Activity of a New Cephalosporin, CXA-101 (FR264205), against β-Lactam-Resistant Pseudomonas aeruginosa Mutants Selected In Vitro and after Antipseudomonal Treatment of Intensive Care Unit Patients
Open Access
- 1 March 2010
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 54 (3), 1213-1217
- https://doi.org/10.1128/aac.01104-09
Abstract
CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. We evaluated the activity of CXA-101 against a highly challenging collection of β-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit (ICU) patients. The in vitro mutants investigated included strains with multiple combinations of mutations leading to several degrees of AmpC overexpression ( ampD , ampDh2 , ampDh3 , and dacB [PBP4]) and porin loss ( oprD ). CXA-101 remained active against even the AmpD-PBP4 double mutant (MIC = 2 μg/ml), which shows extremely high levels of AmpC expression. Indeed, this mutant showed high-level resistance to all tested β-lactams, except carbapenems, including piperacillin-tazobactam (PTZ), aztreonam (ATM), ceftazidime (CAZ), and cefepime (FEP), a cephalosporin considered to be relatively stable against hydrolysis by AmpC. Moreover, CXA-101 was the only β-lactam tested (including the carbapenems imipenem [IMP] and meropenem [MER]) that remained fully active against the OprD-AmpD and OprD-PBP4 double mutants (MIC = 0.5 μg/ml). Additionally, we tested a collection of 50 sequential isolates that were susceptible or resistant to penicillicins, cephalosporins, carbapenems, or fluoroquinolones that emerged during treatment of ICU patients. All of the mutants resistant to CAZ, FEP, PTZ, IMP, MER, or ciprofloxacin showed relatively low CXA-101 MICs (range, 0.12 to 4 μg/ml; mean, 1 to 2 μg/ml). CXA-101 MICs of pan-β-lactam-resistant strains ranged from 1 to 4 μg/ml (mean, 2.5 μg/ml). As described for the in vitro mutants, CXA-101 retained activity against the natural AmpD-PBP4 double mutants, even when these exhibited additional overexpression of the MexAB-OprM efflux pump. Therefore, clinical trials are needed to evaluate the usefulness of CXA-101 for the treatment of P. aeruginosa nosocomial infections, particularly those caused by multidrug-resistant isolates that emerge during antipseudomonal treatments.Keywords
This publication has 28 references indexed in Scilit:
- Interplay of Efflux System, ampC , and oprD Expression in Carbapenem Resistance of Pseudomonas aeruginosa Clinical IsolatesAntimicrobial Agents and Chemotherapy, 2006
- Involvement of the MexXY-OprM Efflux System in Emergence of Cefepime Resistance in Clinical Strains of Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2006
- Multidrug-Resistant Pseudomonas aeruginosa : Risk Factors and Clinical ImpactAntimicrobial Agents and Chemotherapy, 2006
- Molecular Mechanisms of β-Lactam Resistance Mediated by AmpC Hyperproduction inPseudomonas aeruginosaClinical StrainsAntimicrobial Agents and Chemotherapy, 2005
- Contribution of clonal dissemination and selection of mutants during therapy to Pseudomonas aeruginosa antimicrobial resistance in an intensive care unit settingClinical Microbiology & Infection, 2005
- Carbapenem resistance mechanisms in Pseudomonas aeruginosa: alterations of porin OprD and efflux proteins do not fully explain resistance patterns observed in clinical isolatesAPMIS, 2005
- Molecular Characterization of an Epidemic Clone of Panantibiotic-Resistant Pseudomonas aeruginosaJournal of Clinical Microbiology, 2005
- National Surveillance of Antimicrobial Resistance in Pseudomonas aeruginosa Isolates Obtained from Intensive Care Unit Patients from 1993 to 2002Antimicrobial Agents and Chemotherapy, 2004
- Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection PotentialAntimicrobial Agents and Chemotherapy, 2004
- The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infectionJournal of Internal Medicine, 1998