Pharmacokinetics and pharmacodynamics of oral cephalosporins as critical factors in choice of antibiotics

Abstract

The pharmacology of antimicrobial agents can be divided into two major components: pharmacokinetics and pharmacodynamics. They provide a general interrelationship between the concentration of a given antibiotic at a particular site and the activity of the antibiotic against the causative organism. Pharmacodynamics have been upgraded in the last 10 years and the principles that link concentrations of antibiotics within the body system and their effects have been outlined in order to determine the optimal dosing interval [1,2]. Beta-lactam antibiotics have a time-dependent killing activity, and usually do not have large post-antibiotic effects (PAEs). The parameter which better correlate pharmacodynamics with pharmacokinetics is the duration of time with concentrations higher than the minimal inhibitory concentration (MIC) (T\MIC) [1–3]. Different cephalosporins nevertheless, have demonstrated the occurrence of a concentration-dependent PAE, both in vitro and in vivo for Gram-negative organisms, without any difference between oral and parenteral molecules and with constant exclusion of Pseudomonas aeruginosa strain [3–10]. This phenomenon may contribute to the high clinical efficacy of these derivatives [1,4]. (Table 1). From experimental studies on animal models it was demonstrated that cephalosporins do not need to exceed the MIC for the entire dose interval for successful therapy and 40–70% of the interval is probably satisfactory [1,3]. Cephalosporins represent almost half of all beta-lactams and are generally divided into a generational classification of four generations. Among oral derivatives there are compounds of the 1st generation (i.e. cephalexin and cefadroxil), the 2nd generation (i.e. cefaclor, cefprozil and cefuroxime-axetil) and the 3rd generation (i.e. the methoximinic cephalosporins such as cefixime, ceftibuten, cefpodoxime proxetil and cefetamet pivoxil) [11,12] (Table 2). This classification is based mainly on the antimicrobial activity and beta-lactamase behaviour of the different compounds. On the basis of the common causative organisms, the second generation cephalosporins will be preferable for the treatment of respiratory tract infections since they are active against Gram-positive and Gram-negative strains and are partially resistant to beta-lactamase hydrolysis [11,12]. Bioavailability is one of the main criteria for the selection of oral cephalosporins from a pharmacokinetic point of view. Generally, the cephem derivatives with intrinsic bioavailability (cephalexin, cefaclor, and cefprozil) are highly absorbed, while for cefuroxime axetil, the absorption ranges from 36 to 52% of the administered dose. All these cephalosporins however, with the exception of cefatrizine, have linear kinetics. The majority of these antibiotics are eliminated primarily by the kidney, with elimination half-lives generally under 2 h with a dose interval of 8 or 12 h [11–15] (Table 3). A similar behaviour is observed with the 3rd generation cephalosporins. Ceftibuten is highly absorbed, while for pro-drugs and cefixime, the absorption does not normally exceed 50% of the dose. It may also not be uniform, depending on saturable transport [11,16,17]. Many compounds therefore exhibit non-linear pharmacokinetic properties, since increasing doses lead to relatively decreasing peak concentrations and area under the serum concentration–time curve (AUC) values, mainly in relation to proportionally reduced bioavailability [16,17]. * Corresponding author: Tel.: +39-055-4271 ext. 310; fax: +39055-4271 ext. 280. E-mail address: novelli@server1.pharm.unifi.it (A. Novelli).