Ventilator Associated Pneumonia Dilemmas in Diagnosis & Treatment

Ventilator Associated Pneumonia Dilemmas in Diagnosis & Treatment

Ram E. Rajagopalan,MBBS, AB (Int Med) AB (Crit Care)

Department of Critical Care Medicine

SUNDARAM MEDICAL FOUNDATIONChennai

Goals of the Talk

Basic epidemiological concernsWhy is diagnosis difficult?Methods of diagnosis & controversies Principles of Rx & concerns__________________________________________________________________

Not A discussion of risk factors for VAP or prevention

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; 165:867-903

Incidence of VAPWorldwide: <20 / 1000 ventilator days

0

5

10

15

20

25

30

Inci

den

ce (

%)

1 2 4 6 8 10 12 14

Ventilator Days

VAP Incidence

Clinical averages: All ~9%Med ICU ~17%Med/ Surg ICU ~9%

Developing Nation ICUs

24.1 cases /1000 ventilator days

4x as frequent as in the US NNIS

AJRCCM 2002; 165: 867-903Ann Int Med 2006; 145: 582-91

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)

Developing Nation ICUs(International Nosocomial Infection Control Consortium)

Ventilator Associated Pneumonia:

INICCPs. 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: 867-903

Ann Int Med 2006; 145: 582-91

Diagnosis: Which Gold Standard?Histopathology (post-mortem; full lung)

Histopathology (open lung biopsy)

Microbiology (lung aspirate)Microbiology (distal bronchial sample)

Microbiology (proximal airway)

Clinical

Too rigid ?

Too lax ?

JAMA. 2007;297:1583-1593

Likelihood Ratiosand probability ofdisease

Clinical Diagnosis

AJRCCM 2003; 168: 173-79

When clinicians are asked to “judge”the probability of VAP each individualgives different “weights” to clinical findings

In a study of clinical diagnosis Sensitivity = 50 / Specificity = 49 No difference between trainees &

experienced clinicians

Radiographic FindingsAlveolar infiltrate

Air bronchogram

Silhouette

AtelectasisFissure-abutment

Radiology

Clinical signs alone or in combo have no predictive value

New InfiltrateLR + 1.7 (posterior ~35%)

Air BronchogramLR +3.8 (posterior = ~50%)

Problems with Dx of VAP

Clinical DefinitionInfiltrate +Fever (or)Leukocytosis (or)Purulent sputum

Chest 1996; 110:1025-34AJRCCM 2002; 165: 867-903

Pulmonary edemaARDS, Atelectasis, Contusion

Thromboemboli, Effusion

No feature has >65%predictive accuracy

Non-specific;Many infectious &

non-infectious aetiologies

Tracheo-bronchitisReactive airways

Onlysome

will have VAP

Clinical +RadiologyNew InfiltrateLR + 1.7 (posterior ~35%)

X-Ray finding + >2 clinical featuresLR +2.8 (posterior ~45%)

Improving Clinical DiagnosisClinical 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

CPIS

CPIS >6LR +2.1 (posterior = ~40%)

CPIS <6 (in suspected VAP)LR-ve 0.08 (posterior =<1%)

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 concordanceChastre & FagonAJRCCM 2002; 165: 867-903.

Obtaining Micro Specimens

Bronchoscopy “Blind”

Broncho-alveolarlavage(BAL)

Need volume >140 cc

ProtectedSpecimen Brush

(PSB)

Small sample

BAL PluggedTelescoping

CatheterUndirectedsampling

Organisms on Gram StainBronchial Aspirate LR + 2.1

Mini BALLR + 5.3 (Posterior ~60%)

BALLR + 18 (posterior ~80%)

< 50% Neutrophils has goodLR- 0.05 (Posterior~1.5%)

Microbiological Culture

Prob

abili

ty

1 2 3 4 5 6

VAP

Log CFUs

No VAP

CCM 2003; 31: 2544 – 51.

Routine culture of sputumDoes not differentiate infection vs. colonization

Microbiological Culture

PSB BAL(103) (104)

Sens ~90 ~80Spec ~95 ~85

Endo-tracheal Aspiration:“Qualitative EA analysis is of little valueEA with quantitative limits (105) is betterPoorer than distal bronchial cultures”

Distal specimens Bronchoscopic sampling idealBlind (non-bronchoscopy) may miss site(poorer sensitivity & specificity)

Chastre & FagonAJRCCM 2002; 165: 867-903.

CultureAlways post-hoc; should have good LR-ve too

Tracheal AspirateLR + 9.6 (Posterior ~ 70%)LR – 0.42 (Posterior ~15%)

BALLR +1.8 (posterior ~35%)LR – 0.8 (posterior ~20%)

Pre-culture DiagnosisElastin fibres (in KOH prep): Sensitivity 52%, Specificity 100% in non-ARDS

Intracellular Organisms; >5% of BAL cells(LR + 6.8)

TriggeringReceptorExpressed onMyeloid cells(TREM-1)

AJRCCM 2002; 165: 867-903.AJRCCM 2002; 166:1320–25NEJM 2004; 350: 451-8.

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 diagnosisAJRCCM 2002; 166:1320–25

Options for the Rx of VAP

Bacteriologicallyconfirmed

Empirical Rx

Directed Rx

Clinicallysuspectedinfection

Attributable mortalityBenefit of early RxMinimal adverse effects

Developing Nation ICUs(International Nosocomial Infection Control Consortium)

Ventilator Associated Pneumonia:

INICCPs. 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: 867-903

Ann Int Med 2006; 145: 582-91

“De-escalation”

Chest 2002; 122:2183–2196.

De-escalate Rx

Lab confirmed

Initial Rxwide-spectrum

Suspectinfection

Culture-basedde-escalation can reduce resistance

Duration of RxRCT in 402 VAP cases; 8 days Rx (n=197) vs. 15 days Rx (n=205)

010203040506070

%

8-day

15-day

*

*

*

JAMA 2003; 290: 2588-98

Duration of Treatment

JAMA 2003; 290: 258-98 D = 15.2% (95% CI: 3.9-26.6)

In most VAP; reducing Rx to 8 days is not worse than 15 day Rx

But not in non-fermenting Gram negs.

VAP

Rec

urre

nce

(%)

Restricted Therapy in VAP

*Singh et alAJRCCM 2000; 162: 505-11.

Oft quoted;

A trial aimedat proving thevalue of restrictingempirical therapy(not “de-escalation”)

Cipro was used as acompromise placebo

Procalcitonin & De-escalation

Lancet 2010; 375: 463–74

PRORATA trial

630 intensive care patients RCT75% 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)

Summary: Dx/Rx of VAPSuspected VAP

CPIS

Observe Look for other

infection

BAL / ?Mini BAL Gram Stain

Neutrophil <50%<6

>6

Neutrophil >50%

No organism seen

Empirical Rx

Organism seenModified Emp. Rx

Summary: Dx/Rx of VAPEmpirical Rx begun

Positive Cx Negative Cx

De-escalate RxModify Rx

Continue Rx?

Completed 7 days; non-MDRPro-calcitonin K / sub-threshold

Sequential CPIS <6?

ET secretions

YesSTOP!

Current Strategy

N Engl J Med 2006;355:2619-30

740 Patients RCT; invasive dx (BAL)vs. Bronchial aspirateMortality identical (18.9 vs. 18.4%)Targeted Rx same (74.2 vs. 74.6%)No D in Abx-free days, LOS, MODS scores

Resistance Mechanisms

Oxa-beta lactamaseMBL / Carbepenemase

Efflux pumps

Porin loss

Amp-C CephalosporinasePlasmid ESBL

N E J Med 2008; 358: 1271-81

Current Day Concerns

Extended Spectrum Beta Lactamase Klebsiella / E coli

Carbepenem Resistant EnterobacteriaceaeNDM > KPC

MDR Non-fermenters Pseudomonas, AcinetobacterStenotrophomonas, Burkholderia

ESBL in the Developing World

Site Location %ESBLKlebsiella E. coli

AIIMS, New Delhi1 Tertiary Hospital 80% -Mathai 10 Tertiary Hosps. - >60%KGMC, Lucknow2 Neonatal ICU 86% 64%SMF, Chennai Nosocomial: ICU 84% 82%SMF, Chennai Comm. Acquired: ICU 53% 44%

China, Shanghai3 University Hospital 51% 24%Latin America4 SENTRY, Pneumonia 44% 29%

1: Ind J Med Res 2002;115:153-7 2: J Med Microb 2003; 52: 421-5 3: Zhou Yi Xue Za Zhi 2002;82:1476-9 4: Diag Mic Inf Dis 2002; 44: 301-11

KPC? Not our kind of poison!

Lancet ID 2013; 13: 785–96 Klebsiella pneumoniae Carbepenemase

NDM; The ‘Desi’ threat

Lancet ID 2010; 10: 597-602

The “New Delhi” Metalobetalactamase

Treatment of CRE

Colistin and Polymixin B are the onlyantibiotics 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

Considering the “concentration” dependent PDAUC / MIC ratio is the best predictor of success

Modelling studies suggest the need for a loading doseNo RCTs on efficacy

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 hours82% clinical cure

Colistin in Rx of CRE

*CID 2012; 54: 1720

Optimizing CarbepenemsTime-dependent PDDuration > MIC best predictor of adequacy

1 gm imipenem infused over 1 hour q8vs. 500 mg imipenem infused over 3 hours q8CRAB & Pseudomonas VAPNo clinical outcome differences

54%

75%

Int J Anti Agent 2009; 33: 290-1

Deadly Tigecycline!

CID 2012; 54: 1699–709

Meta-analysis10+3 trials7434 patients

Mortality:Risk dif: 0.7% (p=0.01)

No heterogeneityNo difference with indications

Non-cure Rates

CID 2012; 54: 1699–709

2.7% (0.6-5.2)risk difference for non-cure; implies mortality is due inefficacy of Rx

No heterogeneityNot affected by indication or comparator Rx

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 toxicityEmergence of resistance during Rx*

Not recommended for primary Rx if alternatives are available.

*CID 2008; 46: 567-70

Combination TherapySystematic review; MDR Acinetobacter infection

12 studies; 1040 patientsOnly 3/12 studies draw a positive conclusion

Carbepenem + Ampi/SulbactamCarbepenem + ColistinMixed: Colistin + RifSulbactam +AGTigecycline + Colistin + RifTigecycline +Rif + Amik

“The available data preclude a firm recommendation with regard to combination treatment or monotherapy.”

42-77% Clinical Success

33-67% Microbial

eradicationEur J Clin Mic & ID 2014; Epub