Abstract
ABSTRACTWe asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against A. baumannii. Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of A. baumannii pneumonia. TAZ alone lacked in vitro activity against MRSA or A. baumannii. The addition of TAZ to DAP resulted in a 2- to 5-log10 reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and A. baumannii by LL37 in vitro. TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
Highlights
We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen
We have previously shown that the growth of MRSA with concentrations of -lactam antibiotics at a fraction of the MIC enhances the vulnerability of MRSA to killing by host cationic defense peptides, including the human cathelicidin LL37 [5, 6]
Among the Gram-negative bacteria, A. baumannii is problematic since none of the newly developed antibiotics focused on expanding treatment options for infections by Gram-negative pathogens provide any further benefit above what had already been available
Summary
We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Since BLIs have scant antimicrobial activity on their own and are not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study. To extend our studies to potential innate immune potentiation, we examined the effects of BLIs on the activity of the endogenous antimicrobial peptide human cathelicidin LL37 against both MRSA and A. baumannii. (This work was presented in part at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], September 2015, San Diego, CA [24].)
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