Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
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β-lactams increase the antibacterial activity of daptomycin against clinical MRSA strains and prevent selection of DAP-resistant derivatives
Shrenik Mehta, Christopher Singh, Konrad B. Plata, Palas K. Chanda, Arundhati Paul, Sarah Riosa, Roberto R. Rosato and Adriana E. Rosato*
Author Affiliations: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, TX
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens both in health care and community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin, bacteremia and right-side endocarditis caused by MRSA. Resistance to DAP (DAP<SUP>R</SUP>) has been reported in MRSA and is mostly accompanied with parallel decrease in oxacillin resistance, process known as ?see-saw? effect. Our study provides evidence that the see-saw effect applies to other β-lactams and carbapenems of clinical use including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC) and imipenem (IMP) in heterogeneous DAP<SUP>R</SUP>-MRSA but not in MRSA expressing homogeneous β-lactam resistance. The combination DAP/β-lactam in terms of antibacterial efficacy was evaluated in isogenic DAP<SUP>S/R</SUP> MRSA originally obtained from patients that failed DAP monotherapy. Both in-vitro (MIC, synergy kill-curve) and in-vivo (wax worm model) approaches were used. In these models, DAP/β-lactam was proven highly synergistic against both heterogeneous and homogenous clinical DAP<SUP>R</SUP>-MRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge reverting the increased repulsion provoked by DAP alone, effect that may favor the binding of DAP to the cell surface. An ease of in-vitro mutant selection was observed when DAP<SUP>S</SUP>-MRSA strains were exposed to DAP. Importantly, the association DAP/β-lactams prevented the selection of DAP<SUP>R</SUP> variants. In summary, our data show that DAP/β-lactam combination may significantly enhance both the in-vitro and in-vivo efficacy of anti-MRSA therapeutic options against DAP<SUP>R</SUP>- infections, and represent an option in preventing DAP<SUP>R</SUP> selection in persistent or refractory MRSA infections.
FOOTNOTES
* Corresponding author: The Methodist Hospital Research Institute, 6670 Bertner Ave., Room R6-113, Houston, TX 77030, Phone: 713-441-4369, Fax: 713-441-2895. e-mail: aerosato@tmhs.org
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Shrenik Mehta, Christopher Singh, Konrad B. Plata, Palas K. Chanda, Arundhati Paul, Sarah Riosa, Roberto R. Rosato and Adriana E. Rosato*
Author Affiliations: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, TX
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens both in health care and community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin, bacteremia and right-side endocarditis caused by MRSA. Resistance to DAP (DAP<SUP>R</SUP>) has been reported in MRSA and is mostly accompanied with parallel decrease in oxacillin resistance, process known as ?see-saw? effect. Our study provides evidence that the see-saw effect applies to other β-lactams and carbapenems of clinical use including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC) and imipenem (IMP) in heterogeneous DAP<SUP>R</SUP>-MRSA but not in MRSA expressing homogeneous β-lactam resistance. The combination DAP/β-lactam in terms of antibacterial efficacy was evaluated in isogenic DAP<SUP>S/R</SUP> MRSA originally obtained from patients that failed DAP monotherapy. Both in-vitro (MIC, synergy kill-curve) and in-vivo (wax worm model) approaches were used. In these models, DAP/β-lactam was proven highly synergistic against both heterogeneous and homogenous clinical DAP<SUP>R</SUP>-MRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge reverting the increased repulsion provoked by DAP alone, effect that may favor the binding of DAP to the cell surface. An ease of in-vitro mutant selection was observed when DAP<SUP>S</SUP>-MRSA strains were exposed to DAP. Importantly, the association DAP/β-lactams prevented the selection of DAP<SUP>R</SUP> variants. In summary, our data show that DAP/β-lactam combination may significantly enhance both the in-vitro and in-vivo efficacy of anti-MRSA therapeutic options against DAP<SUP>R</SUP>- infections, and represent an option in preventing DAP<SUP>R</SUP> selection in persistent or refractory MRSA infections.
FOOTNOTES
* Corresponding author: The Methodist Hospital Research Institute, 6670 Bertner Ave., Room R6-113, Houston, TX 77030, Phone: 713-441-4369, Fax: 713-441-2895. e-mail: aerosato@tmhs.org
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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