sepsis in oncologic and hematologic patients fileacute hypoxemic respiratory failure in...

Peter Pickkers

Department of Intensive Care Medicine

Fellow-onderwijs, 2017

Sepsis in oncologic and hematologic patients

Bone marrow transplants

Cancer

2009

Also in the Netherlands?

Radboudumc Nijmegen, the Netherlands

To explore trends over time in admission prevalence and (risk-adjusted) mortality of critically ill haematological patients and compare these trends to those of several subgroups of patients admitted to the medical intensive care unit (medical ICU patients).

A total of 1,741 haematological and 60,954 non-haematological patients admitted to the medical ICU were analysed.

Fraction of hematological patients compared to

total number of medical ICU-patients

Leuko’s ≥ 1.0

Leuko’s < 1.0

Increase p=0.007

Compared to

medical admission patients

Risk-adjusted hospital mortality rate significantly decreased in both the haematological and non-haematological group with an OR of 0.93 (95 % CI 0.92–0.95) per year.

Compared to

severely ill medical admission patients

Compared to

severely ill medical admission patients

No effect of leukopenia

142 patients 431 patients 401 patients

149 patients

Hospital survival 1-year survival ICU survival

Major challenges critical care specialists will face with cancer patients in the next 10 years • Increasing numbers both of patients diagnosed with cancer and of cancer survivors

• Increasing need for ICU management of cancer patients due to intensive therapeutic regimens and highly

toxic targeted therapies

• Increasing number of cancer survivors remaining severely immunocompromised, with advanced age and

comorbidities

• Urgent need to improve medical skills of ICU specialists, develop remote patient management, and set up

expert networks

• Achieving a consensus on the standard of care to be offered for critically ill cancer patients in industrialized

countries

• Establishing universal criteria for the timing of ICU admission for cancer patients

• Establishing, validating, and spreading standard procedures and protocols to optimize patient management

and outcomes

• Improving our understanding of organ dysfunction with the hope of improving organ recovery and

increasing the proportion of patients fit for intensive curative treatments

• Gathering multicenter data on outcomes associated with time-limited trials, with a special focus on the

balance between avoiding both premature end-of-life decisions and giving nonbeneficial care

• Introducing early palliative care for critically ill cancer patients

Acute Hypoxemic Respiratory Failure in Immunocompromised Patients: The Efraim Multinational Prospective Cohort Study Elie Azoulay, Peter Pickkers, Marcio Soares, Anders Perner, Jordi Rello, Philippe Bauer, Andry van de Louw, Pleun Hemelaar, Virginie Lemiale, Fabio Silvio Taccone, Ignacio Martin Loeches, Tine Sylvest Meyhoff, Jorge Salluh, Peter Schellongowski, Katerina Rusinova, Nicolas Terzi, Sangeeta Mehta, Massimo Antonelli, Achille Kouatchet, Andreas Barratt-Due, Miia Valkonen, Precious Pearl Landburg, Fabrice Bruneel, Ramin Brandt Bukan, Frédéric Pène, Victoria Metaxa, Anne Sophie Moreau, Virginie Souppart, Gaston Burghi, Christophe Girault, Ulysses V.A. Silva, Luca Montini, Francois Barbier, Lene B Nielsen, Benjamin Gaborit, Djamel Mokart, Sylvie Chevret. For the Efraim investigators and the Nine-I study group.

665

183

119 112 106

72 7155 46 42 36 31 31 30 21

50

100

200

300

400

500

600

700

no

mb

re d

'in

clu

sio

ns

Pays

France

Netherland

Brazil

Denmark

Spain

USA

Belgium

Austria

Czech Rep

Italy

Canada

Norway

Finland

Ireland

England

Uruguay

1611 immunocompromized patients admitted to 68 ICUs in 16 countries for acute hypoxemic

respiratory failure

596 (37.0%) received first line intubation

and mechanical ventilation (IMV)

ICU mortality: 44.4% Hospital

mortality: 52.5%

920 (57.1%) were not intubated at ICU admission and received standard O2, noninvasive ventilation (NIV) or high flow oxygen

through nasal cannula (HFNC)

496 (53.9%) received

Standard O2 only

190 (38.3%) needed IMV

ICU mortality: 51% Hospital

mortality: 59%

187 (20.3%) received HFNC

only



mortality: 65%

158 (17.2%) received NIV

only



mortality: 55%

79 (8.6%) received HFNC

and NIV



mortality: 44%

95 (5.9%) missing data on initial

oxygenation strategy



mortality: 33%

Pro

bab

ilit

y o

f In

tub

atio

n a

nd

Me

chan

ical

Ve

nti

lati

on

Time (days) since ICU admission

P (Log Rank test) = 0.9422

Standard Oxygen

High Flow Oxygen through nasal cannula (HFNC)

Noninvasive ventilation (NIV) with standard oxygen within NIV sessions

Noninvasive ventilation with HFNC within NIV sessions

Age (per year) 0.92 (0.86-0.99)

High Flow Oxygen (HFNC) 0.77 (0.59-1.01)

Noninvasive ventilation (NIV) 0.94 (0.69-1.28)

NIV + HFNC 0.74 (0.51-1.09)

Chronic Respiratory Insufficiency 0.76 (0.54-1.08)

SOFA score at ICU admission 1.09 (1.06-1.13)

Acute Respiratory Distress Syndrome 1.47 (1.05-2.07)

Pneumocystis jirovecii Pneumonia 2.11 (1.42-3.14)

Invasive Pulmonary Aspergillosis 1.85 (1.21-2.85)

Undetermined ARF etiology 1.46 (1.09-1.98)

Age (per year) 0.92 (0.86-0.99)



NIV + HFNC 0.74 (0.51-1.09)







Age (per year) 0.92 (0.86-0.99)



NIV + HFNC 0.74 (0.51-1.09)







Initial ventilation strategy (with standard Oxygen as reference)

Etiology of the Acute Respiratory Failure (ARF)

Increased risk of intubation and mechanical ventilation

Hazard Ratios (95% Confidence Intervals)

ARDS (according to the Berlin definition, with PaO2/FiO2>300 as the reference)

Age (per year) 1.18 (1.09-1.27)

Intercept 0.06 (0.03-0.11)

Direct admission to the ICU 0.69 (0.54-0.87)

Odd Ratios (95% Confidence Intervals)

Day 1 SOFA score withoutrespiratory items

1.12 (1.08-1.16)

Severe ARDS 1.60 (1.03-2.48)

Moderate ARDS 1.46 (0.98-2.18)

Mild ARDS 1.30 (0.83-2.05)

Need for intubation and mechanical ventilation (IMV, with no intubation as the reference)


First line IMV 2.55 (1.94-3.29)

IMV after failure of NIV+HFNC 2.31 (1.09-4.91)

IMV after standard oxygen failure 4.16 (2.91-5.93)

IMV after high flow oxygen (HFNC) failure 5.54 (3.27-9.38)

IMV after noninvasive ventilation (NIV) failure 3.65 (2.05-6.53)

Increased risk of hospital mortality

Recent changes to previously held beliefs pertaining to the management of critically ill cancer patients

• It is wrong to state that cancer-related characteristics (e.g., type of cancer, neutropenia, cancer-related

complications) are the main prognostic factors among the pre-acute illness conditions

• It is wrong to state that de-escalation of antibiotics is unsafe in neutropenic patients with septic shock

• It is wrong to state that FOB-BAL is mandatory in the diagnostic workup of patients with ARF and

pulmonary infiltrates

• It is wrong to state that noninvasive ventilatory support strategies should be the rule in patients with ARF,

as they improve survival and reduce intubation rates

• It is wrong to state that our ability to identify patients likely to benefit from ICU admission or not is optimal

• It is wrong to state that prognostic scores can assist in ICU admission triage decisions

• It is wrong to state that intensivists and oncohematologists should plan care separately to avoid conflicts

• It is wrong to state that outcomes in high-volume centers are the same as in general hospitals

• It is wrong to state that one should wait for resolution of organ failure before starting chemotherapy

• It is wrong to state that the ICU is not the place for palliative care and should be restricted to cancer

patients with full-code status

Conclusions

• “The times they are a changin’”

• Mortality is twice as high compared to the medical ICU patient, but similar

to the cirrhosis, the heart failure patient

• Neutropenia is no issue at all

• Long-term outcome/QoL of survivors is similar to others

“ “

Gastheer: De IC patiënt

P. Pickkers

Intensive Care

Invasieve Candida infecties

Candidemie:

Nummer 4 oorzaak van ‘bloodstream infections’ in

de Verenigde Staten.

M.n. relevant bij IC patienten en onafhankelijk

geassocieerd met morbiditeit en mortaliteit.

Het probleem

Candidemie en mortaliteit

Garey KW et al, CID 2006

Time to fluconazole therapy in 230 patients with candidemia

Independent determinants of mortality:

APACHE II score

Time to start fluconazole (AOR, 1.42; p = 0.0009)

0

5

10

15

20

25

30

35

culture Day 1 Day 2 Day ≥3

Days to start of fluconazole

Ho

spit

al M

ort

alit

y (%

)

40

Morrell M, et al. AAC 2005

157 patients – 2001-2004

Independent determinants of hospital mortality:

APACHE II score (one-point increments) (p <0.001)

Administration of antifungal therapy >12 hours after the first positive blood culture (AOR, 2.09; p = 0.018)

http://aac.asm.org/content/vol49/issue9/images/large/zac0090552070001.jpeg

Timely initiation of therapy

Kollef, CID 2012

Source control

Kollef, CID 2012

Timely initiation of therapy

• Tijdig starten vermindert mortaliteit • Maar tijd tot identificatie duurt vaak lang… • Sensitiviteit bloedkweken 70%

• Vroege diagnose en snelle identificatie van organisme is essentieel!

• Redenen om over profylactische behandeling na te denken.

Morrell, AAC 2005;48; Kollef CID 2012; Azoulay CCM 2012

Maar er zijn ook nadelen…

• Kosten

• Resistentievorming

• Wat is er bekend en • welke afwegingen moeten wij maken?

Treatment strategies in ICU

Timing is everything!

Strategies in ICU: background


Leon, CCM 2009; Bassetti Crit Care 2010


• Profylactic / Preventative

• Empirical • Pre-emptive • Targeted

Schuster; Annals of Int Med 20008

Playford, J Antimicrob. Chemother. 2006

Strategies in ICU: prophylaxis

NNT 94

Strategies in ICU: prophylaxis

Discussie en Conclusies • Candida infectie ontstaat door endogene

kolonisatie • Fluconazol profylaxe geeft risico voor candidemie • de incidentie van kolonisatie en invasieve

candidiasis • Geen shift richting resistente Candida species • Generalisering van de resultaten niet mogelijk

(wellicht alleen gebruik bij gekoloniseerde patiënten)


• Profylactic / Preventative

• Empirical • Pre-emptive • Targeted


Een prospectieve studie naar empirische therapie in niet-neutropene IC-patienten • Fluconazol vs placebo

• bij 270 volwassen ICU patienten • > 96 uur opgenomen , APACHE II >16 koorts > 4 dagen zonder ander focus

op de IC + empirisch breedspectrum antibiotica voor mi 4 van de

voorafgaande 6 dagen en tenminste 24 uur CVC catheter in situ



Invasieve schimmelinfecties: 5 vs 9% (NS), mortaliteit 24 vs 22% (NS)

Identificeren van hoog-risicopatienten

Leon, CCM 2009; Bassetti Crit Care 2010

Blumberg et al: the National Epidemiology of Mycoses Survey

(NEMIS) Data prospectief verzameld op 6 Chirurgische ICUs in de VS

42 BSIs in 4276 patients were identified during a 2-year period (0.9 %)

Blumberg et al. Risk Factors for Candidal Bloodstream Infections in Surgical

Intensive Care Unit Patients: The NEMIS Prospective Multicenter Study.

Clin Inf Dis 2001;33:177-86

Voorspellen van hoog-risicopatienten

Candida infection

+ - pos a b

Risk factor PPV: a/a+b neg c d

The positief voorspellende waarde was < 5%

PPV: < 3%

< 3%

< 3%

The positive predictive value of colonization was <3%

Ostrosky-Zeichner: New approaches to the risk of Candida in the intensive care unit.

Curr Opin Infect Dis 2003;16:533-537

Ostrosky-Zeichner: New approaches to the risk of Candia in the intensive

care unit. Curr Opin Infect Dis 2003;16:533-537

Ostrosky-rule:

* > 4 dagen ICU * én tenminste: AB en/of CVL

* én tenminste 2 van: TPN, dialyse, major surgery, pancreatitis,

steroiden andere immuunsupressie

>>>> kans op 9,9 % op candidemie

(ICAAC M505, 2003)

Pre-emptive therapy of Candidemia and Invasive Candidiasis

Currently three options:

• Candida score

• Colonisation index • 1,3 Beta Di Glucan

Antonelli, CCM 2011; Leon CCM 2006 and 2009; Ostrovsky 2009; poster ECCMID 2012; Eggiman, Annals of Intensive Care 2011; Bassetti, Crit Care 2010

Strategies in ICU: Candida score

Leon, CCM 2006

1

1

1

2

1600 IC patienten >7 dgn opgenomen

Strategies in ICU: Candida score

Leon, CCM 2006

Candida score ≥ 3 Sensitivity 81% Specificity 75% PPV 18% NPV 98%

Achtergrondprevalentie: 5-6%

Pre-emptive therapy of Candidemia

• Candida scores

• CS ≥ 3 iedere IC patient behandelen?, afkappunt op > 4 leggen??

Leon CCM 2006 and 2009


• Colonisation Index (CI) en Corrected Colonisation Index (CCI)

Pittet 2004;

Kwantificering wordt toegepast van het aantal kolonies: het aantal kwantitatief sterk gekoloniseerde lokaties


Pittet 2004;

PPV 60%

PPV 100%

NB: Op basis van retrospectieve data

C.I. wordt berekend als het aantal positieve Candida lokalisaties op het totaal aantal gemeten lokaties. CCI idem maar betekent dat een kwantificering is toegepast van het aantal kolonies

Pre-emptive therapy of Candidemia and Invasive Candidiasis

Posteraro, Crit Care 2011

Candida score (CS) ≥ 3

Colonisation index ≥ 0.5

95 high-risk patienten, Prevalentie 17% (!) BG PPV 72% NPV 99%

In deze studie

• 95 high risk IC patienten naast en CI en CS een BDG bepaald

• NPV van BDG erg hoog, bijna 100%: de test kan dus gebruikt worden om IFI uit te

sluiten, minder om het aan te tonen

• Prevalentie in deze studie groep was 16,9% (in Nederlandse IC’s gemiddeld 1%) dus

high risk populatie.Vraag is hoe de PPV zal uitvallen in een populatie waarin de

prevalentie lager is

• De NPV in deze populatie bleek 99%. Evengoed geldt echter dat in een populatie

met een zeer hoge voorafkans op invasieve candida infectie (25-50%) de NPV zal

dalen…

Hoe zit het met de kosten?

Het effect van de a priori kans

Incidentie 40% 2%

Effect profylaxe 50% reductie 50% reductie Absolute risicoreductie 20% 1% NNT 5 100

Kosten van fluconazol, 50 Euro x 5 dagen = 250 Euro per patiënt

Totale kosten 1250,- Euro 25.000,- Euro per invasieve candidiasis die wordt voorkomen

Wa kos da?

Geschatte kosten verlengde opname door invasieve candidiasis:

20.000,- Euro Incidentie 40% 2%

Winst: 18750,- Euro Verlies 5000,- Euro

Dus profylactisch gebruik van fluconazol op een IC waar candida geen groot probleem is kost geld en geeft mogelijk het risico op resistentie.

Practische leidraad?

1 van: A.b.-gebruik/CVL

+ 2 van: TPN, RRT, major surgery, pancreatitis, steroiden

Zou bij ons meer dan de helft van de patiënten betekenen...

Praktische leidraad Bij sepsispatienten

>7 dgn op de IC Koorts ondanks a.b. Geen ander focus

2 risicofactoren (>1 a.b.>3dgn, GI surgery, abd process, steroids, imm suppr, DM, RRT)

Kolonisatie

Kweek bloed, urine, sputum Antifungale therapie

Re-evaluatie op dag 3.


Ergosterol

-(1,6)-Glucan

Mannoproteins

-(1,3)-Glucan

GS

Fungal cell wall and antifungal targets

Ergosterol

-(1,6)-Glucan

Mannoproteins

-(1,3)-Glucan

-(1,3)-Glucan synthesis

GS

Polyenes – bind to ergosterol: Amphotericin B, lipid formulations of Amphotericin B, nystatin

Azoles – inhibit CYP450 enzyme responsible for ergosterol synthesis: Fluconazole,

voriconazole, itraconazole, posaconazole

Echinocandins – inhibit enzyme: Anidulafungin, caspofungin, micafungin

Forest plot of the pooled sensitivity and specificity of measuring serum or plasma (1→3)-β-D-glucan levels for the diagnosis of proven or probable invasive fungal infections.

Karageorgopoulos D E et al. Clin Infect Dis.2011


• Beta Di Glucan: CII evidence volgens de 2012 ESCMID richtlijn

• Dure test • Waarde van de test sterk afhankelijk van studie populatie

Antonelli, CCM; Leon CCM 2006 and 2009; Ostrovsky 2009; poster ECCMID 2012; Eggiman, Annals of Intensive Care 2011 Bassetti, Crit Care 2010

Clinical approach for the patient with proven candidaemia

• The ICU patient with a blood culture positive for yeasts

• Species and susceptibility as yet unknown

• Which initial therapy to start?

Compound Recommendation References Comment

Anidulafungin 200→100 mg A I Reboli NEJM 2007 Kett Int J Antimicrob Agents 2008

Caspofungin 70→50 mg A I Mora-Duarte NEJM 2002 Pappas Clin Infect Dis 2007

Micafungin 100 mg A I Kuse Lancet 2007 Pappas Clin Infect Dis 2007

L-Amphotericin B 3 mg/kg B I Kuse Lancet 2007 Dupont Crit Care 2009

Voriconazole 6→3 mg/kg bid B I

Kullberg Lancet 2005 Ostrosky-Zeichner Eur J Clin Microbiol Infect Dis 2003 Perfect Clin Infect Dis 2003

Fluconazole 800→400 mg B–C I

Anaissie Clin Infect Dis 1996 Rex NEJM 1994 Rex Clin Infect Dis 2003 Philips Eur J Clin Microbiol Infect Dis 1995 Reboli NEJM 2007

AmB lipid complex 5 mg/kg C II Anaissie ICAAC 1995 Ito Clin Infect Dis 2005

AmB deoxycholate 0.7–1 mg/kg

D I

Bates Clin Infect Dis 2001 Anaissie Clin Infect Dis 1996 Rex NEJM 1994 Philips Eur J Clin Microbiol Infect Dis 1995 Mora-Duarte NEJM 2002

Therapy of candidaemia

Echinocandin success rates in ICU patients

Re

spo

nse

rat

e (

%)

68

56 63

66

46

67

Mic

afu

ngi

n

L-A

mp

ho

teri

cin

B

Cas

po

fun

gin

Am

ph

ote

rici

n B

Flu

con

azo

le

An

idu

lafu

ngi

n

N=97 N=230 N=63

DiNubile et al. J Crit Care 2007;22:237–244; Dupont et al. Crit Care 2009;13:R159; Kett & Cubillos. Int J Antimicrob Agents 2008;32:S99–S102

Echinocandin mortality rates in ICU patients

45

40 38

35

22

17 Mo

rtal

ity

rate

(%

)

Mic

afu

ngi

n

L-A

mp

ho

teri

cin

B

Cas

po

fun

gin

Am

ph

ote

rici

n B

Flu

con

- az

ole

An

idu

la-

fun

gin

N=97 N=230 N=63

DiNubile et al. J Crit Care 2007;22:237–244; Dupont et al. Crit Care 2009;13:R159; Kett & Cubillos. Int J Antimicrob Agents 2008;32:S99–S102

Reboli et al. N Engl J Med 2007;356:2472–2482

Anidulafungin candidaemia study

success at EOIVT by pathogen

(N=61) (N=74)

C. albicans

(N=45) (N=45)

Non-albicans

*Patients with a single baseline pathogen

Anidulafungin

Fluconazole

Difference driven by C. albicans infections!

81.1

62.3

71.1

60.0

n=60 n=38 n=32 n=27

75.6

60.2

∆15.4% p=0.009

∆18.8% p=0.015

∆11.1% p=0.26

All patients

80

100

40

60

0

20

Su

ccess (

%)

Agent Recommendation References Comment

Anidulafungin 200→100 mg

A I Reboli NEJM 2007 Kett Int J Antimicrob Agents 2008

• Broad spectrum • Resistance rare • Fungicidal • Less active against • C. parapsilosis • Safety profile • Few drug–drug interactions

Caspofungin 70→50 mg

A I Mora-Duarte NEJM 2002 Pappas Clin Inf Dis 2007

• As above

Micafungin 100 mg

A I Kuse Lancet 2007 Pappas Clin Inf Dis 2007

• As above

Liposomal AmB 3 mg/kg

B I Kuse Lancet 2007 Dupont Crit Care 2009

• Similar efficacy as micafungin • Greater toxicity


Compound Recommendation References Comment

Voriconazole 6→3 mg/kg bid

B I

Kullberg Lancet 2005 Ostrosky-Zeichner Eur J Clin Microbiol Infect Dis 2003 Perfect Clin Inf Dis 2003

• Limited spectrum compared

with echinocandins

• Drug–drug interactions

Fluconazole 800→400 mg

B-C I

Anaissie Clin Inf Dis 1996

Rex NEJM 1994 Rex Clin Inf Dis 2003

Philips Eur J Clin Microbiol Infect Dis 1995

Reboli NEJM 2007

• Limited spectrum

• Inferior to anidulafungin

• Preferred for C. parapsilosis

AmB lipid complex 5 mg/kg

C II Anaissie ICAAC 1995

Ito CID 2005

AmB deoxycholate 0.7–1 mg/kg

D I

Ullmann Clin Inf Dis 2006

Bates Clin Inf Dis 2001

Anaissie Clin Inf Dis 1996

Rex NEJM 1994 Philips Eur J Clin Microbiol Infect Dis 1995

Mora-Duarte NEJM 2002

• Greater toxicity


Echinocandins chemical structure

Boucher et al, Drugs 2004;64:1997–2020

Caspofungin Glarea lozoyensis

Micafungin Coleophoma empetri

Anidulafungin Aspergillus nidulans

Pharmacology: metabolism, elimination, bioavailability and protein binding

Anidulafungin Caspofungin Micafungin

Metabolism Non-hepatic chemical degradation

Hepatic metabolism by hydrolysis and

N-acetylation

Spontaneous non-hepatic chemical degeneration

Hepatic metabolism by arylsulfatase and

catechol-O-methyltransferase

Volume of distribution V1 = 10 L V2 = 23 L

V1 = 8 L V2 = 4 L

V1 = 9 L V2 = 8 L

Half-life Around 24 hours 9–11 hours (beta phase) 45 hours (gamma phase)

10–17 hours

Elimination/excretion Urine <1%; Faeces 30% (of which 10%

parent compound)

Urine 41% (of which 1% parent compound)

Faeces 34%

Urine 12% Faeces 71%

Protein binding >99% 93–97% >99%

Oral bioavailability <5% <5% <5%

Loading dose Yes Yes No

Damle et al, Antimicrob Agents Chemother 2009;53:1149–1156; Dodds Ashley et al, Clin Infect Dis 2006;43:S28–S39; Anidulafungin EMA SPC, Caspofungin EMA SPC; Micafungin EMA SPC; Dowell et al, J Clin Pharmacol 2004;44:590–598; Wurtwein et al, Antimicrob Agents Chemother 2012;56:536–543; Ikawa et al, Antimicrob Agents Chemother 2009;64:840–844

Interacting drug

Anidulafungin Caspofungin Micafungin

Effect on interacting drug

Effect on anidulafungin


Effect on caspofungin


Effect on micafungin

Ciclosporin – Increased AUC by 21% – Increased AUC by 35% – –

Itraconazole Not determined Not determined – – Increased AUC

by 22% –

Mycophenolate mofetil

Not determined Not determined – – – –

Nifedipin Not determined Not determined Not determined Not determined Increased AUC

by 18% –

Posaconazole Not determined Not determined – – – –

Prednisolone Not determined Not determined Not determined Not determined – –

Rifampicin (enzymatic inducers)

– – Not determined 60% increased on day 1;

30% decreased on day 14 –

Sirolimus Not determined Not determined Not determined Not determined Increased AUC

by 21% –

Tacrolimus – – Reduced Cmin

by 26% – – –

Voriconazole – – Not determined Not determined – –

Drug interactions for echinocandins

Anidulafungin EMA SPC, Caspofungin EMA SPC; Micafungin EMA SPC; Dowell et al, J Clin Pharmacol 2005;45:227–233; Dowell et al, J Clin Pharmacol 2005;45:1373–1382; Keirns et al, Antimicrob Agents Chemother 2007;51:787–790; Krishna et al, J Clin Pharmacol 2011;51:84–92; Stone et al, Antimicrob Agents Chemother November 2004;48:4306–4314; Scientific discussion section Cancidas, Mycamine and Ecalta http://www.ema.europe.eu

No dose adjustment of echinocandins in renal failure

Dowell et al, J Clin Pharmacol 2007;47:461–70; Hebert et al, J Clin Pharmacol 2005;45:1145–1152; Caspofungin data available at scientific discussion section Cancidas http://www.ema.europe.eu

Caspofungin similar to anidulafungin and micafungin. Caspofungin does not require dose-adaptation in renal failure. An increase in AUC of 31, 49 and 30 % was observed, respectively, in moderate, severe and end stage renal disease (n=36 with 70 mg single dose).

Influence of hepatic dysfunction

Dowell et al, J Clin Pharmacol 2007;47:461–470; Hebert et al, J Clin Pharmacol 2005;45:1145–1152; Mistry et al. Clin Pharmacol 007;47:951–961

** For the calculation of micafungin clearance, a body weight of 70 kg was used

Clinical approach for the patient with proven candidaemia

• The ICU patient with a blood culture positive for yeasts

• Should CVC be removed?

Intravascular catheters and candidaemia

The debate goes on …

Does removal decrease mortality?

Australia (n=266)

Removal of central

venous catheter within

5 days decreased

mortality (p < 0.01)

0 10 20 30

1.00

0.75

0.50

0.25

0.00

Analysis time (days)

Catheter removed after diagnosis Catheter not removed after diagnosis

Survivor function for removal of catheter

No, mortality not reduced:

• Rodriguez Clin Microbiol Infect 2007

• 172 patients (any antifungal, 2002–2003)

No, mortality not reduced:

• Vos & Oude Lashof (unpublished)

• 370 patients on voriconazole vs AmB→Flu

Slavin et al. J Antimicrob Chemother 2010

Pro

bab

ility

of

surv

ival

Recent large dataset: remove CVC or not?

Nucci et al.

• Data from pivotal micafungin trials

• Micafungin 100 mg versus liposomal amphotericin B

• Micafungin 100 mg versus micafungin 150 mg versus caspofungin

• Total dataset: n=842

Multivariate analysis: outcome and mortality not affected by CVC removal

• CVC became irrelevant

• OR for cure: 1.20 (95% CI 0.89–1.69)

• OR for survival: 1.25 (95% CI 0.88–1.75)

• Outcomes and mortality driven by APACHE II score, age and persistence of

neutropenia

Hypothesis: Echinocandins sterilise the catheter as they are active in biofilms

Nucci et al. Clin Infect Dis 2010;51:295–303

Catheter management

• 1915 patients, individual patient-level pooled analysis

• Overall mortality, CVC retention 41% versus CVC removal 28% (p <0.0001)

APACHE II Quartile

Survivor function for removal of catheter

Mo

rtal

ity

(%)

100

80

60

40

20

0

1 2 3 4

Retained Removed

*

*

*

Andes, Kullberg, et al. Clin Infect Dis 2012

Population Intervention Recommendation References

Non-neutropenic patients with candidaemia

Remove intravascular catheters

B II Andes CID 2012 Nucci CID 2010 Liu J Infect 2009 Weinberger J Hosp Inf 2005 Leroy Crit Care Med 2009 Rex CID 1995 Almirante J Clin Microbiol 2005 Rodriguez Clin Microbiol Infect 2007 Kucharikova Antimicrob Agents Chemother 2010 Kuhn Antimicrob Agents Chemother 2002 Mukherjee Int J Antimicrob Agents 2009

Catheter management

Samenvattend

• Recommendations for prophylaxis, empirical therapy, or the use of β-

glucan or other biomarkers do not significantly differ from previous guidelines

• Echinocandins as the first choice for treatment of candidaemia/invasive candidiasis in most patients

• CVC removal is recommended independently of antifungal choice

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