Resistance (Kays) Flashcards
What are PBPs?
penicillin-binding proteins; the enzymes vital for cell wall synthesis, cell shape, and structural integrity
What is the most important PBP and why?
transpeptidase
it catalyzes final cross link between sugar and peptide in peptidoglycan molecule
What are the 3 types of genetic exchange that lead to resistance?
- conjugation
- transduction
- transformation
What is conjugation?
direct contact or mating via sex pilli (most common)
What is transduction?
genes transferred via bacteriophages (viruses) between bacteria
What is transformation?
uptake of “free floating” DNA from the environment then gets integrated into the hosts DNA
Plasmids or transposons:
- transferred from organism to organism
- self-replicating
- extrachromosomal DNA
plasmid
What are the 3 main mechanisms of bacterial resistance?
- enzymatic inactivation
- alteration of target site
- altered permeability of bacterial cell
Give examples of antibiotic resistance via enzymatic inactivation.
- beta-lactamases
- aminoglycoside-modifying enzyme
Give examples of antibiotic resistance via alteration of the target site.
- PBPs
- cell wall precursors
- ribosomes
- DNA gyrase/topoisomerase
Give examples of antibiotic resistance via altered permeability of the bacterial cell.
- efflux pumps
- porin changes
What are beta-lactamases and how do they work?
they inactivate beta-lactam antibiotics by hydrolyzing/splitting the amide bond
What gene in beta lactamases are we expected to know?
AmpC
Which bacteria typically contain AmpC?
SPICE
(serratia, pseudomonas, indole-positive proteus, citrobacter, enterobacter)
What drugs are beta-lactamase inhibitors?
- tazobactam
- clavulanic acid
- sulbactam (resistance to the SPICE organisms has happened)
- avibactam (lactamase inhibited in SPICE by this drug does happen)
How is AmpC induced?
the gene is normally repressed; when a beta-lactam is present, the gene gets DEREPRESSED which causes beta-lactamase production
when inducer is removed, the gene gets repressed again
What antibiotics are strong inducers of AmpC?
- Penicillin G
- Ampicillin
- 1st gen cephalosporins
- Cefoxitin
- Clavulanic acid = potent inducer of AmpC beta-lactamases
SPICE are typically constitutively making beta-lactamases… what antibiotics should we avoid using because of developed resistance?
avoid 3rd generation cephalosporins
ESBLs are seen most frequently in what bacteria?
- K. pneumoniae
- E.Coli
ESBLs are _____ mediated and tend to hydrolyze _______ and ______.
plasmid mediated;
hydrolyze PCNs and cephalosporins
What drug may be useful for the CTX-M enzyme of ESBLs?
tazobactam
What is normally the treatment of choice for ESBLs?
carbapenems
What are the 3 most important carbapenemases?
- KPC (klebsiella pneumoniae carbapenemase)
- OXA-type (seen in acinetobacter)
- NDM (New Dehli metallo-beta-lactamases)
True or false: CRE can last in the body for a maximum of 6 months.
False; carbapenemase-resistant enzymes can last in the body for 12 months (bacteria can get spread allllll over)
NDM-1 is resistant to all antibiotics except what?
Colistin
What is the best way to treat CRE bugs?
serine carbapenemase = ceftazidime + avibactam
NDM-1/metallo-beta-lactamase = aztreonam
What are the aminoglycoside modifying enzyme mechanisms? (3 total)
- acetylation
- nucleotidylation
- phosphorylation
Aminoglycoside-modifying enzyme:
they modify the structure by transferring an indicated chemical group to a ___________;
this will impair ______ and/or _______
to a specific side chain
impair cellular uptake/binding to ribosome
Bifunctional enzyme that modifies aminoglycosides:
mainly seen in what bacteria?
the enzyme leads to high level resistance to ______ but not _______
mainly seen in ENTEROCOCCI
resistance to gentamicin
not resistant to streptomycin
Resistance mechanisms:
What are examples of altered target sites - PBPs?
- S. Pneumoniae resistant to PCN and cephalosporins
- Staphylococci is resistant to methicillin via mecA gene
Methicillin resistance is seen in which antibiotics because of what gene?
staphylococci; mecA gene
The mecA gene encodes for production of a new PBP that is called ______.
PBP2A or PBP2’
How does vancomycin normally work as an antibiotic?
inhibits cell wall synthesis by binding to D-alanine-D-alanine terminus of pentapeptide (a peptidoglycan precursor)
What bacteria is known to have vancomycin resistance through the VanA gene?
S. Aureus = VRSA
How does the VanA gene cause resistance?
D-Ala-D-Ala part becomes D-Ala-D-Lac and vancomycin can’t bind
Altered ribosomal targets lead to resistance in what antibiotics?
- macrolides
- azolides
- aminoglycosides
- tetracyclines
- clindamycin
Altered DNA gyrase/topoisomerases lead to resistance in which drug class?
This resistance is seen in what organisms most?
fluoroquinolones
seen in S. Pneumoniae and gram-negative
What are some drugs that have had reported chromosomal/plasmid mediated resistance with efflux pumps?
- Macrolides/Azolides
- Carbapenems
What bug has had reported efflux pump resistance to macrolides/azolides?
S. Pneumoniae
What bug has had reported efflux pump resistance to carbapenems?
P. Aeruginosa
For P. Aerugonisa that’s resistant to carbapenems, which carbapenem is best to use? (because it does not get effluxed out)
imipenem
Porins will typically allow a drug to go through it when the drug is…
- small or large?
- more or less negative?
- hydrophobic or hydrophillic?
- small
- less negative charges (prefers zwitterionic charge)
- hydrophillic
Mutations in porins are seen most commonly in what organisms?
Enterobacteriaceae and P. Aeruginosa
What resistance mechanisms are most common for beta-lactam drugs?
- hydrolysis (aka beta lactamase)
- altered target site
- efflux
What resistance mechanisms are common for aminoglycosides?
- aminoglycoside modifying enzymes
- altered target site
- efflux
What resistance mechanisms are most common for glycopeptides (aka vancomycin)?
altered cell wall precursors (D-Ala-D-Lac)
What organism has intrinsic resistance to beta-lactams?
Mycoplasma
What organisms have intrinsic resistance to vancomycin?
gram-negative (no peptidoglycan)
What organism has intrinsic resistance to cephalosporins?
enterococci
What organisms have intrinsic resistance to aminoglycosides?
anaerobes
P. Aeruginosa: common resistance mechanisms?
- ESBLs
- Efflux Pump
- Reduced outer membrane permeability
K. Pneumoniae: common resistance mechanisms?
carbapenemases
E. Coli: common resistance mechanisms?
ESBL
S. Aureus: common resistance mechanisms?
- Methicillin resistance (mecA)
- Vancomycin resistance
Enterococci: common resistance mechanisms?
vancomycin resistance via altered cell wall precursors
