Section 2 - Drug regimen design

Section 2 - Applied Pharmacokinetics

Drug regimen design

Pharmacodynamics
Pharmacodynamics is the study of the relationship between serum concentration and therapeutic effect. For antibiotics, the time course of antimicrobial activity must be understood before one can design a rational drug regimen.

Rational dosing of antimicrobial agents
From the viewpoint of pharmacodynamics, antimicrobial agents may be divided into three major groups.

Group I
ß-lactams

These agents have a kill rate that is concentration-independent as long as the concentration is above the minimum inhibitory concentration (MIC). Also, these agents have no significant post-antibiotic effect (PAE). PAE is the persistent suppression of bacterial growth following antibiotic exposure.

Strategy for best results: maximize exposure time during which the plasma concentration exceeds MIC. This may be achieved by giving smaller doses more frequently; ultimately, continuous IV infusion of ß-lactams would achieve the best results. In fact, when penicillin was first introduced, it was administered by continuous infusion; only later was it given intermittently, largely for the sake of convenience.

Group II
Vancomycin, carbapenems, macrolides, and clindamycin

These agents have a kill rate that is concentration-independent as long as the concentration is above the MIC. Also, these agents also have an intermediate post-antibiotic effect, therefore serum levels may be allowed to drop below the MIC for a short period.

Strategy for best results: maximize exposure time during which the plasma concentration exceeds MIC. This may be achieved by giving smaller doses more frequently (i.e., 500 mg 6 hrs is better than 1000 mg q 12 hrs).

Group III
Aminoglycosides, fluoroquinolones, and metronidazole

These agents have concentration-dependent kill rate and a significant post-antibiotic effect. The PAE exhibited by this group will prevent bacterial regrowth when tissue levels fall below the MIC for an extended period of time.

Strategy for best results: Aim for a "good peak" to maximize the ratio of Peak to MIC (or the 24 hour AUC to MIC ratio). This is achieved by giving larger doses less frequently. In the case of aminoglycosides, "give the kidney a break" too by allowing for a short (2 - 4 hrs) drug-free period to minimize nephrotoxicity.

Some practical considerations

Choose practical, convenient doses and administration schedules.
Odd doses and schedules may lead to errors in administration.

Consider a loading dose.
Some drugs, which are usually administered without a loading dose, may require a loading dose in order to quickly attain therapeutic levels.

Measure SDC's when indicated.
Accurate assessment requires steady-state SDC's (4-5 times the estimated half-life).

Closely monitor the clinical status of the patient.
Careful observation for signs of drug toxicity is imperative.

Section 2 - Applied Pharmacokinetics