Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii

January 25, 2017 at 2:31 pm

Antimicrobial Agents & Chemotherapy February 2017 V.61 N.2 e01745-16

George Sakoulas, Warren Rose, Andrew Berti, Joshua Olson, Jason Munguia, Poochit Nonejuie, Eleanna Sakoulas, Michael J. Rybak, Joseph Pogliano, and Victor Nizet

aUniversity of California—San Diego School of Medicine, La Jolla, California, USA

bSharp Healthcare System, San Diego, California, USA

cUniversity of Wisconsin—Madison School of Pharmacy, Madison, Wisconsin, USA

dDepartment of Biological Sciences, University of California—San Diego, La Jolla, California, USA

eEugene Appelbaum College of Pharmacy, Wayne State University, Detroit, Michigan, USA

fSkaggs School of Pharmacy, University of California—San Diego, La Jolla, California, USA

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. 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.



Entry filed under: Antimicrobianos, Bacterias, Bacteriemias, Metodos diagnosticos, Resistencia bacteriana, Sepsis, Update.

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