cefiderocol and Gram-Negative-Bacterial-Infections

This systematic review aimed to explore the recent trends in the epidemiology, risk factors, and antimicrobial susceptibility of two emerging opportunistic pathogens, Stenotrophomonas maltophilia and Elizabethkingia anophelis .. Since 2020, numerous outbreaks of S. maltophilia and E. anophelis have been reported worldwide. Most of these outbreaks have been associated with healthcare facilities, although one outbreak caused by E. anophelis in France was considered a community-associated infection. In terms of antimicrobial susceptibility, trimethoprim/sulfamethoxazole (TMP-SMZ), levofloxacin, and minocycline have exhibited good efficacy against S. maltophilia . Additionally, cefiderocol and a combination of aztreonam and avibactam have shown promising results in in vitro susceptibility testing. For E. anophelis , there is currently no consensus on the optimal treatment. Although some studies have reported good efficacy with rifampin, TMP-SMZ, piperacillin/tazobactam, and cefoperazone/sulbactam, minocycline had the most favourable in vitro susceptibility rates. Cefiderocol may serve as an alternative due to its low minimum inhibitory concentration (MIC) against E. anophelis . The role of vancomycin in treatment is still uncertain, although several successful cases with vancomycin treatment, even with high MIC values, have been reported.. Immunocompromised patients are particularly vulnerable to infections caused by S. maltophilia and E. anophelis , but the optimal treatment strategy remains inconclusive. Further research is necessary to determine the most effective use of conventional and novel antimicrobial agents in combatting these multidrug-resistant pathogens.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Cefiderocol; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Stenotrophomonas maltophilia; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Cefiderocol is a novel injectable siderophore cephalosporin that hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug-resistant (MDR) organisms such as carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii. It was approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials that demonstrated noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase 3 clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician's armamentarium against MDR gram-negative infections.

Topics: Anti-Bacterial Agents; Carbapenems; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

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 antibiotic and first of its kind approved by the Food and Drug Administration for the treatment of complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older caused by susceptible organisms. Cefiderocol's unique mechanism of iron chelation improves Gram-negative membrane penetration as the bacteria's iron uptake mechanism recognizes the chelated iron antibiotic and iron for entry. This also allows for the evasion of cefiderocol from cell entry-related resistance mechanisms.. This review covers the mechanism of action, resistance mechanisms, pharmacokinetics in various patient populations, and pharmacodynamics. Relevant literature evaluating efficacy and safety are discussed.. Limited treatment options are available for the treatment of carbapenem-resistantorganisms. Clinical trials have demonstrated that cefiderocol is no worse than alternative treatment options for cUTIs and HABP/VABP, but more data are currently available to support the use of beta-lactam beta-lactamase inhibitor agents, where susceptible. Mortality differences demonstrated in patients with pneumonia and bloodstream infections must further be explored and logistical and practical considerations regarding susceptibility testing and use as monotherapy vs. combination therapy must be considered prior to confidently recommending cefiderocol for regular use in systemic infections.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Iron; Microbial Sensitivity Tests

Cefiderocol is a new antimicrobial with a chemical structure similar to ceftazidime and cefepime. In this review we will focus on the role of cefiderocol in different clinical scenarios produced by resistant Gram-negative microorganisms, especially to carbapenems. In infections caused by Gram-negative microorganisms, inappropriate antibiotic treatment increased the risk of mortality almost fourfold. In patients with hospital-acquired infection and septic shock; with sepsis and poor functional reserve due to fragility; in immunocompromised patients; and in those with local ecology, individual history of colonization or previous infection and risk factors for carbapenem-resistant Enterobacteriaceae (CRE) such as the presence of chronic multi-morbidities, the best option would be to start an active empirical treatment against gram-negative bacteria resistant to carbapenems and later in 24-36 h with the information obtained from the cultures we could decide on a definitive empirical or directed treatment and avoid unnecessary overuse of these antibiotics. Cefiderocol would be in these cases a good candidate due to its excellent in vitro activity against all classes of beta-lactamase-producing Gram-negatives (including carbapenemase class A, B and D producers), as well as against non-fermenting Gram-negatives such as P. aeruginosa, Acinetobacter spp. and S. maltophilia. It is necessary to optimize the use of new antibiotics such as cefiderocol, guaranteeing the best available treatment to patients while delaying the emergence and spread of resistance.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa

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

Cefiderocol is a novel catechol-substituted siderophore cephalosporin that binds to the extracellular free iron, and uses the bacterial active iron transport channels to penetrate in the periplasmic space of Gram-negative bacteria (GNB). Cefiderocol overcomes many resistance mechanisms of these bacteria. Cefiderocol is approved for the treatment of complicated urinary tract infections, hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in the case of adults with limited treatment options, based on the clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In the CREDIBLE-CR trial, a higher all-cause mortality was observed in the group of patients who received cefiderocol, especially those with severe infections due to Acinetobacter spp. Further phase III clinical studies are necessary in order to evaluate cefiderocol´s efficacy in the treatment of serious infections.

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

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Design; Drug Resistance, Multiple; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem; Sisomicin; Tazobactam; Tetracyclines

Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against β-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.

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

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

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

To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field.. Novel agents, both belonging to β-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future.. The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azabicyclo Compounds; beta-Lactams; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Imipenem; Microbial Sensitivity Tests; Polymyxins; Sisomicin; Tazobactam; Tetracyclines

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem; Molecular Structure; Randomized Controlled Trials as Topic; Siderophores

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Boronic Acids; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Meropenem; Tazobactam

The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms.. This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms. We also explore the pharmacokinetics of this new compound as well as results from preclinical and clinical studies.. There is an urgent need for novel antimicrobial agents to address the emergence of multidrug-resistant pathogens, which are an increasing cause of morbidity and mortality worldwide. Our understanding of multidrug-resistance and bacterial biochemical pathways continues to expand, and the development of cefiderocol specifically targeting siderophore-mediated iron transport shows potential in escaping mechanisms of drug resistance. Cefiderocol, which demonstrates a favorable side effect profile, has the potential to become first-line therapy for our most aggressive and lethal multidrug-resistant Gram-negative pathogens.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Delivery Systems; Drug Design; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Siderophores

Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection.. This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient's treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5-14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected.. With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent.. The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.

Topics: Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Delivery of Health Care; Gram-Negative Bacterial Infections; Hospitals; Humans; Microbial Sensitivity Tests; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Sepsis; Standard of Care

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

Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia.. We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7-14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23.. Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI -6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events.. Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria.. Shionogi.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Double-Blind Method; Female; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Male; Meropenem; Pneumonia, Bacterial

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; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

The 68-year-old patient presented with fever, general malaise and physical weakness in neutropenia during a known relapse of acute myeloid leukaemia after allogeneic stem cell transplantation.. Due to immune suppression, an empiric antibiotic therapy with piperacillin/tazobactam was started. The 4MRGN screening was positive. For this reason, therapy was switched empirically to ceftazidime/avibactam plus colistin. A tongue ulcer with abscess formation and phlegmonous soft tissue reaction was revealed as the focus of the infection. Several microbiological probes including a blood culture discovered. Die Vorstellung der 68-jährigen Patientin erfolgte bei hohem Fieber, allgemeinem Unwohlseisn und körperlicher Schwäche in der Neutropenie bei Rezidiv einer akuten myeloischen Leukämie nach allogener Stammzelltransplantation.. Aufgrund der bestehenden Immundefizienz wurde eine kalkulierte antibiotische Therapie mit Piperacillin/Tazobactam begonnen. Bei positivem 4MRGN-Screening wurde diese kalkuliert auf Colistin und Ceftazidim/Avibactam umgestellt. Diagnostiziert wurde ein Zungenulkus mit Abszessbildung und phlegmonöser Weichteilreaktion. In mehreren mikrobiologischen Proben, inklusive einer Blutkultur, gelang der Nachweis eines. Vierfach multiresistente gramnegative Bakterien (4MRGN) sind aufgrund ihrer Resistenz gegenüber 4 bakterizid wirkenden Hauptantibiotikagruppen (Acylureidopenicilline, Cephalosporine der 3. Generation, Carbapeneme, Fluorchinolone) nur schwer therapierbar. Der vorliegende Fall zeigt für Cefiderocol eine gute klinische Wirksamkeit – auch bei Erregern, die gegen Antibiotika wie Colistin und Ceftazidim/Avibactam resistent sind und er verdeutlicht, wie wichtig eine antibiogrammgerechte Therapie ist.

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Communicable Diseases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Neoplasm Recurrence, Local; Neutropenia

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Treatment of infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) is challenging and new active antibiotics are needed urgently. This study describes the efficacy and safety of cefiderocol in a retrospective series of 13 patients with severe CR-GNB infection and limited treatment options. Pseudomonas aeruginosa was the predominant CR-GNB (n=8), followed by Burkholderia cepacia (n=3), Sthenotrophomona maltophilia (n=1) and KPC-producing Klebsiella pneumoniae (n=1). The source of infection was nosocomial pneumonia in 92.3% of cases (12/13), of which 11 cases were ventilator-associated pneumonia. Five patients were lung transplant recipients (38.5%). The median duration of treatment was 10 days (range 6-21 days). No severe adverse effects required reducing the dose or interrupting the treatment. Clinical and microbiological cure were assessed 7 days after the end of treatment, and achieved in 84.6% (11/13) of patients. Crude mortality at day 28 was observed in 23.1% (3/13) of cases. Cefiderocol is a valid alternative for the treatment of susceptible CR-GNB infections in patients with limited therapeutic options.

Topics: Anti-Bacterial Agents; Carbapenems; Cefiderocol; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Retrospective Studies; Salvage Therapy

Cefiderocol is a novel siderophore cephalosporin with promising activity against most carbapenem-resistant Gram-negative bacteria (CRGNB). However, extensive postmarketing experiences are lacking. This study aimed to analyse the early experience on cefiderocol postmarketing use at three tertiary care hospitals in Italy.. We retrospectively included patients with infections caused by CRGNB treated with cefiderocol at three Italian tertiary care hospitals from 1 March 2021 to 30 June 2022. A multivariate Cox model was used to identify predictors of 30 day mortality. A propensity score (PS) analysis with inverse probability weighting (IPW) was also performed to compare the treatment effect of cefiderocol monotherapy (CM) versus combination regimens (CCRs).. The cohort included 142 patients (72% male, median age 67 years, with 89 cases of Acinetobacter baumannii infection, 22 cases of Klebsiella pneumoniae, 27 cases of Pseudomonas aeruginosa and 4 of other pathogens). The 30 day all-cause mortality was 37% (52/142). We found no association between bacterial species and mortality. In multivariate analysis, a Charlson Comorbidity Index >3 was an independent predictor of mortality (HR 5.02, 95% CI 2.37-10.66, P < 0.001). In contrast, polymicrobial infection (HR 0.41, 95% CI 0.21-0.82, P < 0.05) was associated with lower mortality. There was no significant difference in mortality between patients receiving CM (n = 70) and those receiving a CCR (n = 72) (33% versus 40%, respectively), even when adjusted for IPW-PS (HR 1.11, 95% CI 0.63-1.96, P = 0.71).. Real-life data confirm that cefiderocol is a promising option against carbapenem-resistant Gram-negative infections, even as monotherapy.

Topics: Acinetobacter Infections; Aged; Anti-Bacterial Agents; Carbapenems; Cefiderocol; Cephalosporins; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Retrospective Studies

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Gram-Negative Bacterial Infections; Hematologic Neoplasms; Humans; Pneumonia; Stenotrophomonas maltophilia

Cefiderocol is a siderophore cephalosporin with potent antibacterial activity against a broad range of Gram-negative pathogens, including multidrug-resistant strains. Siderophore antibiotics bind ferric iron and utilize iron transporters to cross the cell membrane. In the biofilm setting, where antibiotic resistance is high but iron scavenging is important, cefiderocol may have advantageous antimicrobial properties. In this study, we compared the antimicrobial activity of cefiderocol to that of seven commonly used antibiotics in well-characterized multidrug-resistant pathogens and then determined their efficacy in the biofilm setting. MIC

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

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Topics: Achromobacter denitrificans; Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Gram-Negative Bacterial Infections; Humans

Cefiderocol is a novel siderophore cephalosporin that forms a complex with extracellular free ferric iron, which leads to transportation across the outer cell membrane to exert its bactericidal activity through cell wall synthesis inhibition. This pharmacological property has rendered cefiderocol active against several clinically relevant MDR Gram-negative bacteria as evidenced by several in vitro and in vivo studies. Cefiderocol was first approved by the US FDA on 14 November 2019 for the treatment of complicated urinary tract infections. On 28 September 2020, cefiderocol was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. The FDA-approved indications are based on clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In APEKS-cUTI, cefiderocol demonstrated non-inferiority to imipenem/cilastatin for the treatment of complicated urinary tract infection caused by MDR Gram-negative bacteria. In APEKS-NP, cefiderocol demonstrated non-inferiority to meropenem for treatment of nosocomial pneumonia. However, in CREDIBLE-CR, higher all-cause mortality was observed with cefiderocol compared with best available therapy for the treatment of severe infections caused by Gram-negative bacteria, primarily in the subset of patients with Acinetobacter spp. infections. Several case reports/series have demonstrated clinical success with cefiderocol for a variety of severe infections. The purpose of this article is to review available data on the mechanism of action, in vitro and in vivo data, pharmacokinetics, pharmacodynamics, susceptibility testing, efficacy and safety of cefiderocol to address its role in therapy.

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Siderophores

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

We are writing this letter to provide an update of published information on antibiotics for cystic fibrosis (CF) pulmonary exacerbations to the State of the Art articles by Zobell et al. Information on meropenem-vaborbactam and cefiderocol were not available when the original articles were published. These new antibiotics, approved in 2017 and 2019, possess antipseudomonal properties like the other carbapenems and cephalosporins in the original articles however, existing literature refers to their use for other less common bacteria. As patients with CF age, the microorganisms in their bacterial cultures change and some can colonize multiple or uncommon bacterial species including, Burkholderia, Achromobacter, and Stenotrophomonas spp. In 2019, these nonlactose fermenting bacterial species made up for approximately 15% of respiratory microorganisms cultured in pediatric patients. Though infrequent, compared to Staphylococcus aureus or Pseudomonas aeruginosa, these bacteria are opportunistic pathogens and patients at the highest risk for these infections include those with CF. Like other Gram negative bacteria, Burkholderia, Achromobacter, and Stenotrophomonas spp., are frequently drug resistant and can make treatment extremely challenging, thus it is crucial that data for treatment of these less common pathogens be evaluated.

Topics: Anti-Bacterial Agents; Boronic Acids; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem

The in vitro activity of cefiderocol was evaluated against Gram-negative bacilli isolated from patients in Canadian intensive care units from 2015 to 2017 using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method and interpretive criteria. All 800 isolates of Gram-negative bacilli tested were susceptible to cefiderocol (MIC ≤4 μg/ml), including isolates of ESBL-producing (n=40), AmpC-producing (n=6), and carbapenem-nonsusceptible (n=21) Enterobacterales, carbapenem-nonsusceptible (n=54) and multidrug-resistant (n=29) Pseudomonas aeruginosa, Stenotrophomonas maltophilia (n=66), and Acinetobacter baumannii (n=11).

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Canada; Carbapenems; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Siderophores; Stenotrophomonas maltophilia

Cystic fibrosis is associated with significant morbidity and early mortality due to recurrent acute and chronic lung infections. The chronic use of multiple antibiotics without pathogen eradication increases the possibility of extensive drug resistance or even pan-drug resistance (PDR). It is imperative that new or alternative treatment options be explored. We present a clinical case of a 10-year-old female cystic fibrosis patient, infected with a PDR Achromobacter spp. She was treated with cefiderocol, meropenem/vaborbactam, and bacteriophage therapy (Ax2CJ45ϕ2) during two separate admissions in an attempt to clear her infection and restore baseline pulmonary function. The Centers for Disease Control and Prevention confirmed antibiotic susceptibilities, which showed resistance to both cefiderocol and meropenem/vaborbactam. However, after using all three agents concomitantly during the second treatment course, our patient's pulmonary function improved dramatically, and the Achromobacter spp. could not be isolated from sputum samples obtained 8 and 16 weeks after completion of therapy. Overall, the treatment regimen consisting of cefiderocol, meropenem/vaborbactam, and bacteriophage was safe and well-tolerated in our patient.

Topics: Achromobacter; Anti-Bacterial Agents; Bacteriophages; Boronic Acids; Cefiderocol; Cephalosporins; Child; Combined Modality Therapy; Cystic Fibrosis; Drug Combinations; Drug Resistance, Bacterial; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem

Topics: Acinetobacter; Anti-Bacterial Agents; Burkholderia cepacia; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Europe; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; North America; Pseudomonas aeruginosa; Siderophores; Stenotrophomonas maltophilia

Topics: Animals; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases.. A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs.. In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa ) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae , 14 Enterobacter cloacae and 11 Providencia stuartii ) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/L. For K. pneumoniae , E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/L, respectively. Tigecycline was the second most active antibiotic, followed by colistin.. Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Inpatients; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Pseudomonas aeruginosa; Thienamycins; Tigecycline