Anti-inflammatory and immunomodulatory strategies in VAP - Lessons from adult Intensive Care

Transcription

1 Anti-inflammatory and immunomodulatory strategies in VAP - Lessons from adult Intensive Care Charles Feldman Professor of Pulmonology Charlotte Maxeke Johannesburg Academic Hospital University of the Witwatersrand

2 Disclosures Acted on the advisory board and/or received honoraria for lectures from pharmaceutical companies manufacturing and/or marketing macrolide antibiotics (Abbott, Aspen-GSK, Pfizer, Sandoz)

3 Adjunctive Therapies in VAP Macrolides Corticosteroids Statins Nebulised antibiotics Other

4 Macrolides Assessed for eligibility (n=218) PLACEBO Allocated to intervention (n=100) Received allocated intervention (n=100) Enrolment Randomisation Allocation Excluded (n=18) Not meeting inclusion criteria (n=19) Refused to participate (n=0) Other reasons (n=0) CLARITHROMYCIN Clarithromycin 1g IVI for 3 days Allocated to intervention (n=100) Received allocated intervention (n=100) Lost to follow-up (n=0) Discontinued intervention (n=0) Follow-up Lost to follow-up (n=0) Discontinued intervention (n=1) Reason for discontinuation: SAE: bronchospasm Analysed (n=100) Excluded from analysis (n=0) Analysis Analysed (n=100) Excluded from analysis (n=0) Giamarellos-Bourboulis EJ et al. Clin Infect Dis 2008;46:

5 Cumulative Incidence of Resolution of VAP 80% % of resolved cases 60% 40% 20% Clarithromycin Placebo 0% Time (days) Giamarellos-Bourboulis EJ et al. Clin Infect Dis 2008;46:

6 Cumulative Time to Weaning from MV 80% % of de-intubated patients 60% 40% 20% Clarithromycin Placebo 0% Time (days) Giamarellos-Bourboulis EJ et al. Clin Infect Dis 2008;46:

7 Cumulative Time to Death from Sepsis 80% % of dead patients 80% 60% 40% Placebo Clarithromycin 20% 0% Time (days) Giamarellos-Bourboulis EJ et al. Clin Infect Dis 2008;46:

8 Review of Macrolides - Key Points Macrolides inhibit production of proinflammatory cytokines in animal models of acute lung infection Macrolides inhibit quorum sensing of P. aeruginosa that allows creation of biofilms and firm adherence to the airways Retrospective data suggest that addition of a macrolide has survival benefit in severe CAP One randomised clinical study in patients with VAP proved that administration of intravenous clarithromycin was accompanied by earlier resolution of pneumonia Mouktaroudi M et al. Curr Opin Infect Dis 2012; 25:

9 Sites of Action that Make Macrolides Promising Adjunctive Options for Nosocomial Infections mucin IL-1β, IL-6, IL-8 Airway epithelium Alveolar space Macrophage TNFα, IL-6 influx by circulating macrophages Macrolides P. aeruginosa Circulating mononuclear cells lasl+rhla expression epithelial junctions lymphocyte apoptosis TNFα Mouktaroudi M et al. Curr Opin Infect Dis 2012; 25:

10 Main Effects of Treatment with Clarithromycin Serum ShMODS IL-10.TNFα Monocytes Non-ShMODS mcd86 TNFα Non-ShMODS TNFα Non-ShMODS mtrem-1 TNFα ShMODS mtrem-1 ShMODS Apoptosis mcd86 TNFα IL-6 ShMODS IL Rx Rx Rx Spyridaki A et al. Antimicrob Agents Chemother 2012; 56:

11 Comparative Survival until day 90 of Patients Enrolled RCT of clarithromycin 1g for 3 days (n=100) versus placebo (n=100) describing long-term mortality and costs Survival (%) Placebo Clarithromycin All cause mortality was 60% in placebo arm and 43% in C arm (p=0.023) 20 Comparisons day 29 to day 90 X 2 P-value 0 Log-rank (Mantel-Cox) Breslow (Generalised Wilcoxon) Tarone-Ware < < < Survival (days) Patients alive Placebo Clarithromycin Day Day Day Day Day Day Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

12 Comparative Cumulative Hospitalisation Cost Cumulative cost of hospitalisation ( ) Mean cumulative costs on day 25 (p=0.048) and on day 45 (p=0.011) were significantly different Placebo 100 patients Clarithromycin 100 patients P< Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

13 Comparative Cumulative Hospitalisation Cost Cumulative cost of hospitalisation ( ) Placebo 51 patients Clarithromycin 62 patients P< Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

14 Comparative Cumulative Hospitalisation Cost Antimicrobials patients Cumulative cost of hospitalisation ( ) Clarithromycin Placebo Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

15 Comparative Cumulative Hospitalisation Cost Laboratory and Radiology patients Cumulative cost of hospitalisation ( ) Clarithromycin Placebo Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

16 Comparative Cumulative Hospitalisation Cost Interventions patients Cumulative cost of hospitalisation ( ) Placebo Clarithromycin Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

17 Comparative Cumulative Hospitalisation Cost Hospital beds patients Cumulative cost of hospitalisation ( ) Placebo Clarithromycin Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

18 Cumulative Cost of Drugs other than Antimicrobials patients Cumulative cost of hospitalisation ( ) Placebo Clarithromycin P< Days of hospitalisation Tsaganos T et al. Antimicrob Agents Chemother 2016; 60:

19 Systemic Corticosteroid Treatment Chronic use Acute exacerbation of previous condition Treatment of new state Treatment of pneumonia Hospital admission New diagnosis HAP/VAP diagnosis Ranzani et al, Clin Pulm Med 2015; 22:

20 Ranzani OT et al. Critical Care Med 2012; 40: Corticosteroids Screened patients after daily rounds in 6 ICUs (n = 6 420) Patients with ICU-acquired pneumonia (n = 323) Patients analysed (n = 316) Not analysed (n = 07): Missing variables (n = 07) Without systemic steroid group (n = %) Systemic steroid group (n = %) NV-ICUAP (n = 81-42%) VAP (n = %) NV-ICUAP (n = 46-37%) VAP (n = 79-63%) Required intubation (n = 46-57%) Oxygen support (n = 35-43%) Required intubation (n = 32-70%) Oxygen support (n = 14-30%) 3 lost to follow-up after hospital discharge (censored) 0 lost to follow-up after hospital discharge (censored) Deaths at 28 days (n = 54-28%) Deaths at 28 days (n = 49-39%)

21 Characteristics of Corticosteroid Use on Diagnosis of ICU-acquired Pneumonia Indication n, (%) Exacerbation of respiratory diseases Neurological disorders Septic shock Long-term use of steroids Multiple reasons Others Administered drug n, (%) Methylprednisolone Dexamethasone Hydrocortisone Prednisolone Prevalence of long-term use, n (%) Cumulative dose, median (interquartile range) Length of treatment, days Total dose, mg Average daily dose, mg/day 41 (33) 34 (27) 18 (14) 12 (10) 11 (9) 9 (7) 67 (54) 34 (27) 22 (18) 2 (2) 29 (23) 6 (3-10) 380 ( ) 50 (34-142) Ranzani OT et al. Critical Care Med 2012; 40:

22 Outcome Variables No treatment (n = 191) Corticosteroid (n = 125) p Septic shock after diagnosis, n (%) Nonventilator ICU-acquired pneumonia that needed mechanical ventilation after diagnosis, n (%) 27 (14) 11 (9) (57) 32 (70) 0.22 Nonresponsive to treatment, n (%) Appropriate empiric treatment, n (%) 106 (56) 98 (83) 72 (58) 69 (78) Length of mechanical ventilation, d Median (IQR) 13 (7-22.5) 14 (9-24) 0.44 Mean ± SD 18 ± ± Ventilator-free days at 28, d Median (IQR) 3.5 ( ) 0 (0-21) 0.41 Mean ± SD 10 ± 11 9 ± Length of ICU stay, d Median (IQR) 16 (10-29) 15 (9.5-29) 0.96 Mean ± SD 22 ± ± Length of hospital stay, d Median (IQR) 37 (19-59) 38 (20-55) 0.89 Mean ± SD 45 ± ± Ranzani OT et al. Critical Care Med 2012; 40:

23 Ranzani OT et al. Critical Care Med 2012; 40: day Survival of Patients in ICU Survival Corticosteroids No treatment No. patients at risk Corticosteroids 125 No treatment Time (days since pneumonia diagnosis) Log-rank test: P value:

24 Ranzani OT et al. Critical Care Med 2012; 40: day Mortality - Cumulative Dosage of Corticosteroid Treatment of 125 patients with Previous Corticosteroids 1.0 Risk of 28-day mortality Propensity-adjusted association: Adj. HRL 1.610; 95% CI ; p = % IC Risk of death 95% IC Cumulative dosage of steroid (mg/d)

25 Days on Corticosteroid Treatment before Clinical Suspicion % CI Risk for high bacterial burden Adj: HR: 2.896; 95% CI ; p = (per 10 mg/day in methylprednisolone equivalent) Days on corticosteroid treatment before clinical suspicion 95% CI Ranzani OT et al. Critical Care Med 2012; 40:

26 Etiological Diagnosis of Pneumonia No treatment (n = 191) Corticosteroid (n = 125) p Any respiratory track sample, n (%) Etiologic diagnosis, n (%) Finally definite by: 182 (95) 116 (61) 118 (94) 88 (70) Tracheobronchial aspirates Invasive method Sputum Other Potentially drug-resistant bacteria, n (%) Polymicrobial pneumonia, n (%) 88 (77) 19 (16) 4 (3) 5 (4) 53 (28) 15 (8) 73 (83) 13 (15) 2 (2) - 34 (27) 13 (10) > Non-fermenting Gram-negative bacilli, n (%) Pseudomonas aeruginosa Enteric Gram-negative bacilli, n (%) Staphylococcus aureus, n (%) Methicillin sensitive Methicillin resistant 35 (18) 32 (17) 37 (19) 37 (19) 21 (11) 16 (8) 34 (27) 31 (25) 23 (18) 17 (14) 14 (11) 3 (2) > S. pneumoniae, n (%) H. influenzae, n (%) Other bacteria Aspergillus fumigatus, n (%) 4 (2) 7 (4) 9 (5) 1 (1) 5 (4) 1 (1) 7 (6) 5 (4) Ranzani OT et al. Critical Care Med 2012; 40:

27 Ranzani OT et al. Critical Care Med 2012; 40: Serum Levels of Inflammatory Biomarkers C-reactive protein day 1, mg/dl No treatment Corticosteroid p 15.6 ( ) 10.2 ( ) C-reactive protein day 3, mg/dl 12.5 ( ) 7.5 ( ) <0.001 Procalcitonin day 1, ng/ml 0.45 ( ) 0.30 ( ) Procalcitonin day 3, ng/ml 0.38 ( ) 0.21 ( ) Midregional proadrenomedullin day 1, nmol/l 1.38 ( ) 1.10 ( ) 0.19 Midregional proadrenomedullin day 3, nmol/l 1.39 ( ) 0.96 ( ) IL-6 day 1, pg/ml 192 (84-492) 94 (24-239) <0.001 IL-6 day 3, pg/ml 104 (54-275) 56 (13-149) IL-8 day 1, pg/ml 104 (63-205) 79 (52-162) 0.10 IL-8 day 3, pg/ml 85 (42-168) 79 (45-162) 0.96 Tumour necrosis factor-α day 1, pg/ml 9 (5-16) 6 (4-9) Tumour necrosis factor-α day 3, pg/ml 9 (6-19) 6 (4-11) 0.003

28 Total admissions in ICU (01/01/ /01/2013) n = 5923 Statins Total suspected VAP episodes (01/01/ /01/2013) n = 631 Total analysed suspected VAP episodes n = 349 Excluded because: Inclusion into a clinical trial testing statins (n=52) Missing data (n=22) CPIS < 5 points and ATB D1 = 0 (n=208) n = 282 Statin naïve patients n = 256 Statin previous users n = 93 Drug discontinued after ICU admission n = 41 Drug continued after ICU admission n = 52 Bruyere R et al. Critical Care 2014; 18: R83

29 Survival of Patients with Suspected VAP Prior Statin Use Naïve patients Cumulative survival Previous users Time elapsed since VAP onset (days) Bruyere R et al. Critical Care 2014; 18: R83

30 Independent Predictors of 30-day Mortality in Patients with Suspected VAP Hazard ratio 95% CI P Steroids during VAP <0.01 Cirrhosis <0.01 Age <0.01 SAPS II <0.01 SOFA day <0.01 Statin prior exposure Bruyere R et al. Critical Care 2014; 18: R83

31 Patients with Suspected VAP Drug Continuation Statin continuation Cumulative survival Statin discontinuation Time elapsed since VAP onset (days) Bruyere R et al. Critical Care 2014; 18: R83

32 Independent Predictors of 30-day Death in the Statin Previous Users Subset of Patients with Suspected VAP Hazard ratio 95% CI P Age <0.01 SOFA day 1 value Statin continuation after ICU admission Bruyere R et al. Critical Care 2014; 18: R83

33 Independent Predictors of 30-day Death in the Statin Previous Users Subset of Patients with Clinically Suspected VAP and Tracheal Aspirate Positive Culture Hazard ratio 95% CI P Age <0.01 SOFA day 1 value <0.01 Statin continuation after ICU admission Bruyere R et al. Critical Care 2014; 18: R83

34 1303 Patients assessed for eligibility 1003 Excluded 150 Elevated ALT, AST, or CK level 149 Statins given after intubation 118 Previous VAP episode 110 Enrolled in another trial within 30 days 79 Decision for treatment limitation 77 Treatment contraindicating statins 55 Terminal illness 50 Liver failure 41 ICU too busy 30 Next of kin declined consent 30 Organisational failure 29 Bone marrow asplasia 29 Continuous gastric tube aspiration 21 No gastric tube 8 Younger than 18 years 2 Pregnant 25 Other 300 Randomised 147 Randomised to receive simvastatin (60mg) 147 Received simvastatin as randomised 147 Randomised to receive placebo 147 Received placebo as randomised 147 Included in analysis 7 Excluded 4 Withdrew consent 3 Denied consent 138 Included in analysis 9 Excluded 6 Withdrew consent 3 Denied consent Papazian L et al. JAMA 2013; 310:

35 Proportions of Non-survivors 25 Probability of death, % Simvastatin Placebo 0 0 No. at risk Simvastatin 146 Placebo Time from randomisation (days) Papazian L et al. JAMA 2013; 310:

36 Main Study Outcomes No. (%) [95% CI] Outcome Simvastatin (n = 146) Placebo (n = 146) Between-Group Difference, % (95% CI) P Mortality Day 28 (primary outcome) 31 (21) [15, 29] 21 (15) [10, 22] 6 (-3, 15) 0.10 Day (15) [10, 22] 16 (12) [7, 18] 3 (-5. 11) 0.39 ICU 38 (26) [20, 34] 30 (22) [16, 29] 4 (-5, 14) 0.40 Hospital 43 (30) [23, 37] 38 (28) [21, 36] 2 (-8. 12) 0.72 Papazian L et al. JAMA 2013; 310:

37 Nebulised Antibiotics in MV Patients The safety of nebulization of antibiotics has been proven in numerous studies Efficacy as adjunctive treatment to intravenous regimens or as monotherapy has been demonstrated in ventilator-associated pneumonia or ventilatorassociated tracheobronchitis due to MDR or susceptible pathogens However, due to the heterogeneity of studies, multiple meta-analyses fail to demonstrate a clear effect Clarification of indications, standardisation of technique and implementation of clinical practice guidelines, based on new large-scale trials will lead to the optimal use of nebulized antibiotics Poulakou G et al. Expert Rev Anti Infect Ther 2017 [E-Pub]

38 Role of Aerosolised Colistin in VAP: Systematic Review and Meta-analysis Potentially relevant studies identified and screened for retrieval from electronic search: 361 Studies excluded on basis of title or abstract: 328 Studies retrieved in full text: 33 Studies included in the systematic review: 16 Studies excluded based on exclusion criteria: 17 No clear definition of VAP: 4 Reviews: 3 Less than 5 patients: 3 No separate data on AS colistin: 2 No separate data on VAP: 2 No data on outcomes of interest: 1 Use of AS polymyxin B: 1 Patients with ventilator-assisted tracheobronchitis: 1 Single-arm studies (systematic review only): 8 Comparative studies (meta-analysis): 8 Valachis A et al. Crit Care Med 2015; 43:

39 Clinical Response: IV Colistin versus AS and IV Colistin Adjunctive AS colistin IV colistin Odds Ratio Odds Ratio Study or subgroup Events Total Events Total Weight M-H Fixed 95% CI M-H Fixed 95% CI Doshi 2013 Kalin 2012 Kofteridis 2010 Korbila 2010 Naesens 2011 Péres-Pedrero 2011 Rattanaumpawan 2010 Tumbarello % 11.1% 11.7% 11.2% 0.9% 1.3% 21.2% 28.7% 1.86 (0.82, 4.21) 0.24 (0.05, 1.05) 1.56 (0.62, 3.94) 2.53 (1.11, 5.76) 5.25 (0.49, 5.80) 3.00 (0.26, 34.57) 0.92 (0.42, 2.02) 1.86 (1.05, 3.27) Total events (95% CI) Total events % 1.57 (1.14, 2.15) Heterogeneity: Chi 2 = 11.05, df = 7 (P = 0.14). I 2 = 37% Test for overall effect: Z = 2.77 (P = 0.006) Favours IV colistin Favours AS + IV colistin Valachis A et al. Crit Care Med 2015; 43:

40 Overall Mortality: IV Colistin versus AS and IV Colistin AS + IV colistin IV colistin Odds Ratio Odds Ratio Study or subgroup Events Total Events Total Weight M-H Fixed 95% CI M-H Fixed 95% CI Doshi 2013 Kalin 2012 Kofteridis 2010 Korbila 2010 Naesens 2011 Rattanaumpawan 2010 Tumbarello % 4.5% 14.9% 16.0% 4.8% 11.5% 29.4% 0.46 (0.20, 1.06) 1.41 (0.40, 4.91) 0.42 (0.17, 1.07) 0.83 ( ) 0.05 (0.00, 1.17) 1.10 (0.50, 2.44) 0.89 (0.51, 1.54) Total events (95% CI) Total events % 0.74 (0.54, 1.01) Heterogeneity: Chi 2 = 7.98, df = 6 (P = 0.24). I 2 = 25% Test for overall effect: Z = 1,88 (P = 0.06) Favours AS + IV colistin Favours IV colistin 100 Valachis A et al. Crit Care Med 2015; 43:

41 Anti-inflammatory Therapy in VAP Macrolides - may accelerate resolution of VAP and weaning from MV in surviving patients and delaying death in those who die of sepsis and possibly offer long-term survival benefit and reduction of costs of hospitalisation Corticosteroids - should be used cautiously in ICU patients since this treatment is strongly associated with increased risk of death in ICU-acquired pneumonia Statins - prior use and continuation in ICU, after adjusting for confounders, was associated with better survival in VAP patients while adjunctive statin therapy in patients with suspected VAP did not improve 28-day survival

42 CS Adjunctive Therapy in Children Paediatric severe sepsis (ICD-9 plus mechanical ventilation and vasoactive infusions) overall mortality was 24% and use of CS, older age and haematologic-oncologic diagnoses were independent predictors of mortality History of CS use in clinical medicine has been colourful, noisy and always controversial and the safety and efficacy of CS as a general adjunctive therapy for paediatric septic shock has not been established Assessment of adjunctive CS on genome response in paediatric septic shock documented that genes corresponding to adaptive immunity-related signalling were down-regulated significantly in the CS relative to controls, with a similar pattern with genes corresponding to glucocorticoid receptor signalling pathways Markovitz BP et al. Pediatr Crit Care Med 2005; 6: Zimmerman JJ et al. Pediatr Crit Cae Med 2007; 8: Wong HR et al. Am J Respir Crit Care Med 2014; 189:

43 CS Adjunctive Therapy in Children All steroid drug classes posses biological plausibility to offer a beneficial clinical effect among children with septic shock, but none has undergone rigorous, prospective assessment in a large, high-quality paediatric interventional trial Zimmerman JJ. Pediatr Clin North Am 2017; 64:

44 Statin Adjunctive Therapy in Children Kawasaki disease is treated in 10-20% of children with IVIG and have an almost 9-fold increased risk of CAA Approximately 80-90% of children who go on to CAA have abnormal coronary artery dimension on their first echo which can identify high-risk cases Additional adjunctive therapies suggested include CS, TNF inhibitors, calcineurin inhibitors and IL-1 blockers Animal studies have suggested that statins may be beneficial in blocking CAA progress but it is unlikely that these therapies will be studied in large randomised controlled trials due to sample size and funding constraints Campbell AJ et al. J Infect 2016; 72 suppl: S1-S5

45 Colistin Adjunctive Therapy in Children Aerosolised colistin (5mg/kg base activity of aerosolised colistin methanesulfonate every 12h for 14, 14, and 16 days) in two pre-term and one term neonate with Acinetobacter baumannii and Pseudomonas aeruginosarelated VAP unresponsive to previous antibiotics was found to be safe and tolerable Aerosolised colistin (1,000,000 IU (33.4mg) twice daily) as monotherapy for pre-term infants with A. baumannii-related VAP were cured with no clinical or laboratory adverse events Both authors indicate the need for larger, controlled trials to establish the dose and corroborate the findings Celik IH et al. Eur J Pediatr 2012; 171: Kang CH et al. Perdiatr Pulmonol 2014; 49:

46 Pulmozyme Adjunctive Therapy in Children Prospective, randomised, blinded pilot study to compare adjunctive dornase alfa therapy (2.5mg nebulised via ETT) to sham therapy in infants with VAPI showed a trend to decreased oxygen requirements which did not reach statistical significance with no side effects Scala M et al. Pediatr Pulmonol 2017; 52:

47 Increasing antibiotic consumption Greater infection related patient morbidity and mortality Greater emergence of antibiotic resistance Increased administration of inappropriate initial therapy Kollef M. Chest 2016 [E-pub]