current treatment options for candida terapia antimicotica.pdf · current treatment options for...

Current treatment options for Candida bloodstream infections

Marco Falcone Dipartimento di Sanità Pubblica e Malattie Infettive

Scuola Superiore di Studi Avanzati

“Sapienza” Università di Roma

Martin et al N Engl J Med 2003;348:1546-54

The epidemiology of sepsis in the United States from 1979 through 2000

Variations in Organism-Specific Severe Sepsis Mortality in the United States: 1999-2008*.

Crit Care Med 2015; 43:65-77.

Reasons of the increase of invasive Candida infections

Improvement in diagnostic methods

CVC/intravascular device use

Immunosuppression

ICU patients

New populations at risk

Kullberg & Arendrup, N Engl J Med 2015; 373:1445-53

Wisplinghoff H et al. Clin Infect Dis 2004; 39: 309-17

Mortality for candidemia

Mortality for candidemia: an update

Khatib et al. Mycoses. 2016.

Retrospective examination of candidemia in adults hospitalized from 2007 to 2015 in a Michigan hospital

Which is the best treatment of candidemia?

The early diagnosis…

Clin Infect Dis 2012; 54:1739-46

Diagn Microbiol Infect Dis 2009; 64: 402-407

(1,3)-b-D-Glucan- based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study

False positive: 25%

Posteraro B et al, J Antimicrob Chemother 2016; 71: 2262–2269

T2 Magnetic Resonance Assay for the Rapid Diagnosis of

Candidemia in Whole Blood

T2MR and T2 Candida: time to detection!

Pfaller MA et al. Future Microbiol. 2016;11:103-17

Recognize patients at risk

IDENTIFY RISK FACTORS

Kullberg & Arendrup, N Engl J Med 2015; 373:1445-53

Risk stratification in ICU patients: Candida score

Leon C et al. Crit Care Med 2009; 37:1624 –1633

Are Candidemia episodes all the same?

Internal Medicine

Wards

Surgery

Hematologic patients

ICU

Nosocomial

Community-onset

Complicated vs

uncomplicated candidemia

Early vs late candidemia

Internal Medicine

Wards

Bassetti et al. J Clin Microbiol 2013; 51(12):4167-72

%

Internal Medicine Surgery/ICU/Oncology Total= Ematology 995

Features of candidemia in

Internal Medicine

Cancer/ Hematologic malignancies

Comorbidities

Organ failure (kidney, heart, liver)

Diabetes/ Metabolic syndrome

Immunosuppressive therapy

COPD/

Respiratory failure

Anti- TNF-α drugs

Methods: Retrospective multicenter cohort study was conducted in 3 large teaching italian hospitals, in a 3-year period (January 2012 – December 2014). Hospitals participating to this study were: Nuovo Santa Chiara Hospital in Pisa, Umberto I Hospital in Rome, Santa Maria della Misericordia in Udine. Consecutive candidemic episodes in afebrile patients and matched febrile controls were enrolled during the three years study period (case/control ratio 1:1.). Controls were matched for age, sex, time of admission and comorbidities. Patients without fever represented 40% of the overall candidemia cases

Am J Med. 2016 Jul 22. pii: S0002-9343(16)30727-6

Am J Med. 2016 Jul 22. pii: S0002-9343(16)30727-6

Am J Med. 2016 Jul 22. pii: S0002-9343(16)30727-6

Variables

Group 1 (n = 64)

Low probability of

fever

Group 2 (n = 132)

Intermediate probability

of fever

Group 3 (n = 98)

High probability

of fever

P

Intravascular device (CVC/PICC)

0 (0%) *, § 70 (53%) # 89 (91%) < 0.001

Diabetes mellitus 59 (92%) *, § 70 (53%) # 18 (18%) < 0.001

Δ Time admission to candidemia

5 [2 - 8] °, § 2 [1 – 6] # 18 [12 - 31] < 0.001

C. difficile infection 20 (31%) § 26 (20%) # 5 (5%) < 0.001

Falcone et al. submitted

Assessment of risk factors for nosocomial candidemia in non-neutropenic patients hospitalized in Internal

Medicine wards: a multicenter study

DERIVATION COHORT 322 candidemia vs 644 matched controls Policlinico Umberto I (Rome) Azienda Ospedaliera Universitaria Pisana (Pisa) San Giovanni-Addolorata (Rome)

EXTERNAL VALIDATION COHORT University Hospital of Trieste

Univariate analysis Multivariate analysis

OR 95.0% CI p-value

OR 95.0% CI p-value

Lower Upper Lower Upper

Immunosuppressive therapy 2.993 2.269 3.949 <0.001

2.127 1.444 3.133 <0.001

Previous antibiotic therapy 4.179 3.138 5.566 <0.001

2.992 2.025 4.420 <0.001

TPN 8.123 5.746 11.483 <0.001

4.032 2.543 6.393 <0.001

COPD 3.147 2.198 4.507 <0.001

4.253 2.591 6.083 <0.001

Diabetes mellitus 2.701 2.050 3.560 <0.001

4.676 3.135 6.973 <0.001

Concomitant iv glycopeptide therapy 6.935 3.733 12.884 <0.001

4.685 2.148 10.216 <0.001

IBD 6.682 2.426 18.409 <0.001

4.988 1.546 16.097 0.007

PICC 8.276 5.586 12.262 <0.001

5.006 2.932 8.548 <0.001

Recent CDI 7.641 4.417 13.217 <0.001

7.376 3.663 14.850 <0.001

Severe sepsis/septic shock 16.869 10.225 27.829 <0.001

9.815 5.397 17.851 <0.001






RISK FACTOR Points

Severe sepsis/septic shock +2.5

Recent Clostridium difficile infection +1.5

TPN +1

COPD +1

Concomitant glycopeptide therapy +1

IBD +1

PICC +1

Diabetes mellitus +1

Previous antibiotic therapy +0.5

Immunosuppressive therapy +0.5


AUC 0.910, 95% CI 0.892-0.929, p<0.001

AUC 0.840, 95% CI 0.790-0.891, p<0.001

DERIVATION COHORT (N=966) VALIDATION COHORT (N=279)

Figure 1. ROC curve of Candida score in the derivation and in the validation cohort.

Panel A Panel B




Approach to invasive candidiasis

No disease Cultures/ antigen

Signs and symptoms

Cultures/ histopathology Sequelae

Prophylaxis Pre-emptive Empiric

Crude mortality 40%

Treatment Morbidity/ mortality

Broad-spectrum antibiotic

Catheters

Neutropenia, steroids

Surgery, etc. In hospital mortality doubles if antifungal therapy is not started within 12 hours*

* Morrell et al. Antimicrob Agent Chemother2005;49;3640.

Glucan, PCR

Antifungal therapy of suspected/proven candidemia:

Which drug?

Treatment of Candida in non-neutropenic patients (ESCMID guidelines 2012)

Blood culture positive for yeast

or empiric therapy (CIII)

Start antifungal therapy

(AII)

Strongly recommended:

echinocandin (AI)

Moderately recommended:

L-AMB or voriconazole (BI)

Marginally recommended:

fluconazole or ABLC (CI)

Not recommended (D): Conventional Amphotericin B

Itraconazole Posaconazole Combination

Clin Microbiol Infect. 2012 Dec;18 Suppl 7:19-37.

Treatment of Candida in non-neutropenic patients (IDSA guidelines 2016)

Start antifungal

therapy

Echinocandin Strongly recommended

(strong recommendation; high-quality evidence)

L-AMB Reasonable alternative if there is intolerance,limited

availability, or resistance to other antifungal agent (strong recommendation; high-quality evidence)

Fluconazole Acceptable alternative in not critically ill patients

(if not fluconazole-resistant Candida species) (strong recommendation; high-quality evidence)

Not recommended : Conventional Amphotericin B

Itraconazole Posaconazole Combination

Pappas et al, Clin Infect Dis 2016; 62(4):e1-50.

Voriconazole Recommended as step-down oral therapy for selected cases of

candidemia due to C. krusei (strong recommendation; low-quality evidence)

Anidulafungin Echinocandin B0 (Aspergillus nidulans)

Caspofungin Derived from Pneumocandin B0

(Glarealozoyensis) Micafungin FR90130 (Coleophomaempedra)

The echinocandins era

Rho1p

Fks1

p

Fks2

p

GTP binding site

UDP-glucose

Beta-1,3 glucan synthase complex

Target of Echinocandin Antifungals

Yeast

Fungal Cell Wall

beta 1,3 glucans beta1,6 glucans

mannoproteins

Beta 1,3 glucan synthase

Chitin

Lipid bilayer with ergosterol

Beta 1,3 glucan chain

Echinocandins: summary of properties

• Rapid, fungicidal activity

• Broad spectrum against yeasts

(reduced susceptibility for C. parapsilosis)

• Activity on biofilm

• Good safety profile

• Few drug interactions

Overall treatment success in the modified intent to treat population of RTCs evaulating echinocandins

Kuse et al.

MFC AMB

Reboli et al.

ANF FLC

Mora-Duarte etal

CFG AMB

Overall 89% 89% 75% 60% 73% 61%

C. albicans 88% 89% 81% 62% 64% 57%

C. krusei 83% 86% ND ND ND ND

C. glabrata 83% 80% 56% 50% 77% 80%

C. parapsilosis 89% 87% 64% 83% 70% 65%

C. tropicalis 92% 95% 93% 50% 85% 71%

Lancet 2007; 369: 1519-27. N Engl J Med 2007; 356: 2472-82. N Engl J Med 2002;347:2020-29

Clin Infect Dis 2012; 54: 1115

Stepdown to fluconazole

Pappas et al, Clin Infect Dis 2016; 62(4):e1-50.

Methods: Phase IV, open-label, noncomparative study, involving 44 centers across the US and four centers in the Republic of Korea (study period: July 2007 and June 2010) All patients received 200 mg IV anidulafungin as a single loading dose and 100 mg IV anidulafungin daily thereafter for a maximum of 28 days After 5 days’ IV anidulafungin, investigators could transition patients to an oral azole if they met the following criteria: •ability to tolerate oral therapy; •afebrile for > 24 hours; •hemodynamically stable; •not neutropenic; •documented clearance of Candida from the bloodstream

Vazquez et al. BMC Infectious Diseases 2014, 14:97

Vazquez et al. BMC Infectious Diseases 2014, 14:97

Patients in the early switch subpopulation had global response rates that were higher than the MITT population at all time points

Septic Thrombophlebitis

Septic pulmonary embolism

Mycotic aneurism

Endophtalmitis

Neprhitis

Osteomyelitis, spondylodiscitis

Sepsis/ Septic shock

Endocarditis

Complications of candidemia

Antifungal 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 + + + + – – –

INTRAOCULAR PENETRATION OF VORICONAZOLE AND

CASPOFUNGIN IN A PATIENT WITH FUNGAL ENDOPHTHALMITIS

• Concentrations of caspofungin and voriconazole were determined

in the ocular fluid, and in a concomitantly taken plasma sample.

• Caspofungin concentration in the aqueous was 0.28 mg/L, with a

simultaneous plasma concentration of 4.70 mg/L.

• Voriconazole levels were 3.47 mg/L in the aqueous and 7.45 mg/L

in plasma, respectively.

Spriet I et al.. J Antimicrob Chemother 2009 Oct;64:877-8.

Medicine (Baltimore) 2009; 88:160-8

Candida endocarditis: a systematic literature review from 1997 up to 2014 and analysis of case series from SEI study group.

Giuliano S, Falcone M…and Venditti M, ongoing work

Candida endocarditis: a systematic literature review from 1997 up to 2014 and analysis of case series from SEI study group


Variable PVE (%)

N=64 NVE (%)

N=76 p value

Age (years), median ± sd 56.4 ± 16.8 53.6 ± 19.5 0.3

Male sex 38 (59.4) 48 (63.2) 0.6 Chronic liver disease 10 (15.6) 17 (22.4) 0.3 Malignancy 1 (1.6) 21 (27.6) <0.001

Previous endocarditis 16 (25.0) 5 (6.6) 0.002

Diabetes mellitus 7 (10.9) 7 (9.2) 0.7

Renal disease 2 (3.1) 6 (7.9) 0.2

Autoimmune disease 4 (6.3) 2 (2.6) 0.4

COPD 2 (3.1) 2 (2.6) 1.0

IBD 2 (3.1) 0 0.2 Pancreatitis 1 (1.6) 3 (3.9) 0.6 Previous antibiotic exposure (30 days) 13 (20.3) 32 (42.1) 0.006 Glucocorticoids 3 (4.7) 5 (6.6) 0.7 Previous abdominal surgery 3 (4.7) 25 (32.9) <0.001 Previous cardiac surgery 16 (25.0) 6 (7.9) 0.006 IVDU 8 (12.5) 16 (21.1) 0.2 CVC 5 (7.8) 20 (26.3) 0.004 TPN 0 6 (7.9) 0.03 Length of therapy (days) 42.0, 28.0 42.0, 30.0 0.6 Surgical therapy 40 (62.5) 37 (48.7) 0.1 Time to death (days) 22.5, 39.0 30.0, 47.0 0.1 Overall mortality 27 (42.8) 26 (34.2) 0.3


The process of biofilm formation might be even more relevant in PVE than in NVE pathogenesis

p < 0.001




p = 0.015

Kaplan-Meier survival analysis to compare survival of patients with PVE and NVE

current treatment options for candida terapia antimicotica.pdf · current treatment options for...

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