cefiderocol and Critical-Illness

Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator.. A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance.. At 0 h, the difference between the pre- and post-oxygenator concentrations was - 4 ± 4% (range 0 to - 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p = 1.0).. The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.

Topics: Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Critical Illness; Extracorporeal Membrane Oxygenation; Humans

Cefiderocol is a broad-spectrum cephalosporin antibiotic and is indicated in patients with difficult-to-treat Gram-negative bacterial infections. Cefiderocol is applied as a 2-4-times daily prolonged 3-h infusion. The therapeutic target of cefiderocol suggests that continuous infusion (CI) may be advantageous, since it is more likely to achieve 100% of time of the unbound concentration above the minimal inhibitory concentration (MIC). However, limited information on cefiderocol as CI has been assessed. We present a case of a critically ill 37-year-old woman with continuous venovenous haemofiltration (CVVH) treated with a CI of cefiderocol for multidrug-resistant Pseudomonas aeruginosa. She received 4 g per 24 h, in accordance with the recommendations for the total daily dose during CVVH with an effluent flow rate of 2.1-3 L/h. We evaluated intraperitoneal, plasma arterial pre- and postfilter and ultrafiltrate (urine) total cefiderocol concentrations and discussed the pharmacokinetics in respect to the CVVH settings. The predicted unbound plasma concentrations during CI resulted in 6.8-9.5-fold higher concentrations than the adopted MIC of 2 mg/L for cefiderocol against P. aeruginosa. The optimal time of the unbound concentration >MIC target of cefiderocol was met during the sampling period, suggesting adequate exposure during the total treatment period. The obtained intraperitoneal concentration indicated adequate cefiderocol exposure at the site of infection. Continuous infusion of 4 g cefiderocol per 24 h led to sufficient plasma concentrations in our anuric critically ill patient treated with CVVH. This case is supportive to the use of cefiderocol as continuous infusion.

Topics: Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Continuous Renal Replacement Therapy; Critical Illness; Female; Humans

The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population.. The aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations.. The PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate.. The overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h.. The optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.

Topics: Anti-Bacterial Agents; Bayes Theorem; Cefiderocol; Cephalosporins; Clinical Trials, Phase III as Topic; Continuous Renal Replacement Therapy; Critical Illness; Humans; Microbial Sensitivity Tests; Renal Replacement Therapy

Carbapenemase-producing Enterobacterales (CPE) represent a public health concern. The limited antimicrobial options against CPE have led to the development of novel antimicrobial molecules. In the present study, we characterized the genetic determinants associated with the resistance to ceftazidime/avibactam (CAZ-AVI), meropenem/vaborbactam (MER-VAB), imipenem/relebactam (IMI-REL) and cefiderocol (CFD) in a carbapenemase-producing Klebsiella pneumoniae strain isolated from a critically ill patient.. Genomic DNA was sequenced using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Assemblies were performed with a de novo approach using short-read, hybrid and long-lead assembly approaches. Final assembly was manually curated and carefully verified. Circular elements were screened for antimicrobial-resistance genes, porins, virulence factors and prophage regions.. KPC-Kp (KPC-producing Klebsiella pneumoniae) BO743 was resistant to all novel β-lactams including CAZ-AVI, MER-VAB, IMI-REL and CFD. The genome of strain BO743 is composed of a single chromosome of 5 347 606 bp and three circular plasmids of 363 634 bp (pBO743-363Kb), 120 290 bp (pBO743-120Kb) and 54 339 bp (pBO743-54Kb). Sequence analysis demonstrated that KPC-Kp BO743 co-harboured bla. The description of the genome of KPC-Kp cross-resistant to novel βL-βLICs and cefiderocol reveals the presence of numerous antimicrobial resistance genes including bla

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Chromatography, High Pressure Liquid; Critical Illness; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Coinfection; Continuous Renal Replacement Therapy; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia; Stenotrophomonas maltophilia

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Compassionate Use Trials; Critical Illness; Drug Resistance, Multiple, Bacterial; Humans; Influenza, Human; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pneumonia; Treatment Outcome