Echinocandins in the ICU
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Echinocandins in the ICU

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Overview of candidiasis, antifungal pharmacology and the role of echinocandins

Overview of candidiasis, antifungal pharmacology and the role of echinocandins

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  • In this presentation we will look at the role for the echinocandins in the management of fungal infections within the ICU.

Echinocandins in the ICU Echinocandins in the ICU Presentation Transcript

  • Echinocandins in the ICU Do we really need them ( yet )? Dr. Andrew Ferguson MEd FRCA FCARCSI DIBICM FCCP Assistant Professor of Medicine (Critical Care) and Anesthesia, Dalhousie University Consultant in Anaesthesia and Intensive Care Medicine, Craigavon Area Hospital, United Kingdom
  • Overview
    • Epidemiology
    • Antifungal drug targets and mechanisms
    • Antifungal resistance mechanisms
    • Side-effect profiles and drug interactions
    • Choosing a drug - what is the evidence?
    • Expert opinions: Echinocandins – who/when?
  • EPIDEMIOLOGY
  • Clinically relevant fungi/molds Normal flora: Candida spp . Ubiquitous: Aspergillus spp. Cryptococcus spp. Mucor spp. Endemic geographical: Blastomyces spp. Coccidioides spp. Histoplasma spp . Emerging: Scedesporium spp. Fusarium spp. Trichosporin spp.
  • Epidemiology of Candida BSI Wisplinghoff H et al. Nosocomial bloodstream infection in US hospitals. Analysis of 24,179 cases From a prospective nationwide surveillance study. Clin Infect Dis 2004; 39: 309-317.
    • 4 th most common cause of nosocomial BSI, 3 rd of ICU BSI
    • Represents 8-11% of all nosocomial BSI
    • HIGH mortality + attributable mortality 15-25% for candidaemia
    • Non-albicans increasing, especially in cancer patients
  • Candida species distribution Author Year N albicans glabrata parapsilosis tropicalis krusei Pfaller et al 2001-04 > 5000 51-60% 10% 12% 9% 5% Guinea et al 1984-2006 307 43.9% 6.2% 39.7% 5.5% 1.6% Mora-Duarte et al 1997-01 224 35 - 54% 9.2-12.8% 18.3-19.8% 12.8-19.8% 0.9-4% Kuse et al 2003-04 392 43 - 44% 8-11% 13-16% 23-26% 3-4% Reboli et al 2003-04 245 59 - 64% 16-25% 10-14% 9-12% n/a Kullberg et al 1998-03 370 43 - 51% 15-17% 16-18% 13-21% 1-2% Garey et al 2002-05 230 56% 17% 11% 7% 3% Parkins et al 1999-04 207 52% 22% 6% 6% 5% Playford et al 2001-04 183 62% 17.9% 7.8% 5.6% 3.9% Azole S-DD Increased MIC to echinocandin ? clinical significance Azole R
  • Candida Spp. In-vitro Sensitivity S = sensitive I = Intermediate R = Resistant S-DD = Sensitive Dose-dependent Species Fluconazole Itraconazole Posaconazole Voriconazole Ampho B Echinocandins C. albicans S S S S S S C. tropicalis S S S S S S C. parapsilosis S S S S S S (to I?) C. dubliniensis S to S-DD S S S S S C. glabrata S-DD to R S-DD to R S to I S to I S to I S C. krusei R S-DD to R S to I S to I S to I S C. lusitaniae S S S S S to R S
  • Independent risk factors for Candida BSI Schelenz S. Management of candidiasis in the intensive care unit. J Antimicrob Chemother 2008; 61 Suppl 1: i31-i34. Blumberg HM et al . Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis 2001; 33: 177-86. Independent Variable Relative risk Odds ratio Abdominal surgery 7.3 Triple lumen CVC 5.4 Acute renal failure 4.2 Parenteral nutrition 3.6 Multiple antibiotics 12.5 Candida elsewhere 10.4 ICU > 7 days 9.8
  • Therapeutic Options Ampho B Deoxycholate Liposomal Ampho B (Ambisome) Ampho B Colloidal Dispersion (ABCD) Ampho B Lipid Complex (ABLC) Itraconazole, Fluconazole, Voriconazole Posaconazole, Ravuconazole Caspofungin , Micafungin, Anidulafungin Flucytosine Polyenes Azoles Echinocandins Antimetabolite
  • Hidden Costs of Therapy Drug Acquisition Costs Adverse Effect Costs Therapy Failure Costs Total Therapy Associated Costs
  • ANTIFUNGAL DRUG TARGETS
  • Fungal Cell Wall Targets Fungal cell Mannoproteins  -(1,6)-glucan  -(1,3)-glucan Chitin Phospholipid bilayer of cell membrane Cell membrane and cell wall Ergosterol  -(1,3)-glucan synthase Squalene DNA/RNA Synthesis Ergosterol Synthesis Pathway
  • Cell membrane Ergosterol Azole Squalene Ergosterol Synthesis Pathway Toxic sterols Accumulation of toxic sterols in cell membrane Inhibition of 14-  -demethylase Azoles
  • Cell membrane Ergosterol Amphotericin B Binding to ergosterol, Intercalation of cell membrane K + Na + Ca ++ Ca ++ Na + K + Leakage of intracellular cations and proteins Polyenes
  • ß(1,3) glucan synthase glucan synthase inhibitor Inhibition of ß(1,3) glucan synthase Depletion of ß(1,3) glucans in cell wall Echinocandins Mannoproteins ß(1,6)-glucan ß(1,3)-glucan Chitin Phospholipid bilayer of cell membrane
  • Cytosine permease Cytosine deaminase Phosphorylation Inhibition of thymidylate synthase FdUMP Conversion to deoxynucleosides Inhibition of DNA synthesis Inhibition of Protein Synthesis FdUMP FUTP Substitution for uracil 5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine; FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate; FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate Flucytosine 5-FC 5-FC 5-FU dUMP dTMP 5-FC
  • Fungal Cell Wall Targets Fungal cell Mannoproteins  -(1,6)-glucan  -(1,3)-glucan Chitin Phospholipid bilayer of cell membrane Cell membrane and cell wall Ergosterol  -(1,3)-glucan synthase Squalene DNA/RNA Synthesis AZOLES POLYENES ECHINOCANDINS FLUCYTOSINE Ergosterol Synthesis Pathway
  • ANTIFUNGAL DRUG RESISTANCE
  • Amphotericin B Resistance
    • In vivo resistance rare
    • Mechanisms:
      • Reduced ergosterol content (ERG2/ERG3 genes)
      • Altered sterols e.g. fecosterol : reduced affinity
      • Altered sterol:phospholipid ratio
      • Stationary growth phase
    • In vitro has been described with:
      • C. lusitaniae, C. krusei, C. neoformans
      • A. terreus, Fusarium spp.
  • Azole Resistance
    • Primary: C. krusei, Aspergillus, C. glabrata
    • Secondary: C. albicans, C. dubliniensis
    • Mechanisms:
      • Altered target (14-  demethylase)
      • Overexpression of target (14-  demethylase)
      • Energy-dependent efflux systems
      • Altered sterol and/or phospholipid composition
  • Echinocandin Resistance
    • Rare but emerging in Candida
    • FKS1 gene encodes glucan synthase
    • Mutation => resistance
    • Decrease sensitivity of glucan synthase
      • by 1000-fold or more !
    • ? confer cross-resistance
  • ADVERSE-EFFECTS & INTERACTIONS
  • Adverse Effects
    • * widely varying definitions in literature make comparison very difficult.
    • much less data available for caspofungin and voriconazole
    Product data sheets Girois SB et al. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2005; 24: 119-130. Effect AMB-D L-AMB Fluconazole Voriconazole Caspofungin Fever 34.2% 29.2% 1.4% 5.8% 13-27% Nausea 19.2% 12.2% 2% 5.4% ? Rash 2.9% 2.6% 0 ? ? Bronchospasm 7.2% 2.6% 0 ? ? Nephrotoxicity 33.2%* 14.6%* - 8-21%* 2.7%* Abnormal LFT’s 16%* 14%* 2%* 10-18%* 14-18%* Abnormal vision - - - 18.7% -
  • Comparative nephrotoxicity
  • Azoles and the P450 System
  • Enzyme inducers and Azole Levels 3A4 2C19 2D6 2C9 1A2 2E1 2A6 2B6 2C8 Fluconazole (~ 50%) Voriconazole (~50%) Isoniazid Rifampicin Phenytoin Carbamezepine Phenobarbital Ritonovir St. John’s Wort Reduction in AUC/C Max
  • Azole Inhibition of CYP P450 Increased serum concentration of Oral hypoglycemics Warfarin Cyclosporin Cyclophosphamide Tacrolimus Sirolimus Phenytoin Carbamezepine Benzodiazepines Calcium channel blockers Statins Isoniazid Rifabutin Quinidine Protease inhibitors (e.g. ritonavir) Busulfan Vincristine Cyclophosphamide Digoxin Loratidine Opioids e.g. alfentanil Taxels Proton pump inhibitors and others… 2C19 polymorphism in 5% caucasians and 20% Asians leads to increased voriconazole levels
  • Itraconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.
  • Fluconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.
  • Voriconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.
  • Echinocandin Interactions
    • Caspofungin
        • Decreased AUC for tacrolimus by 20%, C Max 16%
        • Cyclosporin increases caspo AUC by 35% - watch LFTs
        • Use dose of 70 mg/day if receiving concurrent P450 inducers e.g. phenytoin, dexamethasone, rifampicin, carbamazepine
    • Micafungin
        • Increased AUC for sirolimus by 21% : monitor
        • Increased AUC for nifedipine by 18%, C Max by 41%
    • Anidulafungin
        • D egradation in bloodstream – organ independent
        • ? increased anidulafungin AUC with cyclosporin
    Morris MI. Echinocandins in the management of invasive fungal infections. Part 1. Am J Health-Syst Pharm 2006; 63(18): 1693-1703.
  • CHOOSING A DRUG – EVIDENCE
  • Therapy Classification Cultured Candida Colonisation Signs of sepsis ? source Prophylactic Presence of Risk Factors Targeted Prophylactic Targeted Empiric Empiric (No colonisation) Candida Colonisation Targeted Adapted from Grenouillet F et al. J Invasive Fungal Infect 2007; 1(2): 42–9.
  • What we know…
    • Early adequate therapy improves outcome
      • OR for death with appropriate therapy = 0.46 (p=0.05)
      • Therapy started day 0 mortality = 15%
      • Therapy started day 1 mortality = 24%
      • Therapy started day 2 mortality = 37%
      • Therapy started beyond day 2 mortality = 41%
    • Wrong drug at wrong time = poor outcome
    • Parkins MD et al . J Antimicrob Chemother 2007; 60: 613-8.
    • Garey KW et al . Clin Infect Dis 2006: 43: 25-31.
    • Morrell M et al . Antimicrob Agents Chemother 2005: 49: 3640-3645.
  • Treatment related mortality risk 1. Retention of CVC 2. Inadequate initial fluconazole dose 3. Therapy delayed > 48 hrs Labelle AJ et al . Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med 2008; 36: 2967-2972. Retrospective cohort 245 pts with C-BSI 111 in ICU
  • Therapeutic Problem Areas
    • New pathogenic ‘fungal’ species
    • Slow microbiological diagnosis
    • Variable drug bioavailability
    • Drug toxicity & interactions
    • Resistance or breakthrough infection
    • Efficacy issues – naïve assumptions
  • Diagnostic Methods - Candida Guery BP et al . Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis. Intensive Care Med 2008 DOI 10.1007/s00134-008-1338-7 Marker Sensitivity Specificity 1->3  D glucan 70% 87.1% Mannans (antigen + antibody) 80 93 C. Albicans germ tube antibody IFA IgG 84.4 94.7 PCR 90.9 100
  • Clinical Efficacy Against IC NB Response is NOT 100% !! - ? combined therapy Drug Response % Author Caspofungin 73.4 Mora-Duarte et al Ampho B deoxycholate 61.7 Micafungin 89.6 Ruhnke et al Liposomal Ampho B 89.5 Anidulafungin 75.6 Reboli et al Fluconazole 60.2 Voriconazole 65 Kullberg et al Ampho B deoxycholate/fluconazole 71 Fluconazole 70 Rex et al Ampho B deoxycholate 79
  • Comparative in vivo efficacy
  • Making the choice – we need to know…
    • Severity of illness
    • Azole exposure
    • Comorbidity
    • Is the patient neutropenic
    • Patient age
    • Length of hospital stay
    • Residence in ICU
    • Hospital epidemiology of Candida spp.
    • Presence of CVCs and catheters
  • Echinocandin vs. Biofilm 0 10 20 30 40 50 60 70 80 90 100 0.5 2 16 FLU AMB CAS % Viability (XTT) Antifungal Conc (  g/mL) Ramage et al. Antimicrob Agent Chemother 2002;46:3634 Antifungal Killing vs. Biofilm- Embedded Candida spp. C. parapsilosis has higher MIC to caspo but ? not clinically relevant
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 575 potentially relevant articles 552 excluded for non-random design 23 for detailed evaluation 2 conference abstracts 10 excluded: 1 RCT of different anidulafungin doses 1 RCT monoclonal antibody to HSP 1 incompatible inclusion criteria 4 duplicate publications 1 RCT preventive therapy ! RCT empirical therapy in neutropenia 1 ongoing no results 15 included in meta-analysis
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 All-cause mortality: Fluconazole vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Clinical treatment failure: Fluconazole vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Microbiological failure: Fluconazole vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Adverse event discontinuation: Fluconazole vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 All-cause mortality: Echinocandin vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Clinical treatment failure: Echinocandin vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Microbiological failure: Echinocandin vs other antifungal
  • Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Adverse event discontinuation: Echinocandin vs other antifungal
    • Avoid Fluconazole as single empirical drug for patients with severe infections (inferior microbiological eradication)
    • Superior efficacy for anidulafungin vs fluconazole
    • Comparable efficacy for caspofungin and micafungin vs amphotericin B formulations
    • Echinocandins better safety profile than azoles/polyenes
    • Echinocandins may be considered first-line treatment for empirical treatment of candidemia
    • Liposomal amphotericin B equally good alternative if organ function permits
    Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Conclusions
  • Candidemia & NOT neutropenic
    • Fluconazole
        • 1 st line if stable with no azole exposure and no risk for resistant species
    • Voriconazole – downsides…
        • Less predictable pharmacokinetics
        • More frequent drug interactions and adverse effects
        • Not totally predictable against fluconazole resistant Candida spp
    • Liposomal Ampho B
        • Renal toxicity & infusion side-effects – tolerable for many pts
    • Echinocandins
        • Consistent success in trials
        • Very few interactions, once daily dosing
        • Higher MIC for C. parapsilosis but ? Relevant clinically
  • Candidemia - neutropenic
    • Strategy not as well defined
    • Fluconazole
        • Often already used as prophylaxis – if so, avoid
    • Liposomal Ampho B or echinocandin
        • Choice based on organ impairment
    • Voriconazole if ? coexistent mold infection
  • CHOOSING A DRUG – OPINION
  • When to Treat Pappas PG. The patient with candidemia: treatment choices and algorithms. Current Fungal Infection Reports 2008; 2: 112-119.
  • Ostrosky-Zeichner L, Pappas P. Crit Care Med 2006; 34: 857–863
  • Guinea J et al . Empirical treatment of candidemia in intensive care units: fluconazole or broad-spectrum agents? Medical Mycology 2008 DOI 10.1080/13693780802415556
    • “ Guidelines from different societies and groups agree that broad-spectrum empirical coverage should be used with ICU patients with suspected invasive candidiasis, but the scientific basis for this recommendation is often weak, non-existent, or based on specific settings”
    • “ IDSA guidelines…recommend caspofungin or amphotericin B in cases of invasive candidiasis in unstable patients while fluconazole should be employed for stable patients”
  • Guery BP et al. Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment. Intensive Care Med 2008 DOI 10.1007/s00134-008-1339-6
    • “ Patients who are hemodynamically unstable with septic shock or who have signs of severe sepsis require potent therapy, with a broad spectrum agent that has minimum toxicity”
    • “ To achieve this aim, echinocandins are a preferred first choice …Alternatively, lipid formulations of amphotericin B may be used in unstable patients”
  • Ruhnke M et al. New options for treatment of candidemia in critically ill patients. Clin Microbiol Infect 2008; 14 Suppl 4: 46-54
    • “ Fluconazole may be the drug of first choice in clinically stable patients who are not on azole prophylaxis and with proven fluconazole-susceptible Candida spp…
    • … initial broad-spectrum therapy has become a standard approach, especially in unstable patients
    • … caspofungin may be regarded as a first choice drug for severely ill, clinically unstable patients with organ dysfunction, especially patients with neutropenia”
    • No justification to drop fluconazole: safety, overall efficacy, low cost
    • Azoles may be more better in meningitis, endophthalmitis, and candiduria
    • Relapse rates of candida esophagitis appear higher with echinocandins
    • Engl J Med 2007; 356: 24
    “ However, in critically ill patients who are hemodynamically unstable and have candidemia, especially when the infection is associated with previous or concurrent exposure to azoles, echinocandins appear to be the drugs of first choice”
  • The Consensus
    • If you’re really sick... echinocandin or L-AMB*
    • If you’ve been on azoles... echinocandin or L-AMB*
    • If you might have aspergillus... voriconazole
    • If you’re stable with likely albicans... fluconazole
    • Candida on line... echinocandin or L-AMB*
    • So going back to the original question....
    YES we really do need the echinocandins!
  •  
  •  
  • Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis Jorge Mora-Duarte, M.D., Robert Betts, M.D., Coleman Rotstein, M.D., Arnaldo Lopes Colombo, M.D., Luis Thompson-Moya, M.D., Juanita Smietana, B.S., Robert Lupinacci, M.S., Carole Sable, M.D., Nicholas Kartsonis, M.D., John Perfect, M.D. and the Caspofungin Invasive Candidiasis Study Group N Engl J Med 2002; 347; 25: 2020-2029
    • Double-blind trial caspofungin v amphotericin B deoxycholate
    • 224 patients with invasive candidiasis
    • Successful outcome in 73.4% with caspofungin and 61.7% with ampho B
    • Less nephrotoxicity with caspofungin
    • Caspofungin appears at least as effective as ampho B
    • Caspofungin has considerably less toxicity
    • Few neutropenic patients in trial - further evaluation needed in this group
  • Anidulafungin versus Fluconazole for Invasive Candidiasis Annette C. Reboli, M.D., Coleman Rotstein, M.D., Peter G. Pappas, M.D., Stanley W. Chapman, M.D., Daniel H. Kett, M.D., Deepali Kumar, M.D., Robert Betts, M.D., Michele Wible, M.S., Beth P. Goldstein, Ph.D., Jennifer Schranz, M.D., David S. Krause, M.D., Thomas J. Walsh, M.D., for the Anidulafungin Study Group N Engl J Med 2007; 356(24): 2472-2482 Randomized, double-blind, international, multicenter study. Anidulafungin non-inferior to fluconazole in the treatment of invasive candidiasis
  • Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia Thomas J. Walsh, M.D., Hedy Teppler, M.D., Gerald R. Donowitz, M.D., Johan A. Maertens, M.D., Lindsey R. Baden, M.D., Anna Dmoszynska, M.D., Ph.D., Oliver A. Cornely, M.D., Michael R. Bourque, M.S., Robert J. Lupinacci, M.S., Carole A. Sable, M.D. and Ben E. dePauw, M.D., Ph.D. N Engl J Med 2004; 351; 14: 1391-1402 Multinational, double-blind trial 1095 patients, Caspofungin v liposomal AMB Empirical therapy for persistent fever and neutropenia Caspofungin non-inferior to standard therapy Caspofungin less nephrotoxicity and adverse events
  • Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis Peter G. Pappas, Coleman M. F. Rotstein, Robert F. Betts, Marcio Nucci, Deepak Talwar, Jan J. De Waele, Jose A. Vazquez, Bertrand F. Dupont, David L. Horn, Luis Ostrosky-Zeichner, Annette C. Reboli, Byungse Suh, Raghunadharao Digumarti, Chunzhang Wu, Laura L. Kovanda, Leah J. Arnold, and Donald N. Buell Clinical Infectious Diseases 2007; 45:883–93 International, randomized, double-blind trial in adults with invasive candidiasis Micafungin (100 mg) v micafungin (150 mg) v caspofungin (70 mg then 50 mg daily) Micafungin non-inferior to caspofungin
  • Bibliography
      • Lichtenstern C et al. Efficacy of caspofungin in invasive candidiasis and candidemia – de-escalation strategy.
    • Mycoses 2008; 51 (Suppl. 1): 35-46.
    • Bohme A et al. Treatment of invasive fungal infections in cancer patients – recommendations of the infectious diseases working oarty (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2008 October 14 th (Online) . Accessed at DOI: 10.1007/s00277-008-0622-5.
    • Garey KW et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a
    • multi-institutional study. Clin Infect Dis 2006; 43: 25-31.
    • Thursky KA et al. Recommendations for the treatment of established fungal infections. Intern Med J 2008; 38: 496-520.
    • Hof H. Developments in the epidemiology of invasive fungal infections – implications for the empiric and targeted antifungal therapy. Mycoses 2008; 51 (Suppl. 1): 1-6.
    • Ruhnke M et al. New options for the treatment of candidaemia in critically ill patients. Clin Microbiol Infect 2008; 14 (Suppl. 4): 46-54.
    • Schelenz S. Management of candidiasis in the intensive care unit. J Antimicrob Chem 2008; 61 (Suppl. 1): i32-i34.
    • Guery BP et al . Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis. Intensive Care Med 2008 Oct (Online). Accessed at DOI: 10.1007/s00134-008-1338-7.
    • Guery BP et al . Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment. Intensive Care Med 2008 Oct (Online). Accessed at DOI: 10.1007/
    • s00134-008-1339-6.
  • Bibliography
      • Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. J Antimicrob Chemother
      • 2008; 61 (Suppl. 1): i19-i30.
      • Labelle AJ et al. Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit
      • Care Med 2008; 36(11): 2967-2972.
      • Karthaus M, Cornely OA. Treatment options for candidaemia. Mycoses 2007; 50 (S1): 44-49.
      • Guinea J et al. Empirical treatment of candidemia in intensive care units: fluconazole or broad-spectrum
      • antifungal agents? Medical Mycology 2008: 1-6 iFirst article. Accessed at DOI: 10.1080/13693780802415556.
      • Pappas P. The patient with candidemia: treatment choices and algorithms. Current Fungal Infection Reports
      • 2008; 2: 112-119.
    • Parkins MD et al. Adequacy of empirical antifungal therapy and effect on outcome among patients with
    • invasive candida species infections. J Antimicrob Chemother 2007; 60: 613-618.
    • Mean M et al. Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care 2008; 12: 204. Accessed at DOI: 10.1186/cc6212. Available online at http://ccforum.com/content/12/1/204 .
    • Gafter-Gvilli A et al. Treatment of invasive candidal infections: systematic review and meta-analysis. Mayo Clin Proc 2008; 83(9): 1011-1021.
    • Morris MI. Echinocandins in the management of invasive fungal infections. Am J Health-Syst Pharm 2006; 63: 1693-1703.
  • Bibliography
    • Zaoutis TE et al . The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005: 41: 1232-1239.
    • Morgan J et al . Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 2005: 26: 540-547.
    • Blumberg HM et al . Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis 2001; 33: 177-86.
    • Grenouillet F et al. Preemptive antifungal therapy in critically ill surgical patients. J Invasive Fungal Infect 2007; 1(2): 42–9.
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