Pharmacodynamics of penicillin are unaffected by bacterial growth phases of Streptococcus pneumoniae in the mouse peritonitis model.
The correlation between pharmacokinetic parameters and the in-vivo effect of antibiotics in relation to bacterial growth phases was evaluated using the mouse peritonitis model with a penicillin-resistant pneumococcus. Different 8 h dosing regimens were applied, with different total doses and initiated at different times during the bacterial growth phase. The effect was measured as the decline in bacterial counts in the peritoneal cavity. The pharmacokinetic parameters showed major changes during the phases of growth, as the serum elimination of penicillin decreased during the infection. The same effect of dosing regimens was observed in the exponential and stationary phases. In two regimens where T(>MIC) (the time the serum concentration exceeded the MIC) was 50% of the treatment period, a significantly better effect was achieved with a 2 hourly regimen than with a regimen with treatments every 20 min. The T(>MIC) of each dose was shown to be a critical parameter for achieving an effect in all growth phases. The maximum effect of penicillin, a 5-6 x log10 decline in bacterial counts in the peritoneum of the mice, was achieved when T(>MIC) was >50% of the treatment time or longer than approximately 40 min of each dose. The 50% effective dose for protection after a single injection, ED50, was measured in the different phases of the infection and found to increase with the duration of the pneumococcal infection, while mice treated 24 h after challenge were beyond therapeutic range. The correlation between the effect of penicillin and pharmacokinetic parameters appears to follow the same rules during the different in-vivo growth phases of pneumococci.
Knudsen
J D
JD
Department of Research and Development, Statens Serum Institut, Copenhagen, Denmark.
Frimodt-Møller
N
N
Espersen
F
F
D000818:Animals; D001202:Ascitic Fluid / Q000382:microbiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D005260:Female; D051379:Mice; D010400:Penicillin G / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010403:Penicillin Resistance; D010406:Penicillins / Q000493:pharmacokinetics / Q000494:pharmacology*; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development
D010406:Penicillins; D010400:Penicillin G