scholarly journals Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

2020 ◽  
Author(s):  
Andrea Miró-Canturri ◽  
Rafael Ayerbe-Algaba ◽  
Raquel del Toro ◽  
Jerónimo Pachón ◽  
Younes Smani
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Immune System ◽  
Acinetobacter Baumannii ◽  
Therapeutic Efficacy ◽  
Multidrug Resistant ◽  
Tamoxifen Treatment ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
E Coli

AbstractThe development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposing to be used as monotherapies or in combination with clinically relevant antibiotics, has become an urgent need. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice infected by Acinetobacter baumannii, Pseudomonas aeruginosa or Escherichia coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days reduced the release of MCP-1 and its signalling pathway IL-18 and phosphorylated ERK1/2. This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from bone marrow to blood. Indeed, the treatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood; and increased the mice survival from 0% to 60-100%. Tamoxifen treatment of neutropenic mice infected by these pathogens increased mice survival up to 20-60%. Furthermore, susceptibility and time-kill assays showed that the metabolites of tamoxifen, N-desmethyltamoxifen, hydroxytamoxifen and endoxifen, the three together exhibited MIC90 values of 16 mg/L and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites parallels’ an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen present a therapeutic efficacy against MDR A. baumannii, P. aeruginosa and E. coli in experimental models of infections and can be repurposed as new treatment for GNB infections.ImportanceAntimicrobial resistance in Gram-negative bacilli (GNB) is a global health treat. Drug repurposing, a novel approach involving the search of new indications for FDA approved drugs is gaining interest. Among them, we found the anti-cancer drug tamoxifen, which presents very promising therapeutic efficacy. The current study showed that tamoxifen presents activity in animal models of infection with MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli by modulating the traffic of innate immune system cells and the antibacterial activity presented by its three major metabolites produced in vivo against these GNB. Our results offer a new candidate to be repurposed to treat severe infections caused by these pathogens.

scholarly journals Epidemiology of Multidrug-resistant Bacteria Isolated from Hospitalized Patients in a Regional Central Hospital in China

2020 ◽  
Author(s):  
Jixun Zhang ◽  
Rui Li ◽  
Zhenzhong Liu ◽  
Chao Wang
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Hospitalized Patients ◽  
Resistant Bacteria ◽  
Central Hospital ◽  
Gram Negative ◽  
E Coli ◽  
Significant Difference ◽  
The Impact

Abstract Objectives: Considering the dynamic changes of MDR, we did an up-to-date study and analyzed the impact of MDR on the outcome of patients. Design: Collected MDR isolated from hospitalized patients between June 2018 and May 2020 and performed retrospective analysis. Setting: This study was conducted in a public regional central hospital in China.Patients: 1156 patients with MDR infections.Results: Total 1291 MDRS were isolated, intensive care unit (ICU) accounted for 32.3% as the most. The main samples were sputum (75.1%) and 89.6% MDR were Gram-negative. The most common MDR were Acinetobacter baumannii, carbapenemase-producing K. pneumoniae, Pseudomonas aeruginosa, ESBL-producing E. coli. Methicillin-resistant Staphylococcus aureus (MRSA) and ESBL-producing K.pneumoniae. 35.6% were nosocomial infections and 64.4% were community-acquired infections. There was a statistically significant difference in mortality between patients infected with MDR and those with non-MDR (7.4% [32/432] vs 2.6% [17/655]; P = 0.001). The Acinetobacter baumannii and Klebsiella pneumoniae were mainly sensitive to tigecycline. The Pseudomonas aeruginosa was mainly sensitive to amikacin and levofloxacin. More than 80% of the Escherichia coli were sensitive to tigecycline and carbapenems. More than 90% of MRSA were sensitive to vancomycin, linezolid, and quinoprptin / daptoptin.Conclusions: The MDRS are mainly gram-negative bacteria. ICU contributes most MDR and pulmonary infection is the main origin of MDR. MDR infection is an independent risk factor for death. ESBL-producing Enterobacteriaceae, especially carbapenemase producing Enterobacteriaceae, should be paid more attention. This study is helpful to understand the distribution of MDR in hospital and the extent of antibiotic resistance.

scholarly journals Carbapenem and colistin-resistant bacteria in North Lebanon: Coexistence of mcr-1 and NDM-4 genes in Escherichia coli

2021 ◽  
Vol 15 (07) ◽  
pp. 934-342
Author(s):  
Charbel Al-Bayssari ◽  
Tania Nawfal Dagher ◽  
Samar El Hamoui ◽  
Fadi Fenianos ◽  
Nehman Makdissy ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Ionization Time ◽  
E Coli ◽  
Flight Mass Spectrometry ◽  
Carbapenem Resistant ◽  
The Matrix

Introduction: The increasing incidence of infections caused by multidrug-resistant bacteria is considered a global health problem. This study aimed to investigate this resistance in Gram-negative bacteria isolated from patients hospitalized in North-Lebanon. Methodology: All isolates were identified using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Antibiotic susceptibility testing was achieved using disk diffusion, E-test and Broth microdilution methods. Phenotypic detection of carbapenemase was carried out using the CarbaNP test. RT-PCR, standard-PCR and sequencing were performed to detect resistance genes and oprD gene. Conjugal transfer was carried out between our isolates and Escherichia coli J53 to detect the genetic localization of resistance genes. MLST was conducted to determine the genotype of each isolate. Results: Twenty-three carbapenem-resistant Enterobacterales of which eight colistin-resistant Escherichia coli, and Twenty carbapenem-resistant Pseudomonas aeruginosa were isolated. All isolates showed an imipenem MIC greater than 32 mg/mL with MICs for colistin greater than 2 mg/L for E. coli isolates. All the Enterobacterales isolates had at least one carbapenemase-encoding gene, with E. coli isolates coharboring blaNDM-4 and mcr-1 genes. Moreover, 16/20 Pseudomonas aeruginosa harbored the blaVIM-2 gene and 18/20 had mutations in the oprD gene. MLST revealed that the isolates belonged to several clones. Conclusions: We report here the first description in the world of clinical E. coli isolates coharboring blaNDM-4 and mcr-1 genes, and K. pneumoniae isolates producing NDM-6 and OXA-48 carbapenemases. Also, we describe the emergence of NDM-1-producing E. cloacae in Lebanon. Screening for these isolates is necessary to limit the spread of resistant microorganisms in hospitals.

scholarly journals In Vitro Activity of Colistin (Polymyxin E) against 3,480 Isolates of Gram-Negative Bacilli Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007-2008

2009 ◽  
Vol 53 (11) ◽  
pp. 4924-4926 ◽  
Author(s):  
A. Walkty ◽  
M. DeCorby ◽  
K. Nichol ◽  
J. A. Karlowsky ◽  
D. J. Hoban ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Gram Negative ◽  
Polymyxin E

ABSTRACT The in vitro activity of colistin was evaluated versus 3,480 isolates of gram-negative bacilli using CLSI broth microdilution methods. The MIC90 of colistin was ≤2 μg/ml against a variety of clinically important gram-negative bacilli, including Escherichia coli, Klebsiella spp., Enterobacter spp., Acinetobacter baumannii, and Pseudomonas aeruginosa. All multidrug-resistant (n = 76) P. aeruginosa isolates were susceptible to colistin (MIC, ≤2 μg/ml). These data support a role for colistin in the treatment of infections caused by multidrug-resistant P. aeruginosa.

scholarly journals Cefepime/tazobactam as a new treatment option for multidrug resistant gram negative bacilli

2019 ◽  
Vol 7 (6) ◽  
pp. 2278
Author(s):  
Roshni Agarwal ◽  
Vaibhav Agarwal ◽  
Anjali Tewari ◽  
Parwati Upadhyay
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
In Vitro Susceptibility ◽  
Gram Negative ◽  
E Coli ◽  
New Treatment

Background: Every time an antibiotic is used, whether appropriately or not, the probability of the development and spread of antibiotic resistant bacteria is increased. Thus, multidrug resistant bacteria particularly ESBL (Extended spectrum β­lactamase), Amp C and carbapenemases producing gram negative bacilli have emerged as a major health problem all over the world. Considering new treatment options as a carbapenems sparing and resistance prevention modality, this study was aimed to know the in vitro susceptibility pattern of Cefepime/Tazobactam (CPM/TZ) in comparison to other β-Lactam/ β-Lactamase inhibitors (BL/BLI) and carbapenems against GNB.Methods: A prospective study was conducted on all clinical samples received for a period of about 1 year. Identification and susceptibility of all isolates was done by Vitek 2 Compact system. Susceptibility of CPM/ TZ was done by disc diffusion method on the basis of CLSI guidelines. Both fermenters (E. coli and Klebsiella pneumoniae) and non-fermenters (Acintobacter baumanii and Pseudomonas aeruginosa) were included in the study.Results: Out of 550 GNB isolates the most common was E. coli (61.8%), Acintobacter baumanii (16%), Klebsiella pneumoniae (14.9%) and Pseudomonas aeruginosa (7.3%). Cefepime/tazobactam had a much higher susceptibility of 68% compared to cefepime (28%). Among the BL/BLI combinations tested cefepime/tazobactam (68%) showed the maximum percentage of susceptibility followed by cefoperazone/sulbactam (61.5%) and piperacillin/tazobactam (57.6%). Amongst all GNB isolates cefepime/tazobactam (68%) sensitivity was very much comparable to imipenem (71.8%) and meropenem (69.6%).Conclusions: CPM/TZ exhibited the best in vitro activity in comparison to the other BL/BLI. This new combination of cefepime/tazobactam appears to be a promising alternative therapeutic option to carbapenems. Clinical studies are needed to confirm this in vitro study result.

scholarly journals Fluorescence High-Throughput Screening for Inhibitors of TonB Action

2017 ◽  
Vol 199 (10) ◽  
Author(s):  
Brittany L. Nairn ◽  
Olivia S. Eliasson ◽  
Dallas R. Hyder ◽  
Noah J. Long ◽  
Aritri Majumdar ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
High Throughput ◽  
High Throughput Screening ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Compound Libraries

ABSTRACT Gram-negative bacteria acquire ferric siderophores through TonB-dependent outer membrane transporters (TBDT). By fluorescence spectroscopic hgh-throughput screening (FLHTS), we identified inhibitors of TonB-dependent ferric enterobactin (FeEnt) uptake through Escherichia coli FepA (EcoFepA). Among 165 inhibitors found in a primary screen of 17,441 compounds, we evaluated 20 in secondary tests: TonB-dependent ferric siderophore uptake and colicin killing and proton motive force-dependent lactose transport. Six of 20 primary hits inhibited TonB-dependent activity in all tests. Comparison of their effects on [59Fe]Ent and [14C]lactose accumulation suggested several as proton ionophores, but two chemicals, ebselen and ST0082990, are likely not proton ionophores and may inhibit TonB-ExbBD. The facility of FLHTS against E. coli led us to adapt it to Acinetobacter baumannii. We identified its FepA ortholog (AbaFepA), deleted and cloned its structural gene, genetically engineered 8 Cys substitutions in its surface loops, labeled them with fluorescein, and made fluorescence spectroscopic observations of FeEnt uptake in A. baumannii. Several Cys substitutions in AbaFepA (S279C, T562C, and S665C) were readily fluoresceinated and then suitable as sensors of FeEnt transport. As in E. coli, the test monitored TonB-dependent FeEnt uptake by AbaFepA. In microtiter format with A. baumannii, FLHTS produced Z′ factors 0.6 to 0.8. These data validated the FLHTS strategy against even distantly related Gram-negative bacterial pathogens. Overall, it discovered agents that block TonB-dependent transport and showed the potential to find compounds that act against Gram-negative CRE (carbapenem-resistant Enterobacteriaceae)/ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Our results suggest that hundreds of such chemicals may exist in larger compound libraries. IMPORTANCE Antibiotic resistance in Gram-negative bacteria has spurred efforts to find novel compounds against new targets. The CRE/ESKAPE pathogens are resistant bacteria that include Acinetobacter baumannii, a common cause of ventilator-associated pneumonia and sepsis. We performed fluorescence high-throughput screening (FLHTS) against Escherichia coli to find inhibitors of TonB-dependent iron transport, tested them against A. baumannii, and then adapted the FLHTS technology to allow direct screening against A. baumannii. This methodology is expandable to other drug-resistant Gram-negative pathogens. Compounds that block TonB action may interfere with iron acquisition from eukaryotic hosts and thereby constitute bacteriostatic antibiotics that prevent microbial colonization of human and animals. The FLHTS method may identify both species-specific and broad-spectrum agents against Gram-negative bacteria.

scholarly journals Mutant Prevention Concentrations of Four Carbapenems against Gram-Negative Rods

2010 ◽  
Vol 54 (6) ◽  
pp. 2692-2695 ◽  
Author(s):  
Kim Credito ◽  
Klaudia Kosowska-Shick ◽  
Peter C. Appelbaum
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Gram Negative ◽  
Clinical Strains ◽  
E Coli

ABSTRACT We tested the propensities of four carbapenems to select for resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii mutants by determining the mutant prevention concentrations (MPCs) for 100 clinical strains with various ß-lactam phenotypes. Among the members of the Enterobacteriaceae family and A. baumannii strains, the MPC/MIC ratios were mostly 2 to 4. In contrast, for P. aeruginosa the MPC/MIC ratios were 4 to ≥16. The MPC/MIC ratios for β-lactamase-positive K. pneumoniae and E. coli isolates were much higher (range, 4 to >16 μg/ml) than those for ß-lactamase-negative strains.

scholarly journals Geraniol Restores Antibiotic Activities against Multidrug-Resistant Isolates from Gram-Negative Species

2009 ◽  
Vol 53 (5) ◽  
pp. 2209-2211 ◽  
Author(s):  
Vannina Lorenzi ◽  
Alain Muselli ◽  
Antoine François Bernardini ◽  
Liliane Berti ◽  
Jean-Marie Pagès ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Essential Oil ◽  
Acinetobacter Baumannii ◽  
Enterobacter Aerogenes ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Gram Negative

ABSTRACT The essential oil of Helichrysum italicum significantly reduces the multidrug resistance of Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Combinations of the two most active fractions of the essential oil with each other or with phenylalanine arginine β-naphthylamide yield synergistic activity. Geraniol, a component of one fraction, significantly increased the efficacy of β-lactams, quinolones, and chloramphenicol.

scholarly journals Characteristics of and risk factors for biliary pathogen infection in patients with acute pancreatitis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shayan Chen ◽  
Jiyu Shi ◽  
Minghui Chen ◽  
Jun Ma ◽  
Zhaowei Zeng ◽  
...  
Keyword(s):  
Risk Factors ◽  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Acute Pancreatitis ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Negative

Abstract Background Infection in patients with acute pancreatitis, especially severe acute pancreatitis patients, is a common and important phenomenon, and the distributions and drug resistance profiles of bacteria causing biliary infection and related risk factors are dynamic. We conducted this study to explore the characteristics of and risk factors for bacterial infection in the biliary tract to understand antimicrobial susceptibility, promote the rational use of antibiotics, control multidrug-resistant bacterial infections and provide guidance for the treatment of acute pancreatitis caused by drug-resistant bacteria. Methods The distribution of 132 strains of biliary pathogenic bacteria in patients with acute pancreatitis from January 2016 to December 2020 were analyzed. We assessed drug resistance in the dominant Gram-negative bacteria and studied the drug resistance profiles of multidrug-resistant bacteria by classifying Enterobacteriaceae and nonfermentative bacteria. We then retrospectively analyzed the clinical data and risk factors associated with 72 strains of Gram-negative bacilli, which were divided into multidrug-resistant bacteria (50 cases) and non-multidrug-resistant bacteria (22 cases). Results The main bacteria were Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli had a 66.67% detection rate. Acinetobacter baumannii had more than 50.00% drug resistance to carbapenems, ESBL-producing Klebsiella pneumoniae had 100.00% drug resistance, and Pseudomonas aeruginosa had 66.67% resistance to carbapenems. Multivariate logistic regression analysis suggested that the administration of third- or fourth-generation cephalosporins was an independent risk factor for Gram-negative multidrug-resistant biliary bacterial infection in acute pancreatitis patients. Conclusion Drug resistance among biliary pathogens in acute pancreatitis patients remains high; therefore, rational antimicrobial drug use and control measures should be carried out considering associated risk factors to improve diagnosis and treatment quality in acute pancreatitis patients.

scholarly journals Distribution of Extended-Spectrum β-Lactamase (ESBL)-Encoding Genes among Multidrug-Resistant Gram-Negative Pathogens Collected from Three Different Countries

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 247
Author(s):  
Khaled S. M. Azab ◽  
Mohamed Ali Abdel-Rahman ◽  
Hussien H. El-Sheikh ◽  
Ehab Azab ◽  
Adil A. Gobouri ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Saudi Arabia ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
Extended Spectrum ◽  
Resistant Strains ◽  
Encoding Genes

The incidence of Extended-spectrum β-lactamase (ESBL)-encoding genes (blaCTX-M and blaTEM) among Gram-negative multidrug-resistant pathogens collected from three different countries was investigated. Two hundred and ninety-two clinical isolates were collected from Egypt (n = 90), Saudi Arabia (n = 162), and Sudan (n = 40). Based on the antimicrobial sensitivity against 20 antimicrobial agents from 11 antibiotic classes, the most resistant strains were selected and identified using the Vitek2 system and 16S rRNA gene sequence analysis. A total of 85.6% of the isolates were found to be resistant to more than three antibiotic classes. The ratios of the multidrug-resistant strains for Egypt, Saudi Arabia, and Sudan were 74.4%, 90.1%, and 97.5%, respectively. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa showed inconstant resistance levels to the different classes of antibiotics. Escherichia coli and Klebsiella pneumoniae had the highest levels of resistance against macrolides followed by penicillins and cephalosporin, while Pseudomonas aeruginosa was most resistant to penicillins followed by classes that varied among different countries. The isolates were positive for the presence of the blaCTX-M and blaTEM genes. The blaCTX-M gene was the predominant gene in all isolates (100%), while blaTEM was detected in 66.7% of the selected isolates. This work highlights the detection of multidrug-resistant bacteria and resistant genes among different countries. We suggest that the medical authorities urgently implement antimicrobial surveillance plans and infection control policies for early detection and effective prevention of the rapid spread of these pathogens.

scholarly journals In vitro activity of antimicrobial peptide CDP-B11 alone and in combination with colistin against colistin-resistant and multidrug-resistant Escherichia coli

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaitlin S. Witherell ◽  
Jason Price ◽  
Ashok D. Bandaranayake ◽  
James Olson ◽  
Douglas R. Call
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptide ◽  
Membrane Integrity ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
E Coli ◽  
Minimal Media

AbstractMultidrug-resistant bacteria are a growing global concern, and with increasingly prevalent resistance to last line antibiotics such as colistin, it is imperative that alternative treatment options are identified. Herein we investigated the mechanism of action of a novel antimicrobial peptide (CDP-B11) and its effectiveness against multidrug-resistant bacteria including Escherichia coli #0346, which harbors multiple antibiotic-resistance genes, including mobilized colistin resistance gene (mcr-1). Bacterial membrane potential and membrane integrity assays, measured by flow cytometry, were used to test membrane disruption. Bacterial growth inhibition assays and time to kill assays measured the effectiveness of CDP-B11 alone and in combination with colistin against E. coli #0346 and other bacteria. Hemolysis assays were used to quantify the hemolytic effects of CDP-B11 alone and in combination with colistin. Findings show CDP-B11 disrupts the outer membrane of E. coli #0346. CDP-B11 with colistin inhibits the growth of E. coli #0346 at ≥ 10× lower colistin concentrations compared to colistin alone in Mueller–Hinton media and M9 media. Growth is significantly inhibited in other clinically relevant strains, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. In rich media and minimal media, the drug combination kills bacteria at a lower colistin concentration (1.25 μg/mL) compared to colistin alone (2.5 μg/mL). In minimal media, the combination is bactericidal with killing accelerated by up to 2 h compared to colistin alone. Importantly, no significant red blood hemolysis is evident for CDP-B11 alone or in combination with colistin. The characteristics of CDP-B11 presented here indicate that it can be used as a potential monotherapy or as combination therapy with colistin for the treatment of multidrug-resistant infections, including colistin-resistant infections.

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