Pharmacokinetics and Dynamics of Antimicrobial Drugs Flashcards
What is MIC? How does it compare to MBC?
MIC is the mean inhibitory concentration and is the amount of drug needed to stop bacterial growth.
MBC is mean bactericidal concentration and is the concentration at which 99.99% of bacteria are killed
What is “breakpoint”?
The concentration of antibiotic below which the bacteria is susceptible
What is post-antibiotic effect?
Persistent suppression of microbial growth after the removal of antibiotics from the medium (used for aminoglycosides to reduce ototoxic and nephrotoxic effects)
What is time-dependent killing?
How does it compare to concentration-dependent killing?
The mechanism of bacterial killing depends on the amount of time where the concentration is above the MIC whereas concentration dependent killing is the mechanism of killing depends on the peak concentration (Cmax) above the MIC and NOT the time
What three factors determine the outcome of an infection?
- characteristics of the infecting organism (innate susceptibility to antimicrobials/acquired resistance)
- Characteristics of the host- site of infection
- Choice of appropriate antimicrobial therapy
What is susceptibility testing?
What type of infection are they used for?
What can it not be used for?
Testing done in a micro lab to get an idea about what antimicrobials might treat an infection.
Used for bacteria and yeasts
Not used for moulds or parasites
What are the three main susceptibility tests?
- Broth dilution- inoculate a tube containing a defined inoculum with bacteria and test different concentrations of antimicrobial of interest. Measure turbidity of the broth. MIC is where growth is inhibited completely
- Kirby-Bauer Disk Diffusion- place antibiotic impregnated disk on agar plate that has been inoculated with a bacteria lawn. Measure zone of inhibition of growth. Larger diameter= better
- E-test= lab tech places a strip which has a gradient of increasing antimicrobial concentration. Where the zone of growth inhibition starts will align with the MIC
Why is MIC used more commonly than MBC when doing susceptibility tests?
Because MBC requires doing viable counts and plating bacteria or yeast on agar plates and is labor-intensive
What are the three ways a bacteria can be reported from susceptibility testing?
- susceptible- standard dosage of antimicrobial will be effective at treating infection
- Intermediate- antimicrobial may be effective at high enough concentrations
- Resistant- growth could not be inhibited by concentrations within the therapeutic index for the drug
A bactericidal drug will kill over _______ of the bacteria in the solution over a 24 hour period. This is known as a greater than ______log kill.
99.99%
greater than 3 log kill
(99%-2logs killed is bacteriostatic)
What are the major bactericidal drugs?
- Penecillin/Cephalosporins/carbopenems
- Fluoroquinolone
- Aminoglycoside
- Vancomycin
- Daptomycin
- Metronidazole
- Rifampin
What are the major bacteriostatic drugs?
- tetracycline
- sulfanomides
- macrolides
- clindamycin
- linezolid
What is the “90-60” rule?
What does this tell us about host factors?
Infections susceptible to antimicrobials work 90% of the time.
Infections resistant to antimicrobials work 60% of the time.
This tells us that host factors are critical in determining outcome more than just knowing MIC
Susceptibility testing is more likely to help us______________________ than to select ______________________.
rule out drugs that are least likely to succeed than to select ones that will work
What are the only 2 anti-fungal drugs to undergo renal excretion?
- amphotericin
- fluconazole
All the rest are hepatic with biliary or renal excretion of metabolites
What are areas of the body where antibiotic concentrations tend to be lower?
- Brain- BBB
- CSF
- Eye - Blood/Retinal Barrier
- Bone
- Abscesses- low pH inactivates aminoglycosides
- prostate gland
- biliary tract
- intracellularly
Why do abscesses have low concentrations of antibiotics?
They have a low pH which inactivates some (like aminoglycosides)
The antibiotics must diffuse into the abscess from a blood vessel at the edge of the abscess
You must drain it first!
Why are bacteriacidal drugs the drugs of choice for endocarditis?
Endocarditis is inflammation in the heart (usually vegetation on a valve).
Very few phagocytic cells are within the vegetation so you want to use bactericidal drugs
Why are prosthetic devices unique when considering what antimicrobials to use?
They allow for the formation of biofilms and many antimicrobials cannot penetrate the biofilm
Drugs that show post-antibiotic effects are usually ones which show ___________-dependent killing.
How is post-antibiotic effect measured in vitro?
Concentration dependent
It is measured by exposing a broth to antibiotic for a period of time followed by dilution to 1/100 or 1/1000 of MIC and taking samples to check viable counts and regrowth.
Time delay before growth is the length of the post-antibiotic effect
What three major antimicrobials demonstrate concentration-dependent killing with prolonged persistent effect (PAE)?
- Aminoglycosides
- Quinolones
- Metronidazole
Dosing : max conc. ratio PEAK/MIC
What three antimicrobials demostrate time-dependent killing with no PAE?
- Penecillin
- Cephalosporin
- Vancomycin
What 4 drugs are Time AND Concentration dependent with prolonged PAE?
- Vancomycin
- Macrolides
- Clindamycin
- Imipenem
Max time of exposure
Maximum killing for a time-dependent drug occurs when drug concentration/MIC is a ratio of ______.
2-4
How does one increase efficiency of time-dependent drugs?
increase frequency of administration, extend infusion time, infuse continuously
For concentration dependent killing, it is recommended that the Cmax/MIC ratio be ______.
Cmax is 10times greater than MIC
One daily dose can increase bacterial killing and limit toxicity
Fluroquinolones have ______________dependent killing and their ______/MIC ratio is what correlates with clinical success.
concentration dependent and AUC/MIC determines success
Aminoglycosides + ______________ will be synergistic for treating endocarditis.
B-lactams (penicillins)
What are the drugs that are chelated and inhibited by milk and cations?
Fluoroquinolones and tetracycline
What does rifampin have a drug interaction with?
It induces p450 so any drug that is metabolized by p450 will be rapidly depleted
