TY - JOUR
T1 - Combination antibiotic exposure selectively alters the development of vancomycin intermediate resistance in staphylococcus aureus
AU - Zheng, Xuting
AU - Berti, Andrew D.
AU - McCrone, Sue
AU - Roch, Melanie
AU - Rosato, Adriana E.
AU - Rose, Warren E.
AU - Chen, Baiyi
N1 - Funding Information:
This study was supported in part by NIH-1R01AI132627-01 (W.E.R.) and NIH-1R56AI102503-01A1 (A.E.R.). We thank Ben August (UW School of Medicine, Electron Microscope Facility) for technical assistance.
Funding Information:
Xuting Zheng was supported by the international scholar program from China Medical University.
Funding Information:
Xuting Zheng was supported by the international scholar program from China Medical University. This study was supported in part by NIH-1R01AI132627-01 (W.E.R.) and NIH-1R56AI102503-01A1 (A.E.R.). We thank Ben August (UW School of Medicine, Electron Microscope Facility) for technical assistance.
Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/2
Y1 - 2018/2
N2 - Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN-intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin (FOF), gentamicin (GEN), meropenem (MEM), rifampin (RIF), piperacillin-tazobactam (TZP) or trimethoprim-sulfamethoxazole (SXT). In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any β-lactam limited the VAN MIC increase to 1-4 mg/L throughout the 28-day exposure, with CFZ and TZP as the most effective agents (VAN MIC=1-2 mg/L). Similar MIC trends occurred with the lipo-/glyco-peptide agents daptomycin and telavancin, where β-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non β-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4-16 mg/L emerging during weeks 2-4 of treatment. VAN plus β-lactam decreased CWT significantly whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus β-lactam suppress the development of VISA. Rational selection of VAN plus β-lactam should be further explored as a long-term combination treatment of MRSA infections due to their ability to suppress VAN resistance.
AB - Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN-intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin (FOF), gentamicin (GEN), meropenem (MEM), rifampin (RIF), piperacillin-tazobactam (TZP) or trimethoprim-sulfamethoxazole (SXT). In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any β-lactam limited the VAN MIC increase to 1-4 mg/L throughout the 28-day exposure, with CFZ and TZP as the most effective agents (VAN MIC=1-2 mg/L). Similar MIC trends occurred with the lipo-/glyco-peptide agents daptomycin and telavancin, where β-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non β-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4-16 mg/L emerging during weeks 2-4 of treatment. VAN plus β-lactam decreased CWT significantly whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus β-lactam suppress the development of VISA. Rational selection of VAN plus β-lactam should be further explored as a long-term combination treatment of MRSA infections due to their ability to suppress VAN resistance.
KW - Antimicrobial combinations
KW - Glycopeptides
KW - Staphylococcus aureus
KW - Vancomycin resistance
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UR - http://www.scopus.com/inward/citedby.url?scp=85041073663&partnerID=8YFLogxK
U2 - 10.1128/AAC.02100-17
DO - 10.1128/AAC.02100-17
M3 - Article
C2 - 29158272
AN - SCOPUS:85041073663
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
M1 - e02100-17
ER -