1. Gestione pratica delle infezioni fungine in terapia intensiva
Matteo Bassetti
Clinica Malattie infettive
A.O.U. San Martino
Genova

2. Hospital mortality (%) Delay in start of antifungal treatment (hours)
Relationship between hospital mortality and the timing of antifungal treatment 35 30 25 20
Hospital mortality (%) 15
This study provides further evidence that delayed treatment results in increased mortality.1
There is a need to focus on improved diagnosis of fungal infections, so that they can be treated early and adequately to reduce mortality.
Morrell M, et al. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49:3640–3645. 10 5
< 12
12–24
24–48
> 48
Delay in start of antifungal treatment (hours)
Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

3. Mortality associated with Candida infections in ICU
Variable
Mortality rate (%)*
Department
Medical
Surgical 58 37
Candida species
C. albicans
C. parapsilosis
C. glabrata 36 33 69
Overall 41
*Crude mortality.
Tortorano AM, et al. 3rd TIMM. Turin, Italy,28–31 Oct 2007; Oral communication O.07

4. Fluco in High-risk SICU patients
260 surgical ICU patients (stay > 3days) randomized
to double-blind oral antifungal prophylaxis
0.6
Placebo
0.5
Proportion infected
0.4
0.3
Fluconazole
0.2
0.1
p < 0.01 by log-rank test
Days 7 14 21 28
Pelz Ann Surg 233: , 2001

5. Prophylaxis in the (S)ICU
Pelz et al., Ann Surg 233: , 2001
Fluco vs. placebo in extremely high risk ICU
Placebo: 16% rate of invasive candidiasis
This rates equals that in BMT
Fluco 400/d: 8% rate
P < 0.01
A very unusual population
Median APACHE III = 60, lots of liver transplant
Applicability in most ICUs is unclear

6. Sandven et al.: Low-risk surgical patients
Double-blind single-dose antifungal prophylaxis in
109 patients with intra-abdominal perforation
60 % NS 50
43% 40
34% NS 30 NS 20
14%
10%
10% 10
7,5%
Emergence of
colonization
Complications
Death
Sandven CCM 2002

7. RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS
Garbino et al. Intensive Care Med 2002;28: 53
78%
P<0.01 66
30%
P<0.001 39
41% NS 3% 7% 6%
P=0.014 20 40 60 80
100 %
Success of
prophylaxis
Emergence
colonization
by Candida
Death
from
any cause
Invasive
candidosis
Candidemia
Fluconazole 100 mg/d
Placebo

8. Antifungals in critically ill and surgical patients: meta-analysis
Impact on Candidal infections
Impact on mortality
NNT= 94
NNT in high-risk= 9
NNT in low risk= 188
Playford et al. JAC 2006; 57: 628–638

9. PROPHYLACTIC FLUCONAZOLE…..
HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort

10. ……..BUT HAS ELIMINATED CANDIDA COLONISATION! More patient comfort
DID NOT REDUCE MORTALITY
HAS SELECTED RESISTANT CANDIDA SPECIES

11. ◊ incidence of candidemia episodes/10 000 patient-days/year; ■ DDD’s of fluconazole x 100 pts/days
Shift from CA to CNA
Bassetti M et al. BMC Infect Dis 2006; 10: 621

12. Restriction of prophylactic fluconazole use Bassetti et al – JAC 2009; 64:625-629
Med-surg ICU (500 adm./an)
108 months (Jan 99-Dec 2007)
Overall prevention of NI unchanged
213 candidemia (1.42/ patient-days)
albicans (46%), parapsillosis (22%), glabrata 13%
Intervention:
Janv 1999-Janv 2003: Extensive Prophylaxis
Janv 2003-Dec 2007:Incitation not to do
Statistical analysis:
Segmented linear regression
Objectives: Candida spp. are the most important non-bacterial pathogens in critically ill patients. The
aim of this study was to evaluate trends in the incidence of candidaemia and the distribution of
Candida albicans and non-albicans over a 9 year period (1999–2007), and to assess their relationship
with fluconazole use.
Methods: This was an interventional cross-over study. Patients admitted to the intensive care unit
(ICU) who developed a clinically and microbiologically documented candidaemia were analysed.
Fluconazole was used as prophylaxis in critically ill patients until 2002; from January 2003 infectious
disease consultants strongly discouraged its use. Fluconazole use, measured as defined daily dose
per 1000 patient-days, was calculated. The main outcome of the study is the evaluation of the restriction
policy in terms of change in fluconazole use and in incidence of candidaemia.
Results: During the 108 month period (January 1999–December 2007), a total of 213 episodes of candidaemia
(average incidence 1.42 episodes/10000 patient-days/year, range 0.36–3.02 episodes) were
recorded in a mixed medical and surgical ICU in Italy. C. albicans was the most prevalent isolated
species (n598, 46%); non-albicans (n5115, 54%) were mainly represented by Candida parapsilosis
(n546, 22%) and by Candida glabrata (n528, 13%). Segmented regression analysis of the interrupted
time series showed that a change in the fluconazole prophylactic strategy resulted in a significant
reduction in fluconazole use from the second semester of A dramatic decrease in the incidence
of fungaemia due to C. non-albicans was observed from the second semester of 2003 (intervention
effect in the second semester of 2007: 22.31/10000 patient-days); minor changes in the incidence of
C. albicans fungaemia emerged (intervention effect in the second semester of 2007: 20.23/10000
patient-days).
Conclusions: The study showed a clear correlation between fluconazole use control and decreasing
incidence of non-albicans candidaemia. Even if fluconazole remains a first-line treatment option in
several cases of invasive candidiasis, its prophylactic use should be carefully evaluated.

13. Incidence of Candidemia and fluconazole in ICU
Stop fluco
Stop fluco
Non-albicans candidaemia
C. albicans candidaemia X
Bassetti M et al. J Antimicrob Chemother 2009: 64:625-9.

14. So what about pre-emptive therapy with predicitive rules?

15. Candida Score
Leon C et al. Crit Care Med 2006; 34:

16. Candida score validation
León C et al Crit Care Med. 2009;37:

17. Other Predictive rules
The best performing predictive rule was:
Patients in the ICU >4 days
AND
Any systemic antibiotic (days 1–3) OR
Central venous catheter (days 1–3)
AND at least two:
Total parenteral nutrition (days 1–3)
Any dialysis (days 1–3)
Major surgery (days -7–0)
Pancreatitis (days -7–0)
Any use of steroids (days -7–3)
Immunosuppressive agents (days -7–0)
Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis 2007

18. CONTROLS: healthy volunteers
(13)-β-D-GLUCAN CONCENTRATIONS
_____
BG values
Pg/ml
_____
_____
_____
CBSI
PCBSI
NCBSI
CONTROLS
CBSI: proven Candida BSI PCBSI: possible Candida BSI NCBSI: no Candida BSI
CONTROLS: healthy volunteers
Horizontal bars indicate median values
Del Bono V et al. 49th ICAAC, 2009

19. Criteria to start pre-emptive antifungal therapy
Pz. In ICU ≥ 4 days.
Abx in the last 7 days O
CVC from 7 days
2 of the following:
Total parenteral nutrition (days 1–3)
Any dialysis (days 1–3)
Major surgery (days -7–0)
Pancreatitis (days -7–0)
Any use of steroids (days -7–3)
Immunosuppressive agents (days -7–0)
Start antifungal
Candida colonization or
(1-3)-ß-D-glucan

20. Different antifungal strategies
Bassetti M et al. Crit Care 2010 December 1

21. Bassetti M et al. Crit Care 2010 December 1

22. Empiric use of antifungals in the ICU setting
Still no good data clinical for empiric antifungal therapy in the non-neutropenic population
Follow fundamental principles for treating candidemia
Utilize serologic markers, surveillance cultures, and/or a ‘scoring system’ to determine most appropriate use
Duration of therapy not specifically addressed, although the implication is to curtail therapy in stable patients absent positive culture/serologic data
Pappas PG, et al. Clin Infect Dis 2009; 48: 503–35

23. 15 July 2008

24. Schuster et al, Ann Intern Med 2008
Double-blind, placebo-controlled trial with fluconazol 800 mg (x 14d)
in 270 adult IC-patients:
4 days of fever (>38.3°C)
ICU stay > 96h
APACHE II ≥ 16
Broad spectrum antibiotics
Central line ≥ 24h
Fluconazol Placebo % CI / P-value
n (ITT)
Success (36%) (38%) –1.32; P = 0.78
Invasive mycosis (5%) (9%) RR 0.57; 0.22–1.49
30-Day mortality (24%) (17%) RR 1.36; 0.82–2.24
Schuster et al, Ann Intern Med 2008

25. Susceptibility profile of Candida species
Dodds Ashely ES et al. Clin Infect Dis 2008 ; 43: S28–39

26. Distribution of the Candida spp. In vitro susceptibility to fluconazole
305 isolates identified, 210 isolates tested
17% fluconazole-R or S-DD (using validated susceptibility testing methods)
Leroy et al. Crit Care Med 2009; 37:1612–1618

27. In vitro susceptibility to fluconazole in patients naïve and previously exposed to azoles in ICU
Leroy et al. Crit Care Med 2009; 37:1612–1618

28. Initial empiric antifungal treatment (n=271)
Fluconazole
Caspofungin
Voriconazole
Caspofungin + Fluconazole
Liposomal amphotericin B
Amphotericin B deoxycholate
Itraconazole
Caspofungin + Voriconazole
Amphotericin B lipid complex
Amphotericin B deoxycholate + Fluconazole
Amphotericin B deoxycholate + Flucytosine
Amphotericin B deoxycholate + Voriconazole
Liposomal amphotericin B + Caspofungin
Liposomal amphotericin B + Flucytosine
Leroy et al. Crit Care Med 2009; 37:1612–1618

29. Risk factors for fluconazole resistance
Odds ratio
95 percent confidence Limits
P - value
Neoplasia
2.9
1.4 – 5.9
≤ 0.005
Prior fluconazole use
3.8
1.7 – 8.2
≤ 0.001
Cisterna R et al. J Clin Microbiol 2010; doi: /JCM

30. IDSA- Candidemia in non-neutropenic
If species is unknown, either fluconazole (800mg loading dose, 400 mg daily) or an echinocandin is appropriate initial therapy for most adult patients (AI)
An echinocandin is favored if
Moderately severe to severe illness,
Recent azole use for treatment or prophylaxis (AIII), or
Isolate is known to be C. glabrata or C. krusei (BIII)
Fluconazole for patients who are
less critically ill and
who have no recent azole exposure (AIII).
Move from candin to fluconazole when isolates likely susceptible to fluconazole (e.g., C. albicans) and patient is clinically stable (AIII)
Remove or exchange intravenous catheters
Treat for two weeks after clearance of bloodstream

31. Treatment in ICU Clinical Infectious Diseases 2009; 48:503–35
Empirical treatment(IA)
yes (A-III)
No (A-III)
fluconazole
echinocandin
Azole exposure
High risk of C. glabrata or krusei ? Or severe (A-III)
yes No
Clinical Infectious Diseases 2009; 48:503–35

32. Sensitive to fluconazole
Secondary adapted to results. Invasive candidiasis - IDSA 2009
Clinical Infectious Diseases 2009; 48:503–35
Clinicaly stable
Yes No
Known fungi
Sensitive to fluconazole
C. parapsilosis
C. Glabrata (B-III)
C krusei (A-I)
Yes (B-III) No
fluconazole
AmB-L
echinocandin

33. Major changes from the previous IDSA Guidelines (2004)
Emphasis on fluconazole and echinocandins as the ‘preferred choices’ for proven/suspected IC
De-emphasis on AmB and LFAmB under most circumstances
Concept of step down therapy is strongly encouraged
There is little distinction made between the echinocandins

35. Antifungal drug studies candidaemia
P=.39
P=.04
P=.09
P=.82
P=.27
P=.009
P=.64
76%
73%
71%
72%
74%
72%
62%
70%
69%
60%
56%
53%
Fluconazol (800)
Amfotericine B + Flu
Caspofungin
Micafungin
L-Amfotericine B
Amfotericine B
Amfotericine B Fluconazol
Voriconazole
Fluconazole
Anidulafungin
Fluconazol
50%
Fluconazole
AMB
Phillips, 1995
Flu
AMB + Flu
Rex, 2003
AMB
Caspofungin
Mora-Duarte, 2002
Caspofungin
Micafungin
Pappas, 2007
Micafungin
Liposomal AMB
Kuse, 2007
Anidulafungin
Fluconazole
Reboli, 2007
Voriconazole
AMB->Flu
Kullberg, 2005
MITT - Investigator-Assessed Response at End of Treatment (%)
Adapted from Kullberg BJ, et al. Lancet. 2005

36. Chemical Structures Caspofungin Micafungin Anidulafungin
Glarea lozoyensis
Coleophoma empetri
Aspergillus nidulans
H2N HO OH HO OH HO O O HO O O NH OH NH NH
H3C HO O
H3C NH NH NH O
Currently, 3 echinocandins are commercially available: caspofungin, micafungin, and anidulafungin.1,2
The echinocandins are structurally related cyclic peptides with similar cyclic hexapeptide cores but different side chains3–5:
Caspofungin has a fatty-acid side chain
Micafungin has a complex aromatic side chain (3,5 diphenyl-substituted isoxazole)
Anidulafungin has an alkoxytriphenyl (terphenyl) side chain
These side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity.3,6
Anidulafungin, unlike caspofungin and micafungin, is insoluble in water due to its hydroxyl and methyl side chains, and therefore requires a special companion diluent, 20% (w/w) dehydrated alcohol in water for injection, for reconstitution.1,2,7
Micafungin is a light-sensitive molecule that must be protected from light.1
Anidulafungin is synthesized from the fermentation product of Aspergillus nidulans; caspofungin and micafungin are derived from other naturally occurring substances.1,2
H2N N O N O
N H O N H
H2N O H N OH
H3C O HN OH N O O O HN OH H
H3C HO NH O
CH3 HO NH O H
CH3
CH3
CH3
CH3 O N O N O HO NH O HO
H N
H N O H H HO
H3C
H N O OH OH OH S OH OH O O OH O OH O O O HO HO HO
H3C
Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281.
Note to countries: Information about anidulafungin and micafungin based on US labels may not apply to your local markets. Please consult the local labels for these products and revise contents accordingly.
References
Mycamine™ (micafungin sodium) For Injection. US Prescribing Information, Astellas Pharma US, Inc., June 2006.
Eraxis™ (anidulafungin) For Injection. US Prescribing Information, Roerig Division of Pfizer Inc, February 2007.
Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol. 1994;48:471–497.
Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis. 1997;10:449–458.
Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362:1142–1151.
Debono M, Turner WW, LaGrandeur L, et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38:3271–3281.
Rapp RP. Changing strategies for the management of invasive fungal infections. Pharmacotherapy. 2004;24:4S–28S.

37. Attività in vitro delle echinocandine nei confronti di Candida spp.
Organismo
MIC90 (µg/ml)
Numero di isolati
Micafungina
Caspofungina
Anidulafungina
C. albicans
2.869
0.03
0.06
C. parapsilosis
759 2 1
C. glabrata
747
0.015
0.12
C. tropicalis
625
C. krusei
136
0.25
C. guilliermondii 61
C. lusitaniae 58
0.5
C. kefyr 37
C. famata 24
Candida spp. 30
Micafungin is more potent in vitro than both caspofungin and anidulafungin against C. glabrata and remained active against a strain of C. glabrata that was non-susceptible to both anidulafungin and caspofungin.1
Micafungin has also been shown to be active against isolates with acquired or inherent resistance to polyenes and azoles.1
Pfaller MA, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol 2008; 46:150–156.
Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6

38. Pharmacology: Metabolism, Elimination, Bioavailability, and Protein Binding
Caspofungin
Micafungin
Anidulafungin
Metabolism
Hepatic metabolism by hydrolysis and N-acetylation
Spontaneous nonhepatic chemical degeneration
Hepatic metabolism by arylsulfatase and catechol-O-methyltransferase
Nonhepatic chemical degradation
Elimination/excretion
Urine 41%
Feces 34%
Urine + feces 82.5%
Feces 71%
Urine <1%
Feces ≈30%
Protein Binding
97%
>99%
Oral Bioavailability
<5%
Dialyzable No
The primary metabolic mechanism for caspofungin is mediated by hepatic enzymes, which is also the reported mode of metabolism for micafungin. Caspofungin also secondarily undergoes spontaneous chemical degradation, the primary metabolic mechanism for anidulafungin.1,2
There are significant differences in the elimination pathways for the echinocandins. Caspofungin is excreted in approximately equal proportions via the urine and feces; micafungin and anidulafungin are primarily excreted via the feces.1,2
Protein binding for the echinocandins ranges from 97% for caspofungin to over 99% for micafungin and anidulafungin.1,2
Protein binding for anidulafungin was previously reported as 84%.3
The clinical significance of protein binding for the echinocandins has not been established.4
Oral bioavailability is poor (<5%) for all of the echinocandins,5 and therefore these drugs must be administered parenterally.6
None of the echinocandins is dialyzable.1,2,7
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.
References
Mycamine™ (micafungin sodium) For Injection. US Prescribing Information, Astellas Pharma US, Inc., June 2006.
Eraxis™ (anidulafungin) For Injection. US Prescribing Information, Roerig Division of Pfizer Inc, February 2007.
Eraxis™ (anidulafungin) For Injection. US Prescribing Information, Roerig Division of Pfizer Inc, March 2006.
Theuretzbacher U. Pharmacokinetics/pharmacodynamics of echinocandins. Eur J Clin Microbiol Infect Dis. 2004;23:805–812.
Dodds Ashley ES, Lewis R, Lewis JS, el al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006;43:S28–S39.
Wagner C, Graninger W, Presterl E, Joukhadar C. The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications. Pharmacology. 2006;78:161–177.
Morrison VA. Echinocandin antifungals: review and update. Expert Rev Anti Infect Ther. 2006;4:325–342.

39. Prior antifungal therapy
Echinocandin studies
Mora-Duarte
Kuse
Reboli
Caspo
AMB
Mica
L-AMB
Anidu
Fluco
Apache <20
80,7 80 72 76 83
Apache > 20
19,3 20 28 24 21 17
Prior antifungal therapy 56 67 NA
C. albicans 35 54
42,6
44,2 64 59
C. parapsilosis
19,8
18,3
15,8 10 14
C. glabrata
12,8
9,2
11,4
7,9 16 25
C. krusei 4
0,9 3
3,7
Excl..
Excl.
Neutropenia (< 500)
8,7 12 2
Fav. response (EOT)
64,9
89,6
89,5
75,6
60.2
Mortality
34,2
30,4
22,8
31,4

40. Echinocandins Approved Indications EMEA
Empirical Therapy in Febrile Neutropenic Pts
Therapy in Proven Infections
Therapy of Oesophageal Candidiasis
Prophylaxis of Candida- Infections in HSCT Patients
Candida spp.
Aspergillus spp.
Caspofungin
Children
Yes
(Salvage therapy) No
Adults
(Salvage Therapy)
Anidulafungin
Micafungin*
Yesa
* The decision to use micafungin should take into account a potential risk for the development of liver tumours. Micafungin should therefore only be used if other antifungals are not appropriate

41. Candida colonization Is frequent in ICU patients
The gut is the main portal of entry in neutropenic patients
The skin is an important source of candidemia in non-neutropenic patients
Tracheal colonization reflect oropharyngeal colonization and is not associated with candidal pneumonia in non- neutropenic ICU patients

43. Independent predictors for outcome:
Is Candida colonization of CVC in non-candidemic an indication for antifungals?
58 pts ( 91% in ICU)
Independent predictors for outcome:
ultimately fatal underlying disease (P = 0.02)
severe sepsis, septic shock or multiorgan failure (P = 0.05).
Antifungal therapy does not seem to have a significant influence on clinical outcome
Perez-Parra A et al. Intensive Care Med 2009; 35:707–712

44. OUTCOME OF CANDIDEMIA IN THE UK 1997-99 IMPACT OF CATHETER MANAGEMENT
No treatment (n=31)
58%
No line removal + antifungal
(n=29)
31%
26%
Day 30 mortality
overall (n = 163)
14%
Line removal + antifungal
(n=91)
Kibbler et al. J Hosp Infect 2003; 54:18-24

45. Early removal of central venous catheter in patients with candidemia does not improve outcome
Nucci M et al. Clin Infect Dis 2010; 51:295–303

46. Early removal of central venous catheter in patients with candidemia does not improve outcome
Nucci M et al. Clin Infect Dis 2010; 51:295–303

47. Candidemia in cancer patients: Impact of early removal of catheter
Liu CY et al. J Infect 2009; 58:

48. BIOFILM

49. Inadequate antifungal therapy
OR (95% CI) P
Inadequate antifungal therapy
2.35 ( )
0.03
Infection biofilm-forming Candida species
2.33 ( )
0.007
APACHE score
1.03 ( )
0.001
Tumbarello et al JCM 2007

50. Biofilm Production by Candida spp

51. Mortality by Biofilm-Producing Isolates

52. Activity against Candida biofilms
L-AMB
L-AMB
Kuhn et al AAC :1773