5 – Principles of Antimicrobial Therapy Flashcards
What is an antibiotic?
- Substance produced by bacteria and active against other bacteria
What is an antimicrobial?
- Substance (either naturally produced or synthetic) that is active against microbes
o Bacteria
o Fungi
o Protozoa
How is it possible that there is salmonella in ‘free from’ chicken with resistance? (even when never treated with it)
- INTRINSIC RESISTANCE
What do you consider when choosing an antimicrobial therapy? (questions you will ask)
- Where is the infection located?
- Will the antimicrobial distribute to the infection site?
- Will the antimicrobial be effective in the pathogen’s environment
- What is the appropriate drug formulation and dosage regimen?
- What is the most appropriate DURATION of therapy?
- What adverse drug reactions or toxicities may occur?
- For food animals, can you stay ‘on label’?
Where is the infection located?
- If in urine=easier
- If have a ‘barrier’=harder to get microbials there
Will the antimicrobial be effective in pathogen’s environment? Ex. abscess
- Rifampin, florfenicol and tetracycline work well
- *pH is different in abscesses
- Various that are not effective
- *superficial: usually don’t treat with antimicrobials (usually open it and clean it)
What antimicrobials are INEFFECTIVE in abscess? (ex. in horses)
- Aminoglycosides
- Beta-lactams
- Trimethoprim/sulpha
What is appropriate drug formulation and dosage regimen?
- Ideal to have the drug concentrated
- Avoid GI being exposed to them
- Ex. IV regional infusion (occlude vein and will leak out)
- Ex. interosseous infusion (into medullary cavity of the bone)
- Ex. ‘beads’ with surgeries
- *none are foul proof
What is the most appropriate DURATION of therapy?
- Ex. Convenia lasts in body for a LONG time
- Less control
- Especially if drugs lasts multiple weeks but infection is cleared in a few days
What does successful antimicrobial therapy require? (2 thoughts)
- Administering sufficient dose so that bacteria at site of injection are KILLED?
- Sufficiently SUPPRESSED so that they can be eliminated by host’s immune system?
High plasma drug concentrations are ASSUMED to be advantageous
- Large concentration of drug to DIFFUSE from plasma into various tissues and body fluids
- Soft tissue infections: most bacteria are located in ECF
o So concentration in plasma will resemble amount in the ECF (equilibrium between them) - *exception: new macrolide drugs have very low plasma concentrations, but extremely high tissue concentrations
o Bind to leukocytes and are carried to site of infection (ex. lungs)
Minimum inhibitory concentration (MIC)
- Lowest drug concentration that INHIBITS bacterial growth
- Dose to reach target plasma concentration of 2-10x the MIC
o Depends on the drug
Minimum bactericidal concentration (MBC)
- Lowest drug concentration to KILL 99.9% of the bacteria
- Often can’t reach it as the concentration is so high
o May reach toxic levels
Mutant prevention concentration (MPC)
- MIC of the LEAST-susceptible (ex. more resistant) single-step mutant bacterial population
- Hard to reach or unsafe (SUPER HIGH!)
What happens if local drug concentration is less than MIC? (susceptibility testing)
- No effect
- *Resistant
What happens if local drug concentration equals MIC? (susceptibility testing)
- Doubtful effect
- *intermediate
What happens if local drug concentration is more than MIC? (susceptibility testing)
- Effective
- *susceptible
What are S, I and R based on?
- Achievable PLASMA levels
- But concentration at site of infection, may be very different
- *works well for things like septicemia or wounds
MIC determination using microdilution
- Low drug concentration=lots of growth
- MIC is when there is NO more growth
- Ex. can get no growth but then growth reappears
Agar disk diffusion
- Measure zones of inhibition
- Qualitative, NOT quantitative
E-test
- Strip with antimicrobial gradient
- Expensive
- MIC like results
MIC of bacterial populations
- MIC50 or MIC90
- It can help and give you an idea of how susceptible it is, but does not guarantee efficacy
What are some key points for antimicrobial susceptibility testing with Culture & Susceptibility (C&S) panel?
- Guides your decision by providing, which pathogen and susceptibility of them
- Does NOT guarantee drug success or failure
- Wont have C&S result immediately
o Need to select initial therapy empirically
o Why its worth remembering likely pathogen and susceptibility
What does susceptibility testing NOT account?
- Host immune system
- Drug distribution in body
- Drug efficacy in plasma/tissue vs. broth/agar
- Bacterial growth rate and inoculum size
- Mixed infections
- Infection environment
- In vivo antimicrobial
When assessing antimicrobial efficacy what do you want to compare?
- Those with therapy to those without therapy
- *animals will also get better on their own, compare the 2 percentages!
Genomics for susceptibility testing
- ID key genetic determinants of resistance (eg. mecA, ampC genes)
- *future diagnostic approach for fast, accurate and cheap antimicrobial susceptibility testing
- **end goal: that clinics will be able to test genes and then treat
o Just because it has the gene, does not mean it will be resistant, but it likely will be
What are the antimicrobial categories?
- Bactericidal
- Bacteriostatic
- **not absolute, do NOT choose therapy based on them
o NOT that relevant
Bactericidal antimicrobials
- Ratio of MBC to MIC is <4-6
- Ex. possible to obtain concentrations in the patient that will kill 99.9% of bacteria
Bacteriostatic antimicrobials
- Ratio of MBC to MIC is large
- Ex. its not safe or feasible to administer enough antimicrobial to kill 99.9% of bacteria
What is the Post-Antibiotic Effect (PAE)
- Bacterial growth remains suppressed after the [antimicrobial] has dropped below MIC (‘no drug’)
- may be reason that many dosage regimens are effective, despite not maintaining concentrations >MIC
o *may allow for LONGER INTERVAL BETWEEN DOSES (convenience, $, AE) - *dependent on specific combo of antimicrobial and bacteria
PAE and fluroquinolones
- Long with gram positives and gram negatives
What are important drugs with short PAE?
- Penicillins
- Cephalosporins
- Trimethoprim/sulphas
- *likely need to dose them for longer
When looking at bacterial kill-curve studies, they show 2 ‘categories’ of antimicrobials, what are they?
- Concentration dependent
- Time dependent
Concentration dependent antimicrobials
- More drug you have and more exposure you have relative to MIC=better it will be
a. AUC : MIC want it at least 10x
b. Cmax : MIC want it 125x
How do you know if a antimicrobial is concentration dependent?
- As concentration of drug goes up=getter stepper=killing more
Time dependent antimicrobials
- Time above MIC is important!
o Doesn’t matter if 2x, 5x, or 10x over MIC - *important concentrations do NOT drop quickly or too much over time
- When does the tissue or plasma concentration ‘hit’ the MIC?
- *want at least 50% of dosing interval want concentration to be above MIC
- *dosing more often is better (x2 a day is likely fine, but going to 4x not necessary)
o May be poor client compliance
If doing infrequent dosing, what can be used to prolong exposure?
- ‘long-acting form’
o Slow absorbing (‘flip-flop’) formulations (ex. long-acting OTC)
o High protein binding (cefovecin) - *sometimes concentrations reached are NOT high enough=not sufficient
Problems interpreting time over MIC: oral vs IV
- IV: increase and then decrease, lots of time not above MIC
- Oral: above MIC for first bit and then lower
- *both have same time above MIC, but way they get there is different
- *neither is ideal, but either could be effective
How do you know if an antimicrobial is time dependent?
- When you increase dose but there is not benefit past a point
- *longer you have concentrations above MIC=max efficacy
Why is getting the dose right so important?
- *Important to know HOW TO DOSE
How are vet antimicrobials categorized?
- *based on importance in HUMAN HEALTH
- Very high: limited or no alternatives
o *can be appropriate to use in some cases, but need to UNDERSTAND WHY
- Very high: limited or no alternatives
- High: not limited
- Medium: not used in human med, but maybe limited alternatives
- Low: not used in human med at all (ex. ionophores)
