Infezioni fungine invasive di interesse internistico

Dott. Marco Falcone

Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa (Italy)

Bassetti et al. J Clin Microbiol 2013; 51(12):4167-72

%

Internal Medicine Surgery/ICU/Oncology Ematology

Features of candidemia in

Internal Medicine

Cancer/ Hematologic malignancies

Comorbidities

Organ failure (kidney, heart, liver)

Diabetes/ Metabolic syndrome

Immunosuppressive therapy

COPD/ Respiratory failure

Anti- TNF-α drugs

• All consecutive patients (>18 years) with candidemia

• Hospitalized in 6 IMWs, 2 surgical wards, and 1 ICU

• January 2007 and December 2014

106 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.

Int J Infect Dis 2016; 52: 49-54

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

Variable

IMWs n = 51

Others n = 55

p-Value

Surgery n = 31

ICU n = 24

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

IMWs n = 51

Others n = 55

Surgery n = 31

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%)

<0.01

30-day mortality

32 (62.7%)

12 (38.7%)

27 (75%)

0.01

1) More frequently in frail or elderly patients

2) More difficult to diagnose

3) More frequently delayed therapy

4) Need of early diagnostic tools

Candidemia in Internal Medicine wards

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

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

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

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. 2017 Mar 14

Eur J Intern Med. 2017 Mar 14

Clin Infect Dis 2018; 27 July

Falcone M et al. Antimicrob Agents Chemother 2015; 60:252-7

Bloodstream infections secondary to Clostridium difficile infection: risk factors

and outcomes

Falcone M et al. Antimicrob Agents Chemother 2015; 60:252-7

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

Bloodstream infections secondary to Clostridium difficile infection: risk factors

and outcomes.

Multivariate analysis of factors associated to primary BSI during CDI

Falcone M et al. Antimicrob Agents Chemother 2015; 60: 252-7.

Patogenesi della candidemia nel paziente internistico

Chemioterapia, IBD, C. difficile

Falcone M et al. Expert Rev Anti Infect Ther 2016; 14:679-85

Pathogenesis of candidemia following Clostridium difficile infection

Falcone M et al. Expert Rev Anti Infect Ther 2016; 14:679-85

Management of candidemia following Clostridium difficile infection

Treatment of Candida in non-neutropenic patients (IDSA guidelines 2016)

Start antifungal

therapy

Echinocandin Strongly recommended

(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)

Fluconazole Acceptable alternative in not critically ill patients

(if not fluconazole-resistant Candida species) (strong recommendation; high-quality evidence)

Not recommended : Conventional Amphotericin B

Itraconazole Posaconazole Combination

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

Voriconazole Recommended as step-down oral therapy for selected cases of

candidemia due to C. krusei (strong recommendation; low-quality evidence)

Antifungal PK: Drug Distribution

+, ≥50% of serum concentrations. –, <10% of serum concentrations. *Predicted.

1. Dodds-Ashley ES, et al . Clin Infect Dis. 2006;43:S28-S39. 2. Groll AH, et al. Adv Pharmacol. 1998;44:343-500.

3. Eschenauer G, et al. Ther Clin Risk Manage. 2007;3:71-97.

Liver/ Spleen Kidneys

Gut/gall bladder Lungs

Brain/ CSF Eyes

Bladder/urine

AMB + + + + – – – 5FC + + + + + + + FLU + + + + + + + ITR + + + + – – – VOR + + + + + + – POS* + + + + – – – Echino + + + + – – –

Stepdown to fluconazole

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

Multicenter study 2012-2014

1. Policlinico Umberto I, Sapienza 2. San Giovanni Hospital 3. Cisanello hospital, Pisa 4. Trieste Hospitale 5. Torvergata, Rome

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

Exclusion criteria • Neutropenia

Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score–adjusted analysis

Falcone M et al, submitted

Flow chart

Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score–adjusted analysis

Falcone M et al, submitted

0%

10%

20%

30%

40%

50%

60%

Septic shock Non-septic shock

53,8%

14,3%

49,5%

31,9%

30-d

ay m

orta

lity

rate

s

ECHNo ECH

p= 0.567

p= 0.002

30-day mortality: univariate analysis

Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score–adjusted analysis

Falcone M et al, submitted

Cox regression adjusted for Propensity-score

HR

95.0% CI

p-value Lower Upper

Patients with candidemia with septic shock

Echinocandins 1.248 0.790 1.970 0.342

Patients with candidemia without septic shock

Echinocandins 0.407 0.212 0.779 0.007

30-day mortality: multivariate analysis, PS asjusted

Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score–adjusted analysis

Falcone M et al, submitted

30-day survival: Kaplan-Meyer curves

p= 0.459

p<0.001

Impact of initial antifungal therapy on the outcome of patients with candidemia and septic shock: a propensity score–adjusted analysis

Falcone M et al, submitted

Which is the best treatment of candidemia?

The early diagnosis…

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

Aspergillosis Neutropenic Non-neutropenic

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

“Multiple formazioni nodulari solide a margini regolari e densità disomogenea con livelli idro-aerei

Multiple formazioni nodulari satelliti Diffusi addensamenti parenchimali a vetro smerigliato”

Underlying diseases and presisposition to fungal infections

Mazzone et al Italian Journal of Medicine 2012;6(2) Suppl:19-35

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 Cellular immune response: -Impaired neutrophils and monocytes chemotaxis - Phagocytosis defect

Yeasts

Nephrotic syndrome -IgG loss with urine - loss of complement factors

Yeasts

Liver disease and autoimmune hepatitis

- Cellular immune response: -Impaired neutrophils and monocytes chemotaxis - Phagocytosis defect - activation of T lymphocytes-> activation of B lymphocytes and antibodies production

Aspergillus infection, cutaneous yeast infections

Advanced solid cancer Cellular and humoral immunity affected. Predisposing factors: chemotherapy, steroids, malnutrition, antibiotic therapy, total parenteral nutrition

Yeasts and filamentous fungi

End-stage liver disease predisposes to Aspergillus infection

• Derangements of both humoral and cell-mediated immunity.

• Significant decline in peripheral blood CD3 and CD4 T- lymphocyte count.

• Impaired phagocytosis and chemotaxis, decreased complement levels, and reduced antigen opsonization.

Clin Microbiol Infect. 2009 Nov 10

Diagn Microbiol Infect Dis 2014; 80:83-6