Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models

Abstract

Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible 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 cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 μg/ml and the other for which the penicillin MIC was 1.0 μg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations 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 counts 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 concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (∼6 log ₁₀ CFU/ml), followed by the thigh (∼3 log ₁₀ CFU/thigh), and being the lowest in the lung (∼1 log ₁₀ CFU/lung). In the rabbit model the maximal effect was ∼6 log ₁₀ CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T _>MIC was ≥65% of the experimental time and C _max was ≥15 times the MIC, and in the rabbit model bactericidal activity became marked when T _>MIC was ≥35%, C _max was ≥5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the C _max /MIC ratio and T _>MIC , the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.