1 / 53

Gestione pratica delle infezioni fungine in terapia intensiva

Gestione pratica delle infezioni fungine in terapia intensiva. Matteo Bassetti Clinica Malattie infettive A.O.U. San Martino Genova. Relationship between hospital mortality and the timing of antifungal treatment. 35. 30. 25. 20. Hospital mortality (%). 15. 10. 5. 0. < 12. 12–24.

robyn
Download Presentation

Gestione pratica delle infezioni fungine in terapia intensiva

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Relationship between hospital mortality and the timing of antifungal treatment 35 30 25 20 Hospital mortality (%) 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

  3. Mortality associated with Candida infections in ICU *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 0 7 14 21 28 Pelz Ann Surg 233:542-548, 2001

  5. Prophylaxis in the (S)ICU • Pelz et al., Ann Surg 233:542-548, 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% 7,5% 10 0 Complications Emergence of colonization Death Sandven CCM 2002

  7. P<0.01 100 % P<0.001 78% 80 66 NS 60 53 41% 39 40 30% NS P=0.014 20 7% 6% 3% 0 0 Success of prophylaxis Emergence colonization by Candida Death from any cause Invasive candidosis Candidemia RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS Garbino et al. Intensive Care Med 2002;28:1708-1717 Fluconazole 100 mg/d Placebo

  8. Antifungals in critically ill and surgical patients: meta-analysis • NNT= 94 • NNT in high-risk= 9 • NNT in low risk= 188 Impact on Candidal infections Impact on mortality 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 (1.42/10 000 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

  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; 34:730- 737

  16. Candida score validation León C et al Crit Care Med. 2009;37:1624-33

  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. (13)-β-D-GLUCAN CONCENTRATIONS _____ BG values Pg/ml _____ _____ _____ PCBSI NCBSI CONTROLS CBSI 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. 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 95% CI / P-value n (ITT) 133 137 Success 44 (36%) 48 (38%) 0.69–1.32; P = 0.78 Invasive mycosis 6 (5%) 11 (9%) RR 0.57; 0.22–1.49 30-Day mortality 29 (24%) 22 (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 Cisterna R et al. J Clin Microbiol 2010; doi:10.1128/JCM.00920-10

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

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

  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

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

  35. H N Chemical Structures Caspofungin Anidulafungin Micafungin Glarea lozoyensis Coleophoma empetri Aspergillus nidulans OH HO HO OH H2N O O HO HO O O OH NH NH NH H3C O H3C HO NH NH O NH H2N N O N O N H3C NH O O OH HN H OH O H2N O N O OH O HN O NH O H3C NH H CH3 HO HO CH3 H O CH3 N CH3 CH3 O N O O NH HN HO HO HN HO H H H3C O HN OH O OH OH OH S O O OH OH O O O OH 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.

  36. Attività in vitro delle echinocandinenei confronti di Candida spp. Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6

  37. Pharmacology: Metabolism, Elimination, Bioavailability, and Protein Binding Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.

  38. Echinocandin studies

  39. Echinocandins Approved IndicationsEMEA * 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

  40. 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

  41. 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

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

  43. 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

  44. 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

  45. Candidemia in cancer patients: Impact of early removal of catheter Liu CY et al. J Infect 2009; 58:154-160

  46. BIOFILM

  47. Tumbarello et al JCM 2007

  48. P = 0,04 Biofilm Production by Candida spp

More Related