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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
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
What is the example of primary resistance used in class?
E. coli to vancomycin
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.
name 2 types of genetic alterations that may confer secondary resistance
- spontaneous mutations (point mutations)
- acquisition of new genetic material
How might a bacteria acquire new genetic material (3 ways)?
transfer of genetic material between bacteria that are in cellular contact with each other
transfer of genetic material via a bacteriophage (virus)
uptake and incorporation of exogenous DNA
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
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
Are beta-lactamases produced by G+ or G- microorganisms?
many of both
How do beta-lactamases work?
they inactivate beta-lactam antibiotics by splitting the amide bond of the B-lactam ring
Is production of B-lactamases constitutive or inducible?
Can be either
Examples of microorganisms with inducible B-lactamases
- Enterobacter spp
- Citrobacter freundii
- Serratia marcescens
- Pseudomonas aeruginosa
Agents that are potent inducers of B-lactamases
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
In which bacteria are ESBLs most commonly found?
Where are bacterial ESBL genes located?
What are AmpC-type Beta-lactamases active against?
All B-lactams except cefepime and carbapenems
Which type of Beta-lactamases are not inhibited by B-lactamase inhibitors?
In which bacteria are AmpC-type Beta-lactamases usually found?
- K. pneumoniae
- Enterobacter spp
- C. freundii
- M. morganii
- S. marcescens
- P. aeruginosa
Where are bacterial AmpC-type Beta-lactamase genes located?
- (expression may be inducible)
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
Name 4 types of antibiotic inactivating enzymes
- aminoglycoside resistance modifying enzymes
- chloramphenicol acetyltransferase
- erythromycin esterase
At what point do aminoglycoside resistance modifying enzymes work?
as the aminoglycoside is transported across the cell wall of the microorganism
In which microorganisms are aminoglycoside resistance modifying enzymes commonly observed?
enterococci exhibiting high-level aminoglycoside resistance
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)
3 ways bacterial cellular membranes can be altered to give resistance
- Porin channels
- Transport proteins
- Efflux pumps
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
How do efflux pumps work?
They are proteins that actively pump the agent out of the bacteria
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
What is MRSA's resistance secondary to?
the production of an altered PBP
How is resistance transferred in MRSA?
via plasmids or transposons
What is the treatment of choice for MRSA?
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
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
What may be a treatment option for VISA?
What about VRSA isolates suggests transfer of resistance determinants from enterococci rather than just a point mutation?
they had mecA and vanA genes
What common community-acquired infections does S. pneumoniae cause?
- otitis media
From what patients are penicillin-resistant isolates of S. pneumoniae commonly isolated?
children < 6 years of age
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
What gives S. pneumoniae resistance to penicillin?
Does antimicrobial resistance in vitro translate to clinical resistance?
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.
Is enterococcus an increasingly common nosocomial or community-acquired pathogen?
What antimicrobials are enterococcus intrinsically resistant to?
What must therapy be combined with for a cidal effect upon enterococci?
What is acquired resistance of enterococci to penicillins due to?
alterations in PBPs
What negates synergy in enterococcus?
high-level aminoglycoside resistance is conferred by production of aminoglycoside modifying enzymes
What is vanco-resistance in enterococcus secondary to?
alterations in the D-ala-D-ala linkages in cell wall precursors
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
Enterococcus treatment strategies
- vanco, linezolid, daptomycin, and streptogramins
- intermittent vs. continuous infusions of B-lactams and vanco
- traditional vs. once-daily dosing of aminoglycosides
6 strategies to prevent the spread of antibiotic resistance
- patient education
- knowledge of local susceptibility patterns
- prescriber education
- develop guidelines for appropriate antimicrobial usage
- hand washing
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