The Antibiotic Development Pipeline for Multidrug-Resistant Gram-Negative Bacilli: Current and Future Landscapes

2010 ◽  
Vol 31 (S1) ◽  
pp. S55-S58 ◽  
Author(s):  
George H. Talbot
Keyword(s):  
Multidrug Resistant ◽  
Clinical Development ◽  
Gram Positive ◽  
Gram Negative ◽  
Antibiotic Development ◽  
Development Pipeline ◽  
Early Clinical Development

Development of antibiotics to treat infections caused by multidrug-resistant gram-negative bacilli has lagged significantly behind development of antibiotics to treat infections with gram-positive pathogens. Although a few promising drugs have entered early clinical development, more must be done to preserve the utility of currently available antibiotics and to ensure a pipeline of efficacious, safe antibacterials.

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 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 Cyathea gigantea (Cyatheaceae) as an antimicrobial agent against multidrug resistant organisms

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Kathakali Nath ◽  
Anupam Das Talukdar ◽  
Mrinal Kanti Bhattacharya ◽  
Deepshikha Bhowmik ◽  
Shiela Chetri ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Property ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Synergistic Activity ◽  
Gram Positive ◽  
Traditional Use ◽  
Gram Negative ◽  
Multidrug Resistant Organisms

Abstract Background Rapid emergence of multidrug resistant (MDR) organisms in hospital and community settings often result into treatment failure, thus leading the clinicians with fewer treatment options. Cyathea gigantea, an ethnomedicinally important fern used in cuts and wound infections. So, if this medicinal plant is used in treating the MDR infections then it might bring certain relief in future treatment options. Methods Antibacterial activity of C. gigantea against MDR bacteria was assed using well diffusion and broth microdilution methods to determine the diameters of growth inhibition zones, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Synergistic activity was also determined with the conventional antibiotics by disc diffusion method followed by FIC index of each of the tested antibiotic was calculated. The active extract was then subjected to fractionation by column chromatography and antibacterial activity was done with each of the collected fractions. Results Crude extract of C. gigantea was found to be active against all the tested organisms. The MIC was 200 μg/ml against Gram-positive i.e., Staphylococcus aureus ATCC 25923 and 400 μg/ml against Gram-negative i.e., Escherichia coli ATCC 25922 and Pseudomonas aeruginosa PAO1, while the MBC was 400 μg/ml in case of Gram-positive and 800 μg/ml for Gram-negative. The synergistic activity revealed that the plant extract increased the antibacterial property of the studied antibiotics and the FIC index showed that significant synergistic activity was shown by ciprofloxacin followed by tetracycline, ampicillin and oxacillin. Antibacterial activity with the fractionated extract showed that the FR II, FR III and FR IV were active against both Gram-positive and Gram-negative bacteria, whereas FR I, FR V and FR VI did not show antibacterial property against any of the tested bacteria. Conclusions Extracts of C. gigantea was found active against both selected Gram-positive and Gram-negative organisms and thus offers the scientific basis for the traditional use of the fern. The present study also provides the basis for future study to validate the possible use against multidrug resistant organisms.

scholarly journals In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Gregory G. Stone ◽  
Patricia A. Bradford ◽  
Margaret Tawadrous ◽  
Dianna Taylor ◽  
Mary Jane Cadatal ◽  
...  
Keyword(s):  
Nosocomial Pneumonia ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Ventilator Associated Pneumonia ◽  
Phase 3 ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

scholarly journals Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

Membranes ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 181 ◽  
Author(s):  
Carole Ayoub Moubareck
Keyword(s):  
Current Knowledge ◽  
Acquired Resistance ◽  
Epidemiological Studies ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Bacterial Membranes ◽  
Antibiotic Development ◽  
Outer Membranes ◽  
Initial Discovery ◽  
Clinical Interest

Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.

scholarly journals In Vitro Study of Antimicrobial Percutaneous Nephrostomy Catheters for Prevention of Renal Infections

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Nylev Vargas-Cruz ◽  
Ruth A. Reitzel ◽  
Joel Rosenblatt ◽  
Mohamed Jamal ◽  
Ariel D. Szvalb ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Biofilm Formation ◽  
In Vitro Study ◽  
Percutaneous Nephrostomy ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Fungal Organisms

ABSTRACT Percutaneous nephrostomy (PCN) catheters are the primary method for draining ureters obstructed by malignancy and preventing a decline of renal function. However, PCN catheter-related infections, such as pyelonephritis and urosepsis, remain a significant concern. Currently, no antimicrobial PCN catheters are available for preventing infection complications. Vascular catheters impregnated with minocycline-rifampin (M/R) and M/R with chlorhexidine coating (M/R plus CHD) have previously demonstrated antimicrobial activity. Therefore, in this study, we examined whether these combinations could be applied to PCN catheters and effectively inhibit biofilm formation by common uropathogens. An in vitro biofilm colonization model was used to assess the antimicrobial efficacy of M/R and M/R-plus-CHD PCN catheters against nine common multidrug-resistant Gram-positive and Gram-negative uropathogens as well as Candida glabrata and Candida albicans. Experimental catheters were also assessed for durability of antimicrobial activity for up 3 weeks. PCN catheters coated with M/R plus CHD completely inhibited biofilm formation for up to 3 weeks for all the organisms tested. The reduction in colonization compared to uncoated PCN catheters was significant for all Gram-positive, Gram-negative, and fungal organisms (P < 0.05). M/R-plus-CHD PCN catheters also produced significant reductions in biofilm colonization relative to M/R PCN catheters for Enterobacter spp., Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, C. glabrata, and C. albicans (P < 0.05). M/R-plus-CHD PCN catheters proved to be highly efficacious in preventing biofilm colonization when exposed to multidrug-resistant pathogens common in PCN catheter-associated pyelonephritis. M/R-plus-CHD PCN catheters warrant evaluation in a clinical setting to assess their ability to prevent clinically relevant nephrostomy infections.

Increasing frequency of gram-positive cocci and gram-negative multidrug-resistant bacteria in spontaneous bacterial peritonitis

2013 ◽  
Vol 33 (7) ◽  
pp. 975-981 ◽  
Author(s):  
Alexandra Alexopoulou ◽  
Nikolaos Papadopoulos ◽  
Dimitrios G. Eliopoulos ◽  
Apostolia Alexaki ◽  
Athanasia Tsiriga ◽  
...  
Keyword(s):  
Spontaneous Bacterial Peritonitis ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Bacterial Peritonitis ◽  
Gram Positive Cocci

scholarly journals Microbial Profile of Various Catheter Tips among Hospitalized Patients

2018 ◽  
Vol 5 ◽  
pp. 32-38
Author(s):  
Pushpa Man Shrestha ◽  
Nisha Thapa ◽  
Navraj Dahal ◽  
Nabaraj Adhikari ◽  
Upendra Thapa Shrestha
Keyword(s):  
Antimicrobial Susceptibility ◽  
Susceptibility Testing ◽  
Descriptive Analysis ◽  
Multidrug Resistant ◽  
Antimicrobial Susceptibility Testing ◽  
Resistance Pattern ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Klebsiella Spp

Objectives: This study aimed to identify the microbiological profile of various catheter tips, and multidrug resistance pattern of extended spectrum β-lactamase (ESBL) producing E. coli and Klebsiella spp. isolates. Methods: A descriptive analysis of 263 catheter tip specimens processed for culture and antimicrobial susceptibility testing was carried out in B&B Hospital, Lalitpur. Five different types of catheter tips were analyzed for microbiological growth and antimicrobial susceptibility testing. Results: Among catheter tips, the highest percentage of microbial growth was observed in tracheostomy tip. Monomicrobial growth was recorded in 82.9% catheter tips and polymicrobial growth was observed in 17.1% tip samples. Of 180 isolates, gram negative rods (76.6%) followed by yeast (19.4%) and gram-positive cocci (3.9%) were isolated. Gram negative Acinetobacter spp. (25%) and Pseudomonas spp. (23.3%) and gram-positive Enterococcus spp. (2.2%) were the most frequently isolated bacteria. However, carbapenam was the most effective antibiotic for both groups. Conclusion: Of the total isolates tested, 61.4% were found to be multidrug resistant (MDR). Among gram negative rods, 22.2% E. coli and 27.3% Klebsiella spp. were confirmed as ESBL producer. It is recommended to apply standard protocol during insertion and removal of catheter which may help in managing nosocomial infection associated with catheters.

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