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

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

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

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

Defining an ESBL

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

Categorizing a β-lactamase

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

Detecting Extended Spectrum β-Lactamase

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

Inducing β-lactamase

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

Therapeutic Strategies

Carbapenems Cefepime Fluoroquinolones β-lactam/β-lactamasecombinations PolymyxinsAminoglycosides

PharmacokineticConsiderations

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

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

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

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

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

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

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

Agent-Specific Considerations

Penicillin

Clavulanic Acid N SO 4 - O N O H2NH2N Avibactam

Cephalosporin

Carbapenem

Livermore, DM Clin Microbiol Infect 2008; 14 (Suppl. 1): 3-10 Bush K, Jacoby G Antimicrob Agents Chemother 2010; 54(3): McDougall C, J Pediatr Pharmacol Ther 2011;16(1): 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): References/Further Reading

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

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

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

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