Antimicrobial Resistance Flashcards
What are the two forms of antimicrobial resistance?
Innate Resistance and Acquired Resistance
Resistance before drug exposure/resistance due to morphology of bacteria is…
Innate Resistance
Resistance due to antibiotic usage OR accumulation of resistant strains is…
Acquired Resistance
G+ bacteria are resistant to polymyxins because they lack LPS on their cell surface (no negative charge). This is an example of…
Innate Resistance
G- bacteria are resistant to vancomycin because it is too large to cross outer membrane by diffusion. This is an example of…
Innate Resistance. G- bacteria are resistant to most glycopeptides
Intracellular bacteria are resistant to ß-lactams because ß-lactams are poorly taken up by animal cells. This is an example of…
Innate Resistance
Chlamydia and Mycoplasma are resistant to ß-lactams because they lack peptidoglycan cell walls. This is an example of…
Innate Resistance
Resistant strains developing as result of treatment is an example of…
Acquired Resistance
Resistant bacteria exist in the environment, but are initially rare in…
Patients
Chromosomal mutations can migrate to plasmid or transposon and then transfer to other bacteria. This is an example of:
Acquired Resistance
Antibiotic use increases incidence of resistance in patient populations due to:
Acquired Resistance
Chronic infections or infections that involve a biofilm should use which type of drug?
Bactericidal, ex: Rifampin
Which type of drugs inhibit cell growth and rely on the immune response for complete clearance of the microbe?
Bacteriostatic
All drugs that are inhibitors of protein synthesis are bacteriostatic. The one exception is:
Aminoglycosides
What is the MIC?
Minimum Inhibitory Concentration. It is the lowest concentration of drug that will INHIBIT MICROBIAL GROWTH
Which tests measure MIC?
Kirby-Bauer and E strip
What does antimicrobial resistance do the MIC? Increase or Decrease?
Increase ! Resistance makes the MIC higher so that you need a higher dosage to inhibit growth.
What is the reason for antimicrobial resistance increasing from low levels to high levels over time?
The MIC keeps getting higher, so the drug dose that causes resistance keeps getting higher as well.
The breakpoint is the MIC that determines whether the microbe is susceptible to treatment or resistant. If the breakpoint is BELOW the MIC, is the microbe S, I, or R?
The microbe is resistant–R. The amount of drug administered is LOWER than the minimum amount needed to inhibit growth (MIC).
The breakpoint is the MIC that determines whether the microbe is susceptible to treatment or resistant. If the breakpoint is ABOVE the MIC, is the microbe S, I or R?
The microbe is susceptible–S. The amount of drug administered is HIGHER than min. amount needed to inhibit growth (MIC).
The breakpoint gives more info about what will work best on the infection, rather than the MIC, because:
The breakpoint tells you whether or not the bacteria will be susceptible to the amount of drug you want to administer.
What is the MBC?
The Minimum Bactericidal Concentration. The lowest amount of drug that will KILL the bacteria
What are the 3 mechanisms of resistance?
- Exclusion
- Altered target
- Enzymatic Inactivation
The cell wall and G- outer membrane serve as barriers to outside substances. This is an example of size EXCLUSION. Lack of specific transporter mechanisms can also exist in exclusion. Are these acquired or innate mechanisms?
Innate
A cell that alters membrane lipids to reduce drug binding or drug diffusion through membrane is an example/ of which type of mechanism of resistance
Acquired Exclusion.
Increasing expression of existing efflux pumps or altering other transport properties is what type of mechanism of resistance?
Acquired Exclusion. Increased expression is often induced IN PRESENCE of the drug.
AA substitutions that reduce the affinity of the drug for its target (PBPs, ribosomes, polymerases etc) is an example of which mechanism of resistance?
Altered Target
What limits the mutations in Altered Target resistance?
The alteration must still enable functionality
Does resistance occur quicker with a single target site or multiple target sites? Why?
Single target sites. The bacteria doesn’t have to change much else other than that one site. Easier for bacteria to make the change it needs, and still function while excluding the antibiotic. Increasing Resistance.
Multiple target sites hurts the bacteria bc it has to make so many changes in order to still thrive
Newer drugs take advantage of a single target site or multiple target sites?
Multiple! Decreases likelihood for resistance
Which mechanism of resistance involves little sacrifice on the microbe’s part?
Enzymatic Inactivation, like we see with ß-lactamases
Porin proteins in G- bacteria can alter exclusion properties to exclude ß-lactams. This is an example of innate or acquired resistance?
Acquired.
Thickening of the cell wall in Vancomycin-Intermediate Staph Aureus (VISA) provides intermediate resistance. Vancomycin cannot get through. This is an example of:
Acquired Exclusion (?)
What are the most important targets to consider in altered target resistance?
Penicillin-binding proteins (PBPs)
There are multiple transpeptidases in a bacterium, some more essential than others, so by reducing affinity for ß-lactam, and still being able to mediate cross-linking, the bacteria can overcome treatment
Methicillin-resistant Staph Aureus (MRSA) is a hospital and community acquired infection. How is it transferred?
The mecA gene is acquired on a transposon and inserted into a chromosome
What does mecA, the gene involved in MRSA (methicillin-resistant Staph Aureus), encode?
An altered PBP. It resists binding by all ß-lactams.
mecA is acquired on a transposon and inserted into a chromosome.
Streptococcus and Neisseria species utilize which mechanism of resistance?
Acquired Altered PBPs. They forms “mosaics” from other species. They are both competent for transformation, so this plus subsequent homologous recombination can explain the mosaicism.
What is Vancomycin’s mechanism of resistance?
It binds to the terminal D-ala D-ala pair instead of the PBPs
How does Vancomycin-Resistant Enterococcus (VRE) get its resistance?
The vanA gene. This gene encodes an enzyme that synthesizes D-ala D-lactate so that vancomycin CANNOT recognize this pair, thus cannot take effect.
VRE (Vancomycin-Resistant Enterococcus) inhibits Vancomycin but still enables what?
Cross-linking. The D-ala D-lactate encoded in vanA gene is still recognized by essential PBPs
The vanA gene in VRE (vancomycine-resistance enterococcus) has been seen in what other infection?
Vancomycin-Resistant Staph Aureus (VRSA–rare). Believed to be acquired from Enterococcus
What is the drug of choice for MRSA?
What other drug can be used?
Vancomycin, Linezolid
The first ß-lactamase described was in what organism?
What is required for this drug to work in this organism?
Staph Aureus (plasma encoded penicillinase)– it is a G+ bacteria, so enzyme is secreted into immediate environment
Requires high density of bacteria to effectively work
What does ß-lactamase cleave?
Penicillin and Ampicillin, not later versions like Methicillin and Cephalosporins
G- bacteria also have acquired plasmids encoding ß-lactamase. Where are they secreted in these organisms?
The periplasm. It reaches a higher concentration than G+ exoenzymes
ß-lactamases play a more prominent role in the resistance of which type of bactera–G+ or G-?
G-. it reaches a higher concentration in the periplasm of G- bacteria.
TEM ß-lactamase was first isolated in E.Coli and then spread to many other G- bacteria. The first TEM isolated only cleaved which antibiotic?
Now, TEM can cleave lots of different antibiotics, making it a what?
Ampicillin, Extended-Spectrum ß-lactamase (ESBL)
What do Extended-spectrum ß-lactamases cleave?
Penicillins, broad-spectrum cephalosporins. This is a problem!
What organisms are Extended-spectrum ß-lactamases (ESBLs) most often associated with ?
E.Coli and Klebsiella
There are over 200 types of ESBLs, 3 common types are:
Which antibiotic do various strains of E.Coli and Klebsiella remain sensitive to?
- TEMs (over 140)
- SHVs (over 60)
- CTX-M (over 40)
Carbapanem
Carbapenem is the antibiotic that most strains of E.Coli and Klebsiella remain sensitive to, however Carbapenemases exist. Most commonly in which organism?
Klebsiella pneumoniae (KPC)
KPC is multidrug resistant and very hard to purge in hospitals. Resistance is spreading to other Gram- and enterobacteriaceae
Most G- bacteria encode a chromosomal enzyme against an antibiotic. What is that enzyme called?
Cephalosporinase
Many G- bacteria encode a chromosomal Cephalosporinase. Some have high levels of it, other low. Explain the variation here.
High levels of cephalosporinase are needed to fend off cephalosporin.
Low levels fends off poorly absorbed ß-lactams
G- bacteria require a high level of expression of cephalosporinase in order to fend off cephalosporin– if you have a penicillin-resistant strain, you may be able to treat it with:
Cephalosporin
Early penicillins and cephalosporins were effective against which bacteria? Ineffective against which?
Effective: G+
Ineffective: G- due to chromosomal cephalosporinases
Early ß-lactamases (like penicillin and cephalosporins) were not effective against G- bacteria due to the cephalosporinases, subsequent generations have improved activity against G- bacteria. Which “latest generation” species in particular produces a lot of ß-lactamases ?
Pseudomonas species
Tetracyclines are antibiotics that target which cell function?
Translation
Tetracyclines target translation in a bacterial cell. Resistance is common towards these drugs. What is the main mechanism of resistance? Is it innate or acquired?
Efflux pumps – Exclusion. Acquired
Tetracyclines target translation in a bacterial cell. Resistance is common towards these drugs. What is the main mechanism of resistance? What is another mechanism of resistance?
Efflux pumps: main
protection of ribosome target by masking proteins: other
Macrolides are antibiotics that target which cell function?
Translation
Macrolides are antibiotics that target translation. What are their mechanisms of resistance?
- Altered target in Strep pneumo, Staph, B. gonorrhea
2. Efflux pumps
Chloramphenicol is a type of antibiotic that targets which cell function?
Translation
Chloramphenicol is a type of antibiotic that targets translation. What is its mechanism of resistance? Which of the 3 over-arching mechanisms of resistance does this fall under?
Acetylation. Enzymatic Inactivation
Which mechanism of resistance (of the 3) is the most robust? Why?
Enzymatic Inactivation. There is no sacrifice in activity on the organism’s part.
Why doesn’t natural resistance occur in bacteria against Fluoroquinolones?
They are completely synthetic
Initially, people thought resistance to fluoroquinolones were due to AA substitution , altering DNA gyrase. But now, it is documented that the resistance is in what?
plasmid-encoded resistance in G- enterics
The plasmid-encoded resistance that exists against fluoroquniolones also exists in that same plasmid for which antibiotics? What is this termed as?
ß-lactamase and aminoglycosides. This is termed multi-drug resistance
Which antibiotic should you AVOID using in G- enteric infections?
Fluoroquinolones. Due to the plasmid-encoded resistance
Plasmid-mediated and altered target resistance are two forms of resistance against fluoroquniolones. What is another form?
Efflux pumps (exclusion)
