ICU病房抗真菌经验性治疗课件

1、 ICU病房抗真菌经验性治疗Empiric Antifungal Therapy in the ICURamzi Moufarrej, M.DChief of Critical CareZayed Military Hospital / Abu Dhabi ICU病房抗真菌经验性治疗Introduction Invasive fungal infections have increased significantly over the last 2 decades. aging population with life sustaining therapies like renal dialy

2、sis broad spectrum antimicrobial therapy and invasive medical devices bone marrow transplantation (BMT) & solid organ transplantation (SOT) intensive chemotherapy for malignancies HIV/AIDS epidemic. ICU病房抗真菌经验性治疗National Epidemiology of Mycosis Survey (NEMIS) was a prospective, multicenter study con

3、ducted 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 hours. Among 4276 patients, 42 CBSIs occurred. Adapted from Blumberg HM et al, and the NEMIS Study Group

4、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 nutrition with intralipid (RR 3.6) Prior surgery specially GI (RR 7.3) Indwelling central line ?

5、 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 SOT ICU病房抗真菌经验性治疗Invasive MycosisCandidiasisAspergillosisDecreasing immunitySOT or BMTM

6、ICU or SICUBarrier immunity Barrier plus cellular immunityOncology ICU病房抗真菌经验性治疗 Polyenes Amphotericin B (AmB) or Liposomal AmB (kidney toxicity) Azoles Fluconazole 400-800 mg/day (liver toxicity, CYP450) Voriconazole (liver toxicity, visual disturbances, CYP450) Posaconazole (liver toxicity, CYP450

7、) 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, presence of drug-drug interactions,

8、 presence of hardware, immuno -suppresion, site of disease ex. urine.Treatment of Invasive Mycosis ICU病房抗真菌经验性治疗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; Groll AH, Walsh

9、 TJ Expert Opin Invest Drugs 2001;10(8):15451558.Cell membranePolyenes AmB (sterols) Azoles Fluconazole (CYP450)Cell wall Echinocandins Caspofungin (Glucan synthesis inhibitors) ICU病房抗真菌经验性治疗Focus on Candidiasis Invasive Candida infections: 4th most common nosocomial bloodstream infection in the USA

10、 with 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.Coa

11、gulase-negative staphylococci390831.9Staphylococcus aureus192815.7Enterococci135411.1Candida species9347.6Pathogen No. of Isolates Incidence (%) ICU病房抗真菌经验性治疗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

12、Participant Group Antimicrob Agents 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):50

13、0S-503S). Garbino J. et al. 2002. Medicine;81:425-433. ICU病房抗真菌经验性治疗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 o

14、nly 50%). We can define ICU risk factors for candidiasis and target 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, a

15、nd low toxicity ideal for empiric therapy and combination therapy options.Prophylaxis and treatment of invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis. 2004:23; 739-744. ICU病房抗真菌经验性治疗Major Risk Factors Prior antibiotic use, central venous catheters, total parenter

16、al nutrition, major surgery within the preceding week, steroids, dialysis and immunosuppression. 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 critic

17、ally ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007 ICU病房抗真菌经验性治疗Risk Factor SelectionUnderlying diseaseAntibioticsColonizationFeverSelectionSkin ormucosadamageInfectionMalignancyDiabetesRenal diseaseCTD on steroidsMalnutrition on TPNMechanical Ventilation 48hBu

18、rnsInstrumentsCV Catheter Knife ICU病房抗真菌经验性治疗Invasive Candidiasis After Colonization and BacteremiaBacteremiaColonizationAcuteInvasiveCandidiasis81 patientsYES 35NO 46 - + +14 24 8 - + + 7 13 15 10001853%Guiot et al. CID.1994;18:525-32 ICU病房抗真菌经验性治疗Laboratory Diagnosis Microbiology methods: Recovery

19、 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 IC in the at-risk patient. Blood culture is positive in less than 50% of patients with autopsy proven IC. Molecular methods: early identificat

20、ion ex PNA FISH Serological methods: early diagnosis ex. 1,3 beta D glucan assay. Histopatholgic methods. ICU病房抗真菌经验性治疗Clinical DiagnosisThe clinical manifestations of IC are nonspecific, but may include: Fever and progressive sepsis with multi-organ failure despite antibiotics. Invasive candidiasis

21、 (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 important. Ophthalmic lesions (Candida endophthalmitis). A fundoscopic evaluation for the presence of Candida endoph

22、thalmitis should be performed in patients with candidemia. ICU病房抗真菌经验性治疗Therapy of IC in the ICU A definitive diagnosis of IC may be delayed when the clinical and laboratory tools readily available to clinicians are used to assess patients for Candida infection. A delay in diagnosis will unfortunate

23、ly 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 basis of individual patient factors before a definitive diagnosis is made. *Morrel M et al. 2

24、005. Antimicrob Agents Chemother. 49(9): 3640-5.*Garey K et al. 2006. Clin Infect Dis. 43: 25-31. ICU病房抗真菌经验性治疗Can we wait for the blood culture results in candidemia? Retrospective cohort analysis 1/2001-12/2004: N=157 patients with candidemia. Delay in empiric Rx of candidemia till after blood cul

25、tures 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 ICU病房抗真菌经验性治疗Treatment of Suspected Invasive Candidiasis (Definitions)

26、 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 therapy is initiated with early evid

27、ence 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 is started because a cancer

28、 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). ICU病房抗真菌经验性治疗Timing of Interventionbasic diseaserefractory feveras

29、pecific symptom early markers specific symptomsuppressive RxinfectionProgression EmpiricPre-emptiveProphylacticDirected ICU病房抗真菌经验性治疗Prophylactic, Preemptive or Empiric Use of Anti-fungals PROS High Mortality Difficulty in Diagnosis Undetected Infection Reduced systemic mycoses and improved mortalit

30、y with prophylaxis CONS Toxicity Expense Diagnosis not certain Too much treatment without infection Too little treatment with infection ICU病房抗真菌经验性治疗Fluconazole Prophylaxis and Colonization of Neutropenic PatientsWinston et al. Ann Intern Med. 1993;118:495-503 ICU病房抗真菌经验性治疗Candida prophylaxis in the

31、 Surgical ICU(patients with high risk 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 r

32、educed candida infection in critically ill surgical 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 iden

33、tify predictive factors. Combination of DM, HD, TPN, broad-spectrum 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. ICU病房抗真菌经验性治疗Candida Prophylaxis in MICU & SICU (MV 48h & ex

34、pected LOS 72h)Garbino et al. Intensive Care Med. 2002;28:1708-17Incidence of IC=16%Incidence of IC=5.8% ICU病房抗真菌经验性治疗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

35、 in severely immunocompromised hosts (neutropenia, BMT, or solid organ transplantation). Distinction between prophylactic & preemptive therapy needed specially in ICU. Risk ? Dose?. ICU病房抗真菌经验性治疗Assessment of Preemptive Treatment to prevent severe candidiasis in SICU Before/after intervention study

36、(2 years prospective & historical) Systematic mycological screening on all patients admitted to the SICU 5 days, immediately at admittance and then weekly until discharge. Patients with colonization index 0.4 (used to assess intensity of mucosal colonization) received early preemptive antifungal Rx

37、(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 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

38、with progression of risk factors as fever, duration of antibiotics & mechanical ventilation to assess risk. ? more aggressive surveillance cultures vs. preemptive or empiric therapy. ICU病房抗真菌经验性治疗Serological Methods ? early aid in empiric therapy decision making Plasma beta-D-glucan, a cell wall con

39、stituent of fungi, was measured before starting antifungal therapy empirically on postoperative patients, colonized with candida & having risk factors for candida infection. 47% of those with positive test responded to Rx but 9% of those negative responded (p.01) (OR= 13). Number of sites colonized

40、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 assay was useful for deciding whether to start empiric therapy.Takesue Y et al. World J Surg. 2004; 28(6): 6

41、25-30. ICU病房抗真菌经验性治疗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 successfully reduce the rate of candida infections in subjects at risk. It will also test if

42、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 recruiting participants. Mycoses Study Group, August 2007 ICU病房抗真菌经验性治疗Consideration

43、s 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 recent exposure to azoles prior to current episode or signifi

44、cant 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 central nervous system infection avoid echinocandins. Can us

45、e liposomal amphotericin B, fluconazole or voriconazole. Urinary ex. cystitis select fluconazole or 5-flucytosine. ICU病房抗真菌经验性治疗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 effect(p 3 days and unresponsive to antibact

46、erial 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 Fluconazole more cost-effec

47、tive. 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. ICU病房抗真菌经验性治疗Algorithm for Empiric TherapyEmpiric treatment for invasive candidiasis based on the hemodynamic status of the

48、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

49、 recent 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 42:244251 ICU病房抗真菌经验性治疗Summary (Empiric Therapy) In the patient with septic shock risk factors for candidemia sh

50、ould be evaluated. If Candida 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, recen

51、t GI surgery, neutropenia, hemodynamic 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

52、: CCM 2008 ICU病房抗真菌经验性治疗Directed Therapy Azoles: Fluconazole 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 patients. Amphotericin B: active but is not superior to other therapies and therefore does not justify the ris