1. Justin Jones, PharmD, BCPS Critical Care Pharmacist Sanford Medical Center, Fargo Bent or Broken? Re-evaluating the β-lactam backbone for ESBL-producing organisms

2. Recommend effective antimicrobial therapy against extended-spectrum Recommend effective antimicrobial therapy against extended-spectrum β-lactamase producing pathogens β-lactamase producing pathogens Objective

3. Background Background Defining extended spectrum β-lactamase Defining extended spectrum β-lactamase Categorizing β-lactamase Categorizing β-lactamase Detecting extended spectrum β-lactamase Detecting extended spectrum β-lactamase Induction of β-lactamase Induction of β-lactamase Therapeutic Strategies Therapeutic Strategies PK/PD considerations PK/PD considerations Updated MIC breakpoints Updated MIC breakpoints Agent-specific considerations Agent-specific considerations Outline

4. ESBL Extended spectrum β-lactamase PK Pharmacokinetic PD Pharmacodynamic MIC Minimum inhibitory concentration CA Clavulanic acid AUC Area under the curve fT>MIC fraction of time drug concentration > MIC CLSI Clinical and Laboratory Standards Institute EUCAST European Committee on Antimicrobial Susceptibility Testing Abbreviations

5. Defining an ESBL

6. Broad spectrum, clavulanate-inhibited β-lactamase, able to hydrolyze an oxyimino-cephalosporin at rates at least 10% that of benzylpenicillin Novel β-latamase families (CTM-X, PER, KPC) Hydrolysis rates < 10% that of benzylpenicillin Resistant to inhibition by CA (class C, D, 2ber) Extended hydrolysis activity (ie. carbapenems, aztreonam) Livermore 2008

7. Categorizing a β-lactamase

8. Bush-Jacoby group Molecular ClassDistinctive Substrate Inhibited by CA/TZB Enzymes 1CCephalosporinsNoAmpC, FOX-1, ACT- 1, MIR-1 1eCCephalosporinsNoGC1, CMY-37 2aAPenicillinsYesPC1 2bAPenicillins, early cephalosprorins YesTEM-1, TEM-2, SHV-1 2beAExtended-spectrum cephalosporins YesTEM-3, SHV-2, CTX- M-15 2brAPencillinsNoTEM-30, SHV-10 2berAExtended spectrum cephalosporins NoTEM-50 2cACarbenicillinYesPSE-1, CARB-3 2ceACarbenicillin, cefepimeYesRTG-4 2dDCloxacillinVariableOXA-1, OXA-10 2deDExtended spectrum cephalosporins VariableOXA-11, OXA-15 2dfDCarbapenemsVariableOXA-23, OXA-48 2eAExtended spectrum cephalosporins YesCepA 2fACarbapenemsVariableKPC-2, IMI-1, SME-1 3aBCarbapenemsNoIMP-1, VIM-1, CcrA, IND-1 3bBCarbapenemsNoCphA, SFH-1 Classification of Beta-Lactamase Bush 2010

9. Detecting Extended Spectrum β-Lactamase

10. 4 ug/mL Ceftriaxone Detection of Resistance CefotaximeCefotaxime + CA 4 ug/mL 0.5 ug/mL Detection of β-lactamase

11. Inducing β-lactamase

12. Inducible Resistance AmpD AmpRAmpC β-lactamase β-lactam Cell wall degradation products Cell Wall Induction of Resistance AmpD AmpR AmpC β-lactamase Cell wall degradation products Cell Wall Stable De-repression McDougall 2011

13. Therapeutic Strategies

14. Carbapenems Cefepime Fluoroquinolones β-lactam/β-lactamasecombinations PolymyxinsAminoglycosides

15. PharmacokineticConsiderations

16. fT > MIC Concentration Time MIC AUC C max Parameters of interest AUC/MIC Cmax/MIC T>MIC

17. Log 10 Kill of ESBL vs Non-ESBL Producing Enterobacteriacea Andes 2005

18. DrugSIR Aztreonam</= 816>/= 32 Cefotaxime</= 816-32>/= 64 Ceftazidime</= 816>/= 32 Ceftriaxone</= 816-32>/= 64 Pre-2010 CLSI Breakpoints for enterobacteriaceae Dudley 2013

19. DrugCLSI Breakpoint Usual Regimen% Attainment of breakpoint PK/PD Breakpoint Cefotaxime8/16-32/641 gram every 8 hours31/2/4 Ceftriaxone8/16-32/641 gram every 24 hours01/2/4 2 grams every 24 hours12/4/8 PK/PD considerations in MIC breakpoints Andes 2005

20. MIC (mg/dL)% Response% Failure </= 18119 26733 42773 >/= 81189 Clinical outcomes by MIC in 42 patients with bacteremia due to E. coli and K. pneumoniae treated with cephalosporin monotherapy Andes 2005

21. SIR </= 48>/= 16 </= 12>/= 4 </= 48>/= 16 </= 12>/= 4 Post-2010 DrugSIR Aztreonam</= 816>/= 32 Cefotaxime</= 816-32>/= 64 Ceftazidime</= 816>/= 32 Ceftriaxone</= 816-32>/= 64 Pre-2010 CLSI Breakpoints for enterobacteriaceae Dudley 2013

22. Probability of attaining fT>MIC of 50% for previous and new MIC breakpoints Dudley 2013

23. Agent-Specific Considerations

24. Penicillin

25. Clavulanic Acid N SO 4 - O N O H2NH2N Avibactam

26. Cephalosporin

27. Carbapenem

28. Livermore, DM Clin Microbiol Infect 2008; 14 (Suppl. 1): 3-10 Bush K, Jacoby G Antimicrob Agents Chemother 2010; 54(3):969-976 McDougall C, J Pediatr Pharmacol Ther 2011;16(1): 23-30 Andes D, Craig A Clin Microbiol Infect 2005 (Suppl. 6):10-17 Dudley M, Ambrose P, Bhavnami S, Clin Infect Dis 2013;56(1 May):1301-1309 References/Further Reading

29. Justin Jones, PharmD, BCPS Critical Care Pharmacist Sanford Medical Center, Fargo Bent or Broken? Re-evaluating the β-lactam backbone for ESBL-producing organisms Questions/Comments

30. 1.Cases of cephalosporin/carbapenem failure in low-MIC ESBL producers 2.Routine clinical susceptibility testing is less precise than research testing 3.No direct testing/reporting will lead to a loss in infection control information 4.Inoculum effect Arguments Agains

31. Strong InducersWeak Inducers Good Substratesampicillin, cephalosporins (1 st generation), cefoxitin ceftazidime, ceftriaxone, cefotaxime, piperacillin, ticarcillin, aztreonam Poor Substratesimipenemmeropenem, cefepime AmpC Induction Profiles McDougall 2011

32. SpeciesCephalosporinsCarbapenemsPenicillins Enterobacter61/548 (11.3%)4/114 (3.5%)6/91 (6.6%) Citrobacter1/39 (2.5%)NA Serratia0/37 (0%)NA Morganella0/21NA Pseudomonas77/719 (10.7%)85/262 (32.4%)85/633 (13.4%) Clinical studies on the emergence of resistance to antimicrobials McDougall 2011