Antibiotic resistance Flashcards
What is meant by the ‘abx era’ and the ‘post-abx era’?
Abx era = term used to describe the time since the widespread availability of abx to treat infection
Post-abx era = term used to describe the time after widespread abx resistance has reduced the availability of abx to treat infection
What does MRSA stand for?
meticillin resistance stapaureus
What does VRE/GRE stand for?
Vancomycin/ glycopeptide resistance enterococci
What does ESBL stand for?
Extended spectrum beta-lactamase producing enterobacteriaceae
What does MDR-TB stand for?
Multi-drug resistant tuburculosis
What does XDR-TB stand for?
Extremely drug resistance TB
Name 5 common organisms resistant to the drugs traditionally used to treat them?
1) MRSA
2) VRE/GRE
3) ESBL
4) MDR-TB
5) XDR-TB
Other than those which are common name 2 organisms also resistant to many abx?
1) Enterobacteriaceae resistant to amoxicillin, ciprofloxacin, gentamicin, carbapenems
2) Pseudomonas resistant to ceftazidime, carbapenems etc.
How does the risk of abx resistance effect empiric therapy? 2
- Risk of under-treatment - if traditional abx is used so dont kill the organism
- Risk of excessively broad-spectrum treatment - if risk of resistance is taken into account
How does the risk of abx resistance effect targeted therapy? 3
Requires the use of alternatives which may be:
1) Expensive - eg. linezolid, tigecycline, daptomycin vs. flucoxacillin for MRSA
2) Last line - eg. meropenem vs. ciprofloxacin for multi-resistant enterobacteriaceae
3) Toxic - eg. colistin vs. meropenem for NDM-1 producers
What are the 4 reasons for use of sensitivity testing?
1) To enable transition from empiric to targeted therapy
2) To explain treatment failures
3) To provide alternative abx in case of treatment failure or intolerence/adverse effects
4) To provide alternative oral abx when IV therapy is no longer required
What is the basic principle abx sensitivity testing?
1) Culture of micro-organism in the presence of antimicrobial agent - solid or liquid media
2) Determine whether minimum MIC is above a predetermined breakpoint level - high enough to kill the organism and sustained in the body for long enough using practible dosing regimes
In terms of abx sensitivity testing what is meant by a ‘breakpoint level’?
The breakpoint level is a known value. Its the concentration of that abx which can feasibly be available in the body
What are the 5 steps in abx sensitivity testing?
1) Add organism
2) Add abx
3) Incubate
4) Read and interpret results
5) Clinical interpretation (measure size of zone of inhibition around abx disc)
Why can microtitre plate (liquid media) susceptibility testing be more useful that solid media testing?
You can use the abx at varying concentrations and get a more accurate measurement of the MIC
Give 3 main limitations of abx sensitivity testing?
1) The infection may not be caused by the organism which has been cultured
2) The correlation between antimicrobial sensitivity and clinical response is not absolute
3) Certain organisms are ‘clinically resistant’ to microbial agents even when in vitro testing indicates susceptibility
Why are some organisms clinically resistant to microbial agents even when in vitro testing indicates susceptibility? Give an example
Resistance genes may be expressed in vivo in response to abx exposure
eg. AmpC beta-lactamase genes in enterbacteriaceae
Give the 6 common resistance mechanisms?
1) No target - hence no effect
2) Reduced permeability - drug cant get in
3) Altered target - no effect on altered target
4) Over-expression of target - effect diluted
5) Enzymatic degradation - produce an enzyme which destroys the drug
6) Efflux pump - drug expelled from bacterial cell
What is a common reason for absent target causing abx resistance?
Used to treat fungal or viral infections - ie. treatment fails as the infection is non bacterial
Why are gram negative bacteria resistant to vancomycin?
Gram negatives have an outer membrane which is impermeable to vancomycin
ie. mechanism is reduced permeability
Why are anaerobic organisms resistant to gentamicin?
Uptake of aminoglycosides requires O2 dependent active transport mechanisms - no O2 in anerobes
By what mechanism is MRSA resistant to flucoxacillin?
Altered target
Altered penicillin binding protein which does not bind beta lactams
By what mechanism is VRE resistant to vancomycin?
Altered target
Altered peptide sequence in gram-positive peptidoglycan
By what mechanism are gram-negative bacilli resistant to trimethoprim?
Altered target
Mutations in dhr (dihydrofolate reductase gene)
One mechanism of resistance to penicillins and cephalosporins is enzyme degradation, which enzyme is produced to break them down?
B-lactamases (including ESBLs and NDM - 1)
A mechanism of resistance to gentamicin is enzyme degradation, which enzyme is produced to break it down?
Aminoglycoside modifying enzymes
A mechanism of resistance to chloramphenicol is enzyme degradation, which enzyme is produced which breaks it down?
Chloramphenicol acetyltransferase (CAT)
Drug efflux as a mechanism of resistance is used against which 2 abx?
1) Multi abx - specially in gram-negative organisms
2) Antifungal triazoles and candida ssp
Mechanisms of resistance are usually encoded in how many genes?
Single genes eg. those for abx modifying enzymes and altered abx targets
Resistance genes tend to be encoded in what?
plasmids - circular strand of transferred within species and less commonly between species, mainly by conjugation
Which 2 structures enable horizontal transmission of resistance genes?
transposons and integrons
What is meant by a cassette and transponsons and integrons?
transponsons and integrons are dna sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosomes - they often contain a cassette with multiple resistance genes
What is meant by vertical transfer of resistance?
Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell division
Describe the steps in horizontal transmission of abx resistance genes? 6
1) gene on plasmid
2) gene may stay on plasmid and/or integrate into the chromosome
3) plasmid transferred between organisms by conjugation
4) gene may stay on plasmid and/or integrate into chromosome
5) ‘new’ organism has abx resistance
6) abx resistance transferred on cell division
Give the 5 consequences of abx exposure in terms of the development of resistance?
1) sensitive strains exposed to abx at sub lethal conditions eg. clinical and agricultural
2) Chance of survival will be enhanced by development of resistance (spontaneous mutation, aquisition of resistance genes)
3) Resistant strain will out compete sensitive strains
4) Resistance perpetuated by vertical transfer
5) Mixtures of sensitive and resistant strains (eg. normal gut flora) exposed to abx - resistant strains have a survival advantage and will become the dominant colonising strains, subsequent endogenous infection more likely to be caused by resistant strains
What 4 steps can be taken to avoid problems with using abx?
1) Never use an abx unless absolutely necessary
2) Always use the most narrow spectrum agent available
3) Use combination therapy if indicated
4) Be willing to consult expert information sources
