antimicrobial therapy Flashcards
Anti“biotic”
-substance produced by
bacteria, and active against other bacteria
Anti“microbial”
-substance (either naturally produced or synthetic) that is active against
microbes, including bacteria, fungi, protozoa
infection site in antimicrobial therapy ex abscess
-depending on where the infection is we have to choose an antibiotic which will get to the site of the infection
-ex> abscess are walled off and hard to get antimicrobials into.
-not likely to be effective are aminoglycosides, B lactams, trimeth/ sulfa.
things to think about when choosing an antimicrobial therapy
- Where is the infection located?
- Will the antimicrobial distribute to the infection site?
-what are the AE of the drug?
-What is the appropriate drug
formulation and dosage regimen?
-Will the antimicrobial be effective in the pathogen’s environment?
-For food animals can you stay
“on label”?
-cost
-parmacodynamics and pharmacokinetis
-risk
goal of antimicrobial therapy
-sufficiently suppress the bacteria and infection so that they can be eliminated by the host’s immune system?
-don’t need to kill all bacteria most of the time.
-just want enough drug so that the infection stops proliferating.
high plasma [ ] in blood
-High plasma drug concentrations are
assumed to be advantageous.
-higher in blood means higher everywhere else
-not always true
-for soft tissue infections (wounds, pyoderma) most bacteria are located ESF so works in equilibrium with plasma so good indicator.
- Exceptions exist: new macrolide drugs
have very low plasma concentrations but
extremely high tissue concentrations: Bind to leukocytes, carried to site of infection (lungs)
MIC
-Minimum Inhibitory Concentration (MIC)
lowest drug concentration that inhibits bacterial growth
Dose to reach target [plasma] of 2-10x the MIC
-determined by microdilution, disk diffusion (qualitative), E-tests.
Minimum Bactericidal Concentration (MBC)
lowest drug concentration to kill 99.9% of the bacteria
Mutant Prevention Concentration (MPC)
MIC of the least-susceptible (i.e. more resistant) single-
step mutant bacterial population
susceptibility testing
-helps guide theraputic decisions. does not gaurantee drug success OR failure.
-predictions can be WRONG: does not account for:
-host immune system, drug distribution, drug efficacy in plasma/ tissues, bacterial growth rate, mixed infections.
Susceptibility Testing Limitations
- Assumes drug concentrations are only reached via
SYSTEMIC administration - LOCAL administration may reach much higher concentrations
Genomics
- Identify key genetic determinants of resistance (e.g., mecA, ampC genes)
- Future diagnostic approach for fast, accurate, and cheap
antimicrobial susceptibility testing?
-uses whole genome sequenxing and metagenomics for AMR detection.
-theres a large disconnet between our understanding of AMR genotype and phenotype.
Bactericidal
Ratio of MBC to MIC is < 4-6
i.e., it’s possible to obtain concentrations in the patient that will kill 99.9% of the bacteria
-Categories are NOT absolute!
Do NOT choose therapy based on cidal vs static!
-ex floroquinolines
Bacteriostatic
Ratio of MBC to MIC is large
i.e., it’s not safe or feasible to administer enough antimicrobial
to kill 99.9% of the bacteria
Categories are NOT absolute!
Do NOT choose therapy based on cidal vs static!
ex. tetracyclines
Post-Antibiotic Effect (PAE)
Bacterial growth remains suppressed after the [antimicrobial] has dropped below MIC. still working even though drug isn’t there anymore.
May be the reason that many dosage regimens are effective, despite not maintaining concentrations > MIC
MAY allow for longer interval between doses
PAE is dependent on the specific combo of antimicrobial & bacteria
PK-PD Integration for Antimicrobials concentration vs time dependent
Bacterial kill-curve studies show that antimicrobials can be:
* Concentration dependent:
AUC0-24 hr: MIC, the more drug and higher exposure you have the better.
Cmax: MIC, bigger the exposure to MIC better it works.
* Time dependent T > MIC, high exposure or concentration isn’t as important as time they spend above MIC of pathogen. And concentration can’t drop below MIC and stay below
approach for time vs concentration dependant therapy
-For concentration (i.e., dose)-dependent killers, more is better.
- For time-dependent killers, dosing more often is better.
Same dose, but divided more times/day
BUT: may be poor client compliance with frequent dose regimens
Infrequent dosing requires “long-acting” form
Slow absorbing (“flip-flop”) formulations
e.g., long acting OTC, CCFA (Excede)
High protein binding (cefovecin)
Beta lactams structure
-penicillin, cephalosporins
-B lactam ring: resistance mechanism breaks down the ring with beta-lactamase’s.
penicillins used in vet med
- Crystalline penicillin G (Na+ or K+)
– Sterile formulations for injection (human drugs) IV!
– Soluble powder for drinking water (vet drugs non-sterile) - Procaine Penicillin GVM
– “white” injectable penicillin (short acting daily injections or long acting in oil. IM or SC ONLY.
– Oral feed premixes - Benzathine Penicillin GVM
– “Long-acting” injectable penicillin (Duplocillin LA) IM or SC only
-make sure always look at label as there are many different types of penicillin formulations.
penicillin G: mechanism of action
-Act by disrupting synthesis of bacterial cell wall:
* Inhibit the Penicillin-Binding Proteins (PBPs) found
on the outside of bacterial cell membrane
* This interferes with enzymes (transpeptidase) needed
for peptidoglycan synthesis (part of cell wall)
* Causes lysis of growing bacterial cells
– Bactericidal – but only if bacteria is actively growing
Penicillin G: Mechanism of Action in different bacteria types
– Gram (+)
* lots of peptidoglycan in cell wall
* High affinity of PBPs for β-lactams=works good on gram +
– Gram (–)
* Lesser peptidoglycan in cell wall
* Lower affinity of PBPs for β-lactams, doesn’t work as well on gram -, cant penetrate the cell wall.
-dosed in IU. 1 IU = 0.6 ug pen G
penicillin G resistance
- some gram + (staph) have Penicillinase or β-lactamase enzymes so not susceptible to penicillin. (but can be susceptible to cephalosporins)
- Inability of β-lactam to penetrate bacterial cell wall
-gram -: no susceptible to penicillin: Can’t penetrate cell wall
-gram -: not susetable to endogenous b-lactamase producer.
Penicillin G (Benzylpenicillin):
Spectrum of Activity
-Many Gram (+) (ex strep)
(but NOT most Staph,
which make β-lactamase)
-many anaerobes
Gram (+)
* Actinomyces species
* Trueperella pyogenes
* Some Bacillus anthracis,
Corynebacterium, Erysipelothrix
rhusiopathiae, and Listeria spp.
A few Gram (-)
* Some Histophilus & Pasteurella
Most anaerobes
* Fusobacterium, some Clostridium, some Bacteroides
Penicillin G (Benzylpenicillin): resistance bacteria
Most Gram (-)
* Produce β-lactamase
* Can’t penetrate cell wall
* Low affinity PBP
Most Staph spp.
* Produce β-lactamase
