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Table of Contents

February 2020; Volume 64,Issue 2

Commentaries

  • Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)
    Commentary
    Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)

    The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and ...

    Jason M. Pogue, Ronald N. Jones, John S. Bradley, David R. Andes, Sujata M. Bhavnani, George L. Drusano, Michael N. Dudley, Robert K. Flamm, Keith A. Rodvold, Paul G. Ambrose
    and on behalf of the United States Committee on Antimicrobial Susceptibility Testing (USCAST)
  • Free
    Precision Medicine and Mysteries in Clinical Microbiology: Rationalizing Epidemiology, Genotype, and Phenotype To Guide Therapeutics
    Commentary
    Precision Medicine and Mysteries in Clinical Microbiology: Rationalizing Epidemiology, Genotype, and Phenotype To Guide Therapeutics

    Whole-genome sequencing (WGS) using MinION was used to characterize high-risk clones of Escherichia coli and Klebsiella pneumoniae harboring blaNDM-5, blaOXA-181, and blaCTX-M-15, as well as Pseudomonas aeruginosa harboring bla...

    Federico Perez, Robert A. Bonomo

Minireviews

  • Antimicrobial Therapy in the Context of the Damage-Response Framework: the Prospect of Optimizing Therapy by Reducing Host Damage
    Minireview
    Antimicrobial Therapy in the Context of the Damage-Response Framework: the Prospect of Optimizing Therapy by Reducing Host Damage

    By design, antimicrobial agents act directly on microbial targets. These drugs aim to eliminate microbes and are remarkably effective against susceptible organisms. Nonetheless, some patients succumb to infectious diseases despite appropriate antimicrobial therapy. Today, with very few exceptions, physicians select antimicrobial therapy based on its activity against the targeted organism without consideration of how the regimen affects...

    Liise-anne Pirofski, Arturo Casadevall
  • Antibiotic Resistance and Epigenetics: More to It than Meets the Eye
    Editor's Pick Minireview
    Antibiotic Resistance and Epigenetics: More to It than Meets the Eye

    The discovery of antibiotics in the last century is considered one of the most important achievements in the history of medicine. Antibiotic usage has significantly reduced morbidity and mortality associated with bacterial infections. However, inappropriate use of antibiotics has led to emergence of antibiotic resistance at an alarming rate. Antibiotic resistance is regarded as a major health care challenge of this century.

    ...
    Dipannita Ghosh, Balaji Veeraraghavan, Ravikrishnan Elangovan, Perumal Vivekanandan

Challenging Clinical Case in Antimicrobial Resistance

  • Free
    Simultaneous Infection with <em>Enterobacteriaceae</em> and <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> Harboring Multiple Carbapenemases in a Returning Traveler Colonized with <span class="named-content genus-species" id="named-content-2">Candida auris</span>
    Challenging Clinical Case in Antimicrobial Resistance
    Simultaneous Infection with Enterobacteriaceae and Pseudomonas aeruginosa Harboring Multiple Carbapenemases in a Returning Traveler Colonized with Candida auris

    We report our clinical experience treating a critically ill patient with polymicrobial infections due to multidrug-resistant Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa in a 56-year-old woman who received...

    Ayesha Khan, William C. Shropshire, Blake Hanson, An Q. Dinh, Audrey Wanger, Luis Ostrosky-Zeichner, Cesar A. Arias, William R. Miller

Mechanisms of Action: Physiological Effects

  • Efficacy of Voriconazole against <span class="named-content genus-species" id="named-content-1">Aspergillus fumigatus</span> Infection Depends on Host Immune Function
    Mechanisms of Action: Physiological Effects
    Efficacy of Voriconazole against Aspergillus fumigatus Infection Depends on Host Immune Function

    Antifungal therapy can fail in a remarkable number of patients with invasive fungal disease, resulting in significant morbidity worldwide. A major contributor to this failure is that while these drugs have high potency in vitro, we do not fully understand how they work inside infected hosts.

    Emily E. Rosowski, Jiaye He, Jan Huisken, Nancy P. Keller, Anna Huttenlocher
  • Open Access
    TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug’s Uncoupler Activity
    Mechanisms of Action: Physiological Effects
    TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug’s Uncoupler Activity

    The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity. Thus, uncoupling electron transport from ATP synthesis appears to be a second mechanism of action of this antimycobacterial drug. Here, we show that the new BDQ analogue TBAJ-876 did not retain the parental drug’s protonophore activity. Comparative time-kill analyses revealed that both compounds exert the same...

    Jickky Palmae Sarathy, Priya Ragunathan, Christopher B. Cooper, Anna M. Upton, Gerhard Grüber, Thomas Dick
  • Open Access
    Biochemical Activity of Vaborbactam
    Editor's Pick Mechanisms of Action: Physiological Effects
    Biochemical Activity of Vaborbactam

    The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring. Inhibition of β-lactamase activity with small-molecule drugs is a proven strategy to restore the potency of many β-lactam antibiotics.

    Ruslan Tsivkovski, Olga Lomovskaya

Mechanisms of Resistance

  • Biofilms of <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span> Complex Can Be Sensitized to Antibiotics by Disaggregation and Oxygenation
    Mechanisms of Resistance
    Biofilms of Mycobacterium abscessus Complex Can Be Sensitized to Antibiotics by Disaggregation and Oxygenation

    Pulmonary infection with the multidrug-resistant Mycobacterium abscessus complex (MABSC) is difficult to treat in individuals with cystic fibrosis (CF). MABSC grows as biofilm aggregates in CF patient lungs, which are known to have anaerobic niches. How aggregation and anoxic conditions affect antibiotic tolerance is not well understood. We sought to determine whether...

    Mette Kolpen, Peter Østrup Jensen, Tavs Qvist, Kasper Nørskov Kragh, Cecillie Ravnholt, Blaine Gabriel Fritz, Ulla Rydahl Johansen, Thomas Bjarnsholt, Niels Høiby
  • Meningococcal Quinolone Resistance Originated from Several Commensal <em>Neisseria</em> Species
    Mechanisms of Resistance
    Meningococcal Quinolone Resistance Originated from Several Commensal Neisseria Species

    Quinolone resistance is increasing in Neisseria meningitidis, with its prevalence in China being high (>70%), but its origin remains unknown. The aim of this study was to investigate the donors of mutation-harboring gyrA alleles in N. meningitidis. A total of 198 ...

    Mingliang Chen, Chi Zhang, Xi Zhang, Min Chen
  • <em>In Vitro</em> Derivation of Fluoroquinolone-Resistant Mutants from Multiple Lineages of <span class="named-content genus-species" id="named-content-1">Haemophilus influenzae</span> and Identification of Mutations Associated with Fluoroquinolone Resistance
    Mechanisms of Resistance
    In Vitro Derivation of Fluoroquinolone-Resistant Mutants from Multiple Lineages of Haemophilus influenzae and Identification of Mutations Associated with Fluoroquinolone Resistance

    Haemophilus influenzae is a pathogenic bacterium that causes respiratory and otolaryngological infections. The increasing prevalence of β-lactamase–negative high-level ampicillin-resistant H. influenzae (high-BLNAR) is a clinical concern. Fluoroquinolones are alternative agents to β-lactams. However...

    Hiroyuki Honda, Toyotaka Sato, Masaaki Shinagawa, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Koji Kuronuma, Satoshi Takahashi, Hiroki Takahashi, Shin-ichi Yokota
  • Mutations in Ribosomal Protein RplA or Treatment with Ribosomal Acting Antibiotics Activates Production of Aminoglycoside Efflux Pump SmeYZ in <span class="named-content genus-species" id="named-content-1">Stenotrophomonas maltophilia</span>
    Mechanisms of Resistance
    Mutations in Ribosomal Protein RplA or Treatment with Ribosomal Acting Antibiotics Activates Production of Aminoglycoside Efflux Pump SmeYZ in Stenotrophomonas maltophilia

    Aminoglycoside resistance in Stenotrophomonas maltophilia is multifactorial, but the most significant mechanism is overproduction of the SmeYZ efflux system. By studying laboratory-selected mutants and clinical isolates, we show here that damage to the 50S ribosomal protein L1 (RplA) activates SmeYZ production. We also show that gentamicin and minocycline, which...

    Karina Calvopiña, Punyawee Dulyayangkul, Matthew B. Avison
  • Inhibition Activity of Avibactam against <span class="named-content genus-species" id="named-content-1">Nocardia farcinica</span> β-Lactamase FAR<sub>IFM10152</sub>
    Editor's Pick Mechanisms of Resistance
    Inhibition Activity of Avibactam against Nocardia farcinica β-Lactamase FARIFM10152

    Nocardia farcinica, one of the most frequent pathogenic species responsible for nocardiosis, is characterized by frequent brain involvement and resistance to β-lactams mediated by a class A β-lactamase. Kinetic parameters for hydrolysis of various β-lactams by FARIFM10152 from strain IFM 10152 were determined by spectrophotometry revealing a high catalytic...

    David Lebeaux, Clément Ourghanlian, Delphine Dorchène, Daria Soroka, Zainab Edoo, Fabrice Compain, Michel Arthur
  • PFM-Like Enzymes Are a Novel Family of Subclass B2 Metallo-β-Lactamases from <span class="named-content genus-species" id="named-content-1">Pseudomonas synxantha</span> Belonging to the <span class="named-content genus-species" id="named-content-2">Pseudomonas fluorescens</span> Complex
    Mechanisms of Resistance
    PFM-Like Enzymes Are a Novel Family of Subclass B2 Metallo-β-Lactamases from Pseudomonas synxantha Belonging to the Pseudomonas fluorescens Complex

    A carbapenem-resistant Pseudomonas synxantha isolate recovered from chicken meat produced the novel carbapenemase PFM-1. That subclass B2 metallo-β-lactamase shared 71% amino acid identity with β-lactamase Sfh-1 from Serratia fonticola. The blaPFM-1 gene was chromosomally located...

    Laurent Poirel, Mattia Palmieri, Michael Brilhante, Amandine Masseron, Vincent Perreten, Patrice Nordmann
  • Dissecting <em>erm</em>(41)-Mediated Macrolide-Inducible Resistance in <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span>
    Mechanisms of Resistance
    Dissecting erm(41)-Mediated Macrolide-Inducible Resistance in Mycobacterium abscessus

    Macrolides are the cornerstone of Mycobacterium abscessus multidrug therapy, despite that most patients respond poorly to this class of antibiotics due to the inducible resistance phenotype that occurs during drug treatment. This mechanism is driven by the macrolide-inducible ribosomal methylase encoded by erm(41), whose expression is activated by the...

    Matthias Richard, Ana Victoria Gutiérrez, Laurent Kremer
  • Differential Sensitivity of Mycobacteria to Isoniazid Is Related to Differences in KatG-Mediated Enzymatic Activation of the Drug
    Mechanisms of Resistance
    Differential Sensitivity of Mycobacteria to Isoniazid Is Related to Differences in KatG-Mediated Enzymatic Activation of the Drug

    Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M...

    Tali H. Reingewertz, Tom Meyer, Fiona McIntosh, Jaryd Sullivan, Michal Meir, Yung-Fu Chang, Marcel A. Behr, Daniel Barkan
  • Diverse and Flexible Transmission of <em>fosA3</em> Associated with Heterogeneous Multidrug Resistance Regions in <span class="named-content genus-species" id="named-content-1">Salmonella enterica</span> Serovar Typhimurium and Indiana Isolates
    Mechanisms of Resistance
    Diverse and Flexible Transmission of fosA3 Associated with Heterogeneous Multidrug Resistance Regions in Salmonella enterica Serovar Typhimurium and Indiana Isolates

    We identified fosA3 at a rate of 2.6% in 310 Salmonella isolates from food animals in Guangdong province, China. The fosA3 gene was genetically linked to diverse antibiotic resistance genes (ARGs), including mcr-1, blaCTX-M-14/55, oqxAB, and rmtB. These gene combinations were embedded in heterogeneous fosA3-containing multidrug resistance regions on the...

    Liang-Xing Fang, Qi Jiang, Guo-Hui Deng, Bing He, Ruan-Yang Sun, Jin-Fei Zhang, Dao-Ji Cen, Yuan-Yuan Miao, Dong Wang, Wen-Ying Guo, Jian Sun, Ya-Hong Liu, Xiao-Ping Liao
  • Activity of Imipenem-Relebactam against a Large Collection of <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> Clinical Isolates and Isogenic β-Lactam-Resistant Mutants
    Mechanisms of Resistance
    Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic β-Lactam-Resistant Mutants

    Imipenem and imipenem-relebactam MICs were determined for 1,445 Pseudomonas aeruginosa clinical isolates and a large panel of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms. Imipenem-relebactam showed the highest susceptibility rate (97.3%), followed by colistin and ceftolozane-tazobactam (both 94.6%).

    Pablo A. Fraile-Ribot, Laura Zamorano, Rocío Orellana, Ester del Barrio-Tofiño, Irina Sánchez-Diener, Sara Cortes-Lara, Carla López-Causapé, Gabriel Cabot, Germán Bou, Luis Martínez-Martínez, Antonio Oliver, on behalf of the GEMARA-SEIMC/REIPI Pseudomonas Study Group

Susceptibility

  • Susceptibility of <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> Recovered from Cystic Fibrosis Patients to Murepavadin and 13 Comparator Antibiotics
    Susceptibility
    Susceptibility of Pseudomonas aeruginosa Recovered from Cystic Fibrosis Patients to Murepavadin and 13 Comparator Antibiotics

    The objective was to determine the in vitro antimicrobial susceptibility of Pseudomonas aeruginosa isolates cultured from cystic fibrosis (CF) patients and explore associations between strain sequence type and susceptibility. Fourteen antibiotics and antibiotic combinations, including the novel antibacterial peptide murepavadin, were tested for activity...

    Miquel B. Ekkelenkamp, Rafael Cantón, María Díez-Aguilar, Michael M. Tunney, Deirdre F. Gilpin, Francesca Bernardini, Glenn E. Dale, J. Stuart Elborn, Jumamurat R. Bayjanov, Ad Fluit
  • <em>In Vitro</em> Susceptibility Testing of GSK656 against <em>Mycobacterium</em> Species
    Susceptibility
    In Vitro Susceptibility Testing of GSK656 against Mycobacterium Species

    In this study, we aimed to assess the in vitro susceptibility to GSK656 among multiple mycobacterial species and to investigate the correlation between leucyl-tRNA synthetase (LeuRS) sequence variations and in vitro susceptibility to GSK656 among mycobacterial species. A total of 187 mycobacterial isolates, comprising 105 Mycobacterium tuberculosis...

    Wenzhu Dong, Shanshan Li, Shu’an Wen, Wei Jing, Jin Shi, Yifeng Ma, Fengmin Huo, Fei Gao, Yu Pang, Jie Lu
  • <em>In Vitro</em> Susceptibility of <em>Fusarium</em> to Isavuconazole
    Susceptibility
    In Vitro Susceptibility of Fusarium to Isavuconazole

    To evaluate the in vitro susceptibility of Fusarium to isavuconazole, 75 clinical isolates were identified using matrix-assisted laser desorption ionization–time of flight mass spectrometry and then tested with a broth microdilution method (EUCAST) and the gradient concentration strip (GCS) technique. The activity of isavuconazole overall was shown to be limited, with an MIC50 of >16 μg/ml, without...

    A. Broutin, J. Bigot, Y. Senghor, A. Moreno-Sabater, J. Guitard, C. Hennequin
  • <em>In Vitro</em> Activity of Plazomicin Compared to Amikacin, Gentamicin, and Tobramycin against Multidrug-Resistant Aerobic Gram-Negative Bacilli
    Susceptibility
    In Vitro Activity of Plazomicin Compared to Amikacin, Gentamicin, and Tobramycin against Multidrug-Resistant Aerobic Gram-Negative Bacilli

    The worldwide spread of multidrug-resistant Enterobacterales is a serious threat to public health. Here, we compared the MICs of plazomicin, amikacin, gentamicin, and tobramycin against 303 multinational multidrug-resistant Gram-negative bacilli. We followed Clinical and Laboratory Standards Institute (CLSI) guidelines and applied CLSI breakpoints as well as those of the European Committee on Antimicrobial Susceptibility...

    Wim A. Fleischmann, Kerryl E. Greenwood-Quaintance, Robin Patel
  • Open Access
    Meropenem-Vaborbactam Activity against Carbapenem-Resistant <em>Enterobacterales</em> Isolates Collected in U.S. Hospitals during 2016 to 2018
    Susceptibility
    Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018

    The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South...

    Mariana Castanheira, Timothy B. Doyle, Valerie Kantro, Rodrigo E. Mendes, Dee Shortridge

Antiviral Agents

  • Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses <em>In Vitro</em> and in Humanized Mice
    Antiviral Agents
    Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

    Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently closed circular DNA (cccDNA)—the viral minichromosome—in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment.

    Franck Amblard, Sebastien Boucle, Leda Bassit, Bryan Cox, Ozkan Sari, Sijia Tao, Zhe Chen, Tugba Ozturk, Kiran Verma, Olivia Russell, Virgile Rat, Hugues de Rocquigny, Oriane Fiquet, Maud Boussand, James Di Santo, Helene Strick-Marchand, Raymond F. Schinazi
  • Open Access
    Analysis of the Potential for <em>N</em><sup>4</sup>-Hydroxycytidine To Inhibit Mitochondrial Replication and Function
    Antiviral Agents
    Analysis of the Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function

    N4-Hydroxycytidine (NHC) is an antiviral ribonucleoside analog that acts as a competitive alternative substrate for virally encoded RNA-dependent RNA polymerases. It exhibits measurable levels of cytotoxicity, with 50% cytotoxic concentration values ranging from 7.5 μM in CEM cells and up to >100 μM in other cell lines.

    Zachary M. Sticher, Gaofei Lu, Deborah G. Mitchell, Joshua Marlow, Levi Moellering, Gregory R. Bluemling, David B. Guthrie, Michael G. Natchus, George R. Painter, Alexander A. Kolykhalov
  • Open Access
    A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein
    Editor's Pick Antiviral Agents
    A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein

    Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b.

    John DeVincenzo, Dereck Tait, John Efthimiou, Julie Mori, Young-In Kim, Elaine Thomas, Lynn Wilson, Rachel Harland, Neil Mathews, Stuart Cockerill, Kenneth Powell, Edward Littler
  • Comparative Therapeutic Potential of ALX-0171 and Palivizumab against Respiratory Syncytial Virus Clinical Isolate Infection of Well-Differentiated Primary Pediatric Bronchial Epithelial Cell Cultures
    Antiviral Agents
    Comparative Therapeutic Potential of ALX-0171 and Palivizumab against Respiratory Syncytial Virus Clinical Isolate Infection of Well-Differentiated Primary Pediatric Bronchial Epithelial Cell Cultures

    Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections in young infants. There are no RSV-specific treatments available. Ablynx has been developing an anti-RSV F-specific nanobody, ALX-0171. To characterize the therapeutic potential of ALX-0171, we exploited our well-differentiated primary pediatric bronchial epithelial cell (WD-PBEC)/RSV infection model, which replicates several hallmarks of RSV disease ...

    Lindsay Broadbent, Hong Guo Parke, Lyndsey J. Ferguson, Andrena Millar, Michael D. Shields, Laurent Detalle, Ultan F. Power

Epidemiology and Surveillance

  • Comparison of Two Typing Methods for Characterization of Azole Resistance in <span class="named-content genus-species" id="named-content-1">Aspergillus fumigatus</span> from Potting Soil Samples in a Chinese Hospital
    Epidemiology and Surveillance
    Comparison of Two Typing Methods for Characterization of Azole Resistance in Aspergillus fumigatus from Potting Soil Samples in a Chinese Hospital

    To understand the characterizations of azole resistance in Aspergillus fumigatus from potting soil samples in the hospital, a total of 58 samples were collected. Among 106 A. fumigatus samples obtained, 5 isolates from 4 soil samples located in the gerontology department were identified as azole-...

    Hong Fan, Yong Chen, Liping Duan, Jingya Zhao, Chunping Qin, Haifeng Li, Jinke Sun, Li Han

Experimental Therapeutics

  • Linker Editing of Pneumococcal Lysin ClyJ Conveys Improved Bactericidal Activity
    Experimental Therapeutics
    Linker Editing of Pneumococcal Lysin ClyJ Conveys Improved Bactericidal Activity

    Streptococcus pneumoniae is a leading human pathogen uniquely characterized by choline moieties on the bacterial surface. Our previous work reported a pneumococcus-specific chimeric lysin, ClyJ, which combines the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) enzymatically active domain (EAD) from the PlyC lysin and the cell wall binding domain (CBD)...

    Hang Yang, Dehua Luo, Irina Etobayeva, Xiaohong Li, Yujing Gong, Shujuan Wang, Qiong Li, Poshi Xu, Wen Yin, Jin He, Daniel C. Nelson, Hongping Wei
  • New Triazole NT-a9 Has Potent Antifungal Efficacy against <span class="named-content genus-species" id="named-content-1">Cryptococcus neoformans</span> <em>In Vitro</em> and <em>In Vivo</em>
    Experimental Therapeutics
    New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

    In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo.

    Ren-Yi Lu, Ting-Jun-Hong Ni, Jing Wu, Lan Yan, Quan-Zhen Lv, Li-Ping Li, Da-Zhi Zhang, Yuan-Ying Jiang
  • A Fluorinated Phenylbenzothiazole Arrests the <span class="named-content genus-species" id="named-content-1">Trypanosoma cruzi</span> Cell Cycle and Diminishes the Infection of Mammalian Host Cells
    Experimental Therapeutics
    A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

    Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted...

    Roberto I. Cuevas-Hernández, Richard M. B. M. Girard, Sarai Martínez-Cerón, Marcelo Santos da Silva, Maria Carolina Elias, Marcell Crispim, José G. Trujillo-Ferrara, Ariel Mariano Silber
  • Second-Generation Antidiabetic Sulfonylureas Inhibit <span class="named-content genus-species" id="named-content-1">Candida albicans</span> and Candidalysin-Mediated Activation of the NLRP3 Inflammasome
    Experimental Therapeutics
    Second-Generation Antidiabetic Sulfonylureas Inhibit Candida albicans and Candidalysin-Mediated Activation of the NLRP3 Inflammasome

    Repurposing of currently approved medications is an attractive option for the development of novel treatment strategies against physiological and infectious diseases. The antidiabetic sulfonylurea glyburide has demonstrated off-target capacity to inhibit activation of the NLRP3 inflammasome in a variety of disease models, including vaginal candidiasis, caused primarily by the fungal pathogen...

    David J. Lowes, Kirk E. Hevener, Brian M. Peters
  • Activity of Different Antistaphylococcal Therapies, Alone or Combined, in a Rat Model of Methicillin-Resistant <span class="named-content genus-species" id="named-content-1">Staphylococcus epidermidis</span> Osteitis without Implant
    Experimental Therapeutics
    Activity of Different Antistaphylococcal Therapies, Alone or Combined, in a Rat Model of Methicillin-Resistant Staphylococcus epidermidis Osteitis without Implant

    We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) osteitis without implant to compare the efficacy of vancomycin, linezolid, daptomycin, ceftaroline, and rifampin either alone or in association with rifampin. A clinical strain of MRSE was inoculated into the proximal tibia. Following a 1-week infection period, rats received either no...

    S. Albac, D. Labrousse, D. Hayez, N. Anzala, D. Bonnot, P. Chavanet, E. Aslangul, D. Croisier
  • Efficacy of Bacteriophages in a <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span> Nondiabetic or Diabetic Foot Infection Murine Model
    Experimental Therapeutics
    Efficacy of Bacteriophages in a Staphylococcus aureus Nondiabetic or Diabetic Foot Infection Murine Model

    This study investigated the in vivo efficacy of three bacteriophages combined compared with linezolid in two mouse models (nondiabetic and diabetic) of Staphylococcus aureus foot infection. In both models, a single injection of bacteriophages in the hindpaw showed significant antibacterial efficacy. Linezolid was as effective as bacteriophages in nondiabetic...

    S. Albac, M. Medina, D. Labrousse, D. Hayez, D. Bonnot, N. Anzala, F. Laurent, T. Ferry, A. Dublanchet, P. Chavanet, C. Fevre, D. Croisier
  • Exebacase Demonstrates <em>In Vitro</em> Synergy with a Broad Range of Antibiotics against both Methicillin-Resistant and Methicillin-Susceptible <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span>
    Experimental Therapeutics
    Exebacase Demonstrates In Vitro Synergy with a Broad Range of Antibiotics against both Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus

    In vitro synergy between an antimicrobial protein lysin (cell wall hydrolase) called exebacase and each of 12 different antibiotics was examined against Staphylococcus aureus isolates using a nonstandard medium approved for exebacase susceptibility testing by the Clinical and Laboratory Standards Institute. In the checkerboard assay format, fractional...

    Aubrey Watson, Karen Sauve, Cara Cassino, Raymond Schuch
  • Open Access
    Rifabutin Is Active against <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span> in Mice
    Editor's Pick Experimental Therapeutics
    Rifabutin Is Active against Mycobacterium abscessus in Mice

    There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus. Here, we...

    Thomas Dick, Sung Jae Shin, Won-Jung Koh, Véronique Dartois, Martin Gengenbacher
  • Inhibiting Fungal Echinocandin Resistance by Small-Molecule Disruption of Geranylgeranyltransferase Type I Activity
    Experimental Therapeutics
    Inhibiting Fungal Echinocandin Resistance by Small-Molecule Disruption of Geranylgeranyltransferase Type I Activity

    Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. However, therapeutic efforts to thwart echinocandin resistance have been hampered by a lack of fungal specific drug targets.

    Qiangqiang Sun, Kang Xiong, Yuncong Yuan, Jing Yu, Lianjuan Yang, Chao Shen, Chang Su, Yang Lu
  • <em>In Vivo</em> Pharmacodynamic Evaluation of Omadacycline against <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span> in the Neutropenic Mouse Pneumonia Model
    Experimental Therapeutics
    In Vivo Pharmacodynamic Evaluation of Omadacycline against Staphylococcus aureus in the Neutropenic Mouse Pneumonia Model

    Omadacycline is an effective therapy for community-acquired bacterial pneumonia (CABP). Given its potent activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA), we sought to determine the pharmacodynamic activity and target pharmacokinetic/...

    Alexander J. Lepak, Miao Zhao, Karen Marchillo, Jamie VanHecker, David R. Andes

Clinical Therapeutics

  • High Heterogeneity of Multidrug-Resistant <em>Enterobacteriaceae</em> Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous β-Lactams
    Editor's Pick Clinical Therapeutics
    High Heterogeneity of Multidrug-Resistant Enterobacteriaceae Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous β-Lactams

    Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels.

    Ana Djukovic, Eva M. González-Barberá, Jaime Sanz, Alejandro Artacho, Iván Peñaranda, Beatriz Herrera, María José Garzón, Miguel Salavert, José Luis López-Hontangas, Karina B. Xavier, Bernhard Kuster, Laurent Debrauwer, Jean-Marc Rolain, Miguel A. Sanz, Joao B. Xavier, Carles Ubeda
  • A Randomized, Double-Blind, Placebo-Controlled Trial (TAURCAT Study) of Citrate Lock Solution for Prevention of Endoluminal Central Venous Catheter Infection in Neutropenic Hematological Patients
    Clinical Therapeutics
    A Randomized, Double-Blind, Placebo-Controlled Trial (TAURCAT Study) of Citrate Lock Solution for Prevention of Endoluminal Central Venous Catheter Infection in Neutropenic Hematological Patients

    Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients.

    Carlota Gudiol, Montserrat Arnan, Manuela Aguilar-Guisado, Cristina Royo-Cebrecos, Isabel Sánchez-Ortega, Isabel Montero, Cecilia Martín-Gandul, Júlia Laporte-Amargós, Adaia Albasanz-Puig, Sermed Nicolae, Maria Perayre, Damaris Berbel, Cristian Tebe, Judith Riera, Anna Sureda, José Miguel Cisneros, Jordi Carratalà
  • Population Pharmacokinetics and Pharmacogenetics of Ethambutol in Adult Patients Coinfected with Tuberculosis and HIV
    Clinical Therapeutics
    Population Pharmacokinetics and Pharmacogenetics of Ethambutol in Adult Patients Coinfected with Tuberculosis and HIV

    This study aimed to characterize the population pharmacokinetics and pharmacogenetics of ethambutol in tuberculosis-HIV-coinfected adult patients. Ethambutol plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, in 63 patients receiving ethambutol as part of rifampin-based fixed-dose combination therapy for tuberculosis were analyzed using nonlinear mixed-effects modeling.

    Jesper Sundell, Emile Bienvenu, Sofia Birgersson, Angela Äbelö, Michael Ashton
  • Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients
    Clinical Therapeutics
    Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

    Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect...

    Xuemei Wu, Raman Venkataramanan, Ryan M. Rivosecchi, Chenxiao Tang, Rachel V. Marini, Ryan K. Shields, Cornelius J. Clancy, M. Hong Nguyen
  • Predictors of Mortality in Bloodstream Infections Caused by <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> and Impact of Antimicrobial Resistance and Bacterial Virulence
    Clinical Therapeutics
    Predictors of Mortality in Bloodstream Infections Caused by Pseudomonas aeruginosa and Impact of Antimicrobial Resistance and Bacterial Virulence

    Whether multidrug resistance (MDR) is associated with mortality in patients with Pseudomonas aeruginosa bloodstream infections (BSI) remains controversial. Here, we explored the prognostic factors of P. aeruginosa BSI with emphasis on antimicrobial resistance and virulence. All...

    Raúl Recio, Mikel Mancheño, Esther Viedma, Jennifer Villa, María Ángeles Orellana, Jaime Lora-Tamayo, Fernando Chaves

Pharmacology

  • Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis
    Pharmacology
    Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis

    Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24...

    Nithya Srinivas, Mackenzie Cottrell, Kaitlyn Maffuid, Heather A. Prince, Julie A. E. Nelson, Nicole White, Craig Sykes, Evan S. Dellon, Ryan D. Madanick, Nicholas J. Shaheen, Daniel Gonzalez, Angela D. M. Kashuba
  • Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients
    Pharmacology
    Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients

    Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size...

    C. C. Llanos-Paez, C. E. Staatz, R. Lawson, S. Hennig
  • Activity of Aerosolized Levofloxacin against <span class="named-content genus-species" id="named-content-1">Burkholderia cepacia</span> in a Mouse Model of Chronic Lung Infection
    Pharmacology
    Activity of Aerosolized Levofloxacin against Burkholderia cepacia in a Mouse Model of Chronic Lung Infection

    Burkholderia cepacia complex is an opportunistic pathogen capable of causing chronic pulmonary infections. These studies were conducted to demonstrate the activity of aerosolized levofloxacin in a chronic mouse lung infection model caused by B. cepacia isolates from patients with cystic fibrosis....

    Mojgan Sabet, David C. Griffith
  • <em>Ex Vivo</em> Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects
    Pharmacology
    Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects

    The ex vivo bactericidal activity and pharmacodynamics of fosfomycin in urine were evaluated in 18 healthy subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses or vice versa. Serial urine samples were collected before and up to 24 h after dosing on days 1 and 5. Eight bacterial strains with various genotypic and phenotypic susceptibilities to fosfomycin were used for all...

    E. Wenzler, K. M. Meyer, S. C. Bleasdale, M. Sikka, R. E. Mendes, K. L. Bunnell, M. Finnemeyer, S. L. Rosenkranz, L. H. Danziger, K. A. Rodvold
    and for the Antibacterial Resistance Leadership Group

Letters to the Editor

  • Polymorphism Existence of Mobile Tigecycline Resistance Gene <em>tet</em>(X4) in <span class="named-content genus-species" id="named-content-1">Escherichia coli</span>
    Letter to the Editor
    Polymorphism Existence of Mobile Tigecycline Resistance Gene tet(X4) in Escherichia coli
    Huangwei Song, Dejun Liu, Ruichao Li, Yulin Fu, Weishuai Zhai, Xiao Liu, Tao He, Congming Wu, Li Bai, Yang Wang
  • Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam
    Letter to the Editor
    Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam
    Xianshi Zhou, Fanwei Wu
  • Emergence of KPC-2-Producing <span class="named-content genus-species" id="named-content-1">Raoultella ornithinolytica</span> Isolated from a Hospital Wastewater Treatment Plant
    Letter to the Editor
    Emergence of KPC-2-Producing Raoultella ornithinolytica Isolated from a Hospital Wastewater Treatment Plant
    Xiaohui Chi, Jing Zhang, Hao Xu, Xiao Yu, Ping Shen, Jinru Ji, Chaoqun Ying, Beiwen Zheng, Yonghong Xiao
  • Reply to Zhou and Wu, “Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam”
    Letter to the Editor
    Reply to Zhou and Wu, “Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam”
    Jien-Wei Liu, Yen-Hsu Chen, Wen-Sen Lee, Jung-Chung Lin, Ching-Tai Huang, Hsi-Hsun Lin, Yung-Ching Liu, Yin-Ching Chuang, Hung-Jen Tang, Yao-Shen Chen, Wen-Chien Ko, Min-Chi Lu, Fu-Der Wang
  • <em>In Vitro</em> Antifungal Susceptibility of the Emerging Multidrug-Resistant Pathogen <span class="named-content genus-species" id="named-content-1">Candida auris</span> to Miltefosine Alone and in Combination with Amphotericin B
    Letter to the Editor
    In Vitro Antifungal Susceptibility of the Emerging Multidrug-Resistant Pathogen Candida auris to Miltefosine Alone and in Combination with Amphotericin B
    Yongqin Wu, Marissa Totten, Warda Memon, Chunmei Ying, Sean X. Zhang

Erratum

  • Free
    Erratum for Khabibullina et al., “Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides”
    Erratum
    Erratum for Khabibullina et al., “Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides”
    Nelli F. Khabibullina, Andrey G. Tereshchenkov, Ekaterina S. Komarova, Egor A. Syroegin, Dmitrii I. Shiriaev, Alena Paleskava, Victor G. Kartsev, Alexey A. Bogdanov, Andrey L. Konevega, Olga A. Dontsova, Petr V. Sergiev, Ilya A. Osterman, Yury S. Polikanov

Author Correction

  • Free
    Correction for Kempker et al., “A Pharmacology Perspective on Simultaneous Tuberculosis and Hepatitis C Treatment”
    Author Correction
    Correction for Kempker et al., “A Pharmacology Perspective on Simultaneous Tuberculosis and Hepatitis C Treatment”
    Russell R. Kempker, Wael A. Alghamdi, Mohammad H. Al-Shaer, Gena Burch, Charles A. Peloquin

Masthead

  • Free
    Editorial Board
    Masthead
    Editorial Board
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Antimicrobial Agents and Chemotherapy: 64 (2)

In This Issue

volume 64, issue 2
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  • Commentaries
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  • Challenging Clinical Case in Antimicrobial Resistance
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  • Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling
  • Fact versus Fiction: a Review of the Evidence behind Alcohol and Antibiotic Interactions
  • New Perspectives on Antimicrobial Agents: Remdesivir Treatment for COVID-19
  • Updated Approaches against SARS-CoV-2
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