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.”

Critical Care 2010; 14: 244.

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

Total parenteral nutrition 1 p

Severe sepsis 2 p

Candida Pluricolonization 1 p

Surgery 1 p

Posteraro et al in press

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: randomized clinical trialsEchinocandins: randomized clinical trials

Antimicrob Agents Chemother 2002; 46: 1773-780

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

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

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35

36

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

43

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