1. Amsterdam
June 2012
Accuracy and cost-effectiveness
in diagnosis of CRBSI
BJ Rijnders, MD, PhD
Internal Medicine
Section Infectious Dis.
Erasmus MC
Rotterdam
The Netherlands
B.Rijnders@erasmusmc.nl

2. General introduction
Accuracy of CRBSI diagnosis:
What is accurate?
Best possible sensitivity, specificity, PPV NPV, reproducibility
But inevitably: very high sensitivity ≈ decrease in specificity / PPV
Accuracy of in vitro culture methods: Maki vs sonication vs other ?
Accuracy of in vivo culture methods: DTTP / surface cultures / other ?
2

3. General introduction
Accuracy of CRBSI diagnosis:
We should look for an optimal balance between:
- Avoidance of delayed catheter removal in patients with CRBSI
and severe sepsis: S. aureus, Candida
- Avoidance of unnecessary catheter removal/reinsertion
* In particular in pts with long-term CVC
* In particular in pts at risk for CVC insertion complications
3

4. Topics of today on diagnosis:
1. Maki versus sonication
2. The ins, outs and problems of D T T P
3. Surface Cultures Surveillance
4. When (not)to pull the trigger/CVC?
4

5. To roll or to sonicate?
5

6. To roll or to sonicate?
Roll plate (Maki):
Sonication:
6
6

8. n=1000 tip cultures in random order (33% positive)
Gold standard: Positive culture in at least 1 of the 3 techniques
=> Short-term CVC: Roll-plate preferred (sonication with100cfu cut-off)
Bouza E et al. Clin Inf Dis 2005

9. “Long-term CVC” in this study >6 days in situ
“Long-term CVC” Roll-plate as good as sonication (100cfu cut-off)
But what in truly long term CVC?
Bouza E et al. Clin Inf Dis 2005

10. 313 Hickman catheters
Dwell time 55 days
25% of tips were positive
40 patients with CRBSI (DTTP or tip + peripheral BC)
Often treated with vancomycine before catheter was removed
Slobbe L et al. J Clin Microb 2009
10
10

11. Guembe M et al. J Clin Microb 2012
11
11

12. To roll or to sonicate?
35 years after Maki’s publication:
Maki DG et al. A semiquantitative culture method for identifying
intravenous catheter–related infection. N Engl J Med 1977; 296:1305–9.
Let’s keep on rolling !

13. Topics of today on diagnosis:
1. Maki versus sonication
2. The ins, outs and problems of D T T P
3. Surveillance surface cultures
4. When (not)to pull the trigger/CVC?
13

14. In vivo diagnosis of CRBSI
i. Catheter brush: Don’t try this at home!
ii. Acridine orange leucocyte cytospin: Labour intensive
iii. Quantitive BC: Not available/labour intensive/expensive
iv. DTTP: Differential time to positivity
Qualitative BC with continuous
CO2 measurement
- BacTalert
- BacTec
- …
B Rijnders et al. Crit Care Med 2001
14

15. 15

16. DTTP = Time needed for the peripheral BC to become positive
Minus
Time needed for the “catheter BC” to become positive
e.g. 13.3 hrs - 8.3 hrs
= DTTP 5.0
e.g. 13.3 hrs - 11.9 hrs
= DTTP 1.4
In oncology patients DTTP > 2 hrs accurately predicts CBSI
- Lancet 1999. Vol 354. Sept 25. 1071--1077. Blot F et al. 94 % PPV 91 % NPV
- J Clin Microbiology. Jan. 2003, p. 118–123. Seifert H et al. 88 % PPV 75 % NPV
- Ann Intern Med. 2004; 140: 18-25. Raad I et al. 87 % PPV 85 % NPV
16

17. Raad I et al. Ann Intern Med. 2004; 140: 18-25. 17

18. Raad I et al. Ann Intern Med. 2004; 140: 18-25.
18

19. Raad I et al. Ann Intern Med. 2004; 140: 18-25.
19

20. “Although the test seems to have excellent sensitivity and specificity, the
authors do not discuss the consequences of the sample collection strategy
required to measure differential time to positivity (1)“
! 216 (3.5%) of the 6138 paired cultures were both positive
! In 603 (9.8%) only the CVC blood culture was positive
==> Catheter-drawn blood cultures more likely false positive than cultures
obtained through venipuncture (2)
=> Inappropriate AB use
=> Inappropriate CVC removal
=> Delay in diagnosis of other origin of fever/sepsis
(1) T Barton et al. Ann Intern Med 2004 (2) Desjardin JA et al. Ann Intern Med. 1999
20

21. A Randomized and Prospective Study of 3 Procedures for the Diagnosis of
Catheter-Related Bloodstream Infection without Catheter Withdrawal
ICU setting, 3 year study
• Arterial catheters excluded
• 10 ml blood culture through every lumen + peripheral for DTTP
• 10 ml blood culture through every lumen + peripheral for quantitative BC
• 3 cm  exit site culture + swab culture of all hubs at time of CVC removal
• 5cm tip culture (roll-plate method)
 DTTP > 2 hours
 Quantitative CVC BC culture 5x the peripheral BC
 Surface culture positive if ≥15cfu/plated
 CRBSI gold standard: Tip positive + peripheral BC positive with same strain
=> 204 episodes of sepsis in 104 pts with CVC in place
=> 28 CRBSI
Bouza E Clin Inf Dis 2007
21

22. A Randomized and Prospective Study of 3 Procedures for the Diagnosis of
Catheter-Related Bloodstream Infection without Catheter Withdrawal
CONCLUSION: CR-BSI can be assessed without CVC withdrawal in ICU pts who have
catheters inserted for a short time
Convenience, use of resources, and expertise should determine choice
Because of ease of performance, low cost, and wide availability, we recommend
combining superficial cultures and peripheral BC to screen for CR-BSI, leaving DTTP
as a confirmatory and more specific technique.
Bouza E Clin Inf Dis 2007
22

23. A Randomized and Prospective Study of 3 Procedures for the Diagnosis of
Catheter-Related Bloodstream Infection without Catheter Withdrawal
BUT:
⇒ Do we have to sample all lumina all the time as in this study?
⇒ What to do when only CVC blood culture is positive?
⇒ What did they do with the “excluded” arterial catheters?
Arterial and dialysis catheters were excluded because:
* To much blood would have to be taken during each sepsis episode
* “ It is well known that arterial catheters are very rarely the origin of
bloodstream infection, and in a study involving patients with major
heart surgery, arterial catheters accounted for only 0.15% of the
cases of bloodstream infection “
 Several other reports
Bouza E Clin Inf Dis 2007 Rijnders BJ Clin Inf Dis 2007
23

24. What about the arterial line ?
All studies in English literature that prospectively
examined the risk of BSI associated with arterial catheters
and provide sufficient data to calculate a rate of infection
per 100 catheters and 1000 days.
Data from Safdar N, Maki DG et al unpublished 24

25. What about the arterial line ?
2.7/1000
2.0/1000
Versus catheterdays
catheterdays
for CVC
Data from Safdar N, Maki DG et al unpublished 25

26. 1.
What about the arterial line ? ed am 201
M
C are odstre in
l. Crit d blo survey
R et a relate -year
hio eter- 8
cc ath f an unit.
Pirra ial c o
sults e care l
Most recent large study onte r :r
incidence siv e of arterial catheter related BSI:Arteria ”
Ar ions inten 1. t
ct
infe gical 201 respec
r e Med et no
Barcelona, Spain a su rit Car n’t g
M E. C hey do
A total of 1543 AC were inserted for 14,437 p ters: “T days.
R upcatheter
he
cat 5.
200 entral
The incidence of AC-related bloodstream infections nd c f was ed
are M l a(ACR-BSI) o
3.53 episodes per 1000 catheter days.Cr i t C rteria and ter-
l. a n
et a udy of nizatio athe unit
s.
eO t lo c e
Tr aor ctive s ter co enous ive car
e e lv s
P rosp s cath entra in inten
u c
v eno l- and remia
a
rteri d bact
e er
a thet e
te 5. Ca ? If w
rela 200 nted
ed
ar e M preve o!
.C rit C an be usly to
c
d e rs BJ ction e serio
Rijn ed infe erial lin
t t
rela the ar
J Infect. 2011 Aug;63(2):139-43. Esteve F et al. take 26

27. BUT:
⇒ Do we have to sample all lumina all the time?
171 CRBSI, all lumina sampled + peripheral BC, DTTP >2hrs as gold standard
Eliminating 1 lumen in triple lumen
CVC led to missed diagnosis in 16%
Eliminating 2 lumina in triple lumen
CVC led to missed diagnosis in 32%
Eliminating 1 lumen in double lumen
CVC led to missed diagnosis in 27%
M Guembe et al. Clin Inf Dis 2010
27

28. BUT:
Sampling all lumina => Optimal sensitivity
Sampling all lumina => much more false positive/contamination
=> decrease in specificity / PPV
In low incidence setting: PPV even lower
M Guembe et al. Clin Inf Dis 2010
28

29. Topics of today on diagnosis:
1. Maki versus sonication
2. The ins, outs and problems of D T T P
3. Surveillance surface cultures
- Previous study: Surface cultures taken at time of new episode
of sepsis has good NPV
- But is physician able to standby for 48 hours in pnt with sepsis?
Surveillance surface cultures may help
29

30. The challenge of anticipating catheter tip colonization in major heart
surgery patients in the intensive care unit: Are surface cultures useful?
Prospective study in 131 cardiosurgical ICU pts admitted for >4 days
From day 5 on: Surveillance hub and insertion site skin cultures/3 days
561 catheters (CVC + AC + Sw-Ganz): 3712 surface cultures
133 positive tips, 15 CRBSI
Bouza E et al. Crit Care Med 2005; 33:1953–1960.
30

31. 130 patients studied: 15 CRBSI episodes
6 secundary BSI
10 primary BSI
All CRBSI occurred with positive previous surface cultures
9 (60%) extraluminal, 3 (20%) endoluminal, 3 both
Considering all previous skin and hub cultures as a single test:
Se 100% (skin cultures only: 80%)
Sp 64.7%
PPV 7.2%
NPV 100% (skin only: 98%)
Bouza E et al. Crit Care Med 2005; 33:1953–1960.
31

32. Topics of today on diagnosis:
1. Maki versus sonication
2. The ins, outs and problems of D T T P
3. Surveillance surface cultures
4. When (not)to pull the trigger/CVC?
Are there other ways to assist the ICU physician to standby for
48 hours at bedside of a patient with new episode of sepsis?
32

33. 100 consecutive ICU patients in which the physician had decided to
remove the catheters for “suspected” catheter-related infection
- Blood cultures through every line in place
- Periferal blood culture
- All catheters were removed (166 catheters) and cultured
3 (…) pnts with CRBSI (positive tip + positive peripheral blood cult.)
9 patients with non-CRBSI (negative tip + positive blood culture)
Rijnders BJ et al. Crit Care Med 2001;29:1399-1403
33

34. = 63 with all negative
blood cultures
34

35. In every study that includes ICU patients with suspected CRI,
the diagnosis can be confirmed during follow up in only
small minority
e.g. 28 of 204 patients Clin Inf Dis feb. 2007. E. Bouza et al.
6 of 68 patients JAMA 2001;286(6):700-7. Merrer, J et al.
3 of 100 patients ! Crit Care Med 2001 Rijnders BJ et al.
The art of removing catheters when suspicion is high
The art of leaving catheters in place for FUO in a “stable” ICU patient

36. 80-90% of catheter removed in vain …
36

37. Is systematic catheter removal beneficial for every “suspected” catheter
related infection ?
Watchful waiting or Immediate catheter removal
in ICU patients with suspected catheter-related infection ?
Included: All consecutive ICU pts in which CVC change for suspected
CR-infection was planned by the treating physician.
Excluded:1. Haemodynamically unstable patient
2. Confirmed bacteremia
3. Suppuration or frank erythema at insertion site
4. <500/mm3 neutrophils, intravascular FB
B Rijnders et al. Intensive Care Med 2004. Vol 30. p1073-80.
C Brun-Buisson. Intensive Care Med 2004. Vol 30. p1005-7. 37

38. 38

39. Methods:
Measurements:
During the 10 days after inclusion : T, CRP, SOFA score
WBC count, AB use was registered.
All catheters were cultured when removed.
Endpoints:
• Evolution of fever/SOFA score/CRP in SOC versus WW group ?
• Duration of ICU stay in WW versus SOC group ?
• Number of CVCs removed in WW versus SOC group ?
• Are exclusion criteria selecting for pts with CRBSI ?
39

40. Results:
Study team was contacted for 144 patients
64 of 144 pts (44.5%) could be included.
Reasons for excluding 80 of 144 evaluated patients:
(n=)
Bloodstream infection 36
HD unstable 31
Inflamed/purulent ins. site 18
High risk patient 12
Other 4
40

41. Pts with suspec-
ted CRI (n=144)
80 excluded
(92 CVCs)
No BSI
(n=33)
BSI (n=47)
No CRBSI
(n=27)
CRBSI (n=20)
64 included
(80 CVCs)
SOC (n=32, 38 CVC) WW (n=32, 42 CVC)
41

42. Pts with suspec-
ted CRI (n=144)
80 excluded
(92 CVCs)
No BSI
(n=33)
BSI (n=47)
No CRBSI
(n=27)
CRBSI (n=20)
64 included
(80 CVCs)
SOC (n=32, 38 CVC) WW (n=32, 42 CVC)
- 38/38 CVC removed - 16/42 CVC removed
- 2 CRBSI - 3 CRBSI
42

43. SOC WW
CVC changes 38/38 16/42 p<0.01
CRBSI 2 3 p>0.2
Duration of Hosp. 42 34 p>0.2
ICU Mortality 10/32 8/32 p>0.2
T (°C) d1 37.9 38.4 p=0.02
d5 37.6 37.6 p>0.2
d 10 37.5 37.4 p>0.2
CRP (mg/l) d 1 128 155 p>0.2
d5 100 134 p>0.2
d 10 85 104 p=0.15
SOFA score d 1 6.1 6.9 p>0.2
d5 5.4 6.2 p>0.2
d 10 5.3 5.8 p>0.2
43

44. SOC WW
CVC changes 38/38 16/42 p<0.01
CRBSI 2 3 p>0.2
Duration of Hosp. 42 34 p>0.2
ICU Mortality 10/32 8/32 p>0.2
T (°C) d1 37.9 38.4 p=0.02
d5 37.6 37.6 p>0.2
d 10 37.5 37.4 p>0.2
CRP (mg/l) d 1 128 155 p>0.2
d5 100 134 p>0.2
d 10 85 104 p=0.15
SOFA score d 1 6.1 6.9 p>0.2
d5 5.4 6.2 p>0.2
d 10 5.3 5.8 p>0.2
44

45. Definitions
Catheter-related sepsis:
= Fever disappeared after catheter-removal (+/- positive tip)
In many patients fever would have disappeared without catheter
removal anyway !
Disappearance of fever does not prove that the catheter was the cause !
= ASPECIFIC DEFINITION
Watchfull waiting is a valid option
45

46. 1366 patients, 2101 catheters, 66 CRBSI
CNS CRBSI: Mortality with early (6/21) = late removal (3/9) P = 0.9
Other CRBSI: Mortality with late (6/9) > early removal (7/27) P = 0.05
Mortality not different in pts without septic shock: 18.2 vs. 25%; P = 0.450
Garnacho-Montero J et al. Risk factors and prognosis of catheter-related bloodstream infection in critically ill patients:
a multicenter study. Intensive Care Med. 2008 Dec;34(12):2185-93. 46

47. Topics of today on diagnosis:
1. Maki versus sonication
2. The ins, outs and problems of D T T P
3. Surveillance surface cultures
4. When (not)to pull the trigger/CVC?
47

48. Cost-effectiveness catheter diagnosis infection
Search in pubmed 109
English -9
1992-2012 -15
Not on urinary, intracranial,
peritoneal dialysis catheters -40
Only on specifically on cost-E -39
of CVC infection diagnosis
=1
48

49. General issues:
Too sensitive/aspecific testing
=> Costs of unnecessary treatment
=> Complications of unnecessary treatment
Too insensitive testing
=> Cost of longer hospital stay
=> Cost of missed diagnosis (S. aureus)
49

50. Cost-effectiveness of CRBSI diagnosis:
JCM 1998: Blood Cultures Positive for Coagulase-Negative Staphylo-
cocci: Antisepsis, Pseudobacteremia, and Therapy of Patients
1000 USD additional treatment costs for pt with contaminated BC
JAMA 1991: contaminant blood cultures and resource utilisation: The
true consequences of false pos. results
4500 USD additional treatment costs for pt with contaminated BC
⇒ Attention to sterile technique !
Non-tunneled CVC replacement (1995): 700USD
Blood / tip / surface culture = 35 euro
50

51. QUESTIONS ?
51