48. Antibiotic Resistance Flashcards
What are the effects of antibiotic resistance?
- Increases mortality
- challenges control of infectious diseases
- threatens a return to the pre-antibiotic era
- increases the costs of health care
- jeopardizes health-care gains to society
What drug is resserved to treat MRSA?
vancomycin. Enterococci in our gut is naturally resistant to this.
What are the mechanisms of antibiotic resistance?
- Natural resistance
- Genetic Mechanisms - acquired
- Non-Genetic Mechanisms (growth phases)
- Directed at antibiotic itself -
Degrading the drug
Modifying the drug - New or Altered target
antibiotic no longer binds
e.g. PBPs - PBP2a in MRSA - Altered transport
Actively pumping drug out - efflux pump
porins no longer influx drug - Metabolic by-pass
metabolic change D-ala-D-lac and vancomycin
1) Metabolic by-pass ~ e.g. vancomycin D-ala-D-lac
2) Efflux pump
3) Overproduction of target ~ trimethoprim
4) Intrinsic impermeability
5) Altered or new target ~ e.g.
- Ribosome
- Porin
- PBPs – peptidoglycan synthesis
- DNA gyrase
- RNA polymerase
- Mcr1 & colistin
6) Drug inactivation ~ e.g. e.g. beta-lactamase
Expand on natural resistance to antibiotics
natural barriers, porins, export pump
- G+ve peptidoglycan - highly porus - no barrier to diffusion
- G-ves outer membrane - barrier resistance advantage
Expand on genetic mechanisms of resistance to antibiotics
CHROMOSOME-MEDIATED * Due to spontaneous mutation: - in the target molecule - in the drug uptake system Mutants are SELECTED ; they are NOT induced
PLASMID-MEDIATED
- Common in Gram-negative rods
- Transferred via conjugation
- Multidrug resistance
Describe gene transfer in bacteria
1) Transformation - fragment of DNA from another bacterial cell
2) Transduction - Fragment of DNA from another bacteria cell inside the phage (former phase host)
3) Conjugation - 2 cells come together and they form pili and exchange chromosomal DNA or plasmid DNA
How do gram+ and gram- bacterias become resistant to B-lactams?
They get a B-lactamase (penicilinase)
* Gram+ve = Alteration of the transpeptidase enzyme
PBP
* Gram-ve = Alteration of porins
How does Augmentin/co-amoxiclav work?
- Combo of Clavulanic acid
and amoxicillin - Clavulanic acid is an inhibitor of B-lactamases – this will then allow the amoxicillin to work
- No anti-bacterial activity of its own
Beta-lactam Resistance in Gram –ve bacteria ~ bacteria becomes 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
Expand on Vancomycin Resistance
- Acquisition of van operon by transposition
- Makes D-ala-D-lactate - prevents vancomycin binding
Expand on non-Genetic mechanism of antibiotic resistance
- Inaccessibility to drugs - (e.g., abscess, TB lesion)
* Stationary phase/vegetations and biofilms - (non-susceptible to inhibitors of cell wall synthesis)
How do we prevent/overcome 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 the treatment changes for Neisseria gonorrhoeae.
- a single I/M penicillin, but then penicillin resistance increased
- Ciprofloxacin (inhibits DNA gyrase) and then resistance increased
- single oral dose – cefixime
- NOW ceftriaxone + Azithromycin ~ but increasing MIC
Expand on Carbapenems
broad spectrum antibiotics
of last resort for Gram negative bacteria
e.g. E.coli or Klebsiella (CREs)
New strains destroy antibiotics -> resistant
- acquired a new gene, ndm1
- extended spectrum beta lactamase - ESBLs
