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Beta Lactam: To Extend or not to Extend: That is the Question!

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Beta Lactam: To Extend or not to Extend: That is the Question!

  1. 1. β-Lactam To Extend or not to Extend: That is the Question! Hassan M. Al Tomy BSc Pharm, BCPS Pharmaceutical Care Department King Abdullah Medical City
  2. 2. Objective To introduce the concept of extended infusion beta lactam To present the evidence of EI Assess the “pillars” of evidence in support of extended
  3. 3. Outlines Introduction PK/PD of Beta-Lactam PK/PD Evidences Clinical outcomes evidences Cost Adverse Drug Reactions Summary
  4. 4. Why Modified administration method is the Current Focus of Research Introduction
  5. 5. Introduction
  6. 6. New systemic antibacterial agents approved by FDA Boucher H W et al. Clin Infect Dis. 2013;56:1685-1694 Resistance
  7. 7. Systemic Antibacterial Drug Approvals Since 2000 Antibiotic Approval Date Linezolid 2000 Cefditoren pivoxil 2001 Ertapenem 2001 Gemifloxacin 2003 Daptomycin 2003 Telithromycin 2004 Tigecycline 2005 Doripenem 2007 Telavancin 2009 Ceftaroline fosamil 2010 Boucher H W et al. Clin Infect Dis. 2013;56:1685-1694
  8. 8. What Can We Do? Improve the antibiotic pipeline Antimicrobial stewardship program
  9. 9. “Optimization of antimicrobial dosing based on individual patient characteristics, causative organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the drug is an important part of antimicrobial stewardship (A-II)” “Examples of these principles in practice include prolonged or continuous infusion of b-lactams” Dellit, Owens et al. Clin Infect Dis 2007, 44(2), 159-177
  10. 10. Are the current β-lactam doses adequate
  11. 11. Open, prospective, multicenter study in four ICUs 80 patient with severe sepsis or septic shock The percent of patients who attained the target PK profile was Meropenem (75%) Ceftazidime (28%) Cefepime (16%) Piperacillin-tazobactam (44%) Taccone, F. S., et al. Crit Care 2010 14(4):R126.
  12. 12. Open label , prospective study 53 ICU patients treated with CRRT and receiving either meropenem , piperacillin tazobactam, cefepime or ceftazidime Conclusions: In septic patients receiving CRRT recommended doses of b-lactams for Pseudomonas aeruginosa are adequate for Meropenem for piperacillin-tazobactam, cefepime and ceftazidime; for higher doses and/or extended infusions should be used to optimise serum concentrations. Seyler et al. Crit Care 2011, 15:R137
  13. 13. Prospective, multinational pharmacokinetic point- prevalence study including 8 β-lactam antibiotics. 384 ICU patients across 68 hospitals in 10 countries the median APACHE II score was 18 16% did not achieve 50% f T>MIC Roberts, J.A., et al. Clin Infect Dis, 2014. 58(8): p. 1072-83
  14. 14. What Is Prolonged Infusion Is it FDA approved
  15. 15. Prolonged Infusion
  16. 16. History Eagle et al. 1950, 1953, Schmidt and Walley 1951 Jawetz 1946; Schmidt et al. 1949 More frequent dosing or continuous infusion of penicillin resulted in a superior outcome compared to once or twice daily dosing
  17. 17. Pharmacodynamics/Pharmacokinetics Abdul-Aziz, M.H., et al., Ann Intensive Care, 2012. 2(1): p. 37.
  18. 18. β-Lactam Pharmacodynamics For penicillins, fT>MIC must be: >30% of dosing interval to produce bacteriostasis ≥50% of dosing interval for optimum (maximal) bactericidal effect Required %T>MIC for maximal bactericidal effect: ~60-70% for cephalosporins ~50% for penicillins ~40% for carbapenems Clin Infect Dis 2007;44:357-363
  19. 19. Pharmacodynamics/Pharmacokinetics 2 1 4 8 16 32 64 128 256 2 4 6 8 10 12 14 16 18 20 22 24 Time in hours Concentrationmg/L 1g Q8h T1/2= 2hr
  20. 20. 2 1 4 8 16 32 64 128 256 2 4 6 8 10 12 14 16 18 20 22 24 Time in hours Concentrationmg/L 1g Q8h 2g Q8h Pharmacodynamics/Pharmacokinetics T1/2= 2hr
  21. 21. 2 1 4 8 16 32 64 128 256 2 4 6 8 10 12 14 16 18 20 22 24 Time in hours Concentrationmg/L 1g Q8h 2g Q8h 1g Q6h Pharmacodynamics/Pharmacokinetics T1/2= 2hr
  22. 22. 2 1 4 8 16 32 64 128 256 2 4 6 8 10 12 14 16 18 20 22 24 Time in hours Concentrationmg/L 1g Q8h 2g Q8h 1g Q6h 500mg Q4h Pharmacodynamics/Pharmacokinetics T1/2= 2hr
  23. 23. Mouton JW, Vinks AA Clin Pharmacokinet , 2005, 44(2):201–210
  24. 24. Macvane, Kuti et al. Int J Antimicrob Agents, 2013. 105– 113
  25. 25. Piperacillin/Tazopactam Lodise, T. P., et al. Pharmacotherapy, 2006. 26 (9), 1320-32.
  26. 26. Meropenem Lodise, T. P., et al. Pharmacotherapy, 2006. 26 (9), 1320-32.
  27. 27. Cefepime Lodise, T. P., et al. Pharmacotherapy, 2006. 26 (9), 1320-32.
  28. 28. Extended and continuous-infusions with same daily doses had similar bactericidal exposure Both dosing strategies improved PD profile over intermittent-infusion regimens: Probability of achieving 50% fT>MIC at 16 µg/mL: 67.8% for intermittent regimen 3.375 g q6hr (13.5 g/day) 100% for Extended & continuous-infusions (12 g/day) Probability of achieving 50% fT>MIC at 32 µg/mL was: 45% for high intermittent dose 4.5 g q6hr (18 g/day) 90% for Extended & continuous infusions (16 g/day) Kim et al. Pharmacotherapy 2007;27(11):1490–1497
  29. 29. How Can We Maximize T>MIC ? Increasing the dosing frequency Using a higher dose Increasing the duration of infusion (extended infusion) Using a continuous infusion Administration of a drug that interferes with elimination (e.g. probenicid) Replace with a therapeutically equivalent antibiotic with a longer T1/2 van Zanten, A.R., Crit Care Med, 2009. 37(6): p. 2137-8.
  30. 30. WOW! It’s great PD/PK evidences is very strong I will apply EI
  31. 31. Are Those PD/PK evidences reflected on clinical outcome BUT, Wait
  32. 32. Dissociation Between Preclinical Data and Clinical Reports Comparative clinical studies had previously failed to demonstrate significant differences in pts outcome Two meta-analyses of these clinical trials found similar outcomes between CI and IB This dissociation prevented global practice shift toward CI of β-Lactam antibiotics Kasiakou SK. Lancet Infect Dis 2005, 5:581 Roberts JA. Crit Care Med 2009, 37:2071
  33. 33. Recent Meta-Analysis
  34. 34. 14 studies 1229 patient 8 studies were retrospective, 3 prospective , and 3 RCTs 6 studies (302 patients) reported on carbapenems, 7 (806 patients) on piperacillin/tazobactam, and 1 on both classes of antibiotics 6 studies evaluated patients with pneumonia, whereas the remaining studied patients with several types of infections. In 8 of 14 studies the causative pathogens were gram-negative bacteria only Falagas ME et al. Clin Infect Dis 2013 56: 272-282.
  35. 35. Falagas M E et al. Clin Infect Dis. 2013;56:272-282 Mortality
  36. 36. Falagas M E et al. Clin Infect Dis. 2013;56:272-282 Mortality
  37. 37. Falagas M E et al. Clin Infect Dis. 2013;56:272-282 Clinical Cure
  38. 38. 26 studies (n=2899 patients) critically ill patients 13 (RCTs) (n=782 patients) and 13 cohort studies (n=2,117 patients) Chantet al. Crit Care 2013,17:R279
  39. 39. Effects of pharmacodynamic-based antibiotic dosing on ICU and hospital mortality grouped by RCT versus cohort studies Chantet al. Crit Care 2013,17:R279
  40. 40. Effects on clinical failure, grouped by RCT versus cohort studies Chantet al. Crit Care 2013,17:R279
  41. 41. Effects on ICU length of stay Chantet al. Crit Care 2013,17:R279
  42. 42. Effects on mortality separated by class of antibiotic Chantet al. Crit Care 2013,17:R279
  43. 43. Effects on mortality Chantet al. Crit Care 2013,17:R279
  44. 44. 29 studies with 2206 patients 18 RCTs, 3 prospective comparative studies and 8 retrospective studies Teo, J., et al., Int J Antimicrob Agents, 2014. Volume 43, Issue 5, 2014, 403 - 411
  45. 45. Mortality Teo, J., et al., Int J Antimicrob Agents, 2014. Volume 43, Issue 5, 2014, 403 - 411
  46. 46. Teo, J., et al., Int J Antimicrob Agents, 2014. Volume 43, Issue 5, 2014, 403 - 411 Clinical Success
  47. 47. Subgroup Analysis Mortality Clinical Success No. of studies No. of patients Summary risk ratio (95% CI) No. of studies No. of patients Summary risk ratio (95% CI) RCTs 10 779 0.83 (0.57-1.21) 14 1125 1.05 (0.99-1.12) Non-RCTs 9 841 0.57 (0.43-0.76) 5 421 1.34 (1.02-1.76) Penicillins 8 974 0.60 (0.45-0.82) 6 491 1.08 (0.94-1.25) Cephalosporins 5 191 0.92 (0.52-1.63) 9 662 1.11 (0.98-1.25) Carbapenems 4 274 0.74 (0.42-1.28) 3 333 1.16 (0.93-1.46) Equivalent daily dose 10 813 0.82 (0.56-1.20) 10 934 1.22 (1.05-1.43) APACHE II score ≥15 10 861 0.63 (0.48-0.81) 8 663 1.26 (1.06-1.50) All studies 19 1620 0.66 (0.53-0.83) 19 1546 1.12 (1.03-1.21) Teo, J., et al., Int J Antimicrob Agents, 2014. Volume 43, Issue 5, 2014, 403 - 411
  48. 48. What about cost BUT
  49. 49. Cost After implementation of EI approach total daily dose of Tazocin was reduced by 25%–50% which reduce a total annual cost of Tazocin from $275,000 to $135,475 - $206,250∼ Costs associated with continuous infusion ceftazidime, $627 ± 388, were significantly lower (p≤0.001) than with intermittent infusion, $1007 ± 430. EI cefepime save $23,183 per patient compared with intermittent infusion Use of EI meropenem significant reduce antibiotic cost, whichwas $1038.83±51.08 in the intermittent dosing group and$684.06±36.25 in EI group Lodise, T. P., Jr., et al. Clin Infect Dis,2007. 44(3): 357-363 McNabb, J.J., et al., Pharmacotherapy, 2001. 21(5): p. 549-55. Bauer, K.A., et al.,. Antimicrob Agents Chemother, 2013. 57(7): p. 2907-1 Wang, D., Int J Antimicrob Agents, 2009. 33(3): p. 290-291.
  50. 50. Adverse Reaction No significant difference in rate of ADR between EI and Intermittent infusion In meta-analysis of 14 studies no significant differences between the 2 treatment groups Chytra et al. Critical Care 2012, 16:R113 Falagas M E et al. Clin Infect Dis. 2013;56:272-282
  51. 51. Advantages Disadvantages More predictable antibiotic PK profiles Relatively new antibiotic administration method thus requiring intensive educational effort to update clinical staff on the administration method prior to implementation Lower antibiotic daily dose may be appropriate with continuous infusion Requires special infusion pumps and infusion bags that are costly Reduced drug acquisition costs when lower antibiotic doses are used Stability May be more effective in special populations Abdul-Aziz, M.H., et al., Ann Intensive Care, 2012. 2(1): p. 37.
  52. 52. Clinical Outcome EvidencePK/PD Evidence Extended Infusion
  53. 53. Conclusion Overall, available evidence from PK-PD, clinical outcomes, and pharmacoeconomic studies consistently suggest that EI administration of PIP-TAZ is a safe, efficacious, cost-effective, and potentially superior strategy compared with traditional 30-minute infusions Extended infusion of β-lactams is unlikely to be advantageous for all hospitalized pts It may be very beneficial for specific groups, such as critically ill pts and pts with higher MIC pathogens such as MDR Pseudomonas, Acinetobacter , Carbapenem resistant Enterobacteriacae A large a prospective multicentered, randomized trial is needed

Notas do Editor

  • New systemic antibacterial agents approved by the US Food and Drug Administration per 5-year period, through 2012. Modified from Spellberg 2004 [23].
  • Forest plot depicting the risk ratios of clinical cure of patients receiving extended or continuous versus short-term infusion of carbapenems and piperacillin/tazobactam, stratified by continuous and extended infusion. Vertical line, “no difference” point between the 2 regimens; squares, risk ratios; diamonds, pooled risk ratios; horizontal lines, 95% confidence interval. Abbreviation: CI, confidence interval.

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