1. Gram Negative Resistance Mechanisms: Running Out of Options
Evan Lantz, Pharm.D., BCPS
Clinical Pharmacist Specialist – Infectious Diseases
Spartanburg Regional Healthcare System
10/27/16

2. Disclosures
I have no conflicts of interest to disclose.

3. Pharmacist Objectives
I. Recognize the threat posed by antimicrobial resistance.
II. Explain mechanisms of antimicrobial resistance in gram-negative organisms.
III. Apply concepts of antimicrobial stewardship to combat resistance.

4. Background Antimicrobials are unique among medications
Individual exposure can harm others
No restrictions on prescribing
Estimated that 30% of outpatient antibiotic prescriptions are inappropriate
Resistance among many bacteria is on the rise
JAMA 2016;315(17):

5. Bad Bugs, No Drugs: ESCAPE
Enterococcus faecium
Staphylococcus aureus
Clostridium difficile
Acinetobacter baumanii
Pseudomonas aeruginosa
Enterobacteriaceae
E. coli, Klebsiella spp., Enterobacter spp., etc…
CID 2009;49:

11. Antibiotic Resistance Threats

12. “Antibiotic resistance is one of the biggest threats to global health today”
WHO:
In the European Union it is estimated that each year:
Resistance causes 25,000 deaths
Costs > $1,500,000,000 (USD) in expenses
CDC
In the United States it is estimated that each year:
2,000,000 people infected with resistant pathogens
Resistance causes 23,000 deaths
Costs ~ $35,000,000,000 (USD) in expenses

13. Emerg Infect Dis 2011;17(10):

14. P&T 2015;40(4):

15. Pharmacist Objectives
I. Recognize the threat posed by antimicrobial resistance.
II. Explain mechanisms of antimicrobial resistance in gram-negative organisms.
III. Apply concepts of antimicrobial stewardship to combat resistance.

16. What is MDR, XDR, PDR?
Clin Micro Infect 2012;18(3):

17. What is MDR, XDR, PDR?
Clin Micro Infect 2012;18(3):

18. Overgrowth of Resistant Organisms
Selective Pressure
Overgrowth of Resistant Organisms
Antibiotic Use
Resistant X X X X X X X X X X X X X X X X X
Wild-Type

20. JID 1999;179:163-71

21. BMJ 2010;340:c2096

22. P&T 2015;40(4):

25. 12/28: PTZ

26. 12/28: PTZ

27. 12/28-1/12: PTZ ↓
1/12: meropenem

28. 12/28-1/12: PTZ ↓
1/12-22: meropenem
1/22: Cipro + tobra inh

29. 12/28-1/12: PTZ ↓
1/12-22: meropenem
1/22: Cipro + tobra inh

30. 12/28-1/12: PTZ ↓
1/12-22: meropenem
1/22: Cipro + tobra inh

31. 1/22/16 – 1/30/16 Cipro + Tobra Inh:
12/28/15 – 1/12/16 Piperacillin/tazobactam: ↓
1/12/16 – 1/22/16 Meropenem:
1/22/16 – 1/30/16 Cipro + Tobra Inh:
And after 33 days of broad spectrum abx…

33. Change in the binding site
Antibiotic
Site of Activity
Susceptible
Resistant
Example: Plasmid-mediated colistin resistance caused by the MCR-1 gene
Lancet Infect Dis 2016;16(2):

34. Cell wall modification

35. Enzymatic degradation
β-lactamase
β-lactam
Hydrolysis
Inactivated drug
Free enzyme

36. AAC 2010;54(3):

37. Extended Spectrum β-lactamase (ESBL)
AmpC
Class A Carbapenemase
Class B
Metallo-β-lactamase
Examples
SHV, TEM, CTX-M
KPC
NDM, VIM, IMP
Plasmid v Chromosomal
(there are exceptions!)
Plasmid
Chromosomal
&
Select
β-lactam options
Piperacillin/tazo?
Ceftolozane/tazo
CefTAZ/avi
Carbapenems
Cefepime?
None
β-lactamase inhibitors work?
Variable No
Clin Microbiol Rev 2010;23(1):
CID 2013;57(6):
AAC 2006;50(6):

38. Pharmacist Objectives
I. Recognize the threat posed by antimicrobial resistance.
II. Explain mechanisms of antimicrobial resistance in gram-negative organisms.
III. Apply concepts of antimicrobial stewardship to combat resistance.

39. Antimicrobial Stewardship
“Antimicrobial stewardship refers to coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration”
Optimize clinical outcomes
Minimize toxicity and other adverse effects
Limit cost of treatment
Limit selection of antimicrobial resistance

40. Four Actions to Fight Resistance
Prevent infections and prevent the spread of resistance
Track resistant bacteria
Improve the use of today’s antibiotics
Promote the development of new antibiotics and develop new diagnostic tests for resistant bacteria
CID 2007;44:

41. Four Actions to Fight Resistance
Prevent infections and prevent the spread of resistance
Track resistant bacteria
Improve the use of today’s antibiotics
Promote the development of new antibiotics and develop new diagnostic tests for resistant bacteria
CID 2007;44:

42. Definitions Minimum Inhibitory Concentration (MIC)
Lowest concentration of an antimicrobial that inhibits growth of a bacteria

43. Definitions Breakpoint
The MIC used to designate whether a bacteria is susceptible or resistant
Defined, and often unique, for each bacteria-antimicrobial combination

44. De-escalation
Reduction in the spectrum of activity of administered antibiotics through:
discontinuation of accessory agents
switching to an agent with a narrower spectrum
Goals:
Reduce selection/colonization of MDR bacteria
Reduce infection with MDR bacteria
Reduce antibiotic consumption/cost
Reduce LOS, mortality, future complications

45. Extended Infusion PTZ ESBL AmpC KPC MBL +/- -
Pharmacotherapy 2007;27(11):

46. Pharmacotherapy 2007;27(11):1490-1497

47. Clin Micro Rev 2016;29(4):

48. Cefepime Susceptible Dose-Dependent
Susceptibility breakpoint based on a dosing regimen of cefepime 1g q12h
ESBL
AmpC
KPC
MBL
+/- -
CLSI

49. Cefepime Susceptible Dose-Dependent
J Antimicrob Chemother 2014;69:

50. Cefepime Susceptible Dose-Dependent
Know what SDD means → the dose matters!
Coordinate with the Microbiology Lab to identify SDD Enterobacteriaceae isolates and communicate this information to providers
Utilize higher dosing especially in invasive infection

51. Carbapenems
ESBL
AmpC
KPC
MBL + -
J Clin Pharmacol 2013;54(3):

52. Carbapenems
ESBL
AmpC
KPC
MBL + -
J Clin Pharmacol 2013;54(3):

53. Ceftolozane/Tazobactam
Indicated for treatment of
Complicated intra-abdominal infection w/ metronidazole
Complicated urinary tract infection
ESBL
AmpC
KPC
MBL +
+/- -
Zerbaxa® [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2015.

54. Ceftazidime/Avibactam
Indicated for treatment of
Complicated intra-abdominal infection w/ metronidazole
Complicated urinary tract infection
ESBL
AmpC
KPC
MBL + -
Avycaz® [package insert]. Parsippany-Troy Hills, NJ: Allergan, Plc; 2016.

55. Polymyxins Discovered in 1950s
Before contemporary drug approval structure
Avoided for decades due to toxicity and availability of more reliable agents
Re-emerged due to resurgence of MDR GNR
Much debate about colistin v. polymyxin B today
ESBL
AmpC
KPC
MBL +

56. In the Pipeline
As of March 2016, an estimated 37 antibiotics were under development for the U.S. market
Phase One: 11
Phase Two: 13
Phase Three: 13
Of these 37 antibiotics:
11 could potentially treat MDR pathogens
16 have activity against CDC “urgent” threat level pathogens
Only 1 in 5 of ID products that enter human testing are approved for patients
The PEW Charitable Trusts, “Antibiotics Currently In Clinical Development,” accessed Oct. 13, 2016,

57. Antimicrobial resistance is one of our most serious health threats
Antimicrobial resistance is one of our most serious health threats. Infections from resistant bacteria are now too common, and some pathogens have even become resistant to multiple types or classes of antibiotics. The loss of effective antibiotics will undermine our ability to fight infectious diseases and manage the infectious complications common in vulnerable patients undergoing chemotherapy for cancer, dialysis for renal failure, and surgery, especially organ transplantation, for which the ability to treat secondary infections is crucial. When first-line and then second-line antibiotic treatment options are limited by resistance or are unavailable, healthcare providers are forced to use antibiotics that may be more toxic to the patient and frequently more expensive and less effective. Even when alternative treatments exist, research has shown that patients with resistant infections are often much more likely to die, and survivors have significantly longer hospital stays, delayed recuperation, and long-term disability. Efforts to prevent such threats build on the foundation of proven public health strategies: immunization, infection control, protecting the food supply, antibiotic stewardship, and reducing person-to-person spread through screening, treatment and education. Dr. Tom Frieden, MD, MPH Director, U.S. Centers for Disease Control

58. Gram Negative Resistance Mechanisms: Running Out of Options
Evan Lantz, Pharm.D., BCPS
Clinical Pharmacist Specialist – Infectious Diseases
Spartanburg Regional Healthcare System