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Antimicrobial Agents and Chemotherapy, September 2006, p. 2951-2956, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00232-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Successful Therapy of Experimental Endocarditis Caused by Vancomycin-Resistant Staphylococcus aureus with a Combination of Vancomycin and ß-Lactam Antibiotics

Paige M. Fox,¹ Russell J. Lampen,² Katrina S. Stumpf,¹ Gordon L. Archer,^1,2 and Michael W. Climo^1,2,3*

Departments of Microbiology and Immunology,¹ Medicine, Virginia Commonwealth University School of Medicine,² Hunter Holmes McGuire Veteran Affairs Medical Center, Richmond, Virginia³

Received 22 February 2006/ Returned for modification 18 April 2006/ Accepted 10 June 2006

VRS1 is the first isolated strain of vancomycin-resistant Staphylococcus aureus (VRSA) found to carry the vanA gene complex previously described in Enterococcus. Under vancomycin pressure, VRS1 makes aberrant cell walls consisting of stem tetrapeptide and depsipeptide that lack the terminal D-Ala-D-Ala residues targeted by vancomycin. Previous data have suggested that this aberrant cell wall is not cross-linked by PBP2a, the enzyme responsible for cell wall transpeptidation in the presence of ß-lactam antibiotics. We examined the efficacy of treating VRS1 with a combination of vancomycin and ß-lactam antibiotics in vitro and in vivo. We found that the MIC of oxacillin for VRS1 decreased from >256 µg/ml to <1 µg/ml in the presence of vancomycin. Using the rabbit model of endocarditis, we treated VRS1-infected rabbits with nafcillin alone, vancomycin alone, or a combination of nafcillin and vancomycin. Treatment with nafcillin in combination with vancomycin cleared bloodstream infections within 24 h and sterilized 12/13 spleens (92%), as well as 8/13 kidneys (62%), following 3 days of treatment. Mean aortic valve vegetation counts were reduced 3.48 log₁₀ CFU/g with the combination therapy (compared to untreated controls) and were significantly lower than with either vancomycin or nafcillin given alone. VRS1 was extremely virulent in this model, as no untreated rabbits survived the 3-day trial. Treatment of clinical infections due to VRSA with the combination of vancomycin and ß-lactams may be an option, based on these results.

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* Corresponding author. Mailing address: Hunter Holmes McGuire Veteran Affairs Medical Center, 1201 Broad Road Boulevard, Section 111-C, Richmond, VA 23249. Phone: (804) 675-5018. Fax: (804) 675-5437. E-mail: michael.climo{at}med.va.gov.

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Antimicrobial Agents and Chemotherapy, September 2006, p. 2951-2956, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00232-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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