The importance of pharmacodynamic properties in treatment of penicillin resistant Streptococcus pneumoniae.
As a short résumé, the major result according to each objective listed in chapter 1 will be repeated. 1. Adjusting and characterisation of the mouse peritonitis model for studying the treatment of pneumococci. The mouse peritonitis model was adjusted to study pneumococci with serotypes of low virulence to mice, by supplementing the inoculum with 5 (vt/vol)% mucin. This made the infection lethal with inoculi of 10(6) cfu/ml that also made the study of a bacterial growth phase possible (Knudsen et al., I). The immune modelling effect of mucin lasted less than four hours (chapter 2). The experimental infection in the mice was studied during time; The highly reproducible bacterial growth-phase was characterised as exponential growth in approximately 16 h, followed by an stationary phase until approximately 24 h post-challenge. A decline phase, not very reproducible, was found after 24 h, and in this phase the mice were beyond therapeutic range (Knudsen et al., III). The efficacy of treatment as effect on bacterial counts, was as good in the stationary phase as in the exponential phase (Knudsen et al., III). The pharmacokinetic properties of penicillin were studied during the infection, the serum elimination was slower in severely ill, than in newly challenged and in healthy mice (Knudsen et al., III). The survival of mice in this experimental model did not correlate with the decline in bacterial counts in blood or peritoneal cavity (Knudsen et al., III, den Hollander et al., V). 2. To compare the efficacy of antibiotics against pneumococci in vitro and in vivo A highly statistically significant correlation was found between determinations of effect in vitro (MIC's) and in vivo (ED50's) for penicillin and ten pneumococcal strains, and for four cephalosporins and three pneumococcal strains (Knudsen et al., I, II). One cephalosporin, cefepime, was shown better in vivo than expected from the cumulated in vitro data from four other cephalosporins, but no explanation for that observation was found (Knudsen et al., II). Working with an immunocompetent model, the killing of bacteria in vivo can not always be predicted from in vitro time kill curves, as the immune system will contribute to the bacterial killing,--a higher kill rate of penicillin on pneumococci was found in vivo as compared to in vitro (Knudsen et al., I, III). The killing of pneumococci in different dosing regimens of azithromycin in mice, was not directly correlated to kill rate using the same concentration profiles in an advanced in vitro pharmacokinetic model; but the CMAX as the most important pharmacodynamic parameter for survival of mice was also the most important parameter for killing of bacteria in vitro (Hollander et al., V). Doses of various antibiotics providing only a bacteriostatic in the mice, can be appropriate in the treatment of the lethal infection and providing survival of mice (Knudsen et al., III, den Hollander et al., V). A regrowth of bacteria in-between active doses of drug could not be found in counts in vivo which can be attributed to the immune system of the mice. (Knudsen et al., III, den Hollander et al., V). The favourable MIC's of teicoplanin, with MIC50 and MIC90 four times lower than of vancomycin for pneumococci, were not observed in vivo, as the ED50's 50% and 90% percentiles for teicoplanin were more than half of the values for vancomycin. This could be explained by the high degree of protein binding of teicoplanin in mouse serum. The use of mouse serum in the MIC determination instead of the traditionally used media, could give a better prediction of the efficacy in mice (Knudsen et al., VI). 3. The efficacy of beta-lactams against pneumococci The efficacy in vitro of penicillin and five cephalosporins against pneumococci with various susceptibilities was concentration independent above four times the MIC, and the killing was independent of the level for the MIC's and independent on which beta-lactams used, but depending on the strains tested (Knudsen et al., I, II). The MIC's of five cephalosporins correlated positively and significantly to each other, and to MIC's of penicillin when strains with various susceptibilities were tested (Knudsen et al., II). In vivo a significant correlation between the effective doses and the MIC's for beta-lactams was found within the range, where effective concentration are achievable (Knudsen et al., I, II). In the study of pneumococci with various susceptibility to penicillin, it was found, that independent of the penicillin susceptibilities, the most important parameter for treatment with penicillin of pneumococci was the T > MIC (Knudsen et al., I). Penicillin treatment of bacteria in different phases of growth in vivo, showed that the most important parameter for growth was the T > MIC, also in the stationary phase (Knudsen et al., III). 4. (ABSTRACT TRUNCATED)
Knudsen
J D
JD
Statens Serum Institut, Copenhagen.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D010538:Peritonitis / Q000188:drug therapy; D011008:Pneumococcal Infections / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects*
D000900:Anti-Bacterial Agents