scholarly journals 165. Cefiderocol Treatment for Serious Infections Caused by Carbapenem-resistant Bacteria: Post-hoc Analysis of Outcomes by Pathogen in the CREDIBLE-CR Study

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S212-S212
Author(s):  
Yuko Matsunaga ◽  
Mari Ariyasu ◽  
Miki Takemura ◽  
Yoshinori Yamano ◽  
Kiichiro Toyoizumi ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Carbapenem Resistance ◽  
Bloodstream Infections ◽  
Resistant Bacteria ◽  
Open Label ◽  
Gram Negative ◽  
Mitt Population ◽  
Carbapenem Resistant ◽  
Serious Infections ◽  
Tract Infections

Abstract Background The efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, for the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative pathogens was assessed in the CREDIBLE-CR study. The current analysis evaluated clinical and microbiological outcomes by baseline CR pathogen. Methods An open-label, prospective, randomised 2:1, Phase 3 study (CREDIBLE-CR; NCT02714595) was conducted in adult patients with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia, bloodstream infections or sepsis, and complicated urinary tract infections caused by CR Gram-negative pathogens. Patients received either intravenous (IV) CFDC 2g, q8h, 3-h infusion, or IV best available therapy (BAT: up to 3 drugs in combination), for 7–14 days (extendable to 21 days). Clinical and microbiological outcomes were assessed in the CR microbiological intent-to-treat (CR-MITT) population by CR pathogen, baseline MIC and by mechanism of carbapenem resistance at test of cure (TOC). Only summary statistics were collected. Results In the CR-MITT population (CFDC N=80; BAT N=38), Acinetobacter baumannii (46.3% and 44.7%), Klebsiella pneumoniae (33.8% and 31.5%), and Pseudomonas aeruginosa (15% and 26%) were the most frequent pathogens in CFDC and BAT arms, respectively. For all CR pathogens, clinical cure rates were achieved in 52.5% in the CFDC arm and 50.0% in the BAT arm at TOC; rates were similar between treatment arms by baseline CR pathogen (Table 1). Numerically higher clinical cure and microbiological outcomes were observed with CFDC for Enterobacterales (Table 1), especially against NDM-producing bacteria or those with porin-channel mutations (Table 1). CFDC MIC values ranged between ≤0.03 and 4 μg/mL, except for one pathogen (Table 2). Microbiological outcomes for CR A. baumannii, CR K. pneumoniae, and CR P. aeruginosa at TOC by baseline MICs of ≤4 μg/mL ranged between 0–40%, 0–100%, and 0–100%, respectively; at MIC ≤4 μg/mL, clinical and microbiological outcomes were equal (Table 2). Conclusion CFDC, via a novel mechanism of entry and its stability against β-lactamases, was effective against serious infections caused by CR pathogens with various resistance mechanisms or baseline MIC values. Disclosures Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Masahiro Kinoshita, MPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

scholarly journals 1271. Efficacy and Safety of Cefiderocol and Best Available Therapy in Patients with Serious Infections Caused by Carbapenem-Resistant Gram-Negative Infections: Results of the Pathogen-Focused Phase 3 CREDIBLE-CR Study

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S652-S653
Author(s):  
Matteo Bassetti ◽  
Roger Echols ◽  
Yuko Matsunaga ◽  
Simon Portsmouth ◽  
Mari Ariyasu ◽  
...  
Keyword(s):  
Panel Member ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Gram Negative ◽  
Mitt Population ◽  
Carbapenem Resistant ◽  
Serious Infections ◽  
All Cause Mortality ◽  
Acinetobacter Spp ◽  
Tract Infections

Abstract Background The CREDIBLE-CR study assessed the efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, in the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative (GN) bacteria. Methods CREDIBLE-CR was an open-label, prospective, randomized 2:1, Phase 3 study (NCT02714595) in patients with nosocomial pneumonia (NP), bloodstream infections/sepsis (BSI/Sepsis), or complicated urinary tract infections (cUTI) with evidence of CR GN pathogens. Adults received intravenous CFDC 2 g, q8h, 3-h infusion or best available therapy (BAT; up to 3 drugs) for 7–14 days (extendable to 21 days). The primary endpoint at test of cure in the CR microbiological intent-to-treat (CR-MITT) population was clinical cure (NP, BSI/Sepsis) or microbiological eradication (cUTI). Secondary endpoints were clinical and microbiological outcomes, all-cause mortality (ACM) and safety. Only descriptive statistics were pre-specified. Results A total of 101 patients received CFDC and 49 received BAT (CR-MITT: CFDC n=80, BAT n=38): 50% had pneumonia, 31.4% BSI/Sepsis, and 18.6% cUTI (Table 1). Most frequent CR pathogens were Acinetobacter baumannii (45.8%), Klebsiella pneumoniae (37.3%), and Pseudomonas aeruginosa (23.7%). CFDC monotherapy was given to 83% of patients, while BAT monotherapy to 29% of patients. Primary outcome in the CFDC and BAT arms was achieved in 50.0% and 52.6% in NP, 43.5% and 42.9% in BSI/Sepsis, and 52.9% and 20.0% in cUTI patients (Figure). CFDC was highly efficacious vs CREs and NDM-producing pathogens. Day 28 ACM was 24.8% (25/101) with CFDC and 18.4% (9/49) with BAT. Rescue therapy was given more frequently in the BAT than CFDC arm. Mortality results by pathogen showed an imbalance in Acinetobacter spp. infections (Table 2) with a higher rate in the CFDC arm than BAT arm. ICU and shock at randomization were more frequent in the CFDC arm than in the BAT arm in Acinetobacter spp. infections (Table 2). No safety concerns related to CFDC emerged. Table 1. Baseline demographics and characteristics (CR-MITT population) Figure. CREDIBLE-CR study primary efficacy endpoints and secondary outcomes at test-of-cure visit in CR-MITT population. Table 2. All-cause mortality by baseline pathogen inpatients with or without Acinetobacter spp. infection (safety population) Conclusion Efficacy of CFDC was demonstrated in this descriptive pathogen-focused study, including CREs, metallo-NDM producers and CR non-fermenters. Baseline imbalances of ICU and shock in the subset of infections with Acinetobacter spp. may have contributed to the mortality difference between CFDC and BAT arms. Disclosures Matteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Roger Echols, MD, Shionogi Inc. (Consultant) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

scholarly journals An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

2020 ◽  
Vol 9 (9) ◽  
pp. 1454
Author(s):  
Hari P. Nepal ◽  
Rama Paudel
Keyword(s):  
Bacterial Infections ◽  
Carbapenem Resistance ◽  
Therapeutic Options ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
Carbapenem Resistant ◽  
The World

Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.

scholarly journals Trends of Bloodstream Infections in a University Greek Hospital during a Three-Year Period: Incidence of Multidrug-Resistant Bacteria and Seasonality in Gram-negative Predominance

2017 ◽  
Vol 66 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Fevronia Kolonitsiou ◽  
Matthaios Papadimitriou-Olivgeris ◽  
Anastasia Spiliopoulou ◽  
Vasiliki Stamouli ◽  
Vasileios Papakostas ◽  
...  
Keyword(s):  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Blood Cultures ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Carbapenem Resistant

The aim of the study was to assess the epidemiology, the incidence of multidrug-resistant bacteria and bloodstream infections’ (BSIs) seasonality in a university hospital. This retrospective study was carried out in the University General Hospital of Patras, Greece, during 2011–13 y. Blood cultures from patients with clinical presentation suggestive of bloodstream infection were performed by the BacT/ALERT System. Isolates were identified by Vitek 2 Advanced Expert System. Antibiotic susceptibility testing was performed by the disk diffusion method and E-test. Resistance genes (mecA in staphylococci; vanA/vanB/vanC in enterococci; blaKPC/blaVIM/blaNDM in Klebsiella spp.) were detected by PCR. In total, 4607 (9.7%) blood cultures were positive from 47451 sets sent to Department of Microbiology, representing 1732 BSIs. Gram-negative bacteria (52.3%) were the most commonly isolated, followed by Gram-positive (39.5%), fungi (6.6%) and anaerobes bacteria (1.8%). The highest contamination rate was observed among Gram-positive bacteria (42.3%). Among 330 CNS and 150 Staphylococcus aureus, 281 (85.2%) and 60 (40.0%) were mecA-positive, respectively. From 113 enterococci, eight were vanA, two vanB and two vanC-positives. Of the total 207 carbapenem-resistant Klebsiella pneumoniae (73.4%), 202 carried blaKPC, four blaKPC and blaVIM and one blaVIM. A significant increase in monthly BSIs’ incidence was shown (R2: 0.449), which may be attributed to a rise of Gram-positive BSIs (R2: 0.337). Gram-positive BSIs were less frequent in spring (P < 0.001), summer (P < 0.001), and autumn (P < 0.001), as compared to winter months, while Gram-negative bacteria (P < 0.001) and fungi (P < 0.001) were more frequent in summer months. BSIs due to methicillin resistant S. aureus and carbapenem-resistant Gram-negative bacteria increased during the study period. The increasing incidence of BSIs can be attributed to an increase of Gram-positive BSI incidence, even though Gram-negative bacteria remained the predominant ones. Seasonality may play a role in the predominance of Gram-negative’s BSI.

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 Identification of blaGIM-1 in Acinetobacter variabilis isolated from the hospital environment in Tamil Nadu, India

2019 ◽  
Author(s):  
Prasanth Manohar ◽  
Murugavel Ragavi ◽  
Ashby Augustine ◽  
Hrishikesh MV ◽  
Nachimuthu Ramesh
Keyword(s):  
Tamil Nadu ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Hospital Environment ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Hospital Environments ◽  
Surveillance Programs

AbstractBackgroundEmergence of carbapenem resistance mechanisms among Gram-negative bacteria is a worrisome health problem. Here, we focused on to identify the presence of carbapenem-resistant bacteria among the samples collected from hospital environments in Tamil Nadu.MethodsA total of 30 hospital environmental samples were collected between August 2017 and January 2018 from hospitals located in Chennai and Vellore such as lift switches, stair rails, switchboards, nursing desks, used nursing gloves, door handles, wheelchairs, touch screens, chairs and from pillars inside the hospitals.Results and discussionA total of 22 carbapenem-resistant Gram-negative bacteria were isolated that included Escherichia coli, Klebsiella sp., Enterobacter sp., Salmonella sp., Pseudomonas aeruginosa and Acinetobacter sp. Interestingly, blaGIM-1 was detected in Acinetobacter variabilis strain isolated in samples collected from hospitals. Unlike other studies, the identified GIM-1 was not plasmid encoded, and this is the first report for the presence of GIM-1 (German imipenemase) in India.ConclusionExtensive surveillance programs are necessary to trace the uncontrolled spread of carbapenem-resistance genes in order to reduce the rapid spread of resistance.

scholarly journals Direct Testing for KPC-Mediated Carbapenem Resistance from Blood Samples Using a T2 Magnetic Resonance Based Assay

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 950
Author(s):  
Giulia De Angelis ◽  
Riccardo Paggi ◽  
Thomas J. Lowery ◽  
Jessica L. Snyder ◽  
Giulia Menchinelli ◽  
...  
Keyword(s):  
Resistance Genes ◽  
Carbapenem Resistance ◽  
Bloodstream Infections ◽  
Resistance Testing ◽  
Blood Samples ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Direct Testing ◽  
Two Samples ◽  
Encoding Genes

Molecular-based carbapenem resistance testing in Gram-negative bacterial bloodstream infections (BSIs) is currently limited because of the reliance on positive blood culture (BC) samples. The T2Resistance™ panel may now allow the detection of carbapenemase- and other β-lactamase encoding genes directly from blood samples. We detected carbapenem resistance genes in 11 (84.6%) of 13 samples from patients with BC-documented BSIs (10 caused by KPC-producing Klebsiellapneumoniae and 1 caused by VIM/CMY-producing Citrobacter freundii). Two samples that tested negative for carbapenem resistance genes were from patients with BC-documented BSIs caused by KPC-producing K. pneumoniae who were receiving effective antibiotic therapy. In conclusion, our findings suggest that the T2Resistance™ panel can be a reliable tool for diagnosing carbapenem-resistant Gram-negative bacterial BSIs.

scholarly journals Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S559-S564 ◽  
Author(s):  
Roger Echols ◽  
Mari Ariyasu ◽  
Tsutae Den Nagata
Keyword(s):  
Complicated Urinary Tract Infection ◽  
Development Program ◽  
Bloodstream Infections ◽  
The United States ◽  
Clinical Development ◽  
European Medicines Agency ◽  
Open Label ◽  
Site Specific ◽  
Gram Negative ◽  
Carbapenem Resistant

AbstractHistorically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.

scholarly journals Epidemiological characteristics and antimicrobial susceptibility among carbapenem-resistant non-fermenting bacteria in Brazil

2016 ◽  
Vol 10 (06) ◽  
pp. 544-553 ◽  
Author(s):  
Vanessa Cordeiro Dias ◽  
Claudio Galuppo Diniz ◽  
Ana Claudia de Oliveira Peter ◽  
Andre Netto Bastos ◽  
Victor Quinnet de Andrade Bastos ◽  
...  
Keyword(s):  
Genetic Markers ◽  
Antimicrobial Susceptibility ◽  
Carbapenem Resistance ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Disk Diffusion Method ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Acinetobacter Spp ◽  
Epidemiological Characteristics

Introduction: Non-fermenting Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are widespread in the environment and are increasingly associated with nosocomial infections. Extensive and indiscriminate use of antibiotics in hospitals has contributed to an increased number of infections caused by these microorganisms, that are resistant to a wide variety of antimicrobials, including β-lactams. This study aimed to isolate and identify carbapenem-resistant Acinetobacter spp. and P. aeruginosa from hospitalized patients, to determine their antimicrobial susceptibility patterns and to screen for blaOXA-23, blaOXA-24, blaOXA-51, blaOXA-58, and blaOXA-143 genes among the isolated bacteria. Methodology: Antimicrobial resistance patterns were performed using the disk-diffusion method. Genetic markers related to carbapenem resistance were screened by polymerase chain reaction. Results: Carbapenem-resistant Acinetobacter spp. (n = 44) and P. aeruginosa (n = 28) samples were isolated from patients admitted to a tertiary hospital. Polymyxin B was the only effective drug for all isolates. Considering the oxacillinase gene screening, genetic markers were observed only in Acinetobacter isolates. The most frequent genotype observed was blaOXA-23+/blaOXA-51+ (45.5%), followed by blaOXA-51+/blaOXA-143+ (41%). The oxacillinase genes blaOXA-24 and blaOXA-58 were not detected. High mortality rates (> 70%) were observed. Conclusions: The data suggest the need for rational use of antimicrobials associated with early diagnosis of multidrug-resistant bacteria, especially considering non-fermenting Gram-negative rods, which are widespread in hospitals. The findings of blaoxa-51‑ strains suggest the occurrence and spread of non-A. baumannii species throughout our hospitals. Effective implementation of surveillance programs in hospitals is needed to reduce infectious and resistant intra- and inter-species bacteria.

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