terapia della candidosi invasiva · candidiasis no disease cultures/ antigen signs and symptoms...

Terapia della candidosi invasiva

Marco FalconeDipartimento di Sanità Pubblica e Malattie Infettive

Scuola Superiore di Studi Avanzati

“Sapienza” Università di Roma

Therapy of invasive candidasis

Clancy, Nguyen. Clin Infect Dis. 2013;56:1284-92

Which is the best treatment of candidemia?

The early diagnosis…

Approach to invasive candidiasis

No diseaseCultures/antigen

Signs andsymptoms

Cultures/histopathologySequelae

ProphylaxisPre-emptive Empiric

Crude mortality40%

Treatment Morbidity/mortality

Broad-spectrum antibiotic

Catheters

Neutropenia, steroids

Surgery, etc.In hospital mortality doubles ifantifungal therapy is not startedwithin 12 hours*

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

Glucan,T2

Clin Infect Dis 2012; 54:1739-46

Methods:

Retrospective multicenter cohort study was conducted in 3 large teaching italianhospitals, in a 3-year period (January 2012 – December 2014). Hospitals participatingto 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 controlswere enrolled during the three years study period (case/control ratio 1:1.). Controlswere 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

Treatment of candidemia and

invasive candidasis

Special compartments(e.g. intra-abdominal

Candidasis)EMPIRIC TARGETED

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

Ann Intern Med 2008; 149: 83-90

270 ICU patients with fever despite broad-spectrum antibiotic therapy

The EMPIRICUS (Empirical Antifungal Treatment in ICU)Randomized Clinical Trial

• Multicenter• Randomized• Double-blind• From July 20, 2012, to February 7, 2015

• Intervention: 14-day empirical treatment with micafungin (100 mg iv) vs placebo

Timsit JF et al. JAMA. 2016;316:1555-1564

• Study population: adult patients with suspected invasive candidiasis hospitalized in ICU


Study population: adult patients with suspected invasive candidiasis

Inclusion Criteria

Critically ill adult patients with the followingcriteria:

(1) mechanically ventilated at least 5 days;(2) with at least 1 colonization site (other thanrectal swab or stool) positive for Candidaspecies using traditional culture methods;(3) at least 1 additional organ dysfunction;(4) previous treatment for more than 4 daysusing broad-spectrum antibacterial agentswithin the last 7 days;(5) 1 arterial or central vein catheter(6) 1 new finding of ICU-acquired sepsis ofunknown origin

Exclusion Criteria

(1)neutrophil count of less than 500/mm3;(2)previous bone marrow or solid organtransplantation;(3)ongoing systemic immunosuppressant agenttherapy other than corticosteroids at doses lowerthan 2 mg/kg/d of prednisolone or equivalent;(4)antifungal treatment with an echinocandinagent formore than 1 day or with any other antifungalagent for morethan 72 hours during the week prior to inclusion



Micafungin did not significantly improve

the primary outcome of 28-day invasive

fungal infection–free survival


68% of patients in the micafungin group versus

60,2% of patients in the placebo group were

alive and free from invasive fungal infection at

day 28

Primary endpoint


• HRs substantiallyfavoring themicafungin group forpatients with:

• SOFA score > 8• β-D-glucan levels >80

pg/mL• β-D-glucan levels of

250 pg/mL• Candida scores at ≥3• colonization index

≥50%

Not statistically significant!


Primary endpoint in prespecified patient subgroups

The EMPIRICUS Randomized Clinical Trial: explanations of results


• Primary endpoint

• Results…

• Calculation of sample size, small subgroups samplesunable to detect differences…

After the first dose of micafungin, the mean (SD) Cmax levelwas 7.26 (2.43) mg/L (median, 7.4[IQR, 5.4-9.2]), the mean(SD) Cmin level was 1.6 (0.54) mg/L (median, 2.1[IQR, 1.4-3.1]), and the mean (SD) AUC was 78.2 (33.2) mg.h/L.

Micafungin Pharmacokinetics in EMPIRICUS trial

QUESTION

Is the exposure to micafungin similar between critically ill patients and healthy patients?

Are higher doses necessary in critically ill patients?

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

Much lower exposure in this cohort of ICU patients than the exposure described in theliterature.Using an unpaired t test (on mean exposure standard deviation [SD] and number of patients),the exposure in this cohort appeared to be significantly lower than that in healthy volunteers

Lempers VJ et al. Antimicrob Agents Chemother. 2015;59:4403-9

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

Four possible explanations for the lower exposure of micafungin:

(i)altered protein binding,

(ii)changes in metabolic route,

(iii)impact of disease severity,

(iv)a higher average body weight in this cohort than in reference

populations

Lempers VJ et al. Antimicrob Agents Chemother. 2015;59:4403-9

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)

Moderatelyrecommended:

L-AMB or voriconazole (BI)

Marginally recommended:

fluconazole or ABLC (CI)

Not recommended (D):Conventional Amphotericin B

ItraconazolePosaconazoleCombination

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

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

Start antifungal

therapy

EchinocandinStrongly recommended

(strong recommendation; high-quality evidence)

L-AMBReasonable alternative if there is intolerance,limited

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

FluconazoleAcceptable alternative in not critically ill patients

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

Not recommended :Conventional Amphotericin B

ItraconazolePosaconazoleCombination

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)

Description of the phase III studies comparing echinocandins to standard of care

1N Engl J Med. 2002;347:2020-9. 2 N Engl J Med. 2007;356:2472-82.3Lancet. 2007;369:1519-27

Clin Infect Dis 2012; 54: 1115

• 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 Therapy

• Several treatment options

• Improved tolerability and availability of

oral formulations

• Expanding spectrum of pathogens

• Combination therapy-standard of care?

• Cost !!!

Old Era New Era

522 candidemia episodes

- Policlinico Umberto I (Rome)- Policlinico Tor Vergata (Rome)- San Giovanni-Addolorata (Rome)

- University Hospital of Trieste

Impact of echinocandins therapy on survival of candidemia in patients with or without septic shock

- Azienda Ospedaliera Universitaria Pisana (Pisa)

Falcone M,……… Venditti M, Menichetti F, in preparation

Impact of echinocandins therapy on survival of candidemia in patients with or without septic shock

Patients with candidemia without septic

shock (N=302)

Survivors

N= 217 (71.8%)

Non survivors

N=85 (28.2%)

Patients with candidemia with septic

shock (N=220)

Survivors

N=92 (41.8%)

Non survivors

N=128 (58.2%)

Multicenter study episodes of candidemia in Internal Medicine wards

Falcone M,…..Andreoni M, Venditti M, Menichetti F, in preparation

Patients with candidemia without septic shock

(N=302)

Survivors

N= 217 (71.8%)

Non survivors

N=85 (28.2%) p value

Male 99 (45.6%) 42 (49.4%) 0.553

Age 75 (65-84) 81 (72-89) 0.031

Antifungal chemotherapy

No therapy within the first 24 h

Azole within the first 24 h

Echinocandins within the first 24 h

Amphotericin b within the first 24 h

19 (8.8%)

123 (56.7%)

72 (33.2%)

3 (1.4%)

14 (16.5%)

59 (69.4%)

12 (14.1%)

0

0.053

0.042

0.001

0.276

Patients with candidemia without septic shock

Falcone M,…..Venditti M, Menichetti F, in preparation

Patients with candidemia with septic shock

Patients with candidemia with septic shock

(N=220)

Survivors

N=92 (41.8%)

Non survivors

N=128 (58.2%) p value

Male 37 (40.2%) 61 (47.7%) 0.274

Age 80 (71-86) 80 (72-87) 0.908

Antifungal chemotherapy

No therapy within the first 24 h

Azole within the first 24 h

Echinocandins within the first 24 h

Amphotericin b within the first 24 h

8 (8.7%)

48 (52.2%)

36 (39.1%)

-

39 (30.5%)

47 (36.7%)

42 (32.8%)

-

<0.001

0.022

0.334

-


Propensity-score adjusted Cox regression

HR p-value

Lower Upper

Patients with candidemia

with septic shockEchinocandins 0.811 0.547 1.202 0.297

Patients with candidemia

without septic shockEchinocandins 0.376 0.198 0.711 0.003

Impact of echinocandins in patients with septic shock and without septic shock

Cox regression analysis (Propensity score adjusted)


Patients without septic

shock, received

echinocandins

Patients without septic

shock, not received

echinocandins

Patients with septic shock,

received echinocandins

Patients with septic shock,

not received echinocandins

Kaplan Meier curves in patients with septic shock and without septic shock receiving echinocandins


Sequential therapy- stepdown to fluconazole

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

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

Therapy of invasive candidasis

Intra-abdominal candidiasis: the guidelines—forgotten non-candidemic invasive candidiasis

Montravers P et al, Intensive Care Med 2013; 39:2226–2230

Echinocandins in peritoneal fluid

FUNGICIDAL EFFECT 128 X MIC

Mycoses. 2013;56(6):623-30

Anidula/Caspo/Mica

serum

Peritoneal collection

J Antimicrob Chemother 2015;70:2854-2861

Variable FKS mutation

(n=13)

No FKS mutation

(n=59)

UnivariateOR 95%, CI:p value

Mean age (range) 56 (24-74) 62 (28-97) NA/NA/0.11

Male gender 11 (85%) 32 (54%) 4.64, 0.88-45.84, 0.06

Underlying conditions

Gastrointestinal disorder 11 (85%) 30 (51%) 5.31, 1.01-52.39, 0.03

Renal dysfunction 6 (46%) 38 (64%) 0.47, 0.12-1.91, 0.22

Hemodialysis 2 (15%) 26 (45%) 0.23, 0.02-1.22, 0.07

Diabetes 3 (23%) 31 (53%) 0.27, 0.04-1.22, 0.07

GI surgery previous 30 days (%)

7 (54%) 26 (44%) 1.48, 0.37-6.02, 0.52

Presence of CVC (%) 12 (92%) 53 (90%) 1.36, 0.14-67.6, 0.79

Prior episode of CG candidemia (%)

3 (23%) 1 (2%) 17.6, 1.18-928.21, 0.02

Echinocandin exposure prevoius 60 days

9 (69%) 6 (10%) 19.88, 3.84-110.7, <0.01

FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia

Beyda et al, Clin Infect Dis. 2014;59:819-25

FKS mutations were identified in 18% of 72

patients with C. glabrata

Treatment failure occurred in 30% of 57 patients who received an echinocandin and was more common in patients with FKS mutants (6 of 10; 60%) compared

with non-FKS mutants (11 of 47; 23%)

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 + - + + – – –

Septic

Thrombophlebitis

Septic pulmonary embolism

Mycotic

aneurism

Endophtalmitis

Neprhitis

Osteomyelitis,

spondylodiscitis

Sepsis/

Septic

shock

Endocarditis

Complications of candidemia

Ocular Manifestations of Candidemia

370 nonneutropenic patients with candidemia

Randomization 2:1 ratio to receive either voriconazole or amphotericin B followed by

fluconazole

Patients received treatment for at least 2 weeks after the most recent positive blood culture, for a

maximum duration of 8 weeks. Patients were followed up until 12 weeks after EOT

Fundoscopy at:Baselineday 7 of treatment2 weeks and 6 weeks after the end of antifungal therapy (EOT)at 12 weeks after EOT if clinically indicated

If Candida endoftalmitis

or chorioretinitis

Oude Lashof et al. Clin Infect Dis 2011;53:262–268


Duration of therapy after the first negative blood culture: median 14 days (range, 0–57 days) in groups with ocular involvement


Echinocandins Compared to Fluconazole for Candidemia of a Urinary Tract Source: A Propensity Score Analysis

Cuervo G et al. Clin Infect Dis 2017; 64:1374-79

High-Dose Micafungin for Preterm Neonates and

Infants with Invasive and Central Nervous

System Candidiasis

Auriti C, Falcone M….Pai MH. Antimicrob Agents Chemother 2016; 70:7333-7339

18 pre-term newborns with invasive candidasis

High-Dose Micafungin for Preterm Neonates and

Infants with Invasive and Central Nervous System

Candidiasis

- Suggested EMEA dosage of micafungin in neonates 2 mg/kg/day

0

20

04

00

60

08

00

Mic

afu

ng

in A

UC

24

(h

*mg

/L)

8 9 10 11 12 13 14 15Dose (mg/kg)

5th-95th Percentile (observed) Median (observed)

5th-95th Percentile (model predicted) Median (model predicted)

Individual Bayesian Estimated (external validation)

Auriti C, Falcone M….Pai MH. Antimicrob Agents Chemother 2016; 70:7333-7339

Differs from antibacterial stewardship

• Antibacterial

– Clear relationship between antimicrobial usage and resistance

– Clear relationship between clinical failure and resistance

– Focus on “start strong then focus”

• Antifungal

– Focuses mainly on treatment outcome

– Identifying fungal infections

- Reducing empiric treatment

- Improve diagnosis

– Optimising treatment

• TDM

– Controlling costs

Agrawal S, et al J Antimicrob Chemother 2016;71:37-42.

It’s all about the

patient

terapia della candidosi invasiva · candidiasis no disease cultures/ antigen signs and symptoms...

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