Pharmacodynamics of beta-lactam antibiotics. Studies on the paradoxical and postantibiotic effects in vitro and in an animal model.

The pharmacodynamics of antibiotics, i.e. the rate of killing and the time before regrowth of surviving bacteria, may be important factors for determination of the dosage interval. In the present study the effect of protein binding, antibiotic concentrations, bacterial growth phase and bacterial inoculum on the rate of bacterial killing was investigated. The postantibiotic effect (PAE) was also studied in vitro and in vivo. The killing rate of S. aureus did not differ when the bacteria were exposed to the same free concentrations of dicloxacillin in medium with and without albumin. Protein binding per se did thus not diminish the bactericidal activity. A paradoxically reduced bactericidal effect was noted when S. aureus was exposed to high concentrations of dicloxacillin, cloxacillin and benzylpenicillin. For determination of PAE of imipenem on Ps. aeruginosa, counts of viable bacteria were compared with assay of bacterial intracellular ATP. Both methods demonstrated a PAE for the strains tested at an inoculum of 10(6) cfu/ml. At an inoculum of 10(8) cfu/ml no PAE was found, which coincided with a lack of bactericidal effect. Both the PAE and the bactericidal effect were restored with aeration of the cultures, indicating insufficient penetration of imipenem to the target sites at low oxygen tension. An in vivo model in rabbits with implanted tissue cages was developed for evaluation of the PAE. Group A beta-hemolytic streptococci showed a PAE of approximately 2 h in vivo, which correlated well with the PAE found in vitro. Despite that streptococci in postantibiotic phase (PA-phase) were non-multiplying, such bacteria were killed as efficiently as previously untreated controls when exposed to 10xMIC of penicillin both in vitro and in vivo. However, streptococci in PA-phase were much more sensitive to the repeated challenge to subinhibitory concentrations of penicillin than previously untreated controls. In vivo, no difference in sensitivity to sub-MIC penicillin concentrations between streptococci in PA-phase and untreated controls was seen, probably due to the presence of host factors in the tissue cage fluid. It seems that for streptococci, subinhibitory antibiotic concentrations are more important for the sucess with intermittent dosing than the PAE, especially when a normal host defence is present.