Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

Antibiotics, Journal Year: 2023, Volume and Issue: 12(12), P. 1729 - 1729

Published: Dec. 14, 2023

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, novel siderophore cephalosporin, and sulbactam-durlobactam, bactericidal β-lactam-β-lactamase inhibitor combination, have been approved the Food Drug Administration for of A. infections. In this review, we discuss mechanisms action resistance cefiderocol antimicrobial susceptibility isolates these drugs, as well effectiveness sulbactam/durlobactam-based regimens against CRAB. Overall, sulbactam-durlobactam show an excellent activity The review studies evaluating efficacy therapy CRAB indicates it is non-inferior colistin/other treatments infections, with better safety profile. Combination not associated improved outcomes compared monotherapy. Higher mortality rates are often prior patient comorbidities severity underlying infection. Regarding current data from pivotal trial case reports suggest antibiotic combination could be valuable option in critically ill patients affected particular where no other appears effective.

Language: Английский

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Adaptive resistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii (CRAB): microbiological and clinical issues

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e30365 - e30365

Published: April 26, 2024

Language: Английский

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Highly Effective Biocides against Pseudomonas aeruginosa Reveal New Mechanistic Insights Across Gram-Negative Bacteria

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(11), P. 3868 - 3879

Published: Oct. 23, 2024

Pseudomonas aeruginosa is a major nosocomial pathogen that persists in healthcare settings despite rigorous disinfection protocols due to intrinsic mechanisms conferring resistance. We sought systematically assess cationic biocide efficacy against this using panel of multidrug-resistant P. clinical isolates. Our studies revealed widespread resistance commercial disinfectants are the current standard care, raising concerns about their efficacy. To address shortcoming, we highlight new class quaternary phosphonium compounds highly effective all members panel. understand difference efficacy, mechanism action were carried out, which identified discrete inner-membrane selective target. Resistance selection implicated SmvRA efflux system (a transcriptionally regulated, inner membrane-associated system) as determinant This also two bolaamphiphile antiseptics, octenidine and chlorhexidine, was further validated herein. In sum, work highlights, for first time, specific contrasts with prevailing model indiscriminate membrane interactions amphiphiles paving way future innovations disinfectant research.

Language: Английский

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Risk of Underexposure and Lack of Efficacy of Cefiderocol by Reduced Dosing in Japanese Patients With Gram-Negative Bacterial Infections

Therapeutic Drug Monitoring, Journal Year: 2025, Volume and Issue: unknown

Published: May 2, 2025

Background: Recently, a cost-saving, dose-reducing strategy for cefiderocol against gram-negative bacteria with low minimum inhibitory concentrations (MICs) was proposed as an alternative to the standard dosing (ie, 2 g every 8 hours, 3-hours infusion). The objectives of this article are summarize available evidence on efficacy, safety, pharmacokinetics (PK), and pharmacodynamics support rationale approved assess any risk underexposure reduced doses 1 hours or 12 hours) regarding higher MICs. Methods: Published data from phase 1–3 clinical, preclinical effectiveness, surveillance studies were reviewed, new population PK simulations conducted. Results: Most carbapenem-resistant isolates displayed MICs up 4 mg/L. Single multiple cefiderocol, g, tested in clinical studies, which confirmed linear profile, metabolism, renal clearance, penetration into lungs soft tissues. Phase 2–3 randomized controlled have demonstrated efficacy safety at renally adjusted versus comparators patients complicated urinary tract infections, nosocomial pneumonia, bloodstream infection/sepsis caused by various carbapenem-susceptible -resistant pathogens. Population models incorporating predicted that regimen contrast doses, would achieve high probability target attainment isolates, 2–4 mg/L across infection types patient populations. Conclusions: Administering low-dose reduce treatment-related costs will lead treatment failure prolonged hospitalization incur further expenses. Therefore, is strongly recommended.

Language: Английский

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Siderophore cephalosporins

EcoSal Plus, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

ABSTRACT Siderophore cephalosporins are designed to exploit bacterial nutrient uptake systems gain accelerated across the outer membrane of Gram-negative bacteria. They contain iron (III) binding motifs that allow them form complexes will be recognized as potential substrates by iron-siderophore transport systems. Research during last five decades has culminated in approval for clinical use siderophore cephalosporin cefiderocol, which incorporates accumulated learning from investigations structural features enhance resistance toward hydrolysis β-lactamases, promote permeability, and confer long pharmacokinetic half-life human host.

Language: Английский

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From Clinical Trials to Real-World Experiences: Evidence About Cefiderocol Use and Potential Role in Empirical Therapy

Infectious Diseases and Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Cefiderocol is a novel siderophore cephalosporin that has gained attention for its potent activity against multidrug-resistant (MDR) Gram-negative pathogens, making it valuable addition to the antimicrobial armamentarium. Its efficacy in treating complicated urinary tract infections (cUTIs) and nosocomial pneumonia been well-established, although challenges remain regarding role Acinetobacter baumannii possible emergence of resistance. The decision use cefiderocol as monotherapy or combination should be guided by pathogen susceptibility, clinical severity, local epidemiology. Then, potential serve an effective empirical therapy, careful stewardship, further research are essential maximize therapeutic benefits ensure long-term efficacy. This review explores cefiderocol, resistance development, heteroresistance, treatment regimens. We discuss data about trials real-world evidence assess future antibiotic

Language: Английский

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The Multifaceted Landscape of Healthcare-Associated Infections Caused by Carbapenem-Resistant Acinetobacter baumannii

Microorganisms, Journal Year: 2025, Volume and Issue: 13(4), P. 829 - 829

Published: April 5, 2025

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an emerging and important major cause of nosocomial infections, posing a significant challenge to clinicians worldwide. The intrinsic acquired resistance mechanisms exhibited by CRAB, associated with its ability persist in healthcare environments, have transformed it into critical public health concern. clinical implications CRAB infections include severe manifestations, like ventilator-associated pneumonia bloodstream infections. These are often increased morbidity mortality, particularly critically ill patients, such as those intensive care units, immunocompromised, undergoing invasive procedures. Considering these characteristics, the therapeutic armamentarium for treatment increasingly limited, strains exhibit broad range antibiotics, including carbapenems new β-lactam inhibitors, which considered last-line agents many bacterial An role represented cefiderocol data from real-world evidence. aim this narrative review discuss main topics infection strategies prevention, management, therapy.

Language: Английский

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Carbapenem-resistant Gram-negative bacteria exhibiting clinically undetected cefiderocol heteroresistance leads to treatment failure in a murine model of infection

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: May 9, 2025

Introduction Carbapenem-resistant (CR) Gram-negative pathogens are classified by the WHO as critical threats due to limited therapeutic options. Cefiderocol (CFD), a novel siderophore cephalosporin, shows promise but remains unapproved in China. This study investigated prevalence, clinical impact, and genetic mechanisms of cefiderocol heteroresistance (CFD-HR) CR ESBL-producing isolates from China, where CFD unapproved. Methods A total 407 were analyzed. CFD-HR was identified population analysis profiles (PAPs). Clinical relevance assessed through disk diffusion susceptibility testing, time-kill assays, murine peritonitis model. Genetic stability elucidated whole-genome sequencing (WGS) fitness cost assays. Results prevalence 17.4% (16/92) carbapenem-resistant A. baumannii (CRAB), 27.9% (24/86) P. aeruginosa (CRPA), 23.8% (10/42) E. coli (CRE), ≤10% (1/10 8/177 ). Although 72.9% (43/59) HR CFD-susceptible diffusion, assays showed that 66.7% (4/6) strains required ≥8 mg/L (vs. 4 for non-HR) prevent regrowth. In vivo , achieved 100% (3/3) survival non-HR infections only 16.7% HR-infected mice. WGS transient alterations subpopulations, including sitABCD duplications oprD mutations vgrG SNPs which reverted after antibiotic withdrawal. Fitness revealed unstable growth deficits 33.3% (2/6) correlating with instability. Discussion These findings highlight significance CFD-HR, even susceptible isolates, underscore need improved diagnostic methods detect monitor cross-resistance, offering insights regions transitioning implementation.

Language: Английский

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Rates of resistance and heteroresistance to newer β-lactam/β-lactamase inhibitors for carbapenem-resistant Enterobacterales

JAC-Antimicrobial Resistance, Journal Year: 2024, Volume and Issue: 6(2)

Published: March 5, 2024

Abstract Background Heteroresistance (HR), the presence of antibiotic-resistant subpopulations within a primary isogenic population, may be potentially overlooked contributor to newer β-lactam/β-lactamase inhibitor (BL/BLI) treatment failure in carbapenem-resistant Enterobacterales (CRE) infections. Objectives To determine rates susceptibility and HR BL/BLIs ceftazidime/avibactam, imipenem/relebactam meropenem/vaborbactam clinical CRE isolates. Methods The first isolate per patient year from two >500 bed academic hospitals 1 January 2016 31 December 2021, were included. Reference broth microdilution (BMD) was used antibiotic susceptibility, population analysis profiling (PAP) HR. Carbapenemase production (CP) determined using Carba NP assay. Results Among 327 isolates, 46% Enterobacter cloacae, 38% Klebsiella pneumoniae 16% Escherichia coli. By BMD, 87% 98% susceptible three antibiotics tested. From there incremental decreases each BL/BLIs. detected species–antibiotic combination, with highest (26%) found K. isolates imipenem/relebactam. or resistance at least one BL/BLI by PAP 24% 65% these had detectable CP. Conclusion Twenty-four percent tested either resistant heteroresistant (HR) BL/BLIs, an overall decrease ∼10% over 6 years. While remain active against most CRE, findings support need for ongoing stewardship better understanding implications CRE.

Language: Английский

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Frequency of cefiderocol heteroresistance among patients treated with cefiderocol for carbapenem-resistant Acinetobacter baumannii infections

JAC-Antimicrobial Resistance, Journal Year: 2024, Volume and Issue: 6(5)

Published: Sept. 3, 2024

Abstract Background Cefiderocol exhibits potent in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAb), but this has not consistently translated to improved outcomes among patients. heteroresistance, or the presence of a resistant subpopulation, been proposed as one possible explanation. The objective study was explore associations between heteroresistance and patients with CRAb infections. Methods Baseline isolates were collected from 27 consecutive USA Italy. susceptibility tested by broth microdilutions triplicate. Heteroresistance defined population analysis profiling duplicate. Resistance mechanisms strain relatedness evaluated through comparative genomic analysis. Results Overall, 59% infecting identified cefiderocol-heteroresistant; rates higher Italy (79%) than (38%). median Charlson Comorbidity SOFA scores 4 5, respectively; 44% had pneumonia, which most common infection type. Rates 28-day clinical success survival 30% 73%, respectively. By microdilution, cefiderocol MICs ≥1 mg/L associated failure ≤0.5 (81% versus 55%). numerically infected cefiderocol-heteroresistant compared susceptible Whole-genome sequencing premature stop codon TonB-dependent receptor gene piuA six isolates, all heteroresistant. Conclusions This pilot supports hypothesis that treatment may be and/or heteroresistance. Further studies are needed confirm these findings.

Language: Английский

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