This document discusses methicillin-resistant Staphylococcus aureus (MRSA). It begins by outlining high mortality rates from S. aureus bacteremia before antibiotics. It then describes the discovery of penicillin and the subsequent evolution of antibiotic resistance in S. aureus. Key points include S. aureus developing resistance first to penicillin, then methicillin through acquisition of the mecA gene. The document discusses the rise of healthcare-associated and later community-associated MRSA strains, their virulence factors and ability to cause disease. It also notes the emergence of livestock-associated MRSA strains that can infect both animals and humans.
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. The Antibiotic Era
Ernst Chain, Alexander Fleming, and
Howard Florey; shared 1945 Nobel Prize in
Medicine
Penicillium mold
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. 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
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
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. 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. Mobilized by Bacteriophage?
Donor DNA S. epidermidis
SCCmec
SCCmec
mecA encodes for PBP2A, which is not
Inactivated by methicillin/oxacillin
17. S. aureus lineages (e.g. clonal
backgrounds, genotypes, strains)
MLST-defines
clonal complexes
and/or sequence
types
Feil et al. J. Bact. 2003
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
22. Clinical Disease due to CA-MRSA
Pyomyositis
Necrotizing
Pneumonia
Purpura fulminans,
Necrotizing fasciitis
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
26. 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?
27. 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
28. 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
29. 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
30. 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
31. 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.
32. 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)
33. 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)
34. 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
35. 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?
Editor's Notes
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.