INVASIVE FUNGAL INFECTIONS

INFEZIONI FUNGINE
IN MEDICINA INTERNA
Prof. Ercole Concia
Sepsi micotiche aumentate del 207% dal 1979 al 2001
NEJM 2003;348:1546-54
Candide isolate da emocolture e CVC: distribuzione
per aree di degenza (2010-2011)
Udine 23 ottobre 2012
VERONA
G. Lo Cascio
Quale realtà? Isolati da BSI
4,4%
6%
100%
AOUI BSI
5%
5.3%
Funghi Lieviti
Yeasts
80%
Anaerobi
Anaerobes
60%
Gram +
Gram - F
40%
Gram - NF
20%
0%
2011
2011
2012
2012
2013
2013
2014
2014Giu
AOUI - Azienda Ospedaliera Universitaria Integrata Verona
Incidenza Candidiasi AOUI VR 2008-2014
AOUI
BT
BR
9
7
6
5
4
3
2
1
2014
2013
2012
2011
2010
2009
0
2008
n casi su 10.000 gg degenza
8
anno
AOUI VR - Azienda Ospedaliera Universitaria Integrata Verona
2
8
14.2
48.5
21.
3
Distribuzione delle diverse specie di Candida negli anni
30%
CKR – C. krusei
CTR – C. tropicalis
CGL – C. glabrata
CPA - C. parapsilosis
CAL – C. albicans
Candida distribution in hospital
Bassetti M et al. PLoS ONE ; 6(9): e24198
Distribuzione delle candidemie per area
di ricovero (%)
29,4
28,2
28,2
UTI
area chirurgica
area medica
14,2
TIN
Candidaemia cases in hospital
955 candidaemia episodes (2008–2010)
Internal med
Haem/onc
ICU
Surgery
80
68
70
60
57
57
50
50
%
43
40
30
30
16 17
20
10
32
32
28
28
25
20
18
16 16
13
10
8
11
6
5
0
0
Udine
Trieste
Rome
Barcelona
Sevilla
Total
Bassetti M, et al. J Clin Microbiol 2013;51;:4167-72
145 episodi di candidemia nosocomiale in 140 pazienti
52% di sesso maschile
età mediana 81 anni
(range interquartile 70-86 anni)
area chirurgica
16%
area medica
68%
area intensiva
16%
CANDIDEMIE NEL TRIVENETO
R. Luzzati 2015
M. Merelli UD
Mortalità cruda a 30 giorni:36,3 %
CVC in situ al momento della candidemia: 81.2%
RIMOZIONE CVC dopo la diagnosi: 74.6%
Rimozione tardiva: 26.2%
CANDIDEMIA PERSISTENTE: 29.6% (mediana 9 giorni)
Fattore protettivo: impostazione terapia idonea (OR 0.6;
95% CI 0.16-0.83; p=0.02)
MORTALITA’ CRUDA A 30 GIORNI: 36.5%
VERONA 2004
Management terapeutico
44.8
%
CID 2004;39: 309-17
MORTALITA “PER” LA CANDIDA O
“CON” LA CANDIDA ?
Relationship Between Hospital Mortality and the
Timing of Antifungal Treatment
Hospital mortality (%)
35
30
25
20
15
10
5
0
< 12
12–24
24–48
> 48
Delay in start of antifungal treatment (hours)
Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640–5
Bassetti CMI 2013
precoce
CASPOFUNGINA
TERAPIA PRECOCE
O TARDIVA
HSU JAC 2010
2
1
5
10
Ruping MJ et al. Drugs 2008:18(14):1941-62
EMOCOLTURE
• Numero raccomandato: 3 set
• Quantità: 60 ml x adulti, distribuire 10 ml in 3
bottiglie per aerobi e 10 ml in 3 bottiglie per
anaerobi
• Timing: prelevare le tre emocolture una dopo
l’altra nell’arco di 30 minuti da tre siti diversi
• SENSIBILITA’: da 50 a 75 %
The median Candida concentration
within a first positive blood culture is 1
CFU/mL
26% - 65% of positive blood cultures
have <1 CFU/mL.
Empiric Therapy: When is it Indicated?
Population
Intention
Intervention
SoR
QoE
Reference
At risk + persistent FUO Reduce overall
mortality
Antifungal
treatment
(unspecified)
C
III
Garey CID 2004
Morrell AAC 2005
Parkins JAC 2007
Kumar Chest 2009
Adult ICU patients with Resolution of
fever despite broadfever
spectrum antibiotics,
APACHE II >16
Fluconazole
400mg/d
D
I
Schuster
Ann Int Med 2008
Definitions:
• Empiric = persistent FUO / Fever driven approach
• Pre-emptive = treatment based on a validated marker / Diagnosis driven approach
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
ß-D-Glucan
• Not specific for Candida
Septifast
• Limited data for
candidemia
No recommendation
In house PCR
• No third party validation
data available
No recommendation
No recommendation
RECOMMENDED (for Fungitell) No
recommendation for other tests. Serial
determinations are recommended
(twice a week). High NPV. Not
validated in children
Beta D Glucan

3 different tests (2 Japan, 1 USA)
Variable quality of data: retrospective vs. prospective;
heterogenous
 Different cut offs used
 “pangungal” – except cryptococcus and mucorales


Sensitivity 45-70%; specificity and NPV high

High false-positives: up to 30% in ICU- bacteraemia,
antibiotics, pre-/analytical contaminations
Influence of ongoing antifungal
prophylaxis/therapy not known
 Costs, complex analytical procedures: automated
assay in the pipeline

Performance of (1-3) – β – D - Glucan
No studies
(patients)
Sensitivity
% (95% Cl)
Specificity
% (95% Cl)
Karageorgopoulos, CID 2011
Proven & probable IFI
16(2979)
77% (67-84)
85% (80-90)
Onishi, JCM 2012
A, IC, PJP
IA, IC 31
PJP 12
80% (77-82)
96% (92-98)
82 % (81-83)
84% (83-86)
15
76% (67-83)
0.85 (73-92)
Karageorgopoulos, CMI 2012
14 (2800)
95& (91-97)
86% (92-90)
Lamoth, CID 2012
For 2 consecutive tests
6 (1771)
50% (64-65)
99% (97-99.5)
Lu, Intern Med 2011
False positive BG results
Haemodialysis using cellulose membranes
Albumin
Intravenous immune globulin
Use of cellulose depht filters for intavenous
administration
• Gauze packing of serosal surfaces (abdominal
surgery)
• Intravenous amoxicillin-clavulanic acid
(AZITROMICIN and PENTAMIDINE inhibit
the BG assay)
•
•
•
•
Markers of sepsis and organ
dysfunction at time of blood culture
Bacterial sepsis
Candida sepsis
P value
n
CRP
PCT
190 [115-316]
12.9 [2.6-81.2]
94 [66-129]
0.71 [0.5-1.1]
0.002
0.001
SOFA
WBC
T (°C)
8 [7-13]
14.3 [10.6-16.4]
38.0 [37.0-38.4]
5[3-8]
11.6 [8.4-15.7]
37.8 [37.0-38.3]
0.010
0.336
0.493
PROCALCITONINA
Journal of Infection 2010; 60:425-430
Dou Y – H et al Diagn Micr Inf Dis 2013
Risk predictive models for INVASIVE
CANDIDIASIS in critically ill patients
Colonization index
Nº sites/Nº sites
screened 2 x weekly
>0.5 or ≥ 0.4 corrected
Candida score
Surgery on ICU admission
TPN
Severe sepsis
Candida colonization
> 3 points
Ostrosky, 2009
4th day of I ICU stay
Major (two): Sepsis + CVC
+ MV + one of
TPN (day 1-3)
Dialysis (day 1-3)
Major surgery (within 7 days)
Pancreatitis (within 7 days)
Immusup/steroids
(within 7 days)
Shorr, 2009
Dupont, 2003
Michalopoulos, 2003
Age > 65 y
Tº < 36.7º
Severe mental status
Cachexia
Previous hospit. 30 days
Healthcare facility
MV
Female gender
Upper GI origin peritonitis
Cardiovasc. failure
BAS 48 h before onset
of peritonitis
MV > 10 days
Nosocomial bacterial
infection
Cardiop. bypass time
> 120 m.
Diabetes mellitus
Lam SW. CCM 2009 - Playford GE. ICM 2009 - Eggimann P. COCC 2010 - Kratzer C. Mycoses 2011
Candidemia in non-neutropenic:
ESCMID vs IDSA
ESCMID 2011
IDSA 2009
Fluconazole
CI
AI
Voriconazole
BI
AI ( alternative agent)
Lip-AMB
B-D I-II
AI ( alternative agents)
D-AMB
DI
AI ( alternative agent)
Echinocandins
AI
AI (for moderately
severe to severe illness and for
patients with recent azole
exposure)
Empiric treatment (as
for candidemia)
CIII
BIII
IDSA additional recommendations
• Prefer echinocandin for severe illness
• Prefer echinocandin in patients with
recent azole exposure
• Remove i.v. catheters, if possible
• Treat for 14 days after first negative BC
and resoluition of signs and symptoms
• Perform ophthalmological examination in
all cases
MAT October 2014
DOT
ANTIFUNGINI IV
MED INT
MS%
±%
IE
53.293
100,0
8,0
100
25.300
47,5
18,9
110
16.292
30,6
11,0
103
ECALTA
6.967
13,1
31,1
121
MYCAMINE
2.041
3,8
59,9
148
2.698
5,1
-36,6
59
1.791
3,4
-22,0
72
ABELCET
300
0,6
24,8
116
FUNGIZONE
606
1,1
-64,6
33
24.573
46,1
5,4
98
7.216
13,5
3,1
95
16.569
31,1
6,5
99
789
1,5
3,8
96
722
1,4
48,6
137
ECHINOCANDINE
CANCIDAS
AMPHOTERICIN B
AMBISOME
AZOLI
VFEND
FLUCONAZOLO
SPORANOX
ALTRO
MAT October 2014
DOT
ANTIFUNGINI IV
ICU
MS%
±%
IE
104.663
100,0
4,6
100
67.453
64,4
14,5
109
CANCIDAS
38.347
36,6
12,4
108
ECALTA
20.990
20,1
9,7
105
8.116
7,8
42,8
137
10.053
9,6
-4,4
91
AMBISOME
8.266
7,9
8,3
104
ABELCET
1.398
1,3
-40,1
57
389
0,4
-29,9
67
26.691
25,5
-11,8
84
9.594
9,2
-21,8
75
16.534
15,8
-3,8
92
563
0,5
-30,9
66
466
0,4
25,3
120
ECHINOCANDINE
MYCAMINE
AMPHOTERICIN B
FUNGIZONE
AZOLI
VFEND
FLUCONAZOLO
SPORANOX
ALTRO
D.P. Andes – CID 2012
Percentuali di resistenza riscontrate in infezioni fungine invasive (302
Candide) in ICU
AM Tortorano 2012
ANIDULA
CASPO
MICA
FLUCON
POSACON
VORICON
3,6
C. albicans
0
0
0
5,3
3,6
5,2
C. parapsilosis
0
0
0
25,8
0
19,3
C. glabrata
0
0
0
9,7
25,8
18,5
C. tropicalis
0
0
0
22,2
C. kruzei
0
0
0
100
14,8
0
16,7
464 candide isolate in 34
centri:tutti gli isolati erano sensibili
all’amfotericina B (MIC < 1 mg /L)
A.M. Tortorano et al Infection 2013
Targeted Treatment of Candidaemia: Duration & Diagnostics
Population
No organ
involvement
Intention
Avoid organ
involvement
Detect organ
involvement
Any
To simplify
treatment
Intervention
SoR
QoE
Reference
Treat for 14 days after the
end of candidaemia
B
II
Oude-Lashof CID 2011
Take 1 blood culture per day
until negative
B
III
No reference found
Transoesophageal
echocardiography
B
IIa
Fernández-Cruz ICAAC
2010
Fundoscopy
B
II
Oude-Lashof CID 2011
Rodriguez Med 2003
Brooks Arch Int Med 1989
Parke Ophthalmol 1982
If CVC, PICC, or intravascular
devices, search for
thrombus
B
III
No reference found
Step down to flucona-zole
after 10 days of IV, if
• Species is susceptible
• Patient tolerates PO
• Patient is stable
B
II
Reboli NEJM 2007
Mora-Duarte NEJM 2002
Pappas CID 2007
CVC, Central venous catheter; PICC, Peripherally inserted central catheter.
•
•
•
•
•
FLUOCONAZOLO…………………………………………….
FLUCONAZOLO…48/72………........ECHINOCANDINA
ECHINOCANDINA…………………………………………..
ECHINOCANDINA……4/5 gg……....FLUCONAZOLO
ECHINOCANDINA……10 gg…………FLUCONAZOLO
Perlin TIMM 2015
Attività in vitro delle echinocandine
nei confronti di Candida spp.
MIC90 (µg/ml)
Organismo
Numero di
isolati
Micafungina
Caspofungina
Anidulafungina
C. albicans
2.869
0.03
0.06
0.06
C. parapsilosis
759
2
1
2
C. glabrata
747
0.015
0.06
0.12
C. tropicalis
625
0.06
0.06
0.06
C. krusei
136
0.12
0.25
0.06
C. guilliermondii
61
1
1
2
C. lusitaniae
58
0.25
0.5
0.5
C. kefyr
37
0.06
0.015
0.12
C. famata
24
1
1
2
Candida spp.
30
0.5
0.25
1
Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6
Drug
ANI
CAS
MICA
Typical
adult dosing
Oral
bioavailability
Cmax
(µg/mL)
200 mg x 1
loading dose then
100 mg/d
<5
6-7
70 mg loading
dose, then 50
mg/d
<5
100 – 150 mg/d;
50 mg/d
(prophylaxis)
<5
AUC
(mgxh/L)
Protei
n (%)
CSF
(%)
Vitreus
(%)
Urine
(%)
Metabolism
Elimination
T½
(h)
Comparative Pharmacokinetic and
Pharmacodynamic Properties of Systemic Antifungal Agents
99
84.0
<5
0
<2
None
Feces
26
PK:PD
(total drug
unless indicated)
Cmax:MIC>10 or
serum
(unbound)
AUC:MIC >20
8-10
119
97.0
<5
0
<2
Hepatic
Urine
30
Cmax:MIC>10 or
serum
(unbound)
AUC:MIC >20
10-16
158
99.0
<5
<1
<2
Hepatic
Feces
15
Cmax:MIC>10 or
serum
(unbound)
AUC:MIC >20
Epatotossicità VS AUC :
Riassunto delle caratteristiche del prodotto
CASPOFUNGIN 1
ANIDULAFUNGIN 2
1. CANCIDAS Riassunto delle Caratteristiche del Prodotto EU. 12/2008.
2. ECALTA Riassunto delle Caratteristiche del Prodotto EU 9/2007.
Tolerability and hepatotoxicity of antifungals in the treatment of IFI
of febrile neutropenia
Percentage of patients with elevation of liver enzymes requiring treatment discontinuation
Azoles
Echinocandins
5%
Secondary
outcome result.
4%
2.7%
Percentage of patients
with elevation of liver
enzymes requiring
treatment
discontinuation
Systematic review
and meta-analysis
(primary population,
head-to-head studies)
N= 8745
3%
1.5%
2%
0.7%
0.4%
1%
0.8%
0.2%
NA
IFI: Invasive Fungal Diseases; NA: Not available
n
af
un
gi
of
un
as
p
C
ul
a
ni
d
A
M
ic
gi
n
n
fu
ng
i
le
az
o
on
Vo
r ic
Fl
uc
on
az
ol
e
ol
e
on
az
Itr
ac
A
m
ph
ot
er
ic
in
B
0%
Wang JL et al. Antimicrob Agents Chemother. 2010;54:2409-19
Indicazioni terapeutiche delle echinocandine
Micafungina
Caspofungina
Anidulafungina
SI
SI
SI
pazienti neutropenici
SI
SI
SI
pazienti pediatrici
SI
≥ 12 MESI
NO
Adulti
SI
NO
NO
Pazienti pediatrici
SI
NO
NO
Neonati
SI
NO
NO
SI
NO
NO
NO
SI
NO
NO
SI
NO
3650
4119
3060
Candidosi invasiva
Profilassi in pazienti HSCT
Candidosi esofagea
Aspergillosi invasiva
Salvataggio
Terapia empirica neutropenia
febbrile
Costo 10 gg 70 Kg
Antifungal lock therapy C.J. Walraven AAC 2013
• Amfotericina desossicolato (0,33mg/ml)
• Amfotericina liposomiale (2,67 mg/ml)
• Caspofungina (3,33 mg/ml)
• Etanolo
Caspofungina
Micafungina
Anidulafungina
Indicazioni
terapeutiche
Ampie
Ampie
Limitate
Indicazioni
pediatriche
SI
SI
NO
Variazione
posologica
?
No
Interazioni
+/-
+/-
+/-
Effetti
collaterali
Limiti
+/-
+
+/-
Warning EMEA
Costo
+++
Studi clinici
limitati
+
Variazioni in
insuff. epatica
++
D. Cattaneo
D. Cattaneo
D. Cattaneo
A.M. Tortorano 2015 ACCP
Antifungal resistance in Candida
Confirmed by mutations
in fsk1 gene
Echinocandins
Candidemia 2009
(464 isolates)*
<2%
(2 C.glabrata,
22.4% in C.parapsilosis
biased by outbreak isolates
Candidemia in ICU
(302 isolates)**
0%
1 C. krusei isolates)
Fluconazole
Amphotericin
B
24.9%
12.6%
(C.krusei + mainly
(C.krusei + mainly
C.glabrata and
C.tropicalis isolates)
C.parapsilosis, C.tropicalis
and C. glabrata isolates)
0%
0%
* Infection 2014
** JMM 2012
Antifungal resistance in Candida:
our experience
Candidemia
2009
(464 isolates)*
Candidemia
in ICU
2006-08
Candidemia in
Lombardia
2014-15
(302 isolates)**
(229 isolates)***
Echinocandins
<2%
0%
0%
Fluconazole
24.9%
12.6%
6.5%
0%
0%
0%
AmphotericinB
* Infection 2014
A.M. TORTORANO 2015 ACCP
** JMM 2012
*** CAND-LO