candidemia: an evidence- based approach · wisplinghoff h et al.clin infect dis 2004; 39: ......
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CandidemiaCandidemia: : anan evidenceevidence--basedbased approachapproach
Dr Marco FalconeDr Marco Falcone
Department of Public Health and Infectious DiseasesPoliclinico Umberto I, “Sapienza” University of Rome
Wisplinghoff H Wisplinghoff H et al.et al. Clin Infect Dis 2004; 39: 309Clin Infect Dis 2004; 39: 309--1717
Mortality for candidemiaMortality for candidemia
Risk for Invasive Risk for Invasive CandidiasisCandidiasisIs a ContinuumIs a Continuum
High-risk patients• Surgery• Leukopenia• Burns• Premature infants
Exposures• ICU >7 days• CVCs• Antibiotics• TPN• Colonization
If candidemia develops…• ~40% die• ~60% survive
MorrellMorrell M M etet al al AntimicrobAntimicrob AgentsAgents ChemotherChemother 2005; 49: 3632.2005; 49: 3632.
Difficulties in the diagnosis ofinvasive candidiasis
No diseaseCultures/antigen
Signs andsymptoms
Cultures/histopathology Sequelae
Prophylaxis Pre-emptive Empiric
Crude mortality40%
Diseas
e bur
den
Treatment Morbidity/mortality
Broad-spectrum antibioticCathetersNeutropenia, corticosteroidsSurgery, etc.
In hospital mortality doubles ifantifungal therapy is not startedwithin 12 hours*
* Morrell et al. Antimicrob Agent Chemother2005;49;3640.
Glucan,PCR
Antifungal prophylaxis
CATEGORIES WHAT DRUGS? HOW LONG?
Patients undergoing solid-organ transplantation ( liver, gut, pancreas)
FluconazoleL-AmbAnidulafungin? Micafungin?
7-14 days after surgery
Neutropenic patients undergoing auto- or allogenic bone marrow transplantation
Fluconazole 6 mg/kg/diePosaconazole 600 mg/dieMicafungin 50mg/die
All the period of neutropenia
Patients with secondary neutropenia.
Fluconazole 6mg/kg/diePosaconazole 600 mg/die
During induction chemotherapy and for the period of neutropenia
AND THE OTHER PATIENTS AT RISK?
Fluconazole(n=122)
Placebo (n=127)
P value
Successes 36% 38% 0.78
Persisting fever 51% 54% ns
Fungus infection 5% 9% 0.24
Shift to other antifungal agent
10% 16% Not given
30-day mortality 24% 17% 0.23
“…Empirical antifungal therapy with fluconazole cannot be recommended for
routine use in ICU patients…rather, it should be reserved for treating documented
infection.”
Colonization Index and Colonization Index and CandidaCandida infections in infections in patients with abdominal surgerypatients with abdominal surgery
P <0.001
Pittet et al Ann Surg 1994; 220: 751
Colonization index in critical patients randomised Colonization index in critical patients randomised to receive fluconazole or placebo to receive fluconazole or placebo
Garbino et al. Intensive Care Medicine 2002; 28: 1708
What are the targets for antifungal therapy?
Cell membraneFungi use principally ergosterol instead of cholesterol
Cell WallUnlike mammalian cells, fungi have a cell wall
DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Antifungal PK: Drug DistributionAntifungal PK: Drug Distribution
+, ≥50% of serum concentrations.–, <10% of serum concentrations.*Predicted.
1. Dodds-Ashley ES, et al . Clin Infect Dis. 2006;43:S28-S39. 2. Groll AH, et al. Adv Pharmacol. 1998;44:343-500.
3. Eschenauer G, et al. Ther Clin Risk Manage. 2007;3:71-97.
Liver/ Spleen Kidneys
Gut/gall bladder Lungs
Brain/CSF Eyes
Bladder/urine
AMB + + + + – – –5FC + + + + + + +FLU + + + + + + +ITR + + + + – – –VOR + + + + + + –POS* + + + + – – –Echino + + + + – – –
Is the AMBIs the AMB--deoxycholate Era Over ?deoxycholate Era Over ?AMB-D
AMB-D
AMB-DAMB-D
Imidazoles Fluconazole Lipid-AMB Echinocandins/Itraconazole New Triazoles
• Amphotericin B cornestone
• Toxicity a limiting factor
• Limited options for prophylaxis or chronic therapy
• Combination therapy often not feasible
• Cost less of a factor
Old vs. New Era of Antifungal Old vs. New Era of Antifungal TherapyTherapy
• Several treatment options
• Improved tolerability and availability of oral formulations
• Expanding spectrum of pathogens
• Combination therapy-standard of care?
• Cost !!!
Old EraOld Era New Era
Bone Marrow Transplantation 2000
“…In this prospective trial, low‐dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but fluconazole was
significantly better tolerated..”
Lipid AMB FormulationsLipid AMB Formulations--SummarySummary
• Efficacy– Lipid formulation = AMB-deoxy
• Nephrotoxicity– L-AMB < ABLC < ABCD << AMB-deoxy
• Infusion related toxicity– L-AMB < ABLC < ABCD < AMB-deoxy
• Product cost (AWP)– L-AMB > ABLC > ABCD > AMB-deoxy
Treatment Guidelines for Candidemia:Treatment Guidelines for Candidemia:Infectious Disease Society of America 2009Infectious Disease Society of America 2009
Cond
ition
Prim
ary
therapy
Alte
rnative
therapy
Amphotericin B deoxycholate or lipid
formulation or voriconazole
Echinocandin then Fluconazole
Fluconazole or voriconazole
Nonneutropenic adults
Chronic disseminated candidiasis
Neutropenic adults
Fluconazoleor echinocandin*
Fluconazole or Amphotericin B deoxycholate or lipid formulation
Echinocandinor Amphotericin B lipid formulation
Pappas PG et al. Clin Infect Dis. 2009;48:503‐535.
IDSA 2009 Guidelines for treatment IDSA 2009 Guidelines for treatment of invasive candidiasisof invasive candidiasis
Echinocandins interactionsEchinocandins interactions
Caspofungin Micafungin Anidulafungin
CYP 3A4 inhibitor? No No No
Drug interactions OATP1B1 transporter?Tacrolimus 20%
CSA CASPO 35%RIF or other inducers CASPO 30%
No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin.
Sirolimus, nifedipine AUC 20%
No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin.
Dosage adjustment in hepatic dysf.
To 35 mg/day in moderate hepatic insufficiency
No dosage adjustment No dosage adjustment
Adverse effects Histamine-rxn with infusion, phlebitis,Asymptomatic transminases
Occasional histamine-rxn with infusion, phlebitis,Asymptomatic transaminases
N&V, headache, hypokalemia, and GGT
Anidulafungin vs. fluconazoleSuccess at primary and secondary timepoints (MITT)
Reboli et al. N Eng J Med 2007;356:2472‐2482
CandidemiaCandidemia and CVC: and CVC: toto removeremove or or notnot??
30
“I don’t want you to make the wrong mistake”
Yogi Berra
31
Remove or not?Evidence- based review
Medline 1966-2000
14 studies evaluated the relationship between CVC removal and outcome
Authors Population Assessment of illness
Effect of CVC removal on survival
Anaisse 1998 476 patients with cancer
SAPS and APACHE III
Modest Modest improvementimprovement
Nucci 1998 54 patients with cancer
Karnofsky scaleNo effectNo effect
Nucci 1998 145 patients; cancer in 34%
Karnofsky scale Increased survivalIncreased survival
Luzzati 2000 189 adults patients; cancer
in 21%
McCabe scale Modest Modest improvementimprovement
32
Remove or not?Evidence- based review
Medline 1966-2000
Authors Population Assessment of illness Effect of CVC removal on survival
Nguyen 1995 472 pts 4-point grading system Increased survivalIncreased survival
Hung 1996 118 pts 4-point grading system Increased survivalIncreased survival
Goodrich 1991 102 BMT recipients None No effectNo effect
Eppes 1989 21 pts None No effectNo effect
Dato 1990 31 pts None Increased survivalIncreased survival
Rex 1994 237 pts; cancer in 61% APACHE II Survival differences non Survival differences non evaluated but lower duration of evaluated but lower duration of
candidemiacandidemia
Lecciones 1992 155 neoplastic pts None No effectNo effect
Girmenia 1996 35 pts None No effectNo effect
Stamos 1995 70 pts ( cancer in 15%) None Increased survivalIncreased survival
Karkowickz 2000 104 infants NTISS Increased survivalIncreased survival
Not available OR;Not confounding
factors
Multivariate statistical analysis
not performed
37
Time to mycological eradication for patients whose Time to mycological eradication for patients whose central venous catheter (CVC) was removed within central venous catheter (CVC) was removed within
24 h (24 h (AA) or 48 h () or 48 h (BB))
38
Removal of CVC?Removal of CVC?Look for other sources!Look for other sources!
Gastrointestinal tract
Infective endocarditis
Septic thrombophlebitis
Renal abscess
Low mortality associated to Low mortality associated to CandidaCandida thrombophlebitis thrombophlebitis of the central veins: literature reviewof the central veins: literature reviewCaccese R, Carfagna P, Falcone M and Venditti M, Med Mycol 2011
Septic bilateral pulmonary candidiasis successfully treated withanidulafungin therapy in two patients with peritoneal carcinomatosis
Marco Falcone1*, Fabio Accarpio2, Mario Venditti1, Antonio Vena3, Simone Sibio2, Paolo Sammartino2 and Angelo Di Giorgio2
Journal of Antimicrobial Chemotherapy, August 2, 2010
Candida Candida endocarditis: recommended endocarditis: recommended therapytherapy
Falcone M et al Medicine (Baltimore) 2009
• Maximum tolerated dose of L-AMB +/- 5-flucytosine
• Surgery, valvular replacement
• Chronic suppressive therapy with oral azoles
• Echinocandins (medical therapy alone in RS-IE) plus surgery followed by oral azoles
ConclusionsConclusions
• Candidemia: importance of early diagnosisand appropriate therapy
• Use of new diagnostic tools and clinicalalgorythm
• Echinocandins first choice for treatment
• Look for complications after CVC removal
Practical approachPractical approach
Retain and treat with antifungal active against Candida biofilm
Candidemia in patient with CVC
CVC short-term
Removal, tip culture
Differential diagnosis: CVC or secondary focus
CVC long-term, tunneled or implanted
• High risk of complications for removal or reinsertion• Response within 24-48 hours of antifungal therapy•No hemodynamic instability•No insertion abscess
• No response after 48 hours of antifungal therapy•Hemodynamic instability•Pocket complications•Infective endocarditis• suspected/onfirmed peripheral embolization
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