1. Terapia delle Micosi Invasive
Trieste, PneumoTrieste 2017
Roberto Luzzati
SC Malattie Infettive, Ospedale Maggiore
Azienda Ospedale/Università ASUITS, Trieste

2. Emerg Infect Dis
2014

3. Emerg Infect Dis 2014

4. EJCMID 2017

6. Principali antifungini disponibili per uso clinico o in sviluppo
Polieni
Amfotericina B (AMB) desossicolato (D-AMB)
AMB liposomiale (L-AMB)
AMB complessi lipidici (ABLC)
Azolici
Fluconazolo
Itraconazolo
Voriconazolo
Posaconazolo
Flucitosina
Echinocandine
Caspofungin
Anidulafungin
Micafungin
Novità approvate o in fase II/IIIa
-Isavuconazolo (Basilea)
-Posaconazolo e.v (MSD)
-echinocandina long-acting
(Cidara, US)

8. ANTIFUNGAL AGENTS Range of Activity for Selected Pathogens
Moulds
Yeasts AMB FCZ ITZ VCZ PCZ IVZ CF MF AF Candida albicans
Candida tropicalis
Candida parapsilosis
Candida krusei
Candida glabrata*
Cryptococcus neoformans
Aspergillus fumigatus
Mucor spp
Rhizopus spp
Fusarium spp
AmBisome® exhibits a broad range of activity against yeasts and moulds, and its activity is comparable to conventional amphotericin B1
Although not depicted in this slide, recent data have suggested that voriconazole has variable activity against Fusarium spp2
1. Adapted from JP Donnelly by Malcolm Richardson. Presented at: New Challenges and New Options in the Treatment of Invasive Fungal Infections in Stem Cell Transplant Patients, a Satellite Symposium at the 20th Annual Meeting of the EBMT; March 24, 2002; Montreux, Switzerland.
2. Vfend [package insert]. New York, NY, United States: Pfizer, Inc; 2002.
* Strains with reduced susceptibility to azoles
AMB, Amphotericin B
Azole: FCZ, Fluconazole; ITZ, Itraconazole; VCZ, Voriconazole; PCZ, Posaconazole; IVZ, Isavuconazolo
Echinocandin: CF, Caspofungin; MF, Micafungin; AF, Anidulafungin
Adapted from JP Donnelly, by Malcolm Richardson.

9. Pathogenesis of Invasive Candidiasis.
Figure 1 Pathogenesis of Invasive Candidiasis. Candida species that colonize the gut invade through translocation or through anastomotic leakage after laparotomy and cause either localized, deep-seated infection (e.g., peritonitis), or candidemia. In patients with indwelling intravascular catheters, candidemia that originates from the gut or the skin leads to colonization of the catheter and the formation of biofilm. Fungi are subsequently released from the biofilm, causing persistent candidemia. Once candidemia has developed, whether from a colonized intravascular catheter or by other means, the fungi may disseminate, leading to secondary, metastatic infections in the lung, liver, spleen, kidneys, bone, or eye. These deep-seated infections may remain localized or lead to secondary candidemia. During candidemia, the fungi in the bloodstream may enter the urine, leading to candiduria. Less frequently, deep-seated candidiasis may occur as a result of ascending pyelonephritis and may either remain localized or lead to secondary candidemia.
Kullberg BJ, Arendrup MC. N Engl J Med 2015;373:

10. S. aureus Pathogen Overall % - rank CLA-BSI % – rank CA-UTI VAP SSI
Infect Control Hosp Epid, 2016
Pathogen
Overall
% - rank
CLA-BSI
% – rank
CA-UTI
VAP
SSI
TOTAL ISOLATES
408,151
96,532
153,805
8,805
149,009
CoNS
7.7 – 5
16,4 – 2
1.6 – 9
0.8 – 9
S. aureus
11.8 – 3
13.2 – 4
2.2 – 8
24.7 – 1
20.7 – 1
Enterocococ. spp
14.7 – 2
17.2 – 1
13.8 – 3
0.9 – 8
Candida spp
11.3 – 4
14.3 – 3
17.8 – 2
2.7 – 6
3.2 – 8
E. coli
15.4 – 1
5.4 – 6
23.9 – 1
5.4 – 5
P. aeruginosa
4.0 – 8
10.3 – 4
16.5 – 2
Klebsiella spp
7.7 – 6
8.4 – 5
10.1 – 5
10.2 – 3
4.7 – 6
Enterobacter spp
4.2 – 8
4.4 – 7
3.7 – 7
8.3 – 4
Proteus spp
2.8 – 9
1.4 – 7
2.8 – 9.
CoNS, coagulase-negative stafilococci; CLABSI, central line associated bloodstream infection; CAUTI, catheter-associated urinary tract infection; VAP, ventilator associated pneumonia; SSI, surgical site inf.

12. EJIM 2017

13. EJIM 2017

14. 2011-2013: 686 adult patients (52% males); mean age 70 + 15 yrs
21%
54%
25%
Infection, 2016
: 686 adult patients (52% males); mean age yrs

15. variables OR (95%CI) P-value 30/266 (11.27) 83/333 (25)
Table 4. Comparison of treatment and outcome
according to ward admission
variables
Surgery/ICUs
(319 pt)
Medicine wards
(367 pt)
OR (95%CI)
P-value
Inadeguate antifungal therapy
30/266 (11.27)
83/333 (25)
2.61 ( )
<0.001
No antifungal therapy
25/266 (9.3)
48/333 (14.4)
1.62 ( )
0.062
Adeguate therapy + CVC removal
147/212 (69.3)
97/208 (46)
0.39 ( )
Surgery/ICUs, surgery and intensive care units; OR, odds ratio (misure quantitative OR per unit); CI, confidence interval; NA, not available
Infection, 2016

16. Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis (ESCMID, 2012)
Intervention
SoR
QoE
Reference
Comment
Anidulafungin 200/100 mg A I
Reboli NEJM 2007
Broad spectrum, resistance rare, fungicidal
Consider local epidemiology (C. parapsilosis, C. krusei)
Safety profile, less drug-drug interactions than caspofungin
Caspofungin 70/50 mg
Betts CID 2009 Mora-Duarte NEJM 2007 Pappas CID 2007
Consider local epidemiology (C. parapsilosis)
Safety profile
Micafungin 100 mg
Kuse Lancet 2007 Pappas CID 2007
Less drug-drug interactions than caspofungin
Consider EMA warning label

17. Interaction of Aspergillus with the host A unique microbial-host interaction
Acute IA
ABPA
Allergic sinusitis
Frequency of aspergillosis
Frequency of aspergillosis
CNPA
Aspergilloma
Immune dysfunction
Immune hyperactivity . 17

19. Clin Infect Dis 2015

20. Clin Infect Dis 2015

21. Lancet 2016

22. Lancet 2016

23. Lancet 2016
Lancet 2016

24. Lancet 2016

25. Patients with Treatment-emergent Adverse Events (TEAEs)
Isavuconazole N=257 %
Voriconazole
N=259
p-value
Patients with any TEAE
96.1
98.5 NS
Study drug-related TEAEs
42.4
59.8
<0.05
Serious TEAEs
52.1
57.5
Study drug-related serious TEAEs
10.9
11.2
TEAEs leading to study drug discontinuation
14.4
22.8
Study drug-related TEAEs leading to discontinuation
8.2
13.5
Death
31.5
33.6
Lancet 2016

26. CCPA CFPA CNPA Chronic cavitary pulmonary aspergillosis
Chronic fibrosing pulmonary aspergillosis
CNPA
Chronic necrotizing pulmonary aspergillosis

29. 63%

30. Effetti Avversi al Voriconazolo (28,5%)
2 casi di EPATITE
2 casi di REAZIONE PEMFIGOIDE
2 casi di ALLUCINAZIONI
SOSPENSIONE del FARMACO
a 3 e 4 mesi
1 caso lievi e transitorie
1 caso grave
CHIRURGIA
Continua terapia
POSACONAZOLO
Sospensione temporanea ripresa a diverso dosaggio
150 mg x3 volte al giorno
Infection 2015

31. Clin Infect Dis 2016

33. Clin Infect Dis 2016

34. AAC 2016

35. Clin Infect Dis 2016