1. Antibiotikatherapie der Sepsis Tobias Welte Klinik für Pneumologie Medizinische Hochschule Hannover

2. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

3. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

4. Welte – Bremen 20.02.2014 Adequate vs inadequate antibiotic therapy Mortality type Hospital mortality (%) p<0.001 Kollef et al. Chest 1999;115:462-74 Hospital mortality and infection-related mortality rates for infected patients from all causes (n=655) receiving either initially inadequate or adequate antimicrobial treatment Prospective US cohort study evaluating 2000 consecutive patients 88/169 114/486 71/169 86/486 17.7%42.0%23.5% 52.1%

5. Welte – Bremen 20.02.2014 Adequate versus inadequate initial antibiotic treatment and mortality Ibrahim et al. Chest 2000;118:146-55 Prospective US study in ICUs (492 bloodstream infections) ICU, intensive care unit Hospital mortality (%) 0 30 40 50 60 70 AdequateInadequate 20 10 Initial antimicrobial treatment p<0.001 91/14 7 98/34 5

6. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

7. Welte – Bremen 20.02.2014 TEST programme = international surveillance with standardised BMD methodology Looking for progression of vancomycin ‘creep’ into vancomycin resistance Changes in vancomycin MIC have been observed in the clinical setting Hawser et al. Int J Antimicrob Agents 2011;37:219-24 p<0.001 YearIsolates Phenotype S. aureusMRSAMSSA 2004-2009 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 20,004 797 (4.0) 8249 439 (5.3) 11,755 358 (3.0) 2004 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 2525 101 (4.0) 1158 65 (5.6) 1367 36 (2.6) 2005 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 2930 62 (2.1) 1411 39 (2.8) 1519 23 (1.5) 2006 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 3612 94 (2.6) 1531 50 (3.3) 2081 44 (2.1) 2007 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 4944 160 (3.2) 2028 78 (3.8) 2916 82 (2.8) 2008 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 4348 253 (5.8) 1481 136 (9.2) 2867 117 (4.1) 2009 All (n) Vancomycin MIC ≥2 µg/mL, n (%) 1645 127 (7.7) 640 71 (11.1) 1005 56 (5.6)

8. Welte – Bremen 20.02.2014 Vancomycin treatment failures increase with MIC Stevens. Clin Infect Dis 2006;42 Suppl 1:S51-7 MIC (μg/mL) Failure rate (%) 0.0 0 10 20 30 40 50 60 0.51.01.52.0 22 27 31 51 Relationship between MIC and vancomycin treatment MIC, minimum inhibitory concentration

9. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

10. Welte – Bremen 20.02.2014 For vancomycin and linezolid –24-hour AUC appears to be the most important PK- PD parameter 1,2 Importance of PK-PD parameters for optimal treatment of MRSA infection 1. Andes et al. Antimicrob Agents Chemother 2002;46:3484-9; 2. Moise PA et al. Am J Health-Syst Pharm. 2000;57:S4-S9. AUC, area under the curve; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; PD, pharmacodynamic; PK, pharmacokinetic MIC Time (h) 24-hour AUC Antibiotic (C) Peak

11. Welte – Bremen 20.02.2014 Time to MRSA eradication with vancomycin Moise-Broder et al. Clin Pharmacokinet 2004;43:925-42 0102030 Days of therapy until bacterial eradication 0 20 40 60 80 100 Culture-positive patients (%) p=0.04 AUC/MIC≥400 (n=18) AUC/MIC<400 (n=16) AUIC, area under the inhibitory curve; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus

12. Welte – Bremen 20.02.2014 Probability of achieving AUIC/MIC ≥400 for vancomycin regimens of varying intensity when C min was between 15 and 20 mg/L Patel et al. Clin Infect Dis 2011;52:969-74 AUIC, area under the inhibitory curve; C min, trough concentration; q12h, every 12 hours; MIC, minimum inhibitory concentration MIC value (mg/L) Percent

13. Welte – Bremen 20.02.2014 Linezolid: high penetration in the lung tissue LinezolidVancomycin 6 hours post-injection ELF: mean 2.03 µg/ml (1-2.77 µg/ml) 1 Healthy volunteers 52% 3 Patients with pneumonia 9-18% 1,5 8 hours post-injection ELF: mean 31.4 µg/ml (8.3-89.2 µg/ml) 2 Healthy volunteers ~400% 2 Patients with pneumonia 105% 4 Data represent the drug level in ELF as a percentage of the simultaneous levels in plasma ELF, epithelial lining fluid 1. Georges et al. Eur J Clin Microbiol Infect Dis 1997;16:385-8; 2. Conte Jr et al. Antimicrob Agents Chemother 2002;46:1475-80; 3. Rybak. Clin Infect Dis 2006;42 Suppl 1:S35-9; 4. Boselli et al. Crit Care Med 2005;33:1529-33; 5. Lamer et al. Antimicrob Agents Chemother 1993;37:281-6 No relationship between clinical outcomes and pharmacokinetics has been established * * * * *

14. Welte – Bremen 20.02.2014 Vancomycin: penetration in the lung tissue Vancomycin 6 hours post-injection ELF: mean 2.03 µg/ml (1-2.77 µg/ml) 1 Healthy volunteers 52% 2 Patients with pneumonia 9-18% 1,3 1. Georges et al. Eur J Clin Microbiol Infect Dis 1997;16:385-8; 2. Rybak. Clin Infect Dis 2006;42 Suppl 1:S35-9; 3. Lamer et al. Antimicrob Agents Chemother 1993;37:281-6 No relationship between clinical outcomes and pharmacokinetics has been established Data represent the drug level in ELF as a percentage of the simultaneous levels in plasma ELF, epithelial lining fluid * * *

15. Welte – Bremen 20.02.2014 Linezolid: high penetration in the lung tissue Linezolid 8 hours post-injection ELF: mean 31.4 µg/ml (8.3-89.2 µg/ml) 1 Healthy volunteers ~400% 1 Patients with pneumonia 105% 2 Data represent the drug level in ELF as a percentage of the simultaneous levels in plasma ELF, epithelial lining fluid 1. Conte Jr et al. Antimicrob Agents Chemother 2002;46:1475-80; 2. Boselli et al. Crit Care Med 2005;33:1529-33; No relationship between clinical outcomes and pharmacokinetics has been established * * *

16. Welte – Bremen 20.02.2014 16 critically ill VAP patients studied at steady state –All with late-onset VAP –12 with organisms: 3 MRSA, 1 MSSA, 8 enteric Gram-negatives (4 enterobacteriaceae and 4 P. Aeruginosa) Serum and ELF concentrations after 2 days of therapy Blood at 10, 20, 30, 45 minutes and 1, 2, 4, 8, 12 hours after infusion BAL 1 and 12 hours after infusion Similar levels in serum and ELF –Range of peak penetration: 34-188% –Range of trough penetration: 28-220% Linezolid: high bioavailability in ELF Boselli et al. Crit Care Med 2005;33:1529-33 Mean steady-state plasma (red circles) and ELF (blue circles) concentrations with NP (n=16). The dotted line represents the susceptibility breakpoint (4 mg/L) of staphylococci for linezolid (1). Error bars represent standard deviations BAL, bronchoalveolar lavage; ELF, epithelial lining fluid; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus; VAP, ventilator-associated pneumonia 0 4 8 12 16 20 Linezolid concentration (mg/L) −1024681012 Time (hours) Serum ELF No relationship between clinical outcomes and pharmacokinetics has been established

17. Welte – Bremen 20.02.2014 Study conducted to assess the efficacy of linezolid vs vancomycin in an MRSA pneumonia model using ventilated pigs The pigs were inoculated with MRSA and received treatment with: –Control (n=10) –Vancomycin twice daily every 12 hours (15 mg/kg; n=10) –Continuous vancomycin infusion (1 g; n=10) –Linezolid twice daily every 12 hours (10 mg/kg; n=10) Linezolid showed better efficacy than vancomycin in this animal model of MRSA pneumonia Efficacy of linezolid compared to vancomycin in an MRSA ventilated pig pneumonia model Martinez-Olondris et al. Crit Care Med 2012;40:162-8 MRSA isolation (%) 100 80 60 40 20 0 BALLung tissue *p<0.05 vs control * * * * * Control Vancomycin Linezolid Vancomycin CI 100 80 60 40 20 0 Affected lung segments (%) ControlVancomycinLinezolidVancomycin CI *p<0.01 vs control; #p<0.01 vs linezolid for severe and absence of pneumonia * * * # # # Severe Moderate Mild No pneumonia BAL, bronchoalveolar lavage; MRSA, methicillin-resistant S. aureus

18. Welte – Bremen 20.02.2014 Prospective randomised study Designed to compare continuous vs intermittent vancomycin in 119 critically ill patients with MRSA infections Microbiological and clinical outcomes and safety were similar No statistically significant difference was found between the two treatment groups Continuous vs intermittent infusion vancomycin Adapted from Wysocki et al. Antimicrob Agents Chemother 2001;45:2460-7 Patients (%) n=30n=28n=15n=13 n=7n=5

19. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

20. Welte – Bremen 20.02.2014 Renal effects related to vancomycin concentration Adapted from Jeffres et al. Clin Ther 2007;29:1107-15 Nephrotoxicity (%) p=0.002 Maximum vancomycin steady-state trough concentrations (  g/mL) a Renal toxicity was defined as increased creatinine by 0.5 mg/dL or doubling of baseline value Aggressive dosing and prolonged administration of vancomycin are associated with a greater risk of nephrotoxicity in patients with MRSA HCAP a Maximum vancomycin serum trough concentrations ≥15 µg/mL (n=49); maximum vancomycin serum trough concentrations <15 µg/mL (n=45) Retrospective US observational single-centre study HCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus

21. Welte – Bremen 20.02.2014 Vancomycin relationships: toxicity and target attainment AUC/MIC ratio ≥400Nephrotoxic event MIC value0.5 mg/L (%) 1.0 mg/L (%) 2.0 mg/L (%) Non-ICU (%) ICU (%) 500 mg IV q12h57150.7310 1000 mg IV q12h905715616 1500 mg IV q12h977938925 2000 mg IV q12h9890571434 Patel et al. Clin Infect Dis 2011;52:969-74 AUC, area under the curve; ICU, intensive care unit; MIC, minimum inhibitory concentration

22. Welte – Bremen 20.02.2014 Vancomycin concentration-time profile Retrospective US study correlating the vancomycin nephrotoxicity with its pharmacokinetics in 166 non-neutropenic patients –Baseline creatinine <2.0 mg/dL –Vancomycin >48 h 21 patients with nephrotoxicty (50% or 0.5 mg/dL increase in the serum creatinine level from baseline) The results indicate that a vancomycin exposure–toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association Lodise et al. Clin Infect Dis 2009;49:507-14 Logistic regression-derived nephrotoxicity probability functions ICU patientsNon-ICU patients ICU, intensive care unit

23. Welte – Bremen 20.02.2014 Consequences of inappropriate MRSA NP therapy Appropriate MRSA NP therapy –Vancomycin MIC creep –PK of vancomycin and linezolid –Nephrotoxicity of vancomycin ZEPHyR study and results Conclusions Outline MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia

24. Welte – Bremen 20.02.2014 ZEPHyR study: design overview and objective Design overview Phase IV, randomised, double-blind, multicentre, international comparator-controlled study in MRSA VAP, HAP or HCAP –Fixed-dose linezolid vs dose-optimised vancomycin –Non-inferiority study with a nested superiority hypothesis Study objective To prospectively assess the efficacy, safety and tolerability of linezolid compared with vancomycin in MRSA nosocomial pneumonia Wunderink et al. Clin Infect Dis 2012;54:621-9 HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus; VAP, ventilator-associated pneumonia

25. Welte – Bremen 20.02.2014 ZEPHyR study: randomisation and interventions Linezolid IV 600 mg q12h Vancomycin IV 15 mg/kg q12h 7-14 days EOT visit EOS visit 7-30 days after EOT  Vancomycin dose adjusted by unblinded pharmacist per local protocols based on trough levels and renal impairment  Gram-negative coverage (not MRSA active) 1:1 randomisation Within 5 days of EOT Wunderink et al. Clin Infect Dis 2012;54:621-9 Follow-up call: survival status at day 60 EOT, end of treatment; EOS, end of study; MRSA, methicillin-resistant S. aureus

26. Welte – Bremen 20.02.2014 Statistically superior clinical efficacy of linezolid vs vancomycin in MRSA NP in the ZEPHyR study Patients with EOS outcome of ‘indeterminate’ were excluded from the efficacy analysis Wunderink et al. Clin Infect Dis 2012;54:621-9 Patients with clinical response (%) p=0.042 95% CI 0.5-21.6 95% CI 0.1-19.8 95% CI 4.9-22.095% CI 4.0-20.7 Primary end point Secondary end points CI, confidence interval; EOS, end of study; EOT, end of treatment; mITT, modified intent-to-treat; MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia; PP, per protocol 95/165 81/174 102/186 92/205 150/180 130/186 161/201 145/214

27. Welte – Bremen 20.02.2014 Statistically-significant higher rates of microbiological success with linezolid vs vancomycin in the ZEPHyR study Wunderink et al. Clin Infect Dis 2012;54:621-9 Patients with microbiological response (%) 95% CI 0.4-21.5 EOS LinezolidVancomycinLinezolidVancomycinLinezolidVancomycinLinezolidVancomycin EOTEOSEOT PP population Patients with respiratory secretions for culture 63.9% (62/97) 68.3% (56/82) 49.0% (73/149) 48.2% (55/114) 36.1% (35/97) 31.7% (26/82) 51.0% (76/149) 51.8% (59/114) 58.1% (97/167) 47.1% (82/174) 81.9% (149/182) 60.6% (114/188) 61.4% (35/57) 50.0% (26/52) 82.6% (76/92) 54.1% (59/109) 95% CI 12.3-30.2 CI, confidence interval; EOS, end of study; EOT, end of treatment; PP, per protocol

28. Welte – Bremen 20.02.2014 Response differences between linezolid and vancomycin remained across most subgroups in the ZEPHyR study Wunderink et al. Clin Infect Dis 2012;54:621-9 Clinical success rate 1 (%) APACHE, Acute Physiological Assessment and Chronic Health Evaluation; EOS, end of study; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; MV, mechanical ventilation

29. Welte – Bremen 20.02.2014 No relationship between vancomycin trough level and outcomes in the ZEPHyR study Adapted from Niederman et al. Am J Respir Crit Care Med 2011;183:A3932 Clinical Median vancomycin trough concentration (µg/mL) Range:3.4-50.8 2.8-43.25.1-45.02.7-41.42.0-42.6 4.1-46.9 738247522315 Microbiological Median vancomycin trough concentration (µg/mL) Range:2.8-50.83.3-43.25.1-45.02.7-36.42.9-42.63.0-46.9 768050492216 End of study

30. Welte – Bremen 20.02.2014 Nephrotoxicity was nearly twice as common in vancomycin patients in the ZEPHyR study (mITT population) Adapted from Wunderink et al. Clin Infect Dis 2012;54:621-9 Patients with nephrotoxicity (%) GFR, glomerular filtration rate Laboratory evidence of nephrotoxicity (0.5 mg/mL increase in serum creatinine if normal at baseline, or 50% increase if abnormal at baseline)

31. Welte – Bremen 20.02.2014 Linezolid has a comparable tolerability profile with vancomycin in the ZEPHyR study Wunderink et al. Clin Infect Dis 2012;54:621-9 a Patient was reported to have ≥1 of the following: renal failure, renal impairment and/or azotaemia AE, adverse event AE, n (%) Linezolid (n=597) Vancomycin (n=587) Anaemia30 (5.2)42 (7.2) Renal failure/impairment/azotaemia a 22 (3.7)43 (7.3) Cardiac arrest11 (1.8)13 (2.2) Thrombocytopenia8 (1.3)13 (2.2) Pancreatitis5 (0.8)1 (0.2) Polyneuropathy—1 (0.2) Pancytopenia/neutropenia4 (0.6)2 (0.4) Paresthesia—1 (0.2)

32. Welte – Bremen 20.02.2014 Similar 60-day mortality with linezolid and vancomycin: the ZEPHyR study  Comparable all-cause 60-day mortality rates 1 –Linezolid arm 15.7%; vancomycin arm 17.0% (ITT population) –Linezolid arm 28.1%; vancomycin arm 26.3% (mITT population) 1. Wunderink et al. Clin Infect Dis 2012;54:621-9; 2. Wunderink et al. Clin Infect Dis 2012;55:163-5 [letter] 20 40 60 80 100 Patients surviving (%) 0 0206080 Time (days) 40100120 Linezolid Vancomycin Linezolid censored Vancomycin censored No pneumonia trial has ever demonstrated an overall mortality difference between antibiotics 2 1109070503010 ITT, intent-to-treat; mITT, modified intent-to-treat Kaplan–Meier survival curves for the mITT population

33. Welte – Bremen 20.02.2014 MRSA NP remains an important healthcare burden Linezolid demonstrated statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in the ZEPHyR study 1 Overall, linezolid demonstrated an acceptable safety and tolerability profile for the treatment of proven MRSA nosocomial pneumonia 1 Linezolid was associated with lower rates of pneumonia-related rehospitalisation versus vancomycin in a US retrospective study 2 Conclusions MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia 1.Wunderink et al. Clin Infect Dis 2012;54:621-9 2. Mullins et al. Poster PIN56 presented at ISPOR 2012

34. Welte – Bremen 20.02.2014