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?