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Antimicrobial pharmacology (Proceedings)

April 1, 2008
Mark Crisman, DVM, DACVIM

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
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  • Our last failure

  • Our last case

Pharmacological Considerations

  • Target

  • Mechanism of action

  • Route of delivery

  • Disposition

  • Metabolism/ elimination

  • Potential for toxicity

Operant Conditioning

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.

  • Pharmacokinetics

What the body does to the drug

Describes the movement of drugs in the body

  • Absorption

  • Distribution

  • Metabolism

  • Elimination

Clinical pharmacokinetics is important for formulating dosage regimens in animals with disease

Pharmacodynamics

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

Break-point MIC

  • 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

Antibiotic Selection

  • 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...

  • Beta-lactams

  • Sulfonamides

  • tetracyclines

Concentration dependent drugs

  • High peak conc. Associated with > clinical efficacy

  • Aminoglycosides

  • fluoroquinolones

Post-antibiotic effect

  • 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

  • Fluoroquinolones

  • Aminoglycosides

Activity considerations

  • 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.

Dose considerations

  • Host defenses determine urgency of therapy

  • Immunocompromise (neonates)= bacteriocidal, High peak concentrations

  • Trough concentrations imperative for aminoglycosides (nephro & oto- toxic)

Interval Considerations

  • 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

Drug Permeability

  • 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...

Tissue Distribution

  • 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

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