Background: Biofilm-associated Pseudomonas aeruginosa infections in cystic fibrosis have limited treatment options. Ceftolozane/tazobactam is a relatively recently available β-lactam/β-lactamase inhibitor combination that has been shown to have preserved activity against difficult-to-treat P. aeruginosa isolates. However, the effectiveness of ceftolozane/tazobactam (C/T), in monotherapy and combination with tobramycin (TOB), has not yet been characterised for the pharmacokinetics of paediatric patients in a dynamic biofilm model.
Methods: Two hypermutable paediatric cystic fibrosis isolates were investigated in 168h dynamic biofilm studies. The dynamic biofilm model simulated representative C/T and tobramycin pharmacokinetics in lung fluid of paediatric patients with cystic fibrosis based on population pharmacokinetic models and lung fluid penetration. Regimens were: C/T 4.5g/day as continuous IV infusion; TOB 10mg/kg 24-hourly as 0.5h intravenous infusions; TOB 300mg 12-hourly inhaled; C/T + intravenous TOB; C/T + inhaled TOB. Total and resistant counts of planktonic and biofilm bacteria were determined. C/T and TOB exposures were confirmed by LC-MS/MS. Bacterial viable counts were mathematically modelled.
Results: Monotherapies of C/T and TOB resulted in amplification of resistance emergence compared to the growth control, although inhaled TOB was more effective than intravenous TOB. Against both isolates, the combination regimens demonstrated synergy and completely suppressed the emergence of C/T and TOB resistant planktonic and biofilm bacterial subpopulations. Mechanism-based modelling incorporating subpopulation and mechanistic synergy well described the antibacterial effects of the combination regimens against both the planktonic and biofilm bacteria. Parameter estimates from the mathematical model suggested longer mean generation times in the biofilm compared to the planktonic state of growth, and a lower maximum killing rate constant of tobramycin against biofilm compared to planktonic bacteria, for both isolates.
Conclusions: Clinically relevant regimens using C/T in combination with intravenous or inhaled TOB were synergistic against hypermutable P. aeruginosa CF isolates from paediatric patients with cystic fibrosis and warrant further investigation.