22: Antimicrobial Resistance

Question 1

What is NDM-1 and why is it important?

Answer 1

• New Delhi Metallo-Beta Lactamase-1
• Transmissable genetic element (plasmid with integrons) encoding multiple antibiotic resistance genes including:
  
  • Carbapenems
  • Beta-lactams
  • Macrolides
  • Quinolones
  • Rifampin
• Novel beta-lactamase hyrolyzes carbapenems and beta-lactams; bacterial efflux pump; genes inactivate macrolides and quinolones.

Question 2

Describe the means of antimicrobial resistance.

Answer 2

• Micro-evolutionary change (point mutations)
  
  • Beta-lactamase mutation extends spectrum
  • rpoB gene mutation alters rifampin binding site
• Macro-evolutionary change (DNA segment rearrangements)
  
  • Transposons carry abx-resist. genes
• Exogenous gene
  
  • Conjugative plasmids transfer resistance between species
  • Via plasmid, phage, etc.

Question 3

What is cross-resistance?

Answer 3

• Single resistance mechanism confers resistance to an entire abx class (e.g., MR confers resistance to all beta-lactams, penicillins and cephalosporins)
• Result of drug efflux pumps, overlapping targets (e.g., macrolides and lincosamides target same ribosome comp.)

Question 4

What is co-resistance?

Answer 4

• Presence of several resistance mechanisms in the same organism

Question 5

What is co-selection?

Answer 5

• Selection of multiple abx-resist genes when one resistance mechanism is selected
• Occurs if both genes are regulated by the same promoter

Question 6

What are integrons?

Answer 6

• Mobile genetic elements present in both GP/N that mediate co-resistance and co-selection
• Express genes under control of single promoter
• Represent “hot spots” for site-specific recombination, allowing integration of nonhomologous sequences
• Transcription correlated with proximity of gene to promoter

Question 7

Describe beta-lactamases.

Answer 7

• GPs: primarily in staphylococci; excreted extracellularly; plasmid-mediated and packaged with other antimicrobial resistant determinants (e.g., aminoglycosides)
• GNs: Extended spectrum beta-lactamases (ESBLs) carried by Klebsiella spp; secreted into periplasmic space; chromosomal or plasmid; single point mutation can change substrate specificity

Question 8

Describe drug target site alteration.

Answer 8

• Enterococcal resistance to vancomycin: altered cell wal precursor side chain that does not bind vancomycin; plasmid-mediated
• Staphylococcal resistance to semisynthetic penicillins: novel penicillin binding protein (2a) w/ reduced affinity to methicillin

Question 9

Describe antibiotic efflux pumps.

Answer 9

• Broad substrate specificity
• Use proton-motive force as means for efflux
• Pump out tetracyclines, beta-lactams, detergents, macrolides, quinolones
• Transfer of this resistance difficult because of complex genetic machinery

Question 10

Describe how foreign DNA is acquired.

Answer 10

• Horizontal gene transfer: common; even between GP/N.
  
  • Conjugation: plasmid transfer of single or multiple resistance genes
  • Transformation: free DNA acquisition of resistance genes by naturally transformable species (e.g., pneumococcus, neisseria)
  • Transduction: bacteriophage - virus-mediated transfer of genes

Question 11

Describe penicillin-resistant pneumococcus.

Answer 11

• Isolates also resistant to tetracycline, chloramphenicol
• Decreased affinity for PBP 2b, structurally altered cell wall
• Caused by uptake of foreign DNA (S. mitis) by naturally competent S. pneumoniae
• Clonal dissemination: expansion of clones, carriage in young children and crowded settings

Question 12

Describe resistance in nosocomial staph aureus infections.