Resistance Mechanisms Flashcards
Mechanism of MRSA IMPORTANT
S. Aureus cell wall is made up of penicillin binding proteins (PBPs) that are the TARGETS of beta-lactams
Beta-lactams bind to PBP 2, and MRSA has PBP 2A which reduces the binding affinity of beta-lactams
ALTERED BINDING SITE
IMPORTANT
Four Main Resistance Mechanisms
Resistance can be
- on the bacterial chromosome (intrinsic)
- On a motile gene element called a plasmid (circular DNA)
- Efflux Pump
- Reduced Permeability
- Enzymatic Inactivation
- Altered binding site
Bacterial Reistance
- Two main ways it occurs
- Why it occurs
INHERITED or ACQUIRED
Inherited
- Bacteria pass on resistance to their progeny
Acquired
- From another bacteria
The production of mutations is partly due to
- Short replication times (some as short as 20 minutes)
- Frequency of mutation is 1 in 10 million cells
C. Diff
- Flora
- How it colonizes
NOT part of the normal flora
- Normal flora does not allow C. Diff to colonize the GI tract
- Alterations of the GI flora (eg antibiotic use, PPIs) allow C. Diff to grow
- Potent spore producer able to live in harsh environments for years, can cause colitis
C. Diff Prevention
- Hand washing
C. Diff Risk Factors
- Antibiotics
- Cancer chemo
- Elderly and serious illness
- Hospital Environments
- Long term care facilities
CDAD (CDI)
C. Diff Associated Diarrhea
- Three episodes of diarrhea in 24 hours for no obvious reason
- Diarrhea must take the shape of the cup that it’s in
- Children under 2 do not have the receptor on GI cells that allows C. Diff to bind
Clinical Presentation of C. Diff Infection (CDI)
- Severe abdominal pain
- Profuse diarrhea
- Intestinal inflammation (colitis)
- Pseudomembranous ulcerative colitis
- Production of scar tissue
- Toxic megacolon
- Death
Enterococcus Spp.
- Overview
- Two species
Gamma hemolytic GPC, used to be called group D strep
Two species
1. Enterococcus faecium
- Enterococcus faecalis
Harmless normal GI flora, but can cause infection in very sick or immunocompromised PTs
VSE or VRE
MRSA Hospital Screening Programs
All high risk patients screened
High risk = anyone who has had any contact with a healthcare facility in the past YEAR
Nasal/perenium swab
If colonized, contact precautions
Prevention of MRSA
WASH HANDS
Resistance Mechanism for VRE
D-ala D-ala to D-lac, altered binding site
Resistance Mechanisms
- Efflux Pump
- Reduced Permeability
Efflux Pump
- Drug gets into bug, bug pumps it out.
- Like a water pump
Reduced Permability
- Bacterial cell wall changes its PORINS
- Changes the size of the porins to not accommodate or allow the drug to enter the bacteria
- The antibiotic is unable to permeate the cells
Resistance Mechanisms
- Enzymatic Inactivation
- Altered Binding Site
Enzymatic Inactivation
- Bacteria produce protein or enzyme that ‘eats up’ the antibiotic
- Eg beta-lactamase break down the penicillins
- Cephalosporinases break down the cephalosporins
**Backwards compatible in terms of broadness (eg carbapenases can also digest penicillins)
Altered Binding Site
- Antibiotic needs something to bind to
- Changes the binding site so that it can’t
Screening for VRE and Prevention
- Rectal swab
If positive, contact precautions
Transmission associated with environmental contamination, hand washing less effective
Sharing Resistance - Conjugation
Conjugation
- MOST COMMON, MOST IMPORTANT
- Gene transfer and recombination in bacteria that requires DIRECT CELL TO CELL CONTACT
- One bacteria, two bacteria, they form a bridge connecting the two
- Copy of donor chromosome is transferred to the other bacteria where recombination occurs
Sharing Resistance - Transduction
- Transfer of resistance via a virus that infects bacteria called a BACTERIOPHAGE
- If a virus carrying the resistance mutation infects a bacteria, the bacteria will then become resistant
Eg A virus with cipro resistance infects salmonella and transfers the resistance to it
QUITE RARE
Sharing Resistance - Transformation
Transformation
- Naked, free-floating DNA is taken up by a bacterial cell and incorporated into the recipient’s genome
- Can be linear or plasmid DNA
- Cell must be a competent cell to take up the DNA
- Strep pneuma does this
Three Main Ways of Sharing Resistance
Genetic recombination occurs within a bacteria, conferring resistance. It then spreads to others by
- Conjugation
- Transformation
- Transduction
- Plasmids are circular dsDNA that can exist and replicate independent of a chromosome
- Not required for cell’s growth
- May integrate with the chromosome, this allows bacteria to transfer their DNA/resistance adaptations via transduction
Treatment for MRSA
- IV vancomycin
Treatment options for CDI
- IV vancomycin
- but vancomycin increases risk of VRE
So people with CDI are more susceptible to VRE
- Reinfection can occur as a result of re-infection or incomplete spore eradication
Fecal microbe therapy
- Transplant stool from someone with healthy gut flora, no c. Diff infection to someone who has c. Diff
Two Types of Resistance Mechanisms
- Any resistance mechanism has a fitness or metabolic cost associated with it
- Lack of selective pressure will result in the loss of a particular resistance mechanism (particularly the ACQUIRED type)
Two Types
1. “Always on” (acquired)
- The minute the bug sees the antibiotic, the antibiotic doesn’t work
- Inducible (intrinsic- following exposure)
- The bacteria must first “see” the antibiotic for a few days
- After a few days, the switch gets turned on and doesn’t respond
Why would a bacteria carry a resistance mechanism?
- Selection pressure
Recall cipro use in the early 2000s (E. coli)
- Virtually no resistance in 2000
- Significant resistance in 2009
- Resistance is waning again
- We now take advantage of this by recycling the first line antibiotics
- Without the active selection pressure, the metabolic demand of maintaining the resistance mechanism outweighs the benefit of carrying the resistance mechanism, and it becomes less prevalent in the population
