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Antimicrobial Agents and Chemotherapy, September 2003, p. 2740-2748, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2740-2748.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Real-Time Monitoring of Bacterial Infection In Vivo: Development of Bioluminescent Staphylococcal Foreign-Body and Deep-Thigh-Wound Mouse Infection Models

Nelly A. Kuklin,1* Gregory D. Pancari,1 Timothy W. Tobery,1 Leslie Cope,1 Jesse Jackson,2 Charles Gill,2 Karen Overbye,2 Kevin P. Francis,3 Jun Yu,3 Donna Montgomery,1 Annaliesa S. Anderson,2 William McClements,1 and Kathrin U. Jansen1

Merck and Co., Inc., West Point, Pennsylvania 19486,1 Merck and Co., Inc., Rahway, New Jersey 07065,2 Xenogen Corporation, Alameda, California 945013

Received 18 October 2002/ Returned for modification 23 January 2003/ Accepted 23 June 2003

Staphylococcal infections associated with catheter and prosthetic implants are difficult to eradicate and often lead to chronic infections. Development of novel antibacterial therapies requires simple, reliable, and relevant models for infection. Using bioluminescent Staphylococcus aureus, we have adapted the existing foreign-body and deep-wound mouse models of staphylococcal infection to allow real-time monitoring of the bacterial colonization of catheters or tissues. This approach also enables kinetic measurements of bacterial growth and clearance in each infected animal. Persistence of infection was observed throughout the course of the study until termination of the experiment at day 16 in a deep-wound model and day 21 in the foreign-body model, providing sufficient time to test the effects of antibacterial compounds. The usefulness of both animal models was assessed by using linezolid as a test compound and comparing bioluminescent measurements to bacterial counts. In the foreign-body model, a three-dose antibiotic regimen (2, 5, and 24 h after infection) resulted in a decrease in both luminescence and bacterial counts recovered from the implant compared to those of the mock-treated infected mice. In addition, linezolid treatment prevented the formation of subcutaneous abscesses, although it did not completely resolve the infection. In the thigh model, the same treatment regimen resulted in complete resolution of the luminescent signal, which correlated with clearance of the bacteria from the thighs.

* Corresponding author. Mailing address: Merck and Co., Inc., P.O. Box 4, WP 26-265, Sumneytown Pike, West Point, PA 19486. Phone: (215) 652-4893. Fax: (215) 652-7320. E-mail: nelly_kuklin{at}merck.com.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2740-2748, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2740-2748.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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