Why we need inhaled antibiotics?

Transcription

1 Athens November 2015 Why we need inhaled antibiotics? Garyfallia Poulakou Consultant, Infectious Diseases 4 th Dept of Internal Medicine, Attikon University Hospital of Athens

2 TRANSPARENCY DECLARATION No conflicts of interest related to this presentation

3 Define the need for adjunctive treatment for Ventilator-associated pneumonia and Ventilatorassociated tracheobronchitis A story of bad bugs, bad drugs, bad conditions and bad assessment tools that jeopardise treatment outcomes in VAP and VAT

4 Bad bugs

5 The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide KPC producers Clinical Microbiology and Infection Volume 20, Issue 9, pages , 11 OCT 2014 DOI: /

6 The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide NDM producers Clinical Microbiology and Infection Volume 20, Issue 9, pages , 11 OCT 2014 DOI: /

7 The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide OXA-48 producers Clinical Microbiology and Infection Volume 20, Issue 9, pages , 11 OCT 2014 DOI: /

8 Colistin: The loss of the last frontier? Increase in colistin resistance rates among Klebsiella pneumoniae Carbapenemaseproducing K. pneumoniae isolates in Italy ( ) Giacobbe DR, et al. Clin Microbiol Infect Resistant to colistin: 43% Monaco M, et al. Euro Surveill. 2014;19(42)

9 Percentages of nosocomial infections treated with colistin/tigecycline ECDC PPS

10 Bad conditions

11 The multifactorial process that leads to VAT and VAP 10 7 bacteria/ml of oral secretions Biofilm Lining the foreign body (Endotracheal Tube) V A T Purulent secretions (Multidrug-resistant) Bacteria Planktonic? Biofilm? Aerosolized antibiotics VAP Systemic antibiotics Purulent secretions in alveoli >10 4 bacteria/ml* Difficulty in treatment is understandable when one examines the pathway of microbial transfer Damaged mucosa Disturbed mucociliary clearance Subglottic secretions Bacterial biofilm Adapted from Palmer LB Curr Opin Pulm Med 2015, 21:

12 VAT can be seen from different viewpoints 1. A local infection with high bacterial inoculum without systemic signs of infection 2. An anatomic area of suppurative infection which may or may not have systemic signs of infection or radiographic changes 3. A precursor of VAP 4. A trigger for recurrence of VAP

13 Clinical and microbiological outcomes are not always desirable in VAT and VAP WHY? Major factors for lack of response may include: the concentrations in the airway may be lower than in the bloodstream parenteral antibiotics often achieve poor perfusion into consolidated regions of the lungs Sub-therapeutic concentrations of antibiotic may lead to a longer duration of treatment, and ultimately result in selection of resistant bacteria the bacteria in this environment may require times the minimum inhibitory concentration for bactericidal activity the presence of biofilm may decrease the efficacy of systemic antibiotics due to lack of penetration Gil-Perotin S,. Crit Care 2012; 16:R93 Mendelman PM, Am Rev Respir Dis 1985; 132:

14 MIC and MPC Minimum amount of drug required to inhibit the growth of an inoculum comprising ~10 5 CFU/ml. This is referred to as the minimum inhibitory concentration (MIC). For drug concentrations above the MIC, bacteria may still exhibit reduced susceptibility (i.e., increased resistance) as a result of the development of genetic mutations The drug concentration that inhibits the growth of mutant organisms is referred to as the mutant prevention concentration (MPC). The MPC is typically assessed at a higher inoculum, in excess of 10 9 CFU/ml. The region of drug concentrations between the MIC and MPC has been designated as the mutant selection window Dong Y AAC 1999

15 Significant improvements in lung targeting following aerosol administration with corresponding low systemic concentrations Comparison of mean serum and bronchial secretion concentrations of amikacin following intravenous administration of a 500 mg dose twice daily and inhalation administration of a 400mg dose of Amikacin Inhale (Bayer) twice daily to pneumonia patients. J.Weers / Advanced Drug Delivery Reviews 85 (2015) 24 43

16 Bad assessment tools?

17 Do we use bad endpoints? Outcome parameters in ICU trials to define failure Strong ( objective ) endpoints Mortality 30 or 90 day mortality Length of mechanical ventilation Length of ICU or hospital stay Weak endpoints (with a subjective component) Clinical cure Microbiological cure Composite endpoints Development of scores Risk Stratification Scores (SAPS, APACHE) Organ Failure Scores (SOFA) Disease Specific Scores (CPIS) confounders-large sample needed Weaning and discharge decisions not universal Correlate with infection Definition varies considerably between studies Correlation to the strong endpoints unclear More focused on the infection Weak correlation to strong endpoints

18 An example of development of new composite outcomes Montgomery et al. suggested a hierarchical composite endpoint based on mortality and ventilator-free days for the adjunctive treatment of VAP. The win-ratio approach resulted in potential reductions in sample size from 3826 patients for a traditional mortality trial, to a more manageable 344 patients for the composite endpoint ISICEM, 2014.Montgomery B,

19 Bad Drugs? in bad conditions

20 The DALI point prevalence PK study Data from 68 ICUs across ten countries A total of 343 critically ill patients receiving eight different b-lactam antibiotics Approximately 20 % of patients fail to attain even the most conservative drug exposure target during empirical treatment (antibiotic concentrations above the MIC during 50 % of the dosing interval) Utilising a higher target (antibiotic concentrations above the MIC throughout the dosing interval), twice this number of patients (40 %) manifest insufficient drug exposures De Waele J et al, Intensive Care Med (2014) 40:

21 Multivariable analysis of risk factors for PK target non-attainment with b-lactams The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets Increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval Conclusion: current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered De Waele J et al, Intensive Care Med (2014) 40:

22 Colistin s Nephrotoxicity in iv route range : 33% 61% Risk Factors of Nephrotoxicity Co administration of other nephrotoxic agents? Daily dose? Length of therapy? Age? Baseline renal impairment? Ascorbic acid (protective against renal toxicity)? Justo JA, Bosso JA. Pharmacotherapy. 2015;35:28 33 Dalfino L, et al. Clin Infect Dis pii: civ717

23 Eur J Clin Pharmacol Oct 2014 Probability to achieve the pharmacokinetic target (C1h/MIC 10) according to the singledosing regimen and the theoretical minimum inhibitory concentration of the strain in the Monte Carlo simulation Mechanically ventilated patients in intensive care units should receive a high amikacin dose in order to maximize the probability of pharmacodynamic target attainment

24 General concepts debated Ventilator-associated tracheobronchitis (VAT) is believed to be an intermediate stage between colonization of the lower respiratory tract and VAP However, more recent data suggests that VAT may be a separate entity Anyhow it still may contribute to increased length of ICU stay and longer duration of MV Craven DE, Chest. 2009;1352: Dallas J, Chest. 2011;139(3):

25 VAT and patients outcomes Aerosolized antibiotics led to significant increases in ventilatorfree days, decreases in systemic antibiotic use, decreases in development of resistant organisms, and importantly, a reduced number of subjects who later developed VAP Nseir S: Curr Opin Infect Dis 2009; 22: Eur Respir J 2002; 20: Nseir S: Infection 2004; 32: Crit Care 2005; 9:R238 R245

26 Ventilator-Associated Tracheobronchitis Increases the Length of Intensive Care Unit Stay The occurrence of VAT was a significant risk factor for increased duration of ICU stay but not of mortality Karvouniaris M et al, Infect Control Hosp Epidemiol 2013;34(8):

27 Untreated VAT progresses to VAP? Timely treated VAT prevents VAP? Treated VAP eliminates VAT? When VAP is present and treated with systemic antibiotics, this more proximal area of infection may persist and lead to a vicious cycle of recurrent infections Alternatively, early treatment of ventilatorassociated tracheobronchitis may prevent progression to VAP

28 How are inhaled antibiotics used in real life? Results from two electronic surveys performed by ESCMI Study Group Infections in the critically Ill Patients

29 ECCMID 2014 Definition and significance of Salvage Treatment for Gram negative infectionsin Critically-ill patients: preliminary results of an ESGCIP survey Garyphallia Poulakou*, Dimitrios K. Matthaiou, Matteo Bassetti, Hakan Erdem, George Dimopoulos, Jean Carlet, Jeff Lipman, Jean François Timsit, Helen Giamarellou, Jordi Rello and the ESGCIP Investigators The study was performed in Sep 2013-Feb 2014 using an electronic platform (SurveyMonkey ). Increased dosing, pharmacokinetic maneuvers, combinations, off label use and use of neglected or revived antimicrobials was explored 144 international respondents Combination of 2 agents against a single pathogen and administration of an antibiotic off-label best fitted the responders beliefs of what constitutes ST Inhaled antibiotics use ranged from 0-30% of the treated patients on the day of the survey

30 The SANEME study The survey was performed from the October 2014 to the 31st of January 2015, using an electronic platform (SurveyMonkey ) Aimed to investigate practices of nebulized antibiotics in mechanically ventilated patients among implicated physicians A total of 192 HCW completed the survey. Between them 135 had administered nebulized antibiotics during the previous week to performing the questionnaire

31 Indications for use of nebulized antibiotics: results from the SANEME study Total (n=87) Neb + IV n (%) Neb alone n (%) VAP treatment 50 (58) 8 (9) VAT treatment 38 (44) 20 (23) Prophylaxis 18 (21) 26 (30) MDRO treatment 58 (67) 9 (10) MDRO colonization 24 (28) 22 (25) Viral infection treatment 20 (23) 14 (16) Fungal prophylaxis 24 (28) 17 (20) Fungal treatment 28 (32) 10 (12) Sole C, et al the SANEME study on behalf of ESGCIP, submitted Neb nebulised antibiotic therapy; IV intravenous antibiotic therapy; VAP ventilator associated pneumonia; VAT ventilator associated tracheobronchitis; MDRO multi-drug resistant organism

32 The SANEME study Conclusions The existence of a multidrug-resistant (MDR) pathogen seems to be the most important factor for the initiation of nebulized antibiotics, mostly after culture identification. VAT and VAP were the most common indications, but dosing regimens were different. Colistimethate sodium, tobramycin, amikacin and colistin sulfate were the more used formulations.

33 Submitted for publication

34 The SANEME study Practices and devices At least 14 different antimicrobials were reported as nebulized in the week preceding completion of the survey. Lack of published pharmacokinetic, clinical outcome or drug administration data supporting many of these drugs. Confidence that the respondents have in antimicrobial nebulization as a mode of delivery? Lack of confidence the respondents have with only systemic therapy?

35 ATS Recommendations The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) HAP guidelines recommend that adjunctive therapy with inhaled aminoglycoside or colistin should be considered in patients with MDR Gramnegative pneumonia/vap, especially for those who are not improving with IV antibiotics (Level III) Am J Respir Crit Care 2005;171:

36 Questions to be answered 1. What are the concentrations of antibiotics needed to eradicate MDROs in the proximal airway in areas of thick purulent secretion 2. What are the best delivery devices to achieve the concentrations necessary to treat VAT and VAP? 3. Can inhaled antibiotics reduce or eliminate systemic antibiotic use and/or decrease the emergence of resistant organisms? 4. Can they make the difference in improving outcomes? 5. A systematic review and meta-analysis with strictly predefined PICO items is under publication RCTs are needed!

37 Conclusions Ventilator-associated respiratory infections caused by increasingly resistant Gram-negative organisms are a challenge for intensivists Inhaled antibiotics when delivered properly may become an important part of treating these infections Locally delivered antibiotics by advanced technology devices may achieve concentrations several times above the required for treatment and development of resistance Local antibiotic delivery can approach better the VAT component of ventilator associated infections RCTs and Guidelines are urgently needed

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