cefiderocol and Urinary-Tract-Infections

The incidence of carbapenem-resistant gram-negative (CRGNB) bacterial infections has increased globally. The wide diversity of strains, multiplicity of infections, and rapid development and spread of resistance are a matter of great concern both in community and hospital settings. Cefiderocol is a novel injectable siderophore containing cephalosporin with potent microbicidal activity against most carbapenem-resistant Enterobacteriaceae (CRE). It has recently been approved by USFDA for the treatment of complicated urinary tract infections (cUTI) caused by susceptible gram-negative microorganisms. This review focuses on the salient pharmacological profile of the drug and the clinical studies that were undertaken. Cefiderocol is first in class injectable siderophore cephalosporin showing potency against carbapenem- resistant Enterobacteriaceae. It has recently been approved by US FDA for the treatment of adult patients with complicated urinary tract infections (cUTI) caused by susceptible Gram-negative microorganisms, where there are limited or no alternative treatment options.

Topics: Adult; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Cefiderocol; Cephalosporins; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Siderophores; Urinary Tract Infections

Cefiderocol is a siderophore cephalosporin recently approved by the United States Food and Drug Administration for the treatment of hospital- and ventilator-acquired bacterial pneumonia and complicated urinary tract infections. However, there is potential for cefiderocol utility for a variety of other infections. The purpose of this systematic review was to identify literature examining the safety and efficacy of cefiderocol for off-label indications.. The PRISMA guidelines were utilized for reporting. Databases searched included PubMed, Scopus, and Embase, from inception to September 2021. Manuscripts describing cefiderocol off-label use in clinical settings were included. Exclusion criteria were studies focused on labeled indications, animal studies, pharmacodynamic/pharmacokinetic studies, in vitro or laboratory studies, and manuscripts in languages other than English or Arabic. Each stage of review utilized two independent investigators, with conflicts resolved and critical appraisal performed. Data regarding presentation, clinical course, and infection characteristics were extracted and descriptively analyzed.. The search identified a total of 985 records, narrowed to a final set of 27 studies. Among studies included were 18 (66.7%) case reports, 8 (29.6%) case series, and 1 (3.7%) phase 3 clinical trial. Cefiderocol was most frequently used off-label for bacteremia/sepsis with or without an identified source in 51 (67.1%) out of a total of 76 included patients. Among case series/reports with available data, 43 of 53 patients (81.1%) received combination antibiotic therapy. The most common pathogens identified included multi/extensively drug-resistant Pseudomonas aeruginosa and/or Acinetobacter baumannii. Various clinical end points were reported, while microbiological end points were reported in 18 (66.7%) studies. Cefiderocol-related side effects were uncommon and rarely use-limiting.. This systematic review depicts relative clinical effectiveness of off-label cefiderocol, most commonly for P. aeruginosa and A. baumannii infections as combination antibiotic therapy. Further study is needed to elucidate the safety and efficacy of cefiderocol across an expanded set of patients and indications.

Topics: Animals; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Off-Label Use; Pseudomonas aeruginosa; Urinary Tract Infections

Infections by antibiotic-resistant microorganisms could be considered a "stealth pandemic" that we fight daily in most hospitals. Some estimates suggest that today 700,000 deaths per year can be attributed to antimicrobial resistance. By the year 2050, it is estimated that this will increase to ten million deaths per year as a result of infections by multidrug-resistant microorganisms. In this context, the availability of antimicrobial therapy that is effective against these pathogens is essential to be able to "save the lives" of our patients. Cefiderocol, a new cephalosporin with a different mechanism of action, will be an essential treatment in many infections caused by resistant aerobic gram-negative bacteria. Cefiderocol has been used to treat patients with complicated urinary tract infections (cUTI); hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HAP); in patients with sepsis and bacteremia, some without an identified primary focus of infection.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Pneumonia, Ventilator-Associated; Urinary Tract Infections

Infections caused by carbapenem-resistant (CR) Enterobacterales and nonfermenters (such as Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia) are a major global health threat. Cefiderocol, a cephalosporin with activity against CR Enterobacterales and nonfermenters, uses the bacteria’s own iron uptake system to gain cell entry, like a Trojan horse. Once inside, the drug disrupts the formation of the bacterial cell wall, killing the bacteria. Cefiderocol is approved for the treatment of serious Gram-negative bacterial infections. In clinical trials, cefiderocol was effective versus carbapenems or best available therapy for complicated urinary tract infections, nosocomial pneumonia and bloodstream infections/sepsis, including those caused by CR bacteria. The drug had a good tolerability and safety profile. Thus, cefiderocol is a useful addition to the current treatment options for adults with cefiderocol-susceptible Gram-negative bacterial infections for whom there are limited treatment options.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Double-Blind Method; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Randomized Controlled Trials as Topic; Urinary Tract Infections

On November 14, 2019, the U.S. Food and Drug Administration (FDA) approved cefiderocol, a siderophore-cephalosporin conjugate antibiotic, for the treatment of adults with complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options. The approval was based on substantial preclinical and clinical data, including in vitro and in vivo work, as well as pharmacokinetic and pharmacodynamic studies that established cefiderocol as an effective agent for the treatment of cUTI. This paper reviews that work and looks ahead to determine how cefiderocol might be used by clinicians in the future.

Topics: Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Humans; United States; Urinary Tract Infections

This article reviews the available data on the chemistry, spectrum of activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and potential place in therapy of cefiderocol.. A literature search through PubMed, Google Scholar, and ClinicalTrials.gov was conducted (2009 to March 2020) using the search terms. All relevant published articles, package inserts, and unpublished meeting abstracts on cefiderocol were reviewed.. Cefiderocol is the first siderophore antibiotic to be approved by the FDA. It was shown to be active against a wide range of resistant Gram-negative pathogens, including multidrug-resistant (MDR). The approval of cefiderocol provides a new option in the treatment of cUTIs and potentially treatment of nosocomial pneumonia caused by resistant Gram-negative pathogens. Given the higher mortality observed with cefiderocol, its use in the treatment of CR Gram-negative infections should be carefully considered.. Cefiderocol shows promising activity against MDR Gram-negative pathogens. Its use in the treatment of serious infections caused by CR Gram-negative bacteria needs further evaluation in phase III clinical studies.

Topics: Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Molecular Structure; Siderophores; Urinary Tract Infections

Cefiderocol (Fetroja

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Siderophores; Urinary Tract Infections

New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).. Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.. Shionogi.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Carbapenems; Cefiderocol; Cephalosporins; Drug Resistance, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Bacterial; Sepsis; Urinary Tract Infections; Young Adult

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Case-Control Studies; Cefiderocol; Cephalosporins; Creatinine; Drug Administration Schedule; Female; Glomerular Filtration Rate; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Models, Statistical; Pyelonephritis; Renal Insufficiency, Chronic; Severity of Illness Index; Siderophores; Urinary Tract Infections

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections.. Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing.. Shionogi & Co Ltd, Shionogi Inc.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Cilastatin, Imipenem Drug Combination; Colony Count, Microbial; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Protease Inhibitors; Treatment Outcome; Urinary Tract Infections; Urine; Young Adult

Topics: Anti-Bacterial Agents; Bacteremia; Cefiderocol; Cephalosporins; Humans; Microbial Sensitivity Tests; Pneumonia; Sepsis; Siderophores; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Humans; Siderophores; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Humans; Siderophores; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Humans; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Administration Schedule; Drug Approval; Humans; Pyelonephritis; United States; United States Food and Drug Administration; Urinary Tract Infections

In 2019, the U.S. Food and Drug Administration approved cefiderocol, a new treatment option for individuals with complicated urinary tract infections. Cefiderocol is a cephalosporin antibiotic indicated for use in adults 18 years or older who have minimal treatment options due to resistance for complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. The recommended dose of cefiderocol is 2 g intravenously every 8 hours infused over 3 hours. The dose is adjusted for individuals with creatinine clearance of less than 60 ml/min or greater than 120 ml/min. Gastrointestinal symptoms such as diarrhea and constipation are the most common adverse events reported by individuals taking cefiderocol.

Topics: Administration, Intravenous; Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Humans; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Humans; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Humans; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Humans; Urinary Tract Infections

Topics: Cefiderocol; Cephalosporins; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Humans; Urinary Tract Infections