scholarly journals Assessment of Ceftazidime-Avibactam 30/20-μg Disk, Etest versus Broth Microdilution Results When Tested against Enterobacterales Clinical Isolates

2022 ◽  
Author(s):  
Renru Han ◽  
Xuelin Yang ◽  
Yang Yang ◽  
Yan Guo ◽  
Dandan Yin ◽  
...  
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Broth Microdilution ◽  
Gram Negative ◽  
Extended Spectrum ◽  
The World ◽  
Multidrug Resistant Pathogens ◽  
Combinational Therapies

Multidrug-resistant Gram-negative bacteria, especially for extended-spectrum β-lactamases-producing and carbapenemase-producing Enterobacterales , are disseminating rapidly around the world. Treatment options for these infections are limited, which prompt the development of novel or combinational therapies to combat the infections caused by multidrug-resistant pathogens.

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 Mechanistic Understanding Enables the Rational Design of Salicylanilide Combination Therapies for Gram-Negative Infections

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Janine N. Copp ◽  
Daniel Pletzer ◽  
Alistair S. Brown ◽  
Joris Van der Heijden ◽  
Charlotte M. Miton ◽  
...  
Keyword(s):  
Rational Design ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Combination Therapies ◽  
Diverse Range ◽  
Gram Negative ◽  
Mechanistic Understanding ◽  
Multiple Drugs

ABSTRACT One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies. IMPORTANCE There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.

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 Combining Colistin with Furanone C-30 Rescues Colistin Resistance of Gram-Negative Bacteria in Vitro and in Vivo

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yishuai Lin ◽  
Xiaodong Zhang ◽  
Liqiong Chen ◽  
Chunyan Xu ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
C 30

Colistin is among the few antibiotics effective against multidrug-resistant Gram-negative bacteria (GNB) clinical isolates. However, colistin-resistant GNB strains have emerged in recent years.

scholarly journals Pathogenicity Genomic Island-Associated CrpP-Like Fluoroquinolone-Modifying Enzymes among Pseudomonas aeruginosa Clinical Isolates in Europe

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
José Manuel Ortiz de la Rosa ◽  
Patrice Nordmann ◽  
Laurent Poirel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Genomic Island ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Genomic Islands ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Genes Encoding

ABSTRACT Many transferable quinolone resistance mechanisms have been identified in Gram-negative bacteria. The plasmid-encoded 65-amino-acid-long ciprofloxacin-modifying enzyme CrpP was recently identified in Pseudomonas aeruginosa isolates. We analyzed a collection of 100 clonally unrelated and multidrug-resistant P. aeruginosa clinical isolates, among which 46 were positive for crpP-like genes, encoding five CrpP variants conferring variable levels of reduced susceptibility to fluoroquinolones. These crpP-like genes were chromosomally located as part of pathogenicity genomic islands.

Antimicrobial Resistance and Prevalence of Extended Spectrum β-Lactamase Among Clinical Isolates of Gram-Negative Bacteria in Riyadh

1995 ◽  
Vol 7 (6) ◽  
pp. 509-514 ◽  
Author(s):  
T. El-Karsh ◽  
A.F. Tawfik ◽  
F. AL-Shammary ◽  
S. AL-Salah ◽  
A.M. Kambal ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Extended Spectrum

scholarly journals Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates

2003 ◽  
Vol 376 (3) ◽  
pp. 801-805 ◽  
Author(s):  
Monique MALLÉA ◽  
Abdallah MAHAMOUD ◽  
Jacqueline CHEVALIER ◽  
Sandrine ALIBERT-FRANCO ◽  
Pierre BROUANT ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Microbial Pathogens ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
High Level ◽  
Antibiotic Efflux

Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2´-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB–TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes.

scholarly journals Extended Spectrum β-Lactamase (ESBL) Producing Multidrug Resistant Gram-Negative Bacteria from Various Clinical Specimens of Patients Visiting a Tertiary Care Hospital

2018 ◽  
Vol 4 ◽  
pp. 1-8
Author(s):  
Albert Ghimire ◽  
Bipesh Acharya ◽  
Reshma Tuladhar
Keyword(s):  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Hospitalized Patients ◽  
Diffusion Method ◽  
Gram Negative Bacteria ◽  
Care Hospital ◽  
Gram Negative ◽  
Clinical Specimens ◽  
Extended Spectrum ◽  
Esbl Producers

Objectives: The purpose of this study was to assess multidrug resistance and Extended Spectrum β-Lactamase (ESBL) production in Gram negative bacterial pathogens.Methods: The study included clinical specimens sent for routine culture and antibiotic susceptibility testing. A total of 469 different clinical specimens were processed according to the standard methodology. The isolates were identified by standard microbiological procedures and subjected to antimicrobial susceptibility testing by modified Kirby-Bauer disk diffusion method. Production of ESBL was determined by combined disk method.Results: Of the total sample processed, 80 (17.0%) Gram negative bacteria were isolated and 82.5% of them were multidrug resistant (MDR). From the total MDR isolates, 47% were ESBL positive. The higher rate of growth among Intensive Care Units (ICUs) patients was found statistically significant. Higher prevalence of MDR isolates was observed in blood and pus specimens. The majority of the ESBL producers were Escherichia coli (38.7%). Higher rate of ESBL producers was detected from blood (55.6%). Polymyxin B, imipenem and amikacin were the most effective antibiotics against Acinetobacter spp. and Pseudomonas aeruginosa whereas imipenem, amikacin, meropenem were the most effective antibiotics against Enterobacteriaceae.Conclusion: Higher prevalence of ESBL producing MDR Gram negative pathogens in hospitalized patients indicates these bacteria are important health care associated pathogens and requires proper infection control measures that check the transfer of MDR and β-lactamase producing bacterial pathogens among the hospitalized patients.

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