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List 3 factors that have contributed to the emergence of antimicrobial resistance
- 1. inappropriate antibiotic use by clinicians
- 2. lack of patient education or ineffective education
- 3. Widespread antimicrobial use in the food production industry
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Discuss the differences between primary and secondary resistance
Primary resistance: naturally occurring, prior antimicrobial exposure not required, predictable, also known as inherent, intrinsic, or native resistance
Secondary resistance: develops following antimicrobial exposure, is not predictable, also known as acquired resistance
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What is the example of primary resistance used in class?
E. coli to vancomycin
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How are resistant subpopulations selected in secondary resistance?
- A population of bacteria is comprised of isolates with varying MICs.
- Those with low MICs are easily killed.
- Resistant subpopulations remain and grow.
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name 2 types of genetic alterations that may confer secondary resistance
- spontaneous mutations (point mutations)
- acquisition of new genetic material
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How might a bacteria acquire new genetic material (3 ways)?
- Conjugation
- Transduction
- Transformation
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Define conjugation
transfer of genetic material between bacteria that are in cellular contact with each other
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Define Transduction
transfer of genetic material via a bacteriophage (virus)
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Define transformation
uptake and incorporation of exogenous DNA
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What are two types of mediated resistance?
- Plasmid-mediated resistance - extrachromosomal double-stranded DNA, self-replicating, intra- or inter- species transfer of DNA, autonomous
- Transposon-mediated resistance ("jumping genes") - DNA fragments, relies on host bacteria or plasmids for replication, intra- or inter- species
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Name 3 commonly expressed mechanisms of resistance
- 1. Antibiotic inactivating enzymes
- 2. Alteration of the antimicrobial target or active site
- 3. Alterations in bacterial cellular membranes
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Are beta-lactamases produced by G+ or G- microorganisms?
many of both
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How do beta-lactamases work?
they inactivate beta-lactam antibiotics by splitting the amide bond of the B-lactam ring
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Is production of B-lactamases constitutive or inducible?
Can be either
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Examples of microorganisms with inducible B-lactamases
- Enterobacter spp
- Citrobacter freundii
- Serratia marcescens
- Pseudomonas aeruginosa
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Agents that are potent inducers of B-lactamases
- cefotaxime
- ceftriaxone
- ceftazidime
- imipenem
- clavulanate
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What are ESBLs and what are they active against?
- Extended-spectrum Beta-lactamases
- Active vs. all B-lactams except cephamycins (cefotatan, cefoxitin), cefepime, and carbapenems
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In which bacteria are ESBLs most commonly found?
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Where are bacterial ESBL genes located?
On plasmids
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What are AmpC-type Beta-lactamases active against?
All B-lactams except cefepime and carbapenems
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Which type of Beta-lactamases are not inhibited by B-lactamase inhibitors?
AmpC-type Beta-lactamases
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In which bacteria are AmpC-type Beta-lactamases usually found?
- K. pneumoniae
- Enterobacter spp
- C. freundii
- M. morganii
- S. marcescens
- P. aeruginosa
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Where are bacterial AmpC-type Beta-lactamase genes located?
- plasmids
- chromosomes
- (expression may be inducible)
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2 strategies to overcome beta-lactamase mediated resistance
- administer large doses of B-lactams to overwhelm the B-lactamases
- combine B-lactams with B-lactamase inhibitors such as tazobactam, clavulanate, and sulbactam
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Name 4 types of antibiotic inactivating enzymes
- beta-lactamases
- aminoglycoside resistance modifying enzymes
- chloramphenicol acetyltransferase
- erythromycin esterase
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At what point do aminoglycoside resistance modifying enzymes work?
as the aminoglycoside is transported across the cell wall of the microorganism
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In which microorganisms are aminoglycoside resistance modifying enzymes commonly observed?
enterococci exhibiting high-level aminoglycoside resistance
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4 ways the antimicrobial target or active site can be altered to confer resistance (with an example of each)
- Penicillin-binding proteins (e.g. Staph aureus resistance to B-lactams)
- Ribosomal binding sites (e.g. Streptococcal resistance to gentamicin)
- Cell wall precursors (e.g. enterococcal resistance to vancomycin
- DNA gyrase (e.g. P. aeruginosa resistance to ciprofloxacin)
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3 ways bacterial cellular membranes can be altered to give resistance
- Porin channels
- Transport proteins
- Efflux pumps
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What are porin channels and how do they work for bacterial resistance?
- portals through the bacterial cell wall
- aqueous interior
- facilitate transport of hydrophilic molecules into the cell
- change in the size or number of porin channels may confer resistance
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How do efflux pumps work?
They are proteins that actively pump the agent out of the bacteria
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What antibiotics are removed by the efflux pumps of E. coli, S. aureus, P. aeruginosa, S. pneumoniae, N. gonorrhoeae, and Candida spp?
- E. coli - TCs and FQs
- S. aureus - TCs and FQs
- P. aeruginosa - FQs
- S. pneumoniae - macrolides
- N. gonorrhoeae - TCs
- Candida spp - azoles
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What is MRSA's resistance secondary to?
the production of an altered PBP
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How is resistance transferred in MRSA?
via plasmids or transposons
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What is the treatment of choice for MRSA?
vancomycin
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While the DOC for MRSA is vanco, what meds might other strains be sensitive to? What others may also be used?
- some strains may be sensitive to TMP/SMX
- may also use linezolid and daptomycin
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What is VISA and what might it be due to?
- Vancomycin intermediate susceptibility (isolate of MRSA)
- May be due to alterations in the cell wall and altered autolytic expression
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What may be a treatment option for VISA?
TMP/SMX
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What about VRSA isolates suggests transfer of resistance determinants from enterococci rather than just a point mutation?
they had mecA and vanA genes
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What common community-acquired infections does S. pneumoniae cause?
- otitis media
- pneumonia
- sinusitis
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From what patients are penicillin-resistant isolates of S. pneumoniae commonly isolated?
children < 6 years of age
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In addition to becoming resistant to penicillins, what other agents is S. pneumoniae developing resistance to? What genes encode for this?
- cephs, macrolides, TMP/SMX, TCs
- mosaic genes
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What gives S. pneumoniae resistance to penicillin?
modified PBPs
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Does antimicrobial resistance in vitro translate to clinical resistance?
not necessarily
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Does a high-level of penicillin resistance in pneumococci mean that penicillin will not work in pneumonia?
No. It has not been clearly associated with PCN failure.
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Is enterococcus an increasingly common nosocomial or community-acquired pathogen?
nosocomial
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What antimicrobials are enterococcus intrinsically resistant to?
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What must therapy be combined with for a cidal effect upon enterococci?
aminoglycosides
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What is acquired resistance of enterococci to penicillins due to?
alterations in PBPs
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What negates synergy in enterococcus?
high-level aminoglycoside resistance is conferred by production of aminoglycoside modifying enzymes
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What is vanco-resistance in enterococcus secondary to?
alterations in the D-ala-D-ala linkages in cell wall precursors
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Name 3 distince genomic variants that are responsible for the expression of vanco resistance in enterococci
- Van A - inducible
- Van B - inducible
- Van C - constitutive
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Enterococcus treatment strategies
- vanco, linezolid, daptomycin, and streptogramins
- intermittent vs. continuous infusions of B-lactams and vanco
- traditional vs. once-daily dosing of aminoglycosides
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6 strategies to prevent the spread of antibiotic resistance
- patient education
- knowledge of local susceptibility patterns
- prescriber education
- develop guidelines for appropriate antimicrobial usage
- vaccination
- hand washing
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