Stewardship in the Setting of Multidrug-Resistant Gram-Negative Organisms

1. Stewardship in the Setting of Multidrug-Resistant Gram-Negative Organisms Pranita D. Tamma, M.D., M.H.S Johns Hopkins University School of Medicine Associate Professor, Pediatrics

2. Disclosures • I have received a research grant from Merck, unrelated to this topic. • I have no conflicts of interest

3. Objectives • Explain mechanisms of carbapenem resistance • Discuss the role of novel β-lactams in the treatment of carbapenem resistant gram-negative organisms • Review approaches to reporting carbapenem-resistant organisms to clinicians

4. How Did We Get Here? • Bacterial resistance is not a new phenomenon • Multidrug resistance has been found in bacteria from environments separated from human activity for millions of years • For decades resistance profiles of gram-negative organisms were relatively stable • Bacterial resistance accelerated with antibiotic overuse Lechuguilla Cave, New Mexico Bhullar, et al. Plos One. 2012;7:e34953.

5. Urgent Threats: Centers for Disease Control and Prevention Clostridiodes difficile Carbapenem-resistant Enterobacteriaceae Neisseria gonorrhoeae

6. Mechanisms of Carbapenem Resistance Zowawi HM, et al. Nat Rev Urol2015;12:570-84.

7. Carbapenemases *Because mobile genetic elements carrying carbapenemase genes may also carry ESBL genes (Class A) and/or AmpC encoding-genes (Class C), anticipated antibiotic susceptibility profiles for β-lactams may appear inconsistent

8. Does Knowing if CRE are Carbapenemase Producing Matter? • Prognosis • The odds of dying within 14 days are more than 4 times greater for CP-CRE compared with non-CP-CRE bacteremicpatients • Spread to other patients • Dissemination between organisms and patients more likely with carbapenemase vs. non-carbapenemase producing organisms • Treatment decisions • Antibiotic selection varies by type of carbapenemase Tamma PD, et al. ClinInfect Dis. 2017;64:257-264.

9. Pranita D. Tamma, Patricia J. Simner

10. US FDA Approved Drugs

11. Aztreonam/Avibactam

12. Aztreonam NDMs, VIMs, IMPs

13. Avibactam Aztreonam ESBLs, AmpCs, KPCs, OXA-48-like NDMs, VIMs, IMPs

14. Activity of Aztreonam/Avibactam Against CRE * In vitro data suggest aztreonam/avibactam is also effective against isolates simultaneously producing both serine and MBL carbapenemases Sader H, et al. Antimicrob Ag Chemother 2018;62:e01856-17.

15. What About P. aeruginosa in General? Susceptible defined as MICs ≤8 mcg/mL for Enterobacteriaceae and MICs ≤4 mcg/mL for Pseudomonas spp. and Acinetobacter spp. Karlowsky JA, et al. Antimicrob Agents Chemother 2017;61:e00427-17.

16. Clinical Data ClinicalTrials.gov Identifiers: NCT02655419, NCT03329092 & NCT03580044

17. Activity of Aztreonam/Avibactam Against MDRGNs Green represents susceptibility anticipated to be >90%, yellow represents susceptibility anticipated to be 30%-90%; red represents intrinsic resistance or susceptibility anticipated to be <30%

18. Aztreonam/Avibactam

19. Cefiderocol

20. Siderophores • Cefiderocol is an injectable siderophore cephalosporin • Innate immune system minimizes available free iron in response to bacterial infections • Most iron is bound to hemoglobin, myoglobin, or the iron binding proteins • Bacterial infections cause upregulation in the production of siderophores • Siderophores are iron-chelating compounds that scavenge for free iron TillotsonGS. Infect Dis (Auckl) 2016;9:45-52. Ito A, et al. Antimicrob Agents Chemother 2016;60:7396-401.

21. Cefiderocol • “Trojan Horse” approach to gain entry into bacteria • Once across the outer membrane it dissociates from the iron molecule and binds to penicillin binding proteins, disrupting cell wall synthesis • Circumvents common resistance mechanisms • Deficiencies in porin expression, upregulation of efflux pumps, serine or metallo-β-lactamases are not expected to cause frank resistance to cefiderocol TillotsonGS. Infect Dis (Auckl) 2016;9:45-52. Ito A, et al. Antimicrob Agents Chemother 2016;60:7396-401.

22. KPC-Producing Enterobacteriaceae 127 international clinical isolates tested Dobias J, et al. Eur J ClinMicrobiol Infect Dis 2017; 36:2319-2327.

23. Metallo-β-lactamase-Producing Enterobacteriaceae 134 international clinical isolates tested Dobias J, et al. Eur J ClinMicrobiol Infect Dis 2017; 36:2319-2327.

24. OXA-48-like Producing Enterobacteriaceae 154 international clinical isolates tested Dobias J, et al. Eur J ClinMicrobiol Infect Dis 2017; 36:2319-2327.

25. Carbapenemase-Producing P. aeruginosa 30 international clinical isolates tested Dobias J, et al. Eur J ClinMicrobiol Infect Dis 2017; 36:2319-2327.

26. Carbapenemase-Producing A. baumannii 85 international clinical isolates tested Dobias J, et al. Eur J ClinMicrobiol Infect Dis 2017; 36:2319-2327.

27. Activity of Cefiderocol Against MDRGNs Green represents susceptibility anticipated to be >90%, yellow represents susceptibility anticipated to be 30%-90%; red represents intrinsic resistance or susceptibility anticipated to be <30%

28. MB-1: A Cautionary Tale

29. MB-1: A Cautionary Tale • MIC50 & MIC90 assays conducted • Mutations in iron transporter gene piuAoccured relatively infrequently • Frequency of 8*10-7 at 4x MIC; none at 8x MIC Tomaras AP, et al. Antimicrob Agents Chemother 2013; 57:4197-4207.

30. MB-1: A Cautionary Tale Control • Variable efficacy of MB-1 against P. aeruginosa clinical isolates • Lack of correlation between in vitro MB-1 MICs and the corresponding level of MB-1 efficacy in vivo • Hypothesis: Increases in endogenously produced P. aeruginosasiderophores downregulate other siderophore receptors, including those used by MB-1 Change Log10CFU after 24 hours MB-1 Isolates Neutropenic thigh model Tomaras AP, et al. Antimicrob Agents Chemother 2013; 57:4197-4207.

31. MB-1: A Cautionary Tale Control • Variable efficacy of MB-1 against P. aeruginosa clinical isolates • Lack of correlation between in vitro MB-1 MICs and the corresponding level of MB-1 efficacy in vivo • Hypothesis: Increases in endogenously produced P. aeruginosasiderophores downregulate other siderophore receptors, including those used by MB-1 Cefiderocol structurally differs from MB-1 and potent activity has been observed in cefiderocol murine thigh models. But, we still need to remain vigilant! Change Log10CFU after 24 hours MB-1 Isolates Neutropenic thigh model Tomaras AP, et al. Antimicrob Agents Chemother 2013; 57(9):4197-4207.

32. Potsmouth S, et al. Lancet Infect Dis 2018; 18:1319-1328. ClinicalTrials.gov Identifiers NCT02321800, NCT02714595, & NCT03032380

33. Cefiderocol

34. Ceftazidime/Avibactam

35. Spectrum of Activity • Active against KPC and OXA-48-like producers • Can consider combining with aztreonam for coverage against metallo-β-lactamases • Ceftazidime-avibactam active against 62-88% of meropenem-nonsusceptibleP. aeruginosa • In a cohort of mostly carbapenem-resistant P. aeruginosa, 62% were susceptible to ceftazidime/avibactam whereas 73% were susceptible to ceftolozane/tazobactam Castanheira M, et al. Antimicrob Ag Chemother 2015; 59:3509-17. Sader HS, et al. Antimicrob Ag Chemother 2017;61. Sader HS, et al. DiagnMicrobiol Infect Dis. 2015; 83:389-94.

36. Emergence of Resistance • Resistance observed during exposure to ceftazidime/avibactam therapy • Most frequently because of an amino acid substitution within or proximal to the omega loop of the KPC enzyme • Emergence of resistance on ceftazidime/avibactam may occur approximately 10% of the time • Mutations conferring resistance to ceftazidime/avibactam may reduce the potency of KPC-2 & KPC-3 enzymes, restoring susceptibility to carbapenems Humphries RM, et al. Antimicrob Ag Chemo 2015;59:6605-7. Humphries RM, et al. Antimicrob Ag Chemo 2017; 61:e00537. Shields R, et al. Clin Infect Dis 2016; 63: 1615-1618. Shields R, et al. Open Forum Infect Dis 2017; 4:ofx101. Gaibani P, et al. J AntimicrobChemother 2018;73:1525-9. Giddins ML, et al. Antimicrob Ag Chemother 2018; 62:e02101-17. Castanheira M, et al. mSphere 2018;3: e00408-18.

37. Patient One Shields RK, et al. Antimicrob Agents Chemother 2017;61:02097-16

38. Patient Two Shields RK, et al. Antimicrob Agents Chemother 2017;61:02097-16

39. Patient Three Shields RK, et al. Antimicrob Agents Chemother 2017;61:02097-16

40. Patient Three Unfortunately, available data suggest this restored carbapenem activity is generally not sustainable so clinical significance is unclear. Shields RK, et al. Antimicrob Agents Chemother 2017;61:02097-16

41. Activity of Ceftazidime/Avibactam Against MDRGNs Green represents susceptibility anticipated to be >90%, yellow represents susceptibility anticipated to be 30%-90%; red represents intrinsic resistance or susceptibility anticipated to be <30%

42. Ceftazidime-Avibactam

43. Ceftolozane/Tazobactam

44. Spectrum of Activity • Broadest P. aeruginosa activity compared with other commercially available β-lactams • Large cohort of carbapenem-resistant P. aeruginosa isolates from US and Europe, ceftolozane-tazobactam was susceptible against 78% • More active against US compared with European P. aeruginosa isolates • ~90% vs. 50% • Activity against P. aeruginosa displaying a mucoid phenotype is less reliable • Activity against extensively drug-resistant P. aeruginosa isolates from cystic fibrosis patients varies between 30-54% of isolates • Resistance generally due to de novo mutations impacting AmpC expression Farrell DJ, et al. Int J AntimicrobAgents 2014;43:533-9. Sader HS, et al. J AntimicrobChemother 2014; 69:2713-22. Wi YM, et al. Antimicrob Ag Chemother 2018; 62: e01970-17. Forrester JB, et al. Open Forum Infect Dis 2018; 5:ofy158. Kuti JL, et al. DiagnMicrobiol Infect Dis 2015; 83:53-5. Grohs P, et al. Antimicrob Ag Chemother 2017;61. e00766-17.

45. Activity of Ceftolozane/Tazobactam Against MDRGNs Green represents susceptibility anticipated to be >90%, yellow represents susceptibility anticipated to be 30%-90%; red represents intrinsic resistance or susceptibility anticipated to be <30%

46. Ceftolozane/Tazobactam

47. Imipenem-cilastatin/Relebactam

48. Available data indicate its activity against OXA-48-like carbapenemases is poor LapueblaA, et al. Antimicrob Ag Chemother 2015; 59:5029-5031.

49. PHASE II Study: cUTIs Adults with cUTIs or pyelonephritis Could convert to ciprofloxacin after 4 days; total duration 4-14 days Imipenem 500/ relebactam 250 mg IV q6h (n=74) Imipenem 500/ relebactam 125 mg IV q6h (n=82) Imipenem 500 mg IV q6h (n=81) Clinical response at discontinuation of IV therapy 97% 99% 99% ClinicalTrials.gov Identifier: NCT01505634

50. PHASE II Study: cIAIs Total duration of therapy 4-14 days Adults with cIAIs 34 patients with imipenem-nonsusceptible infections with good response Imipenem 500/ relebactam 250 mg IV q6h (n=89) Imipenem 500/ relebactam 125 mg IV q6h (n=96) Imipenem 500 mg IV q6h (n=92) Clinical response at discontinuation of IV therapy 96% 99% 95% ClinicalTrials.gov Identifier: NCT01505634