Dose and Confused (Dosing Regimen)

The Plasma Drug concentration is the amount of drug that is circulating in the bloodstream.

What must the PDC exceed in order to be effective?

Must exceed the MIC for the drug to be effective.

What is MIC?

The lowest concentration of an antimicrobial that inhibits visible growth of a microbe.

(A measure of the organism’s susceptibility.)

What occurs when the PDC > MIC?

drug concentration is above the level needed to inhibit the microbe and therapeutic effects are met

Estimated based on pharmacokinetic (PK) parameters are based on what TWO things?

Cmax (maximum concentration reached)

T½ (Half-life) (time it takes for plasma concentration to fall by half)

If PDC > MIC, what does this favor?

selective pressure

What is the lowest concentration that eradicates the inoculum?

Mutant Prevention Concentration

What has been used to describe the concentrations of drug which, if targeted (and achieved) in the patient, is likely to result in resistance?

mutant selection window

The base or lower threshold of the window is the MIC reported by the ____

laboratory

T/F The top of the window is the highest MIC of any of the colonies comprising the infecting population.

True

What is the dosing regimen designed to target?

target cultured MIC

T/F In the normal or otherwise healthy patient, the body's immune defenses should be able to overcome and get rid of this small, residual inoculum

True

When resistant bacteria emerge, the population now has a higher MIC and is generally no longer considered susceptible to the drug.

What should the dosing regimen reach?

Mutant Prevention Concentration (MPC)

T/F The MPC can’t be predicted from the MIC, and diagnostic labs don’t measure it because testing every single bacterial colony would require an impractically large plate.

True

T/F All dosing regimens are the same

Fasle

For all antimicrobials drug concentrations should exceed the ____ of the infecting organism.

MIC

What TWO things must exceed the MIC varies with the drug and to some degree the bug?

the extent and duration that drug concentrations

What are the TWO classes that antimicrobial are broadly based on?

time or concentration dependent

For concentration dependent drugs, what is the dosing regimen based on to determines effectiveness?

the ratio of the peak plasma concentration (Cmax) to the MIC

For time dependent drugs, what helps to determine the effectiveness of the drug?

the key factor is how long the drug concentration stays above the MIC (T>MIC) during the dosing interval.

T/F These definitions are based on a 24 hr dosing period.

True

The mechanism of antimicrobial action determines what?

bactericidal versus bacteriostatic action

What type of drugs tend to be bactercidal?

drugs that target the cell wall or DNA

What type of drugs tend to be bacterstatic?

drugs that inhibit ribosomes

There also are some circumstances in which bacteriostatic drugs might reach bactericidal concentrations, what is an example of this?

such as accumulation in WBC

When is a case when bactericidal drugs act bacteristatic?

if insufficient drug reaches the site of infection

To achieve our soon to be discussed goal of "dead bugs don't mutate", what should be achieved?

bactericidal concentrations should be achieved at the site of infection.

What THREE drug classes are bactericidal?

β-lactams

Aminoglycosides

Quinolones

What bactericidal drug can be potentiated?

(one drug increases the effectiveness of another.)

Sulfonamides

List FOUR of the eight Bacteriostatic drugs?

Chloramphenicol

Tetracyclines

Sulfonamides

Lincomysin

Clindamycin

Erythromycin

Azithromycin

Tylosin

Which of Bacteriostatic drugs might achieve cidal conc. b/c accumulated in selected tissues?

Clindamycin

Erythromycin

Azithromycin

What determines the time course of efficacy of an antimicrobial, meaning how long during a dosing interval the drug remains effective?

mechanism of action

T/F The MOA will influence both the dose and the interval

True

The time course of efficacy is another reason that doses should be designed to surpass the ___

MIC

Drugs that irreversibly bind to or destroy their targets tend to have residual antimicrobial effects even after plasma levels drop is known as what?

post-antibiotic effect (PAE).

T/F The duration of the PAE varies with the drug and the organism but not all drugs exhibit a PAE.

True

Drugs that have a long PAE are usually what kind of drug?

concentration dependent

T/F Concentrations higher than the MIC should be targeted in the patient

True

What category of drugs interfere with their bacterial target irreversibly or cause irreversible effects?

concentration dependent

What does concentration dependent drugs efficacy depend upon?

a sufficient number of drug molecules reaching the infecting inoculum

What is the target PKPDI for concentration-dependent drugs?

doses should be designed such that Cmax be at least 10 X higher than the MIC of the infecting microbe

(Cmax:MIC > 10)

What happens to the efficacy of concentration dependent drugs when you increase the dose?

it increases also

T/F Once the target is inhibited, the drug need not be present during a 48 hr period

False, 24 h

T/F Concentration-dependent drugs generally exhibit excellent post-antibiotic effects, particularly toward gram positive organisms

False, gram negative

Time dependent drugs have a (max/min) PAE

min

How do time dependent drugs bind to their target?

bind reversibly and competitively to their targets

How is the efficacy of time-dependent drugs related to the duration that drug concentrations remain above the MIC (T>MIC)?

The efficacy of time-dependent drugs depends on the length of time that the drug concentration stays above the MIC (T>MIC) during the dosing interval

(the longer it remains above the MIC, the more effective the drug is.)

For "___ ___" drugs, the T>MIC should be most of the dosing interval (at least 75% if not 100%).

lower tier

For ___ ___ drugs ("big guns"), the T>MIC should be 75% of the dosing interval

higher tier

With time dependent drugs, PDC must exceed MIC, but the magnitude depends of what?

drugs 1/2 life

What type of drugs are typically time dependent?

bacteristatic

What are TWO drugs that have a long half life?

Tilmicosin

Cefovecin

For drugs with very short half-lives, such as penicillins, the drug might be given as a ___ ___ ___ in critical patients

constant rate infusion

What are some examples of slow release products? (3)

Procaine, benzathine Penicillins

(Make sure dose achieves MIC)

Me when this exam is on Halloween