Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring tet(X) and mcr-1

ABSTRACTAlternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against E. coli harboring tet(X) and mcr-1 in vitro and in a murine thigh infection model. Zidovudine and tigecycline/colistin combinations achieved synergistic killing and significantly decreased bacterial burdens by >2.5-log10 CFU/g in thigh tissues compared to each monotherapy.

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Heterogeneous and Flexible Transmission ofmcr-1in Hospital-AssociatedEscherichia coli

mBio ◽

10.1128/mbio.00943-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 23

Author(s):

Yingbo Shen ◽

Zuowei Wu ◽

Yang Wang ◽

Rong Zhang ◽

Hong-Wei Zhou ◽

...

Keyword(s):

Escherichia Coli ◽

Genomic Analysis ◽

Multidrug Resistant ◽

Fluoroquinolone Resistance ◽

Gram Negative Bacteria ◽

Colistin Resistance ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Genes Encoding

ABSTRACTThe recent emergence of a transferable colistin resistance mechanism, MCR-1, has gained global attention because of its threat to clinical treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, the possible transmission route ofmcr-1amongEnterobacteriaceaespecies in clinical settings is largely unknown. Here, we present a comprehensive genomic analysis ofEscherichia coliisolates collected in a hospital in Hangzhou, China. We found thatmcr-1-carrying isolates from clinical infections and feces of inpatients and healthy volunteers were genetically diverse and were not closely related phylogenetically, suggesting that clonal expansion is not involved in the spread ofmcr-1. Themcr-1gene was found on either chromosomes or plasmids, but in most of theE. coliisolates,mcr-1was carried on plasmids. The genetic context of the plasmids showed considerable diversity as evidenced by the different functional insertion sequence (IS) elements, toxin-antitoxin (TA) systems, heavy metal resistance determinants, and Rep proteins of broad-host-range plasmids. Additionally, the genomic analysis revealed nosocomial transmission ofmcr-1and the coexistence ofmcr-1with other genes encoding β-lactamases and fluoroquinolone resistance in theE. coliisolates. These findings indicate thatmcr-1is heterogeneously disseminated in both commensal and pathogenic strains ofE. coli, suggest the high flexibility of this gene in its association with diverse genetic backgrounds of the hosts, and provide new insights into the genome epidemiology ofmcr-1among hospital-associatedE. colistrains.IMPORTANCEColistin represents one of the very few available drugs for treating infections caused by extensively multidrug-resistant Gram-negative bacteria. The recently emergentmcr-1colistin resistance gene threatens the clinical utility of colistin and has gained global attention. Howmcr-1spreads in hospital settings remains unknown and was investigated by whole-genome sequencing ofmcr-1-carryingEscherichia coliin this study. The findings revealed extraordinary flexibility ofmcr-1in its spread among genetically diverseE. colihosts and plasmids, nosocomial transmission ofmcr-1-carryingE. coli, and the continuous emergence of novel Inc types of plasmids carryingmcr-1and newmcr-1variants. Additionally,mcr-1was found to be frequently associated with other genes encoding β-lactams and fluoroquinolone resistance. These findings provide important information on the transmission and epidemiology ofmcr-1and are of significant public health importance as the information is expected to facilitate the control of this significant antibiotic resistance threat.

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Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01718-12 ◽

2013 ◽

Vol 57 (3) ◽

pp. 1421-1427 ◽

Cited By ~ 66

Author(s):

Stéphane Corvec ◽

Ulrika Furustrand Tafin ◽

Bertrand Betrisey ◽

Olivier Borens ◽

Andrej Trampuz

Keyword(s):

Escherichia Coli ◽

Foreign Body ◽

Single Agent ◽

Infection Model ◽

Minimal Bactericidal Concentration ◽

Synergistic Activity ◽

Cure Rate ◽

Gram Negative ◽

Content Type

ABSTRACTLimited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain ofEscherichia coli(Bj HDE-1)in vitroand in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBClog) and stationary phase (MBCstat) were 0.12, 0.12, and 8 μg/ml for fosfomycin, 0.25, 32, and 32 μg/ml for tigecycline, 0.25, 0.5, and 2 μg/ml for colistin, and 2, 8, and 16 μg/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistinin vitrowas observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log10CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log10CFU/ml. Fosfomycin was the only single agent which was able to eradicateE. colibiofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (P< 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (P< 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.

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Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in anIn VitroPharmacokinetic/Pharmacodynamic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00703-13 ◽

2013 ◽

Vol 57 (8) ◽

pp. 3738-3745 ◽

Cited By ~ 60

Author(s):

Hee Ji Lee ◽

Phillip J. Bergen ◽

Jurgen B. Bulitta ◽

Brian Tsuji ◽

Alan Forrest ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Population Analysis ◽

Multidrug Resistant ◽

Synergistic Activity ◽

Colistin Resistance ◽

Bacterial Killing ◽

Content Type ◽

High Inoculum ◽

Combination Regimens

ABSTRACTCombination therapy may be required for multidrug-resistant (MDR)Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDRA. baumannii. Studies were conducted over 72 h in anin vitropharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106and ∼108CFU/ml using two MDR clinical isolates ofA. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [Cmax] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 106-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 108-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDRA. baumannii.

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The Intimin-Like Protein FdeC Is Regulated by H-NS and Temperature in Enterohemorrhagic Escherichia coli

Applied and Environmental Microbiology ◽

10.1128/aem.02114-14 ◽

2014 ◽

Vol 80 (23) ◽

pp. 7337-7347 ◽

Cited By ~ 10

Author(s):

Donna M. Easton ◽

Luke P. Allsopp ◽

Minh-Duy Phan ◽

Danilo Gomes Moriel ◽

Guan Kai Goh ◽

...

Keyword(s):

Escherichia Coli ◽

Culture Conditions ◽

Enterohemorrhagic Escherichia Coli ◽

Infection Model ◽

Content Type ◽

E Coli ◽

Uremic Syndrome ◽

Animal Hosts ◽

And Function

ABSTRACTEnterohemorrhagicEscherichia coli(EHEC) is a Shiga-toxigenic pathogen capable of inducing severe forms of enteritis (e.g., hemorrhagic colitis) and extraintestinal sequelae (e.g., hemolytic-uremic syndrome). The molecular basis of colonization of human and animal hosts by EHEC is not yet completely understood, and an improved understanding of EHEC mucosal adherence may lead to the development of interventions that could disrupt host colonization. FdeC, also referred to by its IHE3034 locus tag ECOK1_0290, is an intimin-like protein that was recently shown to contribute to kidney colonization in a mouse urinary tract infection model. The expression of FdeC is tightly regulatedin vitro, and FdeC shows promise as a vaccine candidate against extraintestinalE. colistrains. In this study, we characterized the prevalence, regulation, and function offdeCin EHEC. We showed that thefdeCgene is conserved in both O157 and non-O157 EHEC and encodes a protein that is expressed at the cell surface and promotes biofilm formation under continuous-flow conditions in a recombinantE. colistrain background. We also identified culture conditions under which FdeC is expressed and showed that minor alterations of these conditions, such as changes in temperature, can significantly alter the level of FdeC expression. Additionally, we demonstrated that the transcription of thefdeCgene is repressed by the global regulator H-NS. Taken together, our data suggest a role for FdeC in EHEC when it grows at temperatures above 37°C, a condition relevant to its specialized niche at the rectoanal junctions of cattle.

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ISKpn40-Mediated Mobilization of the Colistin Resistance Gene mcr-3.11 in Escherichia coli

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00851-20 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Yu-Zhang He ◽

Teng-Fei Long ◽

Cai-Ping Chen ◽

Bing He ◽

Xing-Ping Li ◽

...

Keyword(s):

Escherichia Coli ◽

Resistance Gene ◽

Wild Type ◽

Colistin Resistance ◽

Content Type ◽

First Report ◽

E Coli ◽

Target Sites

ABSTRACT The mobile colistin resistance gene mcr-3 has globally disseminated since it was first reported in 2017 in Escherichia coli. In vitro mobilization assays in this study demonstrate the functionality of the composite transposon structure ISKpn40-mcr-3.11-dgkA-ISKpn40 in wild-type and recA− E. coli strains. These transpositions generated 4-bp duplications at the target sites. This is the first report demonstrating the mobility of the mcr-3.11 gene by transposition.

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Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04494-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3109-3116 ◽

Cited By ~ 19

Author(s):

Valéria Szijártó ◽

Luis M. Guachalla ◽

Zehra C. Visram ◽

Katharina Hartl ◽

Cecília Varga ◽

...

Keyword(s):

Escherichia Coli ◽

Monoclonal Antibodies ◽

Human Serum ◽

Significant Proportion ◽

Multidrug Resistant ◽

Bacterial Killing ◽

Content Type ◽

E Coli

ABSTRACTTheEscherichia colisequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assayin vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of actionin vivowas investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to liveE. colicells and thein vitroandin vivoefficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused byE. coliST131-O25b:H4.

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Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01654-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 9

Author(s):

Toyotaka Sato ◽

Yuuki Suzuki ◽

Tsukasa Shiraishi ◽

Hiroyuki Honda ◽

Masaaki Shinagawa ◽

...

Keyword(s):

Escherichia Coli ◽

Parental Strain ◽

Efflux Pump ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Fluoroquinolone Resistance ◽

Content Type ◽

E Coli ◽

Line Drug

ABSTRACT Tigecycline (TGC) is a last-line drug for multidrug-resistant Enterobacteriaceae. We investigated the mechanism(s) underlying TGC nonsusceptibility (TGC resistant/intermediate) in Escherichia coli clinical isolates. The MIC of TGC was determined for 277 fluoroquinolone-susceptible isolates (ciprofloxacin [CIP] MIC, <0.125 mg/liter) and 194 fluoroquinolone-resistant isolates (CIP MIC, >2 mg/liter). The MIC50 and MIC90 for TGC in fluoroquinolone-resistant isolates were 2-fold higher than those in fluoroquinolone-susceptible isolates (MIC50, 0.5 mg/liter versus 0.25 mg/liter; MIC90, 1 mg/liter versus 0.5 mg/liter, respectively). Two fluoroquinolone-resistant isolates (O25b:H4-ST131-H30R and O125:H37-ST48) were TGC resistant (MICs of 4 and 16 mg/liter, respectively), and four other isolates of O25b:H4-ST131-H30R and an isolate of O1-ST648 showed an intermediate interpretation (MIC, 2 mg/liter). No TGC-resistant/intermediate strains were found among the fluoroquinolone-susceptible isolates. The TGC-resistant/intermediate isolates expressed higher levels of acrA and acrB and had lower intracellular TGC concentrations than susceptible isolates, and they possessed mutations in acrR and/or marR. The MICs of acrAB-deficient mutants were markedly lower (0.25 mg/liter) than those of the parental strain. After continuous stepwise exposure to CIP in vitro, six of eight TGC-susceptible isolates had reduced TGC susceptibility. Two of them acquired TGC resistance (TGC MIC, 4 mg/liter) and exhibited expression of acrA and acrB and mutations in acrR and/or marR. In conclusion, a population of fluoroquinolone-resistant E. coli isolates, including major extraintestinal pathogenic lineages O25b:H4-ST131-H30R and O1-ST648, showed reduced susceptibility to TGC due to overexpression of the efflux pump AcrAB-TolC, leading to decreased intracellular concentrations of the antibiotics that may be associated with the development of fluoroquinolone resistance.

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Whole-Genome Sequencing of Multidrug-Resistant Escherichia coli Strains Harboring the mcr-1 Gene, Isolated from Seawater of the Algiers Coast in Algeria

Microbiology Resource Announcements ◽

10.1128/mra.00638-19 ◽

2019 ◽

Vol 8 (34) ◽

Cited By ~ 2

Author(s):

M. Berrazeg ◽

A. Deriet ◽

S. C. J. De Keersmaecker ◽

B. Verhaegen ◽

K. Vanneste ◽

...

Keyword(s):

Escherichia Coli ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Treatment Efficacy ◽

Multidrug Resistant ◽

Whole Genome ◽

Colistin Resistance ◽

Content Type ◽

E Coli

Colistin resistance has emerged worldwide and is threatening the treatment efficacy of multiresistant Escherichia coli strains in humans and animals. Here, we communicate the whole-genome sequencing (WGS) of two colistin-resistant E. coli strains, M49 and M78, with genomes sizes of 4,947,168 and 5,178,716 bp, respectively, isolated from seawaters of the Algiers coast.

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Paenipeptin Analogues Potentiate Clarithromycin and Rifampin against mcr-1-Mediated Polymyxin-Resistant Escherichia coli In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02045-19 ◽

2020 ◽

Vol 64 (4) ◽

Author(s):

Sun Hee Moon ◽

Yihong Kaufmann ◽

En Huang

Keyword(s):

Escherichia Coli ◽

Antimicrobial Resistance ◽

Outer Membrane ◽

Infection Model ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Log Reduction

ABSTRACT Polymyxin resistance mediated by the mcr-1 gene threatens the last-resort antibiotics. Linear lipopeptide paenipeptin analogues 1 and 15 disrupted the outer membrane of Gram-negative pathogens and potentiated clarithromycin and rifampin against mcr-1-positive Escherichia coli from the FDA-CDC Antimicrobial Resistance Isolate Bank. In the presence of paenipeptin, clarithromycin and rifampin resulted in over 3-log reduction of E. coli in vitro. Moreover, paenipeptin-antibiotic combinations significantly reduced E. coli in a murine thigh infection model.

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

Scientific Reports ◽

10.1038/s41598-021-81140-8 ◽

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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