Antimicrobial Resistance + PK/PD Flashcards
What are the distinguishing structural components of gram-positive bacteria?
- thick peptidoglycan layer
- teichoic acids
- does not have porin proteins - they are unnecessary here because there is no outer membrane
- teichoic acids contribute to net negative surface charge of the cell surface
- teichoic acids impact elasticity, porosity, tensile strength, and electrostatic properties of the envelope
What are the distinguishing structural components of gram-negative bacteria?
- thin peptidoglycan layer
- outer membrane
- lipopolysaccharide
- porin proteins
- periplasm
- porin proteins allow for passage of molecules through outer membranes
What structural features do gram-positive and gram-negative bacteria have in common?
- peptidoglycan
- periplasmic space
- cell membrane
Generally compare the sensitivity of gram-positive and gram-negative bacteria to penicillin and lysozymes?
- Gram-positive is generally more susceptible to penicillin
- gram-positive is susceptible to lysozyme
- Gram-negative is generally less susceptible to penicillin and is not sensitive to lysozyme
What are penicillin-binding proteins?
- enzymes vital for cell wall synthesis, cell shape, and structural integrity
transpeptidases, carboxypeptidases, endopeptidases
Which penicillin binding protein is most important?
transpeptidase
- catalyzes the final cross linking in the peptidoglycan structure
What are the two different intrinsic resistance mechanisms?
- absence of target site
- bacterial cell impermeability
Intrinsic resistance means it was always resistance to a given antibiotic
What are the two different acquired resistance mechanisms?
- mutation in bacterial DNA (spontaneously vs selective pressure)
- acquisition of new DNA (chromosomal or extrachromosomal)
Acquired resistance means the pathogen was originally susceptible but developed resistance due to some mechanism
What is an example of intrinsic resistance in which the pathogen lacks the target site for the abx?
cephalosporins vs enterococci
What is an example of intrinsic resistance due to bacterial cell impermeability?
B-lactams vs mycoplasma
What is an example of acquired resistance due to mutation in bacterial DNA?
Stable depression of AmpC
What is an example of acquired resistance due to acquisition of new DNA?
Acquisition of KPC gene in GNRs
Explain the mechanism of acquired resistance through plasmids:
- self-replicating extrachromosomal DNA
- transferable between organisms
one plasmid can encode resistance to multiple antibiotics
How do transposons impact acquired resistance?
- Transposons are genetic elements capable of translocating from one location to another
- move from plasmid to chromosome or vice versa
A single transposon may encode multiple resistance determinants
What are phages?
Viruses that can transfer DNA from organism to organism
What is conjugation?
- DNA shared via mobile genetic elements such as plasmids or transposons
- most common form of acquired resistance
Direct contact or mating via sex pili
What is transduction?
- Transfer of genes between bacteria by bacteriophage
- mechanism of acquired resistance
What is transformation?
- Transfer or uptake of “free floating” DNA from the environment
- DNA is integrated into host DNA
- mechanism of acquired resistance
What are the three types of B-lactamases in Ambler class A?
- narrow-spectrum B-lactamases
- extended-spectrum B-lactamases (ESBL)
- serine carbapenemases
What are the characteristics of narrow-spectrum B-lactamases?
Give example
- narrow-spectrum B-lactamases hydrolyze penicillin and are produced primarily by enterobacterales
- staphylococcal penicillinase
Ambler Class A
What are the characteristics of extended-spectrum B-lactamases (ESBL)?
Give an example
- hydrolyze narrow & extended spectrum B-lactam antibiotics
- present in e. coli
- CTX-M-15
Ambler Class A
What are the characteristics of serine carbapenemases?
give an example
- hydrolyze carbapenems
- KPC-1, KPC-2, KPC-3
Ambler Class A
What are the characteristics of metallo-B-lactamases?
give an example
- hydrolyze carbapenems
- NDM-1
Ambler Class B
What are characteristics of cephalosporinases?
Give an example
- inducible
- Amp-C
Ambler Class C
What are the characteristics of OXA-type B-lactamases?
Give an example
- hydrolyze oxacillin, oxyimino b-lactams, and carbapenems
- OXA-48
Which bacteria produce CTX-M and what is the treatment of choice?
- escherichia coli, klebsiella pneumoniae/oxytoca, and Proteus mirabilis
- tx: carbapenems
carbapenems: meropenem, imipenem, doripenem, ertapenem
Which bacteria produce KPC?
klebsiella pneumonia carbapenemase
- k. pneumoniae
- k. oxytoca
- e. coli
- e. cloacae
- e. aerogenes
- p. mirabilis
What are the treatment options for CRE or bacteria producing KPC?
Carbapenem-resistant enterobacterales
- B-lactam: ceftazidine/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam
- non-B-lactam: plazomicin, eravacycline, omadacycline
Which bacteria produce OXA-type B-lactamases?
- acinetobacter baumannii
- pseudomonas aeruginosa
What are the treatment options for OXA-type B-lactamases?
- limited options
- cefiderocol
- sulbactam/durlobactam
What are the three mechanisms of AmpC resistance?
- inducible via chromosomally encoded AmpC genes
- non-inducible chromosomal resistance via mutations (rare)
- Plasmid-mediated resistance
Which bacteria is AmpC found in?
- Hafnia alvei
- Enterobacter cloacae
- Citrobacter freundii
- Klebsiella aerogenes
- Yersinia enterocolitica
HECK-YES
What is the mechanism of AmpC induction?
- The presence of certain beta-lactam abx will increase production of cell-wall degradation products
- As these products accumulate, they compete with UDP acid peptides for binding to AmpR
- Decreased UDP acid peptides binding to AmpR disables it which therefore increases the production of AmpC
- After beta-lactam exposure ceases –> AmpC levels will return to baseline (unless there is a mutation in regulatory genes)
- If there is a genetic mutation, AmpC will be constantly be derepressed (active) even in the absence of B-lactam trigger
- UDP acid peptides need to bind to AmpR for AmpR to function properly
- AmpR is responsible for repressing AmpC
What is the weak inducer of AmpC that has a high susceptibility to AmpC hydrolysis?
Ceftriaxone
What is the treatment option in the case of AmpC resistance?
cefepime
What is the most common method of AMG resistance?
aminoglycoside
enzymatic inactivation through acetylation, nucleotidylation, or phosphorylation
What is the mechanism of vancomycin resistance in enterococci species?
- Altering the D-Ala D-Ala target site which then prevents vancomycin from binding
- mediated by VanA or VanB
- produces VRE
- Preventing vanc from binding allows the bacteria to continue to build their cell wall and survive even in the presence of vanc
- VRE = vancomycin-resistant enterococcus
What are the treatment options for VRE?
daptomycin or linezolid
How do altered penicillin binding proteins (PBPs) lead to B-lactam resistance?
- the alterations lead to decreased affinity of PBPs for the abx or a change in the amount of PBP produced by bacteria
What is the resistance mechanism that leads to MRSA?
methicillin-resistant staphylococcus aureus (MRSA)
- resistance due to expression of mecA gene
- mecA + PBP2A = MRSA
What are the treatment options for MRSA?
- ceftaroline
- vancomycin
- linezolid
What is responsible for macrolide resistance in s. penumoniae?
altered ribosomal target
What is responsible for fluoroquinolone resistance in gram negative and s. pneumoniae?
- altered DNA gyrase/ topoisomerase IV
When do efflux pumps serve as an important resistance mechanism?
- p. aeruginosa against carbapenems
- s. pneumoniae against macrolide abx
How can mutations impact porins and lead to abx resistance?
- mutations results in loss of specific porins
- seen in enterobacterales and carbapenem-resistant P. aeruginosa
Define bactericidal:
Killing of the organism by acting on areas such as the cell wall, cell membrane, bacterial DNA, ect.
Define bacteriostatic:
Inhibit bacterial replication without killing the organism by inhibiting protein synthesis
What is PAE?
post antibiotic effect
Continued growth inhibition for a variable period after concentration at site of infection has decreased below MIC
Which abx are time-dependent?
T>MIC
- all B-lactams
Time that free drug concentrations remain above MIC
What strategies can be used to optimize B-lactam dosing?
- maximize T>MIC via:
- increase dose, keep same interval
- keep same dose, shorter interval
- continuous infusion (uncommon)
- prolonged infusion (dose over 3-4 hours)
What is the PD target for vancomycin?
AUC/MIC
- goal = 400 - 600
- assumes organism MIC of 1mcg/mL
What is the T>MIC goal for each B-lactam class?
carbapenems, penicillins, cephalosporins
- carbapenems > 40%
- penicilins > 50%
- cephalosporins > 60%
carbapenem has 4 syllables
What is the bactericidal pattern and predictive PK/PD parameter for aminoglycosides?
- concentration-dependent
- Peak/MIC; AUC/MIC
- cidal
What is the bactericidal pattern and predictive PK/PD parameter for B-lactams?
- time-dependent
- T>MIC
- cidal
What is the bactericidal pattern and predictive PK/PD parameter for daptomycin?
- concentration-dependent
- AUC/MIC; Peak/MIC
- Cidal
What is the bactericidal pattern and predictive PK/PD parameter for fluroquinolones?
- concentration-dependent
- AUC/MIC
- cidal
What is the bactericidal pattern and predictive PK/PD parameter for vancomycin?
- time-dependent
- AUC/MIC
- cidal (slowly)
