Antibiotic Action and Resistance Flashcards
What is an antibiotic?
A substance produced by a micro-organism (or a similar substance produced wholly or partly by chemical synthesis) which at low concentrations kill or inhibit the growth of other micro-organisms”
- Antibacterial drugs
- Antifungal drugs
- Antiviral drugs
What is antibiotic resistance?
An organism (bacterium) is resistant when it will not respond to an attainable level of a drug (antibiotic) in living tissue
What are the different mechanisms by which antibiotics work?
- Weaken bacterial cell wall
- Disrupt cell membrane
- Disrupt cell division/DNA replication
- Disrupt synthesis of proteins by RNA
- Disrupt other metabolic processes e.g. folic acid production
Which anti-microbial agents interfere with cell wall synthesis?
b-lactams: Penecillins, cephalosporins, carbapenems, monobactams
Glycopeptides: vancomycin, teicoplanin
Which anti-microbial agents inhibit protein synthesis?
By binding to the 50s ribosomal subunit: macrolides, chloramphenicol, clindamycin, quinupristin-dalfopristin, linezolid
By binding to the 30s ribosomal subunit: aminoglycosides, tetracyclines
By binding to bacterial isoleucyl-tRNA synthetase: mupirocin
Which anti-microbial agents interfere with nucleic acid synthesis?
Inhibit DNA synthesis - fluoroquinolones
Inhibit RNA synthesis - rifampin
Which anti-microbial agents inhibit metabolic pathways?
Sulfonamides
Folic acid analogues
Which anti-microbial agents disrupt bacterial membrane structure?
Polymyxins
Daptomycin
What is the Minimum Inhibitory Concentration (MICs) for Methicillin?
4 to 8 mcg/mL considered to represent borderline or low level resistance
What are the causes of antibiotic resistance?
Inappropriate use of antibiotics
– Worldwide overuse of antibiotic
Extensive use in upper respiratory infections
– Incomplete or incorrect therapeutic regimens
– Availability of antibiotics without prescriptions
Failure of hospital infection control policies
Increased opportunities for dissemination of antibioticresistant bacteria both within and outside the hospital setting
– Global dissemination of particular strains
Widespread use of antibiotics as a “growth enhancer” in agriculture
Describe the scale of the problem of antibiotic resistance
Bacterial multidrug-resistant mortality rate:
25,000 patients die annually in the EU
>63,000 patients in United States die every year from hospital-acquired infections
Estimated economic costs due to infections by multidrug-resistant bacteria in EU (extra healthcare costs and productivity losses) €1.5 billion each year
Cost of treating hospital-acquired infections from just six antibiotic-resistant bacterial species in US estimated to be at least $1.87 billion
Describe the scale of the problem of antibiotic resistance within Europe
Across Europe, an estimated 25,000 people die each year as a result of hospital infections caused by the following 5 resistant bacteria:
• Escherichia coli
• Klebsiella pneumoniae
• Enterococcus faecium
• Pseudomonas aeruginosa
• Methicillin-resistant Staphylococcus aureus (MRSA)
This adds over £1 billion to hospital treatment and societal costs.
How much did the rate of Escherichia coli and Klebsiella pneumoniae bloodstream infections increase in England between 2010 and 2014?
E. coli - 15.6%
K. pneumoniae - 20.8%
What were the 3 most frequently prescribed groups of antibiotics in England 2014?
Penicillins - 45%
Tetracyclines - 22%
Macrolides - 15%
How many people in hospital in England are on an antibiotic at any one time?
1 in 3
How many individuals in England take at least one course of antibiotics each year?
1 in 3
What are the consequences of antimicrobial
resistant bacteria?
• Increased number of hospitalizations
• Increased length of hospitalization
• Increased morbidity and mortality
– Emergence of strains totally resistant to all available antimicrobials
• Choice of more expensive or more toxic therapeutic alternatives
What could be the consequences of a global failure to address the problem of antibiotic resistance?
10 million deaths by 2050 costing £66 trillion
What are the different types of antibiotic resistance?
Inherent / intrinsic
Acquired
1) Chromosomal
2) Transferable
Describe inherent/intrinsic antibiotic resistance
All strains of a given species are resistant to a particular antibiotic, to which they have not had direct exposure
Why are some species inherently resistant to a particular antibiotics?
Inability to permeate cell envelope or lack of target
Give examples of inherent antibiotic resistance
Streptococci - aminoglycosides
Gram negatives - vancomycin
Describe Chromosomal resistance
Vertical gene transfer
Antibiotic pressure causes mutation from sensitive to resistant strain
Give examples of chromosomal resistance
Mycobacterium tuberculosis - streptomycin, rifampicin
Gram negatives – cephalosporins
What are the different mechanism for transferable resistance (horizontal gene transfer)?
Transduction
Conjugation
Transformation
What is conjugation?
Plasmid mediated transfer of single or multiple resistance genes
Most important clinically – spreads easily strain to strain
Plasmids are extra chromosomal DNA that carry resistance (R) factors
Plasmids are common and wide spread and transfer easily among bacteria
What is transduction?
Bacteriophage (virus) mediated transfer of genes
What is Transformation?
Acquisition of free DNA (resistance genes) by naturally transformable species
What are the various mechanisms for antimicrobial resistance?
a) Decreased accumulation of antibiotic
– Permeability barriers - outer membrane Gram negatives - penicillins
– Porin mutation
– Antibiotic efflux pumps -tetracyclines, macrolides
b) Enzymatic antibiotic inactivation or modification
– β-lactamases
c) Alteration of the drug target
– methicillin, vancomycin, macrolides
What are bacterial efflux pumps?
Bacterial efflux pumps are common within bacteria
• Efflux pumps are proteinaceous transporters localised in the cytoplasmic membrane (and outer membrane)
• Active transporters therefore require a source of energy
• Bacterial efflux pumps classified into five major “superfamilies” based on:
– amino acid sequence
– energy source used to export antimicrobial
What are the 5 major “superfamilies” of bacterial efflux pumps?
- Multidrug and toxic compound extrusion family (MATE)
- Major facilitator superfamily (MFS)
- Small multidrug resistance family (SMR)
- Resistance nodulation cell division superfamily (RND)
- ATP-binding cassette superfamily (ABC)
Describe the enzymatic antibiotic inactivation or
modification of b-lactams
Amide bond of the β-lactam ring hydrolysed by β-lactamase
How does alteration of the drug target for macrolides cause antibiotic resistance?
Inhibition of Protein Synthesis
Erythromycin (macrolide) binds to the ribosome causing
- dissociation of tRNA which inhibits the elongation of the protein chain
- bacteriostatic action
Erythromycin resistance is chromosomally mediated,
related to an alteration of the target site (the ribosome)
Alteration (mutation) of one of two adenine residues in the 23S rRNA at the antibiotic-binding site
How do fluoroquinolones work as antibiotics?
Fluoroquinolones block genetic replication by interfering with synthesis of DNA
Bind to enzymes and inhibit DNA replication
- DNA gyrase ( topoisomerase II ) – DNA supercoiling
- topoisomerase IV – required for strand separation during replication
How does resistance to fluoroquinolones occur?
• Mutation to:
DNA gyrase (gyrA) (occasionally) topoisomerase IV (parC)
• Resistance – mutation of genes responsible for enzyme production cause conformational change by incorporating hydrophobic sub-units
• This reduces affinity for fluoroquinolones
How can antibiotic resistance be controlled?
Reduce exposure to antibiotics
Develop new antibiotics
