Tobramycin and bicarbonate synergise to kill planktonic Pseudomonas aeruginosa, but antagonise to promote biofilm survival

AbstractIncreasing antibiotic resistance and the declining rate at which new antibiotics come into use create a need to increase the efficacy of existing antibiotics. The aminoglycoside tobramycin is standard-of-care for many types of Pseudomonas aeruginosa infections, including those in the lungs of cystic fibrosis (CF) patients. P. aeruginosa is a nosocomial and opportunistic pathogen that, in planktonic form, causes acute infections and, in biofilm form, causes chronic infections. Inhaled bicarbonate has recently been proposed as a therapy to improve antimicrobial properties of the CF airway surface liquid and viscosity of CF mucus. Here we measure the effect of combining tobramycin and bicarbonate against P. aeruginosa, both lab strains and CF clinical isolates. Bicarbonate synergises with tobramycin to enhance killing of planktonic bacteria. In contrast, bicarbonate antagonises with tobramycin to promote better biofilm growth. This suggests caution when evaluating bicarbonate as a therapy for CF lungs infected with P. aeruginosa biofilms. We analyse tobramycin and bicarbonate interactions using an interpolated surface methodology to measure the dose–response function. These surfaces allow more accurate estimation of combinations yielding synergy and antagonism than do standard isobolograms. By incorporating predictions based on Loewe additivity theory, we can consolidate information on a wide range of combinations that produce a complex dose–response surface, into a single number that measures the net effect. This tool thus allows rapid initial estimation of the potential benefit or harm of a therapeutic combination. Software code is freely made available as a resource for the community.