More than half of all hospital patients are treated with antibiotics and prescribing practices vary widely, even within hospitals. Efforts to rationalize antibiotic use have been stymied by delays in obtaining specific diagnoses, by the volume of prescriptions written each day and by the difficulty of extracting meaningful data from scattered clinical, laboratory and pharmacy records. But the push is on – from the White House, the CDC, infectious disease specialists, the industry – for more judicious use of antibiotics through antibiotic stewardship programs. Hear how leading health care institutions have moved from education to active surveillance to intervention, reducing infections and lowering costs.

1. 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. 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

3. 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
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4. “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
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5. 5
Lechuguilla caves in
Carlsbad Caverns in
New Mexico, isolated
from surface for >4
million years, no
human contact—
extensive antibiotic
resistance found

6. The Future Unless…
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• Resistance will continue, guaranteed—
death, taxes, resistance

7. 7
"Every system is perfectly designed
to produce the results it gets.”
Dr. Paul Bataldan, Dartmouth

8. 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. 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”)

10. • 70 years of traditional approaches…
Antibiotic Stewardship
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“…. 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. 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. 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. 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. 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. 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. 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. 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. 18
Stewardship: New Psychological Approaches

19. 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

20. 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
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21. 21
Acknowledgments
The Renegades:
• John Bartlett
• David Gilbert
• Paul Ambrose
• George Drusano
• John Rex
• David Shlaes