Dosage schedules of antimicrobial agents: a historical review.

Methods that may be used to design rational dosage schedules of antimicrobial agents are reviewed. Most current schemes are empiric and have not been tested in humans by classic dose-response trials. In some instances, agents whose half-lives in serum differ by as much as 10-to 18-fold are usually given at the same dosage, with the same interval between doses. New derivatives given less frequently may thus appear to be equal in effectiveness to the parent compound given on a standard dosage schedule. Basing of dosage schedules on achievable levels and pharmacokinetic behavior may not be satisfactory. The minimal inhibitory and minimal bactericidal concentrations are measured in vitro under static conditions that differ significantly from the in vivo environment. Dilution end points may cause further deviations from in vivo conditions because of the removal of constituents from serum and body fluid. Concentrations of drug in blood, body fluids, or urine do not necessarily reflect either the distribution of drug in tissues or the kinetics of interaction between the drug and the target microorganism. The lack of continuity in so-called discontinuous dosage is more apparent than real. A system of "kinetic buffers" exists in the body, and some microorganisms can attenuate the effect of intermittent doses. Intermittent dosage schedules are advantageous compared with continuous administration because of improved penetration of drug into tissues, convenience of administration, and better compliance among patients. The magnitude of the dose is limited by potential toxicity. Large doses may be wasteful if smaller amounts are equally effective.