Methicillin-Resistant
Staphylococcus aureus (MRSA)
University of Nebraska Medical Center
Center for Staphylococcal Researc...
Mortality of Staphylococcal Bacteremia in the PreAntibiotic Era
(Keefer CS, N Y State J Med, 1941)

• Overall Mortality fo...
The Antibiotic Era

Ernst Chain, Alexander Fleming, and
Howard Florey; shared 1945 Nobel Prize in
Medicine

Penicillium mo...
Evolution of Antibiotic Resistance in S. aureus
Penicillin
S. aureus

Methicillin

Penicillin-resistant
[1950s]

S. aureus...
Percent Resistance

60

Methicillin-Resistant
Staphylococcus aureus (MRSA)

50
40
30
20
10

Source: National Nosocomial In...
Quintessential Pathogen?

Nizet et al. 2007
Staphylococcal Skin & Soft Tissue Infections

Cellulitis
Staphylococcal Disease due to Metastatic Seeding
Staphylococcal Disease due to Metastatic Seeding:
Endocarditis
Staphylococcal ToxinMediated Diseases
Toxic
Shock
Syndrome

Staphylococcal
Scalded Skin
Syndrome
Staphylococcal Toxin-Mediated
Diseases:
Food Poisoning
S. aureus today
•
•
•
•

Most common cause of endocarditis
Most common cause of nosocomial infection
Most common cause of ...
Community-Acquired MRSA
What is MRSA?
• Methicillin-resistant Staphylococcus aureus
– Methicillin no longer in use (oxacillin/nafcillin)
– Resista...
Three Big Points to Remember
1. β-lactam antibiotics (penicillin and methicillin) inhibit growth of bacteria through the
I...
Mobilized by Bacteriophage?
Donor DNA S. epidermidis

SCCmec
SCCmec

mecA encodes for PBP2A, which is not
Inactivated by m...
S. aureus lineages (e.g. clonal
backgrounds, genotypes, strains)
MLST-defines
clonal complexes
and/or sequence
types

Feil...
Analysis of MRSA isolates (before CA-MRSA
epidemic) with MLST

Enright M. C. et.al. PNAS 2002;99:7687-7692

Copyright © 20...
1999 MMWR
• Four Pediatric deaths in Minnesota and North
Dakota caused by CA-MRSA.
– No known MRSA risk factors
– Suscepti...
Clinical Presentation of CA-MRSA
Clinical Presentation of CA-MRSA
Clinical Disease due to CA-MRSA

Pyomyositis

Necrotizing
Pneumonia

Purpura fulminans,
Necrotizing fasciitis
•

•
•
•
•

Population surveillance in 9 communities (16.5 million persons) in US
– Connecticut, Atlanta, SF, Denver, Port...
PFGE-MRSA USA types
USA 300 epidemic from 2003-present
USA 300 CA-MRSA
• USA 300 MRSA most prominent S. aureus lineage
isolated in the US.
– Not restricted to community
– Isolat...
Enhanced or found in USA300
Lysis of leukocytes
Hla, PSMs, PVL

Common in S. aureus lineages
Lysis of leukocytes
Hla, HlgA...
Kennedy, Adam D. et al. (2008)
Proc. Natl. Acad. Sci.
USA 105, 1327-1332

Unique S. aureus lineages

Success? Why?
1. Phag...
Livestock-Associated MRSA
LA-MRSA
• Cows, sheep, goats, poultry and rabbits
• Most S. aureus strains are host-adapted
– Ho...
Due to rapid exchange of mobile genetic information
(plasmids, MGE, etc) S. aureus has the capability of evolving
rapidly ...
Example 1: ST398-Pig associated
MRSA. Human-Animal-Human
• Widespread in Netherlands, Europe, Asia and the United
States.
...
ST398 population biology

Host adaptation to swine

Human ST398
MSSA

Price, LB et al 2012 mBio

Host adaptation to humans...
Example 2: CC5 adaptation in poultry
• S. aureus major cause of lameness in poultry
industry, the result of osteomyelitis....
CC5 population biology

Host adaptation to Poultry
In Poland ~1970

Human CC5
MRSA

Poultry CC5
Avian specific cysteine pr...
Conclusions
• S. aureus highly adaptive species due to MGE
exchange.
– Many examples of selection and clonal expansion
• S...
Dr. Paul Fey - Livestock-associated Staphylococcus aureus: Recent Trends
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Dr. Paul Fey - Livestock-associated Staphylococcus aureus: Recent Trends

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Livestock-associated Staphylococcus aureus: Recent Trends - Dr. Paul Fey, Professor and Medical Director of Clinical Microbiology Laboratory, University of Nebraska Medical Center, from the 2013 NIAA Symposium Bridging the Gap Between Animal Health and Human Health, November 12-14, 2013, Kansas City, MO, USA.

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  • Introduction of every new class of antimicrobial drug is followed by emergence of resistance.
    By the 1950s, penicillin-resistant S. aureus were a major threat in hospitals and nurseries.
    By the 1970s, methicillin-resistant S. aureus had emerged and spread, a phenomenon that encouraged widespread use of vancomycin.
    In the 1990s, vancomycin-resistant enterococci emerged and rapidly spread; most of these organisms are resistant to other traditional first-line antimicrobial drugs.
    At the end of the century, the first S. aureus strains with reduced susceptibility to vancomycin were documented, prompting concerns that S. aureus fully resistant to vancomycin may be on the horizon.
    In June 2002 the first case of vancomycin-resistant S. aureus was detected.
  • The proportion of pathogens causing hospital-onset infections that are resistant to target antimicrobial drugs continues to increase at an alarming rate.
    Currently, more that 50% of Staphylococcus aureus isolates causing infections in intensive care units are resistant to methicillin; more than 40% are resistant in other hospital units.
  • Analysis of S. aureus isolates with burst. The collection of 914 S. aureus isolates was analyzed by burst, and the five CCs that included MRSA isolates are shown. CCs are named after the ST predicted to be the ancestral genotype (e.g., CC8). The ST prefix is not shown (i.e., 250 corresponds to ST250). The ST of the predicted ancestral genotype is placed in the central circle, SLVs are within the second circle, and double locus variants within the outer dotted circle. Three isolates within CCs but that are not SLVs or double locus variants of the ancestral genotype are also shown (STs 222, 312, and 518). One further small group of isolates for which an ancestral genotype cannot be inferred and three STs that are not members of any CC (singletons) are also shown. The major EMRSA STs are underlined. MRSA STs are shown in red, MSSA STs in blue, and GISA STs in green. In some cases the same ST includes MRSA and MSSA isolates and, for ST5, also GISA isolates. Some MRSA STs include more than one MRSA clone, identified by the presence of different SCCmec types (Table 1). Where more than one, the number of isolates in each ST is shown in parentheses.
  • Dr. Paul Fey - Livestock-associated Staphylococcus aureus: Recent Trends

    1. 1. Methicillin-Resistant Staphylococcus aureus (MRSA) University of Nebraska Medical Center Center for Staphylococcal Research Paul D. Fey, Ph.D. D(ABMM)
    2. 2. Mortality of Staphylococcal Bacteremia in the PreAntibiotic Era (Keefer CS, N Y State J Med, 1941) • Overall Mortality for S. aureus: 82% (only pathogen with greater mortality was B. friedländer (10 cases, 100% mortality) • Mortality in patients under 40 years of age: 75% • Mortality in patients over 40 years of age: 98% 479 cases of bacteremia, S. aureus 2nd most common (122)
    3. 3. The Antibiotic Era Ernst Chain, Alexander Fleming, and Howard Florey; shared 1945 Nobel Prize in Medicine Penicillium mold
    4. 4. Evolution of Antibiotic Resistance in S. aureus Penicillin S. aureus Methicillin Penicillin-resistant [1950s] S. aureus Methicillinresistant [1960s] S. aureus (MRSA) [1997] Vancomycin [1990s] Vancomycin -resistant S. [ 2002 ] aureus Vancomycin intermediateresistant S. aureus (VISA) Vancomycin-resistant enterococci (VRE)
    5. 5. Percent Resistance 60 Methicillin-Resistant Staphylococcus aureus (MRSA) 50 40 30 20 10 Source: National Nosocomial Infections Surveillance (NNIS) System 20 07 20 05 20 03 20 01 19 99 19 97 19 95 19 93 19 91 19 89 0 U.S. Non-Intensive Care U.S. Intensive Care The Nebraska Medical Center
    6. 6. Quintessential Pathogen? Nizet et al. 2007
    7. 7. Staphylococcal Skin & Soft Tissue Infections Cellulitis
    8. 8. Staphylococcal Disease due to Metastatic Seeding
    9. 9. Staphylococcal Disease due to Metastatic Seeding: Endocarditis
    10. 10. Staphylococcal ToxinMediated Diseases Toxic Shock Syndrome Staphylococcal Scalded Skin Syndrome
    11. 11. Staphylococcal Toxin-Mediated Diseases: Food Poisoning
    12. 12. S. aureus today • • • • Most common cause of endocarditis Most common cause of nosocomial infection Most common cause of SSI Most common cause of cellulitis, osteomyelitis, septic arthritis • Common cause of bacteremia, nosocomial pneumonia, foodborne disease, implant infection, abscess, etc
    13. 13. Community-Acquired MRSA
    14. 14. What is MRSA? • Methicillin-resistant Staphylococcus aureus – Methicillin no longer in use (oxacillin/nafcillin) – Resistant to all β-lactam antibiotics • Cephalosporins • Penicillin • Carbapenems
    15. 15. Three Big Points to Remember 1. β-lactam antibiotics (penicillin and methicillin) inhibit growth of bacteria through the Inhibition of Penicillin Binding Proteins (PBPs), which build the cell wall. 2. Almost all (~95%) of S. aureus are resistant to penicillin through the production of a penicillinase, which cleaves the β-lactam ring. Methicillin (or oxacillin) is resistant to the staphylococcal penicillinase. 3. S. aureus becomes resistant to methicillin (oxacillin) through the acquisition of a new penicillin binding protein called PBP2A, which is encoded by the gene mecA. This protein builds the cell wall because it does not bind methicillin. Discuss CA-MRSA for framework to discuss LA-MRSA
    16. 16. Mobilized by Bacteriophage? Donor DNA S. epidermidis SCCmec SCCmec mecA encodes for PBP2A, which is not Inactivated by methicillin/oxacillin
    17. 17. S. aureus lineages (e.g. clonal backgrounds, genotypes, strains) MLST-defines clonal complexes and/or sequence types Feil et al. J. Bact. 2003
    18. 18. Analysis of MRSA isolates (before CA-MRSA epidemic) with MLST Enright M. C. et.al. PNAS 2002;99:7687-7692 Copyright © 2002, The National Academy of Sciences
    19. 19. 1999 MMWR • Four Pediatric deaths in Minnesota and North Dakota caused by CA-MRSA. – No known MRSA risk factors – Susceptible to non-β-lactam antibiotics – Pediatric patients CDC. 1999. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997-1999. Morb. Mortal. Wkly. Rep. 48:707-71
    20. 20. Clinical Presentation of CA-MRSA
    21. 21. Clinical Presentation of CA-MRSA
    22. 22. Clinical Disease due to CA-MRSA Pyomyositis Necrotizing Pneumonia Purpura fulminans, Necrotizing fasciitis
    23. 23. • • • • • Population surveillance in 9 communities (16.5 million persons) in US – Connecticut, Atlanta, SF, Denver, Portland, Monroe Co NY, Davidson Co TN, Ramsey Co MN 8987 cases of invasive SA (31.8/100,000) 58.6 HA-Community Onset; 26.6% HA-Hospital Onset; 13.7% Community Associated 11% Mortality; 6.3/100,000 Extrapolated to US: – 94,360 Infections – 18,650 Deaths Klevins RK, JAMA, 2007
    24. 24. PFGE-MRSA USA types USA 300 epidemic from 2003-present
    25. 25. USA 300 CA-MRSA • USA 300 MRSA most prominent S. aureus lineage isolated in the US. – Not restricted to community – Isolated from Hospital environments – Isolated from companion animals • What is so special about USA300?
    26. 26. Enhanced or found in USA300 Lysis of leukocytes Hla, PSMs, PVL Common in S. aureus lineages Lysis of leukocytes Hla, HlgABC, etc. Production of superantigens Enterotoxins, TSST-1 Sepsis PSMs Moderation of phagocyte ROS Kat, Sod, AhpC/F, TrxA, TrxB, etc. Sequestration of ironIsd system, HrtAB, HssRS, etc Transmission/colonization ACME island? . Resistance to antimicrobial peptides DltABCD, MprF, Sak, etc. Inhibition of phagocyte chemotaxis CHIPS, Eap, etc. Adapted from Wang et al. Nature Medicine 2007. 13:1510-1514
    27. 27. Kennedy, Adam D. et al. (2008) Proc. Natl. Acad. Sci. USA 105, 1327-1332 Unique S. aureus lineages Success? Why? 1. Phage type 80/81 1950’s 2.1960’s Archaic MRSA 3.Toxic Shock Syndrome Toxin-1980’s 4.HA-MRSA USA100-1980’s to present 5.CA-MRSA-1990’s to present USA300 Clonal expansion-”correct” combination of virulence factors time Selection against
    28. 28. Livestock-Associated MRSA LA-MRSA • Cows, sheep, goats, poultry and rabbits • Most S. aureus strains are host-adapted – Host specific virulence factors – Population biology suggests that S. aureus evolved with humans and were transferred to food animals— subsequent adaptation • Some strains have adapted/evolved to colonize multiple hosts including humans – ST1, CC5, ST8, ST398
    29. 29. Due to rapid exchange of mobile genetic information (plasmids, MGE, etc) S. aureus has the capability of evolving rapidly to colonize new hosts Selection pressure Food Animals Humans Selection pressure
    30. 30. Example 1: ST398-Pig associated MRSA. Human-Animal-Human • Widespread in Netherlands, Europe, Asia and the United States. • Additional capability to colonize and cause disease in cattle, sheep, humans. • Pig Farmers readily colonized with ST398, but transmission to other family members not common. Some serious disease including necrotizing pneumonia and endocarditis in humans.
    31. 31. ST398 population biology Host adaptation to swine Human ST398 MSSA Price, LB et al 2012 mBio Host adaptation to humans Swine ST398 MRSA SCCmec Tetr Macrolide/Lincosamider Apramycinr Swine ST398 MRSA SCCmec Tetr Macrolide/Lincosamider Apramycin β-converting prophage (human specific virulence factor)
    32. 32. Example 2: CC5 adaptation in poultry • S. aureus major cause of lameness in poultry industry, the result of osteomyelitis. • Majority of isolates worldwide belong to CC5, which is also a human clone. • Studies suggest a recent jump to poultry from human CC5 isolates in Poland (~40 years ago)
    33. 33. CC5 population biology Host adaptation to Poultry In Poland ~1970 Human CC5 MRSA Poultry CC5 Avian specific cysteine protease Degenerate spa-protein A (lack of IgY binding) Global Dissemination Lowder et al 2009 PNAS
    34. 34. Conclusions • S. aureus highly adaptive species due to MGE exchange. – Many examples of selection and clonal expansion • ST398 Pig-associated MRSA clearly infecting humans. Prevalence unknown in United States. • CC5 isolates in poultry derived from common human CC5 MRSA. • What is selection? Unclear what selects for MRSA in hospital environments. Antibiotics on farm? Other selective pressures?
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