1. Ventilator Associated Pneumonia Dilemmas in Diagnosis & Treatment
Ram E. Rajagopalan,
MBBS, AB (Int Med) AB (Crit Care)
Department of Critical Care Medicine
SUNDARAM MEDICAL FOUNDATION
Chennai

2. Goals of the Talk Basic epidemiological concerns
Why is diagnosis difficult?
Methods of diagnosis & controversies
Principles of Rx & concerns
__________________________________________________________________
Not
A discussion of risk factors for VAP or prevention

3. Definition of VAP* *Ventilator Associated Pneumonia:
Bacterial pneumonia developing de-novo in a patient who has received mechanical ventilation for at least 48 hours
Intubation for mechanical ventilation increases the risk for pneumonia
3x to 21x !
AJRCCM 2002; 165:

4. Incidence of VAP Worldwide: <20 / 1000 ventilator days
Clinical averages: All ~9%
Med ICU ~17%
Med/ Surg ICU ~9%

5. Developing Nation ICUs
SMF (CDC Definition): 3-month survey
VAP / Patients ventilated (%) = 23.4%(13-37)
VAP / 1000 ventilator days = 27.5 (CI; 14-48)
International Nosocomial Infection Control Consortium (INICC)
24.1 cases /1000 ventilator days
4x as frequent as in the US NNIS
AJRCCM 2002; 165:
Ann Int Med 2006; 145:

6. Developing Nation ICUs (International Nosocomial Infection Control Consortium)
Ventilator Associated Pneumonia:
INICC
Ps. Aeruginosa: 24% Ps. Aeruginosa: 26%
Staph Aureus: 20% Enteric Gm neg: 26%
Enteric Gm neg: 14% Staph Aureus: 22%
Strep Species: 12% Acinetobacter: 20%
AJRCCM 2002; 165:
Ann Int Med 2006; 145:

7. Diagnosis: Which Gold Standard?
Too rigid ?
Histopathology (post-mortem; full lung)
Histopathology (open lung biopsy)
Microbiology (lung aspirate)
Microbiology (distal bronchial sample)
Microbiology (proximal airway)
Clinical
Too lax ?

8. Likelihood Ratios
and probability of
disease
JAMA. 2007;297:

9. Clinical Diagnosis When clinicians are asked to “judge”
the probability of VAP each individual
gives different “weights” to clinical
findings
In a study of clinical diagnosis
Sensitivity = 50 / Specificity = 49
No difference between trainees &
experienced clinicians
AJRCCM 2003; 168:

10. Radiographic Findings
Alveolar infiltrate
Silhouette
Atelectasis
Fissure-abutment
Air bronchogram

11. Radiology Clinical signs alone or in combo have no predictive value
New Infiltrate
LR (posterior ~35%)
Air Bronchogram
LR +3.8 (posterior = ~50%)

12. ARDS, Atelectasis, Contusion Thromboemboli, Effusion
Problems with Dx of VAP
Pulmonary edema
ARDS, Atelectasis, Contusion
Thromboemboli, Effusion
No feature has >65%
predictive accuracy
Clinical Definition
Infiltrate +
Fever (or)
Leukocytosis (or)
Purulent sputum
Only
some
will have VAP
Tracheo-bronchitis
Reactive airways
Non-specific;
Many infectious &
non-infectious
aetiologies
Chest 1996; 110:
AJRCCM 2002; 165:

13. Clinical +Radiology New Infiltrate LR + 1.7 (posterior ~35%)
X-Ray finding +
>2 clinical features
LR +2.8 (posterior ~45%)

14. Improving Clinical Diagnosis
Clinical Pulmonary Infection Score
Temperature (0-2)
WBC Count (0-1)
PaO2/FiO2 (0-2)
Chest X-ray (0-2)
Quality of tracheal secretions (0-2)
Progression of infiltrate (0-2)
Culture of aspirate (0-2)
Overall fair inter-rater agreement
k =0.5
Poor with subjective parameters
k =0.2

15. CPIS CPIS >6 LR +2.1 (posterior = ~40%)
CPIS <6 (in suspected VAP)
LR-ve 0.08 (posterior =<1%)

16. Laboratory Diagnosis Gram stain of tracheal aspirates:
Mod sensitivity (82%) &
Very low specificity (27%)
Gram stain of BAL fluid / distal airway specimens
51% full agreement with PSB cultures
39% partial concordance
Chastre & Fagon
AJRCCM 2002; 165:

17. Obtaining Micro Specimens
Bronchoscopy
“Blind”
Broncho-alveolar
lavage
(BAL)
Need volume >140 cc
Protected
Specimen Brush
(PSB)
Small sample
BAL
Plugged
Telescoping
Catheter
Undirected
sampling

18. Organisms on Gram Stain
Bronchial Aspirate
LR + 2.1
Mini BAL
LR (Posterior ~60%)
BAL
LR + 18 (posterior ~80%)
< 50% Neutrophils has good
LR (Posterior~1.5%)

19. Microbiological Culture
Routine culture of sputum
Does not differentiate infection vs. colonization
Probability 
VAP
Log CFUs
No VAP
CCM 2003; 31: 2544 – 51.

20. Microbiological Culture
Endo-tracheal Aspiration:
“Qualitative EA analysis is of little value
EA with quantitative limits (105) is better
Poorer than distal bronchial cultures”
Distal specimens
Bronchoscopic sampling ideal
Blind (non-bronchoscopy) may miss site
(poorer sensitivity & specificity)
PSB BAL
(103) (104)
Sens ~90 ~80
Spec ~95 ~85
Chastre & Fagon
AJRCCM 2002; 165:

21. Culture Always post-hoc; should have good LR-ve too Tracheal Aspirate
LR (Posterior ~ 70%)
LR – 0.42 (Posterior ~15%)
BAL
LR +1.8 (posterior ~35%)
LR – 0.8 (posterior ~20%)

22. Pre-culture Diagnosis
Elastin fibres (in KOH prep):
Sensitivity 52%, Specificity 100% in non-ARDS
Intracellular Organisms; >5% of BAL cells
(LR + 6.8)
Triggering
Receptor
Expressed on
Myeloid cells
(TREM-1)
AJRCCM 2002; 165:
AJRCCM 2002; 166:1320–25
NEJM 2004; 350:

23. Which is the Best Test?
1. No methodology “proves” VAP with sufficient accuracy.
2. Only CPIS <6 and <50% neutrophils on BAL have ability to R/O
3. Gram stains of deep airway secretions are better than bronchial specimens
4. BAL cultures do not add significant value to diagnosis
AJRCCM 2002; 166:1320–25

24. Options for the Rx of VAP
Clinically
suspected
infection
Attributable mortality
Benefit of early Rx
Minimal adverse effects
Empirical Rx
Bacteriologically
confirmed
Directed Rx

25. Developing Nation ICUs (International Nosocomial Infection Control Consortium)
Ventilator Associated Pneumonia:
INICC
Ps. Aeruginosa: 24% Ps. Aeruginosa: 26%
Staph Aureus: 20% Enteric Gm neg: 26%
Enteric Gm neg: 14% Staph Aureus: 22%
Strep Species: 12% Acinetobacter: 20%
AJRCCM 2002; 165:
Ann Int Med 2006; 145:

26. “De-escalation” Suspect infection Initial Rx wide-spectrum
De-escalate Rx
Lab confirmed
Initial Rx
wide-spectrum
Suspect
infection
Culture-based
de-escalation can
reduce resistance
Chest 2002; 122:2183–2196.

27. Duration of Rx RCT in 402 VAP cases;
8 days Rx (n=197) vs. 15 days Rx (n=205) *
JAMA 2003; 290:

28. Duration of Treatment
In most VAP; reducing Rx to 8 days is not worse than 15 day Rx
But not in non-fermenting Gram negs.
VAP Recurrence (%)
JAMA 2003; 290:
D = 15.2% (95% CI: )

29. Restricted Therapy in VAP
Oft quoted;
A trial aimed
at proving the
value of restricting
empirical therapy
(not “de-escalation”)
Cipro was used as a
compromise placebo
*Singh et al
AJRCCM 2000; 162:

30. Procalcitonin & De-escalation
PRORATA trial
630 intensive care patients RCT
75% with respiratory tract infection
(not VAP)
Abx based on routine vs. PCT guided
No mortality difference (21 vs. 20 at 28 d)
K Antibiotic-free days (14 vs. 11.6; p <0.0001)
Lancet 2010; 375: 463–74

31. BAL / ?Mini BAL Gram Stain Observe Look for other infection
Summary: Dx/Rx of VAP
Suspected VAP
BAL / ?Mini BAL Gram Stain
>6
CPIS
Neutrophil <50%
Neutrophil >50%
<6
Observe Look for other infection
No organism seen
Empirical Rx
Organism seen
Modified Emp. Rx

32. Completed 7 days; non-MDR Pro-calcitonin K / sub-threshold
Summary: Dx/Rx of VAP
Empirical Rx begun
ET secretions
Positive Cx
Negative Cx
De-escalate Rx
Modify Rx
Continue Rx?
Yes
STOP!
Completed 7 days; non-MDR
Pro-calcitonin K / sub-threshold
Sequential CPIS <6?

33. Current Strategy 740 Patients RCT; invasive dx (BAL)
vs. Bronchial aspirate
Mortality identical (18.9 vs. 18.4%)
Targeted Rx same (74.2 vs. 74.6%)
No D in Abx-free days, LOS, MODS scores
N Engl J Med 2006;355:

34. Resistance Mechanisms
Oxa-beta lactamase
MBL / Carbepenemase
Efflux pumps
Porin loss
Amp-C Cephalosporinase
Plasmid ESBL
N E J Med 2008; 358:

35. Current Day Concerns Extended Spectrum Beta Lactamase
Klebsiella / E coli
Carbepenem Resistant Enterobacteriaceae
NDM > KPC
MDR Non-fermenters
Pseudomonas, Acinetobacter
Stenotrophomonas, Burkholderia

36. ESBL in the Developing World
Site Location %ESBL
Klebsiella E. coli
AIIMS, New Delhi1 Tertiary Hospital %
Mathai 10 Tertiary Hosps >60%
KGMC, Lucknow2 Neonatal ICU % 64%
SMF, Chennai Nosocomial: ICU % 82%
SMF, Chennai Comm. Acquired: ICU % 44%
China, Shanghai3 University Hospital % 24%
Latin America4 SENTRY, Pneumonia % 29%
1: Ind J Med Res 2002;115: : J Med Microb 2003; 52: : Zhou Yi Xue Za Zhi 2002;82: : Diag Mic Inf Dis 2002; 44:

37. KPC? Not our kind of poison!
Klebsiella pneumoniae Carbepenemase
Lancet ID 2013; 13: 785–96

38. NDM; The ‘Desi’ threat The “New Delhi” Metalobetalactamase
Lancet ID 2010; 10:

39. Treatment of CRE Colistin and Polymixin B are the only
antibiotics with consistent in-vitro sensitivity
Resistance to Polymixins ~10% reported from Taiwan
Hetero-resistance has been reported amongst
susceptible strains in patients with prior Rx*
No clear RCTs on clinical efficacy
*Antimic & Chemo 2008; 52: 351-2

40. Colistin in Rx of CRE Considering the “concentration” dependent PD
AUC / MIC ratio is the best predictor of success
Modelling studies suggest the need for a loading dose
No RCTs on efficacy

41. Colistin in Rx of CRE Dosing schedule:
Small case series of 25 patients with 28 episodes of CRAB, VAP*
Rx with Colistimethate alone;
Loaded 9 million units (270 mg base) +
4.5 million units (135 mg base) q 12 hours
82% clinical cure
*CID 2012; 54: 1720

42. Optimizing Carbepenems
Time-dependent PD
Duration > MIC best predictor of adequacy
1 gm imipenem infused over 1 hour q8
vs. 500 mg imipenem infused over 3 hours q8
CRAB & Pseudomonas VAP
No clinical outcome differences
54%
75%
Int J Anti Agent 2009; 33: 290-1

43. Deadly Tigecycline! Meta-analysis 10+3 trials 7434 patients Mortality:
Risk dif: 0.7% (p=0.01)
No heterogeneity
No difference with indications
CID 2012; 54: 1699–709

44. Non-cure Rates
2.7% ( )
risk difference for non-cure; implies mortality is due inefficacy of Rx
No heterogeneity
Not affected by indication or comparator Rx
CID 2012; 54: 1699–709

45. Limit Tigecycline: Why?
Bacteriostatic drug
Non-linear protein binding;
Very large Vd (5-10L/kg); rapid clearance from the blood
Standard dose (100mg load + 50 bd) will yield average levels 0.6 mg/ml; very near MIC breakpoints (<0.5mg/ml - <2.0mg/ml)
Ineffective + may have ?intrinsic toxicity
Emergence of resistance during Rx*
Not recommended for primary Rx if alternatives are available.
*CID 2008; 46:

46. 33-67% Microbial eradication
Combination Therapy
Systematic review; MDR Acinetobacter infection
12 studies; 1040 patients
Only 3/12 studies draw a positive conclusion
Carbepenem + Ampi/Sulbactam
Carbepenem + Colistin
Mixed:
Colistin + Rif
Sulbactam +AG
Tigecycline + Colistin + Rif
Tigecycline +Rif + Amik
“The available data preclude a firm recommendation with regard to combination treatment or monotherapy.”
42-77% Clinical Success
33-67% Microbial eradication
Eur J Clin Mic & ID 2014; Epub

47. Aerosol Therapy Direct delivery of Rx to infection site
J Tissue Concentration
Levels >> MIC
K Absorption; K Toxicity
Extrapolating success in Cystic Fibrosis to VAP

48. Drug Delivery to Lung Lung Aerosol vs. IV administration Piglet model
Normal lung
Plasma
AJRCCM 2002 ; 165: 171-5

49. Drug Delivery in Pneumonia
Lung
Aerosol vs. IV
administration
Piglet model
Bronchopneumonia
Plasma
AJRCCM 2002 ; 165:

50. Variability of Drug Delivery
In CF, standardized equipment, 3-log variability in sputum drug (tobramycin) concentration is known
Preferential deposition in ET tube (central)
May be of value in K biofilm formation
Preferential deposition in obstructive airways
Res Care 2007; 52:

51. Implications of Variability
The need to standardize
Delivery systems (nebulizers)
Drug formulation & dose
Ventilatory setting
Patient care during nebulized Rx

52. Vibrating Mesh Nebulizer
2-3x higher output than jet nebulizers
No temperature D
% drug delivered to lung
Efficient, but new.
Validation in progress
Res Care 2007; 52:

53. Lung Mechanics & Aerosol Therapy
“Bronchospastic” model
“Non-compliant” model
1s s s s (Insp. time)
Drug delivered 
Volume Control 1
Volume Control 2
Pressure Control
Lung mechanics & ventilatory settings are strong determinants of aerosol delivery
ICM 2003; 29:

54. VAP Treatment Trials “Clinical Success” No effect on: Mortality
Klastersky, 1979
Klastersky, 1972
Brown, 1990
Le Conte, 2000
“Clinical Success”
Favours IV OR Favours aerosol
No effect on:
Mortality
Microbiological success
Toxicity
J Antimic Chem 2007; 60:

55. Critique: The Meta Analyses
Studies across “eras”;
Microbial pattern & resistance very different
Uncertain methodology (e.g. tracheal instillation)
No mortality / toxicity D
? Effect on resistance
VAP vs. HAP unclear
No evaluation of ventilatory end-points

56. Lu, et al…..continued
Randomized 40 patients (no formal power estimate)
Success : 70 vs. 55% (D 15%) was NS
Failure : 15 vs. 30%; NS
Too small for
Mortality
Vent. Weaning
LOS
AJRCCM 2011; 184:
No difference in CT resolution of VAP