Antibiotic Resistance and Stewardship: Where Are We and Where Must We go

Hospital of Tomorrow Conference Washington DC, Monday October 19th, 2015

Brad Spellberg, MD FIDSA FACP

Chief Medical Officer LAC+USC Medical Center

Associate Dean for Clinical Affairs Professor of Clinical Medicine Division of Infectious Diseases Keck School of Medicine at USC

Disclosures (past year)

Grant & Contract Support: NIH, FDA/CITI, Dipexium; Consultant: Adenium, Cempra, The Medicines Company, Medimmune, PTC Therapeutics, Tetraphase; Shareholder: Motif, BioAIM, Synthetic Biologics

2

Antibiotics Are Unique

• Transmissible resistance—not true of any other drug class

• Those that work today won’t work in the future—they must be continually replaced because resistance is constantly eroding their effectiveness

• Every person’s use affects everyone else’s use—they are a shared societal trust/property

Microbes vs. Humans

Microbes Humans Factor

Number on Earth 5x1031 6x109 ∼1022

Mass (metric tons) 5x1016 3x108 ∼108

Generation Time 30 min 30 yr ∼5x105

Time on Earth (yrs) 3.5x109 4x105 ∼104

Microbiology in the 21st century, ASM, 2004; Spellberg et al 2008 Clin Infect Dis 3

“after billions of years of evolution, microbes have most likely invented antibiotics against every biochemical target that can be attacked — and, of necessity, developed resistance mechanisms to protect all those biochemical targets.” Spellberg, Bartlett, Gilbert. NEJM ’13

4

5

Lechuguilla caves in Carlsbad Caverns in New Mexico, isolated from surface for >4 million years, no human contact—extensive antibiotic resistance found

The Future Unless…

6

• Resistance will continue, guaranteed—death, taxes, resistance

7

"Every system is perfectly designed to produce the results it gets.”

Dr. Paul Bataldan, Dartmouth

We Need to Disrupt Dogma

8

• The resistance crisis is the predictable result of how we have managed antibiotics for nearly 80 years

•  If we are to change our present state, we need to challenge assumptions and think disruptively

9

Themes 1.  Must cross the line that separates us

from those who own medicine – payors and regulators

2.  Use technology and economics to drive change—move away from reliance on asking people to change behavior

3.  Stop accepting excuses (e.g., “it’s too hard”…”that’s not how we do it”…”it can’t be done”)

•  70 years of traditional approaches…

Antibiotic Stewardship

10

“…. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out… In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.” - Sir Alexander Fleming, NY Times June 1945

11

What Is Inappropriate Prescribing?

w First, what is it NOT?

Appropriate prescriptions of antibiotics are unrelated to FDA indication, in contrast to other drugs—may be new idea for payors/regulators

An antibiotic with an indication is not necessarily appropriate—and visa versa

12

Why FDA Indication Isn’t the Driver

1. Resistances change over time, but drugs approved only once

2. Indication based on safety and efficacy, doesn’t consider breadth of spectrum—antibiotics that are overly broad should not be used even if they would work

3. Indication is limited to site of infection—bacteria don’t limit themselves to 1 site (consider KPC brain infection), and companies can’t afford to study all sites

13

Inappropriate: On-Label vs. Off-Label • The vast majority of inappropriate antibiotic use in the US is on-label

• Label drives use by enabling marketing

• Upper respiratory tract infections are the bulk of inappropriate use and antibiotics have FDA indications for these infections

• For other infxns, indicated courses too long

•  Indications don’t consider spectrum of activity & alternative narrower agents

14

Move Past Education

• Providers “get” that resistance is a problem and that we overuse antibiotics—patients often do as well

• Education is necessary but not sufficient—educational campaigns alone yield limited results that are not sustainable (Arnold SR, Straus SE. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database Syst Rev. 2005; (4):CD003539. [PubMed: 16235325])

• This is not (primarily) a knowledge deficit

15

Tragedy of the Commons & Fear

• Education and other efforts have not dealt with the fear that drives prescriptions—fear of the unknown, fear of being wrong

• The Tragedy of the Commons results from perceptions of self-benefit vs. societal harm

• Resolving the fear & changing perceptions of self- vs. societal benefit are necessary

16

Tragedy of the Commons & Fear

• Three primary ways to deal with the fear and Tragedy of the Commons are:

1. Provide better information to resolve fear of the unknown

2. Use novel psychological approaches to counter-act fear with other behavioral drivers

3. Use economic forces to align perceptions of self-benefit with societal benefit

17

Stewardship: The Power of Diagnostics

• Fear drives inappropriate abx use

• Fear based on diagnostic uncertainty

• Rapid diagnostics provide psychological reassurance to overcome the fear

18

Stewardship: New Psychological Approaches

19

Stewardship: Benchmarking Abx Use

• Need to align physician and patient self-interest with public interest

• Antibiotic use should be publicly reported and payments to healthcare systems (and possibly providers) benchmarked to reward low use and penalize high use

• Akin to infection prevention—just having a program is not enough, need to arm it with teeth

We need

1. Technological solutions (eg, diagnostics, disinfectants, vaccines)—don’t rely on asking people to change behavior

2. Healthcare policies that align economics with appropriate antibiotic use in humans and animals

Take Home Messages

20

21

Acknowledgments The Renegades: • John Bartlett • David Gilbert

• Paul Ambrose • George Drusano • John Rex • David Shlaes