ArticleAntimicrobial agents and chemotherapy2014
Pseudomonas aeruginosa ceftolozane-tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 127 papers, 1 of them a synthesis that pooled it.
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127 citing papers in PubMed, 1 synthesis or guideline pooled it, 239 citations in OpenAlex.
- What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram-Negative Bacteria? A Systematic Review.Clinical pharmacokinetics · 2019Pooled it
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- L2 β-lactamase contributes to ceftolozane-tazobactam resistance inAntimicrobial agents and chemotherapy · 2026Article
- Variable phage susceptibility ofbioRxiv : the preprint server for biology · 2026Article
- Addressing therapeutic options for KPC-3-producing ST307-Antimicrobial agents and chemotherapy · 2026Article
- A novel mechanism of ceftolozane-tazobactam resistance inbioRxiv : the preprint server for biology · 2026Article
- Identification of a novel natural compound inhibitor targeting AmpC β-lactamase to combat multidrug-resistantFrontiers in microbiology · 2026Article
- Deciphering the emergence of mutations in Pseudomonas aeruginosa after ceftolozane/tazobactam treatment and evaluating therapeutic alternatives.BMC microbiology · 2025Article
- Activity of cefiderocol againstMicrobiology spectrum · 2025Article
- Functional and structural analyses of amino acid sequence variation in PDC β-lactamase reveal different mechanistic pathways toward cefiderocol resistance inAntimicrobial agents and chemotherapy · 2025Article
- Resistance to oxyimino-cephalosporins conferred by an alternative mechanism of hydrolysis by themBio · 2025Article
- Diagnostic algorithm for the detection of carbapenemases and extended-spectrum β-lactamases in carbapenem-resistantMicrobiology spectrum · 2025Article
- Beta-Lactam Antibiotic Concentrations and the Acquisition of Multi-Drug Resistant Bacteria in Critically Ill Patients.Life (Basel, Switzerland) · 2025Article
- Mutational Analysis of Colistin-ResistantPathogens (Basel, Switzerland) · 2025Article
- Newly developed antibiotics against multidrug-resistant and carbapenem-resistant Gram-negative bacteria: action and resistance mechanisms.Archives of microbiology · 2025Review
- Mutant prevention concentrations and phenotypic and genomic profiling of first-step resistance mechanisms to classical and novel β-lactams inAntimicrobial agents and chemotherapy · 2025Article
- In-vitro activity of the novel β-lactam/β-lactamase inhibitor combinations and cefiderocol against carbapenem-resistant Pseudomonas spp. clinical isolates collected in Switzerland in 2022.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Article
- Ceftolozane/tazobactam disrupts Pseudomonas aeruginosa biofilms under static and dynamic conditions.The Journal of antimicrobial chemotherapy · 2025Article
- Mutational signature analysis predicts bacterial hypermutation and multidrug resistance.Nature communications · 2025Article
- Revitalizing cephalosporins: The promise of β-lactamase inhibitor combinations.GMS hygiene and infection control · 2025Article
67 more citing papers are in PubMed but not listed here.
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8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We compared the dynamics and mechanisms of resistance development to ceftazidime, meropenem, ciprofloxacin, and ceftolozane-tazobactam in wild-type (PAO1) and mutator (PAOMS, ΔmutS) P. aeruginosa. The strains were incubated for 24 h with 0.5 to 64× MICs of each antibiotic in triplicate experiments. The tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64× MIC for 7 consecutive days. The susceptibility profiles and resistance mechanisms were assessed in two isolated colonies from each step, antibiotic, and strain. Ceftolozane-tazobactam-resistant mutants were further characterized by whole-genome analysis through RNA sequencing (RNA-seq). The development of high-level resistance was fastest for ceftazidime, followed by meropenem and ciprofloxacin. None of the mutants selected with these antibiotics showed cross-resistance to ceftolozane-tazobactam. On the other hand, ceftolozane-tazobactam resistance development was much slower, and high-level resistance was observed for the mutator strain only. PAO1 derivatives that were moderately resistant (MICs, 4 to 8 μg/ml) to ceftolozane-tazobactam showed only 2 to 4 mutations, which determined global pleiotropic effects associated with a severe fitness cost. High-level-resistant (MICs, 32 to 128 μg/ml) PAOMS derivatives showed 45 to 53 mutations. Major changes in the global gene expression profiles were detected in all mutants, but only PAOMS mutants showed ampC overexpression, which was caused by dacB or ampR mutations. Moreover, all PAOMS mutants contained 1 to 4 mutations in the conserved residues of AmpC (F147L, Q157R, G183D, E247K, or V356I). Complementation studies revealed that these mutations greatly increased ceftolozane-tazobactam and ceftazidime MICs but reduced those of piperacillin-tazobactam and imipenem, compared to those in wild-type ampC. Therefore, the development of high-level resistance to ceftolozane-tazobactam appears to occur efficiently only in a P. aeruginosa mutator background, in which multiple mutations lead to overexpression and structural modifications of AmpC.
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