Nature Chemical Biology (2015)
トリプル β-lactam コンビネーション！
「triple β-lactam combination meropenem-piperacillin-tazobactam (ME/PI/TZ)」
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem-piperacillin-tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA subspecies N315 and 72 other clinical MRSA isolates in vitro and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem-penicillin–β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein-2a (PBP2a) via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing in vivo activity similar to that of linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans.
VCMとGM or rifampin
Clinical data do not support the practice of combining vancomycin with gentamicin or rifampin to improve clinical outcomes for MRSA bacteremia in the absence of a prosthetic device． Short-course, low-dose gentamicin combined with vancomycin for MRSA bacteremia and native valve infective endocarditis (IE) has been associated with an increased risk of nephrotoxicity．In one randomized trial of 42 patients with MRSA endocarditis treated with vancomycin alone or in combination with rifampin, the duration of bacteremia was longer with combination therapy group than in the vancomycin monotherapy group (nine versus seven days). The use of rifampin combination therapy in a study of native valve S. aureus IE did not improve outcomes but was associated with hepatic adverse effects, drug interactions, and emergence of resistance．
DAP と beta-lactam
The combination of daptomycin with beta-lactam antibiotics was shown to be successful for the treatment of patients with persistent MRSA bacteremia in one case series. These patients' isolates also demonstrated reduced susceptibility to daptomycin. The authors demonstrate enhanced daptomycin bactericidal activity and ceftaroline activity in vitro.
Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococc... - PubMed - NCBI
Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococc... - PubMed - NCBI