Synergy with Cell Wall Synthesis Inhibitors is Not Always Observed In the Clinical Setting

Under the right conditions, inhibitors of cell wall synthesis can increase the permeability of aminoglycosides through the peptidoglycan layer of the cell wall, resulting in increased cellular uptake of aminoglycosides, and synergistic killing of sensitive bacteria. However, such synergy has been found to be dependent upon drug concentration (it occurs with concentrations of cell wall synthesis inhibitors above their MIC, combined with aminoglycosides given below their MIC), and has also been found to be dependent on the bacterial strain, as well as the particular drugs used (Taber et al, 1987; Tamma et al, 2012; Hirzel et al, 2016). This variability may explain why evidence for synergy has not been consistently observed in different clinical settings. A systematic review of randomized clinical trials has not shown an advantage to adding an aminoglycoside to a beta lactam antibiotic for treatment of most clinical infections (Marcus et al, 2011), especially when newer broad-spectrum antipseudomonal beta-lactam antibiotics are used (Tamma et al, 2012). In what appears to be an exception to this rule, gentamicin is recommended for combination therapy with cell wall synthesis inhibitors for the treatment of infective endocarditis , based upon the available evidence that such drug combinations are synergistic in this clinical setting (Baddour et al, 2015; Sexton, 2016).