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

Disclosures I have no conflicts of interest to disclose.

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.

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):1864-1873

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;49:992-993

Antibiotic Resistance Threats

“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 http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/ https://www.cdc.gov/drugresistance/

Emerg Infect Dis 2011;17(10):1971-1798

P&T 2015;40(4):277-283

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.

What is MDR, XDR, PDR? Clin Micro Infect 2012;18(3):268-281

What is MDR, XDR, PDR? Clin Micro Infect 2012;18(3):268-281

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

http://textbookofbacteriology.net/resantimicrobial_3.html

JID 1999;179:163-71

BMJ 2010;340:c2096

P&T 2015;40(4):277-283

12/28: PTZ

12/28: PTZ

12/28-1/12: PTZ ↓ 1/12: meropenem

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

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

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

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…

https://www.britannica.com/science/antibiotic-resistance

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):161-168

Cell wall modification http://www.nature.com/nrmicro/journal/v13/n1/images_article/nrmicro3380-f1.jpg

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

AAC 2010;54(3):969-976

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):160-201 CID 2013;57(6):781-788 AAC 2006;50(6):2244-2247

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.

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 https://www.idsociety.org/Stewardship_Policy/

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;44:159-177

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;44:159-177

Definitions Minimum Inhibitory Concentration (MIC) Lowest concentration of an antimicrobial that inhibits growth of a bacteria https://s3.amazonaws.com/classconnection/63/flashcards/1770063/png/untiasdftled-14C098B80F34B8FB393.png

Definitions Breakpoint The MIC used to designate whether a bacteria is susceptible or resistant Defined, and often unique, for each bacteria-antimicrobial combination http://shop.clsi.org/M100-S26.html

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

Extended Infusion PTZ ESBL AmpC KPC MBL +/- - Pharmacotherapy 2007;27(11):1490-1497

Pharmacotherapy 2007;27(11):1490-1497

Clin Micro Rev 2016;29(4):759-772

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

Cefepime Susceptible Dose-Dependent J Antimicrob Chemother 2014;69:871-880

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

Carbapenems ESBL AmpC KPC MBL + - J Clin Pharmacol 2013;54(3):324-330

Carbapenems ESBL AmpC KPC MBL + - J Clin Pharmacol 2013;54(3):324-330

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.

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.

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 + http://sterimaxinc.com/wp-content/uploads/2014/09/polymyxin-b-50mg-300x300.png http://images.medscape.com/pi/features/drugdirectory/octupdate/JHP01070.jpg

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, http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development

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

Gram Negative Resistance Mechanisms: Running Out of Options https://www.i-sense.org.uk/sites/default/files/images/antibiotic-resistance-comic.jpg Evan Lantz, Pharm.D., BCPS Clinical Pharmacist Specialist – Infectious Diseases Spartanburg Regional Healthcare System