Antimicrobial pharmacology (Proceedings)

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

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