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Antimicrobial pharmacology (Proceedings)
Therapeutic decision making is often a difficult and complex process.
Therapeutic decision making
- Often a difficult and complex process
- Often confusing and contradictory information (researchers, horse owners, websites & list serve's)
- Frequently our decisions are based on:
- Our last successful case
- Our last failure
- Our last case
- Mechanism of action
- Route of delivery
- Metabolism/ elimination
- Potential for toxicity
A Historical Perspective
- An ancient peasants house burned down. In it was his pig. When the peasant became hungry enough he tasted the cooked pig and reported its flavor to be miraculous.
- Thereafter, when the villagers wanted to eat roast pig they put one in a house and burned it down.
What the body does to the drug
Describes the movement of drugs in the body
Clinical pharmacokinetics is important for formulating dosage regimens in animals with disease
What the drug does to the body
Describes the action of the drug on the body- typically related to:
- Plasma/serum concentrations (window into the body)
- Exceptions: Macrolides for respiratory disease & other compounds that are 'tissue-loving'
Values poorly defined in horses- we extrapolate desired 'dose' from human or small animal lit.
Drug concentration in the blood stream usually proportional to drug concentration at site of action
Identify the agent
1. Gram stain (+) (-)
2. disk diffusion test; susceptible, intermediate, resistant. (based on human serum concentrations)
3. MIC - more expensive but more info. resistance often a concentration phenom. (minimum concentration of an AB that inhibits growth of a pathogen in vitro)
Kirby-Bauer susceptibility test
Inexpensive & considerable experience in vet.med.
Disadvantage- difficult to standardize, information on relative susceptibility hard to interpret (accurate??) and temptation to choose drug with largest zone (appropriate?)
Tube dilution MIC
- S = Antimicrobials that are most likely to work
- I = Antimicrobial that might work if pharmacokinetics and dosing are right.
- R = Antimicrobial that should not be used
- Automated, excellent accuracy & repeatability, more information on 'relative susceptibility'
- Disadvantages; more expensive and impractical for small labs
MIC for ampicillin- isolate 1= S for soft tissue & urinary tract, isolate 2= I for soft tissue S for UT, isolate 3= R for soft tissue and UT
- Similar to Tube dilution MIC but fewer concentrations
- Less expensive (more drugs/plate)
- More accurate than disk diffusion
- Results available sooner (6-12 hrs) than agar diffusion (24hrs)- automated
- Disadvantages= separate plates for blood, tissues etc..& can not discriminate relative susceptibility in S & R range
Breakpoint MIC for 3 AB's; Ampicillin= R, Cephalothin= I, and Gentamicin= S
- Spectrum of Activity (Gram + or Gram -)
- Microbial Effect (Cidal or Static)
- Bacterial Killing (concentration vs. time dependent)
- Post-Antibiotic Effect (aminoglycosides and fluoroquinolones)
Time dependent vs. Concentration dependent
Time Dependent drugs
- Concentrations need to be above MIC in the body for prolonged period...
Concentration dependent drugs
- High peak conc. Associated with > clinical efficacy
- Continued inhibition of bacterial growth after drug levels fall below MIC (not well understood)
- Drug may not have to be administered as often or as long as other drugs
- The distinction between cidal and static is not always exact.
- Cidal drugs- high peaks are important.
- Static drugs- must maintain plasma conc.
- In conditions where patient is immuno- suppressed (neonates, pleuritis..) cidal AB's are preferable.
- Host defenses determine urgency of therapy
- Immunocompromise (neonates)= bacteriocidal, High peak concentrations
- Trough concentrations imperative for aminoglycosides (nephro & oto- toxic)
- Optimum dose interval = sum of "time required for most effective kill" + "duration of PAE's"
- No method for calculating optimum interval
- Duration of therapy
- Too short = therapeutic failure
- Too long = increase risk of adverse drug events and increase resistance in bacterial population
- "Treat 3 days past the end of clinical signs"
- Clinician experience & accepted practice
"Getting the drug into the horse??"
- Oral administration- many challenges...
- Absorption & tissue distribution determined by drug & species factors (most information defined in humans).
- Generally not ideal in horses
- Drug solubility; gastric pH, particle size, fluid volumes, feed in the stomach etc...
Per Os in the Hoss
- Gastric pH very variable (1.0 to 7.5) with periods of spontaneous alkalinization...
- Volume of fluids in GI tract; humans=5-10L per day total; horses=24L/day + 1.6L/hr of gastric, duodenal & pancreatic secretions
- Feeding- changes pH, alters gastric emptying and GI motility, > secretion of bile
- < oral absorptions noted with sulfa's, doxycycline, rifampin, erythomycin
- Solubilized drug transported (paracellular or transcellular) across intestinal membrane to systemic circulation.
- Complex process- movement through lipid bilayer w/ 4 distinct regions of differing H2O and lipid content.
- Most drugs cross transcellular (passive diffusion)
- Active transport mechanism for some drugs with limited permeability (B-lactams)
- Cephalexin- great active transport in some species- NOT so in horses???
Other factors affecting absorption...GI Disease:
- Colitis results in > transit time = < drug absorbed
- SI obstructive dz > contact time & > absorption
- IR injury= low blood perfusion < drug absorbed
- Alteration in gut microflora- affects drug metabolism and alters bioavailability...
- After the AB is absorbed into circulation- active concentrations MUST reach the site of infection for successful Tx. [Easier said than done!!]
- Requires therapeutic conc of active drug in extracellular space
- Must penetrate tissue barriers (i.e. bood/brain, blood/ocular)
- Tissue Distribution- Interstitial fluid
- ONLY the unbound fraction of a drug is pharmacologically active
- Concentration of AB's in the ISF is a primary indicator for successful Tx
- Plasma protein binding provides reliable estimate of free drug conc in ISF- more predictive of tx success than total plasma conc
- What do tissue concentrations really mean?
- Drug is in the tissue (doesn't really mean drug is in contact with the bacteria)
- If concentrations are higher in tissue than plasma- drug is bound either intra or paracellular
- Local concentration gradient in ISF may occur as drug leaches out of cells
- Generally- ISF concentration of free drug will match free drug concentration in plasma
- Where are the microbes? Intra or extra cellular?
Reasons for Therapeutic Failure
- Wrong diagnosis
- Wrong drug for infection
- Mixed infection
- Resistant strain of bacteria
- Incorrect dosage
- Noncompliance w/ prescribed regimen
- Drug-Drug interaction
- Concurrent underlying disease
- Drug toxicity or adverse effect
- Immune suppression
- Inadequate duration of therapy