Cerebrospinal fluid proteomics reveals the innate immunity and blood-brain barrier dysregulation in a patient with multidrug-resistant ventriculitis treated with intrathecal and intravenous polymyxin B.

is a major pathogen of nosocomial meningitis and ventriculitis. Due to very limited antibiotic treatment options, polymyxins are often used as a last-line therapy. To optimise polymyxin use in the intraventricular environment, cerebrospinal fluid (CSF) proteomics was employed to investigate host-pathogen-polymyxin interactions in a 69-year-old patient with multidrug-resistant ventriculitis treated with a combination of intrathecal (ITH; 50,000 IU q24h/q48h), intraventricular (IVT; 50,000 IU q48h), and intravenous (500,000 IU, q12h) polymyxin B.

Exploring Structure-Activity Relationships and Modes of Action of Laterocidine.

A significant increase in life-threatening infections caused by Gram-negative "superbugs" is a serious threat to global health. With a dearth of new antibiotics in the developmental pipeline, antibiotics with novel mechanisms of action are urgently required to prevent a return to the preantibiotic era. A key strategy to develop novel anti-infective treatments is to discover new natural scaffolds with distinct mechanisms of action.

PhageGE: an interactive web platform for exploratory analysis and visualization of bacteriophage genomes.

Background: Antimicrobial resistance is a serious threat to global health. Due to the stagnant antibiotic discovery pipeline, bacteriophages (phages) have been proposed as an alternative therapy for the treatment of infections caused by multidrug-resistant pathogens. Genomic features play an important role in phage pharmacology.

Transcriptomic investigations of polymyxins and colistin/sulbactam combination against carbapenem-resistant .

Carbapenem-resistant (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B, and colistin/sulbactam combination therapy.

Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii.

Polymyxins are often the only effective antibiotics against the "Critical" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures.

Discovery of Antimicrobial Lysins from the "Dark Matter" of Uncharacterized Phages Using Artificial Intelligence.

The rapid rise of antibiotic resistance and slow discovery of new antibiotics have threatened global health. While novel phage lysins have emerged as potential antibacterial agents, experimental screening methods for novel lysins pose significant challenges due to the enormous workload. Here, the first unified software package, namely DeepLysin, is developed to employ artificial intelligence for mining the vast genome reservoirs ("dark matter") for novel antibacterial phage lysins.

Phage resistance in Klebsiella pneumoniae and bidirectional effects impacting antibiotic susceptibility.

Objectives: Bacteriophage (phage) therapy is a promising anti-infective option to combat antimicrobial resistance. However, the clinical utilization of phage therapy has been severely compromised by the potential emergence of phage resistance. Although certain phage resistance mechanisms can restore bacterial susceptibility to certain antibiotics, a lack of knowledge of phage resistance mechanisms hinders optimal use of phages and their combination with antibiotics.

Distinguishing Inducible and Non-Inducible Resistance to Colistin in Pseudomonas aeruginosa by Quantitative and Systems Pharmacology Modeling at Low and Standard Inocula.

Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled.

Polysaccharide-Targeting Lipid Nanoparticles to Kill Gram-Negative Bacteria.

The rapid increase and spread of Gram-negative bacteria resistant to many or all existing treatments threaten a return to the preantibiotic era. The presence of bacterial polysaccharides that impede the penetration of many antimicrobials and protect them from the innate immune system contributes to resistance and pathogenicity. No currently approved antibiotics target the polysaccharide regions of microbes.

Lipid A Modification and Metabolic Adaptation in Polymyxin-Resistant, New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae.

Polymyxins are last-line antibiotics employed against multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance is rapidly on the rise globally. Polymyxins initially target lipid A of lipopolysaccharides (LPSs) in the cell outer membrane (OM), causing disorganization and cell lysis.

Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B.

Synergistic Effects of Capric Acid and Colistin against Colistin-Susceptible and Colistin-Resistant .

Colistin is a last-line antibiotic against Gram-negative pathogens. However, the emergence of colistin resistance has substantially reduced the clinical effectiveness of colistin. In this study, synergy between colistin and capric acid was examined against twenty-one Gram-negative bacterial isolates (four colistin-susceptible and seventeen colistin-resistant).

Proof-of-concept for incorporating mechanistic insights from multi-omics analyses of polymyxin B in combination with chloramphenicol against Klebsiella pneumoniae.

Carbapenemase-resistant Klebsiella pneumoniae (KP) resistant to multiple antibiotic classes necessitates optimized combination therapy. Our objective is to build a workflow leveraging omics and bacterial count data to identify antibiotic mechanisms that can be used to design and optimize combination regimens. For pharmacodynamic (PD) analysis, previously published static time-kill studies (J Antimicrob Chemother 70, 2015, 2589) were used with polymyxin B (PMB) and chloramphenicol (CHL) mono and combination therapy against three KP clinical isolates over 24 h.

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant .

Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting. A prospective, multi-center clinical trial was undertaken with polymyxin B [2.

Transcriptomic Mapping of Neurotoxicity Pathways in the Rat Brain in Response to Intraventricular Polymyxin B.

Intraventricular or intrathecal administration of polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria caused infections in the central nervous system (CNS). However, our limited knowledge of the mechanisms underpinning polymyxin-induced neurotoxicity significantly hinders the development of safe and efficacious polymyxin dosing regimens. To this end, we conducted transcriptomic analyses of the rat brain and spinal cord 1 h following intracerebroventricular administration of polymyxin B into rat lateral ventricle at a clinically relevant dose (0.

Overexpression of mcr-1 disrupts cell envelope synthesis and causes the dysregulation of carbon metabolism, redox balance and nucleic acids.

Introduction: Rapid dissemination of plasmid-borne polymyxin resistance mcr-1 genes threatens the efficacy of polymyxins. Acquisition of mcr-1 imposes a fitness cost on bacteria; identifying the molecular mechanisms underpinning this fitness cost will help in the development of adjunctive antimicrobial therapies that target polymyxin-resistant Gram-negative pathogens.

Methods: Phenotypic assays and transcriptomics were acquired to investigate the impact of mcr-1 expression on membrane characteristics and transcriptomic responses in Escherichia coli TOP10 carrying the empty vector pBAD (TOP10+pBAD) and harbouring pBAD-mcr-1 (TOP10+pBAD-mcr-1).

Coaching ward pharmacists in antimicrobial stewardship: A pilot study.

Background: Ward pharmacists are well-positioned to enhance the activities of hospital antimicrobial stewardship (AMS) programs by reviewing the appropriateness of antimicrobials and making recommendations to prescribers. However, recent studies have identified gaps in ward pharmacists' AMS practice, knowledge, skills, and confidence which suggests education and training programs are needed.

Objectives: To describe, for the first time, an interactive educational activity - coaching in AMS - targeted at ward pharmacists and explore their perceptions of coaching as a mode of delivering education to improve AMS knowledge, skills, confidence, and practice.

Pharmacokinetics and pharmacodynamics of peptide antibiotics.

Antimicrobial resistance is a major global health challenge. As few new efficacious antibiotics will become available in the near future, peptide antibiotics continue to be major therapeutic options for treating infections caused by multidrug-resistant pathogens. Rational use of antibiotics requires optimisation of the pharmacokinetics and pharmacodynamics for the treatment of different types of infections.

Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens.

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state.

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model.

We evaluated piperacillin-tazobactam and tobramycin regimens against isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MIC 4 mg/L, MIC 0.

Simulated Intravenous versus Inhaled Tobramycin with or without Intravenous Ceftazidime Evaluated against Hypermutable Pseudomonas aeruginosa via a Dynamic Biofilm Model and Mechanism-Based Modeling.

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ). Two hypermutable P.

A polytherapy based approach to combat antimicrobial resistance using cubosomes.

A depleted antimicrobial drug pipeline combined with an increasing prevalence of Gram-negative 'superbugs' has increased interest in nano therapies to treat antibiotic resistance. As cubosomes and polymyxins disrupt the outer membrane of Gram-negative bacteria via different mechanisms, we herein examine the antimicrobial activity of polymyxin-loaded cubosomes and explore an alternative strategy via the polytherapy treatment of pathogens with cubosomes in combination with polymyxin. The polytherapy treatment substantially increases antimicrobial activity compared to polymyxin B-loaded cubosomes or polymyxin and cubosomes alone.

Polymyxin causes cell envelope remodelling and stress responses in mcr-1-harbouring Escherichia coli.

Polymyxins remain important last-line antibiotics against multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is emerging and the mobile polymyxin resistance gene, mcr, is contributing to the wide dissemination of polymyxin resistance, especially among Escherichia coli, with mcr-1 being the most commonly found variant. The objective of this study was to provide mechanistic insights into concentration-dependent transcriptomic responses of mcr-harbouring E.

Differences in Fosfomycin Resistance Mechanisms between Pseudomonas aeruginosa and .

Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat.