In his address to the American Association for the Advancement of Science in 1961, Leake<sup>30 Leake C.D. The scientific status of pharmacology Science 1961 ;  134 : 2069-2079

Cliccare qui per andare alla sezione Riferimenti</sup> delineated the fundamental issues of pharmacology: the dose and pharmacologic response relationship; the identification of the site of drug action; the mechanisms of action of a drug; the absorption, distribution, metabolism, and excretion of a drug; and the chemical structure and biologic activity relationship.<sup>43 Reidenberg M.M. Clinical pharmacology: The scientific basis of therapeutics Clin Pharmacol Ther 1999 ;  66 : 1-8

Cliccare qui per andare alla sezione Riferimenti</sup> An understanding of these pharmacologic issues forms the basis of modern chemotherapeutics. Since the dawn of modern antimicrobial therapy in the 1940s, a plethora of anti-infective compounds have been developed; their mechanisms of action determined; knowledge of their absorption, distribution, metabolism, and excretion elucidated; and their structure-activity relationships established. Since the introduction of penicillin, however, controversy regarding how antimicrobial agents should be administered to maximize the killing of microorganisms has existed.

One early approach described to determine the frequency of the dosing interval for an antimicrobial agent was to multiply the agent's serum half-life by a factor of 4 or 5. The dose itself was the result merely of trial and error. What occurred over a period of time beginning after the introduction of penicillin is what has been termed the 500 mg every 6 hours era by Craig. During this period, antimicrobial agents, regardless of half-life ranging from 0.5 hours to 8 hours, were dosed at 500 mg every 6 hours. This approach to dose and dosing interval selection was used for most antimicrobial agents that were developed for several decades, regardless of pharmacologic class, mechanism of action, or mode of bacterial killing.

This approach prevailed despite the observations of Eagle et al<sup>18 Eagle H. Effect of schedule of administration on therapeutic efficacy of penicillin: Importance of aggregate time penicillin remains at effectively bactericidal levels Am J Med 1950 ;  9 : 280-299  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 19 Eagle H., Fleischman R., Levy M. Continuous vs. discontinuous therapy with penicillin N Engl J Med 1953 ;  238 : 481-488  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 20 Eagle H., Fleischman R., Musselman A.D. Effective concentrations of penicillin in vitro and in vivo for streptococci and pneumococci, and treponema J Bacteriol 1950 ;  59 : 625-643

Cliccare qui per andare alla sezione Riferimenti</sup> in the 1940s and 1950s that the total dose of penicillin necessary to cure syphilitic and streptococcal infection was considerably lower if the drug was administered continuously over 24 hours, rather than by intermittent injection. Eagle et al identified that for penicillin, the primary determinant of efficacy was the duration of time the bacteria were exposed to it. These observations contrasted sharply with those made regarding streptomycin and bacitracin, in which the magnitude of the concentrations of these drugs relative to the minimum inhibitory concentration (MIC) of the microorganism was found to be the determinant of efficacy.<sup>19 Eagle H., Fleischman R., Levy M. Continuous vs. discontinuous therapy with penicillin N Engl J Med 1953 ;  238 : 481-488  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup>

Contemporary data have accumulated from in vitro models of infection, animal models of infection, human volunteer experiments, and clinical trials that have confirmed and expanded on the observations of Eagle et al. Bacterial killing may be described as a function of drug concentration and time of exposure. The product of these pharmacokinetic measures is the area under the serum concentration-versus-time curve (AUC). Over clinically obtainable drug concentrations, simplifying assumptions can be made so that either drug concentration or time of drug exposure is of primary importance. When these assumptions cannot be made, however, both drug concentration and the time of drug exposure must be considered (e.g., the AUC). This knowledge has enabled clinicians finally to establish the best modes of antibiotic administration to maximize the killing of microorganisms.