F-Menichetti

Appropriatezza e gestione del paziente ad
alto rischio con infezione fungina invasiva
Francesco Menichetti, MD
Head, Infectious Diseases Unit
Ospedale Nuovo Santa Chiara
Pisa, Italy
SIMIT 2015
SIMPOSIO MSD
Catania 10 Novembre 2015
Disclosures
• Research grants
Astellas, Gilead, MSD, Pfizer
• Advisor/consultant
Angelini, Astellas, Basilea, Gilead, MSD,
Novartis, Pfizer, Sanofi, Menarini
• Speaker/chairman
Astellas, Gilead, MSD, Novartis, Pfizer
Risk Factors for Invasive Candidiasis
Candidemie 2012-2014
Pisa Hospital: 373 episodes
ICU
67
17%
surgery
89
23%
Others
11
%
internal
medical ward
184
49%
Candidemia 2012-2014
Pisa Hospital: 373 episodes
Isolates
Patients
C. albicans
C. parapsilosis
C. glabrata
C. tropicalis
C. krusei
others
373
351
188
98
38
23
8
22
(50%)
(26%)
(10%)
(6%)
21, 9: e71-e72
Intensive Care Medicine 2015, 41, 8: 1498-1499
Intensive Care Medicine 2015, 41, 8: 1498-1499
Cateteri Venosi Centrali
120.00%
100.00%
80.00%
60.00%
40.00%
20.00%
0.00%
Totale
Medicine Interne
PICC
UTI
altri CVC
PICC medicine vs UTI: p<0,001
Intensive Care Medicine 2015, 41, 8: 1498-1499
Early onset vs. Late onset candidemia
90.00%
81%
80.00%
75%
70.00%
60.00%
59%
50.00%
41%
40.00%
30.00%
25%
19%
20.00%
10.00%
0.00%
Totale
Medicine Interne
EOC(≤ 10 gg)
LOC(> 10 gg)
UTI
Comparison in pairs
between
Very early
Early onset
Late onset
Table 2: Comparison in pairs between very early onset candidemia, early onset candidemia, and late onset
onset
candidemia
candidemia
very early-onset,
candidemia.
candidemia
(n=19)
(n=29)
early-onset and late onset
(n=24)
candidemia
Intensive care unit admission
1/24 (4%)
6/19 (31%)
15/29 (51%)
Hospital stay (days)
6 [3-12]
10 [8-16]
40 [29-69]
Long term care facilities (LTCF)
8/24 (33%)
1/19 (5%)
4/29 (14%)
Transfer from surgical wards
0/24 (0%)
3/19 (16%)
11/29 (38%)
Nasogastric tube
8/24 (33%)
9/19 (47%)
16/29 (55%)
Central venous catheter
1/24 (4%)
PICC
8/19 (42%) 17/29 (59%)
20/24 (83%) 7/19 (37%) 10/29 (34%)
Intensive Care Medicine 2015, 41, 8: 1498-1499
Candidemia in pts with PICC showed to be associated
with higher mortality in comparison with CVC and no CVC use
128 candidemia in IMW, Pisa:
68% with fever, 32% without fever
100
90
80
70
50
40
30
20
10
0
SIRS
Sepsi grave
o shock
settico
Altre
infezioni
Altre
comorbilità
Diabete
mellito
CT o RT
87 pts with fever
41 pts without fever
Terapia
corticosteroidea
Terapia
immunosoppressiva
Decesso
297 candidemia in IMWs in Pisa,
Rome & Udine hospitals
100
90
80
70
60
50
40
30
20
10
0
SIRS
Sepsi grave
o shock
settico
Altre
infezioni
Altre
comorbilità
Diabete
mellito
147 pts with fever
150 pts without fever
CT o RT
Terapia
corticosteroidea
Nessuna
terapia
antifungina
Terapia
immunosoppressiva
Decesso
Pazienti con candidemia
senza febbre
La mancanza di febbre è più frequente nei
pazienti con:
Diabete
Colite da C. difficile
Insorgenza precoce rispetto al ricovero
Terapia con echinocandine
Insufficienza renale, ricoveri ripetuti,
immunosoppressione ma non steroidi
Candidemia, Pisa Hospital 2012-2013
Antifungal
therapy
< 24h
27 (30%)
Med Int
(n=64)
ICU
(n=26)
15 (23,4%)
12 (46,1%)
Serious risk for delay in diagnosis &
24/48h
13 (13,3%)
10 (15,6%)
3 (11,5%)
untimely and inappropriate antifungal
48/72h
8 (8,9%) therapy
5 (7,8%)
3 (11,5%)
>72h
10 (11,1%)
6 (9,4%)
4 (15,4%)
no therapy
22 (27,5%)
20 (35,7%)
2 (8,3%)
In hospital
mortality (%)
39 (43,3%)
24 (37,5%)
15 (57,7%)
224 consecutive patients with septic shock and a positive blood
culture for Candida species.
Kollef M et al. Clin Infect Dis. 2012 Jun;54(12):1739-46
What are the best tests for diagnosing candidaemia?
Specimen
Test
Considerations
Remarks/Recommendations
Serum
Mannan and AntiMannan
• Combined detection
RECOMMENDED
Serial determinations may be
necessary. High NPV
Other antibodies
(such as Serion
ELISA classic)
• Limited data for
candidemia
No recommendation
ß-D-Glucan
Septifast
In house PCR
• Not specific for Candida
• Limited data for
candidemia
• No third party
validation data
available
RECOMMENDED
(for Fungitell) No
recommendation for other tests.
Serial determinations are
recommended (twice a week).
High NPV. Not validated in
children
No recommendation
No recommendation
CAGTA
Antibody against the C.albicans germ-tube
Virulence factor
Ideal strategy
for the management of IFI in ICU pts
• Timeliness: early start is crucial
• Appropriateness: the right drug to the right
patient
• Adequacy: the right schedule for the
specific patient & site of infection
Patient outcome is related to these elements
Echinocandins for IFI in the Critically ill:
a rational choiche
1. Spectrum of activity: C. albicans and non albicans
2. Activity against fluconazole non susceptible Candida
3. Fungicidal activity against the majority of Candida spp.
4. Activity against the biofilm
5. Reliable PK/PD profile
6. Good safety profile
7. Low potential for drug-drug interactions
8. Clinical evidence of efficacy (RCTs)
9. Recommended for critically ill pts (IDSA)
10. Reasonable cost (with respect to vorico and lipo ampho B)
Biofilm activity of antifungals
vs different Candida species
Choi HW et al. Antimicrob Agents Chemother 2007; 51:1520-23
%
 Multidrug resistance common: fluconazole resistance in 36%
Alexander BD, Clin Infect Dis 2013;56:1724-32; Pham CD et al. Antimicrob Agents Chemother 2014;58:4690-6.
• 2009–2012 C. glabrata BSI
sequenced for FKS1/2 mutations
• 13/72 (18%) pt with FKS mutation
• Treatment failure in 17/57 (30%)
receiving echinocandin:
• 6/10 (60%) with mutation
• 11/47 (23%) without
• Prior echinocandin use and GI
disorder predicted failure
Clin Infect Dis 2014;59;819-25
1915 patients from 7 trials;
Overall mortality - 31.4%
Treatment success - 67.4%
Rex et al. (1994): 237 patients, enrollment 1989–1993; fluco vs d-AmB
Mora-Duarte et al. (2002): 239 pts, 1997–2001; caspo vs d-AmB
Rex et al. (2003): 236 pts, 1995–1999; FLU vs d-AmB
Kullberg et al. (2005): 422 pts, 1998–2003; vori vs d-AmB > fluco
Reboli et al. (2007): 245 pts, 2003–2004; anidula vs fluco
Kuse et al. (2007): 264 pts, 2003–2004; mica vs liposomal AmB
Pappas et al. (2007): 595 pts, 2004–2006; mica > fluco vs caspo > fluco
Clin Infect Dis 2012;54(8):1110-22
Mortality and species
• C. tropicalis 41% vs other species 29%; P<0.0001
• C. parapsilosis 22.7% vs other species 33.0%; P<0.001
Mortality
and
treatment
The choice of
antifungal
drug
influence the patient outcome
27% for echinocandins vs 36% for other regimens; P<0.0001
36% for triazoles vs 30% for other drugs; P=0.006
35% for polyenes vs 30% for other drugs; P=0.04
Clin Infect Dis 2012;54(8):1110-22
Invasive
candidiasis
Site-oriented antifungal therapy
• Endocarditis: echinocandins plus lipid Ampho (5FC)
• Chorioretinitis: fluco/lipid Ampho (Intravitreal Ampho B)
• Endophtalmitis: Intravitreal Ampho + Fluco or + lipid
Ampho (vitrectomy)
• Meningitis: lipid ampho +/-5FC (azoles)
• Spondylitis/osteomyelitis: fluconazole or lipid Ampho or
echinocandins
Candida UTI
Asymptomatic candiduria: if neutropenia, LBW
premature infants, pregnancy, urologic procedures
•Fluconazole or amphotericin B
Symptomatic Cystitis, Ascending Pyelonephritis:
•Fluconazole
Fluconazole-resistant strains:
•Amphotericin B
Optimal management
of invasive candidiasis in 2015
 First line echinocandin
-Spectrum + , higher efficacy than fluconazole (C. albicans)
 Local epidemiology/risk group to be considered
 Take into account prior exposure to echinocandin/azoles
-Azole => Candin ; Candin => L-Amb
 Early adequate source control
-Catheter withdrawal (although persistent controversies)
-Abdominal surgery ?
 Early switching (when infection controlled)
 Urgent need for more effective diagnostic methods
Denning & Bromley, Science 2015