Pursuit of next-generation glycopeptides: A journey with vancomycin

2022 ◽  
Author(s):  
Yash Acharya ◽  
Geetika Dhanda ◽  
Paramita Sarkar ◽  
Jayanta Haldar
Keyword(s):  
Multidrug Resistant ◽  
Next Generation ◽  
Glycopeptide Resistance ◽  
Gram Positive ◽  
Life Saving

Vancomycin, a blockbuster antibiotic of the glycopeptide class, has been a life-saving therapeutic against multidrug-resistant Gram-positive infections. The emergence of glycopeptide resistance has however enunciated the need to develop credible...

scholarly journals Genomic Insights into the Distribution and Phylogeny of Glycopeptide Resistance Determinants within the Actinobacteria Phylum

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1533
Author(s):  
Andrés Andreo-Vidal ◽  
Elisa Binda ◽  
Victor Fedorenko ◽  
Flavia Marinelli ◽  
Oleksandr Yushchuk
Keyword(s):  
Biosynthetic Gene Cluster ◽  
Multidrug Resistant ◽  
Glycopeptide Antibiotics ◽  
Glycopeptide Resistance ◽  
Gram Positive ◽  
Health Security ◽  
Resistance Determinants ◽  
Phylogenetic Reconstructions ◽  
Bioinformatics Study ◽  
Self Protection

The spread of antimicrobial resistance (AMR) creates a challenge for global health security, rendering many previously successful classes of antibiotics useless. Unfortunately, this also includes glycopeptide antibiotics (GPAs), such as vancomycin and teicoplanin, which are currently being considered last-resort drugs. Emerging resistance towards GPAs risks limiting the clinical use of this class of antibiotics—our ultimate line of defense against multidrug-resistant (MDR) Gram-positive pathogens. But where does this resistance come from? It is widely recognized that the GPA resistance determinants—van genes—might have originated from GPA producers, such as soil-dwelling Gram-positive actinobacteria, that use them for self-protection. In the current work, we present a comprehensive bioinformatics study on the distribution and phylogeny of GPA resistance determinants within the Actinobacteria phylum. Interestingly, van-like genes (vlgs) were found distributed in different arrangements not only among GPA-producing actinobacteria but also in the non-producers: more than 10% of the screened actinobacterial genomes contained one or multiple vlgs, while less than 1% encoded for a biosynthetic gene cluster (BGC). By phylogenetic reconstructions, our results highlight the co-evolution of the different vlgs, indicating that the most diffused are the ones coding for putative VanY carboxypeptidases, which can be found alone in the genomes or associated with a vanS/R regulatory pair.

scholarly journals NEW INSIGHT ON EPIDEMIOLOGY AND MANAGEMENT OF BACTERIAL BLOODSTREAM INFECTION IN PATIENTS WITH HEMATOLOGICAL MALIGNACIES

2015 ◽  
Vol 7 ◽  
pp. e2015044 ◽  
Author(s):  
Sara Lo Menzo ◽  
Giulia La Martire ◽  
Giancarlo Ceccarelli ◽  
Mario Venditti
Keyword(s):  
Febrile Neutropenia ◽  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Empirical Treatment ◽  
Rational Approach ◽  
Attributable Mortality ◽  
Low Grade ◽  
Gram Positive ◽  
Adequate Treatment ◽  
Gram Negative

Bloodstream infections (BSI) are an important cause of morbidity and mortality in onco-hematologic patients. The Gram-negative etiology was the main responsible of the febrile neutropenia in the sixties and its impact declined due to the use of fluoroquinolone prophylaxis; this situation was followed by the gradual emergence of Gram-positive bacteria also following of the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of currentstrategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant and the appropriate empirical treatment significantly improves the prognosis; on the other hand the delayed adequate treatment of Gram-positive BSI does not seem to have an high impact on survival. The clinician has to be aware of the epidemiology of his institution and of colonizations of his patients in order to choose the most appropriate empiric therapy. Ina setting of high endemicity of multidrug-resistant infections, even the choice of a targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidences.In this review we summarize the current evidences for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant high prevalence setting.

scholarly journals Antibiotic Resistance and Biofilm Production in Catalase-Positive Gram-Positive Cocci Isolated from Brazilian Pasteurized Milk

2020 ◽  
Author(s):  
M.A.A. Machado ◽  
W.A. Ribeiro ◽  
V.S. Toledo ◽  
G.L.P.A. Ramos ◽  
H.C. Vigoder ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Qualitative Evaluation ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Pasteurized Milk ◽  
Biofilm Production ◽  
Diffusion Technique ◽  
Gram Positive Cocci

Background: Milk is a reservoir for several groups of microorganisms, which may pose health risks. The aim of this work was to assess the antibiotic resistance and biofilm production in catalase-positive Gram-positive cocci isolated from Brazilian pasteurized milk. Methods: The bacteria were isolated using Baird-Parker agar and identified by MatrixAssisted Laser Desorption/Ionization-Time-Of-Flight (MALDI-TOF) mass spectrometer. Disk diffusion technique was used to evaluate antimicrobial susceptibility. For qualitative evaluation of biofilm production, the growth technique was used on Congo Red Agar. Results: Totally, 33 out of 64 isolates were identified, including Staphylococcus epidermidis (n=3; 4.7%), Macrococcus caseolyticus (n=14; 21.9%), and Kocuria varians (n=16; 25%). Twenty-two isolates were resistant to at least one antibiotic. Biofilm production was detected in only 5 isolates of K. varians and 1 isolate of S. epidermidis. All 14 M. caseolyticus isolates were resistant to at least one antibiotic; but, multidrug resistant (MDR) isolates were not detected. Among all K. varians isolates, 4 were resistant to at least one antibiotic from three different classes and were considered to be MDR. Conclusion: The presence of antibiotic-resistant M. caseolyticus, S. epidermidis, and K. varians isolates, especially MDRs, in milk samples highlights the possible role of milk as a reservoir of resistance genes

scholarly journals Comparative Analysis of Dalbavancin versus Other Antimicrobial Options for Gram-Positive cocci Infections: Effectiveness, Hospital Stay and Mortality

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1296
Author(s):  
Mar de Pablo-Miró ◽  
Sergi Pujol-Ruiz ◽  
Simona Iftimie ◽  
María del Mar Arenas-Miras ◽  
Inmaculada López-Montesinos ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Length Of Hospital Stay ◽  
Multidrug Resistant ◽  
Ambulatory Setting ◽  
Bivariate Analysis ◽  
Gram Positive ◽  
Healthcare Associated ◽  
Remarkable Reduction ◽  
Gram Positive Cocci ◽  
Control Study

Dalbavancin is a new antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococci, and offers the possibility of administering intravenous therapy once weekly in an ambulatory setting. We conducted a multicenter observational case-control study, comparing all patients who received dalbavancin (cases) with hospitalized patients who were treated instead with daptomycin, linezolid or vancomycin (controls), based on clinical diagnosis, main microorganism involved, and age. The primary outcome was the length of hospital stay after starting the study antimicrobial. Secondary outcomes were 7-day and 30-day efficacy, 30-day mortality, 90-day recurrence, 90-day and 6-month hospitalization, presence of adverse events and healthcare-associated infections; 161 patients (44 cases and 117 controls) were included. Bivariate analysis showed that dalbavancin reduced the total length of hospital stay (p < 0.001), with fewer 90-day recurrences (p = 0.005), 6-month hospitalizations related to the same infection (p = 0.004) and non-related hospitalizations (p = 0.035). Multivariate analyses showed that length of hospital stay was significantly shorter in patients treated with dalbavancin (−12.05 days 95% CI [−17.00, −7.11], p < 0.001), and 30-day efficacy was higher in the dalbavancin group (OR 2.62 95% CI [1.07, 6.37], p = 0.034). Although sample size of the study may be a limitation, we can conclude that Dalbavancin is a useful antimicrobial drug against Gram-positive infections, including multidrug-resistant pathogens, and allows for a remarkable reduction in length of hospital stay with greater 30-day efficacy.

scholarly journals Synthesis, Structure Elucidation, Antibacterial Activities, and Synergistic Effects of Novel Juglone and Naphthazarin Derivatives Against Clinical Methicillin-Resistant Staphylococcus aureus Strains

2021 ◽  
Vol 9 ◽  
Author(s):  
Valentin Duvauchelle ◽  
Chaimae Majdi ◽  
David Bénimélis ◽  
Catherine Dunyach-Remy ◽  
Patrick Meffre ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Antibacterial Properties ◽  
Clinical Importance ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Gram Positive ◽  
Drug Resistant Bacteria ◽  
Mrsa Strains

Infections caused by drug-resistant bacteria are a serious threat to human and global public health. Moreover, in recent years, very few antibiotics have been discovered and developed by pharmaceutical companies. Therefore, there is an urgent need to discover and develop new antibacterial agents to combat multidrug-resistant bacteria. In this study, two novel series of juglone/naphthazarin derivatives (43 compounds) were synthesized and evaluated for their antibacterial properties against various clinical and reference Gram-positive MSSA, clinical Gram-positive MRSA, and clinical and reference Gram-negative bacteria E. coli and P. aeruginosa. These strains are of clinical importance because they belong to ESKAPE pathogens. Compounds 3al, 5ag, and 3bg showed promising activity against clinical and reference MSSA (MIC: 1–8 µg/ml) and good efficacy against clinical MRSA (MIC: 2–8 µg/ml) strains. 5am and 3bm demonstrated better activity on both MSSA (MIC: 0.5 µg/ml) and MRSA (MIC: 2 µg/ml) strains. Their MICs were similar to those of cloxacillin against clinical MRSA strains. The synergistic effects of active compounds 3al, 5ag, 5am, 3bg, and 3bm were evaluated with reference antibiotics, and it was found that the antibiotic combination with 3bm efficiently enhanced the antimicrobial activity. Compound 3bm was found to restore the sensitivity of clinical MRSA to cloxacillin and enhanced the antibacterial activity of vancomycin when they were added together. In the presence of 3bm, the MIC values of vancomycin and cloxacillin were lowered up to 1/16th of the original MIC with an FIC index of 0.313. Moreover, compounds 3al, 5ag, 5am, 3bg, and 3bm did not present hemolytic activity on sheep red blood cells. In silico prediction of ADME profile parameter results for 3bm is promising and encouraging for further development.

scholarly journals Sarconesin II, a New Antimicrobial Peptide Isolated from Sarconesiopsis magellanica Excretions and Secretions

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2077 ◽  
Author(s):  
Andrea Díaz-Roa ◽  
Abraham Espinoza-Culupú ◽  
Orlando Torres-García ◽  
Monamaris M. Borges ◽  
Ivan N. Avino ◽  
...  
Keyword(s):  
Micrococcus Luteus ◽  
Multidrug Resistant ◽  
Peptide Sequence ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Conserved Domain ◽  
Health Institutions

Antibiotic resistance is at dangerous levels and increasing worldwide. The search for new antimicrobial drugs to counteract this problem is a priority for health institutions and organizations, both globally and in individual countries. Sarconesiopsis magellanica blowfly larval excretions and secretions (ES) are an important source for isolating antimicrobial peptides (AMPs). This study aims to identify and characterize a new S. magellanica AMP. RP-HPLC was used to fractionate ES, using C18 columns, and their antimicrobial activity was evaluated. The peptide sequence of the fraction collected at 43.7 min was determined by mass spectrometry (MS). Fluorescence and electronic microscopy were used to evaluate the mechanism of action. Toxicity was tested on HeLa cells and human erythrocytes; physicochemical properties were evaluated. The molecule in the ES was characterized as sarconesin II and it showed activity against Gram-negative (Escherichia coli MG1655, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa PA14) and Gram-positive (Staphylococcus aureus ATCC 29213, Micrococcus luteus A270) bacteria. The lowest minimum inhibitory concentration obtained was 1.9 μM for M. luteus A270; the AMP had no toxicity in any cells tested here and its action in bacterial membrane and DNA was confirmed. Sarconesin II was documented as a conserved domain of the ATP synthase protein belonging to the Fli-1 superfamily. The data reported here indicated that peptides could be alternative therapeutic candidates for use in infections against Gram-negative and Gram-positive bacteria and eventually as a new resource of compounds for combating multidrug-resistant bacteria.

scholarly journals Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2888 ◽  
Author(s):  
Buthaina Jubeh ◽  
Zeinab Breijyeh ◽  
Rafik Karaman
Keyword(s):  
Turning Point ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Medical Interventions ◽  
Gram Positive Bacteria ◽  
New Antibiotics ◽  
Vancomycin Resistant ◽  
New Treatments ◽  
Emergence Of Resistance

The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.

scholarly journals 2287. Real-world Use of Tedizolid Phosphate: A Case Series of Long-Term Tolerability

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S784-S784
Author(s):  
Taylor Morrisette ◽  
Beatriz Da Silva ◽  
Scott W Mueller ◽  
Laura Damioli ◽  
Martin Krsak ◽  
...  
Keyword(s):  
White Blood Cells ◽  
Case Series ◽  
Multidrug Resistant ◽  
Primary Objective ◽  
Term Therapy ◽  
Gram Positive ◽  
Safe Alternative ◽  
Term Tolerability

Abstract Background Tedizolid is an oxazolidinone antibiotic with broad-spectrum Gram-positive activity approved for the treatment of skin and skin structure infections with a 6-day course. Oxazolidinone antibiotics represent appealing options for prolonged antimicrobial therapy due to their available oral formulations with excellent bioavailability and potent in vitro activity against various multidrug-resistant Gram-positive organisms, Mycobacterium spp., and Nocardia spp. Although tedizolid and linezolid offer a similar clinical spectrum based on antimicrobial activity alone, long-term use of linezolid is often limited by serious adverse effects. Preliminary assessments have suggested better tolerability with tedizolid; however, these are limited by shorter exposure duration. The objective of this study was to evaluate the long-term safety and tolerability of tedizolid. Methods Retrospective cohort of adult patients receiving tedizolid for ≥ 28 days, with baseline complete blood cell (CBC) indices available, and CBC indices drawn ≥ 14 days into tedizolid course. The primary objective was to evaluate the long-term tolerability of tedizolid. Results 13 patients met inclusion criteria: median age 61 years (IQR, 51–64 years), 69% male, 85% Caucasian. The majority of patients utilized tedizolid for suppression (85%), and the median duration of tedizolid was 113 days (IQR, 71–204 days). There were no differences in CBC indices when comparing baseline to last laboratory draw throughout tedizolid exposure: platelets (baseline: 203 x 109/L (IQR, 186–283 x 109/L) vs. last: 196 x 109/L (IQR, 161–303 x 109/L; p = 0.65), hemoglobin (baseline: 9.8 g/dL (IQR, 8.8–11.1 g/dL) vs. last: 11.7 g/dL (IQR, 11.0–13.1 g/dL; p = 0.10), and white blood cells (baseline: 6.2 x 109/L (IQR, 5.6–7.6 x 109/L) vs. last: 6.5 x 109/L (IQR, 6.3–7.3 x 109/L; p = 0.45). The final laboratory draws were obtained a median of 78 days (IQR, 44–119 days) into therapy. No patients experienced peripheral neuropathy, optic neuritis/visual changes, or serotonin syndrome during treatment/suppression with tedizolid during the period evaluated. Conclusion Long-term therapy with tedizolid appears to be well-tolerated. Treatment and suppression with tedizolid seems to be a safe alternative to linezolid. Disclosures All authors: No reported disclosures.

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