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Directed therapy for fungal infections - latest advances. Rosemary Barnes Focus on aspergillosis. Total UK antifungal expenditure c £112 million Rising by 9% pa. Problem. Antifungal expenditure is completely out of proportion with the scale of the problem

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problem

Total UK antifungal expenditure c £112 million

Rising by 9% pa

Problem
  • Antifungal expenditure is completely out of proportion with the scale of the problem
    • Incidence of IFD in ICU (candida) <0.6%
    • Aspergillus infection in haematological malignancy (0.5-12%)
    • Aspergillus in SOT <5%
  • Harrison D et al Fungal Infection Risk Evaluation (FIRE) Study. Health Technol Assess 2013;17(3).
  • Pagano L et al. Haematologica 2006; 91: 1068-1075
  • Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170
reasons
Reasons
  • Infection associated with significant morbidity and mortality
  • Signs and symptoms of systemic infection are nonspecific
  • Conventional diagnostic techniques are suboptimal
  • Delays in treatment associated with poorer outcome
choices choices choices
Choices choices choices

Febrile

despite

antibiotics

Empirical therapy

Diagnosis

Change antibiotics

decision tree
Decision tree

yes

Fever

no

decision tree1
Decision tree

yes

no

yes

No diagnosis

Fever

no

yes

no

decision tree2
Decision tree

yes

no

yes

yes

no

yes

no

No diagnosis

Anxiety

Fever

no

yes

yes

no

no

yes

no

decision tree3
Decision tree

yes

no

yes

yes

no

no

yes

yes

no

yes

yes

no

yes

no

no

No diagnosis

Anxiety

Out of hours

Fever

no

yes

yes

yes

no

no

yes

no

no

yes

yes

no

no

yes

no

decision tree4
Decision tree

yes

no

yes

yes

no

no

yes

yes

no

yes

yes

no

yes

no

no

Empirical

therapy

No diagnosis

Anxiety

Out of hours

Fever

no

yes

yes

yes

no

no

yes

no

no

yes

yes

no

no

yes

no

No therapy

aim of a directed strategy
Aim of a directed strategy

include all patients likely to have invasive fungal infection and treat them with the safest and most effective drug

exclude all patients unlikely to have invasive fungal disease and adopt a WAIT-and-SEE policy

consensus criteria
Consensus criteria
  • Aimed to provide definitions for proven, probable and possible fungal infection that could facilitate clinical research
  • Designed for use in clinical trials
    • Highly selective population
    • Not representative of real life clinical practice
    • Focus on specific radiological signs
  • Focus on defining DISEASE
    • needs to shift towards INFECTION
    • Needs a diagnostic approach
      • biomarkers

De Pauw et al CID 2008, 46

the biomarkers
The biomarkers
  • Antigen tests
    • Galactomannan (aspergillus)
    • Beta D glucan (pan-fungal-ish)
    • Lateral flow device
  • Molecular
    • Aspergillus specific
    • Panfungal
    • Commercial (…….)
galactomannan in serum
Galactomannan - in serum
  • useful test in surveillance: high NPV
  • Performance in
    • haematological malignancy better than in SOT
    • neutropenic > corticosteroid treated group
    • Adults >children
  • Influenced by pre-test probability (ie sensitivity increases with prevalence)
  • EORTC/MSG criteria heavily dependent on test being performed
  • Recommended by ECIL
galactomannan meta analyses
Galactomannan – meta-analyses

30 studies > 7000 patients

    • Prevalence 7.7%
    • sensitivity78% (61% to 89%)
    • specificity 81% (72% to 88%).
  • cut-off 0.5: 100 patients:
    • 2 patients with IA, will be missed,
    • 17 patients will be treated unnecessarily
  • cut-off 1.5 OD:
    • 3 IA patients will be missed
    • 5 patients will be treated unnecessarily
  • results were very heterogeneous.
  • Insufficient data to look at clinical utility

http://www.thecochranelibrary.com

slide16
BAL
  • 0.5 approved by FDA
  • On the basis of clinical validity
      • PPV of GM BAL is 100% at an OD index cutoff of ≥3
      • only 76% at ≥ 0.5 (but NPV is high)

Pre test probability

PUO GM pos CT BAL

Maertens et al CID 2009

beta d glucan
Beta D Glucan
  • 4different commercial tests
    • Heterogenous data : retrospective vs. prospective;
    • Different cut offs
    • “panfungal” – except cryptococcus and mucoracous moulds
  • Sensitivity, specificity variable but NPV high
    • High false-positives: up to 30% - bacteraemia, antibiotics, pre-/analytical contaminations
  • complex analytical procedures
  • Analytical validity established
  • Utility data limited
  • Included in EORTC/MSG criteria
beta d glucan meta analysis
Beta D Glucan-meta-analysis
  • 16 studies in 2979 patients
    • Included case-controlled studies
    • Included critical care, HM and solid organ cancer patients
    • Cut off 10-1000 pg/ml
  • Sensitivity 76.8% (67.1%–84.3%)
  • specificity 85.3% (79.6%–89.7%)
  • “area under ROC curve 0.89”
  • “good diagnostic accuracy”

Karageorgopoulos et al Clin Infect Dis 2011;52(6):750

slide19
PCR
  • The UK Fungal PCR consensus group
    • 2004 technically validated candida PCR
    • Made recommendations for aspergillus PCR
  • 2006 European Aspergillus PCR Initiative set up
    • 86 participants in 69 centres in 24 countries
    • defined a standard for PCR for Aspergillus
      • Whole blood
      • Serum
      • plasma
    • optimal methodology to evaluate the performance and impact
    • QCMD available

White et al J MolecDiagn 2006; 8: 376

White et al J Clin Micro 2010: 48 1231

www.eapcri.eu/

slide20
PCR
  • Single negative PCR to exclude disease
  • 2 consecutive PCRs to diagnose IA
    • Sensitivity 88%
    • Specificity 75%
    • DOR22

Mengoli et al Lancet Infectious Diseases. 2009; 9: 89-96

galactomannan eia
Galactomannan EIA
  • Open study
  • 136 episodes of neutropenia
    • Patients receiving flucon prophylaxis
  • daily EIA GM + early CT scanning in neutropenic febrile episodes
  • Antifungal given if 2 consecutive EIA GM results +ve (index ≥ 0.5)
  • and confirmed by BAL or CT

Maertens et al. Clin Infect Dis 2005; 41: 1242

maertens et al
Maertens et al
  • 35% of episodes met criteria for empirical antifungal but only7.7% treated on basis of pre-emptive therapy
  • Duration of fever not affected
  • 22 cases of IFD only one missed
  • 3 breakthrough infections
    • 2 candidaemias
    • 1 mucorales
  • No excess mortality or fungal related death
  • No impact on overall antifungal usage despite deceased empirical use
cordonnier et al cid 2009 48 1043
Cordonnieret al CID 2009 48:1043
  • 293 patients randomised
  • empirical or pre-emptive therapy
  • empirical arm received antifungals if they had persistent/recurrent fever after 4 days
  • pre-emptive patients given antifungal only if they showed
    • clinical and radiological signs of pneumonia/sinusitis
    • positive GM index ≥ 1.5
    • Aspergillus colonization
    • Septic shock
    • CNS signs/periorbital inflammation
    • Diarrhoea/mucositis ≥ grade 3
    • fever > 14 days
cordonnier et al
Cordonnieret al
  • Survival was not significantly
  • “Non inferiority” demonstrated
  • pre-emptive patients had more IFI
    • 9.1% vs 2.7%
  • pre-emptive patients received significantly less antifungals
  • no significant cost savings were achieved
    • Used ampho B deoxycholate first -line
slide26

Empirical vs. pre-emptiveantifungaltherapy

Empirical

Pre-emptive

IFI in Pre-emptive

IFI in Empirical

Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051

pagano et al haematologica 2011 96 1363
Pagano et al Haematologica 2011; 96:1363
  • Observational: Empiric versus “pre-emptive”
    • Data collection 397 HM patients
      • 190 empiric ; 207”pre-emptive”
    • More IFD in pre-emptive arm
    • Increased mortality and antifungal use in “pre-emptive arm”
    • Fever driven, no screening, diagnostic work up not standardized
      • some GM usage, no PCR
      • Pre-emptive group largely diagnosed on basis of HRCT
slide28
randomised study of a PCR directed versus an empirical antifungal

more than 400 SCT patients

Safe

Improved survival at 30 days (not 100)

No reduction in antifungal drug use.

Nested PCR to guide antifungal therapy

42 patients with cancer, neutropenia

AmB required in only 2 patients

PCR

Lin et al. Clin Infect Dis. 2001;33:1621-1627

Hebartet al. Blood 2004;104: 59A.

in cardiff
In Cardiff
  • 549 high-risk haematology patients entering neutropenic pathway 2005-2010
  • audited and followed up for a minumum of 12 months
    • Twice weekly antigen and PCR testing (or GvHD)
    • Itraconazole prophylaxis or AmBisome 7mg/kg/weekly
    • Empiric antifungals not used unless
      • Clinical/mycological evidence of disease
      • Itraconazole levels were subtherapeutic or unmeasured
  • First 125 patients analysed for safety and proof of concept
  • Data collected on compliance, incidence of IFD and efficacy of prophylaxis

Barnes et al Journal of Clinical Pathology 2009

incidence of ifd 2005 2011
Incidence of IFD (2005-2011)
  • Invasive aspergillosis 9.6%
    • 6 histologically proven (2 postmortem)
      • 4 pulmonary (2 with dissemination)
      • 2 invasive sinusitis
    • 47 probable
    • (23 possible IA)
  • Invasive Candidal infection 2%
    • 12 proven
      • 4 C. albicans, 3C. glabrata, 2C. tropicalis, 1C. parapsilosis, 1C. guilliermondii, 1 mixedC. albicans+ C. glabrata
    • 1 probable
  • 2 non-aspergillus moulds
    • 1 Mucoraceous mould, 1 Scedosporiumprolificans
  • Incidence of proven/probable IFD 12.3%
ia disease status of subjects
IA disease status of subjects

By EORTC/MSG diagnostic criteria

  • Proven – 6
  • Probable – 47
  • Possible – 23
  • NEF – 473
  • 248 of NEF showed some signs suggestive of IA
      • EIA positive n=36
      • PCR positive n=136
      • EIA and PCR positive n=75
        • Aspergillus isolated n=5
diagnostic accuracy
Diagnostic accuracy
  • Explore analytical validity. Clinical validity, clinical utility
    • Sensitivity specificity
    • PPV, NPV, LR, DORs
  • Use ROC analysis to explore different thresholds for defining “cases”
      • EORTC/MSG
      • EORTC – GM EIA
      • EORTC + PCR
      • Dual biomarker positivity
      • Multiple positives versus single
statistical parameters
Statistical parameters

By EORTC/MSG criteria

roc plot
ROC plot

PCR + EIA

Proven/prob/poss

Proven/prob

curve (AUC): 0.910 (95% CI: 0.872-0.948)

performance of pcr
Performance of PCR
  • Utility in proven/probable n=53
  • First marker positive
      • PCR in 23
      • EIA in 15
      • PCR and EIA simultaneously positive in 7
      • radiological features in 8
  • In 85% biomarkers preceded specific radiological signs (range 1-118d)
diagnostic accuracy1
Diagnostic accuracy
  • Screening by PCR AND GM EIA can enable a diagnosis of IA to be excluded
  • Positive PCR +GM EIA or multiple positive PCRs or EIAs can be used to accurately diagnosis IA
    • specificity 84.4%; sensitivity >90% DOR>50
  • Biomarkers are earliest markers in 85% of cases
    • Use antifungals more cost effectively
antifungal expenditure
Antifungal expenditure
  • Similar units typically spending £1-2 mill pa
use of biomarkers
Use of biomarkers
  • Regular screening throughout period or risk
  • Screening during fever only
  • Diagnostic testing during refractory fever only
  • Confirmation when specific radiological signs are present
  • None - empiric therapy
strategy used
Strategy Used
  • Influenced by
    • Risk of IFD
      • Prevalence affects utility of diagnostic tests
        • ECIL recommend screening if IFD 5-10%
    • Prophylaxis used
      • Mould active reduces utility of diagnostic tests
    • Availability of
      • Diagnostic tests
      • Protective environments/HEPA filtered air
incidence of ifd after posaconazole therapy
Incidence of IFD after posaconazole therapy

Pagano et al Haematological 2012; 97:963

effect of antifungal therapy
Effect of antifungal therapy

McCulloch et al J Clin Path 2012; 65:83

Marr K A et al. Clin Infect Dis. 2005;40:1762-1769

example

High risk patient

Prevalence8- ≥10%

*For example: PCR and GM, or Multiple GM

No Mould active prophylaxis – Screening regime

Mould active prophylaxis used – Diagnostic regime

Twice weekly screening of blood samples:

Galactomannan,

And Aspergillus PCR

HRCT and BAL when infection suspected

Diagnostic testing during refractory fever with Beta D glucan (serum) and

Aspergillus PCR (BAL and blood or serum), galactomannan (BAL and serum)

Single Positive biomarker

Continue screening process

>1 biomarker positive* triggers diagnostic workup to include relevant radiology and BAL if indicated

Targeted antifungal therapy for clinically diagnosed infection only with biomarker confirmation

No consistent clinical signs or symptoms indicates need for possible pre-emptive therapy

Any consistent clinical signs or symptoms indicates need for antifungal therapy

Example
slide47

exposure

at risk

infection

disease

Pre-emptive

Prophylaxis

Targetted