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Antimicrobial Agents and Chemotherapy, August 2009, p. 3325-3330, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00006-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Levofloxacin in a Murine Pneumonia Model of Pseudomonas aeruginosa Infection: Determination of Epithelial Lining Fluid Targets{triangledown}

Arnold Louie, Christine Fregeau, Weiguo Liu, Robert Kulawy, and G. L. Drusano*

Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, Albany, New York 12208

Received 3 January 2009/ Returned for modification 30 March 2009/ Accepted 8 April 2009

The dose choice for Pseudomonas aeruginosa remains a matter of debate. The actual exposure targets required for multilog killing of organisms at the primary infection site have not been delineated. We studied Pseudomonas aeruginosa PAO1 using a murine model of pneumonia. We employed a large mathematical model to fit all the concentration-time data in plasma and epithelial lining fluid (ELF) as well as colony counts in lung simultaneously for all drug doses. Penetration into ELF was calculated to be approximately 77.7%, as indexed to the ratio of the area under the concentration-time curve for ELF (AUCELF) to the AUCplasma. We determined the ELF concentration-time profile required to drive a stasis response as well as 1-, 2-, or 3-log10(CFU/g) kill. AUC/MIC ratios of 12.4, 31.2, 62.8, and 127.6 were required to drive these bacterial responses. Emergence of resistance was seen only at the two lowest doses (three of five animals at 50 mg/kg [body weight] and one of five animals at 100 mg/kg). The low exposure targets were likely driven by a low mutational frequency to resistance. Bridging to humans was performed using Monte Carlo simulation. With a 750-mg levofloxacin dose, target attainment rates fell below 90% at 4 mg/liter, 1 mg/liter, and 0.5 mg/liter for 1-, 2-, and 3-log kills, respectively. Given the low exposure targets seen with this strain, we conclude that levofloxacin at a 750-mg dose is not adequate for serious Pseudomonas aeruginosa pneumonia as a single agent. More isolates need to be studied to make these observations more robust.

* Corresponding author. Mailing address: Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6304. E-mail: gdrusano{at}ordwayresearch.org

{triangledown} Published ahead of print on 13 April 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3325-3330, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00006-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Harigaya, Y., Bulitta, J. B., Forrest, A., Sakoulas, G., Lesse, A. J., Mylotte, J. M., Tsuji, B. T. (2009). Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant Staphylococcus aureus (MRSA): Implications for Dosing in MRSA Pneumonia. Antimicrob. Agents Chemother. 53: 3894-3901 [Abstract] [Full Text]  


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