ICU病房抗真菌经验性治疗

1、Introduction Invasive fungal infections have increased significantly over the last 2 decades. aging population with life sustaining therapies like renal dialysis broad spectrum antimicrobial therapy and invasive medical devices bone marrow transplantation (BMT) & solid organ transplantation (SOT

2、) intensive chemotherapy for malignancies HIV/AIDS epidemic.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 sur

3、gical and neonatal intensive care units 48 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 co

4、lonization. Acute renal failure (RR 4.2) Parenteral 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 suppressio

5、n and underlying malignancy.Severe immunosuppressive: BMT or 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

6、 (liver toxicity, CYP450) Voriconazole (liver toxicity, visual disturbances, 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 prophyla

7、xis, culture results, local fungal sensitivity, colonization, renal or liver disease, 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 Antimicr

8、ob Chemother 1999;44:151162; Graybill JR et al Antimicrob Agents Chemother 1997;41:17751777; 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 Candid

9、iasis Invasive Candida infections: 4th most common nosocomial bloodstream infection in the USA 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; Andriol

10、e VT J Antimicrob Chemother 1999;44:151162; Uzun O, Anaissie EJ Ann Oncol 2000;11:15171521.Coagulase-negative staphylococci390831.9Staphylococcus aureus192815.7Enterococci135411.1Candida species9347.6Pathogen No. of Isolates Incidence (%)C. glabrata 16%C. albicans 54%C. parapsilosis 15%C. tropicalis

11、 8%C. krusei 2%other Candida spp 5%Adapted from Pfaller MA et al and The SENTRY 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 hi

12、gher incidence of fluconazole resistance.Snydman DR. 2003. Chest 123(Suppl 5):500S-503S). Garbino J. et al. 2002. Medicine;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 c

13、ost ( $44,000/ episode). Difficult to diagnose (cultures positive in only 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, lik

14、e echinocandins and triazoles, with high activity, a broad spectrum, and 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.Major Risk Factors Prior

15、antibiotic use, central venous catheters, total parenteral 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. Ca

16、ndidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007 Risk Factor SelectionUnderlying diseaseAntibioticsColonizationFeverSelectionSkin ormucosadamageInfectionMalignancyDiabetesRenal diseaseCTD on steroidsMaln

17、utrition on TPNMechanical Ventilation 48hBurnsInstrumentsCV Catheter KnifeInvasive Candidiasis After Colonization and BacteremiaBacteremiaColonizationAcuteInvasiveCandidiasis81 patientsYES 35NO 46 - + +14 24 8 - + + 7 13 15 10001853%Guiot et al. CID.1994;18:525-32Laboratory Diagnosis Microbiology me

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

19、rly identification ex PNA FISH Serological methods: early diagnosis ex. 1,3 beta D glucan assay. Histopatholgic methods.Clinical DiagnosisThe clinical manifestations of IC are nonspecific, but may include: Fever and progressive sepsis with multi-organ failure despite antibiotics. Invasive candidiasi

20、s (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 endop

21、hthalmitis 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 clinicians are used to assess patients for Candida infection. A delay in diagnosis will unfortunately result in

22、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. 2005. Antimicr

23、ob 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 candidemia. Delay in empiric Rx of candidemia till after blood cultures turn positive resulte

24、d 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 Suspected Invasive Candidiasis (Definitions) Prophylactic therapy: protective or pre

25、ventive 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 evidence suggesting infection (ex. positive

26、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 patient has remained febrile after seve

27、ral 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 diseaserefractory feveraspecific symptom early markers specific symptomsuppress

28、ive RxinfectionProgression EmpiricPre-emptiveProphylacticDirectedProphylactic, Preemptive or Empiric Use of Anti-fungals PROS High Mortality Difficulty in Diagnosis Undetected Infection Reduced systemic mycoses and improved mortality with prophylaxis CONS Toxicity Expense Diagnosis not certain Too m

29、uch 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 risk for candidemia) Eggiman et al. 1999. CCM 27: 1066-1072. Fl

30、uconazole 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 surgical patients in SICU 3 days. No mortality benefi

31、t. 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-spectrum antibiotics had an invasive

32、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%Incidence of IC=5

33、.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 prophy

34、lactic & 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, immediat

35、ely 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 (fluconazole IV 800mg, then 400 mg/day for 2 wks). Candida infections occurred more frequently in the control cohort (7%

36、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 with progression of risk factors as fever, duration of antibiotics & mechanical ventilation to assess risk. ? mor

37、e aggressive surveillance cultures vs. preemptive 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 candi

38、da & 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 with candida also predicted response. Colonization at 3 sites vs. 1 site (p=0.03) (OR=7.57). In postoperative patients col

39、onized 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): 625-30.Research Ongoing Randomized Study of Caspofungin Prophylaxis Followed by Pre-Emptive Therapy for Invasive Candid

40、iasis 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 caspofungin is useful in treating subjects for this disease when diagnosed using a new blood test that is performed twice weekly, pe

41、rmitting earlier diagnosis than current practice standards. This study is currently recruiting 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, hemo

42、dynamic instability, gut dysfunction or medication noncompliance use IV agents. Prolonged and 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 a

43、gent that is likely to be effective against the specific pathogen.Site of Infection: Ocular or 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

44、; 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 antibacterial therapy for 3 days.(40% all candidemia). Strategies compared: Fluconazole, Caspofungin, AmB and Liposomal AmB. Estimates: R to Fluconazole =5%, cost of C

45、aspofungin = 381$/day, Diflucan=135$/d, IC in target population =10%. Results: Caspofungin the most effective but Fluconazole 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

46、Med;143:857-869.Algorithm for Empiric Therapy Empiric treatment for invasive candidiasis based on the hemodynamic status of the patient. Unstable patients: broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized & the identity of the infecting species is establish

47、ed. In stable patients: fluconazole, provided that the patient is not colonized with fluconazole resistant strains or there has been recent past exposure to an azole ( 48hBurnsInstrumentsCV Catheter KnifeLaboratory 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 IC in the at-risk patient. Blood culture is positive in less than 50% of