

•Unfortunately, little information has been published thus far on use of β-(1,3)-D-glucan tests in the ICU setting

Pema´n J et al. Mycoses 2009. Saragoza R et al. Clin Vaccine Immunol 2009; 16:1527–1528.

•A Spanish group has developed an antibody test against the germ-tube structure of Candida albicans cells developing when growing in culture or invading host tissue (C. albicans IFA IgG, Vircell, Spain).

•Applying this test to various patients populations they have observed that patients with positive CAGTA had a better outcome than those with negative antibodies.

•Direct molecular detection of Candida DNA circulating in blood has been tried for almost two decades, without much success due to the usually low yeast burden, as well as the difficulty of extracting yeast DNA and separating it from human DNA.

Wallet F et al. Clin Microbiol Infect 2010; 16:774–779.

•Many home-made and developed methods have kept hope alive, with local promising results.

•The very first commercially available PCR method designed to detect the 25 most prevalent microorganisms in blood culture (comprising five species of Candida, as well as Aspergillus fumigatus) has been evaluated for a few years now in Europe (Septifast), and reported in about 10 publications.

Wallet F et al. Clin Microbiol Infect 2010; 16:774–779.

SEPTIFAST

•Almost exclusively used at the time of the first blood culture drawing and compared to the performance of blood culture, this PCR has rarely been used as a serial marker during the period at risk preceding the drawing of blood culture.

•Thus it is yet not clear whether this PCR or any other will be useful as an early marker of developing invasive candidiasis.

This increased sensitivity implies mostly C. albicans, whereas twice more C. glabrata were detected by

blood culture than by SF, but the true clinical significance of these findings has not been

systematically assessed and reported.

The performance of the Septifast real-time multiplex PCR

10 studies, 100 febrile episodes or samples each

SEPTIFAST BLOOD CULTURE

19 positive

8 positive

Bille J et al. Curr Opin Crit Care 2010 16:460–464

NEWER TESTS

- Another commercially available multiplex PCR test(Vyoo; SIRS-Lab, Jena, Germany) claims to detectCandida species, but no comparative trial has been published so far.

- An 18S rRNA broad-range PCR following animproved DNA detection method (MolYsis; Molzym,Bremen, Germany) has shown at least twice as manypositive results when compared to blood cultures.

Wellinghausen N et al. J Med Microbiol 2009; 58:1106–1111.

Recent approaches to reduce the delay of positivity from blood cultures:

-fluorescence in-situ hybridization test (PNA FISH AdvanDX, Woburn, Massachusetts, USA) differentiates the five most prevalent species of Candida.

More time consuming and expensive of FISH, allows the identification of more species of Candida than the FISH test does.

PNA FISH

MALDI-TOF-MS

•The recent application to clinical microbiology of an old technique based on the measurement of the molecular masses of proteins and other microbial components from whole bacterial extracts.

•This approach allows the identification of bacteria and yeast from isolated colonies in a few minutes with an accuracy of more than 90% when compared to conventional identification results.

Seng P et al. Clin Infect Dis 2009; 49:543–551.Van Veen SQ et al. J Clin Microbiol 2010; 48:900–907.Marklein G et al. J Clin Microbiol 2009; 47:2912–2917.

Is MALDI-TOF a revolution in the microbiology laboratory [Seng P et al. Clin Infect Dis 2009; 49:543–551] ?

Disclaimer

1-13-CAN-2010-IT-4770-AV1-13-CAN-2010-IT-4770-AV

Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l.

Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l.

Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice.

Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l.

Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l.

Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice.

gestione pratica delle infezioni fungine in terapia intensiva epidemiologia, fattori di rischio e...

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