ICU侵袭性真菌感染治疗策略

1、ICU侵袭性真菌感染治疗策略Marin KollefAssociate Professor of Medicine Washington University School of MedicineSt Louis, Montana, USATreatment Strategies in the ICU: Early Targeted and Empiric TherapiesECCMID 2008 Barcelona, Spain Saturday, 19 April 2008MSD Sponsored SymposiumSuccessful Strategies to Manage Inva

2、sive Fungal Infections: Targeting the Right Patients With Early Appropriate TherapyInvasive Fungal Infections in the ICU: Early Targeted and Empiric TherapiesMarin H. Kollef, MDProfessor of MedicineDirector, Medical Intensive Care UnitDirector, Respiratory Care Services Washington University School

3、of MedicineSt. Louis, MissouriA BALANCING ACTADEQUATEANTIFUNGAL TREATMENTAVOID UNNECESSARYANTIFUNGALS Correct antifungal Rx Combination therapy ? Proper dosing & interval Monitor cultures/labs Susceptibilities ? Colonization vs. infection Duration of therapy Monitor clinical endpoints Diagnostic

4、 evaluationImportance of Fungal Infections in the ICUTypical In Vitro Susceptibility of Candida spp. S=Susceptible S-DD=Susceptible-Dose Dependent I=Intermediate R=ResistantPappas PG et al, Clin Infect Dis 2004;38:161-89; Bartizal K et al, Antimicrob Agents Chemother1997;41:2326-32; Patterson TF. J

5、Chemother 1999;11:504-12; Pfaller MA et al,Antimicrob Agents Chemother 2002;46:1723-7; Pfaller MA et al, J Clin Microbiol 2002;40:852-856.SSSS / RSSC. lusitaniaeSSSS S-DD / RRC. kruseiSS / IS / IS / IS-DD / RS-DD / RC. glabrataSS / IS / IS / ISS / S-DDC. dubliniensisS / I?SSSSSC. parapsilosisSSSSSSC

6、. tropicalisSSSSSSC. albicansCandinsPosaVoriAmBItraFluSpeciesEpidemiologySepsis Causative Organisms: 19792000Martin GS, et al. N Engl J Med. 2003; 348: 1546-1554. Gram-negative bacteriaGram-positive bacteriaFungiNo of Cases of Sepsis1979 81 83 85 87 89 91 93 95 97 99 2001 225,000150,00075,00025,0001

7、5,00010,0005,0000HAI Fungemia: EpidemiologySofair AN, et al. Clin Infect Dis. 2006;43:32-39. DESIGN N=1143 Active surveillance in several regions in the US All patients with candidemia PRIMARY OBJECTIVE Distinction between inpatient and community-associated candidemia OUTCOMES Approximately 1/3 of c

8、ases were community onset Community-onset patients overall met criteria for interaction with the healthcare system Approximate 3-day delay from admission to any antifungal Mortality in HAI fungemia: 26%HAI Fungemia: EpidemiologyType of OnsetCharacteristicInpatient (n=787)Community (n=356)RR (95% CI)

9、PInfecting Candida species Candida albicans384 (49)132 (37)0.76 (0.65-0.89)0.01 Candida glabrata186 (24) 89 (25)1.05 (0.85-1.32) 0.61 Candida parapsilosis 96 (12) 57 (16)1.31 (0.97-1.78) 0.08 Candida tropicalis 88 (11) 53 (15)1.33 (0.97-1.83) 0.08 Candida krusei 5 (0.6) 18 (5)7.96 (2.97-21.2)0.0130-

10、day mortality317 (40) 92 (25)0.64 (0.53-0.78)0.01Sofair AN, et al. Clin Infect Dis. 2006;43:32-39.Selected clinical variables for 1143 patients with candidemia by type of onsetHAI Fungemia: Epidemiology Type of OnsetCharacteristicInpatient (n=787)Community (n=356)RR (95% CI)PComorbid condition HIV i

11、nfection 56 (7) 29 (8)1.14 (0.74-1.76) 0.53 Malignancy193 (24) 73 (21)0.84 (0.67-1.06) 0.13 Neutropenia 83 (10) 37 (10)0.99 (0.68-1.42) 0.93 Diabetes mellitus215 (27)107 (30)1.10 (0.91-1.34) 0.34 Immunosuppressive therapy375 (48) 98 (28)0.58 (0.48-0.69)0.01 Surgery in 3 months prior to candidemia446

12、 (58)102 (29)0.51 (0.42-0.60)0.01 Central venous catheter in place at time of candidemia655 (83)197 (55)0.66 (0.60-0.73)0.01Selected clinical variables for 1143 patients with candidemia by type of onsetSofair AN, et al. Clin Infect Dis. 2006;43:32-39.Illustrative Case StudyCandida Bloodstream Infect

13、ion 69 year-old man Ruptured appendix at OSH 9 days ago Status post surgical repair/drainage Central line for TPN Hemodialysis for ATN Transferred to Barnes-Jewish Hospital Febrile with positive blood culture for Candida albicans 2 days post transferKojic EM, et al. Clin Microbiol Reviews. 2004;17:2

14、55-267.C. albicans Biofilm on Dialysis Catheter Treatment: Fluconazole, 400 mg qd Central line/Dialysis catheter removed Outcome: Patient survivedCandida Bloodstream InfectionClinical Relevance of Biofilms Candida spp. adhere to inert and biological surfaces associated with virulenceCatheter-related

15、 infectionsBiomaterial surfaces (implants, dentures, protheses)Biofilm-associated infections (endocarditis, oropharyngeal candidiasis) High level of antifungal resistanceAzole & polyene resistanceEchinocandin susceptibilityBachmann SP, et al. Antimicrob Agents Chemother. 2002;46:3591-3596. Ramag

16、e G, et al. Antimicrob Agents Chemother. 2002;46:3634-3636. Biofilm Production and Mortality 294 patients with Candida BSI CVC in 213 (72.4%) Biofilm production by species: C. tropicalis 20/28 (71.4%) C. glabrata 6/26 (23.1%) C. albicans 38 of 168 (22.6%) C. parapsilosis 14/64 (21.8%)Tumbarello M, e

17、t al. J Clin Microbiol 2007;45:1843.VariableDied (154)Alive (140) P ValueAge (yr)69 + 1259 + 16 0.001HA-BSI144 (93.5)118 (84.2)0.01C. albicans97 (62.9)71 (50.7)0.03C. Parapsilosis24 (15.5)40 (28.5)0.007CVC123 (79.8)90 (64.2)0.003APACHE II38 + 1627 + 17 0.001Immunosupp.75 (48.7)45 (32.10.003Biofilm (

18、+)56 (36.3)24 (17.1) 48 hrs post culture, isolate resistant.Tumbarello M, et al. J Clin Microbiol 2007;45:1843.Why is Early Therapy Important? Reduced mortality Shorter length of stay “De-escalation Approach” to balance improved outcomes and resistanceMorrell M, et al. Antimicrob Agents Chemother. 2

19、005;49:3640-3645.Inappropriate Therapy for Fungemia Influences Outcome DESIGN N=157 Retrospective cohort study Candidemia PRIMARY OBJECTIVES Determine predictors of outcome Assess prevalence and impact of delay in therapy on mortality in fungemia Inappropriate therapy defined as either delay or use

20、of fluconazole in either C. glabrata or C. krusei OUTCOMES Overall mortality 30% Only 5 patients treated appropriately Inappropriate therapy common with all types of candidemiaInappropriate Therapy for Fungemia Influences Outcome Candida albicans 53.5% Candida parapsilosis15.9% Candida glabrata12.7%

21、 Candida tropicalis12.7% Candida krusei1.3% Mixed fungal isolates3.8%157 Patients with Fungemia 2001 to 200446.5%Morrell M, et al. Antimicrob Agents Chemother. 2005;49:3640-3645.Inappropriate Therapy for Fungemia Influences OutcomeProcesses of Medical CareHospital Survivor (n=107)Hospital Nonsurvivo

22、r (n=50)P ValueCorticosteroid treatment (no. %)26 (24.3)19 (38.0)0.077Vasopressors (no. %) 9 (8.4)11 (22.0)0.017Central vein catheter (no. %)95 (88.8)44 (88.0)0.886Central vein catheter days32.6 46.533.3 54.20.928Mechanical ventilator (no. %)21 (19.6)14 (28.0)0.240Mechanical ventilator days1.7 5.74.

23、8 12.00.033Parenteral nutrition (no. %)31 (29.0) 9 (18.0)0.142ICUc days (no. %)a3.6 9.46.6 12.90.011Hospital days (no. %)12.2 14.914.9 13.20.109Prior antimicrobial therapy (no. %) 83 (77.6)45 (90.0)0.062Prior antifungal therapy (no. %)10 (9.3) 2 (4.0)0.341Morrell M, et al. Antimicrob Agents Chemothe

24、r. 2005;49:3640-3645.Inappropriate Therapy for Fungemia Influences OutcomeVariableAdjusted Odds Ratio95% CIP ValueAPACHE II score(1-point increments)1.241.18-1.310.001Prior antibiotic treatment4.052.14-7.65 0.028Delay in antifungal treatment2.091.53-2.84 0.018Multivariate analysis of independent ris

25、k factors for hospital mortalityMorrell M, et al. Antimicrob Agents Chemother. 2005;49:3640-3645.Inappropriate Therapy for Fungemia Influences Outcome01020304048Delay in Start of Antifungal Treatment (Hours)% Hospital MortalityMorrell M, et al. Antimicrob Agents Chemother. 2005;49:3640-3645.Inapprop

26、riate Therapy for Fungemia Influences OutcomeGarey KW, et al. Clin Infect Dis. 2006;43:25-31. DESIGN N=230 Retrospective, cohort study, 4 centers Candidemia All given fluconazole PRIMARY OBJECTIVE Define impact of time to initiation of fluconazole on survival OUTCOMES 50% of patients in ICU at time

27、of culture Overall mortality approximately 30% Relationship persisted even after removing persons for whom fluconazole was inappropriate01020304050CultureDayDay 1Day2Day3Days to Start of FluconazoleMortality (%)Inappropriate Therapy for Fungemia Influences OutcomeGarey KW, et al. Clin Infect Dis. 20

28、06;43:25-31.Multivariate model of independent risk factors for hospital mortalityVariableAdjusted OR (95% CI)PTime from culture date to start of fluconazole therapy, days1.50(1.09-2.09)0.0138APACHE II score,1-point increments1.13(1.08-1.18)0.001Determinants of Mortality in IFIVariable ORRetained CVC

29、4.9Steroids3.4APACHE II1.2Inadequate3.3fluconazole dose 0 1 2 3 Number of Treatment Related Risk FactorsHospital Mortality (%)P 0.001245 patients with Candida bloodstream infection at BJH who received antifungal therapyLabelle A, et al ICAAC 2007Strategies for Early Therapy of IFI Early identificati

30、on Empiric early treatment Prophylaxis in high risk patients -D-Glucan as a marker for IFIDoes my patient have IFI?Source: Antifungal landscape study Jan 2006 LOS in the ICU Broad-spectrum antibiotics Hemodialysis Candida colonization Severity of illness Mechanical ventilation GI surgery Blood trans

31、fusion CVCs Diabetes TPN Pancreatitis SteroidsIFI :Risk Stratification ToolsLeon C, et al. Crit Care Med. 2006;34:730-737. DESIGN N=1699 Prospective, cohort, observational, multicenter study Patients admitted to ICU Routine surveillance cultures PRIMARY OBJECTIVE Identify variables assoc with candid

32、emia OUTCOMES Proven candidemia: 6% 43% of patients never colonized or infected Score developed to aid in risk stratificationIFI : Risk Stratification ToolsVariableProven Candidal Infection (%)P ValueCrude Odds Ratio (95% CI)Adjusted Odds Ratio (95% CI)Surgery on ICU admission No Yes 6.916.50.0012.6

33、9 (1.76-4.10)2.71 (1.45-5.06)Total parenteral nutrition No Yes 2.815.50.0016.46 (3.48-11.98)2.48 (1.16-5.31)Severe sepsis No Yes 4.528.80.0018.63 (5.49-13.56)7.68 (4.14-14.22)Candida species colonization No Yes 4.212.30.0013.20 (1.85-5.53)3.04 (1.45-6.39)Leon C, et al. Crit Care Med. 2006;34:730-737

34、.Multivariate analysis: Risk factor for proven IFI in 1669 adult patientsReceiver operating characteristics (ROC) curve and area under the ROC curve (AUC) for assessing the discriminating power of the Candida score. Leon C, et al. Crit Care Med. 2006;34:730-737.IFI: Risk Stratification ToolsCandida

35、score = 0.908 x (total parenteral nutrition) + 0.997 x (surgery) + 1.112(multifocal Candida species colonization) + 2.038 (severe sepsis). Candida score (rounded) = 1 x (total parenteral nutrition) + 1 x (surgery) + (multifocal Candida species colonization) + 2 x (severe sepsis). All variables coded

36、 as follows: absent, 0; present, 1. 1.00.90.80.70.60.50.40.30.20.10.0Sensitivity0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0False PositiveROC: AUC 0.847; 95% CI 0.8 to 0.894Piarroux R, et al. Crit Care Med. 2004;32:2443-2449.IFI: Risk Stratification Tools DESIGN N=933 2-yr historical control cohort a

37、nd prospective, before-after study Surgical ICU patients Systemic mycology screening Created corrected colonization index (CCI) (number of highly positive samples/no. of samples cultured) CCI 0.4 considered positive These patients given pre-emptive tx PRIMARY OBJECTIVES Rates of proven candidemia OU

38、TCOMES 117 subjects in after period treated presumptively No emergence of resistance No impact on mortalityIFI: Risk Stratification ToolsPiarroux R, et al. Crit Care Med. 2004;32:2443-2449.P=0.03 P0.012.23.807.002468OverallCandidemiaICU-acquiredCandidemia% of PatientsBeforeAfterIFI: Prediction by Sp

39、eciesShorr AF, et al. Crit Care Med. 2007;35:1077-1083. DESIGN N=245 Retrospective 2-site case study Patients with candidemia(ICU and wards) PRIMARY OBJECTIVE Evaluate prevalence of Candida sp OUTCOMES Approx half of candidemia isnon-albicans No difference in clinical characteristics betweenC. albic

40、ans and other candidemias Non-albicans prevalent outside ICU0102030405060WardICU% of IsolatesC. albicansC. glabrataC. parapsilosisC. tropicalisOtherPathogen distribution based on site of care. C. Candida; ICU, intensive care unit.IFI: Prediction by SpeciesUnable to develop clinical prediction rule t

41、o guide choice of initial antifungal agentShorr AF, et al. Crit Care Med. 2007;35:1077-1083.TestSensitivitySpecificityPositive Predictive ValueNegative Predictive ValueAccuracyIn the ICU, %56.038.518.977.342.0Previous fluconazole, %12.088.220.719.672.6Both in the ICU and previous fluconazole, % 6.09

42、1.116.778.574.7In the ICU or previous fluconazole, %62.034.419.577.540.0Screening for potentially fluconazole-resistant candidemiaRegional Variability of Candida InfectionsPfaller MA et al. J Clin Micro 2008;46:150-156North America -D-Glucan as a Marker for IFICell wall component of yeast and moulds

43、FDA approved 2004 Fungitell assay (Associates of Cape Cod) As an aid to the diagnosis of fungal infectionsDetects invasive disease with: Aspergillus Candida Fusarium Trichosporon Scedosporium AcremoniumDoes not detect Cryptococcus, Zygomycetes Fluconazole prophylaxis Some groups of pts at high risk

44、for fungal infectionsPost-opProlonged gastric leak Potential role for prophylaxis given burden of Candida in this settingFluconazole in the SICU: Impact on Candidal InfectionsOdds ratio.032131.48Study % Weight Odds ratio (95% CI) 0.18 (0.03,0.98) 1 13.7 0.67 (0.25,1.81) 2 19.2 0.51 (0.23,1.11) 3 36.6 0.33 (0.12,0.88) 4 30.4 0.44 (0.27,0.72) Overall (95% CI)Heterogeneity chi-squared =2.25 (d.f. = 3) p = 0.52; Test of OR=1 : z= 3.27 p = 0.001Shorr AF, et al. Crit