Discovery of 1,4-Didydroxy-2-naphthoate Prenyltransferase Inhibitors:  New Drug Leads for Multidrug-Resistant Gram-Positive Pathogens

Abstract Background World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). Methods AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort. Results By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1–2) and 33.1% as serious (Grade 3–5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75–169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually. Conclusions Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

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

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2015.044 ◽

2015 ◽

Vol 7 ◽

pp. e2015044 ◽

Cited By ~ 5

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.

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

Journal of Food Quality and Hazards Control ◽

10.18502/jfqhc.7.2.2886 ◽

2020 ◽

Cited By ~ 1

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

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

Antibiotics ◽

10.3390/antibiotics10111296 ◽

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.

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

Frontiers in Chemistry ◽

10.3389/fchem.2021.773981 ◽

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.

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New Drug Combats Multidrug Resistant Tuberculosis

AJN American Journal of Nursing ◽

10.1097/01.naj.0000428741.78922.18 ◽

2013 ◽

Vol 113 (4) ◽

pp. 29

Author(s):

Diane S. Aschenbrenner

Keyword(s):

Multidrug Resistant ◽

New Drug ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis

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

Molecules ◽

10.3390/molecules24112077 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2077 ◽

Cited By ~ 1

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.

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