Antibiotics Resistance Flashcards
What are the potential effects of antibiotic resistance (5)?
- Increases mortality
- Challenges the control of infectious diseases
- Threatens a return to the pre-antibiotic era
- Increases the costs of health care
- Jeopardizes health-care gains to society
Why should drug resistant bacteria not be considered as superbugs?
They aren’t more pathogenic -> fewer antibiotic options for treatment
Give an example of antibiotic resistant infection that threatens global
healthcare and how it can further evolve?
- Methicillin resistant Staphylococcus aureus (MRSA)
- Can further evolve by co-existing with other organisms - co-infection and genetic exchange -> e.g. vancomycin R+ MRSA
- Another e.g. Enteroccoci: G+ve, Affects gut, Vancomycin, origin - chickens
Describe 6 key paths or targets for antibiotic resistance stating examples? (PART 1)
- Directed at antibiotic itself (drug inactivation): Degrading the drug, Modifying the drug, e.g. beta-lactamase
- New or Altered target (mutation of…): antibiotic no longer binds e.g. PBPs - PBP2a in MRSA
- e.g. Ribosome • Porin • PBPs - Folic acid peptidoglycan synthesis • DNA gyrase Intrinsic • RNA polymerase impermeability, Mcr1 & colisti - Altered transport: Actively pumping drug out -> efflux pump porins no longer influx drug
Describe 6 key paths or targets for antibiotic resistance stating examples? (PART 2)
- Metabolic by-pass: metabolic change D-ala-D-lac and vancomycin
- Intrinsic impermeability
- Overproduction of target e.g. trimethoprim
State the 3 mechanisms of resistance?
- Natural resistance
- Genetic Mechanisms - acquired
- Non-Genetic Mechanisms (growth phases): tolerance (can handle a certain amount of AB)
Describe how natural resistance occurs within both G + ve and G-ve bacteria?
- Drug must reach target - natural barriers, porins, export pump
- G+ve peptidoglycan - highly porus - no barrier to diffusion
- G-ves outer membrane - barrier - resistance advantage
- Porins - single mutation - multiple resistance
Describe the two type of acquired genetic mechanisms of Antibiotic resistance? (PART 1)
- Chromosome-mediated
- A. Due to spontaneous mutation:
- i. in the target molecule
- ii. in the drug uptake system
- Mutants are SELECTED (random); they are NOT induced
Describe the two type of acquired genetic mechanisms of Antibiotic resistance? (PART 2)
- Plasmid-mediated gene exchange
- Common in Gram-negative bacteria
- Transferred (a resistant gene) via conjugation
- Multidrug resistance
Describe the concept behind how bacteria become resistant when using Antibiotics
- As bacteria grows, random mutations can occur which grows itself
- Targeting the strain of mutations using AB
- Ends up killing all sensitive organisms except from mutated strain as its resistant to AB
- Clonal expansion of resistant strains + selection of random mutations
Describe some general features of gene transfer
- Mechanism for genetic heterogeneity and evolution
- Rapid, cross-species
- Used for Virulence (toxins), drug resistance, antigens (immune evasion)
Describe the 3 mechanisms of gene transfer
- Transformation: Bacterial transformation is a process where bacteria take up a fragment of DNA from the environment or another bacterial cell
Describe the 3 mechanisms of gene transfer
- Transduction: The process by which a virus transfers DNA from one bacterium to another.
- Viruses called bacteriophages (phage) are able to infect bacterial cells and use them as hosts to make more viruses.
Describe the 3 mechanisms of gene transfer
- Conjugation: The process by which one bacterium transfers genetic material to another through direct contact.
- During conjugation, one bacterium serves as the donor of the genetic material, and the other serves as the recipient, where it transfer via the conjugal tube
State what genes/enzyme can be altered or acquired to cause resistance to beta-lactams in G + ve and G - ve?
- Gram Positive: B-lactamase (Penicillinase), Alteration of the transpeptidase enzyme (PBP)
- Gram Negative: B-Lactamase (Penicillinase), Alteration of porins
How does penicillinase cause resistance to beta lactams?
Destroys the active part of penicillin molecule (beta-lactam ring)
What are the drugs of augmentin/co-amoxiclav and state its mechanism of action to cause resistance?
- Augmentin/co-amoxiclav are types of penicillin
- A combination of Clavulanic acid + Amoxicillin -> inhibits protein synthesis
- Binds to and inactivates beta-lactamases
- No anti-bacterial activity of its own
State the 4 mechanisms by which beta-lactam resistance arises in G-ve bacteria?
- Porin mutates or new porin type - Multi-resistant: Pencillin can’t get into cell
- PBP - mutates or bacteria acquires a new PBP: Can’t bind
- Acquire alternative forms of / mutations in efflux pumps: penicillins are pumped out faster
- Bacteria acquires a beta-lactamase enzyme: Cleaves beta-lactam ring - inactivates BL
What is the only effective treatment of MRSA and describe its mechanism?
Only effective treatment is vancomycin, a 1.5 kDa glycopeptide
- Binds to terminal D-ala D-ala residues, prevents incorporation of subunit into growing peptide glycan, kills cells as it can’t make peptide
Describe how vancomycin resistance occurs?
- Acquisition of van operon (enzymes) by transposition
- Drives new metabolic pathway
- Makes D-ala-D-lactate (altered target for Vancomycin)
- Prevents Vancomycin binding and inhibition
State the 2 non-genetic mechanisms of AB resistance? (PART 1)
- Inaccessibility to drugs (e.g., abscess, TB lesion)
- Drugs are unable to reach site of infection•
State the 2 non-genetic mechanisms of AB resistance? (PART 2)
- Stationary phase vegetations and biofilms (non-susceptible to inhibitors of cell wall synthesis)
- a. Overall is in a state of drug tolerance as relevant enzymes that AB target are not being used
- b. During the stationary phase, cells switch to a survival mode of metabolism. As growth slows, so too does the synthesis of peptidoglycans, proteins, and nucleic-acids; thus, stationary cultures are less susceptible to antibiotics that disrupt these processes.
- c. By forming a biofilm, bacteria protect themselves from host defense, disinfectants, and antibiotics. Bacteria inside biofilm are much more resistant to antimicrobial agents
- i. Biofilm is a complex structure of microbiome having different bacterial colonies or single type of cells in a group; adhere to the surface
How to prevent/overcome AB 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: Allows for different targets, overcome mutation rates
- Infection control: individual - ward - society
How is gonorrhoea treated?
- Switched to single oral dose - cefixime
- Then i/m ceftriaxone + 1g Azithromycin
- 125mg -> 250mg -> 500mg increasing MIC
- 2019 now 1g and no azithro (due to resistance)
- Can also use Ciproflocaxin (inhibits DNA gyrase), but can cause drug resistance
- Must monitor short term, patient and public health aspects
State the antibiotic used to treat E.coli or klebsiella
Carbapenems - broad spectrum antibiotics of last resort for Gram negative bacteria e.g. E.coli or Klebsiella (CREs)
How resistance has arised for this?
- New strains destroy antibiotics resistant
- Acquired a new gene, ndm1
- Extended spectrum beta lactamase - ESBLS
