Lesson 3.6 - Staphylococcus aureus & MRSA Flashcards
Appearance/characteristics of S. aureus
- Gram (+), cocus
- Organized in clusters
- Common in anterior nares, nasal membrane, nasopharynx, skin, perineum, GI tract & genital tract
In 2017, S. aureus incited _____ bloodstream infections with _______ associated deaths.
- 119,247
- 19,832
Define virulence factors
Expressed as a phenotype
Virulence is ability of an organism to cause disease
Host entry [S. aureus}
- Hair follicle, scratch/cut, needle stic, surgery scars/sutures, respiratory & GI tract
How does S. aureus spread? What happens?
- Spread via circulatory system, infect muscle, heart meninges, kidney, bone
- Leads to pus, tissue necrosis, inflammation, blood clots
- Supprative: pus forming
- Dead neutrophils, macrophages, host cells, fluid
- Supprative: pus forming
Major cause of nosocomial infections*
What does MSCRAAMS stand for? What is it?
-
Microbial Surface Components Recognizing Adhesive Matrix Molecules
- Generic term used to describe adhesive proteins of S. aureus
What are the [3] types of MSCRAAMS?
-
Collagen adhesion
- septic arthritis, osteomyelitis
-
Fibrinogen Binding Protien
- attach to blood clots & injured tissue
-
Fibronectin Binding Protein
- part of and attaches to extracellular matrix
What are types of toxins produced by S. aureus? (8)
- All strains produce at least one of following
- α (alpha) toxin
- ß (beta) toxin
- δ (delta) toxin
- Leukotoxin γ
- Panton-Valentine Leukocidin (PVL)
- Exfoliation toxin
- Enterotoxin
- Super-antigen
α-(alpha) toxin
Lysis of RBC, monocytes, & platelets
β (beta) toxin
sphingomyelinase (degrades sphingomyelin)
δ (delta) toxin
small peptide w/ unk f(x)
Leukotoxin γ (gamma)
alters permeability of luekocytes’ membrane
Panton-Valentine Leukocidin (PVL)
specifically attakcs neutrophils
Exfoliation toxin
scalded skin syndrome; incites separates of skin layers
Enterotoxins
- [6] diff types
- Cause diarrhea & vomiting
- Some withstand cooking
- Response for S. -related food posioning
What are super-antigens?
- Stimulate T-cells w/o usual antigen recognition process
- Can interact w/ 1/5 of T-cells
- Massive (non-specific) activation, cytokine release & systemic inflammation
- Life-threatening
- Can interact w/ 1/5 of T-cells
Describe Toxic Shock Syndrome Toxin No. 1 (TSST-1)
- Super-antigen
- Binds to MHC II receptor of APCs
- Fever, diarrhea, vomiting, shock
What is involved w/ evasion of phagocytes? [S. aureus]
- Coagulase
- Protein A
- Capsule production
- Biofilm formation
What is coagulase?
Enzyme that catalyzes fibrinogen (soluble) to fibrin (insoluble) conversion; allows S. aureus to hide in clots
What is Protein A?
- Cell wall protein that binds to Fc region of IgG
- Prevents Abs acting as opsonins
- Camouflage
What is involved with survival within phagocytes? [S. aureus]
- Carotenoids
- Golden yellow pigment
- Detoxify O2- (reactive O) compounds
- Catalase
- Inactivates H2O2 made by neutrophils
What extracellular enzymes involved in assisting [S. aureus] in spreading?
- Staphylokinase
- Degrades fibrin
- Hyaluronidase
- Degrades hyaluronic acid (retains H2O in skin, joints, eyes)
Antibiotic Resistance Events [Timeline]
Basically, resistance increased over time (evolved)
______ was developed in the late 1950s as a replacement for penicillin.
Methicillin; no longer used clinically
MRSA now stands for
Multiple Drug Resistant S. aureus
MSSA stands for
Methicillin sensitive S. aureus
Roughly ___ of healthy adults colonized by Staphylococcus
- 1/3; anterior nares
- 1-2% healthy adults colonized by MRSA
- 5-6% healthcare workers colonized by MRSA
What type of MRSA transmitted to patients via human hands?
- HA-MRSA: Healthcare-Associated MRSA
- U BETTER WASH UR MF HANDS W SOAP AND WATER OR ALCOHOL-BASED SANITIZER BC AT BEST 50% ADHERE TO IT CORRECTLY IN HEALTH FACILITIES
- Nurses have better hand hygiene than physicians
What is community-associated MRSA?
- Acquired by ppl who haven’t been hospitalized w/in past year
- Present at skin infections (pimples, boils)
- Can survive 8 weeks on acrylic fingernails
- 6 weeks on computer keyboards
- 5 days on bed linen
Where are MRSA strains commonly isolated from?
Pigs, turkeys, cattle & horses; Jumped from humans to livestock and back - dogs and cats have it too
LA-MRSA stands for …
Livestock-associated MRSA
VRSA stands for…
Vancomycin resistant S. aureus
What lead to the evolution of multi-drug resistant S. aureus?
- Altered pencillin binding proteins
- ß-lactamase (SBL, ESBL, MBL)
Function of transglycosylases (Gram + cell wall)
Catalyze ß-1,4 glycosidic bonds
Function of transpeptidase (Gram + cell wall)
Catalyze bond b/t pentapeptide crosslink & D-alanine & removes terminal D-alanine from NAM
What happens to Gram + cell in presence of ß-lactam?
- ß-lactam bind irreversibly to transpeptidase active site
- Transpeptidase catalyze bond b/t ß-lactam & D-ala
- Reminiscient of D-ala-D-ala structure
- Transpeptidase catalyze bond b/t ß-lactam & D-ala
- Gram (+) cell wall can’t survive osmotive pressure
- BOOM!
What are Pencillin Binding Proteins (PBPs)?
- Enzymes involved in peptidoglycan biosynthesis
- Bind penicillin & other ß-lactam antibiotics
- Mutations in PBP genes lead to enzymes w/ low affinity for ß-lactam antibiotics (resistance)
What enzymes are involved in peptidoglycan biosynthesis?
- Penicillin Binding Proteins (PBPs)
- Transpeptidases
- cross-links peptidoglycan chains
- Endopeptidases
- hydrolyze peptide bonds in peptide (not terminal ones)
- Carboxypeptidases
- remove terminal D-ala from pentapeptide side chains of NAM (like a backup for transpeptidases)
- Transpeptidases
What is PBP2a?
- Mutant protein (by HGT) w/ little-no affinity for ß-lactam antibiotics
- MRSA strains have this
What is PBP2? What enzyme involved?
- Wild type sensitive to ß-lactams
- Bifunctional enzyme
- Transpeptidase & transglycosylase
- Cross-links peptidoglycan chains & catalyze ß-1,4 glycosidic bonds b/t NAM & NAG
- UnitProt: Q53729
What is the S. aureus mecA gene?
- Confers resistance to ALL ß-lactam antibiotics
- Codes for PBP2a
- Carried on mobile gene cassette
- HGT!
S. aureus Resistance Cassette Features
- mecA gene (resistance)
-
Casette chromosome recombinase (crr) genes
- Site-specific recombinases responsible for integration & cutting of cassette (transmitted by conjugation)
-
Accessory genes & elements
- May or not be involved in resistance
There are how many versions of categories of SCCmec?
-
13 versions (I-XIII) & abt. 79 subcategories
- size ranges 20-60 kb
- Types I - IV document evolution of resistance
SCCmec I-X & XI
- mecA & mecC = PBP2a variants
- mecRI = regulatory genes
- ccrA & ccrB = specify site-specific recombinases
- J1, J2 & J3 = joining regions
- blaZ = (ß-lactamase allele Z) hydrolze amide bonds
Arrows on image indicates direction of transcription
What are ß-lactam antibiotics? What are its [4] categories?
- Cyclic amide
- Inhibit bacteria from maintaining its cell wall = death
- Categories:
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams (Aztreonam)
What are ß-lactamases? What are its [3] categories?
- Catalyze hydrolysis of amide bond in ß-lactam ring
- Categories:
- Serine ß-lactamases (SBL)
- Extended-spectrum ß-lactamases (ESBLs)
- Metallo-ß-lactamases (MBL)
What are Serine ß-lactamases (SBL)?
-
Confers resistance in some penicillins & cephalosporins
- Active site serine facilitates hydrolysis of ß-lactam ring
-
Nucleophilic attack via serine
- nucleophile replaces f(x) group w/in another nucleophile
- bla genes on plasmids & chromosomes
What are Extended-spectrum ß-lactamases (ESBLs)?
-
Confer resistance to ALL penicillins, ALL cephalosporins, & monobactam (aztreonam)
- NOT cephamycins or carbapenems
What can metallo-ß-lactamases (MBL) hydrolyze?
- Hydrolyze ALL ß-lactams
- Penicllins, cephalosporins, carbapenems singly & ß-lactamase inhibitors
- Aztreonam (monobactam) not affected
How do metallo-ß-lactamases (MBL) work?
- Cleaves amide bond of ß-lactam ring via nucelophilic attack
- OH- donates e- to carbonyl carbon
- Stabilized by Zn1 & Zn2
- Genes ocated on chromosomes & mobile genetic elements
- blaMBL commonly found on integrons, integrated into transponsons; also on plasmids & chromosomes
What are ß-lactamase inhibitors?
- Have a ß-lactam ring, but weak antimicrobial activity
- Bind irreversibily to ß-lactamase active site; permanently inactivates enzyme
- Competitive inhibition
- Co-administered w/ antibiotic = lowers MIC
What is Amoxicillin & Clavulanic Acid?
- Amoxicillin = ß-lactam antibiotic
- Clavulanic Acid = ß-lactamase inhibitor
- Weak if alone
- Combination = tablets or oral suspension
- ie. AugmentinTM
- Greater effect (refer to image)
US MRSA Trends
- Declining Hospital-onset MRSA & MSSA
- Improved practices
- Increasing community-onset MSSA, stable MRSA
MRSA Infection by State (Overview)
- Most: DC at 20.4 per 100,000
- Least: Wyoming at 1.26 per 100,000
Factors associated w/ MRSA
- Income
- Below poverty line = less spacious homes = ^ MRSA
- Race
- Black individuals (insection of education & healthcare access)
- Education
- Lower education = ^ MRSA
- Antibiotic Prescriptions
- Non-ß-lactams use = ^ MRSA
- Lincosamides (clindamycin), glycopeptides (vancomycin) & sulfonamids (sulfamethoxazole/trimethoprim)
- Non-ß-lactams use = ^ MRSA
Global MRSA trends
- Lower MRSA
- Better government, public infrastructure, healthcare investment
- Higher MRSA
- Poor gov, public infrastructure, & more private than public healthcare
