EBM 2015

Infection and sepsisMasterclassIC Schiermonnikoog 2015

Contents• Critical care for Ebola infection

• Current problems with invasive aspergillosis

• Should patients with PJP be isolated?

• Polymixin B hemoperfusion for severe sepsis

• Early antibiotics but for whom?

P1 P2 P3 P4 P5

Journal NEJM 2014 Lancet 2015 Crit Care Med 2015

Crit Care Med 2015

Crit Care Med 2015

Country Germany Germany USA USA USA

Day of transfer D10 D6 D4 D14 D5

MV NIV (D18 - D26) + Intubation D9 - D22

+ + ARDS MV D9 - D26 + Intubation D15 + Intubation D11

Encephalopathy + D14 - D19 ? + Delirium + Decreased consciousness ?

Sepsis + (D12 - Gram- bacteremia)

NE up to 0.5 μg/kg/min Low dose NE NE + vasopressin

Gram- sepsisHigh dose NE Abd. sepsis

Diarrhea +++ > 24 L in first 3 days +++ +++ +++ +++

AKI + (admission creat 170 μmol/l) +++ +++ +++ +++

RRT - CVVHDF D9 - 27 IHD D27 - D 37 RRT until D 34 CRRT D14 - CRRT D11 -

Fluid balance > 30 L + in first week ? ? 16.9 L in 38 hrs ?

Electrolytes Hypokalemia Hyponatremia - Hypokalemia Hypoglycemia ?

Feeding D11 - D16 TPN D17 EN ? ? TPN ?

Survival + LOS ICU 18 D + +

LOS ICU 44 DDied - cardiac arrest on D16

Died - cardiac arrest on D15

Overall…..• 25 patients with EVD in resources-rich settings

• Mortality 20 - 26%

Invasive aspergillosis in the ICU

• International MC (N=30) observational study of ICU patients with evidence of either Aspergillus coloni- zation or IA (AspICU study)

• 563 patients included

47%

36%

17%Proven IAPutativeColonized

Aspergillus Fumigatus (92%)

Taccone FS. Crit Care 2015;19:7

Putative aspergillosis

Blot SI. Am J Respir Crit Care Med 2012;186:56-64

Clinical factsICU stay before first positive culture - 4 days

Patients with 1 positive culture (N = 563)

Number of affected sites (N = 597)

Lung N = 548

Abdomen N = 11

Brain N = 10

Sinus N = 11

Skin N = 9

Vascular N = 8

• Proven 86 (16%) • Putative 203 (37%) • CO 259 (47%)

• Proven 9 (82%) • Putative 0 (0%) • CO 2 (18%)

• Proven 10 (100%) • Putative 0 (0%) • CO 0 (0%)

• Proven 1 (9%) • Putative 3 (27%) • CO 7 (64%)

• Proven 2 (23%) • Putative 3 (33%) • CO 4 (44%)

• Proven 8 (100%) • Putative 0 (0%) • CO 0 (0%)

Taccone FS. Crit Care 2015;19:7

Only 40% of proven/putative aspergillosis had typical chest CT findings 80% had positive serum/BAL GM compared to 18% in CO

Clinical facts70% of patients with proven / putative aspergillosis were in immunosuppressive

state (EORTC) Treatment no effect on survival

%

0

20

40

60

80

Mortality at 12 weeks

Proven Putative CO

38

67

79

%

0

20

40

60

80

Mortality for proven/putative IA

6673

Imuunosuppressed "Normal"NS

Taccone FS. Crit Care 2015;19:7

Azole resistanceSurveillance Collaboration on Aspergillus Resistance in Europe

Azole resistance 3.2%(0 - 26.1%)

Mainly TR34/L98H or TR46/Y121F/T289A resistancemechanism acquired from environment

Case fatality with azole resistance 70% van der Linden JWM. Emerg Infec Dis 2015;21:1041-1044

Azole resistance

Kolwijck E. Submitted

Voriconazol vs voriconazol + anidulafungin with HM or HCT

N = 454, suspected or documented IA

%

0

10

20

30

6 W mortality total group 12 W mortality total group 6 W mortality proven IA

15,7

29,3

19,3

27,339,4

27,5

P = 0.087 P = 0.037P = 0.077

Marr KA. Ann Intern Med 2015;162:81-89

Voriconazol dosing and hypoalbuminemia

• Intra- and interpatient concentration variation

• CYP450-mediated drug-drug interactions

• Genetic polymorphism CYP2C19 enzyme

• Age

• Liver disease

• Coadministration drug with food

• Enteral feeding

• Switch from iv to oral medication

Protein binding

Hypoalbuminemia

More rapid elimination

(Only relevant for PPB > 70%)

Voriconazole PPB only 50% but saturated metabolism and only 2 % excreted unchanged in urine

Voriconazol dosing and hypoalbuminemia

Plas

ma

prot

ein

bind

ing

voric

onaz

ole

(%)

Plasma albumin (g/l)10 15 20 25 30 35 40

30

40

50

60R = 0.67; P < 0.001 R2 = 0.45

Increase in bilirubin also decreases voriconazole plasma protein binding

VRC PPB = 30.5 + 0.668 × [ALB] - 0.1867 × Bilitot

Adjusted VTC = (100 - VRCPPB)/100 ×measured total VTC × 2

Vanstraelen K. Antimicrob Agents Chemother 2015;58:6782-6789

Vanstraelen K. Antimicrob Agents Chemother 2015;58:6782-6789

Should patients with PJP be isolated?

10

100

1000

10000

100000

1000000

10000000m

tLSU

rRN

A co

pies

/m3

Patients with PCP

Patients with colonization

Patients with PCP

Patients with colonization{ {

1 m 5 m

N = 4 N = 10 N = 4 N = 10

Air samples

Le Gal S. Diagn Microbiol Infect Dis 2015;82:137-142

Should patients with PJP be isolated?

Patient with PJP

HCW contact

HCW contact

< 2 m > 5 minPJ DNA detected by nasal swap / oropharyngeal wash

Exhaled air samples

Quantitative PCRif positive

Genotyping

15 PJP patients

13/15 NS + 2/3 OW +

Room AS +7/15 (47%)

Exhaled AS +2/4 (50%)

102 HCW

9 (8.8%) +NS 5OW 4

Exhaled AS +2 1P → 1 HCW

Salade S. Intensive Care Med 2015;41:1716-1718

Polymyxin B hemoperfusion

EUPHRATES RCT septic shock + confirmed endotoxemia

90% reduction in LPS with 2 treatments (2hr)EUPHAS RCT trial 2009

EUPHAS -2 prospective web-based registry

015304560

Mortality

Control PMx

Polymyxin B Hemoperfusion• Prospective MC (18) RCT comparing conventional treatment with

conventional treatment + 2 sessions of polymyxin B hemoperfusion (ABDO-MIX trial)

• Septic shock after surgery for peritonitis

• Primary outcome: mortality at D 28

• Secondary outcomes: mortality at D 90, SOFA score variation within 3 days

Payen DM. Intensive Care Med 2015;41:975-984

Polymyxin B HemoperfusionN = 232

Mor

talit

y (%

)

0

10

20

30

40

Mortality D 28 Mortality D 90

33,6

27,724

19,5

Control Polymyxin BP = 0.10P = 0.14

No differences in change in SOFA scorePayen DM. Intensive Care Med 2015;41:975-984

Hemodynamics with PMx hemoperfusion

0

10

20

30

Pre Post

Inotropicscore

Responders Non-responders

0

0,1

0,2

0,3

0,4

Pre Post

Vasopressordependency index

Responders Non-responders

0

100

200

300

Pre Post

PF-ratio

Responders Non-responders

0

5

10

15

20

Pre Post

Endotoxin level

Responders Non-responders

Responders with septic shock had excessive vasodilatationSugimura M. J Intensive Care 2015;3:14

Rapid adequate initiation of antibiotics essential

Septic shock (N = 2154)

Kumar A. Crit Care Med 2006;34:1589-1596

0.0

0.2

0.4

0.6

0.8

1.0

0-0.5 0.5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36 > 36

Time from onset hypotension (hrs)

Frac

tion

of to

tal p

atie

nts

Cumulative effective antimicrobial initiation

Survival fraction

BUT…..

Early antibiotics for sepsis and septic shock

Prospective study in 426 patients with septic shock

Mor

talit

y (%

)

0

6

12

18

24

Administration of antibiotics after onset of septic shock (hrs)

≤ 1, >1 ≤ 2, >2 ≤ 3, >3 ≤ 4, >4 ≤ 5, >5

NS NS NS NS NS

Ryo SM. Am J Med Sci 2015;349:328-333

Patients treated with early quantitative resuscitation protocol

Relation with 28-D mortality

Adjusted OR 95% CI P-Value

Interval between shock / antibiotic administration 1.15 0.87 - 1.51 0.34

Failure to achieve early resuscitation goals 1.94 1.07 - 3.51 0.03

SOFA score 1.30 1.17 - 1.44 < 0.01

Lactic acid (mmol/l) 1.66 1.11 - 2.49 0.01

Respiratory rate (BPM) 1.09 1.04 - 1.14 < 0.01

Ryo SM. Am J Med Sci 2015;349:328-333

Prospective study in 426 patients with septic shock

Effect of early antibiotics on mortality and hospital LOS

Prospective observational cohort study in 1168 patients with suspected infection in ER

Stratified for 3 categories of disease severity by PIRO score

PIRO 1 - 7 PIRO 8 - 14 PIRO > 14AB < 1 hr / Hospital LOS Corrected HR 1 Corrected HR 1 Corrected HR 1

AB 1 - 3 hrs 1.03 (0.78 - 1.36) 1.02 (0.83 - 1.25) 1.16 (0.86 - 1.58)

AB > 3 hrs 1.46 (1.05 - 2.02) 1.02 (0.75 - 1.38) 1.40 (0.84 - 2.34)

AB < 1 hr / Mortality Corrected HR 1 Corrected HR 1 Corrected HR 1

AB 1 - 3 hrs 2.55 (0.36 - 18.25) 1.25 (0.62 - 2.31) 0.99 (0.53 - 1.87)

AB > 3 hrs 5.31 (0.43 - 68.16) 0.86 (0.28 - 2.63) 1.11 (0.40 - 3.08)

95% received antibiotics within 6 hrs

de Groot B. Crit Care 2015;19:194

Mortality with AB < or > 3 hrs from triage

Ferrer

Puskarich

Galeski

Viyella

Joo

Bruce

Pooled OR

1 520.2 0.5

1.23 (1.14, 1.32)

0.51 (0.22, 1.10)

1.30 (0.70, 2.38)

1.23 (0.35, 1.73)

1.23 (0.99, 2.39)

1.23 (0.49, 2.96)

1.16 (0.92, 1.46)

Sterling SA. Crit Care Med 2015;43:1907-1915

Are cultures still necessary?616 BSI, 180 pneumonia, 110 sterile fluid/tissue specimens

Blood culture

PCR/ EIMS

+ - Total Sens 81%+ 55 173 228 Spec 69%- 13 384 397 PPV 24%

Total 68 557 625 NPV 97%

PCR/EIMS results available < 6 hrs

Lower Respiratory Tract culture

PCR/ EIMS

+ - Total Sens 84%+ 68 49 117 Spec 53%- 13 55 68 PPV 58%

Total 81 104 185 NPV 81%

Vincent JL. Crit Care Med 2015;43:2283-2291

Conclusions• Mortality of severe Ebola cases with MODS is rather low

with modern ICU treatment - dehydration, diarrhea, AKI

• Antibiotics should be administered as soon as possible but only after adequate cultures have been taken

• Voriconazol resistance increases and double therapy may be indicated - be careful with hypoalbuminemia

• PJP could be an airborne transmissible disease

• Polymyxin-B hemoperfusion is not indicated (yet)