Antibiotic Resistance Flashcards
What is the effect of antibiotic resistance?
- Increases mortality
- Challenges control of infectious diseases
- Threatens a return to the pre-antibiotic era
- Increases the costs of health care
- Jeopardises health-care gains to society
Are drug resistant bacteria more pathogenic?
NO
-we just have fewer antibiotic options for treatment
Mechanisms of antibiotic resistance
Drug Inactivating Enzymes Altered/New Target Efflux Pump Intrinsic Impermeability Overproduction of Target Metabolic By-Pass
Drug Inactivating Enzymes
β-lactamase
-acquired by bacteria which destroys β-lactam and make antibiotic inactive
How do we kill bacteria which acquire β-lactamase?
Develop drugs which are resistant to β-lactamases, but then bacteria acquire extended spectrum β-lactamases which will even break down the antibiotics resistant to β-lactamase
How can an altered or new target lead to antibiotic resistance?
Drug target can be mutated and therefore the drug can no longer bind to its target, or bacteria can acquire new targets:
- Ribosome mutation
- Porins→ mutated or new porin expression prevents transport of antibiotics
- DNA gyrase mutation → quinolones won’t work
- RNA polymerase mutation → rifampicin won’t work
- Mcr1 & collistin
- PBPs (penicillin binding proteins) for peptidoglycan synthesis → PBP no longer inhibited by the β-lactam (MRSA acquires PB2a)
How do efflux pumps confer antibiotic resistance?
Bacteria can up-regulate genes which encode efflux pumps or acquire new efflux pumps, resulting in more efflux activity than there is influx of drug, meaning the drug doesn’t accumulate on the inside of bacteria sufficiently to achieve the MIC
Intrinsic impermeability and antibiotic resistance
Some bacteria (especially gram-ve) have membranes that are so impermeable that they are resistant to a whole range of antibiotics
*not due to any mutations, just the natural structure of bacteria
How does overproduction of target lead to antibiotic resistance?
· Bacteria can overcome the effect of competitive inhibitors (antibiotics) in the folic acid synthesis pathway (sulphonamides and trimethoprim) by upregulating the genes that encode for enzymes which produce folic acid, meaning there is more enzyme than there is competitive inhibitor and bacteria produce folic acid
· Bacteria can also induce the metabolic pathways which lead to increase in the synthesis of PABA, precursor for the synthesis of folic acid
Metabolic By-Pass and antibiotic resistance
· Vancomycin antibiotic binds D-ala D-ala terminal residues on the peptidoglycan precursor and prevents incorporation of the peptides into the growing peptidoglycan chain
· Bacteria resistant to vancomycin have acquired a whole set of genes that encode a new biosynthetic pathway which generates a D-ala D-lac terminal on the peptidoglycan precursor to which vancomycin can’t bind
Natural mechanisms of antibiotic resistance
Drugs can’t overcome natural barriers, porin, export pumps of bacteria
Genetic mechanisms of antibiotic resistance
Chromosome Mediated
-spontaneous mutation in the target molecule of drug uptake system
Plasmid Mediated
- acquisition of genes via conjugation
- common in gram-negative rods
Amongst sensitive bacteria, a spontaneous random mutation arises. As soon as an antibiotic is added, all the bacteria without the mutation die and the mutants survive and become resistant to antibiotic → selection of antibiotic resistant bacteria
How are genes transferred in bacteria?
There are 3 mechanisms by which bacteria exchange genetic information which encode drug resistance:
1) Transformation→ uptake of naked DNA from a bacteria which has lysed, taken up by another bacteria
2) Transduction → bacteriophage infects bacteria, taking a bit of DNA from the previous bacterial host and takes it to the next bacterial host
3) Conjugation → two bacterial cells come together and from a pili, through which chromosomal or plasmid DNA is exchanged
Methods by which bacteria develop resistance to β-lactam antibiotics
- Contain β-lactamase enzymes (Penicillinase)
- Acquire a new PBP or mutated PBP (MRSA acquires PB2a)
- Acquire a new porin or mutated porin
- Acquire a new efflux pump or mutated efflux pump
Action of β-lactamase
Penicillinase (β-lactamase) destroys active part of penicillin molecule (β-lactam ring). Antibiotic drug is therefore no longer a competitive structural mimic of the enzymes.
What is Augmentin/Co-amoxiclav?
Amoxicillin (β-lactam antibiotic) + Clavulanic acid (no antibacterial activity)
MOA of Augmentin
Amoxicillin is a slightly broader spectrum β-lactam antibiotic than penicillin. If you want to use this drug to treat bacteria making a β-lactamase enzyme, you need to include clavulanic acid. Clavulanic acid is an inhibitor of β-lactamase enzyme. In combination, the clavulanic acid just blocks the β-lactamase enzyme and therefore permits amoxicillin to exert its effects.
How do organisms develop resistance to Augmentin?
Organisms have now acquired extended spectrum β-lactamases that are not inhibited by clavulanic acid, and therefore the β-lactam is degraded and antibiotic is no longer functional
Action of Vancomycin
binds to terminal D-ala D-ala residues, blocking the enzymes involved in the cross-linking between D-ala D-ala and the long peptidoglycan chain, preventing incorporation of peptides into the growing peptidoglycan (no cross-linking)
How do bacteria achieve vancomycin resistance?
Metabolic By-Pass:
-acquired van operon by transposition, which is a whole set of genes that regulate the biosynthesis of precursor D-ala D-lactate. This prevents vancomycin binding.
Non-Genetic mechanisms of antibiotic resistance
1) Inaccessibility to drugs (e.g. abscess, lesion)
- very difficult to get antibiotics to site of infection and reach MIC
2) Stationary Phase/Vegetations and Biofilms
- many bacteria create biofilms on surfaces, and these are difficult to treat because they form a muco-polysaccharide surface structure that antibiotics can’t get through
- non-susceptible to inhibitors of cell wall synthesis
How do we test for antibiotic resistance?
Agar plates containing bacteria:
-discs containing antibiotics diffuse into the agar plates and stop the bacteria from growing. This is evident from the zones of inhibition around the discs as to whether the bacteria is sensitive or resistant to certain range of antibiotics.
How do we prevent/overcome antibiotic resistance?
Control Use
- Not in animal feeds
- Complete course
- Appropriate prescribing
New or Modified Drugs
- Few in past 25 years
Combination Therapy
- Different targets
- Overcome mutation rates
Infection Control
- Individual-ward-society
Carbapenems
β-lactam antibiotics (not penicillin or cephalosporin) with a broad spectrum of activity
- β-lactamase resistant
- last resort for gram-ve E.coli or Klebsiella (CREs)
How do bacteria (E.coli & Klebsiella) develop resistance to carbapenems?
Acquire extended spectrum β-lactamase enzymes by acquiring a new gene (ndm1) and therefore become carbapenem resistant
Little treatment is available against these organisms → cause urinary tract infections which could spread to blood and be detrimental
