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Welcome to the Jungle: Update on New GNR Agents

Monica V. Mahoney, PharmD, BCPS AQ-ID, BCIDP @mmPharmD Disclosures

• Advisory boards: Qpex, Spero, Tetraphase • Research funding: Merck • Speaker’s bureau: Tetraphase, Cepheid • Off-label uses will be discussed Objectives

1. Identify (recognize) common mechanisms of resistance associated with Gram-negative bacteria 2. Evaluate (assess) the literature for newly approved agents in the treatment of resistant Gram-negative 3. Design (create) an effective treatment regimen for a resistant Gram-negative patient case Each year in the US …

>2.8 million >35,000 -resistant infections deaths

Greater Prolonged Extended Additional disability & costlier hospitalizations doctor treatments visits & death

>$20 billion >$35 billion excess direct healthcare costs lost productivity

2019 Report: https://www.cdc.gov/drugresistance/biggest-threats.html Implicated Gram-Negatives

Carbapenem-resistant Acinetobacter (CRAb) • Candida auris • Clostridioides difficile • -resistant Enterobacterales • Drug-resistant Neisseria gonorrhoeae

Drug-resistant Campylobacter • Drug-resistant Candida • ESBL Enterobacterales • -resistant Enterococcus • MDR-Pseudomonas • Drug-resistant nontyphoidal Salmonella • Drug-resistant Salmonella serotype Typhi • Drug-resistant Shigella • MRSA • Drug-resistant Streptococcus pneumoniae • Drug-resistant TB

Erythromycin-resistant group A Streptococcus • Clindamycin-resistant group B Streptococcus

2019 Report: https://www.cdc.gov/drugresistance/biggest-threats.html 3GCR E. coli

CDDEP Resistance Map. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States. Accessed 11/24/19 Carbapenem Resistant E. coli

CDDEP Resistance Map. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States. Accessed 11/24/19 Carbapenem Resistant K. pneumoniae

CDDEP Resistance Map. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States. Accessed 11/24/19 Carbapenem Resistant Pseudomonas

CDDEP Resistance Map. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States. Accessed 11/24/19 Carbapenem Resistant Acinetobacter

CDDEP Resistance Map. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States. Accessed 11/24/19 Mechanisms of GNR Resistance

Zowawi HM. Nat Rev Urol 2015;12:570-84 Mechanisms of GNR Resistance

1. Decreased permeability

Zowawi HM. Nat Rev Urol 2015;12:570-84 Mechanisms of GNR Resistance

2. Enzymatic modification

Zowawi HM. Nat Rev Urol 2015;12:570-84 Mechanisms of GNR Resistance

3. Altered target sites

Zowawi HM. Nat Rev Urol 2015;12:570-84 Mechanisms of GNR Resistance

4. Active efflux

Zowawi HM. Nat Rev Urol 2015;12:570-84 Question Which of the following currently available could be a treatment option for a metallo-β-lactamase infection? A. Omadacycline + B. Delafloxacin + / C. + / D. Ceftolozane/ + eravacycline Slide courtesy of Rachel Britt, PharmD β-Lactamases

Bacteria- •Different β-lactamases = different drug resistance produced patterns enzymes •Two main β-lactamase classification systems •Ambler Hydrolyze β- •Bush-Jacoby-Medeiros lactam ring •Four Ambler classes • A – Serine ESBLs, carbapenemases • B – MBLs β-lactam • C – AmpC resistance • D – OXA enzymes1

ESBL: extended spectrum β-lactamase , MBL: metallo-β-Lactamase

Ghafourian S, et al. Curr Issues Mol Biol. 2015;17:11-22; Liscio JL, et al. Int J Antimicrob Agents. 2015;46:266-71 Slide courtesy of Rachel Britt, PharmD Metallo-β-Lactamases (MBL)

• Hydrolyze β-lactam ring through the use of zinc ions • Different subclasses and subtypes

Verona integrin-encoded MBL (VIMs) Imipenemase (IMPs) New Delhi MBL (NDMs) • Can be chromosomally-mediated or acquired • Lead to resistance to all β-lactam antibiotics except • Found in Gram-negative organisms, like Enterobacterales

Mojica MF, et al. Curr Drug Targets. 2016;17:1029-50; Cornaglia G, et al. Lancet Infect Dis. 2011;11:381- 93; Wang Z, et al. Curr Opin Chem Biol. 1999;3(5):614-22. β-Lactamases

Ambler Enzyme Type Examples Antibiotic Activity Class (Inhibited by) A Narrow-spectrum TEM-1, TEM-2, Avibactam, clavulanate, tazobactam, SHV-1 vaborbactam A Extended-spectrum SHV, CTX, Avibactam, clavulanate, tazobactam, (ESBL) KLUG vaborbactam A Serine carbapenemase KPC Avibactam, vaborbactam

B Metallo-β-lactamase VIM, IMP, NDM Aztreonam (MBL), carbapenemase C ESBL, cephalosporinase AmpC Avibactam, , ceftolozane, vaborbactam D Carbapenemase OXA Avibactam

Liscio JL. IJAA 2015;46:266-71; Pogue JM. CID 2019;68:519-24 FDA Recap: Last 6 Years Generic Name Brand Name Description Indication Approval Ceftolozane / Zerbaxa Novel anti-Psa + β- cUTI, cIAI, 2014 tazobactam lactamase inhibitor HABP/VABP Ceftazidime / Avycaz Anti-Psa cephalosporin + novel cUTI, cIAI, 2015 avibactam diazabicyclooctane inhibitor HABP/VABP Meropenem / Vabomere Anti-Psa carbapenem + novel boronic cUTI 2017 vaborbactam acid-based inhibitor Plazomicin Zemdri AG not susceptible to AG modifying cUTI 2018 enzymes Eravacycline Xerava Fluorocycline cIAI 2018 – Recarbrio Anti-Psa carbapenem + novel cUTI, cIAI 2019 cilastatin / diazabicylooctane inhibitor Fetroja Novel cephalosporin using iron cUTI 2019 transport mechanisms Psa: Pseudomonas; cUTI: complicated urinary tract infection; cIAI: complicated intra-abdominal infection; HABP: hospital acquired bacterial pneumonia; VABP: ventilator- associated bacterial pneumonia; AG: aminoglycoside; ABSSSI: acute bacterial skin and skin structure infection; CABP: community-acquired bacterial pneumonia Question Which of the following currently available antibiotics could be a treatment option for a metallo-β-lactamase infection? A. Omadacycline + fosfomycin B. Delafloxacin + meropenem/vaborbactam C. Aztreonam + ceftazidime/avibactam D. Ceftolozane/tazobactam + eravacycline Problem Organisms

ESBL CRE

Pseudomonas Acinetobacter Use Your Illusion I: ESBL Question A patient with no relevant medical history presents with a wound infection, sustained from a cut 3 days ago. Blood and wound cultures grow E. coli, with the susceptibilities pending. The primary team wants to change from /tazobactam to meropenem. How do you respond? A. Change to meropenem because the Merino trial proved that meropenem is better than piperacillin/tazobactam. B. Change to because this patient is from the community. C. Continue the piperacillin/tazobactam because the Merino trial studied definitive treatment rather than empiric treatment. D. Change to oral therapy because this is an uncomplicated infection. Preference for ESBL

E. coli or Not susceptible to PTZ 4.5g IV q6h (n=188) K. pneumoniae BSI or MER 1g IV q8h (n=191)

72h 4-14 days post-randomization

Harris PNA. JAMA 2018;320:984-94 PTZ MER Preference for ESBL

E. coli or Not susceptible to PTZ 4.5g IV q6h (n=188) K. pneumoniae BSI ceftriaxone or cefotaxime MER 1g IV q8h (n=191)

72h 4-14 days post-randomization 80% BSI Source

60%

40%

20%

0% UTI IAI CVC SSI PNA F&N MSK SSTI Other ??

Harris PNA. JAMA 2018;320:984-94 PTZ MER Preference for ESBL

E. coli or Not susceptible to PTZ 4.5g IV q6h (n=188) K. pneumoniae BSI ceftriaxone or cefotaxime MER 1g IV q8h (n=191)

72h 4-14 days post-randomization 80% BSI Source 1 Pitt BSI 60% 1 40.3% qSOFA >2 40% 45.7% 2 Charlson 20% 2 21 APACHE II 17.9 0% UTI IAI CVC SSI PNA F&N MSK SSTI Other ?? 0 10 20 30 40 50

Harris PNA. JAMA 2018;320:984-94 PTZ MER The Spaghetti Incident

Interim analysis at 340 patients approaching pre-specified stopping rule 30-Day Mortality:

Harris PNA. JAMA 2018;320:984-94 The Spaghetti Incident

Interim analysis at 340 patients approaching pre-specified stopping rule 30-Day Mortality:

Piperacillin/tazobactam Meropenem 12.3% (23/187) 3.7% (7/191)

Harris PNA. JAMA 2018;320:984-94 Subgroup Analysis – 30d Mortality

40%

30% 27.8%

23.1%

20% 18.8%

14.3%

% Mortality % 10.7% 10.6% 10% 8.2% 6.9% 4.2% 4.8% 3.9% 3.9% 3.1% 3.1%

0% Pitt >4 Pitt <4 Ecoli Klebsiella Approp Inapprop Urine Non-Urine PTZ MER

Harris PNA. JAMA 2018;320:984-94 Piperacillin/tazobactam Distribution

60

50 EUCAST 40 CLSI

30 Frequency

20

10

0

MIC (mcg/mL)

MERINO Trial Supplemental Material Piperacillin/tazobactam Distribution

60 100%

50 75% 67% EUCAST 40 50% 43% CLSI 30% 30 Mortality 25% Frequency 12% 11% 3% 3% 20 0% 0% 1 2 4 8 16 32 64 128 10 MIC (mcg/mL)

0

MIC (mcg/mL)

MERINO Trial Supplemental Material Piperacillin/tazobactam Distribution

60 100%

50 75% 67% EUCAST 40 50% 43% CLSI 30% 30 Mortality 25% Frequency 12% 11% 3% 3% 20 0% 0% 1 2 4 8 16 32 64 128 10 MIC (mcg/mL)

0 Piperacillin/tazobactam Meropenem MIC (mcg/mL) 11.5% (18/157) 3.7% (6/164)

MERINO Trial Supplemental Material Question A patient with no relevant medical history presents with a wound infection, sustained from a cut 3 days ago. Blood and wound cultures grow E. coli, with the susceptibilities pending. The primary team wants to change from piperacillin/tazobactam to meropenem. How do you respond? A. Change to meropenem because the Merino trial proved that meropenem is better than piperacillin/tazobactam. B. Change to cefazolin because this patient is from the community. C. Continue the piperacillin/tazobactam because the Merino trial studied definitive treatment rather than empiric treatment. D. Change to oral therapy because this is an uncomplicated infection. Use Your Illusion II: CRE Question Which of the following has activity against carbapenem-resistant Enterobacteriaceae? A. Ceftolozane/tazobactam B. Meropenem/vaborbactam C. Aztreonam D. Ceftazidime/avibactam

Ceftazidime • Existing anti-Psa cephalosporin • Stable against porin channel changes () • Inactivated by ESBL, KPC enzymes

Ceftazidime Avibactam • Novel non-β-lactam β-lactamase inhibitor • Stable against ESBLs, KPC & OXA-48 enzymes

• Inactivated by MBLs Avibactam

Avycaz PI. Allergan. Madison, NJ 2019; Liscio JL. IJAA 2015;46:266-71 Meropenem/vaborbactam

Meropenem • Existing anti-Psa carbapenem • Stable against ESBL, cephalosporinases • Inactivated by carbapenemases Meropenem

Vaborbactam • Novel boronic-acid β-lactamase inhibitor • Stable against ESBLs, KPC enzymes • Inactivated by MBLs Vaborbactam

Vabomere PI. Melinta. Lincolnshire, IL. 2018 Imipenem-cilastatin/relebactam

Imipenem-cilastatin • Existing anti-Psa carbapenem • Stable against AmpC, ESBL • Inactivated by carbapenemases Imipenem

Relebactam • Novel diazabicylooctane, non-β-lactam, β-lactamase inhibitor • Stable against AmpC, ESBL, KPC • Inactivated by MBL, OXA Relebactam

Sims M. J Antimicrob Chemother 2017;72:2616-26; Lucasti C. Antimicrob Agents Chemother 2016;60:6234-43 Plazomicin

• Semisynthetic aminoglycoside • 3 key modifications protect against most AMEs • No hydroxyl group at 3’ and 4’ • Unsaturated hydroxyethyl group at 6’ • 4-amino-3-hydroxybutanoic acid at N-1 substitution • MOA: • Binds to 30S subunit • Inhibits protein synthesis • Dose: 15 mg/kg IV q24h Amikacin Plazomicin

Zemdri PI. Achaogen. South San Francisco, CA. 2018; ElJaaly K. Drugs 2019 doi: 10.1007/s40265-019-1054-3 In Vitro CRE Studies

100 100 100

90 90 90

80 80 80

70 70 70

% Susceptible % Susceptible % % Susceptible % 60 60 60 9%

50 50 50 MER/VAB CAZ/AVI TIG PLZ AMK TIG CAZ/AVI IMI IMI/REL K. pneumoniae E. coli Enterobacter Enterobacter Estimate K. pneumoniae n=878 n=35 n=29 n=97 n=103

Hackel MA. AAC 2017;62:e01904-17; Castanheira M AAC 2018;62:e00313-18; Papp-Wallace KM. AAC 2018;62:e00174-18 In vivo CRE Studies: CAZ/AVI

CRACKLE Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae

CR-Klebsiella Any CRE

2011 2012 2013 2014 2015 2016

CAZ/AVI availability

van Duin D et al. CID 2018;66:163-71 In vivo CRE Studies: CAZ/AVI

CRACKLE Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae

CR-Klebsiella Any CRE

2011 2012 2013 2014 2015 2016

Infection Source CAZ/AVI availability

8%

10% BSI PNA 46% 14% UTI Wound

22% Other van Duin D et al. CID 2018;66:163-71 In vivo CRE Studies: CAZ/AVI

CRACKLE Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae

CR-Klebsiella Any CRE

2011 2012 2013 2014 2015 2016

Infection Source CAZ/AVI availability

8%

10% BSI PNA 46% 14% UTI CAZ/AVI (n=38) COL (n=99) Wound Hospital mortality 3 (8%) 33 (33%) Other 22% AKI 1 (4%) 5 (11%) van Duin D et al. CID 2018;66:163-71 In vivo CRE Studies: MER/VAB

1x Infection due to BAT • Monotherapy: CAZ/AVI confirmed / • Monotherapy/Combination: suspected CRE MER/VAB 4g IV • • Aminoglycoside 2x q8h (over 3h) • Carbapenem • Tigecycline

Wunderink R. Infect Dis Ther 2018;7:439-55 In vivo CRE Studies: MER/VAB

1x Infection due to BAT • Monotherapy: CAZ/AVI confirmed / • Monotherapy/Combination: suspected CRE MER/VAB 4g IV • Polymyxin • Aminoglycoside 2x q8h (over 3h) • Carbapenem • Tigecycline

Infection Source 9% BSI 11% 47% cUTI/AP

HAP/VAP 34% cIAI

Wunderink R. Infect Dis Ther 2018;7:439-55 In vivo CRE Studies: MER/VAB

1x Infection due to BAT • Monotherapy: CAZ/AVI confirmed / • Monotherapy/Combination: suspected CRE MER/VAB 4g IV • Polymyxin • Aminoglycoside 2x q8h (over 3h) • Carbapenem • Tigecycline

Infection Source MER/VAB (n=32) BAT (n=15) 9% BSI Cure EOT 21 (65.6%) 5 (33.3%) 11% 47% cUTI/AP Cure TOC 19 (59.4%0 4 (26.7%)

HAP/VAP Micro cure EOT 21 (65.6%) 6 (40.0%) 34% Micro cure TOC 17 (53.1%) 5 (33.3%) cIAI 28d mortality 5 (15.6%) 5 (33.3%)

Wunderink R. Infect Dis Ther 2018;7:439-55 In vivo CRE Studies: Plazomicin

PLZ 15 mg/kg q24h + (MER or TGC) CRE HAP/VAP or BSI (goal n=286) COL 5 mg/kg/day + (MER or TGC)

72 h 7-14 days

McKinnell NEJM 2019;380: In vivo CRE Studies: Plazomicin

PLZ 15 mg/kg q24h + (MER or TGC) CRE HAP/VAP or BSI (goal n=286) COL 5 mg/kg/day + (MER or TGC)

72 h 7-14 days PLZ (n=17) COL (n=20) %Δ (90% CI) 28d mortality 4/17 (23.5%) 10/20 (50%) -26.5 (-51.2 to 0.7) d5 BSI clearance 12/14 (85.7%) 7/15 (46.7%) 39 (9.4 to 65.5) ADRs 9/18 (50%) 17/21 (81%) AKI 2/12 (16.7%) 8/16 (50%)

McKinnell NEJM 2019;380: Question Which of the following medications has activity against carbapenem-resistant Enterobacteriaceae? A. Ceftolozane/tazobactam B. Meropenem/vaborbactam C. Aztreonam D. Ertapenem Take Me Down to the Paradise City Question A 55 year old man with epilepsy on valproic acid and levetiracetam presents to the hospital for a suspected pulmonary infection. He has a history of multi-drug resistant infections. Which of the following antibiotics is most appropriate to recommend for empiric therapy? A. Fosfomycin B. Eravacycline C. Meropenem/vaborbactam D. Ceftazidime/avibactam Ceftolozane/tazobactam

Ceftolozane • Novel anti-Psa cephalosporin • Stable against AmpC

• Inactivated by ESBL, carbapenemases Ceftolozane

Tazobactam • Existing β-lactamase inhibitor • Stable against ESBLs, cephasporinases • Inactivated by AmpC, carbapenemases Tazobactam

Zerbaxa PI. Merck. Syracuse, NY. 2018; Liscio JL. IJAA 2015;46:266-71 In vitro MDR Pseudomonas Studies

CLSI Breakpoint = mode n=750 n=4650 100 35% 90 30% 80 70 25% 60 20% 50

40 15% % % Susceptible 30 10% 20 10 5%

0 0% 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 >128 IMI/REL IMI PTZ AMI COL IMI IMI/REL

Karlowsy JA. DMID doi: 10.1016/j.diagmicrobio.2019.05.001; Young K. BMC Microbiol 2019;19:150 In vivo: MDR Pseudomonas

TOL/TAZ ≥ 48h +/- inhaled COL / AG (n=100) MDR or XDR Pseudomonas COL or AG backbone ≥ 48h +/- inhaled COL / AG (n=100)

Infection Type 60% 50% TOL/TAZ COL or AG aOR (95% CI) 40% n=100 n=100 30% Clinical cure 81% 61% 2.63 (1.31-5.30) 20% In-hospital 20% 25% 0.62 (0.30-1.28) 10% mortality 0% VAP HAP UTI Wound Other AKI 6% 34% 0.08 (0.03-0.22) TOL/TAZ COL or AG

Pogue JM et al. CID 2019; doi: 10.1093/cid/ciz816 In vivo CR-Psa: IMI/REL vs. IMI+COL

GNR Infection: 2x IMI/REL 500/250mg IV q6h (n=31) • Non-S to IMI • S to COL & IMI/REL 1x IMI 500mg IV q6h + COL 300mg LD, 150mg IV q12h (n=16)

Min: 5-7 days Max: 21 days Overall Response: • HAP/VAP: 28d all-cause mortality • cIAI: 28d clinical response • cUTI: clinical/micro response ≤ 24h after last dose

Matsch J. CID 2019 doi: 10.1093/cid/ciz530 In vivo CR-Psa: IMI/REL vs. IMI+COL

Infection Sources Organisms 8 20

6 15

4 10

2 5

Frequency Frequency 0 0 HAP VAP cUTI cAP cIAI Citro Enterob K. oxytoca K. pneumo Psa IMI/REL IMI + COL

Matsch J. CID 2019 doi: 10.1093/cid/ciz530 In vivo CR-Psa: IMI/REL vs. IMI+COL

Infection Sources Organisms 8 20

6 15

4 10

2 5

Frequency Frequency 0 0 HAP VAP cUTI cAP cIAI Citro Enterob K. oxytoca K. pneumo Psa IMI/REL IMI + COL IMI/REL IMI + COL %∆ (95% CI) Overall Response 15/21 (71.4%) 7/10 (70.0%) -7.3 (-2.75 to 21.4) Day 28 response 15/21 (71.4%) 4/10 (40.0%) 26.3 (1.3 to 51.5) 28d all-cause mortality 2/21 (9.5%) 3/10 (30.0%) -17.3 (-46.4 to 6.7) Txt-related AKI 3/29 (10.3%) 9/16 (56.3%) -45.9 (-69.1 to -18.4) Matsch J. CID 2019 doi: 10.1093/cid/ciz530 Question A 55 year old man with epilepsy on valproic acid and levetiracetam presents to the hospital for a suspected pulmonary infection. He has a history of multi-drug resistant Pseudomonas aeruginosa infections. Which of the following antibiotics is most appropriate to recommend for empiric therapy? A. Fosfomycin B. Eravacycline C. Meropenem/vaborbactam D. Ceftazidime/avibactam Sweet Child o’ Mine: Acinetobacter Eravacycline • Fluorocycline • Stable against tetracycline resistance mechanisms: • Fluorine at C7 Minocycline • Pyrrolidinoacetamido at C9 C7 • MOA: • Bind to 30s subunit • Inhibit protein synthesis C9 Eravacycline

Heaney M. Annals Pharmacother 2019;53:1124-35; Xerava PI. Tetraphase. Watertown, MA. 2018 In vitro MDR GNR Studies

16 >16 >16 >64 >64 16 32 >64 3232 10 9 8 7 6

mcg/mL 5 4 3 2 1 0 Enterobacterales E.coli K. pneumoniae S. maltophilia A. baumannii CRE n=666 n=15 n=142 n=469 n=503 n=110

ERV TIG MIN AMK Solid: MIC50 Stripe: MIC90

Lawrence KR. ASM Microbe 2018. Poster 630; Zhang Y. J Antibiotics 2016;69:600-4 Eravacycline: In vivo Acinetobacter

IGNITE 1: IGNITE 4:

ERV ETP ERV MER Acinetobacter 8/8 6/6 Acinetobacter 5/5 2/2 Cepha-R 8/8 5/5 ESBL 5/5 1/1 CR-Ab 2/2 4/4 MDR 7/7 4/4

Solomkin JS. JAMA Surgery 2017;152:224-32; Solomkin JS. CID 2018 doi: 10.1093/cid/ciy1029 Meta-analysis for MDR, XDR Acinetobacter

Systematic Review: Network Meta-analysis 29 studies 26 studies

Patients: 2529 Media age: 60 years Pneumonia: 58.5% XDR Acinetobacter: 45.0% MDR Acinetobacter: 41.0%

Kengkla K et al. J Antimicrob Chemother 2018;73:22-32 Meta-analysis for MDR, XDR Acinetobacter

Systematic Review: Network Meta-analysis 29 studies 26 studies

Patients: 2529 Media age: 60 years Pneumonia: 58.5% XDR Acinetobacter: 45.0% MDR Acinetobacter: 41.0%

COL

Kengkla K et al. J Antimicrob Chemother 2018;73:22-32 Meta-analysis for MDR, XDR Acinetobacter

Systematic Review: Network Meta-analysis 29 studies 26 studies

Patients: 2529 Media age: 60 years Pneumonia: 58.5% XDR Acinetobacter: 45.0% MDR Acinetobacter: 41.0%

Clinical cure COL + SUL + TGC = best

COL Micro cure COL + other >> COL; TGC; TGC + other

All-cause mortality COL + other >> SUL + other

Nephrotoxicity COL >> TGC; TGC + other

Kengkla K et al. J Antimicrob Chemother 2018;73:22-32 Don’t You Cry: Review of Current Agents Summary of Current Agents

Drug ESBL CRE CRE CR Pseudo MDR Acineto (KPC) (MBL) TOL/TAZ CAZ/AVI MER/VAB IMI/REL Plazomicin Eravacycline All We Need is Just a Little Patience Question Which of the following antimicrobials uses iron transport mechanisms and a “trojan horse” approach as part of its mechanism of action? A. Eravacycline B. Cefiderocol C. Fosfomycin D. Quinupristin/dalfopristin Coming Attractions

Cefiderocol

Aztreonam/avibactam

Sulopenem

Tebipenem Cefiderocol Siderophore cephalosporin • 3’ catechol substitution

− Utilizes iron transport mechanisms to ↑ Ceftazidime periplasmic [ ] 7 • 7’ carboxypropyl-oxyimino group − Stable against broad β-lactamases 3 Structurally similar to ceftazidime and Cefiderocol cefepime

Cefepime

Zhanel GA. Drugs 2019;79:271-89 Cefiderocol: MOA

www.fetroja.com Accessed: 12/15/19 Cefiderocol: MOA

www.fetroja.com Accessed: 12/15/19 Cefiderocol Mechanisms of Resistance: Organisms: • Enzymatic hydrolysis • Acinetobacter • Porin channel mutations • Pseudomonas • Efflux pump override • Stenotrophomonas • Target site mutations • Gram-positive β-lactamases: • Anaerobes • CTX-M • KPC • NDM • OXA • VIM

Zhanel GA. Drugs 2019;79:271-89 Cefiderocol Mechanisms of Resistance: Organisms: • Enzymatic hydrolysis ✓ • Acinetobacter • Porin channel mutations ✓ • Pseudomonas • Efflux pump override ✓ • Stenotrophomonas • Target site mutations  • Gram-positive β-lactamases: • Anaerobes • CTX-M • KPC • NDM • OXA • VIM

Zhanel GA. Drugs 2019;79:271-89 Cefiderocol Mechanisms of Resistance: Organisms: • Enzymatic hydrolysis ✓ • Acinetobacter • Porin channel mutations ✓ • Pseudomonas • Efflux pump override ✓ • Stenotrophomonas • Target site mutations  • Gram-positive β-lactamases: • Anaerobes • CTX-M ✓ • KPC ✓ • NDM ✓ • OXA ✓ • VIM ✓

Zhanel GA. Drugs 2019;79:271-89 Cefiderocol Mechanisms of Resistance: Organisms: • Enzymatic hydrolysis ✓ • Acinetobacter ✓ • Porin channel mutations ✓ • Pseudomonas ✓ • Efflux pump override ✓ • Stenotrophomonas ✓ • Target site mutations  • Gram-positive  β-lactamases: • Anaerobes  • CTX-M ✓ • KPC ✓ • NDM ✓ • OXA ✓ • VIM ✓

Zhanel GA. Drugs 2019;79:271-89 CR-GNRs: In Vitro

100%

80%

60%

40%

20%

0% Enterobacteriaceae Pseudomonas Acinetobacter Stenotrophomonas n=1022 n=262 n=368 n=217

FDC CAZ/AVI TOL/TAZ CIP COL

Yamano Y. CID 2019;69:S544-51 Cefiderocol (Resistant Pathogens)

CREDIBLE-CR 1x BAT (n=49) • COL monotherapy (15.8%) • COL + TCG (7.9%) Infection due to • COL + AMP/SUL (5.3%) CRE FDC 2g IV q8h* • COL + FOS (5.3%) 2x (n=101) • Non-COL (21.1%)

Infection Source Organisms 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% PNA BSI/Sepsis cUTI Acinetobacter Klebsiella Pseudomonas Ecoli FDC BAT FDC BAT

*could receive 1 additional GNR agent FDA submission dossier: https://www.fda.gov/media/131705/download Cefiderocol Results

Clinical Cure Early End of Test of cure Follow-up assessment therapy (TOC) (FU) Micro Eradication (EA) (EOT)

FDA submission dossier: https://www.fda.gov/media/131705/download Cefiderocol Results

Clinical Cure Early End of TestTest ofof curecure Follow-up assessment therapy (TOC)(TOC) (FU) Micro Eradication (EA) (EOT)

FDA submission dossier: https://www.fda.gov/media/131705/download Cefiderocol Results

Clinical Cure Early End of TestTest ofof curecure Follow-up assessment therapy (TOC)(TOC) (FU) Micro Eradication (EA) (EOT)

Outcomes 80% Cure Micro 60%

40%

20%

0% Overall PNA BSI cUTI Overall PNA BSI cUTI

FDC BAT

FDA submission dossier: https://www.fda.gov/media/131705/download Cefiderocol Results

Clinical Cure Early End of TestTest ofof curecure Follow-up assessment therapy (TOC)(TOC) (FU) Micro Eradication (EA) (EOT)

Outcomes Mortality 80% 40% Cure Micro 60% 30% 40% 20% 20% 10% 0% Overall PNA BSI cUTI Overall PNA BSI cUTI 0% 14-day 28-day Study End FDC BAT FDC BAT

FDA submission dossier: https://www.fda.gov/media/131705/download Aztreonam/Avibactam

Ambler Example Class A TEM-1, TEM- 2, SHV-1 A SHV, CTX, KLUG A KPC B VIM, IMP, NDM C AmpC D OXA

Castanheira M. ECCMID 2013. Poster P1615 Aztreonam/Avibactam

Ambler Example Class

A TEM-1, TEM- Avibactam 2, SHV-1

A SHV, CTX, Avibactam KLUG A KPC Avibactam B VIM, IMP, NDM C AmpC Avibactam

D OXA Avibactam

Castanheira M. ECCMID 2013. Poster P1615 Aztreonam/Avibactam

Ambler Example Class

A TEM-1, TEM- Avibactam 2, SHV-1

A SHV, CTX, Avibactam KLUG A KPC Avibactam B VIM, IMP, Aztreonam NDM C AmpC Avibactam

D OXA Avibactam

Castanheira M. ECCMID 2013. Poster P1615 Aztreonam/Avibactam

Ambler Example

Class 16 64 32 >64 64 >64 >64 >64 32 >64 16 >64 32 >64 4 A TEM-1, TEM- Avibactam 2, SHV-1 3.5 3 2.5 A SHV, CTX, Avibactam KLUG 2

1.5 mcg/mL A KPC Avibactam 1 0.5 B VIM, 0 IMP, Aztreonam NDM

C AmpC Avibactam n=130 MBL isolates

ATM ATM/AVI Solid: MIC50 Stripe: MIC90 D OXA Avibactam

Castanheira M. ECCMID 2013. Poster P1615 Aztreonam/Avibactam: Coming Attractions NCT03580044: n=40 ATM/AVI (+/- MTZ) Serious infection due to MBL- producing GNR n=20 BAT: (COL, FOF, MER, TGC)

NCT03329092: ATM/AVI (+/- MTZ)

Serious infection due to GNR (n=375) MER (+/- COL)

NCT03978091: ATM alone, CAZ/AVI alone, ATM + CAZ/AVI PK study (n=48) Intermittent vs. Continuous www.clinicaltrials.gov Accessed: 7/21/19 Sulopenem & Tebipenem

Oral carbapenem prodrugs • Sulopenem-etzadroxil/probenecid

• Tebipenem-pivoxyl Prodrug

Stable against: Sulopenem • ESBL, AmpC

Inactivated by: Imipenem • KPC, OXA, MBL Similar activity to ertapenem Tebipenem Prodrug

Rubio A ACS Infect Dis 2018;4:1436-8; Mendes RE. ASM Microbe 2018 Poster Sunday-560 Sulopenem: SURE-3

Sulopenem 1000 mg IV q24h Sulopenem-Etzadroxil/Probenecid 500mg  18 years w PO BID cIAI (n=670) Ertapenem 1000 mg IV q24h CIP 500mg PO BID + MTZ 500mg PO QID

 5 days 7-10 days

Iterum Therapeutics Press Release: 12/10/19; www.clinicaltrials.gov Accessed: 4/15/19 Sulopenem: SURE-3

Sulopenem 1000 mg IV q24h Sulopenem-Etzadroxil/Probenecid 500mg  18 years w PO BID cIAI (n=670) Ertapenem 1000 mg IV q24h CIP 500mg PO BID + MTZ 500mg PO QID

 5 days 7-10 days

Primary Endpoint: • 28 day microMITT

Sulopenem Ertapenem 85.5% 90.2%

Iterum Therapeutics Press Release: 12/10/19; www.clinicaltrials.gov Accessed: 4/15/19 Sulopenem: SURE-3

Sulopenem 1000 mg IV q24h Sulopenem-Etzadroxil/Probenecid 500mg  18 years w PO BID cIAI (n=670) Ertapenem 1000 mg IV q24h CIP 500mg PO BID + MTZ 500mg PO QID

 5 days 7-10 days

Primary Endpoint: Adverse Events: • 28 day microMITT Sulopenem Ertapenem Overall 6.0% 5.1% Sulopenem Ertapenem 85.5% 90.2% Diarrhea 4.5% 2.4%

Iterum Therapeutics Press Release: 12/10/19; www.clinicaltrials.gov Accessed: 4/15/19 Question Which of the following antimicrobials uses iron transport mechanisms and a “trojan horse” approach as part of its mechanism of action? A. Eravacycline B. Cefiderocol C. Fosfomycin D. Quinupristin/dalfopristin Nothing Lasts Forever, Even Old ’s Reign Colistin: Mortality Rates Comparator Colistin

CR-Enterobacteriaceae CR-Pseudomonas CR-Acinetobacter CR-GNRs

75% 75% 75% 75%

60% 60% 60% 60%

45% 45% 45% 45%

30% 30% 30% 30%

15% 15% 15% 15%

0% 0% 0% 0% van Duin Wunderink McKinnel Pogue Matsch Kengkla FDA CAZ/AVI MER/VABI PLZ TOL/TAZ IMI/REL Multiple Multiple Summary of Current/Future Agents

Drug ESBL CRE (KPC) CRE (MBL) CR Pseudo MDR Acineto TOL/TAZ CAZ/AVI MER/VAB IMI/REL Plazomicin Eravacycline ATM/AVI Cefiderocol Fosfomycin Tebipenem Sulopenem

Blue font indicates PO option New BL/BLI Comparison

Ceftolozane / Ceftazidime / Meropenem / Imipenem / tazobactam avibactam vaborbactam relebactam Dose 1.5 g IV q8h 2.5 g IV q8h 4 g IV q8h 1.5 g IV q6h 3 g IV q8h (PNA) Infusion time 1 hour 2 hours 3 hours 0.5 hour Dose CrCl < 50 mL/min CrCl < 50 mL/min eGFR < 50 CrCl < 90 mL/min adjustments mL/min/1.73m2 Elimination Renal, mostly as Renal, mostly Renal, ~50% as Renal, ~63% as unchanged drug unchanged drug unchanged drug unchanged drug Notes Must add MTZ for Must add MTZ for Drug only stable for IAI IAI 4 hours (RT) once mixed Cost (day)* $410.19 $1291.71 $1188 ?? ($820.38 PNA)

*per UpToDate 12/15/19 Zerbaxa PI. Merck; Syracuse, NY. 2018; Avycaz PI. Allergan; Madison, NJ 2019; Vabomere PI. Melinta; Lincolnshire, IL. 2018 Tetracycline Comparison

Eravacycline Tigecycline Minocycline Dose 1 mg/kg IV q12h LD: 100 mg IV x 1 LD: 200 mg x 1 MD: 50 mg IV q12h MD: 100 mg q12h Dosage form IV IV IV, PO Infusion time 60 min 30-60 min 60 min Dose Child-Pugh C: Child-Pugh C: None adjustments 1 mg/kg q12h x 2; MD: 25 mg IV q12h then 1 mg/kg q24h (Max dose 200 mg/day) Metabolism CYP 3A4 Negligible Hepatic Excretion Urine (34%), Urine (33%), Urine (5-12%), feces (47%) feces (59%) feces (20-34%)

Xerava PI. Tetraphase. Watertown, MA. 2018; Tygacil PI. Pfizer. Philadelphia, PA. 2018 Tetracycline Comparison

Eravacycline Tigecycline Minocycline ADRs Infusion reaction (7.7%) Nausea (26%) Dizziness (9%) Nausea (6.5%) Vomiting (18%) Fatigue (9%) Vomiting (3.7%) Diarrhea (12%) Pruritis (5%) Diarrhea (2.3%) Abdominal pain (6%) Malaise (4%) Hypotension (1.3%) Headache (6%) Wound dehiscence (1.3%) AST/ALT increase (3%) *Esophagitis Cost (day) * $176.40 ~$300.00 $389.12 (IV) $2.76 (PO)

*per UpToDate 12/15/19

Xerava PI. Tetraphase. Watertown, MA. 2018; Tygacil PI. Pfizer. Philadelphia, PA. 2018 Multiplex Resistance Gene Comparison

Resistance Genes FilmArray Verigene PhenoTest Cepheid Carba-R Gram-negative CTX-M (ESBL) * ✔ IMP (carbapenemase) * ✔ ✔ KPC (carbapenemase) ✔ ✔ ✔ NDM (carbapenemase) * ✔ ✔ OXA (carbapenemase) * ✔ ✔ VIM (carbapenemase) * ✔ ✔ mcr-1 *

*in development, 2nd generation Conclusions

ESBL CRE

• Once susceptibilities known, • Data supports CAZ/AVI, MER/VAB carbapenem preferred & PLZ over colistin • Monotherapy may be sufficient • Potential for ERV, FDC

Pseudomonas Acinetobacter

• Data supports TOL/TAZ, CAZ/AVI, • Still looking for holy grail IMI/REL over colistin • COL triple therapy has data, ERV • FDC?? may be an option • FDC?? If you weren’t a GNR fan before …

Welcome to the jungle, We’ve got fun and games. We got everything you want, Honey, we know the names. We are the people that can find, Whatever you may need. If you got the money, Honey, we got your disease.

Rose, Axl. Appetite for Destruction. 1987 Welcome to the Jungle: Update on New GNR Agents

Monica V. Mahoney, PharmD, BCPS AQ-ID, BCIDP @mmPharmD