最新ICU病房抗真菌经验性治疗课件.ppt

1、ICU病房抗真菌经验性治疗病房抗真菌经验性治疗National Epidemiology of Mycosis Survey(NEMIS)was a prospective,multicenter study conducted at 6 US sites from 19931995 to examine rates of risk factors for the development of candidal bloodstream infections(CBSIs)among patients in surgical and neonatal intensive care units 48

2、 hours.Among 4276 patients,42 CBSIs occurred.Adapted from Blumberg HM et al,and the NEMIS Study Group Clin Infect Dis 2001;33:177186;Garber G Drugs 2001;61(suppl 1):112.Risk for Invasive MycosisNon-Neutropenic related to barrier breakdown,change in colonization.Acute renal failure(RR 4.2)Parenteral

3、nutrition with intralipid(RR 3.6)Prior surgery specially GI(RR 7.3)Indwelling central line?Triple lumen(RR 5.4)Broad spectrum antibiotics Diabetes Burns Mechanical Ventilation SteroidsNeutropenic related to above plus immune cell suppression and underlying malignancy.Severe immunosuppressive:BMT or

4、SOT Invasive MycosisCandidiasisAspergillosisDecreasing immunitySOT or BMTMICU or SICUBarrier immunity Barrier plus cellular immunityOncology Polyenes Amphotericin B(AmB)or Liposomal AmB(kidney toxicity)Azoles Fluconazole 400-800 mg/day(liver toxicity,CYP450)Voriconazole(liver toxicity,visual disturb

5、ances,CYP450)Posaconazole(liver toxicity,CYP450)Echinocandins Caspofungin iv(liver toxicity)Combination ex.AmB/Fluconazole(liver,kidney toxicity)Choice of agents depends on whether the patient on previous azole prophylaxis,culture results,local fungal sensitivity,colonization,renal or liver disease,

6、presence of drug-drug interactions,presence of hardware,immuno-suppresion,site of disease ex.urine.Treatment of Invasive Mycosis Site of Action of Selected Anti-fungal AgentsAdapted from Andriole VT J Antimicrob Chemother 1999;44:151162;Graybill JR et al Antimicrob Agents Chemother 1997;41:17751777;

7、Groll AH,Walsh TJ Expert Opin Invest Drugs 2001;10(8):15451558.Cell membranePolyenes AmB (sterols)Azoles Fluconazole(CYP450)Cell wall Echinocandins Caspofungin(Glucan synthesis inhibitors)Focus on Candidiasis Invasive Candida infections:4th most common nosocomial bloodstream infection in the USA wit

8、h mortality approaching 40%in line related candidemia*In a 3-year(19951998)surveillance study of 49 hospitals in the United States.Adapted from Edmond MB et al Clin Infect Dis 1999;29:239244;Andriole VT J Antimicrob Chemother 1999;44:151162;Uzun O,Anaissie EJ Ann Oncol 2000;11:15171521.Coagulase-neg

9、ative staphylococci390831.9Staphylococcus aureus192815.7Enterococci135411.1Candida species9347.6Pathogen No.of Isolates Incidence(%)C.glabrata 16%C.albicans 54%C.parapsilosis 15%C.tropicalis 8%C.krusei 2%other Candida spp 5%Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Ag

10、ents Chemother 2000;44:747751.Species of Candida Most Commonly Isolated in Bloodstream InfectionsIn an international surveillance study 1997-1998:Since then increase in Candida spp.with higher incidence of fluconazole resistance.Snydman DR.2003.Chest 123(Suppl 5):500S-503S).Garbino J.et al.2002.Medi

11、cine;81:425-433.Invasive Candidiasis in the ICU Common in the ICU(9.8/1000 admissions)with high morbidity(increased LOS 22 days)&mortality(30-40%)resulting in increased cost($44,000/episode).Difficult to diagnose(cultures positive in only 50%).We can define ICU risk factors for candidiasis and targe

12、t the population at highest risk with empiric Rx.Recent increase in Candida spp.resistant to Diflucan.Advances in antifungal therapy have resulted in agents,like echinocandins and triazoles,with high activity,a broad spectrum,and low toxicity ideal for empiric therapy and combination therapy options

13、.Prophylaxis and treatment of invasive candidiasis in the intensive care setting.Eur J Clin Microbiol Infect Dis.2004:23;739-744.Major Risk Factors Prior antibiotic use,central venous catheters,total parenteral nutrition,major surgery within the preceding week,steroids,dialysis and immunosuppression

14、.Intensive care unit length of stay is an important risk factor,with the rate of infections rising rapidly after 7-10 days.Dimopoulos G,et al.Candidemia in immunocompromised and immunocompetent critically ill patients:a prospective comparative study.Eur J Clin Microbiol Infect Dis.2007 Risk Factor S

15、electionUnderlying diseaseAntibioticsColonizationFeverSelectionSkin ormucosadamageInfectionMalignancyDiabetesRenal diseaseCTD on steroidsMalnutrition on TPNMechanical Ventilation 48hBurnsInstrumentsCV Catheter KnifeInvasive Candidiasis After Colonization and BacteremiaBacteremiaColonizationAcuteInva

16、siveCandidiasis81 patientsYES 35NO 46-+14 24 8-+7 13 15 10001853%Guiot et al.CID.1994;18:525-32Laboratory Diagnosis Microbiology methods:Recovery of Candida species from sterile sites(ex.blood,peritoneal fluid)is diagnostic of IC and recovery from multiple non-sterile sites is highly suggestive of I

17、C in the at-risk patient.Blood culture is positive in less than 50%of patients with autopsy proven IC.Molecular methods:early identification ex PNA FISH Serological methods:early diagnosis ex.1,3 beta D glucan assay.Histopatholgic methods.Clinical DiagnosisThe clinical manifestations of IC are nonsp

18、ecific,but may include:Fever and progressive sepsis with multi-organ failure despite antibiotics.Invasive candidiasis(IC)related cutaneous lesions.Macronodular rash frequently confused with drug allergies.A biopsy of the deeper layers of skin particularly the vascularized areas and the dermis is imp

19、ortant.Ophthalmic lesions(Candida endophthalmitis).A fundoscopic evaluation for the presence of Candida endophthalmitis should be performed in patients with candidemia.Therapy of IC in the ICU A definitive diagnosis of IC may be delayed when the clinical and laboratory tools readily available to cli

20、nicians are used to assess patients for Candida infection.A delay in diagnosis will unfortunately result in a delay in initiation of antifungal therapy,which is associated with increased mortality*.Therefore,in the patient with suspected Candida infection,treatment may need to be initiated on the ba

21、sis of individual patient factors before a definitive diagnosis is made.*Morrel M et al.2005.Antimicrob Agents Chemother.49(9):3640-5.*Garey K et al.2006.Clin Infect Dis.43:25-31.Can we wait for the blood culture results in candidemia?Retrospective cohort analysis 1/2001-12/2004:N=157 patients with

22、candidemia.Delay in empiric Rx of candidemia till after blood cultures turn positive resulted in higher mortality.Start of anti-fungal Rx 12 hrs of drawing a blood culture that turns positive had AOR=2.09 for mortality,p=0.018.Morrel M et al.2005.Antimicrob Agents Chemother.49(9):3640-5 Treatment of

23、 Suspected Invasive Candidiasis(Definitions)Prophylactic therapy:protective or preventive therapy given to everyone in a given class(ex.BMT patients who are at very high risk for IC).Preemptive therapy:therapy given to deter or prevent anticipated infection;patients at risk are monitored closely and

24、 therapy is initiated with early evidence suggesting infection(ex.positive Candida cultures at non-sterile sites,clinical suspicion)with the goal of preventing disease.Empirical therapy:therapy guided by practical experience and observation,but with nonspecific evidence in a given patient(ex.therapy

25、 is started because a cancer patient has remained febrile after several days of broad-spectrum antibiotics).Directed therapy:is based on a clinical or laboratory finding indicating that an infection is present(ex.positive blood culture for Candida species).Timing of Interventionbasic diseaserefracto

26、ry feveraspecific symptom early markers specific symptomsuppressive RxinfectionProgression EmpiricPre-emptiveProphylacticDirectedProphylactic,Preemptive or Empiric Use of Anti-fungals PROS High Mortality Difficulty in Diagnosis Undetected Infection Reduced systemic mycoses and improved mortality wit

27、h prophylaxis CONS Toxicity Expense Diagnosis not certain Too much treatment without infection Too little treatment with infectionFluconazole Prophylaxis and Colonization of Neutropenic PatientsWinston et al.Ann Intern Med.1993;118:495-503Candida prophylaxis in the Surgical ICU(patients with high ri

28、sk for candidemia)Eggiman et al.1999.CCM 27:1066-1072.Fluconazole reduced candida peritonitis and colonization in 43 patients with complicated GI surgeries.High risk patients?Was it preemptive therapy.Pelz et al.2001.Ann Surg.233:542-548.Fluconazole reduced candida infection in critically ill surgic

29、al patients in SICU 3 days.No mortality benefit.Predictors included:APACHE II score,fungal colonization,TPN,days to first dose of prophylactic drug.Paphitou et al.2005.Med Mycol.43(3):235-43.327 patients in SICU 3 days were reviewed to identify predictive factors.Combination of DM,HD,TPN,broad-spect

30、rum antibiotics had an invasive candidiasis rate of 16.6%versus a 5.1%rate for patients lacking these characteristics(P=0.001).The rule captured 78%of patients with IC.Candida Prophylaxis in MICU&SICU(MV 48h&expected LOS 72h)Garbino et al.Intensive Care Med.2002;28:1708-17Incidence of IC=16%Incidenc

31、e of IC=5.8%Summary(Candida Prophylaxis)Prophylaxis is effective in the highest risk patients.Prophylaxis reduces the incidence of IC.A positive impact on mortality has not been shown except in severely immunocompromised hosts(neutropenia,BMT,or solid organ transplantation).Distinction between proph

32、ylactic&preemptive therapy needed specially in ICU.Risk?Dose?.Assessment of Preemptive Treatment to prevent severe candidiasis in SICU Before/after intervention study(2 years prospective&historical)Systematic mycological screening on all patients admitted to the SICU 5 days,immediately at admittance

33、 and then weekly until discharge.Patients with colonization index 0.4(used to assess intensity of mucosal colonization)received early preemptive antifungal Rx(fluconazole IV 800mg,then 400 mg/day for 2 wks).Candida infections occurred more frequently in the control cohort(7%vs.3.8%;p=.03).Incidence

34、of SICU-acquired proven candidiasis significantly decreased from 2.2%to 0%(p 18 day 3 or 4 Early risk factor maybe evident from day 1&maybe used with progression of risk factors as fever,duration of antibiotics&mechanical ventilation to assess risk.?more aggressive surveillance cultures vs.preemptiv

35、e or empiric therapy.Serological Methods?early aid in empiric therapy decision making Plasma beta-D-glucan,a cell wall constituent of fungi,was measured before starting antifungal therapy empirically on postoperative patients,colonized with candida&having risk factors for candida infection.47%of tho

36、se with positive test responded to Rx but 9%of those negative responded(p.01)(OR=13).Number of sites colonized with candida also predicted response.Colonization at 3 sites vs.1 site(p=0.03)(OR=7.57).In postoperative patients colonized with candida,&with fever despite antibiotics a beta-D-glucan assa

37、y was useful for deciding whether to start empiric therapy.Takesue Y et al.World J Surg.2004;28(6):625-30.Research Ongoing Randomized Study of Caspofungin Prophylaxis Followed by Pre-Emptive Therapy for Invasive Candidiasis in the ICU.The study will test the possibility that caspofungin can successf

38、ully reduce the rate of candida infections in subjects at risk.It will also test if caspofungin is useful in treating subjects for this disease when diagnosed using a new blood test that is performed twice weekly,permitting earlier diagnosis than current practice standards.This study is currently re

39、cruiting participants.Mycoses Study Group,August 2007 Considerations in Selection of Empiric Antifungal Therapy High-risk host with hematologic cancer,or stem cell transplantation,severe immunosuppression,hemodynamic instability,gut dysfunction or medication noncompliance use IV agents.Prolonged and

40、 recent exposure to azoles prior to current episode or significant liver dysfunction or drug-drug interaction avoid azoles.Pathogen in vitro susceptibility pattern is known for a class of agents,select an agent that is likely to be effective against the specific pathogen.Site of Infection:Ocular or

41、central nervous system infection avoid echinocandins.Can use liposomal amphotericin B,fluconazole or voriconazole.Urinary ex.cystitis select fluconazole or 5-flucytosine.Walsh et al.N Engl J Med.2004;351:1391-1402.Overall adjusted success rate01020304033.9%5033.7%2.6%11.5%10.3%14.5%Nephrotoxic effec

42、t(p 3 days and unresponsive to antibacterial therapy for 3 days.(40%all candidemia).Strategies compared:Fluconazole,Caspofungin,AmB and Liposomal AmB.Estimates:R to Fluconazole=5%,cost of Caspofungin=381$/day,Diflucan=135$/d,IC in target population=10%.Results:Caspofungin the most effective but Fluc

43、onazole more cost-effective.If R to Fluconazole 28%or if IC prevelance=60%or if cost of caspofungin 160$/day then Caspofungin more cost effective.Golan et al.2005.Ann Intern Med;143:857-869.Algorithm for Empiric TherapyEmpiric treatment for invasive candidiasis based on the hemodynamic status of the

44、 patient.Unstable patients:broad-spectrum antifungal agents,which can be narrowed once the patient has stabilized&the identity of the infecting species is established.In stable patients:fluconazole,provided that the patient is not colonized with fluconazole resistant strains or there has been recent

45、 past exposure to an azole(30 days).In contrast,pre-emptive therapy is based on the presence of surrogate markers ex colonization index.Spellberg et al.(2006).Clin Infect Dis 42:244251Summary(Empiric Therapy)In the patient with septic shock risk factors for candidemia should be evaluated.If Candida

46、infection is suspected,treatment will need to be initiated empirically without delay on the basis of individual patient factors before a definitive diagnosis is made*.Choice of agent will rely on local resistance patterns,microbiology data,prior azole therapy,recent GI surgery,neutropenia,hemodynami

47、c stability,&other host factors.Azoles are effective unless high rates of resistance,or neutropenia in which case echinocandins or triazoles should be used.*Surviving Sepsis Campaign:International Guidelines for Management of Severe Sepsis and Septic Shock:CCM 2008Directed Therapy Azoles:Fluconazole

48、 is the most common agent used to treat clinical Candida infections.However,fluconazole has limited activity against C glabrata and C krusei.The evolution of resistance and trends toward more non-albicans species,may limit its role in the future.Triazoles have a role in NCA and immune suppressed pat

49、ients.Amphotericin B:active but is not superior to other therapies and therefore does not justify the risk for toxicity.Liposomal AmB is the least toxic.Echinocandins:shown to be as,if not more,effective than AmB and L-AmB&are not associated with significant resistance.Limited CNS and genitourinary

50、penetration may limit its use.Removal of all foreign objects correlates with better outcomes*C.albicans biofilms formed on an implanted medical device ex.CVC,urinary catheter,ETT,prosthetic heart valve,or pacemaker play a role in the persistence and profileration of Candidiasis.Cells in biofilms are