Hypermutable Pseudomonas aeruginosa are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time-course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and non-hypermutable P. aeruginosa. Static concentration time-kill experiments over 72h assessed meropenem and ciprofloxacin in mono- and combination therapy against PAO1 (non-hypermutable), PAOmutS (hypermutable), and hypermutable isolates CW08, CW35 and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2g q8h as 3h infusion and 3g/day as continuous infusion) and ciprofloxacin (400mg q8h as 1h infusion) in monotherapies and combinations were further evaluated in an 8-day hollow fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48h. The maximum daily doses of 6g meropenem (T>MIC 80-88%) and 1.2g ciprofloxacin (AUC/MIC 176), both given intermittently, in monotherapy failed to supress regrowth and resulted in substantial emergence of resistance (≥7.6log10 CFU/mL resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.