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
The EMPIRICUS (Empirical Antifungal Treatment in ICU)Randomized Clinical Trial
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
Timsit JF et al. JAMA. 2016;316:1555-1564
The EMPIRICUS (Empirical Antifungal Treatment in ICU)Randomized Clinical Trial
Timsit JF et al. JAMA. 2016;316:1555-1564
The EMPIRICUS (Empirical Antifungal Treatment in ICU)Randomized Clinical Trial
Micafungin did not significantly improve
the primary outcome of 28-day invasive
fungal infection–free survival
Timsit JF et al. JAMA. 2016;316:1555-1564
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
The EMPIRICUS (Empirical Antifungal Treatment in ICU)Randomized Clinical Trial
• 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!
Timsit JF et al. JAMA. 2016;316:1555-1564
Primary endpoint in prespecified patient subgroups
The EMPIRICUS Randomized Clinical Trial: explanations of results
Timsit JF et al. JAMA. 2016;316:1555-1564
• 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
-
Falcone M,…..Venditti M, Menichetti F, in preparation
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)
Falcone M,…..Venditti M, Menichetti F, in preparation
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
Falcone M,…..Venditti M, Menichetti F, in preparation
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
Ocular Manifestations of Candidemia
Oude Lashof et al. Clin Infect Dis 2011;53:262–268
Ocular Manifestations of Candidemia
Duration of therapy after the first negative blood culture: median 14 days (range, 0–57 days) in groups with ocular involvement
Oude Lashof et al. Clin Infect Dis 2011;53:262–268
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