Antibiotics Symposium Flashcards
Define antibiotic
Agents produced by micro-organisms that kill or inhibit the growth of other micro-organisms in high-dilution
Why are antibiotics more correctly called antimicrobials
Because most agents are semi-synthetic derivative of antibiotics
How do antibiotics work
They are molecules that bind a target site on a bacteria which are crucial to the survival of the bacterium
What does penicillin binding protein bind to
Cell was to inhibit cell wall synthesis
Role of beta lactams
Bind to the transpeptidase active site
Examples of beta lactams
- Penicillins
Cephalosporins
Carbapenems
GLYCOPEPTIDES
Mechanism of beta-lactams in the body
Block transpeptidase activity and interrupts cross-linking and cell wall synthesis
What antibiotics interfere with nucleic acid synthesis or function
- METRONIDAZOLE
2. RIFAMPICIN
How does Fluroquinolones inhibit DNA synthesis
Inhibit DNA Gyrase
5 antibiotics that inhibit ribosomal activity and protein synthesis
- Aminoglycosides
- Tetracyclines
- Lincosamides
- Macrolides
- Chloramphenicol
Two antibiotics that inhibit folate synthesis and carbon unit metabolism
SULPHONAMIDES
TRIMETHOPRIM
What drug effects bacterium cell membranes
Polymyxins
What part of the ribosome do tetracycline and ahminoglycosides inhibit
30S subunit
What part of the ribosome do macrocodes, Clindamycin, Linezolid, Chloramphenicol, Streptogramins inhibit
50S subunits
What is the role of bacteriostatic antibiotics
Prevent growth of bacteria (stop multiplication)
Reduce exotoxin production
Exotoxin surge is less likely from Gram negative bacteria
How long does it take for bacteriostatic antibiotics to kill 90% of bacteria
18-24 hours
What do we do with bacteriostatic antibiotics before giving them to patients
Produce a minimum inhibitory concentration
How do we carry out a minimum inhibitory concentration
- Tube dilution with antimicrobial agent
- Incubate for 24 hours
- Determine MIC based on turbidity
Define turbidity
Cloudiness of fluid caused by presence of bacteria
Three reasons why bactericidal antibiotics are useful
- Good during poor tissue penetration
- Good when difficult to read infections (TB)
- Eradicates infections quickly
Bacteriostatic vs Bactericidal antibiotics in mechanism
- Bacteriostatic - prevents growth of bacteria
Bactericidal - agent skill bacteria - Bacteriostatic - kill more than 90% in 18-24 hours
Bactericidal - Kill more than 99.9% in 18-24 hours - Bacteriostatic - inhibit protein synthesis, DNA replication, metabolism
Bactericidal - inhibits cell wall synthesis - Bacteriostatic - Reduces toxin production, endotoxin surge less likely, reduced bacterial component release
Bactericidal - Useful if poor penetration, difficult to treat infections or need to treat quickly
Does a low MIC mean its a better antibiotic than those that are higher
No, drugs have to also occupy enough binding sites (high conc/ in microorganism) + STAY there for a sufficient period of time in order for metabolic processes of bacteria to be inhibited
What are two major determinants of anti-bacterial effects
- Concentration
2. Time
Define ‘concentration-dependant killing’
Key parameters how high the concentration is above MIC
Define ‘time-dependant killing’
Key parameter is the time that serum concentrations remain above MIC during dosing interval
How is the value of concentration-dependant killing calculated
Peak conc. / MIC ratio
How is the value of time-dependant killing calculated
t>MIC
What does the antibiotics ability to reach and remain at the site of bacterial infection rely on
Pharmacokinetics
Define pharmacokinetics
The movement of a drug from its administration site to the place of its pharmacological activity and elimination from the body
RELEASE
ABSOPTION
DISTRIBUTION
ELIMINATION
What three factors effect the distribution of an antibiotic
- Which antibiotic will penetrate that site
- pH of the site
- Is the antibiotic lipid-soluble
What other key consideration is there when deciding what antibiotic to use
WHAT IS SAFE FOR THE PATIENT
How do bacteria resist antibiotics
- Change antibiotic target
- Destroy antibiotic
- Prevent antibiotic access
- Remove antibiotic from bacteria
How do bacteria change antibiotic target
Change molecular configuration of antibiotic binding site or masks it
How has Methicillin (Flucloxacillin) been affected by a change in antibiotic target
Can’t bind to PBP of staphylococci (MRSA)
How has Vancomycin been effected by a change in antibiotic target site
- Wall components change in enterococci and reduces binding
How has rifampicin activity been effected by a change in antibiotic target site
Reduced by changes to RNA polymerase in MTP
How have bacteria been able to disable the effect of penicillin
Hydrolysis by the bacterial enzyme beta lactase of beta lactic ring in penicillin and cephalosporins
What is the product of penicillin destruction after B-lactam is removed
Penicilloic acid
Does penicillinase produced by staphylococci inactivate flucloxacillin
No
How do Gram negative bacteria effect ahminoglycosides
Phosphorylate and acetylate them
How do bacteria prevent antibiotic access
Modify the bacterial membrane prone channel, size, number and selectivity
Give an example of prevention of antibiotic access
- Pseudomonas aeruginosa against imipenem
2. Gram negative bacteria against aminoglycosides
How can proteins in bacterial membrane reduce effects of antibiotics
- Proteins in bacterial membranes act as an export or efflux pumps
Example of efflux pumps for antibiotics in S.aureus and s. pneumonia
- Fluoroquinolones
What are Enterbacteriacae resistant to
Tetracyclines
Three ways horizontal gene transfer can take place
- Conjugation
- Transduction
- Transformation
What three ways can bacteria develop resistance
- Naturally
- Spontaneous gene mutation
- Horizontal gene transfer
Define intrinsic resistance
All subpopulations of a species will be equally resistant
Effect of Vancomycin on gram negative bacteria
Can’t penetrate outer membrane
Effect of cephalosporins on enterococci
- PBP not effectively bound
Define acquired resistance
A bacterium which was previously susceptible obtains the ability to resist the activity of a particular antibiotic
What is spontaneous gene mutation
New nucleotide base pair in AA sequence change to enzyme or cell structure reduced affinity or activity of antibiotic
Define conjugation
Sharing extra-chromosomal DNA plasmids
Define transduction
Insertion of DNA by bacteriophages
Define transformation
Picking up naked DNA
In what way has MRSA developed resistance
Transduction of mecA genes
What species is MRSA
S. Aureus
Why is MRSA resistant
Chromosome me contains mecA
mecA encodes penicillin-binding protein 2a
Resistance to all Beta lactic antibiotics + methicillin
How are Vancomycin-resistant enterococci formed
- Plasmid mediated acquisition of gene encoding altered AA on peptide chain preventing vancomycin binding
What increases the resistance of Vancomycin by enterococci
Cephalosporin
How has gram-negative bacteria developed resistance
- Beta-lactamase hydrolyses penicillin
2. Typically remain sensitive to beta-lactamase inhibitors
Describe how resistance has developed ESBL (extended spectrum beta lactase)
Mutation at active site of extended range of antimicrobial resistance inhibits ESBL and allows oxyamino beta-lactam and monobactam inhibition so more extended beta-lactam resistance
When is beta-lactam most sensitive
In vitro NOT in vivo
How is ESBL spread
Plasmid
How has AmpC beta-lactamase resistance developed
- Beta-lactamas inhibitor resistant in vitro and in vivo
What bacteria express AmpC beta-lactamase resistance
Enterobacter and citrobacter
What are bacteria with AmpC Beta-lactamase resistant to
Penicillin
When is AmpC beta-lactamase resistance expressed
Only in the presence of the antibiotic
What are carbapenems
Antimicrobials of last resort to treat infection s due to ESBL or plasmid-mediated AmpC-producing organisms of the enterobacteriaceae family s
What property do carbapenems have
Highly resistant to degradation by beta-lactamases or cephalosporinases
What bacteria developed carbapenemases
Gram-Negative bacteria
How do we test for resistance
- Amount of antibacterial that inhibits visible growth of the microorganism - MIC
What are breakpoint plates
Plates with a specific breakpoint conc. of antibiotic to see if a given inoculum grows or not
Formula for breakpoint conc.
(Cmax/et) x f x s
Max = maximum serum conc. following a state dose at steady state
s = shift factor
t= factor to allow for serum elimination half-life
e = factor by which the Cmax should exceed MIC
