• antibiotics
• antimicrobial efficacy
• pharmacodynamic
• pharmacokinetic
• post-antibiotic effect

• Anti-Bacterial Agents/pharmacokinetics
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/therapeutic use
• Anti-Bacterial Agents/administration & dosage
• Humans
• Bacterial Infections/drug therapy
• Animals
• Microbial Sensitivity Tests
• Bacteria/drug effects

• Antimicrobial resistance
• Bacterial stress response
• Drug target
• Pathogens
• Reporter metabolite

• Bacteria/drug effects
• Bacteria/genetics
• Bacteria/metabolism
• Stress, Physiological
• Anti-Bacterial Agents/pharmacology
• Drug Resistance, Bacterial
• Gene Expression Regulation, Bacterial/drug effects
• Metabolic Networks and Pathways
• Humans
• Pseudomonas aeruginosa/drug effects
• Pseudomonas aeruginosa/genetics
• Klebsiella pneumoniae/drug effects
• Klebsiella pneumoniae/genetics
• Transcriptome
• Escherichia coli/drug effects
• Escherichia coli/genetics
• Microbial Sensitivity Tests
• Gene Expression Profiling

• Uskudar University

• Raoultella ornithinolytica
• antibiotic resistance
• carbapenemase
• waterborne pathogens

• Bloodstream infections
• multidrug resistance
• risk factor

• 70017 Israel Innovatoin Austhority

• Antibacterial activity
• Antifungal activity
• Candida
• Lectin characterization
• Pectobacterium
• Phytopathogens

• Humans
• Animals
• Mice
• Lectins
• Portulaca
• Anti-Infective Agents/toxicity
• Anti-Infective Agents/analysis
• Anti-Bacterial Agents/toxicity
• Plant Leaves/chemistry
• Microbial Sensitivity Tests
• Antifungal Agents/pharmacology

• 407192/2018-2 Conselho Nacional de Desenvolvimento Científico e Tecnológico
• APQ-0108-2.08/14 Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco

• Acinetobacter
• antibiotics
• checkerboard
• combinations
• extensive drug resistance
• resistance

The increasing interest for Galleria mellonella larvae as an infection model is evidenced by the number of papers reporting its use, which increases exponentially since the early 2010s. This popularity was initially linked to limitation of conventional animal models due to financial, technical and ethical aspects. In comparison, alternative models (e.g. models using Caenorhabditis elegans, Drosophila melanogaster or G. mellonella) were cheap, simple to use and not limited by ethical regulation. Since then, similar results have been established with G. mellonella model comparatively to vertebrates, and it is more and more often used as a robust model per se, not only as an alternative to the murine model. This review attempts to summarize the current knowledge supporting the development of this model, both on immunological and microbiological aspects. For that, we focus on investigation of virulence and new therapies for the most important pathogenic bacteria. We also discuss points out directions for standardization, as well as recent advances and new perspectives for monitoring host-pathogen interactions.

• Galleria mellonella
• antibacterial therapies
• infection model
• pathogenic bacteria
• perspectives
• standardization

• multidrug-resistance
• phage cocktail
• phage therapy
• urinary tract infections
• uropathogenic Escherichia coli

Arthropod antimicrobial peptides (AMPs) offer a promising source of new leads to address the declining number of novel antibiotics and the increasing prevalence of multidrug-resistant bacterial pathogens. AMPs with potent activity against Gram-negative bacteria and distinct modes of action have been identified in insects and scorpions, allowing the discovery of AMP combinations with additive and/or synergistic effects. Here, we tested the synergistic activity of two AMPs, from the dung beetle Copris tripartitus (CopA3) and the scorpion Heterometrus petersii (Hp1090), against two strains of Escherichia coli. We also tested the antibacterial activity of two hybrid peptides generated by joining CopA3 and Hp1090 with linkers comprising two (InSco2) or six (InSco6) glycine residues. We found that CopA3 and Hp1090 acted synergistically against both bacterial strains, and the hybrid peptide InSco2 showed more potent bactericidal activity than the parental AMPs or InSco6. Molecular dynamics simulations revealed that the short linker stabilizes an N-terminal 3₁₀-helix in the hybrid peptide InSco2. This secondary structure forms from a coil region that interacts with phosphatidylethanolamine in the membrane bilayer model. The highest concentration of the hybrid peptides used in this study was associated with stronger hemolytic activity than equivalent concentrations of the parental AMPs. As observed for CopA3, the increasing concentration of InSco2 was also cytotoxic to BHK-21 cells. We conclude that AMP hybrids linked by glycine spacers display potent antibacterial activity and that the cytotoxic activity can be modulated by adjusting the nature of the linker peptide, thus offering a strategy to produce hybrid peptides as safe replacements or adjuncts for conventional antibiotic therapy.

• Escherichia coli
• antimicrobial peptide
• glycine spacer
• hybrid peptide
• insect
• scorpion

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anti-Bacterial Agents/administration & dosage
• Anti-Bacterial Agents/adverse effects
• Anti-Bacterial Agents/therapeutic use
• Azabicyclo Compounds/administration & dosage
• Azabicyclo Compounds/adverse effects
• Azabicyclo Compounds/therapeutic use
• Ceftazidime/administration & dosage
• Ceftazidime/adverse effects
• Ceftazidime/therapeutic use
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Drug Combinations
• Female
• Humans
• Infections/drug therapy
• Infections/mortality
• Intraabdominal Infections/drug therapy
• Male
• Meta-Analysis as Topic
• Metronidazole/adverse effects
• Metronidazole/therapeutic use
• Middle Aged
• Multicenter Studies as Topic
• Randomized Controlled Trials as Topic
• Treatment Outcome
• Young Adult
• beta-Lactamase Inhibitors/administration & dosage
• beta-Lactamase Inhibitors/adverse effects
• beta-Lactamase Inhibitors/therapeutic use

• Pfizer
• AstraZeneca
• Novexel

• antibiotic resistance
• bacteriophage
• phage pharmacotherapy
• phage proteins
• phage therapy

• Anti-Bacterial Agents
• Bacteria
• Bacterial Infections
• Bacteriophages
• Humans
• Phage Therapy

• Animals
• Anti-Bacterial Agents/chemistry
• Anti-Bacterial Agents/metabolism
• Anti-Bacterial Agents/pharmacology
• Bacterial Proteins/chemistry
• Bacterial Proteins/metabolism
• Ferric Compounds/chemistry
• Ferric Compounds/metabolism
• Gram-Negative Bacteria/drug effects
• Gram-Negative Bacteria/metabolism
• Gram-Negative Bacteria/pathogenicity
• Humans
• Iron/chemistry
• Iron/metabolism
• Membrane Proteins/chemistry
• Membrane Proteins/metabolism
• Models, Molecular
• Siderophores/chemistry
• Siderophores/metabolism

• 75N93020C00016 NIAID NIH HHS
• R21 AI115187 NIAID NIH HHS

• AMR
• antibiotics
• antimicrobial resistance
• globe
• hazard
• public health

• Anti-Bacterial Agents/therapeutic use
• Anti-Infective Agents
• Bacterial Infections/drug therapy
• Drug Resistance, Bacterial
• Humans
• Public Health

Sepsis is the leading cause of death in infants and children worldwide. The growing drug resistance in nosocomial gram-negative bacteria has resulted in treatment challenges. One of the most common multi-drug-resistant bacteria is Pseudomonas aeruginosa. Resistance to antibiotics used in Pseudomonas aeruginosa infections limits the therapeutic options. We present a tigecycline administration in a 5-month-old infant with patent arterial duct, heart failure, and respiratory failure due to respiratory syncytial virus bronchiolitis with subsequent respiratory distress syndrome and severe sepsis caused by multi-drug-resistant Pseudomonas aeruginosa. Despite combined antibiotic therapy with meropenem, amikacin, and colistin, inflammatory markers increased. Because of life-threatening condition, tigecycline was added to the therapy and was administered intravenously twice daily. Within 48 h, inflammatory markers started to decrease and tigecycline therapy continued for 13 days without adverse effects. Tigecycline used in combination with other antibiotics might be a valuable therapeutic approach in the management of multi-drug-resistant bacteria infections in pediatric patients when conventional antibiotics have failed. Further studies are needed to evaluate the efficacy and safety of tigecycline administration in critically ill pediatric patients.

• Infant
• Multi-drug-resistant Pseudomonas aeruginosa
• Sepsis
• Tigecycline

• chemical biology
• antimicrobials

• Animals
• Blood Chemical Analysis
• Chromatography, High Pressure Liquid
• Colistin/blood
• Colistin/pharmacokinetics
• Rats
• Tandem Mass Spectrometry

• Kuwait University (KU)

The ability of MDR Gram-negative bacteria to evade even antibiotics of last resort is a severe global challenge. The development pipeline for conventional antibiotics cannot address this issue, but antimicrobial peptides (AMPs) offer an alternative solution.

Two insect-derived AMPs (LS-sarcotoxin and LS-stomoxyn) were profiled to assess their suitability for systemic application in humans.

The peptides were tested against an extended panel of 114 clinical MDR Gram-negative bacterial isolates followed by time–kill analysis, interaction studies and assays to determine the likelihood of emerging resistance. In further in vitro studies we addressed cytotoxicity, cardiotoxicity and off-target interactions. In addition, an in vivo tolerability and pharmacokinetic study in mice was performed.

LS-sarcotoxin and LS-stomoxyn showed potent and selective activity against Gram-negative bacteria and no cross-resistance with carbapenems, fluoroquinolones or aminoglycosides. Peptide concentrations of 4 or 8 mg/L inhibited 90% of the clinical MDR isolates of Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Salmonella enterica isolates tested. The ‘all-d’ homologues of the peptides displayed markedly reduced activity, indicating a chiral target. Pharmacological profiling revealed a good in vitro therapeutic index, no cytotoxicity or cardiotoxicity, an inconspicuous broad-panel off-target profile, and no acute toxicity in mice at 10 mg/kg. In mouse pharmacokinetic experiments LS-sarcotoxin and LS-stomoxyn plasma levels above the lower limit of quantification (1 and 0.25 mg/mL, respectively) were detected after 5 and 15 min, respectively.

LS-sarcotoxin and LS-stomoxyn are suitable as lead candidates for the development of novel antibiotics; however, their pharmacokinetic properties need to be improved for systemic administration.

• Animals
• Anti-Infective Agents/adverse effects
• Anti-Infective Agents/isolation & purification
• Anti-Infective Agents/pharmacology
• Antimicrobial Cationic Peptides/adverse effects
• Antimicrobial Cationic Peptides/isolation & purification
• Antimicrobial Cationic Peptides/pharmacology
• Diptera/chemistry
• Drug Resistance, Multiple, Bacterial
• Drug-Related Side Effects and Adverse Reactions/pathology
• Gram-Negative Bacteria/drug effects
• Larva/chemistry
• Male
• Mice

• Klebsiella pneumoniae
• drug target
• flux balance analysis
• genome-scale metabolic networks
• infection
• pathogen

• Aldehyde-Lyases/chemistry
• Aldehyde-Lyases/genetics
• Drug Delivery Systems
• Drug Resistance, Multiple, Bacterial/drug effects
• Genes, Bacterial/genetics
• Genome, Bacterial/drug effects
• Klebsiella Infections/microbiology
• Klebsiella pneumoniae/drug effects
• Klebsiella pneumoniae/genetics
• Klebsiella pneumoniae/metabolism
• Metabolic Networks and Pathways/drug effects
• Metabolic Networks and Pathways/genetics
• Sequence Alignment
• Virulence Factors

Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, sodium deoxycholate (DOC) in growth inhibition and killing of enterobacteria.

Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a β-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella.

We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of nitric oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs.

This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.

• Antimicrobial combination
• Enterobacteria
• Furazolidone
• Nitrofurans
• Sodium Deoxycholate
• Synergy

Antimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria.

A literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients.

Of 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70–100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study.

We did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects.

• A. baumannii
• Enterobacteriaceae
• MDR bacteria
• P. aeruginosa
• Review
• Treatment

• Antibiotic resistance
• Epidemiology
• Phage therapy
• Probiotics
• STD's
• TPU

Linezolid combination therapy is recommended for the treatment of Staphylococcus aureus (S. aureus) infections. However, the optimal regimen of the combination therapy for S. aureus is unknown. The objective of this study was to investigate the antibacterial activity, post-antibiotic effect (PAE), and post-antibiotic subminimum inhibitory concentration (MIC) effect (PA-SME) of linezolid alone and in combination with fosfomycin against eleven clinical isolates of S. aureus.

The synergistic effects and antibacterial activity of linezolid and fosfomycin were assessed by checkerboard and time-kill assays. To determine the PAE and PA-SME, S. aureus strains in the logarithmic phase of growth were exposed for 1, 2, and 3 hours to the antibiotics, alone and in combination. Recovery periods of test strains were evaluated using viable counting after dilution.

Synergistic effects were observed for eight strains and no antagonism was found with any combination. Moreover, linezolid combined with fosfomycin at 4x MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 hours. In addition, both the antibiotics alone and in combination showed increased PAE and PA-SME values in a concentration- and time-dependent manner.

Linezolid combined with fosfomycin exerted a good antibacterial effect against S. aureus, and the combinations have significant PAE and PA-SME.

• PA-SME
• PAE
• combination
• fosfomycin
• linezolid

• Enterobacteriaceae
• Escherichia coli
• Klebsiella pneumoniae
• carbapenem resistance

• antibacterial
• antibiotic
• antimicrobial
• efflux
• hybrid
• permeability

Sepsis is one of the major challenges of today. Although gram-positive bacteria related infections are more prevalent in hospital setting, the highest mortality rate is associated with gram-negative microorganisms especially Enterobacteriaceae. Enterobacteriaceae, including Escherichia coli, Klebsiella spp., Proteus spp., Enterobacter spp. and Serratia spp. Resistance to β-lactams in Enterobacteriaceae is primarily attributed to the production of B-lactamase enzymes with subsequent antibiotic hydrolysis and to a lesser extent by alteration of efflux pump or porins expression. Carbapenem resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii are the most notorious pathogens due to the high incidence of morbidity and mortality especially in the immunocompromised patients in the intensive care unit. The most appropriate antimicrobial therapy to treat CRE is still controversial. Combination therapy is preferred over monotherapy due to its broad-spectrum coverage of micro-organisms, due to its synergetic effect and to prevent development of further resistance. Current suggested therapies for CRE resistance as well as promising antibiotics that are currently under investigation for winning the war against the emerging CRE resistance are reviewed and discussed.

• Carbapenem resistant Enterobacteriaceae
• Sepsis
• Bacteraemia
• Bacteremia
• Treatment
• Antibiotics

• Chemoprevention/methods
• Communicable Disease Control/methods
• Diagnostic Tests, Routine/methods
• Disease Management
• Disease Transmission, Infectious/prevention & control
• Drug Resistance, Bacterial
• Global Health
• Humans
• Incidence
• Point-of-Care Systems
• Sexually Transmitted Diseases/diagnosis
• Sexually Transmitted Diseases/drug therapy
• Sexually Transmitted Diseases/epidemiology
• Sexually Transmitted Diseases/prevention & control

• G1002369 Medical Research Council
• MR/K012126/1 Medical Research Council

• antibiotic resistance
• antibiotics
• bacteriophage

• Pseudomonas aeruginosa biofilm
• antimicrobial coating
• antimicrobial polyester
• cationic polymer coating
• functionalized polyester
• nontoxic antimicrobial polymer

• Animals
• Anti-Bacterial Agents
• Biofilms
• Coated Materials, Biocompatible
• Coumarins
• Humans
• Polyesters
• Pseudomonas aeruginosa

Bacterial heteroresistance has been identified in several combinations of bacteria and antibiotics, and it complicated the therapeutic strategies. Tigecycline is being used as one of the optimal options for the treatment of infections caused by multidrug-resistant Salmonella. This study investigated whether heterorresistance to tigecycline exists in a Salmonella enterica serovar Typhimurium strain harboring the oqxAB-bearing IncHI2 plasmid pHXY0908. MIC and population analyses were performed to evaluate population-wide susceptibility to tigecycline. The effects of efflux pumps on MIC levels were assessed using the efflux pump inhibitor Phe-Arg-β-naphthylamide, measuring intracellular tigecycline accumulation as well as mRNA levels of regulatory and efflux pump genes. DNA sequencing of regulatory regions were performed and plasmid curing from a resistant strain provided an appropriate control. Results showed that MICs of a parental strain with and without pHXY0908 as well as a plasmid-cured strain 14028/Δp52 were 0.5, 1, and 1 μg/mL, respectively. Population analysis profiling (PAP) illustrated that only the pHXY0908-containg strain was heteroresistant to tigecycline. A fraction of colonies exhibited stable profiles with 4- to 8-fold increases in MIC. The frequencies of emergence of these isolates were higher in the plasmid-containing strain pHXY0908 than either the parental or the 14028/Δp52 strain. Phe-Arg-β-naphthylamide addition restored tigecycline susceptibility of these isolates and intracellular tigecycline accumulation was reduced. Heteroresistant isolates of the strain containing pHXY0908 also had elevated expression of acrB, ramA, and oqxB. DNA sequencing identified numerous mutations in RamR that have been shown to lead to ramA overexpression. In conclusions, heteroresistance to tigecycline in Salmonella enterica serovar Typhimurium was manifested in a plasmid-bearing strain. Our results suggest that this phenotype was associated with overexpression of the AcrAB-TolC and OqxAB efflux pumps.

• Salmonella enterica serovar Typhimurium
• efflux pump
• heteroresistance
• plasmid
• tigecycline

• Nosocomial pneumonia
• antibiotics
• ceftazidime+avibactam
• ceftobiprole
• emerging
• plazomicin