Terapia empirica e mirata delle infezioni invasive da Candida
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1 Terapia empirica e mirata delle infezioni invasive da Candida Francesco Menichetti, MD Head, Infectious Diseases Unit Ospedale Nuovo Santa Chiara Pisa, Italy Corso Avanzato di Terapia Antibiotica X Edizione Pisa 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 Pisa Hospital: 373 episodes ICU 67 17% surgery 89 23% Others 11 % internal medical ward %
5 Candidemia Pisa Hospital: 373 episodes 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
6 21, 9: e71-e72
7 Intensive Care Medicine 2015, 41, 8:
8 Intensive Care Medicine 2015, 41, 8: Cateteri Venosi Centrali 120,00% 100,00% 80,00% 60,00% 40,00% 20,00% 0,00% Totale Medicine Interne UTI PICC altri CVC PICC medicine vs UTI: p<0,001
9 Intensive Care Medicine 2015, 41, 8: Early onset vs. Late onset candidemia 90,00% 80,00% 75% 81% 70,00% 60,00% 59% 50,00% 40,00% 41% 30,00% 20,00% 25% 19% 10,00% 0,00% Totale Medicine Interne UTI EOC( 10 gg) LOC(> 10 gg)
10 Comparison in pairs between very early-onset, candidemia. early-onset and late onset candidemia Very early onset candidemia (n=24) Early onset candidemia (n=19) Table 2: Comparison in pairs between very early onset candidemia, early onset candidemia, and Late onset candidemia (n=29) 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%) 8/19 (42%) 17/29 (59%) PICC 20/24 (83%) 7/19 (37%) 10/29 (34%) Intensive Care Medicine 2015, 41, 8:
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 SIRS Sepsi grave o shock settico Altre infezioni Altre comorbilità Diabete mellito CT o RT Terapia corticosteroidea Terapia immunosoppressiva Decesso 87 pts with fever 41 pts without fever
13 297 candidemia in IMWs in Pisa, Rome & Udine hospitals SIRS Sepsi grave o shock settico Altre infezioni Altre comorbilità Diabete mellito CT o RT Terapia corticosteroidea Nessuna terapia antifungina Terapia immunosoppressiva 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 Antifungal therapy Med Int (n=64) ICU (n=26) < 24h 27 (30%) 15 (23,4%) 12 (46,1%) Serious risk for delay in diagnosis & untimely and inappropriate antifungal therapy 24/48h 13 (13,3%) 10 (15,6%) 3 (11,5%) 48/72h 8 (8,9%) 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%)
16 224 consecutive patients with septic shock and a positive blood culture for Candida species. Kollef M et al. Clin Infect Dis Jun;54(12):
17
18 What are the best tests for diagnosing candidaemia? Specimen Test Considerations Remarks/Recommendations Serum Mannan and Anti- Mannan Combined detection RECOMMENDED Serial determinations may be necessary. High NPV Other antibodies (such as Serion ELISA classic) ß-D-Glucan Septifast In house PCR Limited data for candidemia Not specific for Candida Limited data for candidemia No third party validation data available 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 No recommendation
19 CAGTA Antibody against the C.albicans germ-tube Virulence factor
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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)
23
24 Biofilm activity of antifungals vs different Candida species Choi HW et al. Antimicrob Agents Chemother 2007; 51:
25 % Multidrug resistance common: fluconazole resistance in 36% Alexander BD, Clin Infect Dis 2013;56: ; Pham CD et al. Antimicrob Agents Chemother 2014;58:
26 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
27
28 1915 patients from 7 trials; Overall mortality % Treatment success % Rex et al. (1994): 237 patients, enrollment ; fluco vs d-amb Mora-Duarte et al. (2002): 239 pts, ; caspo vs d-amb Rex et al. (2003): 236 pts, ; FLU vs d-amb Kullberg et al. (2005): 422 pts, ; vori vs d-amb > fluco Reboli et al. (2007): 245 pts, ; anidula vs fluco Kuse et al. (2007): 264 pts, ; mica vs liposomal AmB Pappas et al. (2007): 595 pts, ; mica > fluco vs caspo > fluco Clin Infect Dis 2012;54(8):
29 Mortality and species C. tropicalis 41% vs other species 29%; P< 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< % for triazoles vs 30% for other drugs; P= % for polyenes vs 30% for other drugs; P=0.04 Clin Infect Dis 2012;54(8):
30 Invasive candidiasis
31
32 Site-oriented antifungal therapy Endocarditis: echinocandins plus lipid Ampho (5FC) Chorioretinitis: fluco/lipid Ampho (Intravitreal Ampho B) Endophtalmitis: Intravitreal Ampho + Voriconazole or lipid Amphotericin B; vitrectomy Meningitis: lipid ampho +/-5FC (azoles) Spondylitis/osteomyelitis: fluconazole or lipid Ampho or echinocandins
33 Peritonitis Treat empirically for Candida if: Recurrent surgery for bowel perforation or anastomotic leaks Presence of acute necrotizing pancreatitis Post-Liver-Pancreas transplantation Concomitant candidemia Pure peritoneal culture of Candida species Echinocandins, lipid amphotericin B
34
35 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
36 Candida isolation from respiratory secretions in pts with pneumonia A 2-year autopsy study on 232 ICU pts 135 pts with pneumonia No Candida Pneumonia in 77 pts with pneumonia at autopsy & positive TA and/or BAL cultures for Candida in the previous 2 weeks No Candida Pneumonia in the other 58 pts without pre-mortem Candida isolation Meersseman W ICM 2009; 35:
37 Comparison between different antifungals for IC/C Fluconazole Echinocandins Amphotericin B Spectrum of activity limited broad broad Antifungal activity fungistatic mostly fungicidal fungicidal Biofilm activity low mostly active active Safety high very high nephrotoxicity Evidence in IC/C Guidelines (IDSA/ESCMID) Inferior to anidulafungin better than fluco, similar to ampho adequate C III/DI AI BI (liposomal) Cost very low medium very high (liposomal)
38 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
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