Infezioni fungine invasive di interesse internistico Dott. Marco Falcone

Transcription

1 Infezioni fungine invasive di interesse internistico Dott. Marco Falcone Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa (Italy)

2 % Internal Medicine Surgery/ICU/Oncology Ematology Bassetti et al. J Clin Microbiol 2013; 51(12):

3 Organ failure (kidney, heart, liver) Immunosuppressive therapy Comorbidities Features of candidemia in Internal Medicine Anti- TNF-α drugs Diabetes/ Metabolic syndrome Cancer/ Hematologic malignancies COPD/ Respiratory failure

4 All consecutive patients (>18 years) with candidemia Hospitalized in 6 IMWs, 2 surgical wards, and 1 ICU January 2007 and December consecutive patients with candidemia 51 patients in the 6 IMWs 31 in the 2 surgical departments 24 patients in the ICU Int J Infect Dis. 2016;52:49-54.

5 Variable IMW (n= 51) Surgery (n= 31) ICU (n=24) P value Age, years, mean (SD) 75.4 (11.7) 65.9 (15.8) 57.7 (16.4) < 0.01 Assistance in ADL, n (%) 41 (80.3) 13 (41.9) 4 (16.6) <0.01 Antibiotic therapy in prior 90 days, n (%) 28 (54.9) 10 (32.2) 5 (20.8) <0.05 Charlson score, mean (SD) 4.4 (2.3) 3.1 (2) 3 (2) <0.01 Pressure ulcer, n (%) 26 (51.0) 7 (12.6) 0 <0.01 Abdominal surgery in 90 days, n (%) 1 (1.9) 20 (64.5) 12 (50) <0.01 Parenteral nutrition, n (%) 1 (1.9) 17 (54.8) 6 (25) <0.01 Central line catheter, n (%) 8 (15.6) 12 (38.7) 3 (12.5) <0.01 Permacath/PICC line, n (%) 8 (15.6) 12 (38.7) 3 (12.5) <0.01 Heart failure, n (%) 18 (35.2) 1 (3.2) 1 (4.1) <0.01 Dementia, n (%) 11 (21.5) 2 (6.4) 0 <0.05 Solid tumor, n (%) 7 (13.7) 15 (48.3) 3 (12.5) <0.01 Myocardial infarction, n (%) 19 (37.2) 4 (12.9) 2 (8.3) <0.01 Int J Infect Dis 2016; 52: 49-54

6 Variable IMWs n = 51 Others n = 55 Surgery n = 31 ICU n = 24 p-value Time from culture to identification <48 h, n (%) 19 (37.2) 21 (67.7) 13 (54.1) <0.05 Adequate antifungal therapy 10 (19.6) 12 (38.7) 15 (62.5) <0.05 Removal of indwelling catheters, n (%) 11 (21.5) 19 (61.2) 9 (37.5) <0.01 Int J Infect Dis 2016; 52: 49-54

7 IMWs n = 51 Surgery n = 31 Others n = 55 ICU n = 24 P value Antifungal therapy at any time after identification 27 (52.9%) 26 (83.8%) 16 (66.6%) <0.01 Adequate antifungal therapy > 48 h or not treated 41 (80.3%) 19 (61.2%) 9 (37.5%) < day mortality 32 (62.7%) 12 (38.7%) 27 (75%) 0.01 Int J Infect Dis 2016; 52: 49-54

8 Candidemia in Internal Medicine wards 1) More frequently in frail or elderly patients 2) More difficult to diagnose 3) More frequently delayed therapy 4) Need of early diagnostic tools

9 Methods: multicenter case-control study was performed in four tertiary-care hospitals located in different regions in Italy: Policlinico Umberto I, Sapienza University, Rome (1100 beds), San Giovanni-Addolorata Hospital, Rome (700 beds), Azienda Ospedaliera Universitaria Pisana, Pisa (800 beds) and University Hospital of Trieste (840 beds). For each case, two controls matched for age (± 2 years), date of hospital admission and duration of hospitalization were selected (cases:controls ratio 1:2). Multivariate analysis to identify independent risk factors for mortality was performed using a logistic regression model. Eur J Intern Med. 2017; 41:33-38

10 Eur J Intern Med. 2017; 41:33-38

11 Eur J Intern Med. 2017; 41:33-38

12 Risk factors by importance points SEVERE SEPSIS/SEPTIC SHOCK 2.5 RECENT C. difficile INFECTION 2 DIABETES MELLITUS 2 PICC 1.5 TOTAL PARENTERAL NUTRITION 1.5 CONCOMITANT GLYCOPEPTIDE THERAPY 1.5 COPD 1.5 PREVIOUS ANTIBIOTIC THERAPY 1 IMMUNOSUPPRESSIVE THERAPY 0.5 Eur J Intern Med Mar 14

13 Eur J Intern Med Mar 14

14 Clin Infect Dis 2018; 27 July

15 Bloodstream infections secondary to Clostridium difficile infection: risk factors and outcomes Falcone M et al. Antimicrob Agents Chemother 2015; 60:252-7

16 Bloodstream infections secondary to Clostridium difficile infection: risk factors and outcomes Wards of hospitalization Falcone M et al. Antimicrob Agents Chemother 2015; 60:252-7

17 Bloodstream infections secondary to Clostridium difficile infection: risk factors and outcomes. Falcone M et al. Antimicrob Agents Chemother 2015; 60:252-7

18 Multivariate analysis of factors associated to primary BSI during CDI Falcone M et al. Antimicrob Agents Chemother 2015; 60:

19 Patogenesi della candidemia nel paziente internistico Chemioterapia, IBD, C. difficile

20 Pathogenesis of candidemia following Clostridium difficile infection Falcone M et al. Expert Rev Anti Infect Ther 2016; 14:679-85

21 Management of candidemia following Clostridium difficile infection Falcone M et al. Expert Rev Anti Infect Ther 2016; 14:679-85

22 Treatment of Candida in non-neutropenic patients (IDSA guidelines 2016) Echinocandin Strongly recommended (strong recommendation; high-quality evidence) Start antifungal therapy Not recommended : Conventional Amphotericin B Itraconazole Posaconazole Combination Fluconazole Acceptable alternative in not critically ill patients (if not fluconazole-resistant Candida species) (strong recommendation; high-quality evidence) L-AMB Reasonable alternative if there is intolerance,limited availability, or resistance to other antifungal agent (strong recommendation; high-quality evidence) Voriconazole Recommended as step-down oral therapy for selected cases of candidemia due to C. krusei (strong recommendation; low-quality evidence) Pappas et al, Clin Infect Dis 2016; 62(4):e1-50.

23 Antifungal PK: Drug Distribution Liver/ Spleen +, 50% of serum concentrations., <10% of serum concentrations. *Predicted. Kidneys Gut/gall bladder Lungs Brain/ CSF Eyes Bladder /urine AMB FC FLU ITR VOR POS* Echino Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43:S28-S Groll AH, et al. Adv Pharmacol. 1998;44: Eschenauer G, et al. Ther Clin Risk Manage. 2007;3:71-97.

24 Stepdown to fluconazole Pappas et al, Clin Infect Dis 2016; 62(4):e1-50.

25 Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score adjusted analysis Inclusion criteria Patients >18 ys with definitive diagnosis of candidemia (at least one blood cultures positive for Candida spp in patients with signs of infection Multicenter study Policlinico Umberto I, Sapienza 2. San Giovanni Hospital 3. Cisanello hospital, Pisa 4. Trieste Hospitale 5. Torvergata, Rome Exclusion criteria Neutropenia Falcone M et al, submitted

26 Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score adjusted analysis Flow chart Falcone M et al, submitted

27 Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score adjusted analysis 30-day mortality: univariate analysis 60% p= ,8% 49,5% 50% 30-day mortality rates 40% 30% 20% 14,3% p= ,9% ECH No ECH 10% 0% Septic shock Non-septic shock Falcone M et al, submitted

28 Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score adjusted analysis 30-day mortality: multivariate analysis, PS asjusted Cox regression adjusted for Propensity-score Patients with candidemia with septic shock Patients with candidemia without septic shock 95.0% CI HR Lower Upper p-value Echinocandins Echinocandins Falcone M et al, submitted

29 Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score adjusted analysis 30-day survival: Kaplan-Meyer curves p<0.001 p= Falcone M et al, submitted

30 Which is the best treatment of candidemia? The early diagnosis

31 Neutropenic Aspergillosis Non-neutropenic Balloy et al. Infect Immun 2005; 73:

32 Caso clinico Paziente di 51 anni, alcolista cronico, ricovero per epatite alcolica acuta ed encefalopatia Somministrazione di cortisone ad alte dosi III giornata comparsa di febbre e tachipnea, rx torace mostra alcuni addensamenti polmonari bilaterali Inizia meropenem 1 g x 3 + vancomicina 1 g e.v. ogni 12 ore Mancata risposta alla terapia, insufficienza respiratoria grave, trasferimento in UTI Si esegue TC torace

33 Multiple formazioni nodulari solide a margini regolari e densità disomogenea con livelli idro-aerei Multiple formazioni nodulari satelliti Diffusi addensamenti parenchimali a vetro smerigliato

34 Underlying diseases and presisposition to fungal infections Underlying disease Immune system Fungal infection Diabetes mellitus Cellular immune response: -Impaired neutrophils chemotaxis - Phagocytosis defect Yeasts, Filamentous fungi (Mucor, Absidia, Rhizopus in decompensated DM) Chronic renal failure Nephrotic syndrome Liver disease and autoimmune hepatitis Advanced solid cancer Cellular immune response: -Impaired neutrophils and monocytes chemotaxis - Phagocytosis defect -IgG loss with urine - loss of complement factors - Cellular immune response: -Impaired neutrophils and monocytes chemotaxis - Phagocytosis defect - activation of T lymphocytes-> activation of B lymphocytes and antibodies production Cellular and humoral immunity affected. Predisposing factors: chemotherapy, steroids, malnutrition, antibiotic therapy, total parenteral nutrition Yeasts Yeasts Aspergillus infection, cutaneous yeast infections Yeasts and filamentous fungi Mazzone et al Italian Journal of Medicine 2012;6(2) Suppl:19-35

35 End-stage liver disease predisposes to Aspergillus infection Derangements of both humoral and cellmediated immunity. Significant decline in peripheral blood CD3 and CD4 T- lymphocyte count. Impaired phagocytosis and chemotaxis, decreased complement levels, and reduced antigen opsonization.

36 Clin Microbiol Infect Nov 10

37 Diagn Microbiol Infect Dis 2014; 80:83-6