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Updated: Feb 18, 2026
Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Combination Antibiotic Exposure Selectively Alters the Development of Vancomycin Intermediate Resistance in
Xuting Zheng1,2, Andrew D Berti2, Sue McCrone2
1Division of Infectious Disease, The First Hospital of China Medical University, Shenyang, People's Republic of China.
Abstract:
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, gentamicin, meropenem, rifampin, piperacillin-tazobactam (TZP), or trimethoprim-sulfamethoxazole. 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 to 4 mg/liter throughout the 28-day exposure, with CFZ and TZP being the most effective agents (VAN MIC = 1 to 2 mg/liter). Similar MIC trends occurred with the lipo-/glycopeptide 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 to 16 mg/liter emerging during weeks 2 to 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.
Insights
Vancomycin (VAN) plus beta-lactam antibiotics effectively prevent vancomycin-intermediate Staphylococcus aureus (VISA) development in vitro. This combination therapy suppresses resistance and reduces cell wall thickness, offering a promising strategy for treating MRSA infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with vancomycin (VAN) often lead to reduced VAN susceptibility and treatment failure.
- Combination therapy is explored to enhance treatment response, but data on combinations preventing resistance are limited.
Purpose of the Study:
- To identify optimal antibiotic combinations that prevent the emergence of vancomycin-intermediate Staphylococcus aureus (VISA) in vitro.
- To assess the impact of VAN combination therapy on MRSA and VISA strains, including cell wall thickness, carotenoid content, and membrane fluidity.
Main Methods:
- Two MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days to VAN alone or in combination with cefazolin (CFZ), fosfomycin, gentamicin, meropenem, rifampin, piperacillin-tazobactam (TZP), or trimethoprim-sulfamethoxazole.
- Vancomycin susceptibility testing (MIC), cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined.
Main Results:
- VAN combined with any beta-lactam agent limited VAN MIC increase to 1-4 mg/L over 28 days, with CFZ and TZP being most effective (VAN MIC = 1-2 mg/L).
- Beta-lactam combinations with VAN also prevented increased MICs for lipo-/glycopeptide agents like daptomycin and telavancin.
- VAN plus beta-lactam significantly decreased CWT, while VAN with non-beta-lactams increased CWT. No correlation was found between carotenoid content or membrane fluidity and antibiotic exposure.
Conclusions:
- Only VAN plus beta-lactam combination therapy suppressed the development of VISA in vitro.
- Rational selection of VAN plus beta-lactam combinations warrants further investigation for long-term treatment of MRSA infections due to their resistance-suppressing capabilities.
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