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Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa, Elda Righi
Introduction Infections due to multidrug-resistant (MDR) bacteria are burdened by high mortality rates. The development of new compounds to face the global threat of resistance is urgently needed. Combination regimens including "old" high-dose antimicrobials are currently limited by the risk of toxicity, resistance selection, and reduced efficacy. Following the Infectious Diseases Society of America call to develop 10 new antibacterials by 2020, new molecules are currently under development or have become available for use in clinical practice...
June 13, 2018: Expert Opinion on Drug Safety
Tomefa E Asempa, Lindsay M Avery, James M Kidd, Joseph L Kuti, David P Nicolau
PURPOSE: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported. METHODS: Plazomicin injection solution (500 mg/10 mL) was diluted in 0.9% sodium chloride or 5% dextrose for injection to a final volume of 50 mL (final plazomicin concentration, 24 mg/mL), consistent with a 15-mg/kg dose administered to an 80-kg patient (i.e., 1,200 mg). All other i.v. drugs were reconstituted according to manufacturers' recommendations and diluted with 0...
June 12, 2018: American Journal of Health-system Pharmacy: AJHP
M Thwaites, D Hall, D Shinabarger, A W Serio, K M Krause, A Marra, C Pillar
The next-generation aminoglycoside plazomicin, in development for infections due to multi-drug resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 μg/mL and sustained 3-log10 kill against MDR Escherichia coli , Klebsiella pneumoniae and Enterobacter spp...
June 4, 2018: Antimicrobial Agents and Chemotherapy
Kamilia Abdelraouf, Aryun Kim, Kevin M Krause, David P Nicolau
Background : Plazomicin is a next-generation aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae. The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. Methods : ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem and tigecycline MICs were utilized...
June 4, 2018: Antimicrobial Agents and Chemotherapy
Mariana Castanheira, Andrew P Davis, Rodrigo E Mendes, Alisa W Serio, Kevin M Krause, Robert K Flamm
Plazomicin and comparators agents were tested using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 United States hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/90 , 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, applying CLSI breakpoints. The activity of plazomicin was similar among Enterobacteriaceae species with MIC50 values ranging from 0...
June 4, 2018: Antimicrobial Agents and Chemotherapy
Amr Sonousi, Vikram A Sarpe, Margarita Brilkova, Jochen Schacht, Andrea Vasella, Erik C Böttger, David Crich
Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1- N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect...
May 10, 2018: ACS Infectious Diseases
Jesús Rodríguez-Baño, Belén Gutiérrez-Gutiérrez, Isabel Machuca, Alvaro Pascual
Therapy of invasive infections due to multidrug-resistant Enterobacteriaceae (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole...
April 2018: Clinical Microbiology Reviews
Lynn E Connolly, Valerie Riddle, Deborah Cebrik, Eliana S Armstrong, Loren G Miller
Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae , including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis...
April 2018: Antimicrobial Agents and Chemotherapy
Matteo Bassetti, Antionio Vena, Nadia Castaldo, Elda Righi, Maddalena Peghin
PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) bacteria represents a global emerging problem. Delayed prescription of an adequate treatment for VAP has been associated with higher morbidity and mortality. New molecules have been developed to face the need of compounds that are active against resistant Gram-positive and Gram-negative pathogens. The aim of this review is to summarize the current scenario of new therapeutic options for the treatment of VAP...
April 2018: Current Opinion in Infectious Diseases
Andreza Francisco Martins, Larissa Bail, Carmen Antonia Sanches Ito, Keite da Silva Nogueira, Tanise Vendruscolo Dalmolin, Amanda Silva Martins, Jaime Luis Lopes Rocha, Alisa W Serio, Felipe Francisco Tuon
Plazomicin is a next-generation aminoglycoside with activity against Enterobacteriaceae, including carbapenemase-producing Enterobacteriaceae (CPE). The aim of this study was to evaluate the activity of plazomicin against CPE (Klebsiella spp., Escherichia coli, Serratia spp., Enterobacter spp., Citrobacter spp., Morganella spp., Proteus spp., Providencia spp.) from different Brazilian hospitals. A total of 4000 carbapenem-resistant Enterobacteriaceae isolates were collected from clinical samples in 50 Brazilian hospitals during 2013-2015...
March 2018: Diagnostic Microbiology and Infectious Disease
Valérie Denervaud-Tendon, Laurent Poirel, Lynn E Connolly, Kevin M Krause, Patrice Nordmann
Objectives: Plazomicin, a novel aminoglycoside with in vitro activity against MDR Gram-negative organisms, is under development to treat patients with serious enterobacterial infections. We evaluated the activity of plazomicin and comparators against colistin-resistant enterobacterial isolates. Methods: Susceptibility to plazomicin and comparators was tested by broth microdilution for a collection of 95 colistin-resistant enterobacterial isolates collected from 29 hospitals in eight countries...
October 1, 2017: Journal of Antimicrobial Chemotherapy
Yunliang Zhang, Ankita Kashikar, Karen Bush
Background: Carbapenem-resistant Enterobacteriaceae (CRE) represent an urgent threat because few drugs are available to treat infections caused by these pathogens. Plazomicin is a novel aminoglycoside that recently completed a Phase 3 clinical trial for treatment of infections caused by CRE. Methods: A set of 110 characterized unique CRE patient isolates from central Indiana healthcare centres was tested by microbroth dilution for susceptibility to plazomicin, and to reference aminoglycosides and carbapenems...
October 1, 2017: Journal of Antimicrobial Chemotherapy
H Wright, R A Bonomo, D L Paterson
BACKGROUND: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. AIMS: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms...
October 2017: Clinical Microbiology and Infection
María Carmen López Díaz, Esther Ríos, Iciar Rodríguez-Avial, Rosa Janneth Simaluiza, Juan José Picazo, Esther Culebras
This study investigated the in-vitro activity of clinically relevant aminoglycosides and new antimicrobial agents-plazomicin, ceftobiprole and dalbavancin-against 55 methicillin-resistant Staphylococcus aureus (MRSA) isolates producing aminoglycoside-modifying enzymes (AMEs). The checkerboard method was used to assess synergism between plazomicin and four antibiotics (fosfomycin, ceftobiprole, cefoxitin and meropenem), and time-kill assays were performed for the most active combinations. Among the aminoglycosides tested, plazomicin was the most active agent against MRSA, with >90% of isolates being inhibited at a minimum inhibitory concentration (MIC) of ≤1 mg/L...
August 2017: International Journal of Antimicrobial Agents
Maria Del Carmen López-Diaz, Esther Culebras, Iciar Rodríguez-Avial, Esther Rios, José Manuel Viñuela-Prieto, Juan J Picazo, Carmen Rodríguez-Avial
The activity of plazomicin and clinically relevant aminoglycosides was tested against 346 extended-spectrum-β-lactamase/AmpC-producing Escherichia coli urinary isolates, and the results were correlated with the presence of aminoglycoside-modifying enzymes (AMEs). Data showed that plazomicin was very active against all ESBL/AmpC-producing E. coli urinary isolates. Its activity was not related to the AME genes studied.
February 2017: Antimicrobial Agents and Chemotherapy
William M Mega, Melanie Doyle-Eisele, Robert T Cass, Corwin F Kostrub, Robert L Sherwood, Matthew A Metz, Ryan T Cirz
The efficacy of plazomicin for pneumonic plague was evaluated in a non-human primate model. African Green monkeys challenged with a lethal aerosol of Yersinia pestis [median (range) of 98 (15-331) LD50s ] received placebo (n=12) or 'humanized' dose regimens (6.25, 12.5 or 25mg/kg every 24h) of plazomicin (n=52) after the onset of fever for a duration of 5 or 10days. All animals treated with placebo died, while 36 plazomicin-treated animals survived through study end. The majority (33/36) were either in the 10-day (high-/mid-/low-dose) or 5-day high-dose groups...
December 15, 2016: Bioorganic & Medicinal Chemistry
Matthew E Falagas, Andreas D Mavroudis, Konstantinos Z Vardakas
INTRODUCTION: A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians. AREAS COVERED: We searched PUBMED and GOOGLE databases. Combinations of already approved β-lactams or monobactams with new β-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new β-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review...
August 2016: Expert Review of Anti-infective Therapy
Joshua T Thaden, Jason M Pogue, Keith S Kaye
Antimicrobial resistance has been identified by the World Health Organization as "one of the three greatest threats to human health." Gram negative bacteria in particular drive this alarming trend. Carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter species are of particular importance as they are associated with poor clinical outcomes and are common causes for a variety of infections including bacteremia, urinary tract infection, intra-abdominal infections and pneumonia...
May 19, 2017: Virulence
Adamantia Liapikou, Antoni Torres
INTRODUCTION: Hospital-acquired pneumonia (HAP) is one of the leading nosocomial infections worldwide and is associated with an elevated morbidity and mortality and increased hospital costs. Nevertheless, prompt and adequate antimicrobial treatment is mandatory following VAP development, especially in the face of multidrug resistant pathogens. AREAS COVERED: We searched Pubmed and site reports in English language of phase III clinical trials, between 2000-2016 referring to the antibiotic treatment of nosocomial pneumonia...
September 2016: Expert Opinion on Emerging Drugs
Ghady Haidar, Ammar Alkroud, Shaoji Cheng, Travis M Churilla, Bryce M Churilla, Ryan K Shields, Yohei Doi, Cornelius J Clancy, M Hong Nguyen
We compared the in vitro activities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13 Enterobacter isolates possessing both Klebsiella pneumoniae carbapenemase and extended-spectrum β-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL-, 6 KPC-/ESBL+, and 38 KPC-/ESBL- isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL- (25% and 38%, respectively), KPC-/ESBL+ (50% and 17%, respectively), and KPC-/ESBL- (0% and 3%, respectively) isolates...
September 2016: Antimicrobial Agents and Chemotherapy
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