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Stuart B. Levy, MD President of Alliance for the Prudent Use of Antibiotics (APUA)

" Antibiotics are uniquely societal drugs because individual use affects others in the community and environment.”. Stuart B. Levy, MD President of Alliance for the Prudent Use of Antibiotics (APUA) Professor at Tufts University School of Medicine. Centennial Cephalosporins:.

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Stuart B. Levy, MD President of Alliance for the Prudent Use of Antibiotics (APUA)

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  1. "Antibiotics are uniquely societal drugs because individual use affects others in the community and environment.” Stuart B. Levy, MD President of Alliance for the Prudent Use of Antibiotics (APUA) Professor at Tufts University School of Medicine

  2. Centennial Cephalosporins: Strengths and Shortcomings of the Newest Generation Lynn Nguyen, PharmDPGY-2 Infectious Diseases Pharmacy Resident UCSF Medical Center

  3. Disclosures • Lynn Nguyen, PharmD • None • Conan MacDougall, PharmD, MAS, BCPS-AQID • None

  4. General objectives • Define the importance of the clinical topic to the pharmacy staff at UC San Francisco Medical Center • Describe the role of the pharmacist in improving care delivered to patients at UCSF Medical Center • List the challenges and limitations of the clinical topic for pharmacists working at UCSF Medical Center • Discuss common medication dosing, adverse events and how to mitigate these events for patients at UCSF Medical Center • Discuss how UCSF Medical Center policies relate to this therapeutic topic

  5. Learning objectives (continued) • Identify organisms covered (& not covered) by ceftaroline • Explain the rationale and evidence for q8h ceftaroline dosing • Characterize neutropenia associated with ceftaroline • Interpret MICs for ceftaroline, ceftolozane/tazobactam, ceftazidime/avibactam • List beta-lactamases inhibited by avibactam and tazobactam • Compare in vitro activity of ceftolozane/tazobactamand ceftazidime/avibactam • Given an infection due to resistant Enterobacteriacaeor Pseudomonas aeruginosa, identify an appropriate agent for treatment

  6. Pre Questions Text LynnNguyen456 to 22333 to participate

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  10. Troubling times Pastagia M, et al. Emerg Infect Dis. 2012 Jul;18(7):1072-80. Schwaber MJ, et al. J AntimicrobChemother. 2007 Nov;60(5):913-20. Tumbarello M, et al. Epidemiol Infect. 2011 Nov;139(11):1740-9. Satlin MJ, et al. Antimicrob Agents Chemother. 2017 Mar 24;61(4).

  11. Antibiotic resistance at UCSF • S. aureus:41% methicillin-resistant • P. aeruginosa (ICU): 37% meropenem-resistant • Rising from 23% in 2015 • E. coli and K. pneumoniae: ~20% ceftriaxone-resistant (“ESBL”) UCSF Adult Inpatient Susceptibility Data, 2016

  12. Resistance drives innovation

  13. Ceftaroline

  14. Ceftaroline – brief overview

  15. Ceftaroline anti-MRSA mechanism of action • Has enhanced binding affinity to: • PBP-2a (MRSA) • PBP 2x, 2b, and 3 (penicillin-resistant Streptococcus pneumoniae) ceftaroline Laudano JB. J AntimicrobChemother. 2011;66(suppl_3):iii11-iii18.

  16. Ceftaroline in vitro activity Citron DM, et al. Antimicrob Agents Chemother. 2010 Apr;54(4):1627-32. Laudano JB. J AntimicrobChemother. 2011;66(suppl_3):iii11-iii18. Drusano GL. J AntimicrobChemother. 2011 Apr;66 Suppl 3:iii61-7.

  17. Ceftaroline coverage gaps Citron DM, et al. Antimicrob Agents Chemother. 2010 Apr;54(4):1627-32. Laudano JB. J AntimicrobChemother. 2011;66(suppl_3):iii11-iii18.

  18. Ceftaroline activity against resistant S. aureus +FDA breakpoint Sader HS, et al. Antimicrob Agents Chemother. 2013;57(7):3178-3181.

  19. Ceftaroline approval trials and indications File TM, et al. J AntimicrobChemother. 2011 Apr;66 Suppl 3:iii19-32. Low DE, et al. J AntimicrobChemother. 2011 Apr;66 Suppl 3:iii33-44. Corey GR, et al. Clin Infect Dis. 2010 Sep 15;51(6):641-50.

  20. Clinical experience with ceftaroline in off-label indications Casapao AM, et al. Antimicrob Agents Chemother. 2014 May; 58(5): 2541–2546. Polenakovik HM, et al. Int J Antimicrob Agents. 2013 Nov;42(5):450-5.  Pasquale TR, et al. J Chemother. 2015;27:29–34

  21. Ceftaroline 600mg q8h vs. q12h dosing • Rationale for q8h dosing • Ceftaroline has short half-life (2-3 hours) • More frequent dosing may optimize probability of achieving fT>MIC for isolates at the susceptibility breakpoint (1 mg/L) • Lack of clinical evidence to support superior efficacy of q8h dosing • Studies may be underpowered due to low #s of patients with MIC >1 mg/L • Appears to have similar safety profile to q12h dosing Matzneller P, et al. Antimicrob Agents Chemother. 2016 May 23;60(6):3617-25. Zasowski EJ, et al. Antimicrob Agents Chemother. 2017 Jan 24;61(2). Dryden M, et al. J AntimicrobChemother. 2016 Dec; 71(12): 3575–3584.

  22. Ceftaroline-induced neutropenia • Neutropenia associated with prolonged exposure • Median onset 17 days • Counts recover after discontinuation Furtek KJ, et al. J AntimicrobChemother. 2016 Jul; 71(7): 2010–2013. LaVie KW, et al. Antimicrob Agents Chemother. 2015 Oct 26;60(1):264-9.

  23. Case 33M IVDU with MRSA bacteremia found to have mitral valve vegetation on TTE Bacteremia persisted on vancomycin and daptomycin Repeat Bcxwith MRSA: vanc-NS, dapto-NS, linezolid-susceptible, ceftarolineMIC 0.5 mg/L Patient unable to tolerate daptomycin What would you recommend? Does the ceftarolineMIC affect your dosing recommendation? What if MIC = 1? Case adapted from Ho TT, et al. J AntimicrobChemother. 2012 May;67(5):1267-70.

  24. Hospital Course • Treated with ceftaroline 600mg IV q8h • Blood cultures cleared within 48 hours • Completed 6 weeks of ceftaroline • Mitral valve replacement • Clinical resolution Case adapted from Ho TT, et al. J AntimicrobChemother. 2012 May;67(5):1267-70.

  25. Take-home points Ceftaroline • Anti-MRSA cephalosporin • Broad Gram-positive spectrum, including MRSA, VRSA, and some Enterococcus(but not vancomycin-resistant E. faecium) • Active against Enterobacteriaceae and common Gram-negative organisms encountered in CAP • FDA approved dose is 600mg IV q12h • Increasing frequency to q8h for serious infections is common despite lack of clinical evidence • May optimize fT>MIC in S. aureus isolates with MIC >1 mg/L

  26. Ceftolozane/tazobactam &Ceftazidime/avibactam:A Side by Side Comparison

  27. Brief overview c/o MacDougall C.

  28. How does ceftolozane combat P. aeruginosa resistance mechanisms? Cabot G, et al. Antimicrob Agents Chemother. 2014 Jun; 58(6): 3091–3099. Moya B, et al. Antimicrob Agents Chemother. 2010 Sep; 54(9): 3933–3937.

  29. Comparative β-lactamase inhibition Table reproduced from Van Duin D, et al. Clin Infect Dis. 2016 Jul 15;63(2):234-41.

  30. In vitro activity: Enterobacteriaceae Farrell DJ, et al. Antimicrob Agents Chemother. 2013;57:6305-6310 HubandM, et al. Antimicrobial Agents Chemother. 2016;60:2537-2541 c/o MacDougall C.

  31. In vitro activity: Pseudomonas Alatoom A, et al. Int J Infect Dis. 2017;62:39-43. c/o MacDougall C.

  32. Comparative Pseudomonasactivity BuehrleD, et al. Antimicrob Agents Chemother. 2016;60:3227-3231.

  33. Approval trials & indications Presentation Title and/or Sub Brand Name Here

  34. More recent ceftazidime/avibactam trials *non-inferiority demonstrated Torres A, et al. Abstract presented at ECCMID 2017. Wagenlehner, et al. Clin Infect Dis. 2016 Sep 15; 63(6): 754–762. Mazuski JE et al. Clin Infect Dis. 2016;62:1380-1389

  35. Ceftazidime-avibactam vs. colistin for CRE infections Results Prospective, multi-center, observational study Consortium on resistance against carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) n=137 patients with documented CRE infection Patient characteristics: mean 61 y/o, 34% critically ill, 32% with renal failure, 18% immunosuppressed Infection characteristics: 46% bacteremia, 22% pneumonia, 97% K. pneumoniae, 88% colistin-sensitive, 96% CTZ/AVI-sensitive n=38 CTZ/AVI n=99 colistin Median duration: 10 days Combination therapy common (63% CTZ/AVI, 94% colistin, p<0.001) Adjusted absolute risk reduction 23% (95% CI 9%-35%) Van Duin D, et al. Clin Infect Dis. 2017 Sep 4; cix783.

  36. Case 44F with CF, hx MDR PsA colonization, failed recent FQ and pip/tazo courses, admitted for CF exacerbation Sputum culture 1 month PTA What would you start?

  37. Send out to UCLA Would you make any antibiotic changes?

  38. Hospital course • Treated with ceftolozane/tazobactam 3g IV q8h x2 weeks • Discharged w/ improved PFTs 3g IV q8h used in adult CF patients to achieve >90% PTA for P. aeruginosa isolates with MICs up to 8 mcg/mL MonogueML, et al. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6578-6584.

  39. Take-home points More potent activity for Pseudomonas aeruginosa Less costly ceftolozane/tazobactam Susceptibility test is send-out lab ceftazidime/avibactam More reliable coverage of ceftriaxone- andcarbapenem-resistant Enterobacteriaceae Active against AmpC, KPC, and OXA-48 β-lactamases Viable alternative to colistin in CRE infections

  40. Role of the UCSF pharmacist • Recognize when patients with MDR infections are potential candidates for ceftaroline, ceftolozane/tazobactam, or ceftazidime/avibactam • And recommend ID consultation! • Identify ceftaroline as a potential offender in patients who develop drug-induced neutropenia • Ensure appropriate dosing especially for special populations (eg, HD and CF patients) • Understand & apply rationale/evidence for off-label dosing when making recommendations or verifying orders

  41. Post Questions Text LynnNguyen456 to 22333 to participate

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  45. Acknowledgments • Conan MacDougall

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