1. 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

2. 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

3. Risk Factors for Invasive Candidiasis

4. Candidemie 2012-2014 Pisa Hospital: 373 episodes

5. Isolates 373 Patients 351 C. albicans 188 (50%) C. parapsilosis 98 (26%) C. glabrata 38(10%) C. tropicalis 23(6%) C. krusei 8 others 22 Candidemia 2012-2014 Pisa Hospital: 373 episodes

6. 21, 9: e71-e72

7. Intensive Care Medicine 2015, 41, 8: 1498-1499

8. Cateteri Venosi Centrali PICC medicine vs UTI: p<0,001 Intensive Care Medicine 2015, 41, 8: 1498-1499

9. Early onset vs. Late onset candidemia Intensive Care Medicine 2015, 41, 8: 1498-1499

10. Very early onset candidemia (n=24) Early onset candidemia (n=19) Late onset candidemia (n=29) Intensive care unit admission1/24 (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 wards0/24 (0%)3/19 (16%)11/29 (38%) Nasogastric tube8/24 (33%)9/19 (47%)16/29 (55%) Central venous catheter1/24 (4%)8/19 (42%)17/29 (59%) PICC 20/24 (83%)7/19 (37%)10/29 (34%) Comparison in pairs between very early-onset, early-onset and late onset candidemia Intensive Care Medicine 2015, 41, 8: 1498-1499

11. Candidemia in pts with PICC showed to be associated with higher mortality in comparison with CVC and no CVC use

12. 128 candidemia in IMW, Pisa: 68% with fever, 32% without fever 100 90 80 70 40 50 0 30 20 10 SIRSSepsi grave o shock settico Altre infezioni Altre comorbilità Diabete mellito CT o RTTerapia corti- costeroidea Terapia immuno- soppressiva Decesso 87 pts with fever 41 pts without fever

13. 297 candidemia in IMWs in Pisa, Rome & Udine hospitals 100 60 90 80 70 40 50 0 30 20 10 SIRSSepsi grave o shock settico Altre infezioni Altre comorbilità Diabete mellito CT o RTTerapia corti- costeroidea Nessuna terapia anti- fungina Terapia immuno- soppressiva Decesso 147 pts with fever 150 pts without fever

14. 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

15. Candidemia, Pisa Hospital 2012-2013 Antifungal therapy Med Int (n=64) ICU (n=26) < 24h27 (30%)15 (23,4%)12 (46,1%) 24/48h13 (13,3%)10 (15,6%)3 (11,5%) 48/72h8 (8,9%)5 (7,8%)3 (11,5%) >72h10 (11,1%)6 (9,4%)4 (15,4%) no therapy22 (27,5%)20 (35,7%)2 (8,3%) In hospital mortality (%)39 (43,3%)24 (37,5%)15 (57,7%) Serious risk for delay in diagnosis & untimely and inappropriate antifungal therapy

16. Kollef M et al. Clin Infect Dis. 2012 Jun;54(12):1739-46 224 consecutive patients with septic shock and a positive blood culture for Candida species.

18. What are the best tests for diagnosing candidaemia? SpecimenTestConsiderationsRemarks/Recommendations SerumMannan and Anti- Mannan Other antibodies (such as Serion ELISA classic) ß-D-Glucan Septifast In house PCR Combined detection Limited data for candidemia Not specific for Candida Limited data for candidemia No third party validation data available RECOMMENDED Serial determinations may be necessary. High NPV No recommendation RECOMMENDED (for Fungitell) No recommendation for other tests. Serial determinations are recommended (twice a week). High NPV. Not validated in children No recommendation

19. CAGTA Antibody against the C.albicans germ-tube Virulence factor

21. 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

22. 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)

24. Biofilm activity of antifungals vs different Candida species Choi HW et al. Antimicrob Agents Chemother 2007; 51:1520-23

25. Alexander BD, Clin Infect Dis 2013;56:1724-32; Pham CD et al. Antimicrob Agents Chemother 2014;58:4690-6.  Multidrug resistance common: fluconazole resistance in 36% %

26. 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

28. Clin Infect Dis 2012;54(8):1110-22 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

29. 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 Clin Infect Dis 2012;54(8):1110-22 Mortality and treatment 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 The choice of antifungal drug influence the patient outcome influence the patient outcome The choice of antifungal drug influence the patient outcome influence the patient outcome

30. Invasive candidiasis

32. 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

33. 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

34. 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