Management of VAP. Dr Ram Gopalakrishnan

Transcription

1 Management of VAP Dr Ram Gopalakrishnan

2 Disclosures Have received travel grants / advisory board honorariums / lecture fees from: Pfizer GSK MSD Cipla Emcure Novartis

3

4 Ventilator associated pneumonia Attributable mortality is 13%, mainly due to increased length of ICU stay. Always diagnose clinically & then look at cultures to guide antibiotic selection Positive ET culture can reflect Colonization Tracheo-bronchitis VAP Do CT chest when Suspicion high but CXR normal Immunocompromised host Atelectasis, effusions, CHF, ARDS can mimic

5 CPIS score

6 Modified CDC criteria for VAP Am J Infect Control. 2008;36:

7 Diagnosis of VAP Role of Gram stain: absence of bacteria on Gram stain had a high negative predictive value Negative predictive value of Gram stain for a VAP prevalence of 20% 30% was 91% (Clin Infect Dis. (2012) 55 (4): ) positive Gram stain correlated poorly with organisms recovered in culture positive predictive value of Gram stain was only 40%. No additional role above clinical criteria for diagnosis for Clinical pneumonia severity index (CPSI) score Soluble Triggering Receptor Expressed on Myeloid Cells (strem-1) PCT CRP

8 Diagnosis of VAP Guidelines recommend non-invasive sampling with semi-quantitative cultures to diagnose ET tube cultures appropriate No role for bronchoscopy (BAL,PSB) or mini-bal in general PSB With <10 3 CFU/mL BAL With <10 4 CFU/mL If negative, antibiotics should be withheld rather than continued

9 CritCare Med 2013 Mar 29

10 Ventilator associated tracheo-bronchitis (VAT) preceding or evolving into VAP VAP Fever Leukocytosis Purulent tracheal secretions Endotracheal culture positive VAT Fever Leukocytosis Purulent tracheal secretions Endotracheal culture positive CXR shows infiltrate BAL has >10,000 colony count May be hypoxemic or hemodynamically unstable Conventional empiric broad, then narrow therapy No infiltrate BAL has <10,000 colony count Stable? Targeted narrow spectrum short course therapy

11 VAT VAT = VAP infiltrate hypoxemia 1/3 of VAT leads to VAP Treating VAT reduces attributable morbidity (length of stay, cost) but not mortality? Targeted narrow spectrum short course therapy? Aeronebs IDSA: no antibiotics

12 Early vs late onset HAP/VAP Early-onset HAP (and VAP) defined as pneumonia occurring within the first 4 days of hospitalization (or endotracheal intubation) usually carries a better prognosis more likely to be caused by antibiotic-sensitive bacteria eg S.pneumoniae, H.influenzae, MSSA Late-onset HAP and VAP (day 5 or thereafter) more likely to be caused by MDR pathogens higher morbidity and mortality Respiratory viruses appear to be a frequent cause of nosocomial pneumonia (Respir Med 2017 Jan 122:76)

13

14 VACs most VACs are attributable to pneumonia, pulmonary edema, atelectasis, or acute respiratory distress syndrome new definitions do not include radiographic criteria inclusion of an antibiotic criterion in the definition of IVAC will provide hospitals with a routine, widely reportable benchmark for the prescribing of antibiotics in their ICUs

15 Guidelines support obtaining blood cultures & lower respiratory secretions May be pathogenic: Pneumococcus S. aureus Pseudomonas Enterobacteriaceae Non-fermenters Look at the colony count and clinical features Always pathogenic: M. tb Pneumocystis Cryptococcus Histoplasma Strongyloides Rarely pathogenic: CoNS Enterococcus Viridans streptococci Candida

16 Empiric antibiotic management of VAP Empiric therapy for Acinetobacter Pseudomonas ESBL producers Carbapenem resistant organisms Staph aureus (MSSA) IDSA recommends that all hospitals regularly generate and disseminate a local antibiogram Use two agents from different classes if >10% of gram-negative isolates are resistant MRSA coverage only if >10% 20% ofs. aureus isolates are methicillin resistant Aminoglycosides do not reach high lung tissue levels, use only till bacteremia excluded

17

18

19 Which antibiotic? Gram negative coverage Anti-pseudomonal carbapenem Piperacillin-tazobactam Cefoperazone-sulbactam Colistin Tigecycline (in combination) Fosfomycin Minocycline Gram positive coverage Vancomycin Teicoplanin Clindamycin Linezolid

20 Once sensitivities are known De-escalate to narrower spectrum agent on receipt of sensitivities Corticosteroids increase mortality 2.5 fold (Crit Care Med 2012;20:2552)

21 Rationale for nebulized antibiotics antibiotic efficacy against bacteria within purulent secretions may require antibiotic concentrations >10 25 times MIC; these levels cannot be achieved with intravenous therapy alone The finding of low antibiotic concentrations in the secretions and epithelial lining fluid of the lung during intravenous therapy with aminoglycosides is well known Studies of high-dose intravenous colistin have shown that the concentration in the serum is approximately the MIC ofacinetobacter andpseudomonas; concentrations in the lung and airway are lower and, therefore, subtherapeutic. The ongoing use of antibiotics at subtherapeutic levels may lead to the selection of antibiotic-resistant organisms.

22 Dose of nebulized antibiotics Need to deliver drug to alveoli not tracheo-bronchial tree Use vibrating mesh nebulizer Colistin 5 million units q8h (Anesthesiology 2012, Vol.117, ) Dose was calculated according to a 40% extra-pulmonary deposition resulting fraction of colistimethate reaching the respiratory tract was 60% of the initial dose placed in the nebulizer chamber daily dose equivalent to 3 million IU delivered to the respiratory tract every 8 h. Tobramycin 300mg q12h However GNB in India typically resistant Always in conjunction with systemic antibiotics

23 Nebulized aminoglycosides or colistin IDSA: For patients with VAP due to gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins (colistin or polymyxin B), suggest both inhaled and systemic antibiotics, rather than systemic antibiotics alone Delivery to lung tissue questionable No improvement in clinical outcome though microbiological outcome better (J Antimicrob Chemother 2010;65:2645 9, Clin Infect Dis 2010;51: ) Colistin can clog filters No clear clinical benefit of adding amikacin and mechanical adverse effects noted (Am J Resp &Crit Care Med 2011;184:106)

24 IDSA meta-anlaysis on nebulized antibiotics Addition of an inhaled antibiotic to a systemic antibiotic regimen improved the clinical cure rate (RR, 1.29; 95% CI, ) no definitive effects on mortality (RR, 0.84; 95% CI, ) or nephrotoxicity (RR, 1.11; 95% CI, ). There were no other harmful effects attributed to the inhaled antibiotics. When only the trials that evaluated colistin were pooled, the clinical cure rate similarly improved (RR, 1.28; 95% CI, ).

25 Need to deliver drug to alveoli not tracheo-bronchial tree Niederman et al studied an investigational drug-device combination (BAY ) of amikacin formulated for inhalation, using a primary end point 25 times the minimum inhibitory concentration of 256 µg/ml, representing a tracheal aspirate amikacin maximal concentration 6400 µg/ml. Response rates for this end point were 50% for amikacin delivered every 12 hours. Similarly, the administration of 300 mg/120 mg amikacin/fosfomycin combination to mechanically ventilated adults using an investigational vibrating mesh nebulizer achieved tracheal aspirate amikacin concentrations of µg/g and fosfomycin concentrations of 6174 µg/g The results of ongoing randomized trials in VAP are eagerly awaited. Clin Infect Dis. (2016) 62 (8):

26

27 The administration of nebulised antibiotics is formally approved by regulatory bodies for the management of patients with bronchiectasis or cystic fibrosis However, the clinical challenges posed by pan-drug-resistant Gramnegative pathogens are causing significant concern for clinicians. Therefore, despite lacking high-quality efficacy and safety data, clinicians worldwide are increasingly using antibiotic nebulization to optimize the treatment of respiratory infections in invasively mechanically ventilated adult patients

28 Definition of the Population The targeted population was defined as adult critically ill patients with a respiratory infection, receiving support with invasive mechanical ventilation. The respiratory infections considered were ventilator-associated tracheobronchitis (VAT) and ventilator associated pneumonia (VAP). The panel of experts considered severe hospital-acquired pneumonia requiring invasive mechanical ventilation to be equivalent to VAP for the purposes of evaluating the use of nebulized antibiotic therapy. The susceptibility pattern of the pathogens was simplified to being susceptible or resistant (including multidrug- (MDR), extensively drug- or pandrug resistant bacteria Mechanical ventilation could be provided through any kind of invasive artificial airway (orotracheal tube or tracheostomy).

29 Definition of the Intervention ceftazidime, colistin or aminoglycosides studied. Antibiotic delivery needed to be performed with devices generating particles <5 mmin diameter (jet nebulizers, ultrasonic nebulizers) as is required to reach the lung parenchyma.

30 Exclusion criteria Neonatal and paediatric patients Adult patients without invasive mechanical ventilation support including non-invasive mechanical ventilation Colonized patients Patients with cystic fibrosis or other non-cystic fibrosis bronchiectasis Patients receiving support with renal replacement therapies and/or cardiopulmonary support with extracorporeal life support devices

31 List of outcomes. Efficacy Outcomes: Clinical resolution (yes/no; after 8 days of treatment) if one or more of the following occurred: Removal of vital support (ventilation, vasopressors) Improvement of daily organ failure score Improvement of PaO2/FiO2 ratio Inflammatory parameters decrease (CRP/PCT) 30-day mortality (yes/no) Duration of mechanical ventilation (days) Duration of intensive care unit stay (days) Occurrence of superinfection (yes/no) Emergence of resistant strains (yes/no)

32 Safety Outcomes : Systemic toxicity (yes/no; especially nephrotoxicity) Cardiorespiratory complications (yes/no; including hypoxaemia, cough, bronchoconstriction, acute respiratory distress syndrome, problems with the nebulization system such as obstruction of the expiratory filter; arrythmias, cardiorespiratory arrest).

33 Systematic review and meta-analysis Systematic search of the literature- in three different databases (MEDLINE Database, EMBASE and The Cochrane Library) Study selection Only randomized-controlled trials (RCT), observational studies and case series evaluating efficacy and/or safety of the technique were eligible to be included in the metaanalysis

34 Development of recommendations The results of the systematic review and metaanalysis were evaluated under the GRADE methodology (Grading of Recommendations Assessment, Development and Evaluation) to achieve an evidence-based recommendation.

35 Evidence-based recommendations Ventilator-associated pneumonia caused by resistant pathogens: Adjunctive strategy - In mechanically ventilated patients already receiving conventional IV therapy, including colistin or aminoglycosides, for a VAP caused by resistant pathogens, should nebulized antibiotics such as colistin or aminoglycosides be used, as adjunctive therapy to systemic antibiotics to improve clinical outcome?

36 Summary of the evidence Our systematic review identified one RCT and three observational studies, involving a total of 458 patients. No significant difference in clinical resolution rates were observed in the RCT (48 patients; odds ratio 1.30). The meta-analysis of the observational studies showed higher rates of clinical resolution in the group of patients receiving nebulized antibiotics (389 patients; odds ratio 0.51) Significantly shorter duration of mechanical ventilation support (303 patients; 3.72 days less) Significantly lower VAP-related mortality (181 patients; odds ratio 0.5;), even though all-cause mortality did not differ significantly. The safety analysis evidenced a higher incidence of respiratory complications associated with nebulization, and no differences in systemic toxicity (nephrotoxicity and neurotoxicity )

37 Recommendation We suggest avoiding the use of nebulizedantibiotics such as colistinor aminoglycosides, added to conventional IV antibiotic therapy already including IV colistinor aminoglycosidesfor the treatment of VAP caused by resistant pathogens as standard clinical practice. -Weak recommendation -Very low quality of evidence We recommend avoiding their use particularly in patients with severe hypoxaemia (PaO2/FiO2 ratio <200) or having shown signs of poor pulmonary reserve, tending to rapid lung de-recruitment

38 Substitution strategy : In mechanically ventilated patients already receiving conventional IV therapy, for a VAP caused by resistant pathogens, should nebulized antibiotics such as colistin or aminoglycosides be exclusively used?

39 Summary of the evidence Only one observational study addressed the administration of nebulized antibiotics under this strategy, in cancer patients. A jet nebulizer was the device used in this study involving 32 patients. Higher rates of clinical resolution were associated with the administration of nebulized antibiotics (odds ratio 9.53; 95% CI), but no significant differences were found for the rest of the efficacy outcomes analysed Nebulized antibiotic administration was associated with a higher incidence of respiratory complications

40 Recommendation We suggest avoiding the use of nebulizedantibiotics such as colistinor aminoglycosidesinstead of their IV administration for the treatment of VAP caused by resistant pathogens as standard clinical practice. -Weak recommendation -Very low quality of evidence

41 We recommend avoiding their use particularly in patients experiencing severe hypoxaemia (PaO2/FiO2 ratio <200) or demonstrating signs of poor pulmonary reserve, tending to rapid derecruitment.

42 Other categories Ventilator-associated pneumonia caused by antibiotic susceptible pathogens Ventilator-associated tracheobronchitis Non-bacterial respiratory infections

43 Conclusion Nebulization of antibiotics in mechanically ventilated adults with respiratory infections is a practice that is increasingly used despite a lack of standardization and limited evidence on the associated efficacy and safety. Based on a previous systematic review and metaanalysis, this ESCMID panel does not support the use of nebulization of antibiotics in any of the scenarios assessed because the available evidence is weak and heterogeneous Further research to achieve high-quality evidence is urgently needed

44 Summary on role for nebulized antibiotics for VAP as per ESCMID panel recommends avoiding the use of nebulized antibiotics in clinical practice due to a weak level of evidence of their efficacy high potential for underestimated risks of adverse events (particularly, respiratory complications) particularly in patients with severe hypoxaemia (PaO2/FiO2 ratio <200) or having shown signs of poor pulmonary reserve, tending to rapid lung derecruitment Clinical Microbiology and Infection (2017),

45 VAP treatment duration:shorter is RCT fom 2003: Treat for 8 days, non fermenters longer Current IDSA guideline: 7 days Very short antibiotic courses (1 3 days) were associated with outcomes similar to longer courses (>3 days) in patients with suspected VAP but minimal and stable ventilator settings (Clin Infect Dis (2017) 64 (7): ) PCT based Use PCT levels plus clinical criteria to guide duration Common sense: 7 days in general prolong if slow to improve, bacteremia or MDR-O patient should have improved clinically better

46 PCT for duration of therapy Get at baseline, then at 48h, then at time of clinical stability Assisted in limiting duration of therapy RCT of discontinuing antibiotics if PCT concentration had decreased by 80% or more of its peak value or < 0 5 μg/l or lower reduction of duration of treatment (1.22 days) and daily defined doses (2.69) significant decrease in mortality (6.6%). Annals Pharmacotherapy 2014;48(5):577 Lancet ID 2016; Volume 16, No. 7, p , July 2016

47 Carbapenem and beta-lactam resistant Gram negative VAP CR-Pseudomonas CR-Acinetobacter CR Enterobacteriaceae

48 Monotherapy or combination therapy for P aeruginosa VAP? Monotherapy AST known Combination therapy Pending AST in septic shock or at a high risk for death IDSA recommends against aminoglycoside monotherapy Aminoglycosides do not reach high lung tissue levels, use only till bacteremia excluded

49 Pseudomonas aeruginosa bacteremia: one drug or combination therapy? If Pseudomonas in your practice is sensitive: Current concept is that a single effective anti-pseudomonal betalactam antibiotic sufficient First large prospective study: no benefit for combination in both empiric and definitive stages If Pseudomonas in your practice is MDR: Can start with empiric combination therapy To ensure at least one agent effective against a resistant organism to prevent emergence of resistance (no clinical data to support this) No role for adding aminoglycoside after blood culture returns or continuing for entire duration of therapy (Clin Infect Dis 2005;41;149) (Antimicrob Agents Chemother 2003;47:2756) (Clinical Infectious Diseases Advance Access published April 11, 2013)

50 Monotherapy(MT) vs combination(ct) therapy for sepsis due to MDR A.baumannii: analysis of a multicenter prospective cohort No mortality benefit from using CT compared with MT 30 day mortality : MT 23.5% vs CT 24.2 % RR 1.03 CI P=0.94 Multivariate analysis of 30 day survival: also showed no trend towards reduced mortality Problems with the study: Low colistin dose?high rate of inappropriate empirical treatment? Several types of infection CT and MT groups made up of multiple agents Small sample size Did not look into microbiological eradication

51 Comparison of colistin-carbapenem, colistinsulbactam, and colistin plus other antibacterial agents for the treatment of XDR A. baumannii bloodstream infections. Retrospective observational multicenter study 27 Turkish tertiary hospitals Primary outcome: 14 day mortality Secondary outcome: clinical and microbiologic response MT: colistin (36) CT: Colistin+carbapenem (102) Colistin+sulbactam (69) Colistin +other abx (43) Eur J Clin Microbiol Infect Dis, (8): p

52 Comparison of colistin-carbapenem, colistinsulbactam, and colistin plus other antibacterial agents for the treatment of XDR A. baumannii bloodstream infections Eur J Clin Microbiol Infect Dis, (8): p

53 Therapy of MDR Acinetobacter: my recommendations First decide whether true infection or colonization Remove lines, do source reduction Colistin is the cornerstone Monotherapy adequate if single effective antibiotic Try anything else found sensitive eg chloramphenicol Look at MICs rather than just sensitive vs resistant Infuse beta-lactams over 3 hrs

54

55 Strategies for carbapenem resistant Klebsiella High dose carbapenem Cure rates based on MIC 69% if <4 60% if 8 29% if >8 Problem is that MIC50 is 64 and MIC90 is 256 (Vellore) Double carbapenem Ertapenem acts as a suicide substrate, give high dose meropenem 1 hr later Works only vs KPC Combination treatment Tigecycline Fosfomycin Colistin minocycline Exp Rev Anti Infect Ther 2013;11(2)

56 Lancet Infect Dis 2017; 17:

57 Conclusion Interpretation: appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum.

58 The basic problem with studies on CRE All retrospective All studies mostly on KPC But our problem in India is largely NDM-1..

59 Therapy of CR E.coli/Klebsiella: my recommendations First decide whether true infection or colonization Colistin is the cornerstone Attempt synergistic therapy though no RCT: 200 mg tigecycline high dose carbapenem if MIC 4-16 Fosfomycin minocycine Infuse beta-lactams over 3 hrs Add anything else found sensitive eg chloramphenicol Look at MICs rather than just sensitive vs resistant Pray!

60

61 In a nutshell Colistin much more clinical efficacy data perhaps more efficacious low serum levels are a concern with normal renal function Polymyxin B much easier to dose, no change with renal function less nephrotoxic

62 VAP caused by MDR-O: summary Carbapenem if sensitive Combination therapy only till DST known and bacteremia excluded If sensitive to polymyxins alone, parenteral polymyxins Avoid tigecycline monotherapy? Role for nebulized antibiotics (marginal efficacy, safety suspect, doubles cost)

63

64 Ceftazidime-avibactam approved by US FDA Combines the anti-pseudomonal activity of ceftazidime with avibactam Renders it active versus ESBLs and serine beta-lactamases such as KPC-2 Not active against NDM-1 and other MBLs Side effects include vomiting, nausea, constipation and anxiety Approved based upon results from two phase 2 trials for ciai, in combination with metronidazole complicated urinary tract infections (cuti) As good as comparator including carbapenems vs UTI/IAI caused by ceftazidime resistant bacteria (Lancet ID, 20 April, 2016) High rates of resistance to CAZ-AVI in CRE bloodstream isolates associated with the non-outbreak spread of NDM-1 in diverse Enterobacteriaceae species (Clin Infect Dis. (2016)doi: /cid/ciw398) Trial vs standard of care for KPC-2 showed superior outcome (CID 2017)

65 Meropenem-vaborbactam approved by US FDA The U.S. Food and Drug Administration approved meropenem-vaborbactam for adults with complicated urinary tract infections (cuti). Meropenem-vaborbactam was designated as a qualified infectious disease product (QIDP). The safety and efficacy of meropenem-vaborbactam were evaluated in a clinical trial with 545 adults with cuti, including those with pyelonephritis. At the end of intravenous treatment with meropenem-vaborbactam, approximately 98 percent of patients treated with meropenem-vaborbactam compared with approximately 94 percent of patients treated with piperacillin/tazobactam, another antibacterial drug, had cure/improvement in symptoms and a negative urine culture test. The most common adverse reactions in patients taking meropenem-vaborbactam were headache, infusion site reactions and diarrhea. The drug should be active against KPC-2 carbapenemases but not against NDM-1 type carbapenemases seen in India. Trial vs standard of care for KPC-2 stopped early because of superior outcome.

66

67 Arjun R, Gopalakrishnan R, Nambi PS, Kumar DS, Madhumitha R, Ramasubramanian V. Indian J Crit Care Med 2017;21:

68 Combination Therapy for High-Level Meropenem- and Colistin-Resistant Klebsiella pneumoniae Bacteremia 72 patients with resistant bacteremia Overall 30-day crude mortality was 25% with combination therapy and 44% with monotherapy. Use fosfomycin Antimicrob Agents Chemother 2017 Jul 25; 61:e00406

69 In summary Diagnose VAP clinically and start empiric antibiotics based on local antibiogram Carefully distinguish whether a positive ET culture represents VAP, VAT or colonization De-escalate after receipt of sensitivities Treat for 7-8 days or based on PCT Nebulized antibiotics questionable

70 Are you an MD/DNB (Internal Med) interested in an ID career? } DM (Infectious Diseases) } Three year program } CMC, Vellore and AIIMS, New Delhi } FNB (National Board of Examinations): Two year fellowship Apollo Hospitals Chennai & Hinduja Hospital, Mumbai Apollo Hyderabad & Sterling Hospital Ahmedabad added For details go to NBE website } Tamil Nadu Dr. MGR Medical University: Two year fellowship Apollo Hospitals Chennai, Global Hospitals Chennai and CMC, Vellore Contact institutions for details