Antibiotic Resistance Flashcards
Define superbug
- Drug resistant bacteria are NOT MORE pathogenic
* We just have fewer antibiotic options for treatment, so more difficult to treat
What are the risks to antibiotic resistance?
- Increases mortality.
- Challenges control of infectious diseases/
- Threatens return to pre-antibiotic era.
- Increases cost of healthcare.
- Jeopardizes healthcare gains to society.
What are the mechanisms to antibiotic resistance?
- Drug inactivation- bacteria have acquired B-lactamases to destroy antibiotics (B-lactams). Can produce antibiotics that are resistant to this enzyme, but bacteria will acquire new enzymes to break down these as well- extended spectrum b-lactamases (especially in gram negative bacteria).
- Altered or new target- drug can no longer identify mutated bacterial polymerase, for example- happens a lot in tuberculosis. MRSA acquired new penicillin binding protein PBP2a (no longer inhibited by b-lactams). Mutation in ribosomal RNA will prevent protein synthesis affecting drugs to work.
- Porins- can exchange genes for brand new porins, which prevent entry of antibiotics.
- Efflux pump- upregulation of genes that encode efflux pumps or acquire new ones that means drug cannot accumulate to reach MIC before being pumped out.
- Intrinsic permeability- membrane natural structure resists many antibiotics (especially in gram negative bacteria). Not a change/mutation.
- Overproduction of target- such as for folic acid inhibitors (e.g. trimethoprim). Upregulation of genes encoding enzyme target, so more enzyme than competitive inhibitor so bacteria can continue producing product (such as folic acid). Done by overexpressing gene or inducing metabolic pathways that lead to increased synthesis of para-aminobenzoic acid, which is precursor for folic acid.
- Metabolic by-pass- bacteria resistant to vancomycin have acquired a whole set of genes that encode a new biosynthetic pathway that generates a D-ala-lactate intead of D-ala-lac end-terminal so vancomycin can’t bind.
- Overall- natural resistance, genetic mechanisms (acquired) or non-genetic mechanisms (growth phases).
What are the 3 mechansisms of resistance?
Natural resistance
- Genetic Mechanisms - acquired
- Non-Genetic Mechanisms (growth phases)–tolerance
Describe natural resistance
• As opposed to acquired • Drug must reach target o Natural barriers, porins, export pump • G +ve peptidoglycan o Highly porus o No barrier to diffusion • G-ves outer membrane o Barrier resistance advantage • Porins single mutation - multiple resistance
Describe genetic mechanisms to resistance
Chromosome-mediated- due to spontaneous mutation in target molecule, in drug uptake and mutants are selected (antibiotic pressure), not induced.
Plasmid-mediated- common in gram-negative rods, transferred via conjunction and can lead to multidrug resistance.
Describe gene transfer in bacteria
- Mechanism for genetic heterogeneity and evolution
- Rapid, cross-species
- Virulence (toxins), drug resistance, antigens (immune evasion)
- Uptake of naked DNA from one bacteria that has just been lysed.
- Can be infected by a phage
- It normally takes some DNA from the old bacterial host into the new host
- This is called phage transduction
- They come together and form pilli through which DNA is exchanged
- You can exchange chromosomal and plasma DNA
Describe how bacteria can acquire resistance to beta lactams
B-lactamase enzyme cleaves B-lactam ring.
Acquired alternative penicillin binding proteins.
Alteration of porins
What does Augmentin/co-amoxiclav do?
- Clavulanic acid + amoxicillin
- Binds to and inactivates beta-lactamases
- No anti-bacterial activity of its own
- Clavulanic acid is a beta lactamase inhibitor
- Extended spectrum lactamases are not inhibited by clavulanic acid
How does bacteria become resistant to penicillin?
- Produce penicillinases / beta lactamases that cleave the beta lactam ring
- penicillin is inactivated
- Acquire alternative forms of / or mutations in penicillin binding proteins (PBPs)
- penicillin can’t bind
- Acquire alternative forms of / mutations in porins,
- penicillin cannot get into cell
- Acquire alternative forms of / mutations in efflux pumps
- penicillins are pumped out faster
What is used to treat MRSA?
- Only effective treatment is vancomycin, a 1.5 kDa glycopeptide
- Vancomycin blocks the enzymes that do the cross linking
Describe Vancomycin resistance
- Acquisition of van operon by transposition
- Van operon regulates the precursor of the D-ala D-lac
- You can acquire the gene that makes D ala D lac
- The interactions between D ala D lac and the drug is different and is weak as there is one bond missing.
- The drug binds very weakly and so the bacteria can overcome the resistance to vancomycin because we can’t give the drug at a concentration that overcomes the weak affinity to the substrate.
Describe non-genetic mechanisms to bacterial resistance
Inaccessibility to drugs- can’t reach MIC in abscesses and TB lesions, for example.
Stationary phase/vegetative and biofilms- mucopolysaccharide surface structure that prevent antibiotics (cell wall inhibitors from reaching).
How do we prevent antibiotic resistance
- Control use
- Not in animal feeds
- Complete course [DOTS for TB]
- Appropriate prescribing
- New or modified drugs
- Few in past 25 years
- Combination therapy
- Different targets
- Overcome mutation rates
- Infection control
- Individual - ward - society
Describe Neisseria gonorrhoea:
What do we use to treat it?
Used to be treated with single I.V. dose of penicillin (stat dose) and then abstinence for a few days would clear.
Resistance within 15 years rose to 15%.
No longer used and now ciprofloxacin- quinolone inhibiting DNA gyrase (one high dose) but then also got resistance.
Switched to cephalosporin (cefixime)- one oral dose. Gradual resistance.
Then became i/m of ceftriaxone (3rd gen cephalosporin) and azithromycin.
Increasing MIC- so soon might not be able to treat gonorrhoea.
