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First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus
Antimicrob Agents Chemother. 2024 Mar 25:e0161523. doi: 10.1128/aac.01615-23. Online ahead of print.ABSTRACTAT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1,500 mg or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse ...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Xiao-Jian Zhou Jason Lickliter Maureen Montrond Laura Ishak Keith Pietropaolo Dayle James Bruce Belanger Arantxa Horga Janet Hammond Source Type: research

Quorum-sensing regulation of phenazine production heightens Pseudomonas aeruginosa resistance to ciprofloxacin
This study illustrates the role of quorum sensing-mediated phenotypic resistance and suggests a strategy for its prevention.PMID:38526048 | DOI:10.1128/aac.00118-24 (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Lexin Xia Yue Li Yufan Wang Hui Zhou Ajai A Dandekar Feng Xu Meizhen Wang Source Type: research

Role of amino acid 159 in carbapenem and temocillin hydrolysis of OXA-933, a novel OXA-48 variant
In this study, we have characterized a novel variant of OXA-48, OXA-933 with a single D159N change. To evaluate the importance of this residue, point mutations were generated (D159A, D159G, D159K, and D159W), kinetic parameters of OXA-933, OXA-48 D159G, and OXA-48 D159K were determined and compared to those of OXA-48 and OXA-244. The blaOXA-933 gene was borne on Tn2208, a 2,696-bp composite transposon made of two IS1 elements surrounded by 9 bp target site duplications and inserted into a non-self-transmissible plasmid pOXA-933 of 7,872 bp in size. Minimal inhibitory concentration values of E. coli expressing the blaOXA-93...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Mariam Rima Saoussen Oueslati Garance Cotelon Elodie Creton R émy A Bonnin Laurent Dortet Bogdan I Iorga Thierry Naas Source Type: research

 In vitro development of resistance against antipseudomonal agents: comparison of novel β-lactam/β-lactamase inhibitor combinations and other β-lactam agents
Antimicrob Agents Chemother. 2024 Mar 25:e0136323. doi: 10.1128/aac.01363-23. Online ahead of print.ABSTRACTWe subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane-tazobactam (11.4-fold) and cefta...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Mariana Castanheira John H Kimbrough Jill Lindley Timothy B Doyle Jessica M Ewald Helio S Sader Source Type: research

Updated antimicrobial dosing recommendations for obese patients
Antimicrob Agents Chemother. 2024 Mar 25:e0171923. doi: 10.1128/aac.01719-23. Online ahead of print.ABSTRACTThe prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to p...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Ana Castro-Balado Iria Varela-Rey Beatriz Mejuto Cristina Mondelo-Garc ía Irene Zarra-Ferro Teresa Rodr íguez-Jato Anxo Fern ández-Ferreiro Source Type: research

Preventive nasal administration of flagellin restores antimicrobial effect of gentamicin and protects against a multidrug-resistant strain of Pseudomonas aeruginosa 
In this study, we evaluated the prophylactic intranasal administration of flagellin against a multidrug-resistant strain of PA (PAMDR) in mice and assessed the possible synergy with the antibiotic gentamicin (GNT). The results indicated that flagellin treatment before infection decreased bacterial load in the lungs, likely due to an increase in neutrophil recruitment, and reduced signs of inflammation, including proinflammatory cytokines. The combination of flagellin and GNT showed a synergistic effect, decreasing even more the bacterial load and increasing mice survival rates, in comparison to mice pre-treated only with f...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Ana Raquel Maia Adeline Cezard Delphine Fouquenet Virginie Vasseur Benoit Briard Jean-Claude Sirard Mustapha Si-Tahar Virginie Herv é Source Type: research

Infection and antibiotic-associated changes in the fecal microbiota of C. rodentium ϕ stx2 dact -infected C57BL/6 mice
Antimicrob Agents Chemother. 2024 Mar 25:e0005724. doi: 10.1128/aac.00057-24. Online ahead of print.ABSTRACTEnterohemorrhagic Escherichia coli causes watery to bloody diarrhea, which may progress to hemorrhagic colitis and hemolytic-uremic syndrome. While early studies suggested that antibiotic treatment may worsen the pathology of an enterohemorrhagic Escherichia coli (EHEC) infection, recent work has shown that certain non-Shiga toxin-inducing antibiotics avert disease progression. Unfortunately, both intestinal bacterial infections and antibiotic treatment are associated with dysbiosis. This can alleviate colonization r...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Sabrina M ühlen Ann Kathrin Heroven Bettina Elxnat Silke Kahl Dietmar H Pieper Petra Dersch Source Type: research

Outcomes by Candida spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis
Antimicrob Agents Chemother. 2024 Mar 25:e0158423. doi: 10.1128/aac.01584-23. Online ahead of print.ABSTRACTRezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida specie...
Source: Antimicrobial Agents and Chemotherapy - March 25, 2024 Category: Microbiology Authors: Jeffrey B Locke Chris M Pillar Mariana Castanheira Cecilia G Carvalhaes David Andes Jalal A Aram Christina Andrzejewski Ken Bartizal Anita F Das Taylor Sandison George R Thompson Peter G Pappas Source Type: research