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