• The analysis process is intended to organize and integrate an array of relevant information and to provide guidance as to how this information may be used to manage risk 

• The process is composed of:

  • Hazard identification

  • Qualitative antimicrobial resistance risk assessment

    • Release assessment

    • Exposure assessment

    • Consequence assessment

    • Risk estimation

  • Risk management

Hazard Identification

• Hazard - human illness that is caused by a specified antimicrobial-resistant bacteria, is attributable to a specified animal-derived food commodity, and is treated with the human antimicrobial drug of interest

•  Hazard identification - the process of stating the hazard and the conditions that influence the occurrence of that hazard

Example

Hazard Identification

1. Drug/Product Information

   1. Drug:  Miraclemycin, Miracin™

   2. Class:  2nd generation Curalloside; CAS 2002

   3. Use information:

      1. Dosage regimen - Miracin is intended to be administered as an oral solution in drinking water for 5 days

      2. Product indication -     Treatment of swine respiratory disease

      3. Target species - Swine

Example

Hazard Identification

4. Human use information: Although Miracin is not used in human medicine, related drugs in the curallosides class are considered of high importance for treating disease in humans.  Bacteria resistant to miraclemycin would be expected to be cross-resistant to other curallosides.

5. Relevant bacteria/resistance determinants of concern: Campylobacter is the bacteria of primary human health concern. 1st generation curallosides are currently in use in swine for treatment of swine respiratory disease.  Resistance to 1st generation curallosides has not been observed in Campylobacter isolated from swine and from retail pork.

Release Assessment

• Probability that resistant bacteria or resistance determinants are present in the target animal as a consequence of the antimicrobial new animal drug use

•  Probability is ranked as Low, Medium, or High

Factors to Consider in Release Assessment

• Product and drug substance description

• Mechanism and type of action

• Spectrum of activity

• Pharmacokinetics/pharmacodynamics

• Resistance selection pressures

• Prevalence of resistance

• Resistance mechanisms

• Resistance transfer

• Other relevant information

Factors to Consider in Release Assessment

•  The relative significance of any particular factor among all factors pertinent to the release assessment may vary depending on the specific new animal drug under consideration

•  Drug sponsors should consult with FDA to determine the specific factors that should be addressed for the new animal drug in question

Table

Table 1.  Table for collating and summarizing interpretation of relevant factors considered in completing release assessment

Release Assessment of Miracin

Mechanism of activity: Protein synthesis; bactericidal

Spectrum of Activity:Gram-negative, some Gram-positive

Susceptibility data: MIC90 of MIRACIN Against susceptible Gram-negative food borne pathogens is <0.25 µg/mL 

Release Assessment of Miracin

Pharmacokinetics:

1. rapid absorption

2. high bioavailability

3. low protein binding

4. long elimination half-life

5. high penetration into pulmonary tissues and fluids

6. renal elimination

7. gut concentrations low

Pharmacodynamics: 

1. bactericidal

2. time dependent killing

3. exhibits prolonged PAE in vivo

    

Release Assessment of Miracin

Resistance mechanisms:

1. Multiple

   1. DNA point mutation

   2. efflux

   3. permeability changes

Resistance transfer:

1. Infrequent

   1. chromosomal

   2. no evidence of transfer between bacteria

Release Assessment of Miracin

Resistance Selection Pressures:

1. Co-selection

   1. 1st generation curallosides used in  swine

2. Cross resistance

   1. resistance to Miracin predicts decreased susceptibility to the human curalloside, gorillamycin

   2. gorillamycin is the primary treatment for Campylobacter infections in humans

Baseline Resistance Prevalence: 

1. NARMS data

   1. no known resistance to 1st generation curallosides

2. Current literature

   1. published research

   2. NCCLS data

Release Assessment of Miracin

Other factors:

1. In-vitro resistance study

   1. bacteria resistant to 1st generation curallosides exhibit decreased susceptibility to Miracin

   2. however, isolates would still be considered “susceptible” to Miracin based on clinical, pharmacological and microbiological data

   3. resistance to Miracin develops slowly in vitro, via multi-step mutations and at a frequency of less that 1 x 10-10

2. Human use data

   1. related drugs in the curallosides class are considered “highly” important for treating disease in humans

Release Assessment Conclusion of Miracin
Example

What is the likelihood (high, medium, low) that these factors favor resistance emergence or of release of the hazardous agent?

Miracin: Bactericidal drug, some activity against gram-positives;

Campylobacter exhibit low MICs;

PK/PD parameters favorable for minimizing resistance release;

Transfer of resistance is infrequent;

Low baseline resistance;

Low mutation rate;

The release assessment conclusion would be…

Release Assessment Conclusion of Miracin
Example

The release assessment conclusion for Miracin would be a low probability of release.

This data would then be taken into consideration along with the  exposure assessment and consequence assessment.

The risk estimation would then be derived from all 3 assessments (release, exposure, and consequence).

Low, medium, or high

This is then translated into the appropriate risk management strategy

Exposure Assessment

• Probability for humans to ingest the resistant bacteria/resistance determinants in question from the particular relevant food commodity

• Probability is ranked as Low, Medium, or High

Factors to Consider in Exposure Assessment

•  The probability for humans to be exposed to given bacteria via a particular food commodity

• Probability that bacteria of interest (to which humans are exposed) are resistant to a particular antimicrobial drug or possess associated resistance determinants

Example
 Exposure Assessment of Miracin

• The probability for humans to be exposed to given bacteria via a particular food commodity

  • Estimated by considerations of:

    • Per capita consumption of the food commodity

      • pork

    • Probability of contamination of pork by bacteria of interest

      • Campylobacter

Example
Exposure Assessment of Miracin: Consumption

Table B1: Per capita consumption data for red meat, poultry, fish and shellfish for the year 2000

Example
Exposure Assessment of Miracin: Contamination

Table B3: Prevalence of Campylobacer contamination of various animal-derived food commodities and provisional qualitative contamination rankings

Example
Exposure Assessment of Miracin

• Consumption ranking and contamination ranking are merged to derive qualitative ranking for probability that a human is exposed to Campylobacter on pork 

  Table B4: Possible process for ranking qualitatively the probability of human exposure to a given bacteria in a given food commodity

Summarizing Exposure Assessment

• Exposure assessment ranking

  • Derived by integrating the ranking for probability of human exposure (through food) to the bacteria in question

    • High from previous slide

  • With the probability that the bacteria will be resistant to the antimicrobial drug in question

    • Low from release assessment

Summarizing Exposure Assessment

Table 2: Process for characterizing the probability of human exposure to the identified hazardous agent (i.e., specific resistant bacteria or resistance determinants ).

Consequence Assessment

• Probability that human exposure to resistant bacteria/determinants results in an adverse human health consequence

• Based on the medical importance of the antimicrobial drug under review

• Ranked as Low, Medium, or High

Example
Consequence Assessment of Miracin

• Appendix A provides ranking of antimicrobial drugs developed by FDA CDER

•   Miracin is determined to be high from the table of antimicrobial drug rankings
  
  

Risk Estimation

• Integration of the results from the release assessment, exposure assessment, and consequence assessment

• Result is low, medium, or high risk for human health to be adversely impacted by emergence of antimicrobial resistance associated with the use of the drug in animals

Risk Estimation

• Low - Low rankings on all three assessments or two low and one medium

• High- High rankings on all three assessments or two high and one medium

• Medium-All intermediate combinations of the three assessments

Example

 Review of Rankings for Miracin in swine

• Release assessment - low probability of release of Miracin-resistant Campylobacter from use of Miracin as an oral solution in swine

• Exposure assessment - medium probability of exposure of humans to Miracin-resistant Campylobacter from swine

• Consequence assessment - high importance drug ranking

Example
Risk Estimate for Miracin in Swine

• Overall Conclusion of the Qualitative Risk Assessment Process integrating  low, medium , high for the three rankings...

•  Risk estimate for proposed use of Miracin - medium

Next Steps

• Risk management steps are selected based on the risk estimate