ICU病房抗真菌经验性治疗.ppt

Empiric Antifungal Therapy in the ICU Ramzi Moufarrej, M.D Chief of Critical Care Zayed Military Hospital / Abu Dhabi 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) 33:177186; Garber G Drugs 2001; 61(suppl 1):112. Risk for Invasive Mycosis Non-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 ? Triple lumen (RR 5.4) Broad spectrum antibiotics Diabetes Burns Mechanical Ventilation Steroids Neutropenic related to above plus immune cell suppression and underlying malignancy. Severe immunosuppressive: BMT or SOT Invasive Mycosis Candidiasis Aspergillosis Decreasing immunity SOT or BMT MICU or SICU Barrier immunity Barrier plus cellular immunity Oncology 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) 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, presence of hardware, immuno -suppresion, site of disease ex. urine. Treatment of Invasive Mycosis Site of Action of Selected Anti-fungal Agents Adapted from Andriole VT J Antimicrob 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 membrane Polyenes 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 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. Coagulase-negative staphylococci390831.9 Staphylococcus aureus192815.7 Enterococci135411.1 Candida species9347.6 Pathogen 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 Agents Chemother 2000;44:747751. Species of Candida Most Commonly Isolated in Bloodstream Infections In 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. Medicine;81:425-433. Invasive Candidiasis in the ICU Common in the ICU (9.8/1000 admissions) with high morbidity (increased LOS 22 days) 739-744. Major Risk Factors Prior 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. Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007 Risk Factor Selection Underlying disease Antibiotics Colonization Fever Selection Skin or mucosa damage Infection Malignancy Diabetes Renal disease CTD on steroids Malnutrition on TPN Mechanical Ventilation 48h Burns Instruments CV Catheter Knife Invasive Candidiasis After Colonization and Bacteremia Bacteremia Colonization Acute Invasive Candidiasis 81 patients YES 35NO 46 - + + 14 24 8 - + + 7 13 15 100 018 53% Guiot et al. CID.1994;18:525-32 Laboratory 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 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 Diagnosis The clinical manifestations of IC are nonspecific, 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 important. 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 clinicians 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 basis 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 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 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 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 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 Intervention basic disease refractory fever aspecific symptom early markers specific symptom suppressive Rx infection Progression Empiric Pre-emptive Prophylactic Directed Prophylactic, 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 much treatment without infection Too little treatment with infection Fluconazole Prophylaxis and Colonization of Neutropenic Patients Winston et al. Ann Intern Med. 1993;118:495-503 Candida prophylaxis in the 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 reduced 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 identify 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. Candida Prophylaxis in MICU 28:1708-17 Incidence of IC=16% Incidence 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 prophylactic 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 1 143:857-869. Algorithm for Empiric Therapy Empiric treatment for invasive candidiasis based on the hemodynamic status of the patient. Unstable patients: broad-spectrum antifungal agent