Kdy zahajuji léčbu antimykotiky. Novák I, JIP I. interní klinika FN Plzeň

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1 Kdy zahajuji léčbu antimykotiky Novák I, JIP I. interní klinika FN Plzeň

2 Nozokomiální invazivní mykotické infekce jsou život ohrožující infekce Dříve byly diagnostikovány primárně u neutropenických nemocných s hematologickou malignitou Tyto oportunní infekce se začaly objevovat jako významná příčina morbidity a mortality u chirurgických a ICU nemocných Candidy spp. jsou nejčastějšími příčinami invazivních mykotických infekcí (70 90%) Candidy spp. patří mezi top 10 příčin BSI a představují 5 15% všech nozokomiálních infekcí Invazivní candidiasis jsou asociovány se zvýšenou morbiditou, protrahovaným LOS, podstatně zvýšenými náklady na léčbu a vysokou mortalitou (20 70 %) Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302:2323

3 Changes in the Causes of Sepsis Martin NEJM 2003 E Geoffrey Playford, CCM, 2008 George A. Sarosi, Curr Opin Crit Care, 2006 C. non alb 2008

4 Results A total of 105 episodes of IFIs occurred in 5,561 patients during the 18-month study. The main infections were caused by yeasts, more than filamentous fungi (overall incidence of 16.5 cases per 1,000 admissions and 2.3 cases per 1,000 admissions). The overall crude mortality rate was high (42.8 %), for mold infections (61.5 %). All yeast infections were Candida BSI. Over half (59.8 %) were caused by Candida non-albicans, with C. parapsilosis being the most common (61.8 %).

5 Současný stav 1.Největším problémem u nonneutropenických nemocných z invazivních mykotických infekcí jsou Candida. spp. 2.Nárůst C.nonalb. spp. 3.Vyšší riziko neadekvátní léčby!!!

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7 Nosocomial BSI in US Hospitals: Analysis of 24,179 Cases From 1995 to 2002 Wisplinghoff H et al Clin Infect Dis 2004 Aug 1;39(3):309-17

8 Infected Colonized

9 30 days mortality NS Infected Colonized

10 A bedside scoring system ( Candida score ) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization Ruiz-Santana S et al, Crit Care Med 2006 Patient group Neither colonized, nor infected, n=719 Candida spp. colonization, n=883 Nonsurvivors No. Mortality rate % Unifocal, n= % Multifocal, n= % Candida spp. infection, n= %

11 A bedside scoring system ( Candida score ) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization Ruiz-Santana S et al, Crit Care Med 2006 Patient group Neither colonized, nor infected, n=719 Candida spp. colonization, n=883 Nonsurvivors No. Mortality rate % Unifocal, n= % Multifocal, n= % Candida spp. infection, n= %

12 A bedside scoring system ( Candida score ) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization Ruiz-Santana S et al, Crit Care Med 2006 Patient group Neither colonized, nor infected, n=719 Candida spp. colonization, n=883 Nonsurvivors No. Mortality rate % Unifocal, n= % Multifocal, n= % Candida spp. infection, n= %

13 Crit Care Med 2008; 36: pts with Candida BSI who received antifungal therapy were identified 111 pts (45.3%) pts in ICU Factors: 1. retention of a CVC 2. inadequate initial fluconazole dosing 3. antifungal therapy delayed beyond 48 hrs

14 Crit Care Med 2008; 36: mortality 40 pts (36.0%) mortality 72 pts (29.4%),

15 Patofyziologický základ pro vznik invazivních mykotických infekcí u kriticky nemocných

16 Rizikové faktory pro vznik kandidové infekce Kolonizace kůže a sliznic Candida spp. Poškození přirozených bariér: rány, chirurgický intraabdominální výkon, CVK, močový katétr, UPV, GIT dysfunkce CAVE: GIT, kůže a močový trakt jsou hlavní brány vstupu pro kandidové infekce Multifokální kolonizace zvyšuje riziko invazivní mykotické infekce Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R: Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 1994

17 Kolonizace GIT CFU/ml Stomach Duodenum Jejunum Colon

18 Faecal fungal flora in healthy volunteers and inpatients Khatib R et al. Mycoses. 2001;44(5): Volunteers (n = 228) Fungi were detected in 51.8% of volunteers The prevalence increased steadily with age 1. Candida albicans was detected in 62.7% 2. Candida non-albicans species in 22.0% 3. yeasts--other than Candida in 20.3% 4. moulds in 8.5% of volunteers with fungi Inpatients (n = 34) Higher prevalence of yeast (88.2%) C. glabrata was significantly more prevalent C. glabrata appears to be acquired nosocomially

19 Bariérové funkce GIT jsou ovlivněny: 1.Perfuse SBF 2.Substráty GLU starvace 3.Inflamace zánětlivé mediátory

20 Faktory ovlivňující mortalitu při těžké sepsi/septickém šoku Věkové kategorie a komorbidita Lokalizace infekce infekční fokus Infekční agens (C.spp albicans vs non-albicans, Aspergillus etc.) Vícečetná lokalizace (kolonizace vs invazivní infekce)

21 The following risk factors were found in multiple studies to be significantly associated with IFD: 1. Surgery (intraabdominal) 2. Total parenteral nutrition 3. Fungal colonisation and Antifungal medication 4. Renal replacement therapy and acute renal failure 5. Sepsis 6. Mechanical ventilation 7. Diabetes mellitus 8. Cardiopulmonary bypass time 9. Broad-spectrum antibiotics 10. Red blood cell transfusion 11. Central venous catheters 12. Diarrhoea

22 Terapeutický management Priority 1. Hemodynamická stabilizace a kapilární recruitment 2. Kontrola infekce a antimikrobiální léčba 3. Kontrola homeostázy a hemostázy 4. Nutriční intervence 5. Minimalizovat iatrogenní poškození

23 Indikace k léčbě Invazivní mykotická infekce (pozitivní HK) cílená léčba Multifokální kolonizace: krk, sputum, žaludeční obsah, moč, jiné (místo nebo mykoticky kontaminovaný biologický materiál kolonizační index 0,5 a více) preemptivní léčba Unifokální kolonizace: krk, sputum, žaludeční obsah, moč, event.jiné denzita kolonizace preemptivní léčba?! Profylaktická léčba (intraabdominální chirurgie, profylaxe u HOO nemocných)

24 Diagnostika mykotických infekcí

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26 Candidaemia incidence of 6.9 per 1000 ICU patients 7.5% of ICU patients received antifungal therapy Candidaemia increases mortality rates in the range of 20 49% Kett DH et al. Candida BSI in ICU: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 2011; 39: Azoulay E, Dupont H, Tabah A et al. Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 2012; 40(3):

27 Prophylaxis Antifungal prophylaxis has been discussed as a promising approach in ICU patients. At this moment, the optimal target population for antifungal prophylaxis remains unknown, as this question has not been sufficiently addressed in clinical trials. Recommendations. Fluconazole prophylaxis against invasive candidiasis is recommended in patients who recently underwent abdominal surgery and had recurrent gastrointestinal perforations or anastomotic leakages.

28 Diagnosis-driven approach (pre-emptive) We defined pre-emptive therapy as therapy triggered by microbiological evidence of candidiasis without proof of invasive fungal infection. Recommendations Candida isolation from respiratory secretions should never trigger treatment, but rather be interpreted as one site of colonization among others (1,3)- beta-glucan detection in serum or plasma prompting antifungal treatment is marginally supported

29 Fever-driven approach (empiric) We defined empiric therapy as a fever-driven approach in the clinical situation of a patient at risk for invasive candidiasis who is persistently febrile with no microbiological evidence of infection. Diagnosis-driven approach (pre-emptive) We defined pre-emptive therapy as therapy triggered by microbiological evidence of candidiasis without proof of invasive fungal infection.

30 Targeted treatment Candida isolated from a single peripheral blood culture or a single central-line blood culture defines candidaemia Each case of candidaemia, even from surveillance blood cultures in asymptomatic patients requires targeted treatment

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32 Independent predictors of systemic antifungal therapy included patient-related factors: 1. severity 2. emergency surgery 3. malignancy 4. Candida colonization 5. severe sepsis

33 Independent predictors of systemic antifungal therapy included patientrelated factors: severity, emergency surgery, malignancy, Candida colonization, and severe sepsis

34 Independent predictors of systemic antifungal therapy included patientrelated factors: severity, emergency surgery, malignancy, Candida colonization, and severe sepsis

35 Importantly, a continuum exists between Candida colonization and candidemia Colonization index = number of colonized sites/number of sampled sites 0.5 is associated with an increased risk of candidemia with recovery of the same Candida species or genotypes in the colonized sites and bloodstream 28-day mortality in the systemic antifungal therapy group was not significantly higher than in the group not given systemic antifungal therapy (20% vs. 19.2%; hazard ratio, 0.97 [ ]; p.88).

36 Take home message Epidemiologický screening Znát rizikové faktory Unifokální vs multifokální kolonizace Preemptivní léčba vs profylaxe Deeskalace

37 Děkuji za pozornost!