scholarly journals An Update on Eight “New” Antibiotics against Multidrug-Resistant Gram-Negative Bacteria

2021 ◽  
Vol 10 (5) ◽  
pp. 1068
Author(s):  
Erlangga Yusuf ◽  
Hannelore I. Bax ◽  
Nelianne J. Verkaik ◽  
Mireille van Westreenen
Keyword(s):  
Drug Administration ◽  
Food And Drug Administration ◽  
Treatment Options ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
New Antibiotics ◽  
Tract Infections ◽  
The U.S

Infections in the ICU are often caused by Gram-negative bacteria. When these microorganisms are resistant to third-generation cephalosporines (due to extended-spectrum (ESBL) or AmpC beta-lactamases) or to carbapenems (for example carbapenem producing Enterobacteriales (CPE)), the treatment options become limited. In the last six years, fortunately, there have been new antibiotics approved by the U.S. Food and Drug Administration (FDA) with predominant activities against Gram-negative bacteria. We aimed to review these antibiotics: plazomicin, eravacycline, temocillin, cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam. Temocillin is an antibiotic that was only approved in Belgium and the UK several decades ago. We reviewed the in vitro activities of these new antibiotics, especially against ESBL and CPE microorganisms, potential side effects, and clinical studies in complicated urinary tract infections (cUTI), intra-abdominal infections (cIAI), and hospital-acquired pneumonia/ventilator-associatedpneumonia (HAP/VAP). All of these new antibiotics are active against ESBL, and almost all of them are active against CPE caused by KPC beta-lactamase, but only some of them are active against CPE due to MBL or OXA beta-lactamases. At present, all of these new antibiotics are approved by the U.S. Food and Drug Administration for cUTI (except eravacycline) and most of them for cIAI (eravacycline, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam) and for HAP or VAP (cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam).

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®)

2020 ◽  
Author(s):  
Shabnam Naseer ◽  
Edward A Weinstein ◽  
Daniel B Rubin ◽  
Kalavati Suvarna ◽  
Xiaohui Wei ◽  
...  
Keyword(s):  
Drug Administration ◽  
Nosocomial Pneumonia ◽  
Food And Drug Administration ◽  
Treatment Options ◽  
Bloodstream Infections ◽  
Gram Negative Bacteria ◽  
Open Label ◽  
Double Blind ◽  
Gram Negative ◽  
Tract Infections

Abstract In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration NCT02714595.

scholarly journals Activity of ceftolozane/tazobactam against commonly encountered antimicrobial resistant Gram-negative bacteria in Lebanon

2020 ◽  
Vol 14 (06) ◽  
pp. 559-564
Author(s):  
George F Araj ◽  
Dana M Berjawi ◽  
Umayya Musharrafieh ◽  
Nancy K El Beayni
Keyword(s):  
Bacterial Resistance ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
E Coli ◽  
Extended Spectrum Beta Lactamases ◽  
In Vitro Data

Introduction: In view of the continuous rise in Gram-negative bacterial resistance and limited treatment options, Ceftolozane/tazobactam (C/T) is a newly introduced antimicrobial agent in Lebanon for its demonstrated activity against resistant Gram-negative bacteria. However, in vitro data is not available about its activity against commonly isolated bacteria in this country. Methodology: The analysis included clinical isolates, multidrug–resistant (MDR) and extended-spectrum Beta-lactamases (ESBLs), representing 124 Escherichia coli, 75 Klebsiella pneumoniae and 100 Pseudomonas aeruginosa, identified using the MALDI-TOF. The minimum inhibitory concentration (MIC) for C/T was determined by the Etest (Liofilchem, Roseto degli Abruzzi, Italy). In addition, the disk diffusion (DD) test was used to determine the activity of C/T and of the antimicrobials routinely used to test for such pathogens. Results: The C/T activity against the ESBL producers E. coli and K. pneumoniae isolates were similar (MIC90 value of 1 and 1.5 µg/mL, respectively; susceptibility of 100% and 96%, respectively). However, the activity of C/T against the E. coli and K. pneumoniae MDR isolates was much lower (MIC90 value of 256 and 96 µg/mL, respectively; susceptibility of 54% for each). The C/T MIC90 value for the non-MDR P. aeruginosa isolates was 3 µg/mL and ≥ 256 µg/mL for the MDR P. aeruginosa isolates (susceptibility of 96% vs 42% respectively). Overall, the C/T activities show comparable or higher susceptibility to the routinely used antimicrobials. Conclusion: The high in vitro activity of C/T points out its value as a possible alternative to the antimicrobials currently used for treatment of infections caused by such pathogens and would help in minimizing toxicity and bacterial resistance.

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.

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 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.

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.

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.

Cefepime: A Fourth-Generation Parenteral Cephalosporin

1996 ◽  
Vol 30 (12) ◽  
pp. 1414-1424 ◽  
Author(s):  
Michael A Wynd ◽  
Joseph A Paladino
Keyword(s):  
Clinical Trials ◽  
Clinical Efficacy ◽  
Fourth Generation ◽  
Third Generation ◽  
Gram Positive ◽  
Gram Negative ◽  
Beta Lactamases ◽  
Tract Infections ◽  
Third Generation Cephalosporins

OBJECTIVE: To review the chemistry, microbiology, pharmacokinetics, therapeutic efficacy, adverse effect profile, drug interactions, dosing, and administration of cefepime, a new fourth-generation parenteral cephalosporin. DATA SOURCES: A MEDLINE search of the available literature, including clinical trials and reviews, was performed. Abstracts presented at recent scientific conferences and current publications were also reviewed. DATA SELECTION: In vitro and preclinical data were included, as well as data from Phase II and III clinical trials. DATA SYNTHESIS: Cefepime is an extended-spectrum parenteral cephalosporin antibiotic active in vitro against a broad spectrum of gram-positive and gram-negative aerobic bacteria. The gram-positive spectrum is similar to that of cefotaxime, the gram-negative spectrum is similar to that of ceftazidime, and many, though not all, organisms resistant to these two agents remain susceptible to cefepime, prompting the fourth-generation designation. Cefepime has a high affinity for penicillin-binding proteins and, due to its zwitterionic configuration, rapidly penetrates outer-membrane porin channels of bacteria. Beta-lactamases appear to have a low affinity for the drug. Cefepime has a decreased propensity to induce beta-lactamases compared with other beta-lactam antibiotics. Cefepime has a pharmacokinetic disposition similar to that of other renally eliminated cephalosporins, with a half-life of approximately 2 hours. Cefepime has demonstrated clinical efficacy against a variety of infections, including urinary tract infections, pneumonia, and skin and skin structure infections. Cefepime is generally well tolerated. CONCLUSIONS: Cefepime may have several chemical and pharmacologic advantages over currently available third-generation cephalosporins. In vitro data indicate that cefepime retains activity against some, but not all, gram-negative bacteria resistant to third-generation cephalosporins; however, clinical efficacy against infections due to resistant pathogens remains to be established. Cefepime was at least as effective as comparators during clinical trials, and may prove to be a viable alternative to other currently available agents.

Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options

2019 ◽  
Author(s):  
Stamatis Karakonstantis ◽  
Evangelos I Kritsotakis ◽  
Achilleas Gikas
Keyword(s):  
Case Reports ◽  
Controlled Trial ◽  
Treatment Options ◽  
Relevant Literature ◽  
Gram Negative Bacteria ◽  
Term Care ◽  
Gram Negative ◽  
Treatment Regimens ◽  
Synergistic Combinations

Abstract Background The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial. Objectives To consolidate the relevant literature and identify treatment options for PDR GNB infections. Methods A systematic search in MEDLINE, Scopus and clinical trial registries was conducted. Studies reporting PDR clinical isolates were eligible for review if susceptibility testing for all major antimicrobials had been performed. Characteristics and findings of retrieved studies were qualitatively synthesized. Results Of 81 studies reviewed, 47 (58%) were published in the last 5 years. The reports reflected a worldwide dissemination of PDR GNB in 25 countries in 5 continents. Of 526 PDR isolates reported, Pseudomonas aeruginosa (n=175), Acinetobacter baumannii (n=172) and Klebsiella pneumoniae (n=125) were most common. PDR GNB were typically isolated in ICUs, but several studies demonstrated wider outbreak potential, including dissemination to long-term care facilities and international spread. All-cause mortality was high (range 20%–71%), but appeared to be substantially reduced in studies reporting treatment regimens active in vitro. No controlled trial has been performed to date, but several case reports and series noted successful use of various regimens, predominantly synergistic combinations, and in selected patients increased exposure regimens and newer antibiotics. Conclusions PDR GNB are increasingly being reported worldwide and are associated with high mortality. Several treatment regimens have been successfully used, of which synergistic combinations appear to be most promising and often the only available option. More pharmacokinetic/pharmacodynamic and outcome studies are needed to guide the use of synergistic combinations.

scholarly journals Inhibition of the β-barrel assembly machine by a peptide that binds BamD

2015 ◽  
Vol 112 (7) ◽  
pp. 2011-2016 ◽  
Author(s):  
Christine L. Hagan ◽  
Joseph S. Wzorek ◽  
Daniel Kahne
Keyword(s):  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Outer Membranes ◽  
Essential Proteins ◽  
Growth Defects ◽  
Substrate Protein ◽  
Assembly Mechanism ◽  
New Antibiotics

The protein complex that assembles integral membrane β-barrel proteins in the outer membranes of Gram-negative bacteria is an attractive target in the development of new antibiotics. This complex, the β-barrel assembly machine (Bam), contains two essential proteins, BamA and BamD. We have identified a peptide that inhibits the assembly of β-barrel proteins in vitro by characterizing the interaction of BamD with an unfolded substrate protein. This peptide is a fragment of the substrate protein and contains a conserved amino acid sequence. We have demonstrated that mutations of this sequence in the full-length substrate protein impair the protein’s assembly, implying that BamD’s interaction with this sequence is an important part of the assembly mechanism. Finally, we have found that in vivo expression of a peptide containing this sequence causes growth defects and sensitizes Escherichia coli to antibiotics to which they are normally resistant. Therefore, inhibiting the binding of substrates to BamD is a viable strategy for developing new antibiotics directed against Gram-negative bacteria.

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