Fungal Infection in the ICU: Current Controversies Andrew F. Shorr, MD, MPH, FCCP, FACP Washington Hospital Center Georgetown University, Washington, DC
Disclosures I have served as a consultant to, researcher/investigator for, or spoken for: Astellas Astra zeneca Bayer Cubist Pfizer Forest Tetraphase Theravance
Fungi in the ICU Increasing burden and changing epidemiology Growing fluconazole resistance in yeast Isolation of candida does not = infection Prophylaxis routinely used in organ and BM transplant Diagnostics remain a challenge Optimal treatment approaches unclear
Time to Therapy in Candidemia: Mortality Delay in treatment is an independent determinant of hospital mortality All pts (N=157) Delay, 33.1% No delay, 11.1% Hospital Mortality, % 35 30 25 20 15 10 5 0 <12 12-24 24-48 >48 Delay in Start of Antifungal Treatment, h Morrell et al. Antimicrob Agents Chemother. 2005;49:3640-3645.
% Success Pre-emptive Approach: Unhelpful? Schuster SD, et al. Ann Intern Med 2008; 149:83-90 Prospective DBRCT Flu 800 mg/d vs placebo Subjects: ICU pts (4 days) with Fever Prior abx (4 days) CVC in place (1 day) APACHE II >16 Did not require: MV, roids, TPN n=270 Endpoint (pooled): resolution of fever, no breakthrough IFI, no toxicity
Risk Scores to Facilitate Diagnosis? Variable Value Sensitivity 50.0% Specificity 83.0% PPV 10.0% NPV 97.0% % Population Selected by Rule % of IC cases captured 18.0% 50.0% CLEARLY NOT READY FOR PRIME TIME Ostrosky-Zeichner L, et al. Mycoses 2009; 54: 46-51. Clinical decision aid Risk score meant to facilitate risk stratification for Candidemia Rule: MV for 48hrs & Abx for 1-3 d & CVC for 1-3d & 1 of following Surgery Immunosupression Pancreatitis TPN HD Steroids
Prospective Observational Study Improving Pre-emptive GI sgy patients at risk for candidemia/ IAC Goal to determine role for serial Beta-D glucan assay n=89 Strategy/Diagnostics Tissot F, et al. AJRCCM 2013: 188; 1100-9.
Serial Beta D-glucan Anticipates Fungemia & Outperforms Alternatives
Revised IDSA Guidelines for Candidemia Choice of therapy depends on clinical status of the patient and knowledge of species Remove all lines, if feasible Therapy Fluconazole 6 mg/kg/d (400 mg), or a Caspofungin 50 mg/d, anidulafungin 100 mg/d, or micafungin 100 mg/d, or a AMB (0.6-1.0 mg/kg/d for AMB or 3 mg/kg/d for liposomal formulations of AMB) in selected circumstances Treat 2 weeks after last positive blood culture and resolution of signs and symptoms of infection a Transition to fluconazole, when appropriate, is encouraged once the Candida sp is known and the patient is stable. Pappas et al, CID 2009.
Recommendations on Fever-Driven and Diagnosis-Driven Therapy of Candidemia and Invasive Candidiasis Population Intention Intervention SoR QoE Comment ICU patients persistently febrile, but without microbiological evidence To reduce overall mortality Any antifungal C II Adult ICU patients with fever despite broadspectrum antibiotics and APACHE II >16 ICU patients with candida isolated from respiratory secretions ICU patients with positive (1,3)-ß-D-glucan test To resolve fever To cure invasive candidiasis or candidemia early To cure invasive candidiasis or candidemia early Fluconazole 800mg/d Any antifungal D II Any antifungal C II D I Negative trial results APACHE, Acute physiology and chronic health evaluation; NPV, negative predictive value; Low specificity and sensitivity, high NPV, false positive results in presence of haemodialysis, other fungal or bacterial infection, or wound gauze, or albumin or immunoglobulin infusion Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis Intervention SoR QoE Comment Amphotericin B deoxycholate 0.7 1.0 mg/kg D I Substantial renal and infusion-related toxicity Amphotericin B, liposomal 3 mg/kg Amphotericin B, lipid complex any dose Amphotericin B, colloidal dispersion any dose B C D I II II Similar efficacy as micafungin, higher renal toxicity than micafungin Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis Intervention SoR QoE Comment Fluconazole 400-800 mg Itraconazole any dose Posaconazole any dose Voriconazole 6/3 mg/kg/d C D I II D III PO only B I Limited spectrum, Inferiority to anidulafungin (especially in the subgroup with high APACHE scores), may be better than echinocandins against C. parapsilosis Limited spectrum compared to echinocandins Drug-drug interactions Limitation of IV formulation in renal impairment; Need for TDM Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Recommendations on Targeted Treatment of Candidemia and Invasive Candidiasis Intervention SoR QoE Comment Anidulafungin 200/100 mg A I Broad spectrum, resistance rare, fungicidal Consider local epidemiology (C. parapsilosis, C. krusei) Safety profile, less drug-drug interactions than caspofungin Caspofungin 70/50 mg A I Broad spectrum, resistance rare, fungicidal Consider local epidemiology (C. parapsilosis) Safety profile Micafungin 100 mg A I Broad spectrum, resistance rare, fungicidal Consider local epidemiology (C. parapsilosis) Less drug-drug interactions than caspofungin Consider EMA warning label Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Treatment of candida in non-neutropenic patients according to EFISG guidelines 2011-12 Blood culture positive for yeast or empiric therapy (CIII) Start antifungal therapy (AII) Strongly recommended: echinocandin (AI) Moderately recommended: L-AMB or voriconazole (BI) Not recommeded (D): Conventional Amphotericin B Itraconazole Posaconazole Combination Marginally recommended: fluconazole or ABLC (CI) Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Candidaemia in non-neutropenic patients: ESCMID vs IDSA ESCMID 2011 IDSA 2009 Fluconazole CI AI Voriconazole BI AI (alternative agent) Lip-AMB B-D I-II AI (alternative agents) D-AMB DI AI (alternative agent) Echinocandins AI AI (for moderately severe to severe illness and for patients with recent azole exposure) Empiric treatment (as for candidaemia) CIII BIII Cornely OA et al. 21 st ECCMID, Milano 20011 http://www.escmid.org/escmid_library/online_lecture_library/eccmid/21st_eccmid27th_icc_2011_milan/educational_workshops_2011/
Are Echinocandins the Optimal Initial Therapy? Multiple RCTs (n=7) in past with nearly 2000 paitents Compared various treatment strategies Azoles (flu and vori) Ampho b Echinocandins Pathogens variables C. albicans Non C. albicans Conducted across range of severity of illness Did not standardize approach to CVC management What can we glean from all these trials?
Optimal Therapy for Candidemia Meta-analysis/metaregression Patient level data Endpoints Clinical Cure Mortality Cohort: All organisms; n=968 Andes DR, et al. CID 2012; 54: 1110-22.
CVC Management
Optimal Therapy for C. albicans: Fluconazole vs. Echinocandin C. albicans in vitro susceptible to both fluconazole and echinocandins Guidelines recommend use of fluconazole when documented C. albicans Goal to practice good stewardship and preserve echinocandins Is the paradigm shifting?
Optimal Therapy for C. albicans -Secondary Analysis -Large BDRCT -Compares Anidulafungin to Fluconazole -Subjects: Patients with BSI due to C. albicans Reboli AC et al. BMC Infect Dis 2011; 11: 261.
Anidulafungin in C. albicans Variables Independently Associated With Cure Adjusted OR 95% CI APACHE II: 0.94 (0.89-0.98) Anidulafungin: 2.36 (1.06-5.25) Reboli AC et al. BMC Infect Dis 2011; 11: 261.
Do We Need To Be More Aggressive? Retrospective analysis Subjects Candidemia Septic shock Endpoint Mortality Goal to determine interaction of timeliness and source control on outcome Kollef MH, et al. CID 2012:54;1739-46.
Interaction of Therapy & Source Control Source control defined as CVC removal or abcess drainage within 24 hrs of shock onset
Conclusions Fungi cause wide spectrum of disease Must be vigilant Diagnosis difficult but newer technologies and options Treatment frustrating Need to reconsider historic approach
Anti-Infective Treatment Influences Clinical Outcomes