antimicrobial resistance and transfer Flashcards
antibiotic
natural substance produced by a microbe that inhibits growth of another microbe
are antimicrobial agents synthetic?
semi-synthetic: antibiotics tend to undergo synthetic modification
*chemotherapeutic agents are entirely synthetic
Out of the different groups of antimicrobials, which are there most of for humans and why?
antibacterials: easier targets
antifungals, antihelminths, antivirals interact with host cell machinery, more difficult to isolate target cells to pathogens
How might selective toxicity be achieved?
- exploit phenotypic and metabolic differences between the host and pathogen e.g. cell wall structure, production of specific cell intermediates
- antimicrobial agent should target site present in pathogen but not on host; easier to find in prokaryotic vs. eukaryotic cells, very difficult for viruses
- relative: high dose or extended treatment may damage host
what is the therapeutic ratio?
highest dose tolerated without harming patient/
minimum dose required to eliminate pathogen
or: toxic dose (TD50)/effective dose (ED50 = dose required to treat half the population)
Advantage of a high therapeutic ratio?
effective dose, minimal side effects, safer
Antibiotics that have a high and lower therapeutic ratio?
high: B-lactams, macrolides, quinolones
low: aminoglycosides, vancomycin
Factors affecting therapeutic ratio?
- selective toxicity
- immune response e.g. allergic reactions like penicillin in sensitised individuals
- bioavailability of the drug: determined by solubility, metabolism, chemical modification and excretion rates
- effect on normal flora: may promote growth of opportunistic pathogens
- potential for development of resistance: especially for long term treatment
Difference between bactericidal and bacteriostatic drugs?
spectrum
bactericidal agents; usually act rapidly, kill bacteria
bacteriostatic agents; inhibit growth of bacteria, need to be taken for a longer time *bacteria may multiple if drug is discontinued
- can be dose dependent
- some drugs are bacteriostatic to certain organisms, bacteriocidal to others
Broad spectrum agents
- affect a wide range of bacteria
- often given prior to diagnosis
- will impact on normal flora e.g. amoxicillin is active against a wide range of Gram +ve and some Gram-ve organisms
e. g. ceftriaxone (4th generation cephalosporin) has extended action
narrow spectrum agents
affect a limited range of bacteria
e. g. gentamicin: Gram -ve bacteria
e. g. penicillin: Gram +ve bacteria
- administered after diagnosis of infectious agent
Reasons why treatment may be ineffective
- drug not reaching infected areas at effective concentrations: dose is too low, poor bioavailability
- depressed immune system, especially if drug is bacteriostatic
- pathogen may be resistant to drug
- pathogen may release toxins when killed e.g. endotoxin from G-ve cells may cause allergic reactions
- environmental factors may limit drug activity e.g. acid pH in urine
Types of resistance? (4)
intrinsic: some microbes inherently resistant
acquired:
- mutation
- (mobile genetic elements) spread of resistance plasmid
- (mobile genetic elements) spread of resistant gene via transposon
pathways to intrinsic resistance
impermeability, efflux (both lead to reduced drug accumulation), biofilms, enzymatic inactivation
Describe impermeability?
antimicrobial can’t bind to surface of bacterial cell;
- chromosomal mutation can change structure of drug binding site
- or chromosomal mutation leads to changes to the structure of membrane preventing antibiotic entering the cell and e.g. targeting ribosome or DNA replication
what is efflux?
pumps that remove antimicrobial from cell before it can cause damage
located in cell membrane
activated by antibiotic
- can be specific to a bacterial species
- can result in multi drug resistance e.g. MDR pumps/MDR transporters
How do biofilms contribute to resistance?
Poor penetration of antibiotic
slow growth/nutrient limitation
persister cells lead to tolerance of antibiotics: shut down targets of antibiotics rather than become resistant
*persister cells make up 1% of original population - enough for bacteria to develop resistance
How does enzymatic inactivation contribute to resistance?
Existing enzyme can chemically change an antibiotic so it is no longer effective; innately, through modification i.e. acquired
- existing enzymes have functions such as heavy metal detoxification and antimicrobial resistance (environmental)
How do bacteria acquire resistance/what are the 3 mechanisms of horizontal gene transfer (HGT)?
Transformation: integration of DNA fragment or plasmid uptake
Conjugation: one bacteria with a plasmid transferred to another via bridges
Transduction: virus/bacteriophage, occurs during lytic cycle of virulent phage, during viral assembly fragments of host DNA mistakenly packaged into phage head - becomes a generalised transducing particle
What is F factor
conjugative plasmid containing information for formation of sex pilus
attaches a F+ cell to a F- cell for DNA transfer during bacterial conjugation
have insertion sequences that assist in plasmid integration
Cause of multiple drug resistance?
HGT
resistance plasmids found in MRSA (methicillin resistant Staph. aureus)
How to treat MRSA?
methicillin resistant staph. aureus
contains plasmids conferring resistance to ~10 antibiotics
usually sensitive to vancomycin
