Abstract
BACKGROUND: Antimicrobial-resistant pathogens such as Pseudomonas aeruginosa (P. aeruginosa) represent a significant challenge to patients with respiratory diseases including Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), where treatment of such infections is exacerbated by a shortage of new and effective antibiotic classes. One novel approach utilises 'antibiotic enhancers' that potentiate the antimicrobial activity of existing antibiotics. HT61, a small quinolone-derived compound, potentiates the activity of the aminoglycosides tobramycin and gentamicin against Staphylococcus aureus and P. aeruginosa. In this study, we have investigated synergism between tobramycin and HT61 using a panel of tobramycin-sensitive and -resistant clinical isolates of P. aeruginosa from CF patients. METHODS: Microdilution methods and chequerboard analysis were used to evaluate antimicrobial synergy of drug combinations against 63 isolates. Bacterial time-kill assays and biofilm eradication assays were then used to further characterise antimicrobial synergy against 13 selected isolates. RESULTS: 74% of isolates (47/63) demonstrated evidence of either positive interactions (29/63) determined by a Fractional Inhibitory Concentration Index (FICI) ≤ 1.0, or synergy (18/63) determined by an FICI value of ≤ 0.5. Using a sub-selection of these isolates, clear augmentation of tobramycin's antimicrobial activity was observed in both time-kill assays and biofilm eradication assays regardless of FICI classification with significant reductions observed in combination therapies vs monotherapies. CONCLUSIONS: The expansion of previous studies highlighting the potentiating capabilities of HT61 on/with antibiotics in vivo across a further 63 clinical isolates of P. aeruginosa in a laboratory setting further highlights the potential therapeutic benefits of HT61-tobramycin combinations in respiratory diseases associated with drug-resistant P. aeruginosa.