GESITRA 1

New antifungal strategies

Patricia Muñoz, MD. Ph.D. (pmunoz@hggm.es)

Hospital General Universitario Gregorio Marañón

Universidad Complutense de Madrid

Monday, March 2nd 2015 10-10:30

New and upcoming antifungals

Index

1. Present way of using antifungals

Present way of using antifungals

Culture based

Targeted prophylaxis

Empirical/Preemptive therapy based on local epidemiology, risk factors, and clinical scores such as the ‘Candida score’

More common problems

Too much

Empirical therapy in ICU (2/182 treated pts had candidemia) González, Crit Care 2012

Colonization (UTI, RT) Aitken, Ann Pharmacother 2014

Combination therapy or excessive prophylaxis Muñoz, Clin

Transplant 2012

No adjustment to Microbiology results (29-39%) Shah. JAC

2011; Baddley Diagn Microbiol Infect Dis 2004

Too little, too late

Therapy in candidemia first 48h: 7% Bassetti CMI 2013; Aitken, Ann

Pharmacother 2014

Using propensity scores to assess candidaemia- attributable mortality in critically-ill patients

González de Molina et al. Crit Care 2012;16:R105.

Low PPV

5000 € is an estimate of the medium cost of candins in Europe. Personal opinion P. Muñoz

AF use audit (100 patients) Who prescribes what, and why

Onco-hematology

11%

ICUs 52%

Medical

wards 30%

Surgical wards

7%

Cost

Use of antifungals in a general hospital

Valerio, JAC 2014

Oncology & Hematology 25%

ICUs 17%

Medical wards 43%

Surgical wards 15%

DDDs

Risk scores

Prophylaxis with caspofungin does not improve outcome in critical patients with risk factors

Ostrosky L. CID 2014;58(9):1219 – 26

However, we

are not doing

so bad

Cumulative mortality after the first episode of candidaemia

At 7 days: 12.8%

At 30 days: 30.6%

Clin Microbiol Infect. 2014;20(4):O245-54.

Benchmarking. What is a normal AF use?

How many DDDs/ 1,000 patient-days is normal to expend?

Published data: 40 to 296

In our center, a tertiary hospital with very active transplant, oncology and HIV programs, a recent survey showed that

- 65.1 DDDs per 1000 patient-days

- 13% were considered unnecessary

Mondain, 2013; Cook, 2004; Standiford, 2012; Apisarnthanarak, 2010; Lopez-Medrano, 2013; Valerio, 2014

Ideas to take home

Both culture based and risk factor-based approaches have very low sensitivity, increase cost and risk of resistance emergence. However, candidemia mortality has been significantly reduced

Index

1. Present way of using antifungals

2. Stewardship programs

Clinically driven Martín-Peña A. Antimicrob Agents Chemother 2013;57:4664–48.

AFS not indicated in 38.8%

Proven/probable IFI 14.1% (Rel. mort 2.7%)

77% of treated pts did not really needed the AF

Multidisciplinary antifungal stewardship programs

Valerio, JAC 2014

Identify the magnitude of the problem and specific targets

ID consultation 42%

- Medical wards: 54.8%

- ICUs: 28.6%

- Surgical wards: 14.3%

- Oncology-Hematology: 2.4%

Inappropriate prescriptions: 74.1% versus 33.3%, P<0.001

Valerio, JAC 2014

First steps

Education

Knowledge survey (20 questions) Mean score of correct responses was 5.16±1.73 <35% correct answers in:

- Candida: meaning of respiratory cultures, % of Flu-R, indications prophylaxis and empirical therapy, de-escalation

- Aspergillus: indications of L-AMB, GM use, AF combinations, initial therapy of aspergillosis !!!

By departments; before and after educative interventions

Valerio, Enf Infecc Microbiol Clin 2014

Education

Initiate educational activities

General and particular sessions Use the results of the previous surveys Involve members of the AFS team

Produce your own local guidelines

General or for specific departments Local epidemiology, diagnostic criteria, indications, dose

adjustments Members contact telephones Intranet and/or pocket leaflets

First steps

Multidisciplinary

Pharmacy department AF alerts, prescription tools, interactions, advice

Cost: Monitor DDDs or PDDDs. Overall and at unit level

Price negotiation !!!

Expert Pharm: advice to prescribing physicians or daily audit of agreed on protocols

Clinical Microbiology Rapid turnover of lab results (streamlining) Help clinicians with Dx investigations TDM Innovative diagnostic tools: help to stop empirical therapy,

start early antifungals, streamlining

ID physicians

Bedside intervention Prescribing etiquette: health-care models,

perceived loss of autonomy, local leaders in charge

Die of success: when program works, your collaborators will get better work offers (happened in ID and Pharmacy) - Have someone learning the role simultaneously

Always play safe: Prestige of the AFS

AFS program: Clinical and Microbiological results

Health results

Pre-AFS AFS

Voriconazole levels out of range (%) NA 28

AF toxicity (%) NA 4.7

Candidemia related mortality (%) 21.8 13.9

2010 2011 2012 2013

Incidence of candidemia /1000 adm 1.49 1.76 1.43 1.12

C. albicans 0.87 0.83 0.66 0.48

C. parapsilosis 0.27 0.53 0.38 0.35

C. tropicalis 0.09 0.13 0.24 0.12

C. glabrata 0.16 0.22 0.16 0.08

% non albicans Candida 58.5 52.8 53.8 57.1

% Fluconazole Resistance (Candida spp.) 6.3 4.7 4.1 3.4

Valerio M. JAC 2015. In press

Annual cost of antifungals (USD)

3057202 3031328

3773189 3817455

3288292

2871497

2419774

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

-4 -3 -2 -1 1 2 3

Education

Bedside

Sustained

Ideas to take home

Multidisciplinary antifungal stewardship programs performed by dedicated experts are effective, but require great effort and long-term maintained dedication

Index

1. Present way of using antifungals

2. Stewardship programs

3. Biomarkers

Biomarkers

BDG (Associates of Cape Cod Incorporated, USA)

Not Candida-specific and many false positives

Promising tool for the diagnosis of IC (pooled S of 76.8% and Sp of 85.3%) CID 2011; 52: 750

CAGTA (Vircell, Granada, Spain)

Less mortality in treated ICU patients with increasing CAGTA values BMC Infect Dis 2011; 11: 60

Platelia Candida

Lack reproducibility and indeterminate results

Biomarker-driven approach in hematology

• GM EIA, PCR + High resolution CT scan

• No empirical antifungal therapy in patients receiving adequate prophylaxis (TDM)

• Negative GM + PCR: exclude IA

Sensitivity: 98.1%, NPV: 99.6%

• Neither PCR nor GM EIA can be used alone to diagnose IA: PPV <31.7%

Barnes R et al. J Infect 2013;67:206–14.

CAGTA may help differentiate CR-candidemia

50 candidemias: 29 deep-seated IC and 21 Catheter-related or primary

CAGTA was positive in only 1/21 non-deep-seated candidemias (4.76%) (p<0.01)

* Possible deep-seated; ** immunosuppressed patients

CAGTA + CAGTA -

Deep- seated

candidemia

20 (68.96%) 9 (31.03%)**

Non-deep seated

candidemia

1 (4.76%)* 20 (95.24%)

P < 0.001

Martinez M, Muñoz P, et al. Medical Mycology, 2014

Value of combining biomarkers at different cut-offs to rule out IC

31 candidemias (Candida albicans 40%, C. tropicalis 20%, C. parapsilosis 18%, C. glabrata 12%, other 10%) and 50 bacteremias

CAGTA, mannan antigens (MN), anti-mannan antibodies (AMN), and (1→3)-β-D-glucan (BDG)

Manufacturer’s and alternative cut-offs to improve the accuracy of the tests

Candida biomarkers in patients with candidemia and bacteremia

M. Carmen Martínez-Jiménez 1,2 ;Patricia Muñoz* 1,2,3,4 Maricela Valerio 1,2 Roberto Alonso 1,2 Carmen Martos 1 Jesús Guinea 1,2,3 Emilio Bouza 1,2,3,4

1 Clinical Microbiology and Infectious Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 2 Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain. 3 CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Madrid, Spain. 4 Medicine Department, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain

Martinez M. JAC 2015 in press

Biomarkers alone: low S (58-84%); Sp: 65.8-92.0%

Combinations:

CAGTA80+BDG80: S 96.8% and Sp 84%

CAGTA80 + MN75: S 93.5% and Sp 86%

S 100% for C. albicans, C. tropicalis, and C. parapsilosis

Only combinations including BDG detected C. krusei

Candida biomarkers in patients with candidemia and bacteremia

M. Carmen Martínez-Jiménez 1,2 ;Patricia Muñoz* 1,2,3,4 Maricela Valerio 1,2 Roberto Alonso 1,2 Carmen Martos 1 Jesús Guinea 1,2,3 Emilio Bouza 1,2,3,4

1 Clinical Microbiology and Infectious Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 2 Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain. 3 CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Madrid, Spain. 4 Medicine Department, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain

Martinez M. JAC 2015 in press

Candidemia prevalence

NPV

23.6% (present study) 97.7%

10% 99.6%

5% 99.8%

Combination of Candida Biomarkers in Patients Receiving Empirical Antifungal Therapy

Prospective, observational study

100 patients included 63 ICU (44 surgical and 19 medical)

37 non-ICU (13 surgical and 24 medical)

Antifungals indication High-risk gastrointestinal surgery

Sepsis in non-surgical patients (30% each)

Final classification No-IC 58%, proven IC 30%, probable IC 12%

Martínez-Jiménez, M. Carmen, Submitted to CID

No IC 58%

Proven IC 30%

Probable IC

12%

Microbiology and AFS

Patients with suspected IC treated empirically

CAGTA + BDG: NPV 97% (100% in ICU patients)

M-1776

Martinez M. ICAAC 2014

Ideas to take home

Candida biomarkers may help in the identification of CR-candidemia (CAGTA) and in the reduction of the duration of empirical therapy.

The behavior of the biomarkers in non-candidemic forms of IC needs more research.

Index

1. Present way of using antifungals

2. Stewardship programs

3. Candida biomarkers

4. New diagnostic methods

• SeptiFast Roche Molecular Systems

• Standardized system

• ITS regions and fluorescent probes

C. albicans

C. tropicalis

C. parapsilosis

C. glabrata

C. krusei

A. fumigatus

• Diagnosis of sepsis

• Analysis at the time of the first blood culture collection

• Septifast (n=19), blood culture (n=8), and both (n=7)

• Higher sensitivity for C. albicans and lower for C. glabrata

Bille J. Curr Opin Crit Care 2010

DETECTION OF DNA OF Candida

PCR reduces time to therapy

35

Bloos F. J Crit Care (2013) 28 , 2 – 8

VYOO®, SIRS-Lab, Jena, Germany

32 candidemias and 32 matched pts with sepsis (11 + panfungal PCR) AF therapy time reduced from 67.5 h (candidemia) to 31 (PCR)

Candida RT PCR, BD glucan and BC. Deep seated candidiasis

PCR and BC could be enough

PCR better than BDG

(S 89% vs 53-66%)

PCR+BC: 98%

36

Nguyen MH. CID 2012

40 healthy controls and 63 ICU patients with suspected IC (27 later confirmed)

21 candidaemias (16 CR and 5 other sources)

6 abdominal or urological IC with BC -

Samples: 0 and +2, +7, +14 and +21 d

In house MRT-PCR for C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, C. krusei and C. guilliermondii

J Antimicrob Chemother 2014; 69: 3134–3141

S on day 0: 81.4%. 2/21 candidemias neg day 0

Positive on both blood and serum 14/26 ¿which sample to use?

Not through venous catheters (false positives)

J Antimicrob Chemother 2014; 69: 3134–3141

T2MR is the first fully automated technology that directly analyzes whole blood specimens to identify species without the need for prior isolation of Candida species

Nanodiagnostic approach

Mylonakis E. Clin Infect Dis. 2015 Jan 12. pii: ciu959

Specificity 99.4%

Mean time to neg result:4.2 ± 0.9 hours

Sensitivity 91.1%

Mean time for detection 4.4 ± 1.0 hours

88.1% for C. krusei/C. glabrata

NPV: 99.5%-99.0% (5% and 10% prevalence)

Clin Infect Dis. 2015 Jan 12. pii: ciu959. [Epub ahead of print]

Ideas to take home

PCR and T2MRI may represents a breakthrough shift into a new era of molecular diagnostics in fungal infections. Clinical impact needs to be assessed.