Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

AbstractStaphylococcus aureus is a notorious bacterial pathogen that often causes soft tissue and bloodstream infections and invariably garners resistance mechanisms against new antibiotics. Host innate immunity modulated by metabolites has been proved as a powerful strategy against bacterial infections. However, few studies focus on the application of this strategy against S. aureus infection. Here, we identified four metabolite biomarkers, L-proline, L-isoleucine, L-leucine, and L-valine (PILV), by a metabolomics study. In animal models of S. aureus bloodstream infection, exogenous administration of each metabolite or PILV shows an anti-infective effect, while PILV treatment has higher protection than individual metabolite treatment. Each metabolite targets nitric oxide (NO) to kill S. aureus via arginase inhibition, and PILV exhibits additive inhibition of arginase activity that causes further killing. This suppression also contributes to the metabolite-mediated phagocytic killing of S. aureus in human blood. Our finding demonstrates the metabolite-mediated innate immunity as a therapeutic intervention for S. aureus infection.

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MODERN APPROACHES TO ANTIVIRULENT THERAPY OF DISEASES ASSOCIATED WITH STAPHYLOCOCCUS AUREUS

The Medical and Ecological Problems ◽

10.31718/mep.2019.23.3-4.07 ◽

2019 ◽

Vol 23 (3-4) ◽

pp. 26-31

Author(s):

T.O. Kryuchko ◽

O.Ya. Tkachenko ◽

N.V. Kuzmenko ◽

I.N. Nesina ◽

S.M. Tanianska ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Virulence Factors ◽

Bacterial Infections ◽

Effective Means ◽

Bacterial Pathogen ◽

Cross Reactivity ◽

Main Function ◽

Virulence Proteins ◽

New Antibiotics ◽

Active Research

Staphylococcus aureus is a universal bacterial pathogen, which is able to develop the resistance to new antibiotics, by means of virulence factors, whose main function is the spread of diseases by inhibiting the immune factors of host defense. Its wide spread at in-patient departments and also the presence of clinical probationary wards Staphylococcus aureus, resistant to methicillin at out-patient departments, deprive the doctors of effective means for control of the infection. Complications caused by MRSA lead to hospitalization and indices of lethality. The aim of the paper is to analyze the main factors of S. аureus virulence and ways the of its interaction as a result of etiological and pathogenetic treatment. Complexity of treatment of bacterial infections is determined by alternative ways of prevention and treatment of diseases to which bacteria are not able to develop resistance. Along with general mechanisms that form antibiotic resistance, S. aureus produces many individual virulence factors that model the immune response, affecting the survival of the microorganism. The virulence factors produced by S. aureus are diverse and have the ability not only to cause cell lysis, but also to stimulate tissue rejection and destruction. It is important to determine that many specific factors of virulence caused by S. aureus, have ability to change both congenital and adaptive immune reactions including inhibition of complement activation, neutrophils neutralization, phagocytes inhibition. Strategies for inhibiting virulence factors can range from using small inhibitor molecules or full-fledged antibodies to creating toxoids and virulence proteins. Great interest is focused upon those inhibitors that have cross-reactivity with respect to multiple virulence factors, as well as inhibitors, the main target of which is a global regulator with multi-purpose activity, for example, agr operon. Active research into the specific alternative antivirulent treatments for severe diseases caused by S. aureus can potentially settle a number of problems and difficulties of post-antibiotic era.

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Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

Current Protein and Peptide Science ◽

10.2174/1389203721666200915113630 ◽

2020 ◽

Vol 21 (10) ◽

pp. 1011-1026

Author(s):

Bruna O. Costa ◽

Marlon H. Cardoso ◽

Octávio L. Franco

Keyword(s):

Drug Target ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Treatment Strategies ◽

Resistance Mechanisms ◽

Resistant Bacteria ◽

Specific Chemical ◽

Target Interaction ◽

Multiresistant Bacteria ◽

Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

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Prevention of Infection in Adults Receiving Intravenous Antibiotic Treatment via Indwelling Central Venous Access Devices

Reviews on Recent Clinical Trials ◽

10.2174/1574887113666180817125036 ◽

2019 ◽

Vol 14 (1) ◽

pp. 47-49

Author(s):

Basant K. Puri ◽

Anne Derham ◽

Jean A. Monro

Keyword(s):

Bloodstream Infection ◽

Antibiotic Treatment ◽

Central Venous Access ◽

Case Series ◽

Bloodstream Infections ◽

Venous Access ◽

Host Cells ◽

Central Venous ◽

Intravenous Antibiotic ◽

Venous Access Devices

Background: The use of indwelling Central Venous Access Devices (CVADs) is associated with the development of bloodstream infections. When CVADs are used to administer systemic antibiotics, particularly second- or higher-generation cephalosporins, there is a particular risk of developing Clostridium difficile infection. The overall bloodstream infection rate is estimated to be around 1.74 per 1000 Central Venous Catheter (CVC)-days. Objective: We hypothesised that daily oral administration of the anion-binding resin colestyramine (cholestyramine) would help prevent infections in those receiving intravenous antibiotic treatment via CVADs. Method: A small case series is described of adult patients who received regular intravenous antibiotic treatment (ceftriaxone, daptomycin or vancomycin) for up to 40 weeks via indwelling CVADs; this represented a total of 357 CVC-days. In addition to following well-established strategies to prevent C. difficile infection, during the course of the intravenous antibiotic treatment the patients also received daily oral supplementation with 4 g colestyramine. Results: There were no untoward infectious events. In particular, none of the patients developed any symptoms or signs of C. difficile infection, whereas approximately one case of a bloodstream infection would have been expected. Conclusion: It is suggested that oral colestyramine supplementation may help prevent such infection through its ability to bind C. difficile toxin A (TcdA) and C. difficile toxin B (TcdB); these toxins are able to gain entry into host cells through receptor-mediated endocytosis, while anti-toxin antibody responses to TcdA and TcdB have been shown to induce protection against C. difficile infection sequelae.

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Use of Ceftaroline in Hospitalized Patients with and without COVID-19: A Descriptive Cross-Sectional Study

Antibiotics ◽

10.3390/antibiotics10070763 ◽

2021 ◽

Vol 10 (7) ◽

pp. 763

Author(s):

Daniele Roberto Giacobbe ◽

Chiara Russo ◽

Veronica Martini ◽

Silvia Dettori ◽

Federica Briano ◽

...

Keyword(s):

Bacterial Infections ◽

Bloodstream Infections ◽

Cross Sectional Study ◽

Primary Objective ◽

Sectional Study ◽

Cross Sectional ◽

First Line Therapy ◽

Large Teaching Hospital ◽

Secondary Objective ◽

Medical Wards

A single-center cross-sectional study was conducted to describe the use of ceftaroline in a large teaching hospital in Northern Italy, during a period also including the first months of the coronavirus disease 2019 (COVID-19) pandemic. The primary objective was to describe the use of ceftaroline in terms of indications and characteristics of patients. A secondary objective was to describe the rate of favorable clinical response in patients with bloodstream infections (BSI) due to methicillin-resistant Staphylococcus aureus (MRSA-BSI) receiving ceftaroline. Overall, 200 patients were included in the study. Most of them had COVID-19 (83%, 165/200) and were hospitalized in medical wards (78%, 155/200). Included patients with COVID-19 pneumonia were given empirical ceftaroline in the suspicion of bacterial co-infection or superinfection. Among patients with MRSA-BSI, ceftaroline was used as a first-line therapy and salvage therapy in 25% (3/12) and 75% (9/12) of cases, respectively, and as a monotherapy or in combination with daptomycin in 58% (7/12) and 42% (5/12) of patients, respectively. A favorable response was registered in 67% (8/12) of patients. Improving etiological diagnosis of bacterial infections is essential to optimize the use of ceftaroline in COVID-19 patients. The use of ceftaroline for MRSA-BSI, either as a monotherapy or in combination with other anti-MRSA agents, showed promising rates of favorable response.

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Healthcare-Associated Laboratory-Confirmed Bloodstream Infections—Species Diversity and Resistance Mechanisms, a Four-Year Retrospective Laboratory-Based Study in the South of Poland

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052785 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2785

Author(s):

Agnieszka Chmielarczyk ◽

Monika Pomorska-Wesołowska ◽

Dorota Romaniszyn ◽

Jadwiga Wójkowska-Mach

Keyword(s):

Bloodstream Infections ◽

Diagnostic Techniques ◽

Resistance Mechanisms ◽

Infection Prevention And Control ◽

The South ◽

Coagulase Negative Staphylococci ◽

Aminoglycoside Resistance ◽

Gram Negative ◽

Maldi Tof ◽

Carbapenem Resistant

Introduction: Regardless of the country, advancements in medical care and infection prevention and control of bloodstream infections (BSIs) are an enormous burden of modern medicine. Objectives: The aim of our study was to describe the epidemiology and drug-resistance of laboratory-confirmed BSI (LC-BSIs) among adult patients of 16 hospitals in the south of Poland. Patients and methods: Data on 4218 LC-BSIs were collected between 2016–2019. The identification of the strains was performed using MALDI-TOF. Resistance mechanisms were investigated according to European Committee on Antimicrobial Susceptibility Testing, EUCAST recommendations. Results: Blood cultures were collected from 8899 patients, and LC-BSIs were confirmed in 47.4%. The prevalence of Gram-positive bacteria was 70.9%, Gram-negative 27.8% and yeast 1.4%. The most frequently isolated genus was Staphylococcus (50% of all LC-BSIs), with a domination of coagulase-negative staphylococci, while Escherichia coli (13.7%) was the most frequent Gram-negative bacterium. Over 4 years, 108 (2.6%) bacteria were isolated only once, including species from the human microbiota as well as environmental and zoonotic microorganisms. The highest methicillin resistant Staphylococcus aureus (MRSA) prevalence was in intensive care units (ICUs) (55.6%) but S. aureus with resistance to macrolides, lincosamides and streptogramins B (MLSB) in surgery was 66.7%. The highest prevalence of E. faecalis with a high-level aminoglycoside resistance (HLAR) mechanism was in ICUs, (84.6%), while E. faecium-HLAR in surgery was 83.3%. All cocci were fully glycopeptide-sensitive. Carbapenem-resistant Gram-negative bacilli were detected only in non-fermentative bacilli group, with prevalence 70% and more. Conclusions: The BSI microbiology in Polish hospitals was similar to those reported in other studies, but the prevalence of MRSA and enterococci-HLAR was higher than expected, as was the prevalence of carbapenem-resistant non-fermentative bacilli. Modern diagnostic techniques, such as MALDI-TOF, guarantee reliable diagnosis.

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Community-acquired and hospital-acquired respiratory tract infection and bloodstream infection in patients hospitalized with COVID-19 pneumonia

Journal of Intensive Care ◽

10.1186/s40560-021-00526-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Kirstine K. Søgaard ◽

Veronika Baettig ◽

Michael Osthoff ◽

Stephan Marsch ◽

Karoline Leuzinger ◽

...

Keyword(s):

Intensive Care ◽

Tract Infection ◽

Respiratory Tract ◽

Respiratory Tract Infection ◽

Bloodstream Infection ◽

Bacterial Infections ◽

Fungal Infections ◽

Icu Patients ◽

Hospital Acquired Infections ◽

Hospital Acquired

Abstract Objectives SARS-CoV-2 may cause acute lung injury, and secondary infections are thus relevant complications in patients with COVID-19 pneumonia. However, detailed information on community- and hospital-acquired infections among patients with COVID-19 pneumonia is scarce. Methods We identified 220 SARS-CoV-2-positive patients hospitalized at the University Hospital Basel, Switzerland (between 25 February and 31 May 2020). We excluded patients who declined the general consent (n = 12), patients without clinical evidence of pneumonia (n = 29), and patients hospitalized for < 24 h (n = 17). We evaluated the frequency of community- and hospital-acquired infections using respiratory and blood culture materials with antigen, culture-based, and molecular diagnostics. For ICU patients, all clinical and microbial findings were re-evaluated interdisciplinary (intensive care, infectious disease, and clinical microbiology), and agreement reached to classify patients with infections. Results In the final cohort of 162 hospitalized patients (median age 64.4 years (IQR, 50.4–74.2); 61.1% male), 41 (25.3%) patients were admitted to the intensive care unit, 34/41 (82.9%) required mechanical ventilation, and 17 (10.5%) of all hospitalized patients died. In total, 31 infections were diagnosed including five viral co-infections, 24 bacterial infections, and three fungal infections (ventilator-associated pneumonia, n = 5; tracheobronchitis, n = 13; pneumonia, n = 1; and bloodstream infection, n = 6). Median time to respiratory tract infection was 12.5 days (IQR, 8–18) and time to bloodstream infection 14 days (IQR, 6–30). Hospital-acquired bacterial and fungal infections were more frequent among ICU patients than other patients (36.6% vs. 1.7%). Antibiotic or antifungal treatment was administered in 71 (43.8%) patients. Conclusions Community-acquired viral and bacterial infections were rare among COVID-19 pneumonia patients. By contrast, hospital-acquired bacterial or fungal infections were frequently complicating the course among ICU patients.

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1341. Blood Volume Collected for Blood Cultures in Infants with Suspected Neonatal Sepsis in the NICU

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1523 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S682-S682

Author(s):

Maria S Rueda Altez ◽

Lamia Soghier ◽

Joseph M Campos ◽

James Bost ◽

Jiaxiang Gai ◽

...

Keyword(s):

Bloodstream Infection ◽

Blood Volume ◽

Bloodstream Infections ◽

Blood Cultures ◽

Categorical Variables ◽

Continuous Variables ◽

Volume Calculation ◽

Culture Negative ◽

Time Of Collection ◽

Rule Out

Abstract Background Blood cultures have high sensitivity to detect bacteremia in septic neonates when >=1 ml of blood is collected. Neonatologists often cite low confidence in microbiologic sampling as rationale for continuing antibiotics without a focus of infection despite negative blood cultures, resulting in prolonged antimicrobial therapy. We aim to describe the blood culture sample volumes in NICU patients, to identify factors associated with sample volumes < 1ml, and to compare the sample volumes of patients treated for culture-negative sepsis with those with bloodstream infections and those treated for a ≤72-hour sepsis rule-out Methods Data from this observational cohort study were collected retrospectively and prospectively from NICU patients with blood cultures obtained from September 2018 to February 2019. Clinical data were collected through chart review. All inoculated culture bottles were weighed for volume calculation. We determined the association of age, weight, sample source, and time of collection with volume < 1mL. Continuous variables were analyzed using Wilcoxon-Mann-Whitney, and categorical variables using chi-squared test. For aim 3, the volumes of the groups were compared using analysis of variance. Results A total of 310 blood cultures were identified, corresponding to 159 patients. Of these, 49 (16%) were positive. Among the negative blood cultures, 86% were collected in patients who subsequently received antibiotics (Figure 1). Median inoculated volume was 0.6 ml (IQR: 0.1-2.4). Weight and age at time of culture collection, source of sample, and time of collection were not significantly associated with the inoculation of < 1ml of blood. Median volume of blood was 0.6ml (0.3-0.6) for sepsis rule-out, 0.6ml (0.2-0.6) for bloodstream infection, and 0.6ml (0.6-1.4) for culture-negative sepsis. No difference was found among the three groups (p=0.54) Figure 1. Classification of blood cultures identified during study period Conclusion The blood volume collected for cultures in the NICU is lower than recommended. Clinical and environmental characteristics are not significantly associated with the inoculated volume. The volume of blood sampled does not differ in patients with culture-negative sepsis, bloodstream infection and sepsis rule-out, and should not be a justification for longer duration of antibiotic therapy Disclosures All Authors: No reported disclosures

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Phage Resistance Is Associated with Decreased Virulence in KPC-Producing Klebsiella pneumoniae of the Clonal Group 258 Clade II Lineage

Microorganisms ◽

10.3390/microorganisms9040762 ◽

2021 ◽

Vol 9 (4) ◽

pp. 762

Author(s):

Lucia Henrici De Angelis ◽

Noemi Poerio ◽

Vincenzo Di Pilato ◽

Federica De Santis ◽

Alberto Antonelli ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Parental Strain ◽

Bacterial Infections ◽

Capsular Polysaccharide ◽

Galleria Mellonella ◽

Bacterial Pathogen ◽

Phage Resistance ◽

Infection Model ◽

Lytic Phage ◽

Susceptible Host

Phage therapy is now reconsidered with interest in the treatment of bacterial infections. A major piece of information for this application is the definition of the molecular targets exploited by phages to infect bacteria. Here, the genetic basis of resistance to the lytic phage φBO1E by its susceptible host Klebsiella pneumoniae KKBO-1 has been investigated. KKBO-1 phage-resistant mutants were obtained by infection at high multiplicity. One mutant, designated BO-FR-1, was selected for subsequent experiments, including virulence assessment in a Galleria mellonella infection model and characterization by whole-genome sequencing. Infection with BO-FR-1 was associated with a significantly lower mortality when compared to that of the parental strain. The BO-FR-1 genome differed from KKBO-1 by a single nonsense mutation into the wbaP gene, which encodes a glycosyltransferase involved in the first step of the biosynthesis of the capsular polysaccharide (CPS). Phage susceptibility was restored when BO-FR-1 was complemented with the constitutive wbaP gene. Our results demonstrated that φBO1E infects KKBO-1 targeting the bacterial CPS. Interestingly, BO-FR-1 was less virulent than the parental strain, suggesting that in the context of the interplay among phage, bacterial pathogen and host, the emergence of phage resistance may be beneficial for the host.

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Silver (I) N-Heterocyclic Carbene Complexes: A Winning and Broad Spectrum of Antimicrobial Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22052497 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2497

Author(s):

Filippo Prencipe ◽

Anna Zanfardino ◽

Michela Di Napoli ◽

Filomena Rossi ◽

Stefano D’Errico ◽

...

Keyword(s):

Bacterial Infections ◽

Antimicrobial Agents ◽

Antimicrobial Properties ◽

Resistance Mechanisms ◽

Heterocyclic Carbenes ◽

Significant Activity ◽

Bacterial Strains ◽

Development Of Resistance ◽

Starting Point ◽

Catalytic Chemistry

The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

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Antibacterial Compounds from Mushrooms: A Lead to Fight ESKAPEE Pathogenic Bacteria?

Planta Medica ◽

10.1055/a-1266-6980 ◽

2020 ◽

Author(s):

Violette Hamers ◽

Clément Huguet ◽

Mélanie Bourjot ◽

Aurélie Urbain

Keyword(s):

Antibiotic Resistance ◽

Global Health ◽

Pathogenic Bacteria ◽

Resistance Mechanisms ◽

Pathogenic Microorganisms ◽

Bacterial Strains ◽

Antibacterial Compounds ◽

New Antibiotics ◽

Hospital Stays ◽

Antibacterial Potential

AbstractInfectious diseases are among the greatest threats to global health in the 21st century, and one critical concern is due to antibiotic resistance developed by an increasing number of bacterial strains. New resistance mechanisms are emerging with many infections becoming more and more difficult if not impossible to treat. This growing phenomenon not only is associated with increased mortality but also with longer hospital stays and higher medical costs. For these reasons, there is an urgent need to find new antibiotics targeting pathogenic microorganisms such as ESKAPEE bacteria. Most of currently approved antibiotics are derived from microorganisms, but higher fungi could constitute an alternative and remarkable reservoir of anti-infectious compounds. For instance, pleuromutilins constitute the first class of antibiotics derived from mushrooms. However, macromycetes still represent a largely unexplored source. Publications reporting the antibacterial potential of mushroom extracts are emerging, but few purified compounds have been evaluated for their bioactivity on pathogenic bacterial strains. Therefore, the aim of this review is to compile up-to-date data about natural products isolated from fruiting body fungi, which significantly inhibit the growth of ESKAPEE pathogenic bacteria. When available, data regarding modes of action and cytotoxicity, mandatory when considering a possible drug development, have been discussed in order to highlight the most promising compounds.

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