1、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 antimicro
2、bial therapy and invasive medical devices bone marrow transplantation(BMT)&solid organ transplantation(SOT)intensive chemotherapy for malignancies HIV/AIDS epidemic.National Epidemiology of Mycosis Survey(NEMIS)was a prospective,multicenter study conducted at 6 US sites from 19932019 to examine rate
3、s 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 Clin Infect Dis 2019;33:177186;Garber G Drugs 2019;61(su
4、ppl 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 Mec
5、hanical 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?Polyen
6、es 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
7、)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
8、of Selected Anti-fungal Agents Adapted from Andriole VT J Antimicrob Chemother 2019;44:151162;Graybill JR et al Antimicrob Agents Chemother 2019;41:17751777;Groll AH,Walsh TJ Expert Opin Invest Drugs 2019;10(8):1545 1558.Cell membrane Polyenes AmB (sterols)Azoles Fluconazole (CYP450)Cell wall Echino
9、candins 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(20192019)surveillance study of 49 hospitals in the United States.Adapted f
10、rom Edmond MB et al Clin Infect Dis 2019;29:239244;Andriole VT J Antimicrob Chemother 2019;44:151162;Uzun O,Anaissie EJ Ann Oncol 2000;11:15171521.Coagulase-negative staphylococci 3908 31.9 Staphylococcus aureus 1928 15.7 Enterococci 1354 11.1 Candida species 934 7.6 Pathogen No.of Isolates Incidenc
11、e(%)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 surveillan
12、ce study 2019-2019:Since then increase in Candida spp.with higher incidence of fluconazole resistance.Snydman DR.2019.Chest 123(Suppl 5):500S-503S).Garbino J.et al.2019.Medicine;81:425-433.Invasive Candidiasis in the ICU?Common in the ICU(9.8/1000 admissions)with high morbidity(increased LOS 22 days
13、)&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 target the population at highest risk with empiric Rx.?Recent increase in Candida spp.resistant to Diflucan.?Advances in antifunga
14、l 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.Prophylaxis and treatment of invasive candidiasis in the intensive care setting.Eur J Clin Microbiol Infect Dis.2019:23;73
15、9-744.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
16、.Dimopoulos G,et al.Candidemia in immunocompromised and immunocompetent critically ill patients:a prospective comparative study.Eur J Clin Microbiol Infect Dis.2019 Risk Factor Selection Underlying disease Antibiotics Colonization Fever Selection Skin or mucosa damage Infection Malignancy Diabetes R
17、enal 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 35 NO 46 -+14 24 8 -+7 13 15 1 0 0 0 1 8 53%Guiot et al.CID.1994;1
18、8:525-32 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 au
19、topsy 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 despi
20、te 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
21、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
22、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.*Morre
23、l M et al.2019.Antimicrob Agents Chemother.49(9):3640-5.*Garey K et al.2019.Clin Infect Dis.43:25-31.Can we wait for the blood culture results in candidemia?Retrospective cohort analysis 1/2019-12/2019:N=157 patients with candidemia.?Delay in empiric Rx of candidemia till after blood cultures turn p
24、ositive 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.2019.Antimicrob Agents Chemother.49(9):3640-5 Treatment of Suspected Invasive Candidiasis(Definitions)?Prophylactic therapy:protective
25、 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
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 several d
27、ays 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
28、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
29、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.2019.CCM 27:1066-1072.Fluc
30、onazole reduced candida peritonitis and colonization in 43 patients with complicated GI surgeries.High risk patients?Was it preemptive therapy.?Pelz et al.2019.Ann Surg.233:542-548.Fluconazole reduced candida infection in critically ill surgical patients in SICU 3 days.No mortality benefit.Predictor
31、s included:APACHE II score,fungal colonization,TPN,days to first dose of prophylactic drug.?Paphitou et al.2019.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
32、%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.2019;28:1708-17 Incidence of IC=16%Incidence of IC=5.8%Summary(Candida Prophylaxis)?Prophylaxis i
33、s 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&preemptive therapy needed specially in ICU
34、.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 and then weekly until discharge.Patients with co
35、lonization 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 of SICU-acquired proven candidiasis significantl
36、y 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.preemptive or empiric therapy.Serological Methods?early a
37、id 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 those with positive test responded to Rx but 9%of
38、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 assay was useful for deciding whether to start em
39、piric therapy.Takesue Y et al.World J Surg.2019;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 successfully reduce the rate of candida infections i
40、n 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 recruiting participants.Mycoses Study Group,A
41、ugust 2019 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 recent exposure to azoles prior to current
42、 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 central nervous system infection avoid ech
43、inocandins.Can use liposomal amphotericin B,fluconazole or voriconazole.?Urinary ex.cystitis select fluconazole or 5-flucytosine.Walsh et al.N Engl J Med.2019;351:1391-1402.Overall adjusted success rate 0 10 20 30 40 33.9%50 33.7%2.6%11.5%10.3%14.5%Nephrotoxic effect(p 3 days and unresponsive to ant
44、ibacterial 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$/d,IC in target population=10%.?Results:Caspofungin the most effective but Fluconazole more cost-effective.?If
45、 R to Fluconazole 28%or if IC prevelance=60%or if cost of caspofungin 160$/day then Caspofungin more cost effective.Golan et al.2019.Ann Intern Med;143:857-869.Algorithm for Empiric Therapy?Empiric treatment for invasive candidiasis based on the hemodynamic status of the patient.?Unstable patients:b
46、road-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 past exposure to an azole(
47、30 days).?In contrast,pre-emptive therapy is based on the presence of surrogate markers ex colonization index.Spellberg et al.(2019).Clin Infect Dis 42:244251 Summary(Empiric Therapy)?In the patient with septic shock risk factors for candidemia should be evaluated.?If Candida infection is suspected,
48、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,hemodynamic stability,&other hos
49、t 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 2019 Directed Therapy?Azoles:Fluconazole is the most common
50、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
