Methicillin Resistant Staphylococcus Aureus

1
Methicillin Resistant Staphylococcus Aureus

• Barbara Jennings-Spring
• Seminar in Molecular Biology 360
• Smith College

2
What Is MRSA?

• MRSA Is Methicillin Resistant Staph Aureus
• It is a bacteria that is resistant to a
  synthetic penicillin methicillin. Staph aureus
  colonizes skin, nasal passages, and many other
  mucous membranes.
• Also causes a variety of disseminated, lethal
  infections in humans.
• It has the ability to transfer resistant genes
  easily to other species directly and indirectly
• Overuse of antibiotics is the one of the major
  reasons for the evolution of MRSA

3
Overview

• To gain a better understanding of the
  molecular mechanisms involved with (MRSA) and how
  biotechnology continues to combat this super-bug
  in hospitals and communities throughout the
  world.

4
Research

• History Of MRSA
• The Basic Biology Of Staphylococcus Aureus
• Molecular Basis For Virulence
• Clinical Presentation Of Disease
• Detection Of Pathogen
• Biotechnology Treatments
• Public Health Control Strategies
• Political And Social Impediments

5
History Of Antibiotic Resistance

• 1941 Penicillin
• 1943 Streptomycin
• 1945 Cephalosporins
• 1950 Tetracycline
• 1952 Erythromycin
• 1956 Vancomycin
• 1960 Methicillin
• 1962 Lincomycin
• 1962 Quinolones
• 1970 Penems
• 1980 Monobactams
• 2010 Is this the end of an antibiotic era???

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The Basic Phenotypic Characteristics Of
Methicillin Resistant Staphylococcus Aureus

• Gram positive
• Non-motile
• Spherical
• Grows in chains
• Resembles clumps of grapes
• Golden color
• Hemolytic pattern on blood agar
• Produces coagulase and catalase enzymes

7
The molecular genetics of antimicrobial
resistance includes three main pathways

• Microevolutionary changes-a single point mutation
• Macroevolutionary change- rearrangements occur
• Acquisition of foreign DNA

8
What are some examples of how single point
mutations occur over time?

• Beta lactamases will confer resistance to B-
  lactams (penicillins, cephalosporins)
• If you get a single point mutation (substitution
  of base pair) that involves the target action of
  PCN or the cephalosporin drug, you will extend
  the spectum of action of that B-lactamase enzyme
• so that a broad range of the cephalosporin or
  penicillin family will show resistance instead of
  one single cephalosporin or penicillin family
• Mutations on the rpoB gene (RNA polymerase)
  alters antibiotic binding site, preventing drug
  action.

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What Are Some Examples Of Macro Evolutionary
Changes With Resistance?

• Rearrangement of DNA segments-by transposons
• TransposonJumping Gene that contributes to
  antibiotic resistance
• Transposons- Contain genes that are for the
  coding of antibiotic resistance

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How is the Acquisition of Foreign DNA from other
species accomplished?

• Conjugative plasmids Found inside cytoplasm.
• Possess the ability to transfer resistance genes
  to the same and different species
• Horizontal gene transfer is common in bacteria
  and is accomplished by the process known as
  Transformation in Staph. aureus.

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Examples of horizontal Gene Transfers (HGT)

• http//www.bioteach.ubc.ca/Biodiversity/AttackOfTh
  eSuperbugs/

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How Staph Aureus acquires resistance to
methicillin

• http//www.jci.org/cgi/content/full/114/12/1693/F1

http//www.jci.org/cgi/content/full/114/12/1693/F1
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Mechanism of Antibiotic Resistance in MRSA

• http//www.bioteach.ubc.ca/Biodiversity/AttackOfTh
  eSuperbugs/

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Important Virulence Factors for MRSA Cell
Wall Structures

• Cytoplasmic membrane- osmotic barrier
• Consists of thick polysaccharide capsule (slime
  layer adhesin). Capsules are just tricks to
  avoid host defenses
• Petidoglycan-Used for osmotic stability so
  bacterial cell wall does not burst due to
  hypertonic states.
• Protein A- immunological disguise. Inhibits
  oponization , Binds IGs, leukocyte,
  chemoattractant, anticomplementary.
• Techoic Acid-Acts as a receptor for
  bacteriophages. Attachment site for mucosal cell
  receptors.

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Invasive enzymes As Other Virulence Factors

• Coagulase Complex-Produces enzymes that coagulate
  blood and seal off infection
• Protease, lipase, DNase provide nourishment for
  MRSA bacterium
• FAME-Important in abscess formation. Also it
  could change anti-bacterial lipids and prolong
  survival of MRSA in wound.
• Staphylokinase-Plasminogen activator enzyme that
  lyses fibrin clots
• Hyaluronidase-It is the spreading factor
  hydrolyzes haluronic acid in synovial joints

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Virulence Factors Cont Extracellular Products
and Toxins (hemolysins) Of MRSA Invasion

• Leukocidins-The name implies their job!
  Leukocidins kill wbcs. Membrane damaging toxin
• Alpha, beta, delta toxin-binds to cell surface,
  forms pores leaks.
• Superantigens (type 1 toxin) Toxic shock
  syndrome toxin (TSST-1)
• Staphylococcal Enterotoxin-food poisoning
• Exfoliation toxin-scalded skin syndrome

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Virulence Factors Cont Mechanism Of
Superantigens And The Stimulation Of Cytokine
Release
http//textbookofbacteriology.net/staph.html
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Summary of Virulence Determinants Of Staph. Aureus

• http//textbookofbacteriology.net/staph.html

http//textbookofbacteriology.net/staph.html
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Source of MRSA Infections

• Some infections are caused by own epithelial
  flora-self contamination
• Nasal carriage most common
• Hospitals
• Dirty hands, towels, and daycare
• Airborne?????

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Predisposing Factors Of Host Resistance

• Integument injury via surgery
• Burns and trauma
• Foreign objects like indwelling catheters,
  metals, sutures, implants
• A history of chronic bacterial infections with
  multiple rounds of antibiotics
• Hormonal changes and stress
• Immunocompromised (AIDS, Diabetes, Chemo)

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Clinical Manifestations Of MRSA

• The lesion usually starts out as an small cut or
  break in the skin. The lesions can range from
  small abrasions to large, gaping abscesses
• Even the most benign localized abrasion (from
  tampon insertion) can become the fuel for a
  devastating, disseminated MRSA systemic infection
  that do not respond to multi-antibiotic
  combinations

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MRSA Infections Go Everywhere

• Integumental and soft tissue
• Suppurative arthritis-first causative agent
• Osteomyelitis-First causative agent
• Bacteremia-First causative agent
• Pneumonia
• Acute and chronic Endocarditis-1
• Bacterial Meningitis-first causative agent

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Menstrual Toxic Shock By MRSA

• Most major organs fail with disseminated MRSA
  (TSS-1)

www.web.net/terrafemme/ cashnightmare.htm
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More MRSA Infections

• Toxic shock Syndrome-Super absorbent tampons- 1
  causative reason
• Urinary tract Infections
• Scalded skin syndrome and impetigo from picking
  pimples
• Food poisoning-Enterotoxin A in spoiled or
  contaminated food.

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Carbuncle(Boil)

• tahilla.typepad.com/.../ super_bug_091404.jpg

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44 y/o IV drug abuser with back pain and Staph
Osteomyelitis of lumbar spine

• .

Staph osteomyelitis and discitis involving L5,
with extension across the L4-5 disc to erode L4
and extension into S1. The L5 vertebral body is
destroyed. (33.210, 33.250, diskitis) Case 72
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Classic Toxic Shock Scalded Skin Syndrome
www.aafp.org/afp/ 20000815/804.html
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Staph. Aureus Impetiigo

• Dont pick your face!!!!!

www.med.sc.edu85/ fox/staph-impetigo.jpg
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Getting A Lab Diagnosis For MRSA

• http//jcm.asm.org/cgi/content/full/38/6/2378

MRSA
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How Accurate Can Your Diagnosis Of MRSA Be?
http//jcm.asm.org/cgi/content/full/38/6/2378
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Current Drug Treatments For MRSA

• Methicillin-resistant MRSA Drugs of Choice 
• Linezolid(protein synthesis inhibitor),
  Daptomycin,
• Vancomycin
• Alternatives  Synercid, Rifampin
• Third-Line agents  TMP-SMX

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Drugs In Development

• Oritavancin-can be given once daily
• Tigecyclin-orally broad antimicrobial activity
• Dalbavancin- Currently undergoing clinical
  trials. Has long half-life so it can be given
  once per week

(FDA, 2005)
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How Close Is Staph Vaccine?

• Pretty close. The results of the phase 3 testing
  of the vaccine (Staph VAX) will be presented soon
  according to the NIH.

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Public Health Response-What Is Being Done To
Combat MRSA?

• The CDC provides technical help and referrals to
  state and local health departments, doctors,
  nurses, and other professionals
• The CDC provides national program of surveillance
  for serious infections with MRSA.
• CDC launched evidence-based educational campaign
  to prevent antimicrobial resistance
• CDC building national resource library to
  identify genetic patterns or relationships
• CDC researching the role of staph toxins-to
  provide answers for hospitals and researchers
• For more info go to www.cdc.goc

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What can you do to prevent MRSA from attacking
You?

• Keep draining infections of skin, covered with
  clean dry bandages
• Talk to your physician about wound management
  techniques
• Advise family to wash hands frequently with soap
  and water, count to at least 20,especially
  after dressing a gaping wound.
• Avoid sharing personal items such as towel,
  razors, bed linens with people who have sores or
  have come home from the hospital recently
• Wipe objects down with alcohol.
• If you are in the hospital please advise you
  nurse or physician to wash their hands before
  touching you or your hospital equipment

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What Are The Social And Political Costs To Us?
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The Real Cost Of Infectious Diseases Like MRSA
38
Rising Rates Of Resistant Bacterial
InfectionsRising Budget
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Thats All Folks!! Any Questions????

• Staph cells attaching photo courtesy of Dr.
  Sharon peacock- University of Oxford

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References

• 1 Mitchell, David.MRSA.whats New. Inoculum.
  Volume 8, number 2 (1999) 1-12.
• 2 textbookofbacteriology.net/resantimicrobial.ht
  ml
• 3 healthsciences.columbia.edu/
  dept/ps/2007/mid/2006/transcript_02_mid22.pdf
• 4 http//www.bioteach.ubc.ca/Biodiversity/AttackO
  fTheSuperbugs
• 5. Foster, Timothy. The staphylococcus aureus
  superbug.J. clin Ivestigation
• Volume number114 (2004) 1693-1696.
• 6. www.channing.harvard.edu/4a.htm
• 7. ww.ncbi.nlm.nih.gov.
• 8. www.aafp.org/afp/ 20000815/804.html
• 9. Journal of Clinical Microbiology, June 2000,
  p. 2378-2380, Vol. 38, No. 60095-1137/04.000
• 10. www.FDA.com (FDA archives)
• 11.www.postgradmed.com/issues/2001/10_01/hoel.htm
  12. www.cdc.gov/ncidod/hip/aresist/mrsa_CDCactions
  .htm
• 13. www.medscape.com