Dr. Paul Fey - Livestock-associated Staphylococcus aureus: Recent Trends
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Transcript of Dr. Paul Fey - Livestock-associated Staphylococcus aureus: Recent Trends
Methicillin-Resistant Staphylococcus aureus (MRSA)
University of Nebraska Medical Center
Center for Staphylococcal Research
Paul D. Fey, Ph.D. D(ABMM)
Mortality of Staphylococcal Bacteremia in the Pre-Antibiotic 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, 479 cases of bacteremia, S. aureusS. aureus 2nd most common (122) 2nd most common (122)
Ernst Chain, Alexander Fleming, and Howard Florey; shared 1945 Nobel Prize in Medicine
Penicillium mold
The Antibiotic Era
S. aureus
Penicillin
[1950s]
Penicillin-resistant
S. aureus
Evolution of Antibiotic Resistance in S. aureus
Methicillin
[1960s]
Methicillin-resistant S. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
[1990s]
[1997]
Vancomycin
intermediate-resistantS. aureus (VISA)
[ 2002 ]Vancomycin-resistant S.
aureus
Methicillin-ResistantStaphylococcus aureus (MRSA)
U.S. Non-Intensive Care
U.S. Intensive Care
The Nebraska Medical Center
Source: National Nosocomial Infections Surveillance (NNIS) System
Nizet et al. 2007Quintessential Pathogen?
Staphylococcal Skin & Soft Tissue Infections
Cellulitis
Staphylococcal Disease due to Metastatic Seeding
Staphylococcal Disease due to Metastatic Seeding: Endocarditis
Staphylococcal Toxin-Mediated 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 SSI• Most common cause of cellulitis, osteomyelitis,
septic arthritis• Common cause of bacteremia, nosocomial
pneumonia, foodborne disease, implant infection, abscess, etc
Community-Acquired MRSA
What is MRSA?
• Methicillin-resistant Staphylococcus aureus– Methicillin no longer in use (oxacillin/nafcillin)– Resistant to all β-lactam antibiotics
• Cephalosporins• Penicillin• Carbapenems
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 newpenicillin 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
Three Big Points to Remember
SCCmecSCCmec
Mobilized by Bacteriophage?Donor DNA S. epidermidis
mecA encodes for PBP2A, which is not Inactivated by methicillin/oxacillin
S. aureus lineages (e.g. clonal backgrounds, genotypes, strains)
Feil et al. J. Bact. 2003
MLST-definesclonal complexes and/or sequence types
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
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
Clinical Presentation of CA-MRSA
Clinical Presentation of CA-MRSA
Clinical Disease due to CA-MRSA
PyomyositisPurpura fulminans, Necrotizing fasciitis
Necrotizing Pneumonia
• 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
PFGE-MRSA USA typesUSA 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– Isolated from Hospital environments– Isolated from companion animals
• What is so special about USA300?
Common in S. aureus lineagesEnhanced or found in USA300Lysis of leukocytes
Hla, HlgABC, etc.
Production of superantigensEnterotoxins, TSST-1
Moderation of phagocyte ROSKat, Sod, AhpC/F, TrxA, TrxB, etc.
Sequestration of ironIsd system,
HrtAB, HssRS, etc.Resistance to antimicrobial peptides
DltABCD, MprF, Sak, etc.
Inhibition of phagocyte chemotaxisCHIPS, Eap, etc.
Lysis of leukocytesHla, PSMs, PVL
SepsisPSMs
Transmission/colonizationACME island?
Adapted from Wang et al. Nature Medicine 2007. 13:1510-1514
Unique S. aureus lineages
Success? Why?
USA300
Clonal expansion-”correct” combination of virulence factors
time
Selection against
Kennedy, Adam D. et al. (2008) Proc. Natl. Acad. Sci. USA 105, 1327-1332
1. Phage type 80/81 1950’s2.1960’s Archaic MRSA3.Toxic Shock Syndrome Toxin-1980’s4.HA-MRSA USA100-1980’s to present5.CA-MRSA-1990’s to present
Livestock-Associated MRSALA-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
Due to rapid exchange of mobile genetic information (plasmids, MGE, etc) S. aureus has the capability of evolving
rapidly to colonize new hosts
Humans Food AnimalsSelection pressure
Selection pressure
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.
ST398 population biology
Human ST398MSSA
Host adaptation to swine Host adaptation to humans
Swine ST398MRSA
SCCmecTetr
Macrolide/Lincosamider
Apramycinr
Swine ST398MRSA
SCCmecTetr
Macrolide/Lincosamider
Apramycinβ-converting prophage
(human specific virulence factor)
Price, LB et al 2012 mBio
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)
CC5 population biology
Human CC5MRSA
Host adaptation to PoultryIn Poland ~1970
Poultry CC5Avian specific cysteine protease
Degenerate spa-protein A (lack of IgY binding)
Lowder et al 2009 PNAS
Global Dissemination
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?