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Biofilm growth, mucoid phenotype and proficient resistance development by hypermutable strains dramatically limit the efficacy of current therapies for Pseudomonas aeruginosa chronic respiratory infection (CRI) in cystic fibrosis (CF) patients. We evaluated the activity of the new cephalosporin CXA-101, ceftazidime, meropenem and ciprofloxacin against biofilms of wild-type PAO1 and its mucoid (mucA), hypermutable (mutS) and mucoid-hypermutable derivatives, and analysed the capacity of these strains to develop resistance during planktonic and biofilm growth.MICs and MBCs were determined by microdilution, and mutant frequencies were determined at 4× and 16× the MICs. Biofilms were formed using a modified Calgary device and were incubated for 24 h with 0×, 1×, 4× or 16× the MIC of each antibiotic. Biofilms were plated, and total cells and resistant mutants enumerated.CXA-101 showed concentration-independent biofilm bactericidal activity, being the most potent agent tested at 1× the MIC for wild-type, mucoid and hypermutable strains. The spontaneous mutant frequencies for CXA-101 were extremely low (<5 × 10−11), even for the hypermutable strain at low concentrations (4× the MIC), in sharp contrast to the other antipseudomonal agents. Accordingly, mutants resistant to 4× the MIC of CXA-101 did not emerge in biofilms for any of the strains/concentrations tested.These data strongly suggest that resistance to CXA-101 (at least 4× the MIC) cannot be driven by single-step mutations, either in planktonic or in biofilm growth. CXA-101 shows encouraging properties for the treatment of CRI by P. aeruginosa, which need to be further evaluated in animal models and pertinent clinical trials.