Antibiotic Resistance Flashcards
Why is resistance a global concern?
Antibiotic resistance:
Increases mortality
challenges control of infectious diseases
threatens a return to the pre-antibiotic era
increases health care costs
jeopardizes health-care gains to society
Drug resistant bacteria are NOT MORE pathogenic, we just have fewer antibiotic options for treatment
History of Methicillin resistant Staphylococcus aureus
Gram +ve, pyogenic cocci, casues surgical sepsis and endocarditis
Stapholoccus became methicillin resistant by acquiring a new penicillin binding protein (one of the enzymes involved in cross linking) that is no longer competitively inhibited by methicillin.
how can MRSA become Vancomycin R+ MRSA?
Co-infection and genetic exchange
3 bacteria (Enterococci, Acinetobacters, MRSA) all live in the gut and exchange genes, so you end up with vancomycin resistant MRSA
Mechanisms of antibiotic resistance
- DRUG INACTIVATION
- bacteria acquiring mutations to inactivate drugs, eg. beta-lactamase is an enzyme that bacteria have acquired that will destroy and therefore inactivate beta lactams - MUTATED/ALTERED TARGET OR ACQUISITION OF A NEW TARGET
- e.g RNA polymerase mutating so rephampsin drug can no longer bind
- MRSA acquired a new PBP called PPE2A which is no longer inhibited by the beta lactam that targets it
- bacteria acquiring a gene for a new transport protein, incorporated into cell membrane and prevents antibiotics entry
- porin mutation, changing porin properties and prevents antibiotics entry - EFFLUX PUMP
- pump out antibiotics/anything the bacteria doesn’t want inside the cell
- acquisition of an efflux pump or overexpression of the efflux pump gene - more activity of the efflux pump than there is antibiotic entering the cell via the porins.
- so this means the drug never accumulates sufficiently enough to achieve the MIC. - INTRINSIC PERMEABILITY
- some bacteria are ‘intrinsically resistant’, their membranes are so impermeable they are resistant to a range of antibiotics and not because they have mutated or acquired a gene, but because their natural structure infers resistance. - OVERPRODUCTION OF TARGET
- bacteria can overcome the effects of competitive inhibitors like sulfonomides, which inhibit folic acid synthesis, by overproducing the target and upregulating the genes that encode for those enzymes. This means there is more enzyme than competitive inhibitor, overcoming the effects of the antibiotic. - METABOLIC BY-PASS
- for a bacteria to become resistant to vancomysin, that must have acquired a whole set of genes that encode a whole biosynthetic pathway, and instead of generating a D-ala D-ala terminal on the pentapeptide precursor, it generates D-ala D-lac, which vancomycin cannot bind to.
Mechanisms of Resistance
Natural resistance
Genetic Mechanisms - acquired genes
Non-Genetic Mechanisms (growth phases)
Natural resistance
- the natural impermeability that some bacteria have, the drug needs to reach the target and has to go through natural barriers, porins and an export pump
G+ve, peptidoglycan, highly porus, no barrier to diffusion
G-ve outer membrane acts as a barrier, gives it a resistant advantage
genetic resistance
Chromosome-mediated
Due to spontaneous mutation in the target molecule or drug uptake system
Mutants are SELECTED ; they are NOT induced
Plasmid-mediated
Common in Gram-negative rods
Transferred via conjugation
Multidrug resistance
How do bacteria exchange genetic information and transfer genes that encode for genetic resistance?
- Transformation – uptake of naked DNA from a lysed bacteria into another bacteria
- Transduction – infected by a bacteriophage (virus) that has taken info from its previous bacterial host and has now transferred it into its new bacterial host.
- Conjugation – not all bacteria undergo conjugation but some do. Here, they come together and form pilli through which DNA is exchanged. Chromosomal and plasmid DNA can be exchanged.
Resistance to Beta-Lactams
gram positive
- ß -Lactamase (Penicillinase)
- alteration of the transpeptidase enzyme (PBP)
gram negative
- ß -Lactamase (Penicillinase)
- alteration of porins
Penicillinase destroys active part of penicillin molecule
what is Augmentin/co-amoxiclav?
Clavulanic acid + amoxicillin
Amoxicillin is a slightly broader spectrum antibiotic than penicillin. Clavulanic acid is an inhibitor of a beta lactamase enzyme, blocks it and therefore allows the amoxicillin to work. This is why you give these 2 together.
Organisms now have acquired extended spectrum beta lactamases, that are not inhibited by clavulanic acid and therefore the bacteria still remains resistant.
Beta-lactam Resistance in Gram –ve bacteria
alteration of porins
Beta lactam has to get through the pore to block the PBP’s
- Porin mutates or new porin type
Multi-resistant
-penicillin cannot get into cell - PBP - mutates or bacteria acquires a new PBP - this is what MRSA does
- penicillin can’t bind - bacteria acquires a beta-lactamase enzyme, which comes along and degrades the drug (cleaves beta lactam ring)
- penicillin is inactivated
(4. acquire alternative forms of / mutations in efflux pumps
- penicillins are pumped out faster)
vancomycin?
glycopeptide drug
binds to terminal D-ala D-ala residues, prevents incorporation of subunit into growing peptidoglycan
-inhibits cell wall synthesis
RESISTANCE = D-ala-D-lactate, gene for this are acquired through phage mediated or conjugated mediated transmission of genes
vancomycin binds weakly, the bacteria can overcome it
Non-Genetic Mechanism
Inaccessibility to drugs
-When treating some parts of the body, its difficult to get to the level of MIC you need in order to have an effect, for example lesions in TB or deep abscesses – its difficult to get antibiotics to the site of infection
Stationary phase/vegetations and biofilms
(non-susceptible to inhibitors of cell wall synthesis)
-Bacterial infections sit on surfaces and create biofilms and colonies – antibiotics can’t get through the biofilm.
Disc diffusion test for antibiotic susceptibility testing
Drugs are assessed for resistance via the agar plates and looking at the zones of inhibition
How to prevent/overcome antibiotic resistance
control antibiotic use
-not in animal feeds
New or modified drugs
-few in past 25 years
Combination therapy
- different targets, overcome mutation rates
Infection control
- individual - ward - society
