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

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

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

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

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

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 ?

Likelihood Ratios and probability of disease JAMA. 2007;297:1583-1593

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: 173-79

Radiographic Findings Alveolar infiltrate Silhouette Atelectasis Fissure-abutment Air bronchogram

Radiology Clinical signs alone or in combo have no predictive value New Infiltrate LR + 1.7 (posterior ~35%) Air Bronchogram LR +3.8 (posterior = ~50%)

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

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

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

CPIS CPIS >6 LR +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 concordance Chastre & Fagon AJRCCM 2002; 165: 867-903.

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

Organisms on Gram Stain Bronchial Aspirate LR + 2.1 Mini BAL LR + 5.3 (Posterior ~60%) BAL LR + 18 (posterior ~80%) < 50% Neutrophils has good LR- 0.05 (Posterior~1.5%)

Microbiological Culture Routine culture of sputum Does not differentiate infection vs. colonization Probability  1 2 3 4 5 6 VAP Log CFUs No VAP CCM 2003; 31: 2544 – 51.

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: 867-903.

Culture Always post-hoc; should have good LR-ve too Tracheal Aspirate LR + 9.6 (Posterior ~ 70%) LR – 0.42 (Posterior ~15%) BAL LR +1.8 (posterior ~35%) LR – 0.8 (posterior ~20%)

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: 867-903. AJRCCM 2002; 166:1320–25 NEJM 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 diagnosis AJRCCM 2002; 166:1320–25

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

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

“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.

Duration of Rx RCT in 402 VAP cases; 8 days Rx (n=197) vs. 15 days Rx (n=205) * JAMA 2003; 290: 2588-98

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: 258-98 D = 15.2% (95% CI: 3.9-26.6)

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: 505-11.

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

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

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?

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;355:2619-30

Resistance Mechanisms Oxa-beta lactamase MBL / Carbepenemase Efflux pumps Porin loss Amp-C Cephalosporinase Plasmid ESBL N E J Med 2008; 358: 1271-81

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

ESBL in the Developing World Site Location %ESBL Klebsiella 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! Klebsiella pneumoniae Carbepenemase Lancet ID 2013; 13: 785–96

NDM; The ‘Desi’ threat The “New Delhi” Metalobetalactamase Lancet ID 2010; 10: 597-602

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

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

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

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

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

Non-cure Rates 2.7% (0.6-5.2) 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

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: 567-70

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

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

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

Drug Delivery in Pneumonia Lung Aerosol vs. IV administration Piglet model Bronchopneumonia Plasma AJRCCM 2002 ; 165: 1375-81

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: 866-84

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

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: 866-84

Lung Mechanics & Aerosol Therapy “Bronchospastic” model “Non-compliant” model 1s 2s 1s 2s (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: 1145-50

VAP Treatment Trials “Clinical Success” No effect on: Mortality Klastersky, 1979 Klastersky, 1972 Brown, 1990 Le Conte, 2000 “Clinical Success” .001 .01 .1 1 10 100 1000 Favours IV OR Favours aerosol No effect on: Mortality Microbiological success Toxicity J Antimic Chem 2007; 60: 1216-26

Critique: The Meta Analyses Studies across “eras”; 1970-2000 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

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: 106-15 No difference in CT resolution of VAP