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Background This study aimed to evaluate the accuracy of procalcitonin (PCT) serum concentrations to diagnose Gram-negative bacteremia and the association of PCT serum concentrations with more specific pathogens and the focus of infection. Methods Secondary analysis of the prospectively collected patient-level dataset from a cluster randomized quality improvement trial was performed. The trial included sepsis patients with organ dysfunction treated in the participating intensive care units from 2011 to 2015. Test performance for the prediction of Gram-negative bacteremia was assessed by receiver operating curve analysis. Independent effects of specific pathogen groups and foci of infection on PCT concentrations were assessed by linear logistic regression models. Results Blood cultures (BC) and PCT concentrations had been taken in 4858 of 6561 documented patients. PCT was significantly higher in Gram-negative bacteremia compared to Gram-positive bacteremia or candidemia ( p  < 0.001). The area under the curve was 0.72 (95% confidence interval 0.71–0.74) for the prediction of Gram-negative bacteremia compared to all other blood culture results including negative blood cultures. The optimized cutoff value was 10 ng/ml (sensitivity 69%, specificity 35%). PCT differed significantly between specific groups of pathogens ( p  < 0.001) with highest concentrations in Escherichia coli , Streptococcus species and other Enterobacteriaceae . PCT was highest in urogenital followed by abdominal infection and lowest in respiratory infection ( p  < 0.001). In a linear regression model, Streptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT values independent of the pathogen. Conclusions Serum PCT concentrations are higher in patients with Gram-negative bacteremia than in patients with Gram-positive bacteremia or candidemia. However, the discriminatory power of this difference is too low to guide therapeutic decisions. Variations in PCT serum concentrations are not determined solely by Gram-negative or Gram-positive bacteria but are also affected by distinct groups of pathogens and different foci of infection. Trial registration ClinicalTrials.gov, NCT01187134 . Registered on 23 August 2010.

To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78). Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers.

Background： Aerosolized amikacin （AA） is a current option for the management of ventilator-associated pneumonia （VAP） caused by multidrug-resistant Gram-negative bacteria （MDR-GNB）, as it is reported that AA could increase the alveolar level of the drug without increasing systemic toxicity. This study aimed to evaluate the efficacy and safety of AA as an adjunctive therapy for VAP caused by MDR-GNB. Methods： In this single-center, double-blind study conducted in a 36-bed general Intensive Care Unit （ICU） in a tertiary hospital from June 2014 to June 2016, 52 ICU patients with confirmed MDR-GNB VAP were randomized to two groups （AA group, n - 27 and placebo group, n = 25）. Amikacin （400 rag, q8h） or saline placebo （4 ml, q8h） was aerosolized for 7 days. The attending physician determined the administration of systemic antibiotics for VAP. Patients were tbllowed up for 28 days. Bacteriological eradication, clinical pulmonary infection score （CP1S）, and serum creatinine were assessed on day 7 of therapy. New resistance to amikacin, cure rate of VAP, weaning rate, and mortality were assessed on day 28. Results： The baseline characteristics of patients in both groups were similar. At the end of the treatment, 13 of the 32 initially detected bacterial isolates were eradicated in AA group, compared to 4 of 28 in placebo group （41% vs. 14%, P - 0.024）. As for patients, 11 of 27 patients treated with AA and 4 of 25 patients treated with placebo have eradication （41% vs. 16%, P = 0.049）. The adjunction of AA reduced CPIS （4.2 ± 1.6 vs. 5.8 ± 2.1, P = 0.007）. New drug resistance to amikacin and the change in serum creatinine were not detected in AA group. No significant differences in the clinical cure rate in survivors （48% vs. 35%, P = 0.444）, weaning rate （48% vs. 32%, P = 0.236）, and mortality （22% vs. 32%, P = 0.427） were detected between the two groups on day 28. Conclusions： As an adjunctive therapy of MDR-GNB VAP, AA successfully eradicated existing MDR organisms without inducing new resistance to amikacin or change in serum creatinine. However, the improvement of mortality was not found.

Increasing antibiotic resistance in multidrug-resistant (MDR) Gram-negative bacteria (MDR-GNB) presents significant health problems worldwide, since the vital available and effective antibiotics, including; broad-spectrum penicillins, fluoroquinolones, aminoglycosides, and β-lactams, such as; carbapenems, monobactam, and cephalosporins; often fail to fight MDR Gram-negative pathogens as well as the absence of new antibiotics that can defeat these \"superbugs\". All of these has prompted the reconsideration of old drugs such as polymyxins that were reckoned too toxic for clinical use. Only two polymyxins, polymyxin E (colistin) and polymyxin B, are currently commercially available. Colistin has re-emerged as a last-hope treatment in the mid-1990s against MDR Gram-negative pathogens due to the development of extensively drug-resistant GNB. Unfortunately, rapid global resistance towards colistin has emerged following its resurgence. Different mechanisms of colistin resistance have been characterized, including intrinsic, mutational, and transferable mechanisms. In this review, we intend to discuss the progress over the last two decades in understanding the alternative colistin mechanisms of action and different strategies used by bacteria to develop resistance against colistin, besides providing an update about what is previously recognized and what is novel concerning colistin resistance.

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins—a class of natural products with weak activity and limited spectrum—to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections. Chemical optimization of arylomycins results in an inhibitor of bacterial type I signal peptidase that shows activity both against multidrug-resistant clinical isolates of Gram-negative bacteria in vitro and in several in vivo infection models.

Antimicrobial resistance in neonatal sepsis is rising, yet mechanisms of resistance that often spread between species via mobile genetic elements, ultimately limiting treatments in low- and middle-income countries (LMICs), are poorly characterized. The Burden of Antibiotic Resistance in Neonates from Developing Societies (BARNARDS) network was initiated to characterize the cause and burden of antimicrobial resistance in neonatal sepsis for seven LMICs in Africa and South Asia. A total of 36,285 neonates were enrolled in the BARNARDS study between November 2015 and December 2017, of whom 2,483 were diagnosed with culture-confirmed sepsis. Klebsiella pneumoniae ( n  = 258) was the main cause of neonatal sepsis, with Serratia marcescens ( n  = 151), Klebsiella michiganensis ( n  = 117), Escherichia coli ( n  = 75) and Enterobacter cloacae complex ( n  = 57) also detected. We present whole-genome sequencing, antimicrobial susceptibility and clinical data for 916 out of 1,038 neonatal sepsis isolates (97 isolates were not recovered from initial isolation at local sites). Enterobacterales ( K. pneumoniae, E. coli and E. cloacae ) harboured multiple cephalosporin and carbapenem resistance genes. All isolated pathogens were resistant to multiple antibiotic classes, including those used to treat neonatal sepsis. Intraspecies diversity of K. pneumoniae and E. coli indicated that multiple antibiotic-resistant lineages cause neonatal sepsis. Our results will underpin research towards better treatments for neonatal sepsis in LMICs. Genomic and clinical analysis of 916 bacterial isolates from neonates with sepsis in seven low- and middle-income countries (the BARNARDS study) reveals that the main species present were antimicrobial-resistant Klebsiella , Escherichia coli and Enterobacter .

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens 1 . These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that—if successful—will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens 1 , 2 . These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds 3 , 4 . As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s 2 . We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics. Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the quinolones class of antimicrobials one of the most used in inpatients and outpatients. Initially discovered during the search for improved chloroquine-derivative molecules with increased anti-malarial activity, today the quinolones, intended as antimicrobials, comprehend four generations that progressively have been extending antimicrobial spectrum and clinical use. The quinolone class of antimicrobials exerts its antimicrobial actions through inhibiting DNA gyrase and Topoisomerase IV that in turn inhibits synthesis of DNA and RNA. Good distribution through different tissues and organs to treat Gram-positive and Gram-negative bacteria have made quinolones a good choice to treat disease in both humans and animals. The extensive use of quinolones, in both human health and in the veterinary field, has induced a rise of resistance and menace with leaving the quinolones family ineffective to treat infections. This review revises the evolution of quinolones structures, biological activity, and the clinical importance of this evolving family. Next, updated information regarding the mechanism of antimicrobial activity is revised. The veterinary use of quinolones in animal productions is also considered for its environmental role in spreading resistance. Finally, considerations for the use of quinolones in human and veterinary medicine are discussed.

Key Points Vesicles derived from the outer membrane of Gram-negative bacteria, or outer-membrane vesicles (OMVs), are heterogeneous in size and composition, encapsulate soluble periplasmic content and are ubiquitously produced. The difficulty in finding a single molecular or genetic basis for OMV production is probably due to species-dependent differences in envelope architecture, environmental influences on envelope composition and redundancy of OMV-producing pathways. Mutations that subtly affect envelope crosslinking affect OMV production, whereas bacterial mutants that are unable to crosslink the envelope are typically unstable and form lysis products instead of OMVs. Lipopolysaccharide (LPS) subtypes also affect the levels of OMV production, as well as OMV cargo recruitment. OMV cargo may be enriched or excluded compared with its abundance in the bacterial envelope, suggesting that cargo recruitment is a regulated rather than stochastic process. Well-characterized cargoes include virulence factors, antibiotic-degrading enzymes, surface adherence factors, proteases and enzymes that are important for nutrient acquisition. OMVs can serve in bacterial communities as 'public goods' by distributing enzymes that break down extracellular material into nutrients, by recruiting iron, by acting as decoys for bacteriophages or antibiotics and by transferring DNA between cells. The versatile characteristics of OMVs and their immunomodulatory properties can be exploited for bioengineering applications and vaccine development. In this Review, Schwechheimer and Kuehn describe recent developments in elucidating the mechanisms of biogenesis and cargo selection of the outer-membrane vesicles (OMVs) produced by Gram-negative bacteria. They also discuss the functions of OMVs in bacterial physiology and during pathogenesis. Outer-membrane vesicles (OMVs) are spherical buds of the outer membrane filled with periplasmic content and are commonly produced by Gram-negative bacteria. The production of OMVs allows bacteria to interact with their environment, and OMVs have been found to mediate diverse functions, including promoting pathogenesis, enabling bacterial survival during stress conditions and regulating microbial interactions within bacterial communities. Additionally, because of this functional versatility, researchers have begun to explore OMVs as a platform for bioengineering applications. In this Review, we discuss recent advances in the study of OMVs, focusing on new insights into the mechanisms of biogenesis and the functions of these vesicles.