Penicillin pharmacodynamics in four experimental pneumococcal infection models

Clinical and animal studies indicate that with optimal dosing, penicillin m ay still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-suscepti ble pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cag e infection in rabbits. Two multidrug-resistant isolates of Streptococcus p neumoniae type 6B were used, one for which the penicillin MIC was 0.016 mug /ml and the other for which the penicillin MIC was 1.0 mug/ml. Two addition al strains of PNSP were studied in the rabbit. The animals were treated wit h five different penicillin regimens resulting in different maximum concent rations of drugs in serum (C(max)s) and times that the concentrations were greater than the MIC (T(>MIC)s). The endpoints were bacterial viability cou nts after 6 h of treatment in the mice and 24 h of treatment in the rabbits . Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T->MIC and to a lesser extent on the C-max/MIC and the generation time but not on the area under the con centration-time curve (AUC)/MIC. Maximal bactericidal activities were simil ar for both PSP and PNSP, being the highest in the peritoneum and blood (si milar to6 log(10) CFU/ml), followed by the thigh (similar to3 log(10) CFU/t high), and being the lowest in the lung (similar to1 log(10) CFU/lung). In the rabbit model the maximal effect was similar to6 log(10) CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T->MIC was greater than or equal to 65% of the experimental time and C-max was greate r than or equal to 15 times the MIG, and in the rabbit model bactericidal a ctivity became marked when T->MIC was greater than or equal to 35%, C-max w as greater than or equal to5 times the MIG, and the AUC at 24 h/MIC exceede d 25. By optimization of the C-max/MIC ratio and T->MIC, the MIC of penicil lin for pneumococci can be used to guide therapy and maximize therapeutic e fficacy in nonmeningeal infections caused by PNSP.