Cefiderocol: A new cephalosporin stratagem against multidrug resistant gram-negative bacteria

2021 ◽  
Author(s):  
Sharon Ong’uti ◽  
Mary Czech ◽  
Elizabeth Robilotti ◽  
Marisa Holubar
Keyword(s):  
Clinical Trials ◽  
Multidrug Resistant ◽  
Cell Entry ◽  
Phase Iii ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Phase Iii Clinical Trials ◽  
Carbapenem Resistant ◽  
Tract Infections

Abstract Cefiderocol is a novel injectable siderophore cephalosporin which 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 like carbapenem resistant Enterobacterales (CRE), carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii. It was approved by the Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials demonstrating noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase III clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician’s armamentarium against MDR gram-negative infections.

In Vitro Activity of Gepotidacin Against Gram-negative and Gram-positive Anaerobes

2021 ◽  
Author(s):  
Meredith A. Hackel ◽  
James A. Karlowsky ◽  
Michele A. Canino ◽  
Daniel F. Sahm ◽  
Nicole E. Scangarella-Oman
Keyword(s):  
Clinical Trials ◽  
Vitro Activity ◽  
Phase Iii ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Gram Negative ◽  
Phase Iii Clinical Trials ◽  
Agar Dilution

Gepotidacin (formerly GSK2140944) is a first in class triazaacenaphthylene antibacterial currently in Phase III clinical trials. When tested against Gram-negative ( n =333) and Gram-positive ( n =225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates (MIC 90 ) at concentrations of 4 and 2 μg/ml, respectively. Given gepotidacin’s in vitro activity against the anaerobic isolates tested, further study is warranted to better understand gepotidacin’s utility in the treatment of infections caused by clinically relevant anaerobic organisms.

scholarly journals Case Commentary: the Need for Cefiderocol Is Clear, but Are the Supporting Clinical Data?

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Ryan K. Shields
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Salvage Therapy ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Potential Utility ◽  
Gram Negative

ABSTRACT Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.

scholarly journals Clinical Experience of Colistin-Glycopeptide Combination in Critically Ill Patients Infected with Gram-Negative Bacteria

2013 ◽  
Vol 58 (2) ◽  
pp. 851-858 ◽  
Author(s):  
Nicola Petrosillo ◽  
Maddalena Giannella ◽  
Massimo Antonelli ◽  
Mario Antonini ◽  
Bruno Barsic ◽  
...  
Keyword(s):  
Protective Factor ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Causative Agents ◽  
Treatment Onset ◽  
Cox Analysis

ABSTRACTA colistin-glycopeptide combination (CGC) has been shownin vitroto be synergistic against multidrug-resistant Gram-negative bacteria (MDR GNB), especiallyAcinetobacter baumannii, and to prevent further resistance. However, clinical data are lacking. We carried out a retrospective multicenter study of patients hospitalized in intensive care units (ICUs) who received colistin for GNB infection over a 1-year period, to assess the rates of nephrotoxicity and 30-day mortality after treatment onset among patients treated with and without CGC for ≥48 h. Of the 184 patients treated with colistin, GNB infection was documented for 166. The main causative agents were MDRA. baumannii(59.6%), MDRPseudomonas aeruginosa(18.7%), and carbapenem-resistantKlebsiella pneumoniae(14.5%); in 16.9% of patients, a Gram-positive bacterium (GPB) coinfection was documented. Overall, 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), ventilator-associated pneumonia (54.4% versus 71.4%), MDRA. baumanniiinfection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%); there were no differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis performed on patients who survived for ≥5 days after treatment onset showed that the Charlson index (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.44;P= 0.001) and MDRA. baumanniiinfection (HR, 2.51; 95% CI, 1.23 to 5.12;P= 0.01) were independent predictors of 30-day mortality, whereas receiving CGC for ≥5 days was a protective factor (HR, 0.42; 95% CI, 0.19 to 0.93;P= 0.03). We found that CGC was not associated with higher nephrotoxicity and was a protective factor for mortality if administered for ≥5 days.

scholarly journals Cefiderocol, a new antibiotic against multidrug-resistant Gram-negative bacteria

2021 ◽  
Vol 34 (Suppl 1) ◽  
pp. 41-43
Author(s):  
José Tiago Silva ◽  
Francisco López-Medrano
Keyword(s):  
Bacterial Pneumonia ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Tract Infections ◽  
Transport Channels ◽  
Hospital Acquired

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.

Cefiderocol: A Siderophore Cephalosporin

2020 ◽  
Vol 54 (12) ◽  
pp. 1215-1231
Author(s):  
Rania M. El-Lababidi ◽  
John George Rizk
Keyword(s):  
Nosocomial Pneumonia ◽  
Data Extraction ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Study Selection ◽  
Serious Infections ◽  
Wide Range ◽  
Tract Infections

Objective: 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. Data Sources: A literature search through PubMed, Google Scholar, and ClinicalTrials.gov was conducted (2009 to March 2020) using the search terms cefiderocol and S-649266. Abstracts presented at recent conferences, prescribing information, and information from the US Food and Drug Administration (FDA) and the manufacturer’s website were reviewed. Study Selection and Data Extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on cefiderocol were reviewed. Data Synthesis: 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) Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, and Stenotrophomonas maltophilia. Cefiderocol was studied in the treatment of adult patients with complicated urinary tract infections (cUTIs) and nosocomial pneumonia and was well tolerated. In a recently completed prospective study, higher mortality was observed with cefiderocol in the treatment of serious infections caused by carbapenem-resistant (CR) Gram-negative pathogens. Relevance to Patient Care and Clinical Practice: 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. Conclusion: 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.

scholarly journals In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S544-S551 ◽  
Author(s):  
Yoshinori Yamano
Keyword(s):  
Efflux Pump ◽  
Bloodstream Infections ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Highly Active ◽  
Carbapenem Resistant ◽  
Surveillance Programs ◽  
Tract Infections

AbstractCarbapenem-resistant gram-negative bacteria including Enterobacteriaceae as well as nonfermenters, such as Pseudomonas aeruginosa and Acinetobacter baumannii, have emerged as significant global clinical threats. Although new agents have recently been approved, none are active across the entire range of resistance mechanisms presented by carbapenem-resistant gram-negative bacteria. Cefiderocol, a novel siderophore cephalosporin, has been shown in large surveillance programs and independent in vitro studies to be highly active against all key gram-negative causative pathogens isolated from patients with hospital-acquired or ventilator-associated pneumonia, bloodstream infections, or complicated urinary tract infections. The improved structure, the novel mode of entry into bacteria, and its stability against carbapenemases enables cefiderocol to exhibit high potency against isolates that produce carbapenemases of all classes or are resistant due to porin channel mutations and/or efflux pump overexpression. Resistance to cefiderocol is uncommon and appears to be multifactorial.

scholarly journals Ceftazidimeavibactam use in children and adolescents

2021 ◽  
Vol 23 (2) ◽  
pp. 173-183
Author(s):  
Оlga U. Stetsiouk ◽  
Irina V. Andreeva ◽  
А.U. Lekmanov ◽  
Еlena V. Haykina
Keyword(s):  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Pediatric Practice ◽  
Gram Negative ◽  
Hospital Acquired Pneumonia ◽  
Tract Infections ◽  
Hospital Acquired ◽  
Limited Choice ◽  
Intraabdominal Infections

Abstract The increasing number of infections caused by multidrug-resistant gram-negative bacteria in children is a serious problem all over the world. Ceftazidim-avibactam is a promising antimicrobial drug recently approved in Russia for use in pediatric practice. This review provides information on the possible use of ceftazidime-avibactam in children with complicated intraabdominal infections (in combination with metronidazole); complicated urinary tract infections, including pyelonephritis; hospital-acquired pneumonia, including ventilator-associated pneumonia; infections caused by aerobic gram-negative microorganisms in patients with limited choice of antibacterial therapy. Based on the data on the in vitro activity of the drug, the results of clinical studies of pharmacokinetics, safety and efficacy of ceftazidimeavibactam for the treatment of infections in children the main clinical cases in which the use of ceftazidimeavibactam in pediatric practice is most justified and appropriate are identified.

Imipenem/cilastatin/relebactam: A new carbapenem β-lactamase inhibitor combination

2021 ◽  
Author(s):  
Hanine Mansour ◽  
Ahmad El Ouweini ◽  
Elias B Chahine ◽  
Lamis R Karaoui
Keyword(s):  
Clinical Trials ◽  
Drug Therapy ◽  
Drug Combination ◽  
Bacterial Pneumonia ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

Abstract Purpose The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, efficacy, safety, and current regulatory status of a recently approved triple-drug therapy for complicated infections are reviewed. Summary Imipenem/cilastatin/relebactam is a newly approved anti-infective combination of a well-established β-lactam and a new β-lactamase inhibitor for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options; the medication is also indicated for use in treating hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The medication is active in vitro against a wide range of pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenemase-resistant Enterobacterales such as Klebsiella pneumoniae carbapenemase. The addition of relebactam does not restore the activity of imipenem against metallo-β-lactamase (MBL)–producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. Two phase 3 clinical trials of imipenem/cilastatin/relebactam were conducted. In the RESTORE-IMI 1 trial, the efficacy and safety of the triple-drug combination was found to be comparable to that of colistin/imipenem for treatment of infections caused by imipenem-nonsusceptible gram-negative bacteria in patients with HABP or VABP, cUTIs, and cIAIs, with a significantly lower incidence of nephrotoxicity reported with triple-drug therapy. The RESTORE-IMI 2 trial demonstrated the noninferiority of the triple-drug combination to piperacillin/tazobactam for the treatment of HABP and VABP. Commonly reported adverse events in clinical trials included anemia, elevated liver enzymes, electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, phlebitis and/or infusion-site reactions, and hypertension. Conclusion Imipenem/cilastatin/relebactam is a new β-lactam/β-lactamase inhibitor combination with activity against MDR gram-negative bacteria, including many CRE but not including MBL-producing Enterobacterales and carbapenem-resistant Acinetobacter isolates. It is approved for the treatment of cUTIs, cIAIs, HABP, and VABP.

scholarly journals In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

2010 ◽  
Vol 54 (6) ◽  
pp. 2291-2302 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre
Keyword(s):  
Multidrug Resistant ◽  
Unusual Property ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
High Affinity ◽  
Class A ◽  
Carbapenem Resistant ◽  
Lactam Antibiotic ◽  
Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

In Vitro antibacterial activity of lactic acid bacteria isolated from goat’s raw milk of Mostaganem (West Algeria) against Gram negative bacteria responsible for urinary tract infections

2016 ◽  
Vol 6 (1) ◽  
pp. 15-22
Author(s):  
Zergoug Amina ◽  
Cheriguene Abderrahim ◽  
Chougrani Fadela
Keyword(s):  
Antibacterial Activity ◽  
Lactic Acid ◽  
Urinary Tract ◽  
Lactic Acid Bacteria ◽  
Raw Milk ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Tract Infections ◽  
West Algeria

Urinary tract infections (UTI) are a serious bacterial pathological challenges all over the world, leading to respiratory infections, that’s why new strategies don’t cease to develop. Lactic acid bacteria having shown beneficial effects for years in various areas, may prove to be excellent candidates in medical field. The current research focused on the selection of lactic acid bacteria having the potential of an antibacterial activity against Gram negative bacteria responsible for UTI, for an eventual use as a therapeutic agent. A total of 40 isolates were isolated from goat’s raw milk of Mostaganem (West Algeria). In vitro tests were conducted in order to determine the efficiency of the isolates to produce antibacterial agents in interaction with uropathogens. Among 40 isolates, only 10 isolates identified as Lactobacilli and Lactococci were performant. The Screening showed that the inhibitor agent was proteinaceous substance. Therfore, it is noted that a treatment with presence of LAB is very encouraging as a result of the production of bacteriocin-like substance. On the other hand, LAB can be considered as a good alter-native to the large extent to the antibiotics in the treatment of UTI.

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