cefiderocol and Pseudomonas-Infections

This article reviews the mechanisms of. Cefiderocol is active against most known

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; Carbapenems; Cefiderocol; Cephalosporins; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa is one of the most feared nosocomial pathogens. Treatment of P. aeruginosa infections is challenging because of the limited choices of antibiotics and the emergent resistance of the pathogen. The present review aims at addressing the management of P. aeruginosa infections and highlighting the novel antibiotics that show a future promising role.. Novel fluoroquinolones have been recently introduced and show favorable activity. New combinations of β-lactams/β-lactamase inhibitors have been studied in various indications of infections because of P. aeruginosa. Cefiderocol, a new cephalosporin, shows very promising results against P. aeruginosa. Currently, combination therapy is only recommended in limited scenarios. Extended-infusion of β-lactams exhibit clinical benefit. Bacteriophage therapy is a growing field of interest and may have an impactful effect on the treatment of resistant P. aeruginosa.. Factors that guide clinical decisions for empiric and directed P. aeruginosa therapy include the epidemiology, the patient's risk factors, the site of infection, and the available treatment options. Conventional antipseudomonal antibiotics have been used successfully for a long time, but the increase in worldwide resistance necessitates the need for newer agents. Antimicrobial stewardship is essential to preserve the new drugs and prevent future development of resistance.

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; beta-Lactamase Inhibitors; beta-Lactams; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Phage Therapy; Pseudomonas aeruginosa; Pseudomonas Infections

We report in vivo development of cefiderocol (FDC) resistance among four sequential Pseudomonas aeruginosa clinical isolates ST244 recovered from a single patient, without exposure to FDC, which raises concern about the effectiveness of this novel drug. The first recovered P. aeruginosa isolate (P-01) was susceptible to FDC (2 μg/mL), albeit this MIC value was higher than that of a wild-type P. aeruginosa (0.12-0.25 μg/ml). The subsequent isolated strains (P-02, P-03, P-04) displayed increasing levels of FDC MICs (8, 16, and 64 μg/ml, respectively). Those isolates also showed variable and gradual increasing levels of resistance to most β-lactams tested in this study. Surprisingly, no acquired β-lactamase was identified in any of those isolates. Whole-genome sequence analysis suggested that this resistance was driven by multifactorial mechanisms including mutational changes in iron transporter proteins associated with FDC uptake, ampC gene overproduction, and mexAB-oprM overexpression. These findings highlight that a susceptibility testing to FDC must be performed prior to any prescription.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefiderocol; Cephalosporins; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

The emergence and spread of antimicrobial resistance (AMR) in Gram-negative pathogens, such as carbapenem-resistant Pseudomonas aeruginosa, pose an increasing threat to health care. Patients with immunodeficiencies or chronic pulmonary disease, like cystic fibrosis (CF), are particularly vulnerable to Pseudomonas infections and depend heavily on antibiotic therapy. To broaden limited treatment options, this study evaluated the potency of the recently licensed drugs ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), and cefiderocol (FDC) as well as two novel preclinical antibiotics, darobactins B (DAR B) and B9 (DAR B9), against clinical P. aeruginosa isolates derived from respiratory samples of CF patients. We observed high levels of resistance to all three newly licensed drugs, with cefiderocol exhibiting the best activity. From the 66 investigated P. aeruginosa isolates, a total of 53% were resistant to CZA, 49% to C/T, and 30% to FDC. Strikingly, 52 of the evaluated isolates were obtained from CF patients prior to market introduction of the drugs. Thus, our results suggest that resistance to CZA, C/T, and FDC may be due to preexisting resistance mechanisms. On the other hand, our two novel preclinical compounds performed better than (CZA and C/T) or close to (FDC) the licensed drugs-most likely due to the novel mode of action. Thus, our results highlight the necessity of global consistency in the area of antibiotic stewardship to prevent AMR from further impairing the potency of antibiotics in clinical practice. Ultimately, this study demonstrates the urgency to support the development of novel antimicrobials, preferably with a new mode of action such as darobactins B and B9, two very promising antimicrobial compounds for the treatment of critically ill patients suffering from multidrug-resistant Gram-negative (MRGN) infections.

Topics: Adolescent; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefiderocol; Defibrillators, Implantable; Endocarditis; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Eleven

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; Cefiderocol; Humans; Lactams; Pseudomonas aeruginosa; Pseudomonas Infections

To analyse the dynamics and mechanisms of stepwise resistance development to cefiderocol in Pseudomonas aeruginosa.. Cefiderocol resistance evolution was analysed in WT PAO1, PAOMS (mutS mutator derivate) and three XDR clinical isolates belonging to ST111, ST175 and ST235 clones. Strains were incubated in triplicate experiments for 24 h in iron-depleted CAMHB with 0.06-128 mg/L cefiderocol. Tubes from the highest antibiotic concentration showing growth were reinoculated into fresh medium containing concentrations up to 128 mg/L for 7 consecutive days. Two colonies per strain and experiment were characterized by determining the susceptibility profiles and WGS.. Evolution of resistance was significantly enhanced in PAOMS, but was variable for the XDR strains, including levels similar to PAOMS (ST235), similar to PAO1 (ST175) or even below PAO1 (ST111). WGS revealed 2-5 mutations for PAO1 lineages and 35-58 for PAOMS. The number of mutations in the XDR clinical strains ranged from 2 to 4 except for one of the ST235 experiments in which a mutL lineage was selected, thus increasing the number of mutations. The most frequently mutated genes were piuC, fptA and pirR, related to iron uptake. Additionally, an L320P AmpC mutation was selected in multiple lineages and cloning confirmed its major impact on cefiderocol (but not ceftolozane/tazobactam or ceftazidime/avibactam) resistance. Mutations in CpxS and PBP3 were also documented.. This work deciphers the potential resistance mechanisms that may emerge upon the introduction of cefiderocol into clinical practice, and highlights that the risk of resistance development might be strain-specific even for XDR high-risk clones.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Cefiderocol has an excellent in vitro activity on clinical strains of Pseudomonas aeruginosa (P. aeruginosa). However, the resistance of some isolates has been associated with the production of some β-lactamases. Whether some acquired extended-spectrum oxacillinases (ES-OXA) common in this species may compromise the susceptibility of P. aeruginosa to cefiderocol has not been evaluated so far.. Eighteen genes encoding OXA belonging to the major subgroups identified in P. aeruginosa OXA-1 (n = 3); - 2 (n = 5); - 10 (n = 8), and - 46 (n = 2) were cloned into pUCP24 shuttle vector and transferred into reference strain PAO1.. Although production of the OXA-1 subgroup enzymes did not alter cefiderocol MICs, the β-lactamases of OXA-2, OXA-46, and four variants of the OXA-10 subgroup resulted in an 8-fold to 32-fold decrease in susceptibility in the PAO1 background. Interestingly, point mutations Ala149Pro and Asp150Gly in OXA-2 subgroup, Trp154Cys and Gly157Asp in OXA-10 subgroup (all located in the Ω loop), and the duplication of a Thr206 and a Gly207 in the β5-β6 loop of OXA-10 subgroup were related to decreased susceptibility to cefiderocol. We also showed that some ES-OXA, including the most frequent ES-OXA in P. aeruginosa strains, OXA-19 (derived from OXA-10 subgroup), significantly compromised activity of cefiderocol in addition to ceftazidime, ceftolozane/tazobactam, and ceftazidime/avibactam in clinical strains.. This work shows that several ES-OXA have a significant effect on cefiderocol susceptibility. Of concern are the Trp154Cys and Gly157Asp mutations that occur in some of these β-lactamases, as they are associated with a decreased activity of the most recent cephalosporins introduced to combat P. aeruginosa infections.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Hematopoietic Stem Cell Transplantation; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Cerebral Ventriculitis; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Cefiderocol was evaluated by broth microdilution versus 1,050 highly antimicrobial-resistant Pseudomonas aeruginosa clinical isolates from the CANWARD study (2007 to 2019). Overall, 98.3% of isolates remained cefiderocol susceptible (MIC, ≤4 μg/mL), including 97.4% of extensively drug-resistant (XDR) (

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants.. The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies.. For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes.. Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Cyclooctanes; Humans; Imipenem; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Cefiderocol; Cephalosporins; COVID-19; Empyema, Pleural; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: beta-Lactamases; Burkitt Lymphoma; Cefiderocol; Cephalosporins; Child, Preschool; Compassionate Use Trials; Humans; Pseudomonas Infections

Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded

Topics: Adolescent; Anti-Bacterial Agents; Azabicyclo Compounds; Bacteremia; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Osteomyelitis; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Siderophores

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections often represent a therapeutic challenge requiring utilization of older, more toxic antibiotics, or new agents with limited data. Once susceptibility to β-lactam and fluoroquinolone antibiotics has been lost, other therapeutic options such as aminoglycoside or polymyxin antibiotics carry significant adverse effects such as nephrotoxicity, neurotoxicity, and ototoxicity. A novel cephalosporin, cefiderocol, lacks gram-positive and anaerobic activity but offers broad coverage of gram-negative bacteria, including P. aeruginosa. A unique catechol side chain gives it activity as a siderophore, thereby increasing bacterial uptake and decreasing efflux. Additionally, cefiderocol is stable against a wide array of β-lactamases. Despite these promising characteristics, there are minimal data currently available in the literature detailing the use of cefiderocol in the treatment of MDR P. aeruginosa infections. We present a case of a 46-year-old man who developed an MDR P. aeruginosa intraabdominal infection where serious and life-threatening toxicities to aminoglycosides and polymyxin antibiotics led to the utilization of cefiderocol on compassionate use approval. The isolate was susceptible to cefiderocol, and the patient was treated for 28 days of therapy. He demonstrated clinical and radiographic resolution of his infection and was discharged to home.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Compassionate Use Trials; Drug Resistance, Multiple, Bacterial; Humans; Intraabdominal Infections; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

Serious infections such as endocarditis due to extremely drug-resistance gram-negative bacteria are an increasing challenge. Here, we present successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an extended-spectrum beta-lactamase-positive Pseudomonas aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options.

Topics: Aged; Anti-Bacterial Agents; Aortic Valve; beta-Lactamases; Cefiderocol; Cephalosporins; Colistin; Compassionate Use Trials; Drug Resistance, Multiple, Bacterial; Endocarditis, Bacterial; Female; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; beta-Lactam Resistance; Cefiderocol; Cephalosporins; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Klebsiella Infections; Klebsiella pneumoniae; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections