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U.S. Department of Health and Human Services

Advisory Committees

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CDC Data and Perspectives

CDC Data and Perspectives VMAC
September 25, 2006

Patricia M. Griffin MD
Chief, Enteric Diseases Epidemiology Branch
Division of Foodborne, Bacterial  and Mycotic Diseases
National Center for Zoonotic, Vectorborne, and Enteric Diseases
(title is “acting,” all organizations “proposed” due to CDC reorganization)
 

CDC Data and Perspectives VMAC - Slide 1
 

Slide 2

National Antimicrobial Resistance
Monitoring System for Enteric Bacteria
(NARMS) Objectives

  • Monitor antimicrobial resistance among enteric bacteria from humans, foods, and animals
    - Conduct surveillance in all 50 states
  • Focus intervention efforts to decrease the emergence and dissemination of antimicrobial resistance
  • Provide a platform for studies
    • Field investigations
    • Studies of resistant mechanisms 

CDC Data and Perspectives VMAC - Slide 2

Slide 3

Human isolate sampling in CDC NARMS

  • Bacteria are isolated in clinical labs and sent to state health department labs for characterization
  • Isolates sent to CDC
    - Every 20th Salmonella, Shigella, and E. coli O157
    - All Salmonella Typhi, Listeria, and Vibrio
    - Representative sample of Campylobacter from 10 FoodNet sites
CDC Data and Perspectives VMAC - Slide 3
 

Slide 4

What has surveillance shown?

  • Increase in muliti-drug resistant (MDR) Salmonella
    - e.g., Salmonella Typhimurium DT104 and Salmonella Newport
    - Spread of genetic material (plasmids containing genes coding for resistance) to multiple serotypes
  • Emergence of resistance to antimicrobial agents important in human medicine
    - Third generation cephalosporins – Salmonella, E coli
    - Fluoroquinolones – Campylobacter, Shigella, Salmonella including Typhi
CDC Data and Perspectives VMAC - Slide 4
 

Slide 5

Salmonella

  • A leading cause of foodborne illness in U.S.
    - Estimates: 1.4 million infections, 16,000 hospitalizations, and nearly 600 deaths each year (Mead et al, EID 1999)
    - Accounted for ~13% of foodborne disease outbreaks reported to CDC from 1993-1997 (Olsen et al, MMWR 2000)
  • Most infections are self-limited but antibiotics are essential for some serious infections
  • Quinolones (e.g., ciprofloxacin) and 3rd generation cephalosporins (e.g., ceftriaxone) are commonly used for treatment of severe salmonellosis
  • 3rd generation cephalosporins are the primary treatment for severe illness in children 

CDC Data and Perspectives VMAC - Slide 5

Slide 6

Resistant Salmonella cause more severe
infections than susceptible Salmonella

  • Resistant Salmonella strains cause
    - Increased risk of invasive illness and death (Helms et al, JID 2004)
    - Increased risk of bloodstream infection and hospitalization (Varma et al, JID 2005)
    - Increased rate of hospitalization (Varma et al, EID 2005)
     

CDC Data and Perspectives VMAC - Slide 6

Slide 7

3rd generation cephalosporin (3GC) resistance in Salmonella

  • 3GC resistance is most commonly caused by a plasmid carrying resistance genes
  • Definition of “MDR AmpC resistance”: resistant
    - to at least ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, tetracycline (ACSSuT),
    - and to 3GC and amoxicillin-clavulanic acid
  • 1998-2001 – 5-fold increase in the proportion of Salmonella resistant to 3GC (primarily due to emergence of MDR AmpC S. Newport) 

CDC Data and Perspectives VMAC - Slide 7

Slide 8

Where is 3rd generation cephalosporin
(3GC) resistance coming from?

  • Salmonella with MDR AmpC resistance carry a plasmid with genes coding for the CMY-2 enzyme
    - CMY-2 enzyme mediates resistance to 3GC
  • Plasmids that carry genes for the CMY-2 enzymes are spreading to other Salmonella serotypes and other bacteria, e.g., E coli
  • Spread of plasmids may be related to antibiotic pressure from
    - Use of 3GCs
    • Particularly ceftiofur, the only 3GC used in food animals

- Use of other drugs

  • e.g., giving tetracyline to an animal or person carrying a “MDR AmpC”-resistant
    Salmonella will select for survival of strains that are resistant to both tetracycline and 3GC 
CDC Data and Perspectives VMAC - Slide 8
 

Slide 9

Proportion of Salmonella Newport
resistant to at least ACSSuT
 


CDC Data and Perspectives VMAC - Slide 9

Slide 10

Sporadic Salmonella Newport MDR AmpC infections, Massachusetts

  • Nov 2000: MA State lab noted 4 Salmonella Newport MDR AmpC isolates
    - 2 from ill dairy cows   
    - 2 from ill persons --- one was a child who attended a daycare center on a dairy farm
  • Risk factors for human illness include contact with cattle and consumption
    of bovine products (e.g., ground beef, unpasteurized cheese)
CDC Data and Perspectives VMAC - Slide 10
 

Slide 11

Review of cattle isolates,
Massachusetts and Vermont 2000-2001

  • Detected S. Newport MDR AmpC in stools of ill and well dairy cattle
    - Dairy farms with S. Newport MDR AmpC often had illness and deaths in cows
    - On one farm, ill persons and milking cows had same strain
  • Many cow strains had same PFGE pattern as human strains 

CDC Data and Perspectives VMAC - Slide 11

Slide 12

Salmonella Newport MDR AmpC in horses

  • 2004: Salmonella outbreak at New Bolton Center Veterinary Hospital in Pennsylvania
  • Cause was Salmonella Newport MDR AmpC
  • High mortality, closed hospital for 3 months 

CDC Data and Perspectives VMAC - Slide 12

Slide 13

Percentage of all Salmonella with
MDR-AmpC resistance, 1996-2004*
 


CDC Data and Perspectives VMAC - Slide 13

Slide 14

Cumulative number of Salmonella
erotypes with MDR-AmpC resistance, 1996-2004*
 


CDC Data and Perspectives VMAC - Slide 14

Slide 15

MDR-AmpC resistance
jumped to E. coli O157:H7
 

  • 2000-2001: 6 E coli O157:H7 strains isolated from humans in have the
    MDR-AmpC plasmid

CDC Data and Perspectives VMAC - Slide 15

Slide 16

Fourth generation cephalosporins (4GC)
and non-human use

  • In February 2005, WHO convened panel of experts to determine critically important antibacterial agents for human medicine for risk management strategies of non-human use
  • 4GC were ranked as critically important

CDC Data and Perspectives VMAC - Slide 16

Slide 17

4GC are widely used in food animals in Europe 

  • 4GC are the most common extended spectrum cephalosporin used in Europe
  • Very little ceftiofur (3GC) used in Europe
  • 4GC resistance has developed in Salmonella in Europe
    - resistance is due to the CTX-M gene carried on its own plasmid
    - (resistance not due to cmy-2 gene, present in U.S.)
     

CDC Data and Perspectives VMAC - Slide 17

Slide 18

3GC and 4GC

3GC (ceftiofur) used in food animals in U.S.
 Resistance mediated by CMY-2 enzymes encoded on a plasmid
4GC used in food animals in Europe
 Resistance mediated by CTX-M enzymes encoded on a plasmid
CDC Data and Perspectives VMAC - Slide 18
 

Slide 19

Resistance will develop to 4GC, how and where?

  • Possibilities
    - genes encoding the CMY-2 enzyme in MDR Amp-C Salmonella strains may mutate to confer resistance to 4GC
    • this has been done in vitro
- as in Europe, we may find Salmonella strains with plasmids carrying the genes for the CTX-M enzyme
  • To understand and control emergence, we need to know where and how 4GC are used in food animals

CDC Data and Perspectives VMAC - Slide 19

Slide 20

Guidance #152

  • CDC strongly supports the continued use of FDA’s Guidance #152
  • CDC agrees with the sponsor’s “medium” risk estimation based on current guidelines
    - risk estimation could increase should 4GC be judged of critical importance in humans 

CDC Data and Perspectives VMAC - Slide 20

Slide 21

CDC Recommendations

  • CDC recommends extra-label prohibition of cefquinome use in food animals
    - Off-label use could lead to emergence and dissemination of resistance from unknown uses

CDC Data and Perspectives VMAC - Slide 21

Slide 22

CDC Recommendations (cont.)

  • Surveillance is needed to monitor for the emergence and dissemination of 4GC resistance
    - CDC NARMS does not currently screen human Salmonella strains for 4GC resistance
    • CDC could add testing plates to monitor for resistance to 4GC
      - Current resources, however, only allow for continuation of existing NARMS activities

CDC Data and Perspectives VMAC - Slide 22

Slide 23

CDC Recommendations (cont.)

  • Information on quantity of 4GC used, by animal type, should be available on an ongoing basis, in a format suitable for public health surveillance purposes
    - including off-label use 

CDC Data and Perspectives VMAC - Slide 23

Slide 24

Thank you 


CDC Data and Perspectives VMAC - Slide 24