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U.S. Department of Health and Human Services

Animal & Veterinary

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Alternatives to Establishing Thresholds

Are threshold models appropriate for all antibiotic resistance? 

David Smith & Judith Johnson
University of Maryland, Baltimore

Outline

Thresholds
Antibiotic Use & Antibiotic Resistance
Commensal vs. Zoonotic
Reasonable Expectation of No Harm
Drug-Centered Policy

What Type of Threshold?

Exposure Threshold
Small, acceptable doses
Larger, unacceptable doses
Toxic Chemical Exposure

Trigger Threshold
No consequence until critical point
Large, irreversible consequence after the critical point
Trigger on a Gun

Set-Point on a Thermostat
Heat is on below set point
Heat turned off above set point

Detection Threshold

Freezing Point

Futility Point

What Type of Threshold?

Proposed FDA Response
By default, antibiotic use is allowed
Monitor resistance until it exceeds the threshold
Withdraw antibiotic from the market
After resistance declines, permit use again.

Threshold is like a set point on a thermostat

How does antibiotic resistance behave?

Antibiotic Use and Antibiotic Resistance Is Resistance like Temperature?

Antibiotic Use and Antibiotic Resistance Is Resistance like Temperature?

Resistance spreads epidemically
Long time before high-level resistance appears
Drug has maximum utility during this period
After HL resistance appears, spread may be rapid
Depends on the mechanism of resistance
High-level resistance (mobile genetic element)
Quantitative resistance (point mutations, no lag)
Resistance Responds to Antibiotic Use
(not just Abuse)

Commensal vs. Zoonotic

Zoonotic
acquired from direct exposure to animal products
ordinarily don’t colonize humans
rarely spread from human to human
Human Commensal
commonly colonize humans without causing harm
infect and cause disease under appropriate conditions
frequently transmitted from human to human
host specific strains of commensal species may exist
rarely, humans are colonized by animal strains or acquire antibiotic resistance genes from animal strains.

Commensal vs. Zoonotic

Zoonotic
RISK: Infection with a resistant zoonotic organism may be untreatable.
Human Commensal
RISK: Infection with a resistant commensal organism acquired from animals may be untreatable.
RISK: Human commensal organism may acquire resistance gene that spread among humans.
Bugs and Drugs How do we Measure Temperature?
Simple in one drug-one bug models.
Ecology of the Human/Animal Gut
300-500 species
up to 1011 organisms per gram
Most species are unnamed, difficult to culture
Each drug selects for resistance in multiple bugs.
Other drugs may affect resistance to a focal drug.
Any animal bug might potentially transfer high level resistance genes to human commensal bugs.
Is there a Reasonable Expectation of No Harm?
How does antibiotic use in animals threaten human medical use?
Does not drive resistance in humans
Expands animal reservoir of high-level resistance genes
Exposes human population to those resistance genes
Resistance in human commensal organisms becomes a problem many years earlier than it would had the drug never been used in animals.
Years of utility in humans may be wasted.
Conclusions
Zoonotic model is inappropriate for a human commensal organisms
FDA Campylobacter risk assessment is not appropriate for streptogramin resistance in E. faecium
The threshold (set point) concept may be appropriate for quantitative but not high-level resistance.
We should preserve new drugs for humans.
Once resistance is common in humans, some use in feed animals may be essentially harmless.

NOTE: Our policy (a trigger) is the OPPOSITE
of the FDA threshold (a set point).

Drug Centered Policy
Maximize the time that a drug is useful to humans
Human threshold (trigger)
Delay approval of antibiotic use in animals.
Use the drug only in humans until clinically significant resistance appears and exceeds the threshold.
After clinically significant resistance in humans exceeds the human threshold, set an animal threshold (set point)
Manage antibiotic resistance in zoonotic organisms using the current proposals.
Farm to Fork How Low do We Set a Threshold?
Farm to Fork How Low do We Set a Threshold?