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Table of Contents

September 2020; Volume 64,Issue 9

Commentary

  • Free
    Clinical Trials of Repurposed Antivirals for SARS-CoV-2
    Commentary
    Clinical Trials of Repurposed Antivirals for SARS-CoV-2

    The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir-...

    Miguel Angel Martinez

Minireviews

  • Open Access
    Povidone Iodine: Properties, Mechanisms of Action, and Role in Infection Control and <em>Staphylococcus aureus</em> Decolonization
    Minireview
    Povidone Iodine: Properties, Mechanisms of Action, and Role in Infection Control and Staphylococcus aureus Decolonization

    Nasal decolonization is an integral part of the strategies used to control and prevent the spread of methicillin-resistant Staphylococcus aureus (MRSA) infections. The two most commonly used agents for decolonization are intranasal mupirocin 2% ointment and chlorhexidine wash, but the increasing emergence of resistance and treatment failure has underscored the need...

    Didier Lepelletier, Jean Yves Maillard, Bruno Pozzetto, Anne Simon
  • Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity
    Minireview
    Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

    Fungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant...

    Gina Wall, Jose L. Lopez-Ribot

Mechanisms of Action: Physiological Effects

  • NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast
    Mechanisms of Action: Physiological Effects
    NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast

    Invasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal...

    Qiannan Liu, Xiaoxu Guo, Guanglie Jiang, Guoxiang Wu, Hao Miao, Kun Liu, Si Chen, Norihiro Sakamoto, Takayoshi Kuno, Fan Yao, Yue Fang
  • A Roadblock-and-Kill Mechanism of Action Model for the DNA-Targeting Antibiotic Ciprofloxacin
    Mechanisms of Action: Physiological Effects
    A Roadblock-and-Kill Mechanism of Action Model for the DNA-Targeting Antibiotic Ciprofloxacin

    Fluoroquinolones, antibiotics that cause DNA damage by inhibiting DNA topoisomerases, are clinically important, but their mechanism of action is not yet fully understood. In particular, the dynamical response of bacterial cells to fluoroquinolone exposure has hardly been investigated, although the SOS response, triggered by DNA damage, is often thought to play a key role. Here, we investigated the growth inhibition of the bacterium...

    Nikola Ojkic, Elin Lilja, Susana Direito, Angela Dawson, Rosalind J. Allen, Bartlomiej Waclaw

Mechanisms of Resistance

  • Open Access
    Plausible Minimal Substrate for Erm Protein
    Mechanisms of Resistance
    Plausible Minimal Substrate for Erm Protein

    Erm proteins methylate a specific adenine residue (A2058, Escherichia coli coordinates) conferring macrolide-lincosamide-streptogramin B (MLSB) antibiotic resistance on a variety of microorganisms, ranging from antibiotic producers to pathogens. To identify the minimal motif required to be recognized and methylated by the Erm protein, various RNA substrates...

    Hak Jin Lee, Young In Park, Hyung Jong Jin
  • Mutational Effects on Carbapenem Hydrolysis of YEM-1, a New Subclass B2 Metallo-β-Lactamase from <span class="named-content genus-species" id="named-content-1">Yersinia mollaretii</span>
    Mechanisms of Resistance
    Mutational Effects on Carbapenem Hydrolysis of YEM-1, a New Subclass B2 Metallo-β-Lactamase from Yersinia mollaretii

    Analysis of the genome sequence of Yersinia mollaretii ATCC 43969 identified the blaYEM gene, encoding YEM-1, a putative subclass B2 metallo-β-lactamase. The objectives of our work were to produce and purify YEM-1 and to complete its kinetic characterization. YEM-1 displayed the narrowest substrate range among known subclass B2 metallo-β-lactamases...

    Paola Sandra Mercuri, Roberto Esposito, Sylvie Blétard, Stefano Di Costanzo, Mariagrazia Perilli, Frédéric Kerff, Moreno Galleni
  • Open Access
    Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance
    Mechanisms of Resistance
    Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance

    Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple...

    M. Van den Kerkhof, D. Mabille, S. Hendrickx, P. Leprohon, C. E. Mowbray, S. Braillard, M. Ouellette, L. Maes, G. Caljon
  • Rapidly Correcting Frameshift Mutations in the <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> <em>orn</em> Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology
    Editor's Pick Mechanisms of Resistance
    Rapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology

    We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (...

    Hassan Safi, Subramanya Lingaraju, Shuyi Ma, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, David Alland
  • Open Access
    <span class="named-content genus-species" id="named-content-1">Candida glabrata</span> Transcription Factor Rpn4 Mediates Fluconazole Resistance through Regulation of Ergosterol Biosynthesis and Plasma Membrane Permeability
    Mechanisms of Resistance
    Candida glabrata Transcription Factor Rpn4 Mediates Fluconazole Resistance through Regulation of Ergosterol Biosynthesis and Plasma Membrane Permeability

    The ability to acquire azole resistance is an emblematic trait of the fungal pathogen Candida glabrata. Understanding the molecular basis of azole resistance in this pathogen is crucial for designing more suitable therapeutic strategies. This study shows that the C. glabrata transcription factor (TF...

    Pedro Pais, Raquel Califórnia, Mónica Galocha, Romeu Viana, Mihaela Ola, Mafalda Cavalheiro, Azusa Takahashi-Nakaguchi, Hiroji Chibana, Geraldine Butler, Miguel C. Teixeira
  • Novel Aminoglycoside-Tolerant Phoenix Colony Variants of <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span>
    Mechanisms of Resistance
    Novel Aminoglycoside-Tolerant Phoenix Colony Variants of Pseudomonas aeruginosa

    Pseudomonas aeruginosa is an opportunistic bacterial pathogen and is known to produce biofilms. We previously showed the emergence of colony variants in the presence of tobramycin-loaded calcium sulfate beads. In this study, we characterized the variant colonies, which survived the antibiotic treatment, and identified three distinct phenotypes—classically resistant...

    Devin Sindeldecker, Kelly Moore, Anthony Li, Daniel J. Wozniak, Matthew Anderson, Devendra H. Dusane, Paul Stoodley
  • Radial Expansion Facilitates the Maintenance of Double Antibiotic Resistances
    Mechanisms of Resistance
    Radial Expansion Facilitates the Maintenance of Double Antibiotic Resistances

    Most microbes live in spatially confined subpopulations. Under spatial structure conditions, the efficacy of natural selection is often reduced (relative to homogeneous conditions) due to the increased importance of genetic drift and local competition. Additionally, under spatial structure conditions, the fittest genotype may not always be the one with better access to the heterogeneous distribution of nutrients. The effect of radial...

    Paulo Durão, Ricardo S. Ramiro, Cátia Pereira, Jernej Jurič, Delfina Pereira, Isabel Gordo
  • Role of Whole-Genome Sequencing in Characterizing the Mechanism of Action of <em>para</em>-Aminosalicylic Acid and Its Resistance
    Mechanisms of Resistance
    Role of Whole-Genome Sequencing in Characterizing the Mechanism of Action of para-Aminosalicylic Acid and Its Resistance

    para-Aminosalicylic acid (PAS) remains one of the drugs of last resort for the treatment of tuberculosis, but its mechanism of action is still not completely understood. The main aim of this project was to identify new potential mechanisms of action and resistance to PAS by performing whole-genome sequencing on PAS-resistant laboratory mutants. A new variant in the folC gene was identified, as well as some other...

    Giovanni Satta, Adam A. Witney, Neelu Begum, Julio Ortiz Canseco, Andrew N. Boa, Timothy D. McHugh
  • Genetic Basis of Azole and Echinocandin Resistance in Clinical <span class="named-content genus-species" id="named-content-1">Candida glabrata</span> in Japan
    Mechanisms of Resistance
    Genetic Basis of Azole and Echinocandin Resistance in Clinical Candida glabrata in Japan

    Infections caused by Candida glabrata have caused worldwide concern, especially when they are associated with increasing echinocandin and azole resistance. In this study, we analyzed the molecular mechanisms of azole and echinocandin resistance in C. glabrata isolates obtained from hospitalized...

    Hazim O. Khalifa, Teppei Arai, Hidetaka Majima, Akira Watanabe, Katsuhiko Kamei
  • Characterization of Large Deletion Mutants of <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> Selected for Isoniazid Resistance
    Mechanisms of Resistance
    Characterization of Large Deletion Mutants of Mycobacterium tuberculosis Selected for Isoniazid Resistance

    Large genomic deletions (LGDs) (6 to 63 kbp) were observed in isoniazid-resistant Mycobacterium tuberculosis mutants derived from four M. tuberculosis strains. These LGDs had no growth defect in vitro but could be defective in intracellular growth and showed various sensitivities toward...

    Catherine Vilchèze, Rajagopalan Saranathan, Brian Weinrick, William R. Jacobs
  • CRISPR-Cas9-Mediated Carbapenemase Gene and Plasmid Curing in Carbapenem-Resistant <em>Enterobacteriaceae</em>
    Mechanisms of Resistance
    CRISPR-Cas9-Mediated Carbapenemase Gene and Plasmid Curing in Carbapenem-Resistant Enterobacteriaceae

    Combating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here, we conducted a proof-of-concept study to demonstrate that CRISPR-Cas9-mediated resistance gene and plasmid curing can effectively resensitize CRE to carbapenems. A novel CRISPR-Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into...

    Mingju Hao, Yuzhang He, Haifang Zhang, Xiao-Ping Liao, Ya-Hong Liu, Jian Sun, Hong Du, Barry N. Kreiswirth, Liang Chen
  • Prevalence of Aminoglycoside Resistance Genes and Molecular Characterization of a Novel Gene, <em>aac(3)-IIg</em>, among Clinical Isolates of the <span class="named-content genus-species" id="named-content-1">Enterobacter cloacae</span> Complex from a Chinese Teaching Hospital
    Mechanisms of Resistance
    Prevalence of Aminoglycoside Resistance Genes and Molecular Characterization of a Novel Gene, aac(3)-IIg, among Clinical Isolates of the Enterobacter cloacae Complex from a Chinese Teaching Hospital

    Members of the Enterobacter cloacae complex are important opportunistic human pathogens capable of causing a wide variety of infections. During recent decades, aminoglycoside-resistant E. cloacae complex isolates have increasingly been reported and have become a major concern. Here, we employed high...

    Xinyi Zhu, Peizhen Li, Changrui Qian, Hongmao Liu, Hailong Lin, Xueya Zhang, Qiaoling Li, Junwan Lu, Xi Lin, Teng Xu, Hailin Zhang, Yunliang Hu, Qiyu Bao, Kewei Li
  • Open Access
    Evidence for Expanding the Role of Streptomycin in the Management of Drug-Resistant <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span>
    Mechanisms of Resistance
    Evidence for Expanding the Role of Streptomycin in the Management of Drug-Resistant Mycobacterium tuberculosis

    In 2019, the WHO tuberculosis (TB) treatment guidelines were updated to recommend only limited use of streptomycin, in favor of newer agents or amikacin as the preferred aminoglycoside for drug-resistant Mycobacterium tuberculosis. However, the emergence of resistance to newer drugs, such as bedaquiline, has prompted a reanalysis of antitubercular drugs in search of...

    Keira A. Cohen, Katharine E. Stott, Vanisha Munsamy, Abigail L. Manson, Ashlee M. Earl, Alexander S. Pym
  • Prolonged Exposure to β-Lactam Antibiotics Reestablishes Susceptibility of Daptomycin-Nonsusceptible <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span> to Daptomycin
    Mechanisms of Resistance
    Prolonged Exposure to β-Lactam Antibiotics Reestablishes Susceptibility of Daptomycin-Nonsusceptible Staphylococcus aureus to Daptomycin

    Daptomycin-nonsusceptible (DAP-NS) Staphylococcus aureus often exhibits gain-in-function mutations in the mprF gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against methicillin-resistant S. aureus (MRSA), may prevent the emergence...

    Rachel E. Jenson, Sarah L. Baines, Benjamin P. Howden, Nagendra N. Mishra, Sabrina Farah, Cassandra Lew, Andrew D. Berti, Sanjay K. Shukla, Arnold S. Bayer, Warren E. Rose
  • Adding Insult to Injury: Mechanistic Basis for How AmpC Mutations Allow <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> To Accelerate Cephalosporin Hydrolysis and Evade Avibactam
    Editor's Pick Mechanisms of Resistance
    Adding Insult to Injury: Mechanistic Basis for How AmpC Mutations Allow Pseudomonas aeruginosa To Accelerate Cephalosporin Hydrolysis and Evade Avibactam

    Pseudomonas aeruginosa is a leading cause of nosocomial infections worldwide and notorious for its broad-spectrum resistance to antibiotics. A key mechanism that provides extensive resistance to β-lactam antibiotics is the inducible expression of AmpC β-lactamase. Recently, a number of clinical isolates expressing mutated forms of AmpC have been found to be clinically...

    Cole L. Slater, Judith Winogrodzki, Pablo A. Fraile-Ribot, Antonio Oliver, Mazdak Khajehpour, Brian L. Mark
  • Open Access
    How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide
    Mechanisms of Resistance
    How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide

    False-susceptible phenotypic drug-susceptibility testing (DST) results for pyrazinamide due to mutations with MICs close to the critical concentration (CC) confound the classification of pncA resistance mutations, leading to an underestimate of the specificity of genotypic DST. This could be minimized by basing treatment decisions on well-understood mutations and by adopting an area of technical uncertainty for phenotypic DST...

    Claudio U. Köser, Daniela M. Cirillo, Paolo Miotto

Susceptibility

  • Antibacterial Effect of Caffeic Acid Phenethyl Ester on Cariogenic Bacteria and <span class="named-content genus-species" id="named-content-1">Streptococcus mutans</span> Biofilms
    Susceptibility
    Antibacterial Effect of Caffeic Acid Phenethyl Ester on Cariogenic Bacteria and Streptococcus mutans Biofilms

    Dental caries is the most common disease in the human mouth. Streptococcus mutans is the primary cariogenic bacterium. Propolis is a nontoxic natural product with a strong inhibitory effect on oral cariogenic bacteria. The polyphenol-rich extract from propolis inhibits S. mutans growth and biofilm...

    Yumei Niu, Kun Wang, Sainan Zheng, Yufei Wang, Qian Ren, Haoran Li, Longjiang Ding, Wei Li, Linglin Zhang
  • From Etest to Vitek 2: Impact of Enterococcal Linezolid Susceptibility Testing Methodology on Time to Active Therapy
    Susceptibility
    From Etest to Vitek 2: Impact of Enterococcal Linezolid Susceptibility Testing Methodology on Time to Active Therapy

    Different linezolid antimicrobial susceptibility testing (AST) methodologies yield various results. In 2018, we transitioned our linezolid AST methodology from the Etest to Vitek 2. We sought to evaluate the impact of this change on antibiotic use among 181 inpatients with vancomycin-resistant enterococcal (VRE) infections. The transition from Etest to Vitek 2 resulted in an increase in linezolid susceptibility (38% versus 96%; P...

    Cynthia T. Nguyen, Cindy Bethel, Natasha N. Pettit, Angella Charnot-Katsikas
  • Antibiotic Susceptibility of NDM-Producing <em>Enterobacterales</em> Collected in the United States in 2017 and 2018
    Susceptibility
    Antibiotic Susceptibility of NDM-Producing Enterobacterales Collected in the United States in 2017 and 2018

    The treatment of infections caused by carbapenem-resistant Enterobacterales, especially New Delhi metallo-β-lactamase (NDM)-producing bacteria, is challenging. Although less common in the United States than some other carbapenemase producers, NDM-producing bacteria are a public health threat due to the limited treatment options available. Here, we report on the antibiotic susceptibility of 275 contemporary NDM-producing ...

    Joseph D. Lutgring, Rocío Balbuena, Natashia Reese, Sarah E. Gilbert, Uzma Ansari, Amelia Bhatnagar, Sandra Boyd, Davina Campbell, Jake Cochran, Jenn Haynie, Justina Ilutsik, Cynthia Longo, Stephanie Swint, J. Kamile Rasheed, Allison C. Brown, Maria Karlsson
  • <em>In Vitro</em> Activities of Ravuconazole and Isavuconazole against Dematiaceous Fungi
    Susceptibility
    In Vitro Activities of Ravuconazole and Isavuconazole against Dematiaceous Fungi

    The in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as...

    Hailin Zheng, Nana Song, Huan Mei, Jiacheng Dong, Dongmei Li, Xiaofang Li, Weida Liu
  • <em>In Vitro</em> Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including <span class="named-content genus-species" id="named-content-1">Bacteroides fragilis</span> Group, <em>Prevotella</em>, <em>Porphyromonas</em>, and <em>Veillonella</em> Species
    Susceptibility
    In Vitro Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including Bacteroides fragilis Group, Prevotella, Porphyromonas, and Veillonella Species

    Tedizolid’s anaerobic activity is unappreciated. In this study, it was active against all 332 anaerobic isolates tested at ≤2 μg/ml except Bilophila wadsworthia and was more active than linezolid against Bacteroides fragilis group species (MIC90, 1 μg/ml versus 2 to 4 μg/ml). Tedizolid...

    Ellie J. C. Goldstein, C. Vreni Merriam, Diane M. Citron

Analytical Procedures

  • Use of a Fluorescence-Based Assay To Measure <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> Membrane Potential Changes in High Throughput
    Analytical Procedures
    Use of a Fluorescence-Based Assay To Measure Escherichia coli Membrane Potential Changes in High Throughput

    Bacterial membrane potential is difficult to measure using classical electrophysiology techniques due to the small cell size and the presence of the peptidoglycan cell wall. Instead, chemical probes are often used to study membrane potential changes under conditions of interest. Many of these probes are fluorescent molecules that accumulate in a charge-dependent manner, and the resulting fluorescence change can be analyzed via flow...

    M. Ashley Hudson, Deborah A. Siegele, Steve W. Lockless

Antiviral Agents

  • <em>In Vitro</em> and <em>In Vivo</em> Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection
    Antiviral Agents
    In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection

    Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule...

    James Hopkins, Tejabhiram Yadavalli, Rahul Suryawanshi, Farreh Qatanani, Ipsita Volety, Ram Koganti, Aqsa Iqbal, Deepak Shukla
  • Monoclonal Antibody Therapy Protects Pharmacologically Immunosuppressed Mice from Lethal Infection with Influenza B Virus
    Antiviral Agents
    Monoclonal Antibody Therapy Protects Pharmacologically Immunosuppressed Mice from Lethal Infection with Influenza B Virus

    Human influenza A and B viruses are highly contagious and cause similar illnesses and seasonal epidemics. Currently available antiviral drugs have limited efficacy in humans with compromised immune systems; therefore, alternative strategies for protection are needed. Here, we investigated whether monoclonal antibodies (MAbs) targeting hemagglutinin (HA) and/or neuraminidase (NA) proteins would protect immunosuppressed mice from severe...

    Bindumadhav M. Marathe, Guha Asthagiri Arunkumar, Peter Vogel, Philippe Noriel Q. Pascua, Jeremy Jones, Richard J. Webby, Florian Krammer, Elena A. Govorkova
  • HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants
    Antiviral Agents
    HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

    The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in...

    Steven J. Smith, Xue Zhi Zhao, Dario Oliveira Passos, Dmitry Lyumkis, Terrence R. Burke, Stephen H. Hughes
  • Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus
    Antiviral Agents
    Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus

    The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (...

    Rebeca S. De Pablo-Bernal, M. Reyes Jimenez-Leon, Laura Tarancon-Diez, Alicia Gutierrez-Valencia, Ana Serna-Gallego, Maria Trujillo-Rodriguez, Ana I. Alvarez-Rios, Yusnelkis Milanes-Guisado, Nuria Espinosa, Cristina Roca-Oporto, Pompeyo Viciana, Luis F. Lopez-Cortes, Ezequiel Ruiz-Mateos
  • Open Access
    ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens
    Antiviral Agents
    ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens

    ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of...

    Katherine E. Squires, Douglas L. Mayers, Gregory R. Bluemling, Alexander A. Kolykhalov, David B. Guthrie, Prabhakar Reddy, Debbie G. Mitchell, Manohar T. Saindane, Zachary M. Sticher, Vindhya Edpuganti, Abel De La Rosa
  • Open Access
    Discovery of M Protease Inhibitors Encoded by SARS-CoV-2
    Antiviral Agents
    Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

    The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C‐like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the M...

    Hui-Chen Hung, Yi-Yu Ke, Sheng Yu Huang, Peng-Nien Huang, Yu-An Kung, Teng-Yuan Chang, Kuei-Jung Yen, Tzu-Ting Peng, Shao-En Chang, Chin-Ting Huang, Ya-Ru Tsai, Szu-Huei Wu, Shiow-Ju Lee, Jiunn-Horng Lin, Bing-Sin Liu, Wang-Chou Sung, Shin-Ru Shih, Chiung-Tong Chen, John Tsu-An Hsu
  • Open Access
    The FDA-Approved Drug Nelfinavir Inhibits Lytic Cell-Free but Not Cell-Associated Nonlytic Transmission of Human Adenovirus
    Antiviral Agents
    The FDA-Approved Drug Nelfinavir Inhibits Lytic Cell-Free but Not Cell-Associated Nonlytic Transmission of Human Adenovirus

    Adenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. Human AdV (HAdV) species B and C, such as HAdV-C2, -C5, and -B14, cause respiratory disease and constitute a health threat for immunocompromised individuals. HAdV-Cs are well known for lysing cells owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening framework and identified an...

    Fanny Georgi, Vardan Andriasyan, Robert Witte, Luca Murer, Silvio Hemmi, Lisa Yu, Melanie Grove, Nicole Meili, Fabien Kuttler, Artur Yakimovich, Gerardo Turcatti, Urs F. Greber
  • Free
    A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19
    Editor's Pick Antiviral Agents
    A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19

    To the best of our knowledge, there is no published study on the use of interferon β-1a (IFN β-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN β-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN β-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir)....

    Effat Davoudi-Monfared, Hamid Rahmani, Hossein Khalili, Mahboubeh Hajiabdolbaghi, Mohamadreza Salehi, Ladan Abbasian, Hossein Kazemzadeh, Mir Saeed Yekaninejad
  • Open Access
    A Retrospective Controlled Cohort Study of the Impact of Glucocorticoid Treatment in SARS-CoV-2 Infection Mortality
    Editor's Pick Antiviral Agents
    A Retrospective Controlled Cohort Study of the Impact of Glucocorticoid Treatment in SARS-CoV-2 Infection Mortality

    Evidence to support the use of steroids in coronavirus disease 2019 (COVID-19) pneumonia is lacking. We aim to determine the impact of steroid use for COVID-19 pneumonia on hospital mortality. We performed a single-center retrospective cohort study in a university hospital in Madrid, Spain, during March of 2020. To determine the role of steroids in in-hospital mortality, patients admitted with severe acute respiratory syndrome...

    Ana Fernández-Cruz, Belén Ruiz-Antorán, Ana Muñoz-Gómez, Aránzazu Sancho-López, Patricia Mills-Sánchez, Gustavo Adolfo Centeno-Soto, Silvia Blanco-Alonso, Laura Javaloyes-Garachana, Amy Galán-Gómez, Ángela Valencia-Alijo, Javier Gómez-Irusta, Concepción Payares-Herrera, Ignacio Morrás-Torre, Enrique Sánchez-Chica, Laura Delgado-Téllez-de-Cepeda, Alejandro Callejas-Díaz, Antonio Ramos-Martínez, Elena Múñez-Rubio, Cristina Avendaño-Solá
    and on behalf of the Puerta de Hierro COVID-19 Study Group
  • Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus
    Antiviral Agents
    Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus

    This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific...

    Danielle P. Porter, Ying Guo, Jason Perry, David L. Gossage, Timothy R. Watkins, Jason W. Chien, Robert Jordan

Epidemiology and Surveillance

  • Antifungal Susceptibility of Clinical Yeast Isolates from a Large Canadian Reference Laboratory and Application of Whole-Genome Sequence Analysis To Elucidate Mechanisms of Acquired Resistance
    Epidemiology and Surveillance
    Antifungal Susceptibility of Clinical Yeast Isolates from a Large Canadian Reference Laboratory and Application of Whole-Genome Sequence Analysis To Elucidate Mechanisms of Acquired Resistance

    To understand the epidemiology and susceptibility patterns of yeast infections in Ontario, Canada, we examined 4,715 clinical yeast isolates submitted to our laboratory for antifungal susceptibility testing from 2014 to 2018. Candida albicans was the most frequently submitted species (43.0%), followed by C...

    Lisa R. McTaggart, Ana Cabrera, Kirby Cronin, Julianne V. Kus
  • Cefazolin Inoculum Effect and Methicillin-Susceptible <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span> Osteoarticular Infections in Children
    Epidemiology and Surveillance
    Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

    Select methicillin-susceptible Staphylococcus aureus (MSSA) strains may produce β-lactamases with affinity for first-generation cephalosporins (1GCs). In the setting of a high inoculum, these β-lactamases may promote the cleavage of 1GCs, a phenomenon known as the cefazolin inoculum effect (CzIE). We evaluated the prevalence and impact of CzIE on clinical outcomes...

    J. Chase McNeil, Lauren M. Sommer, Mary Boyle, Patrick Hogan, Jesus G. Vallejo, Kristina G. Hultén, Anthony R. Flores, Sheldon L. Kaplan, Stephanie Fritz
  • Genomic Analysis Reveals Antibiotic-Susceptible Clones and Emerging Resistance in <span class="named-content genus-species" id="named-content-1">Neisseria gonorrhoeae</span> in Saskatchewan, Canada
    Epidemiology and Surveillance
    Genomic Analysis Reveals Antibiotic-Susceptible Clones and Emerging Resistance in Neisseria gonorrhoeae in Saskatchewan, Canada

    Whole-genome sequencing was used to identify mutations in antibiotic resistance-conferring genes to compare susceptibility predictions with MICs and to ascertain strain types in 99 isolates of Neisseria gonorrhoeae. Genotypes associated with susceptibility, as well as MIC creep or emerging resistance, were noted. Phylogenomic analysis revealed three distinctive clades...

    Nidhi R. Parmar, Reema Singh, Irene Martin, Sumudu R. Perera, Walter Demczuk, Anthony Kusalik, Jessica Minion, Jo-Anne R. Dillon

Experimental Therapeutics

  • Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of <span class="named-content genus-species" id="named-content-1">Trypanosoma cruzi</span>
    Experimental Therapeutics
    Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi

    Pyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a...

    Julianna Siciliano de Araújo, Cristiane França da Silva, Denise da Gama Jaén Batista, Aline Nefertiti, Ludmila Ferreira de Almeida Fiuza, Cristina Rosa Fonseca-Berzal, Patrícia Bernardino da Silva, Marcos Meuser Batista, Maarten Sijm, Titilola D. Kalejaiye, Harry P. de Koning, Louis Maes, Geert Jan Sterk, Rob Leurs, Maria de Nazaré Correia Soeiro
  • Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> Pneumonia-Septicemia Model in Rats
    Experimental Therapeutics
    Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

    Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP...

    Hessel van der Weide, Unai Cossío, Raquel Gracia, Yvonne M. te Welscher, Marian T. ten Kate, Aart van der Meijden, Marco Marradi, Jeffrey A. S. Ritsema, Denise M. C. Vermeulen-de Jongh, Gert Storm, Wil H. F. Goessens, Iraida Loinaz, Cornelus F. van Nostrum, Jordi Llop, John P. Hays, Irma A. J. M. Bakker-Woudenberg
  • Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces <span class="named-content genus-species" id="named-content-1">Toxoplasma gondii</span> Brain Cysts
    Experimental Therapeutics
    Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

    Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute...

    J. Stone Doggett, Tracey Schultz, Alyssa J. Miller, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia Dodean, Lev N. Zakharov, Aaron Nilsen, Michael K. Riscoe, Vern B. Carruthers
  • <em>In Vitro</em> Pharmacodynamics of Fosfomycin against Carbapenem-Resistant <span class="named-content genus-species" id="named-content-1">Enterobacter cloacae</span> and <span class="named-content genus-species" id="named-content-2">Klebsiella aerogenes</span>
    Experimental Therapeutics
    In Vitro Pharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacae and Klebsiella aerogenes

    The increase of carbapenem-resistant Enterobacterales (CRE) and lack of therapeutic options due to the scarcity of new antibiotics has sparked interest toward the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the in vitro pharmacodynamics of fosfomycin against carbapenem-resistant Enterobacter cloacae and...

    Tze-Peng Lim, Jocelyn Qi-Min Teo, Audrey Wei-Ling Goh, Si-Xuan Tan, Tse-Hsien Koh, Winnie Hui-Ling Lee, Yiying Cai, Thuan-Tong Tan, Andrea Lay-Hoon Kwa
  • Efficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse Strains
    Editor's Pick Experimental Therapeutics
    Efficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse Strains

    Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we...

    Jennifer Martynowicz, J. Stone Doggett, William J. Sullivan
  • Open Access
    Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant <span class="named-content genus-species" id="named-content-1">Stenotrophomonas maltophilia</span>
    Experimental Therapeutics
    Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

    The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia,...

    M. Biagi, A. Vialichka, M. Jurkovic, T. Wu, A. Shajee, M. Lee, S. Patel, R. E. Mendes, E. Wenzler
  • Characterization of Amikacin Drug Exposure and Nephrotoxicity in an Animal Model
    Experimental Therapeutics
    Characterization of Amikacin Drug Exposure and Nephrotoxicity in an Animal Model

    Despite excellent in vitro activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically...

    Katrina Chan, Kimberly R. Ledesma, Weiqun Wang, Vincent H. Tam
  • Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent
    Experimental Therapeutics
    Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

    The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low...

    Cristina Lazzarini, Krupanandan Haranahalli, J. Brian McCarthy, John Mallamo, Iwao Ojima, Maurizio Del Poeta
  • Metformin Suppresses Development of the <span class="named-content genus-species" id="named-content-1">Echinococcus multilocularis</span> Larval Stage by Targeting the TOR Pathway
    Experimental Therapeutics
    Metformin Suppresses Development of the Echinococcus multilocularis Larval Stage by Targeting the TOR Pathway

    Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the tapeworm Echinococcus multilocularis. Current chemotherapeutic treatment options based on benzimidazoles are of limited effectiveness, which underlines the need to find new antiechinococcosis drugs. Metformin is an antihyperglycemic and antiproliferative agent that shows activity...

    Julia A. Loos, Valeria A. Dávila, Klaus Brehm, Andrea C. Cumino
  • Open Access
    Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for <span class="named-content genus-species" id="named-content-1">Plasmodium falciparum</span> and <span class="named-content genus-species" id="named-content-2">P. vivax</span>
    Experimental Therapeutics
    Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

    Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select...

    Letícia Tiburcio Ferreira, Juliana Rodrigues, Gustavo Capatti Cassiano, Tatyana Almeida Tavella, Kaira Cristina Peralis Tomaz, Djane Clarys Baia-da-Silva, Macejane Ferreira Souza, Marilia Nunes do Nascimento Lima, Melina Mottin, Ludimila Dias Almeida, Juliana Calit, Maria Carolina Silva de Barros Puça, Gisely Cardoso Melo, Daniel Youssef Bargieri, Stefanie Costa Pinto Lopes, Marcus Vinicius Guimarães Lacerda, Elizabeth Bilsland, Per Sunnerhagen, Bruno Junior Neves, Carolina Horta Andrade, Pedro Vitor Lemos Cravo, Fabio Trindade Maranhão Costa

Clinical Therapeutics

  • New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with <span class="named-content genus-species" id="named-content-1">Trypanosoma cruzi</span>: Clinical, Parasitological, and Serological Assessment after Three Years of Follow-Up
    Clinical Therapeutics
    New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: Clinical, Parasitological, and Serological Assessment after Three Years of Follow-Up

    In a pilot study, we showed that the intermittent administration of benznidazole in chronic Chagas disease patients resulted in a low rate of treatment suspension and therapeutic failure, as assessed by quantitative PCR (qPCR) at the end of treatment. Here, a 3-year posttreatment follow-up study of the same cohort of patients is presented. The treatment scheme consisted of 12 doses of benznidazole at 5 mg/kg of body weight/day in two...

    María Gabriela Álvarez, Juan Carlos Ramírez, Graciela Bertocchi, Marisa Fernández, Yolanda Hernández, Bruno Lococo, Constanza Lopez-Albizu, Alejandro Schijman, Carolina Cura, Marcelo Abril, Susana Laucella, Rick L. Tarleton, María Ailen Natale, Melisa Castro Eiro, Sergio Sosa-Estani, Rodolfo Viotti
  • A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination
    Clinical Therapeutics
    A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination

    Criteria defining bedaquiline resistance for tuberculosis have been proposed addressing an emerging concern. We evaluated bedaquiline phenotypic drug susceptibility testing (pDST) criteria using drug-resistant tuberculosis clinical isolates tested at five reference laboratories. Isolates were tested at the proposed bedaquiline MGIT960 and 7H11 agar proportion (AP) critical concentrations and also at higher dilutions. The epidemiological...

    Nazir Ahmed Ismail, Akio Aono, Emanuele Borroni, Daniela Maria Cirillo, Christel Desmaretz, Rumina Hasan, Satoshi Mitarai, Sadia Shakoor, Gabriela Torrea, Koné Kaniga, Shaheed V. Omar
  • Open Access
    Pharmacist-Driven Implementation of Fast Identification and Antimicrobial Susceptibility Testing Improves Outcomes for Patients with Gram-Negative Bacteremia and Candidemia
    Clinical Therapeutics
    Pharmacist-Driven Implementation of Fast Identification and Antimicrobial Susceptibility Testing Improves Outcomes for Patients with Gram-Negative Bacteremia and Candidemia

    Bloodstream infections (BSI) are associated with increased morbidity and mortality, especially when caused by Gram-negative or fungal pathogens. The objective of this study was to assess the impact of fast identification-antimicrobial susceptibility testing (ID/AST) with the Accelerate Pheno system (AXDX) from May 2018 to December 2018 on antibiotic therapy and patient outcomes. A pre-post quasiexperimental study of 200 patients (100...

    Sahil Sheth, Michael Miller, Angela Beth Prouse, Scott Baker
  • Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis
    Clinical Therapeutics
    Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

    Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy...

    Mohammad H. Al-Shaer, Anne-Grete Märtson, Wael A. Alghamdi, Abdullah Alsultan, Guohua An, Shahriar Ahmed, Yosra Alkabab, Sayera Banu, Eric R. Houpt, David Ashkin, David E. Griffith, J. Peter Cegielski, Scott K. Heysell, Charles A. Peloquin
  • Risk Factors Associated with Antibiotic Treatment Failure of Buruli Ulcer
    Clinical Therapeutics
    Risk Factors Associated with Antibiotic Treatment Failure of Buruli Ulcer

    Combination antibiotic therapy is highly effective in curing Buruli ulcer (BU) caused by Mycobacterium ulcerans. Treatment failures have been uncommonly reported with the recommended 56 days of antibiotics, and little is known about risk factors for treatment failure. We analyzed treatment failures among BU patients treated with ≥56 days of antibiotics from a...

    Daniel P. O’Brien, N. Deborah Friedman, Aaron Walton, Andrew Hughes, Eugene Athan
  • Toward a Single-Dose Cure for Buruli Ulcer
    Editor's Pick Clinical Therapeutics
    Toward a Single-Dose Cure for Buruli Ulcer

    A single dose of Q203 (Telacebec), a phase 2 clinical candidate for tuberculosis, eradicates Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 weeks posttreatment. Clinical use of Q203 may dramatically simplify the clinical management of Buruli ulcer, a neglected mycobacterial disease.

    Sangeeta S. Thomas, Nitin Pal Kalia, Marie-Thérèse Ruf, Gerd Pluschke, Kevin Pethe
  • Population Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial Dosing
    Clinical Therapeutics
    Population Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial Dosing

    Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC (fT>MIC) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a...

    Mohammad H. Al-Shaer, Michael N. Neely, Jiajun Liu, Kartikeya Cherabuddi, Veena Venugopalan, Nathaniel J. Rhodes, Kenneth Klinker, Marc H. Scheetz, Charles A. Peloquin
  • Bacteriophage-Antibiotic Combinations for <span class="named-content genus-species" id="named-content-1">Enterococcus faecium</span> with Varying Bacteriophage and Daptomycin Susceptibilities
    Clinical Therapeutics
    Bacteriophage-Antibiotic Combinations for Enterococcus faecium with Varying Bacteriophage and Daptomycin Susceptibilities

    Concerns regarding increased prevalence of daptomycin (DAP)-resistant strains necessitate novel therapies for Enterococcus faecium infections. Obligately lytic bacteriophages are viruses that target, infect, and kill bacterial cells. Limited studies have evaluated phage-antibiotic combinations against E....

    Taylor Morrisette, Katherine L. Lev, Razieh Kebriaei, Jacinda C. Abdul-Mutakabbir, Kyle C. Stamper, Sandra Morales, Susan M. Lehman, Gregory S. Canfield, Breck A. Duerkop, Cesar A. Arias, Michael J. Rybak
  • Effectiveness of Vancomycin Dosing Guided by Therapeutic Drug Monitoring in Adult Patients Receiving Extracorporeal Membrane Oxygenation
    Clinical Therapeutics
    Effectiveness of Vancomycin Dosing Guided by Therapeutic Drug Monitoring in Adult Patients Receiving Extracorporeal Membrane Oxygenation

    The clinical situation for patients receiving extracorporeal membrane oxygenation (ECMO) is complex, and drug dosing is complicated by significant pharmacokinetic alterations. We sought to describe the frequency of achievement of therapeutic vancomycin concentrations in critically ill patients receiving ECMO with therapeutic drug monitoring (TDM). In this retrospective observational study, we included all critically ill patients...

    Prashanti Marella, Jason Roberts, Karen Hay, Kiran Shekar

Pharmacology

  • Polymyxin-Induced Cell Death of Human Macrophage-Like THP-1 and Neutrophil-Like HL-60 Cells Associated with the Activation of Apoptotic Pathways
    Pharmacology
    Polymyxin-Induced Cell Death of Human Macrophage-Like THP-1 and Neutrophil-Like HL-60 Cells Associated with the Activation of Apoptotic Pathways

    Innate immunity is crucial for the host to defend against infections, and understanding the effect of polymyxins on innate immunity is important for optimizing their clinical use. In this study, we investigated the potential toxicity of polymyxins on human macrophage-like THP-1 and neutrophil-like HL-60 cells. Differentiated THP-1 human macrophages (THP-1-dMs) and HL-60 human neutrophils (HL-60-dNs) were employed. Flow cytometry was...

    Ahmed M. Fathalla, Seong H. Chow, Thomas Naderer, Qi Tony Zhou, Tony Velkov, Mohammad A. K. Azad, Jian Li
  • Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine
    Pharmacology
    Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine

    The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment...

    Julie B. Dumond, Camden P. Bay, Julie A. E. Nelson, Angel Davalos, Andrew Edmonds, Kristina De Paris, Craig Sykes, Kathryn Anastos, Roopali Sharma, Seble Kassaye, Bani Tamraz, Audrey L. French, Stephen Gange, Ighovwerha Ofotokun, Margaret A. Fischl, David E. Vance, Adaora A. Adimora
  • Open Access
    Nonstationary Pharmacokinetics of Caspofungin in ICU Patients
    Pharmacology
    Nonstationary Pharmacokinetics of Caspofungin in ICU Patients

    Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0–24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring...

    Agnieszka Borsuk-De Moor, Justyna Sysiak-Sławecka, Elżbieta Rypulak, Michał Borys, Paweł Piwowarczyk, Grzegorz Raszewski, Dariusz Onichimowski, Mirosław Czuczwar, Paweł Wiczling
  • Unraveling the Gentamicin Drug Product Complexity Reveals Variation in Microbiological Activities and Nephrotoxicity
    Pharmacology
    Unraveling the Gentamicin Drug Product Complexity Reveals Variation in Microbiological Activities and Nephrotoxicity

    The gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture. A liquid...

    Zackery P. Bulman, Ryan Cirz, Darin Hildebrandt, Tim Kane, Zuelay Rosario, Ken Wlasichuk, Minjong Park, Logan D. Andrews
  • Open Access
    Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with <span class="named-content genus-species" id="named-content-1">Schistosoma japonicum</span>
    Pharmacology
    Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicum

    An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and...

    Amaya L. Bustinduy, Ruwanthi Kolamunnage-Dona, Mark H. Mirochnick, Edmund V. Capparelli, Veronica Tallo, Luz P. Acosta, Remigio M. Olveda, Jennifer F. Friedman, William W. Hope
  • Open Access
    Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of <span class="named-content genus-species" id="named-content-1">Plasmodium cynomolgi</span> Infection in Rhesus Macaques
    Pharmacology
    Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques

    Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50...

    Pattaraporn Vanachayangkul, Rawiwan Im-erbsin, Anchalee Tungtaeng, Chanikarn Kodchakorn, Alison Roth, John Adams, Chaiyaporn Chaisatit, Piyaporn Saingam, Richard J. Sciotti, Gregory A. Reichard, Christina K. Nolan, Brandon S. Pybus, Chad C. Black, Luis A. Lugo-Roman, Matthew D. Wegner, Philip L. Smith, Mariusz Wojnarski, Brian A. Vesely, Kevin C. Kobylinski
  • Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> in a Dynamic <em>In Vitro</em> Hollow-Fiber Infection Model
    Pharmacology
    Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

    Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P....

    Aaron J. Heffernan, Fekade B. Sime, Derek S. Sarovich, Michael Neely, Yarmarly Guerra-Valero, Saiyuri Naicker, Kyra Cottrell, Patrick Harris, Katherine T. Andrews, David Ellwood, Steven C. Wallis, Jeffrey Lipman, Keith Grimwood, Jason A. Roberts
  • Open Access
    Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients
    Pharmacology
    Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

    The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of...

    Anne-Grete Märtson, Kim C. M. van der Elst, Anette Veringa, Jan G. Zijlstra, Albertus Beishuizen, Tjip S. van der Werf, Jos G. W. Kosterink, Michael Neely, Jan-Willem Alffenaar
  • Interspecies Differences in Tenofovir Alafenamide Fumarate Stability in Plasma
    Pharmacology
    Interspecies Differences in Tenofovir Alafenamide Fumarate Stability in Plasma

    Tenofovir (TFV) alafenamide fumarate (TAF) is an antiretroviral that has been evaluated in alternative drug delivery systems in several species. The ex vivo stability of TAF was evaluated, and TAF was stable in dog-, sheep-, and macaque-spiked plasma. A negative bias was observed in TAF recovery in rabbit-spiked plasma; there was complete loss of TAF and corresponding overestimation of TFV in rodent-spiked plasma. These data...

    Teresa L. Parsons, Kevin N. Gwenden, Mark A. Marzinke
  • Free
    Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
    Pharmacology
    Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

    Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at...

    Catia Marzolini, Felix Stader, Marcel Stoeckle, Fabian Franzeck, Adrian Egli, Stefano Bassetti, Alexa Hollinger, Michael Osthoff, Maja Weisser, Caroline E. Gebhard, Veronika Baettig, Julia Geenen, Nina Khanna, Sarah Tschudin-Sutter, Daniel Mueller, Hans H. Hirsch, Manuel Battegay, Parham Sendi
  • Semimechanistic Modeling of Eravacycline Pharmacodynamics Using <em>In Vitro</em> Time-Kill Data with MIC Incorporated in an Adaptive Resistance Function
    Pharmacology
    Semimechanistic Modeling of Eravacycline Pharmacodynamics Using In Vitro Time-Kill Data with MIC Incorporated in an Adaptive Resistance Function

    Effective bacterial infection eradication requires not only potent antibacterial agents but also proper dosing strategies. Current practices generally utilize point estimates of the effects of therapeutic agents, even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed in vitro effects to develop a semimechanistic pharmacokinetic-pharmacodynamic model for...

    Ken Nguyen, Timothy J. Bensman, Xiaohui (Tracey) Wei, Jason N. Moore

Letters to the Editor

  • Spread of <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> ST45 Producing GES-5 Carbapenemase or GES-1 Extended-Spectrum β-Lactamase in Newborns and Infants
    Letter to the Editor
    Spread of Klebsiella pneumoniae ST45 Producing GES-5 Carbapenemase or GES-1 Extended-Spectrum β-Lactamase in Newborns and Infants
    E. Literacka, R. Izdebski, P. Urbanowicz, D. Żabicka, J. Klepacka, I. Sowa-Sierant, I. Żak, A. Garus-Jakubowska, W. Hryniewicz, M. Gniadkowski
  • First Report of Foodborne <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> Coharboring <em>bla</em><sub>VIM-1</sub>, <em>bla</em><sub>NDM-1</sub>, and <em>mcr-9</em>
    Letter to the Editor
    First Report of Foodborne Klebsiella pneumoniae Coharboring blaVIM-1, blaNDM-1, and mcr-9
    Hazim O. Khalifa, Ahmed M. Soliman, Takashi Saito, Shizuo Kayama, Liansheng Yu, Junzo Hisatsune, Motoyuki Sugai, Hirofumi Nariya, Ashraf M. Ahmed, Toshi Shimamoto, Tetsuya Matsumoto, Tadashi Shimamoto
  • Urinary Creatinine Clearance and Pharmacokinetics Studies: If We Can Measure It, Why Do We Estimate It?
    Letter to the Editor
    Urinary Creatinine Clearance and Pharmacokinetics Studies: If We Can Measure It, Why Do We Estimate It?
    Catarina M. Silva, Andrew A. Udy, João P. Baptista
  • Emergence of <em>Salmonella</em> Genomic Island 1 Variant SGI1-C in a Multidrug-Resistant Clinical Isolate of <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> ST485 from Egypt
    Letter to the Editor
    Emergence of Salmonella Genomic Island 1 Variant SGI1-C in a Multidrug-Resistant Clinical Isolate of Klebsiella pneumoniae ST485 from Egypt
    Ahmed M. Soliman, Hazem Ramadan, Eslam Ghazy, Liansheng Yu, Junzo Hisatsune, Shizuo Kayama, Motoyuki Sugai, Hirofumi Nariya, Toshi Shimamoto, Charlene R. Jackson, Tadashi Shimamoto

Errata

  • Free
    Erratum for Amblard et al., “Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses <em>In Vitro</em> and in Humanized Mice”
    Erratum
    Erratum for Amblard et al., “Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice”
    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
  • Free
    Erratum for Wang et al., “Cocarriage of Distinct <em>bla</em><sub>KPC-2</sub> and <em>bla</em><sub>OXA-48</sub> Plasmids in a Single Sequence Type 11 Carbapenem-Resistant <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> Isolate”
    Erratum
    Erratum for Wang et al., “Cocarriage of Distinct blaKPC-2 and blaOXA-48 Plasmids in a Single Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Isolate”
    Yao-Chen Wang, Hui-Ling Tang, Yu-Chieh Liao, Chien-Shun Chiou, Ying-Tsong Chen, Ming-Ko Chiang, Min-Chi Lu, Yi-Chyi Lai

Masthead

  • Free
    Editorial Board
    Masthead
    Editorial Board
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Antimicrobial Agents and Chemotherapy: 64 (9)

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volume 64, issue 9
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  • Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2
  • Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling
  • Fact versus Fiction: a Review of the Evidence behind Alcohol and Antibiotic Interactions
  • Povidone Iodine: Properties, Mechanisms of Action, and Role in Infection Control and Staphylococcus aureus Decolonization
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