Inflammatory markers in assessing bacterial infections

and aiding prescribing decisions

Prof. Stephan Harbarth Geneva (Switzerland)

BSAC Spring Meeting 2014 stephan.harbarth@hcuge.ch

•  Several research projects presented in this talk received funding by BRAHMS (Germany)

•  Advisory board: BioMerieux

Disclosures

RApid Point-of-Care test Platforms for Infectious Diseases

Widely used diagnostic tests to assess inflammation vs. infection

•  Erythrocyte sedimentation rate – Earliest indirect method to assess

inflammation •  Differential WBC •  C-reactive protein (CRP) •  Procalcitonin (PCT) •  [IL-6, TNF ….]

Gabay C, Kushner I N Engl J Med 1999, 340:448-54

Schuetz P et al. Swiss Med Weekly 2009; 139: 318-26 (updated)

JAMA 09

ProRATA Lancet 2010

Procalcitonin: a long & complicated story…

ProVAP ERJ 2010

CID 2011 LID 2013

AIM 2011

Ongoing controversy about PCT

Reasons for discrepant conclusions on PCT as a marker of bacterial infection

•  Different assays •  Cut-off range depends on:

–  Clinical setting and type of infection –  Pretest probabilities

•  Poor study design of many observational studies •  Single PCT measurement of limited value •  False positives & negatives (≈10%)

Christ-Crain M & Muller B, Swiss Med Wkly 2005; 135: 451-60

ANTIBIOTIC DURATION

Individualized treatment guidance

Procalcitonin and CRP

The ProCAP Study – Antibiotic Duration

p < 0.001

Standard group ProCT

group

2 4 6 8

10 12 13

20

Ant

ibio

tic d

urat

ion

(day

s)

15 17 19

Standard group ProCT group

0

10

20

30

40

50

60

70

80

90

100

AB started > 4d > 6d > 8d > 10d > 14d > 21d

Ant

ibio

tic P

resc

ripto

in (%

)

Christ-Crain M et al, Am J Respir Crit Care Med 2006

JAMA 2009; 302: 1059-66

Main results

•  In the PCT group, antibiotic exposure significantly lower as compared to controls (35% reduction, p<0.001)

•  Rate of adverse outcomes similar in PCT and control group (15.4% vs. 18.9%)

•  Antibiotic-associated side effects less frequent in the PCT group (19.8% vs. 28.1%; p<0.001)

Schuetz P et al. JAMA 2009; 302: 1059-66

BICAP  study,  CH  

•  Pa#ents  were  treated  with  an#bio#cs  for  a  median  of  10.0  days  (IQR  8.0-­‐12.0)  in  the  monotherapy  vs.  10.0  days  (IQR  7.0-­‐11.0)  in  the  combina#on  arm    

N.  Garin,  unpublished  data  (March  2014)  

Procalcitonin (PCT) guidance allows shortening antibiotic therapy duration in patients with severe

sepsis and septic shock. A randomized clinical trial

Nobre V, Harbarth S, Graf J-D, Rohner P, and Pugin J University Hospitals of Geneva, Switzerland

Am J Respir Crit Care Med 2008; 177: 498–505

To test if a PCT-guided strategy allows

reducing the use of antibiotics in patients

with severe sepsis and septic shock.

Objective

Nobre V et al. Am J Respir Crit Care Med 2008; 177: 498–505

Adults (≥ 18 y) Severe sepsis or septic shock

Intensive Care Unit

PCT group PCT-guided antibiotic

discontinuation

Randomization

Control group Antibiotic discontinuation based on standard practice

Nobre V et al. Am J Respir Crit Care Med 2008; 177: 498–505

Baseline characteristics of patients – Per protocol (n=68 )

Characteristics PCT group (n=31)

Control group (n=37) p value

Nobre V et al. Am J Respir Crit Care Med 2008; 177: 498–505

Primary endpoints

Per protocol analysis

Control group (n=37)

PCT group (n=31)

p value / IRR

Days of AB therapy

10 (3-33) 6 (4-16) 0.003

AB exposure-days

655 504 0.0002 IRR=1.3 (95% CI: 1.1-1.5)

Nobre V et al. Am J Respir Crit Care Med 2008; 177: 498–505

0.70 3.2% 2.7% Infection relapse, %

0.20 22.6% 29.7% Nosocomial infection

0.33 90.3% 83.8% Clinical cure

0.74 16.1% 16.2% 28-days mortality

p value PCT (n=31)

Control (n=37)

Variables

Secondary endpoints

Procalcitonin use at HUG N

umbe

r of P

CT

test

s

 

PCT  value    

(N=2015)  

 

AnBbioBcs  prescribed  

within  24  hrs  

(N=659)  

 

No  anBbioBcs  prescribed  

within  24  hrs  

 (N=1356)  

 

<0.25  ug/L  

 

Inappropriate  prescrip#on  

277  /659=  42.0%  

 

Appropriate  withholding  

779/1356=  57.4  %  

 

>=  0.25  ug  /L,  <  2  ug/L  

 

Indeterminate  

243  /  659=36.9  %  

 

Indeterminate  

397  /  1356=  29.3  %  

 

>2  ug/L  

 

Appropriate  prescrip#on  

139  /  659  =  21.1  %  

 

Inappropriate  withholding  

180/1356=  13.3  %  

UBlisaBon  de  la  PCT  au  Département  de  Médecine  Interne,  2009-­‐2010

N.Garin,  V.Poffet,  S.Harbarth,  A.Perrier  (unpublished  data)

Early antibiotic withdrawal.....

47-y drug abuser, CAP & BSI due to E. coli, stop AB at D13 Lung abscess, requiring prolonged treatment

1315 Patients Assessed for Eligibility 685 Ineligible 158 had expected ICU stay <3 days 138 had SAPS II >65 104 had received AB for >24 hours 99 required prolonged therapy 63 not enrolled for logistic reasons 46 had do-not-resuscitate orders 31 were neutropenic 15 had no medical insurance 12 had been enrolled in other studies 10 refused consent 9 excluded for other reasons

630 Randomized

311 Assigned to the Procalcitonin Group

319 Assigned to the Control Group

307 Included in Analysis

(1 lost to follow-up on day 15)

314 Included in Analysis

(1 lost to follow-up on day 22)

4 withdrew consent 1 randomized twice

The ProRata Trial

4 withdrew consent

Courtesy: Jean Chastre, Paris (Bouadma, Lancet 2010)

PCT group: algorithme

Stopping antibiotics

strongly encouraged

[PCT]<0.25 µg/l Ø[PCT]≥80%/[PCT] max

or0.25≤[PCT]<0.5 µg/l

Stopping antibiotics encouraged

Ö[PCT]/[PCT] previousand

[PCT]≥0.5 µg/l

Changing antibiotics

strongly encouraged

Ø[PCT]<80%/[PCT] maxand

[PCT]≥0.5 µg/l

Continuing antibiotics encouraged

Guidelines for stopping, continuing, or changing antibiotics according to daily measured PCT value

Guidelines for initiating antibiotics according to PCT value Except any situation requiring immediate antibiotic therapy (septic shock, purulent meningitis, etc.)

Obtain second PCT determination 6–12 hours laterif value had been obtained early after the start of the episode

[PCT]< 0.25 µg/l

Antibiotics strongly discouraged Antibiotics discouraged

0.25≤[PCT]<0.5 µg/l [PCT]≥1 µg/l

Antibiotics strongly encouragedAntibiotics encouraged

0.5≤[PCT]<1 µg/l

Stopping antibiotics

strongly encouraged

[PCT]<0.25 µg/l Ø[PCT]≥80%/[PCT] max

or0.25≤[PCT]<0.5 µg/l

Stopping antibiotics encouraged

Ö[PCT]/[PCT] previousand

[PCT]≥0.5 µg/l

Changing antibiotics

strongly encouraged

Ø[PCT]<80%/[PCT] maxand

[PCT]≥0.5 µg/l

Continuing antibiotics encouraged

Guidelines for stopping, continuing, or changing antibiotics according to daily measured PCT value

Guidelines for initiating antibiotics according to PCT value Except any situation requiring immediate antibiotic therapy (septic shock, purulent meningitis, etc.)

Guidelines for initiating antibiotics according to PCT value Except any situation requiring immediate antibiotic therapy (septic shock, purulent meningitis, etc.)

Guidelines for initiating antibiotics according to PCT value Except any situation requiring immediate antibiotic therapy (septic shock, purulent meningitis, etc.)

Obtain second PCT determination 6–12 hours laterif value had been obtained early after the start of the episode

Obtain second PCT determination 6–12 hours laterif value had been obtained early after the start of the episode

[PCT]< 0.25 µg/l

Antibiotics strongly discouraged

[PCT]< 0.25 µg/l

Antibiotics strongly discouraged Antibiotics discouraged

0.25≤[PCT]<0.5 µg/l

Antibiotics discouraged

0.25≤[PCT]<0.5 µg/l [PCT]≥1 µg/l

Antibiotics strongly encouraged

[PCT]≥1 µg/l

Antibiotics strongly encouragedAntibiotics encouraged

0.5≤[PCT]<1 µg/l

Antibiotics encouraged

0.5≤[PCT]<1 µg/l

Courtesy: Jean Chastre, Paris (Bouadma, Lancet 2010)

Did  Clinicians  strictly  follow  the  Algorithm?  

Guidelines  were  not  followed  in  219  episodes  (53%)    

•   65  paBents  did  receive  ABX  despite  PCT  <  0.5  •   4  paBents  did  not  receive  ABX  despite  PCT  >  0.5  •   In  39  paBents  ABX  were  disconBnued  despite  PCT  >  0.5  

•   In  79  paBents  ABX  were  conBnued  despite  PCT  <  0.5  

PCT  acted  as  a  guide,  not  as  a  rule  

Characteristic

PCT Group

(n = 307)

Control Group

(n = 314)

Age, mean (SD), y 61.0 (15.2) 62.1 (15.0)

SAPS II, mean (SD)

SOFA score, mean (SD)

43.8 (16.1)

7.5 (4.4)

43.4 (15.4)

7.2 (4.4)

Mechanical ventilation, No. (%) 211 (68.7) 208 (66.2)

Type of infection, No. (%)

Community-acquired

Hospital-acquired

153 (49.8)

154 (50.2)

173 (55.1)

141 (44.9)

Septic shock, No. (%) 131(42.7) 123 (39.2)

Positive blood cultures, No. (%) 55 (17.9) 53 (16.9)

Procalcitonin, mean (SD), µg/L 12.0 (30.9) 12.0 (32.6)

Courtesy: Jean Chastre, Paris (Bouadma, Lancet 2010)

Use of Procalcitonin to Shorten Antibiotic Exposure in ICU Patients : The ProRata Trial

Bouadma et al. Lancet 2010

All patients VAP Intraabdominal infection

UTI Positive blood cultures

N

CAP

20 14

9.9

6.1

10.6

5.6

9.4

7.3

10.8

8.1

14.5

7.4

12.8

9.8

0

2

4

6

8

10

12

14

16

Dur

atio

n of

trea

tmen

t (da

ys)

314 307 101 79 66 75 18 24 53 55

PCT

Control

Use of Procalcitonin to Shorten Antibiotic Exposure in ICU Patients : The ProRata Trial Bouadma et al. Lancet 2010 P

roba

bilit

y of

Sur

viva

l, %

Days after Inclusion

Procalcitonin Control group

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

OR at D28; 0.81, 90% CI 0.63-1.29 OR at D60; 1.09, 90% CI 0.79-1.51

PCT arm (secondary outcomes): -  ICU LoS increased by one day (p < .004) -  Rate of mechanical ventilation per day increased by 5% -  More broad-spectrum drug escalation -  Shorter time to administration of appropriate antimicrobials

Afshari A et al. Crit Care 2013

PCT  effect  on  mortality  –  recent  meta-­‐analysis  

•  Limited  role  for  the  starBng  of  ABX    -­‐  28%  of  proven  infecBons  had  PCT    <  0.25    -­‐  29%  of  non-­‐infected  paBents  with  PCT  >1  

Corona A et al. J Antimicrob Chemother 2004;54:809-17.

Corona A et al. J Antimicrob Chemother 2004;54:809-17.

And what about CRP ?

CRP better marker for infection than PCT?

•  Suspected CA sepsis

•  CAP, n = 58 (33%)

•  CRP, AUC=0.81 PCT, AUC=0.72

•  CRP better marker for infection?

Kofoed K et al. Crit Care 2007; 11: R38

0 0.

25

0.50

0.

75

1.00

S

ensi

tivity

0.25 0.50 0.75 1.00 1-Specificity

PCT (0.88; 0.84-0.93) CRP (0.76; 0.69-0.83) Leukocytes (0.69; 0.62-0.77) Temperature (0.55; 0.46-0.63)

0

Müller B et al. BMC Infect Dis 2007

Diagnostic accuracy to predict radiographically suspected CAP

Meisner M et al, Crit Care 2006

BMJ review

•  Testing for CRP neither sufficiently sensitive to rule out nor sufficiently specific to rule in bacterial LRTI

•  Poor methodological quality of studies •  Not sufficient evidence to support a wide

introduction of CRP as a rapid test to guide antibiotic prescription

BMJ 2005; 331: 26-29

CRP for monitoring CAP

•  CRP useful for monitoring individual clinical course

•  Marker of delayed resolution of chest infiltrates and complications

•  BUT: No RCT available that investigated specifically the role of CRP for guiding AB treatment duration in CAP

Bruns AH et al. Clin Infect Dis 2007; 45: 983-91 Coelho L et al. Crit Care 2007; 11: R92

Pediatrics 2004;114:1– 8

Conclusions

Take home messages •  PCT: not a perfect biomarker of sepsis,

but currently the most effective tool to: –  Individualize antibiotic use in LRTIs – Reduce AB treatment duration

•  CRP: urgent need for well-designed RCTs •  But:

– any infection is far too complex to be reduced to a single cutoff of any biomarker

– PCT still not cost-beneficial in most countries

Surgeon General‘s Warning

Procalcitonin without Doctors

can do harm!

Doctors without Procalcitonin even more!

Medicine

IS THERE AN INFECTION? IS THERE AN INFECTION?

Medicine

Courtesy: Beat Müller