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Antimicrobial Agents and Chemotherapy, September 2006, p. 2919-2925, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00859-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Effect of Treatment Duration on Pharmacokinetic/Pharmacodynamic Indices Correlating with Therapeutic Efficacy of Ceftazidime in Experimental Klebsiella pneumoniae Lung Infection

Irma A. J. M. Bakker-Woudenberg,^1* Marian T. ten Kate,¹ Wil H. F. Goessens,¹ and Johan W. Mouton²

Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam,¹ Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands²

Received 7 July 2005/ Returned for modification 31 October 2005/ Accepted 18 June 2006

The pharmacokinetic/pharmacodynamic (PK/PD) indices that define the therapeutic effect of the beta-lactam ceftazidime in a rat model of Klebsiella pneumoniae lung infection were investigated in relation to treatment duration and treatment endpoint. Treatment was started 24 h after infection with dosing regimens of 3.1 up to 1,600 mg/kg of body weight/day and dosing every 6, 12, or 24 h. When animals were treated for a relatively short period of 48 h, the duration of time that unbound plasma ceftazidime levels exceeded the MIC of the antibiotic for the infecting strain was the index that best correlated with therapeutic efficacy in terms of significant bacterial killing in the infected lung (microbiological effect). The maximum effect was reached when plasma ceftazidime levels were above the MIC for 60 to 70% of the dosing interval. However, when the treatment duration was extended to a relatively long period of 18 days instead of 48 h and animal survival rate instead of microbiological efficacy was taken as the endpoint, the fAUC/MIC ratio (where AUC is the area under the concentration-time curve) was the PK/PD index that best correlated with therapeutic efficacy. The PK/PD indices that effect 50% survival of rats for the fAUC/MIC ratios were 18.0 (95% confidence interval [95% CI], 16.3 to 19.9), 20.2 (95% CI, 13.8 to 29.4), and 27.9 (95% CI, 21.3 to 36.5) for the schedules of administration of every 6, 12, and 24 h, respectively. The fAUC/MIC needed for 100% survival was >100. We conclude that the PK/PD index that best correlates with outcome is dependent on the duration of treatment and/or the parameter of outcome. The effect of long-term treatment should be studied more extensively in other models of infection.

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* Corresponding author. Mailing address: Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Phone: 31 10 4632175. Fax: 31 10 4633875. E-mail: i.bakker-woudenberg{at}erasmusmc.nl.

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Antimicrobial Agents and Chemotherapy, September 2006, p. 2919-2925, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00859-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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