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

Abstract

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 ␤-lactam antibiotics. We examined the efficacy of treating VRS1 with a combination of vancomycin and ␤-lactam antibiotics in vitro and in vivo. We found that the MIC of oxacillin for VRS1 decreased from >256 g/ml to <1 g/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 log 10 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 ␤-lactams may be an option, based on these results.

Synergy of β-Lactams with Vancomycin against Methicillin-Resistant Staphylococcus aureus: Correlation of Disk Diffusion and Checkerboard Methods

“…This concept is based on several in vitro and animal studies that demonstrated a synergistic effect of vancomycin-␤-lactam combinations against MRSA (6)(7)(8)(9)(10)(11).…”

Spontaneous Deletion of the Methicillin Resistance Determinant, mecA , Partially Compensates for the Fitness Cost Associated with High-Level Vancomycin Resistance in Staphylococcus aureus

“…PBP 2a is not capable of cross-linking peptidoglycan containing stem peptide modified by the van genes (21,39). Although it is not universally seen, there are several observations that MRSA passaged in the presence of increasing concentrations of vancomycin has a decrease in oxacillin resistance or has a deleted mecA (1,36,41).…”

Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin-Nonsusceptible Strains of Methicillin-Resistant Staphylococcus aureus with Evolving Oxacillin Susceptibility (the “Seesaw Effect”)

“…Although uncommon in vivo (3), the seesaw effect was recently observed in a clinical VISA isolate with a retained mecA gene obtained during VAN therapy; of interest, after discontinuation of VAN therapy, the methicillin resistance phenotype was restored (32). Importantly, the combination of VAN and nafcillin has been shown to exert synergistic killing activities in vitro and in an experimental model of infective endocarditis (IE) (8) with both VISA and VRSA strains (14).…”