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Antimicrobial Agents and Chemotherapy, April 2001, p. 1078-1085, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1078-1085.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models

Helga Erlendsdottir,1 Jenny Dahl Knudsen,2 Inga Odenholt,3 Otto Cars,3 Frank Espersen,2 Niels Frimodt-Møller,2 Kurt Fuursted,2 Karl G. Kristinsson,1 and Sigurdur Gudmundsson4,*

Departments of Microbiology1 and Internal Medicine,4 Landspitalinn (University Hospital), Reykjavík, Iceland; Department of Infectious Diseases, University Hospital, Uppsala, Sweden3; and Statens Serum Institut, Copenhagen, Denmark2

Received 27 January 2000/Returned for modification 14 May 2000/Accepted 23 December 2000

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 (Cmaxs) and times that the concentrations were greater than the MIC (T>MICs). 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 Cmax/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 log10 CFU/ml), followed by the thigh (~3 log10 CFU/thigh), and being the lowest in the lung (~1 log10 CFU/lung). In the rabbit model the maximal effect was ~6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T>MIC was >= 65% of the experimental time and Cmax was >= 15 times the MIC, and in the rabbit model bactericidal activity became marked when T>MIC was >= 35%, Cmax was >= 5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/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.

* Corresponding author. Mailing address: Directorate of Health, Laugavegur 116, IS-101 Reykjavik, Iceland. Phone: 354 510 1900. Fax: 354 510 1919. E-mail: sigurdur{at}landlaeknir.is.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1078-1085, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1078-1085.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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