Flashcards in Antibiotic resistance Deck (17):
Give examples of extremely drug resistant microbes?
Meticillin-resistant Staphylococcus aureus (MRSA)
Vancomycin/glycopeptide-resistant enterococci (VRE/GRE)
Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL)
NDM-1 producing Gram-negative bacilli
Multi-drug resistant tuburculosis (MDR-TB)
Extremely-drug resistant tuberculosis (XDR-TB)
How does antibiotic resistance affect empiric therapy?
- Risk of under-treatment if “traditional” antibiotic is used
- Risk of excessively broad-spectrum treatment if risk of resistance is taken into account
How does antibiotic resistance effect targeted therapy?
Requires the use of alternatives which may be expensive, last line or toxic.
What are the main reasons for antibiotic sensitivity testing?
- To enable transition from “empiric” to “targeted” antibiotic therapy
- To explain treatment failures
- To provide alternative antibiotics in case of
- Treatment failure
- Intolerance/adverse effects
- To provide alternative oral antibiotics when IV therapy no longer required
How is antibiotic sensitivity testing performed?
- Culture of micro-organism in the presence of antimicrobial agent
-Determine whether MIC (see previous lecture) is above a predetermined “breakpoint” level
- High enough to kill the organism
- Sustained in the body for long enough using practicable dosing regimens
What are the limitations of antibiotic sensitivity testing?
- The infection may not be caused by the organism that has been tested
- The correlation between antimicrobial sensitivity and clinical response is not absolute
- A patient with an infection caused by a specific micro-organism is more likely to respond if treated with an antibiotic to which the organism is “sensitive” than one to which it is “resistant”
- Certain organisms are “clinically resistant” to antimicrobial agents even where in vitro testing indicates susceptibility
Resistance genes may be expressed in vivo in response to antibiotic exposure
List possible antibiotic resistance mechanisms.
1. No target – no effect
2. Reduced permeability – drug can’t get in
3. Altered target – no effect
4. Over-expression of target – effect diluted
5. Enzymatic degradation – drug destroyed
6. Efflux pump – drug expelled
Give examples of reduced permeability resistance?
- Vancomycin:Gram-negative bacilli
- Gram-negatives have an outer membrane that is impermeable to vancomycin
- Gentamicin:anaerobic organisms
- Uptake of aminoglycosides requires an O2 dependent active transport mechanism
Give examples of target alteration resistance.
- Flucloxacillin: MRSA
- Altered penicillin-binding protein (PBP2’, encoded by MecA gene) does not bind β-lactams
- Vancomycin: VRE
- Altered peptide sequence in Gram-positive peptideoglycan (D-ala D-ala D-ala D-lac)
- Reduces binding of vancomycin 1000-fold1
- Trimethoprim: Gram-negative bacilli
- Mutations in dhr (dihydrofolate reductase gene)
Give examples of enzymatic degradation resistance.
- Penicillins and cephalosporins: β-lactamases (including ESBLs and NDM-1)
- Gentamicin: aminoglycoside modifying enzymes
- Chloramphenicol: chloramphenicol acetyltransferase (CAT)
Give examples of drug efflux resistance.
- Multiple antibiotics, specially in Gram-negative organisms1
- Antifungal triazoles and Candida spp.
Give examples of resistance mechanisms encoded by single genes.
- Antibiotic-modifying enzymes
- e.g. beta lactamases degrade beta lactam ring (penicillins, cephalosporins)
- Aminoglycoside-modiying enzymes (gentamicin)
- Altered antibiotic targets
- Penicillin-binding protein 2’ (“PBP two prime”) in MRSA
- Peptide sequence in VRE peptidoglycan
What are plasmids and how can they transmit resistance?
- Circular DNA sequences transmitted within species and (less commonly) between species
- Mainly by conjugation
What is the horizontal transfer of resistance?
- Enabled by transposons and integrons
- DNA sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosome
- Often contain “cassettes” with multiple resistance genes
What is the vertical transfer of resistance?
Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell-division.
What might happen if antibiotics are used an sub-clinical doses regularly (i.e. in the agricultural industry)
- Chance of survival will be enhanced by development of resistance
- Spontaneous mutation
- Acquisition of resistance genes
- Resistant strain will out-compete sensitive strains
- Resistance perpetuated by vertical transfer