Pharmacokinetics and pharmacodynamics of newer oral cephalosporins - Implications for treatment of community-acquired lower respiratory tract infections

Full knowledge of the inter-relationships between pharmacodynamics and pharmacokinetics is important in choosing an appropriate antibiotic, determining its optimal dosage regimen, and predicting which pharmacokinetic parameter(s) should best correlate with clinical efficacy in the treatment of community-acquired lower respiratory tract infections (LRTIs). Pharmacodynamics of antibiotics deal with the time-course of drug activity and mechanisms of action of drugs on bacteria. In particular, the bactericidal activity of p-lactams such as the cephalosporins is dependent upon the time that serum concentrations remain above the minimum inhibitory concentration (MIC) of a given organism. A significant linear correlation exists between time above MIC (T > MIC) and time to eradication of bacteria from respiratory secretions. Therefore, the goal of a dosage regimen for antibiotics of this type is to maximise the time during which the organism is exposed to the drug, since the bactericidal activity correlates more with duration than with magnitude of dose. Most infections occur in tissue rather than in the blood. Thus, appropriate antibiotic therapy requires achievement of significant concentrations of antibiotics at the site of infection for long enough to eliminate the invading pathogen. At present, few data on the pulmonary disposition of newer oral cephalosporins are available in literature; they are generally limited to the evaluation of penetration of the antibiotic into the sputum and only for part of the dosage interval. The inadequacy of data limits the possibility of a pharmacodynamic investigation. The scarcity of data on the postantibiotic effect of these antimicrobial agents is also a problem. Therefore, at present, it is extremely difficult to prescribe a newer oral cephalosporin for the treatment of a LRTI in accordance with an authentic pharmacodynamic approach. This new approach, which results from the integration of bacteriological characteristics in in vivo pharmacokinetic studies, is extremely important in determining the choice of the appropriate antibiotic and the dosage regimen for treating LRTIs. An oral cephalosporin with good potency as well as a favourable pharmacokinetic profile and that permits concentrations higher than the MIC(90)s of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for almost the entire validated dosage interval in bronchial secretions, can potentially be considered the first choice.