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Table of Contents

August 2020; Volume 64,Issue 8

Minireview

  • Cetylpyridinium Chloride: Mechanism of Action, Antimicrobial Efficacy in Biofilms, and Potential Risks of Resistance
    Minireview
    Cetylpyridinium Chloride: Mechanism of Action, Antimicrobial Efficacy in Biofilms, and Potential Risks of Resistance

    Antimicrobial resistance is a serious issue for public health care all over the world. While resistance toward antibiotics has attracted strong interest among researchers and the general public over the last 2 decades, the directly related problem of resistance toward antiseptics and biocides has been somewhat left untended. In the field of dentistry, antiseptics are routinely used in professional care, but they are also included in...

    Xiaojun Mao, David L. Auer, Wolfgang Buchalla, Karl-Anton Hiller, Tim Maisch, Elmar Hellwig, Ali Al-Ahmad, Fabian Cieplik

Mechanisms of Action: Physiological Effects

  • Chemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal Candidiasis
    Mechanisms of Action: Physiological Effects
    Chemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal Candidiasis

    Candida albicans is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of Candida infections is limited by the paucity of antifungal drug classes. Naturally occurring antimicrobial peptides are promising agents for drug development. CCL28 is a CC chemokine that is abundant in saliva and has in vitro...

    Jie He, Monica A. Thomas, Jaime de Anda, Michelle W. Lee, Emma Van Why, Pippa Simpson, Gerard C. L. Wong, Mitchell H. Grayson, Brian F. Volkman, Anna R. Huppler
  • Transcriptional Inhibition of the F<sub>1</sub>F<sub>0</sub>-Type ATP Synthase Has Bactericidal Consequences on the Viability of Mycobacteria
    Mechanisms of Action: Physiological Effects
    Transcriptional Inhibition of the F1F0-Type ATP Synthase Has Bactericidal Consequences on the Viability of Mycobacteria

    Bedaquiline, an inhibitor of the mycobacterial ATP synthase, has revolutionized the treatment of Mycobacterium tuberculosis infection. Although a potent inhibitor, it is characterized by poorly understood delayed time-dependent bactericidal activity. Here, we demonstrate that in contrast to bedaquiline, the transcriptional inhibition of the ATP synthase in...

    Matthew B. McNeil, Heath W. K. Ryburn, Liam K. Harold, Justin F. Tirados, Gregory M. Cook

Mechanisms of Resistance

  • Open Access
    Insights into the <span class="sc">l</span>,<span class="sc">d</span>-Transpeptidases and <span class="sc">d</span>,<span class="sc">d</span>-Carboxypeptidase of <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span>: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors
    Mechanisms of Resistance
    Insights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors

    Mycobacterium abscessus is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating, with a focus on cell wall synthesis proteins (M. abscessus...

    Khalid M. Dousa, Sebastian G. Kurz, Magdalena A. Taracila, Tracey Bonfield, Christopher R. Bethel, Melissa D. Barnes, Suresh Selvaraju, Ayman M. Abdelhamed, Barry N. Kreiswirth, W. Henry Boom, Shannon H. Kasperbauer, Charles L. Daley, Robert A. Bonomo
  • Fitness Cost and Compensatory Evolution in Levofloxacin-Resistant <em>Mycobacterium aurum</em>
    Mechanisms of Resistance
    Fitness Cost and Compensatory Evolution in Levofloxacin-Resistant Mycobacterium aurum

    We isolated spontaneous levofloxacin-resistant strains of Mycobacterium aurum to study the fitness cost and compensatory evolution of fluoroquinolone resistance in mycobacteria. Five of six mutant strains with substantial growth defects showed restored fitness after being serially passaged for 18 growth cycles, along with increased cellular ATP level. Whole-genome...

    Rui Pi, Qingyun Liu, Howard E. Takiff, Qian Gao
  • KPC-50 Confers Resistance to Ceftazidime-Avibactam Associated with Reduced Carbapenemase Activity
    Mechanisms of Resistance
    KPC-50 Confers Resistance to Ceftazidime-Avibactam Associated with Reduced Carbapenemase Activity

    KPC-50 is a KPC-3 variant identified from a Klebsiella pneumoniae clinical isolate recovered in Switzerland in 2019. Compared to KPC-3, KPC-50 shows (i) a three-amino-acid insertion (Glu-Ala-Val) between amino acids 276 and 277, (ii) an increased affinity to ceftazidime, (iii) a decreased sensitivity to avibactam, explaining the ceftazidime-avibactam resistance, and (...

    Laurent Poirel, Xavier Vuillemin, Mario Juhas, Amandine Masseron, Ursina Bechtel-Grosch, Simon Tiziani, Stefano Mancini, Patrice Nordmann
  • Chromosomal Resistance to Metronidazole in <span class="named-content genus-species" id="named-content-1">Clostridioides difficile</span> Can Be Mediated by Epistasis between Iron Homeostasis and Oxidoreductases
    Editor's Pick Mechanisms of Resistance
    Chromosomal Resistance to Metronidazole in Clostridioides difficile Can Be Mediated by Epistasis between Iron Homeostasis and Oxidoreductases

    Chromosomal resistance to metronidazole has emerged in clinical Clostridioides difficile isolates, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to interpret genetic variations in clinical isolates. We therefore constructed a mismatch repair mutator in...

    Aditi Deshpande, Xiaoqian Wu, Wenwen Huo, Kelli L. Palmer, Julian G. Hurdle
  • Antibiotic Substrate Selectivity of <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> MexY and MexB Efflux Systems Is Determined by a Goldilocks Affinity
    Mechanisms of Resistance
    Antibiotic Substrate Selectivity of Pseudomonas aeruginosa MexY and MexB Efflux Systems Is Determined by a Goldilocks Affinity

    Resistance-nodulation-division (RND) efflux pumps are important contributors to bacterial antibiotic resistance. In this study, we combined evolutionary sequence analyses, computational structural modeling, and ligand docking to develop a framework that can explain the known antibiotic substrate selectivity differences between two Pseudomonas aeruginosa RND...

    Debayan Dey, Logan G. Kavanaugh, Graeme L. Conn
  • Open Access
    Simulating the Influence of Conjugative-Plasmid Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model
    Mechanisms of Resistance
    Simulating the Influence of Conjugative-Plasmid Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model

    Bacterial plasmids harboring antibiotic resistance genes are critical in the spread of antibiotic resistance. It is known that plasmids differ in their kinetic values, i.e., conjugation rate, segregation rate by copy number incompatibility with related plasmids, and rate of stochastic loss during replication. They also differ in cost to the cell in terms of reducing fitness and in the frequency of compensatory mutations compensating...

    Marcelino Campos, Álvaro San Millán, José M. Sempere, Val F. Lanza, Teresa M. Coque, Carlos Llorens, Fernando Baquero
  • <em>In Vitro</em> Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant <em>Enterobacterales</em> with Varying Intrinsic and Acquired Resistance Mechanisms
    Editor's Pick Mechanisms of Resistance
    In Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance Mechanisms

    QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598...

    Kirk Nelson, Debora Rubio-Aparicio, Dongxu Sun, Michael Dudley, Olga Lomovskaya
  • Antimicrobial Susceptibility and Clonality of Vaginally Derived Multidrug-Resistant <em>Mobiluncus</em> Isolates in China
    Mechanisms of Resistance
    Antimicrobial Susceptibility and Clonality of Vaginally Derived Multidrug-Resistant Mobiluncus Isolates in China

    Here, the antimicrobial susceptibility, resistance mechanisms, and clonality of Mobiluncus sp. isolates recovered from gynecological outpatients in China were investigated. Compared to M. mulieris, M. curtisii exhibited higher antimicrobial resistance to metronidazole, clindamycin, and...

    Xueying Zhang, Yongying Bai, Long Zhang, Mohamed S. Draz, Zhi Ruan, Yuning Zhu
  • Proteomic Investigation of the Signal Transduction Pathways Controlling Colistin Resistance in <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span>
    Mechanisms of Resistance
    Proteomic Investigation of the Signal Transduction Pathways Controlling Colistin Resistance in Klebsiella pneumoniae

    Colistin resistance in Klebsiella pneumoniae is predominantly caused by mutations that increase expression of the arn (also known as pbg or pmrF) operon. Expression is activated by the PhoPQ and PmrAB two-component systems. Constitutive PhoPQ activation occurs directly by mutation or following loss of MgrB. PhoPQ may also cross-activate...

    Ching Hei Phoebe Cheung, Punyawee Dulyayangkul, Kate J. Heesom, Matthew B. Avison
  • Persistence Dynamics of Antimicrobial-Resistant <em>Neisseria</em> in the Pharynx of Rhesus Macaques
    Mechanisms of Resistance
    Persistence Dynamics of Antimicrobial-Resistant Neisseria in the Pharynx of Rhesus Macaques

    Pharyngeal infections by Neisseria gonorrhoeae are often asymptomatic, making them difficult to treat. However, in vivo animal modeling of human pharyngeal infections by pathogenic Neisseria species is challenging due to numerous host tropism barriers. We have relied on rhesus macaques to investigate pharyngeal persistence of naturally occurring ...

    Eliza Thapa, Hanna M. Knauss, Benjamin A. Colvin, Benjamin A. Fischer, Nathan J. Weyand
  • A Novel Combination of <em>CYP51A</em> Mutations Confers Pan-Azole Resistance in <span class="named-content genus-species" id="named-content-1">Aspergillus fumigatus</span>
    Editor's Pick Mechanisms of Resistance
    A Novel Combination of CYP51A Mutations Confers Pan-Azole Resistance in Aspergillus fumigatus

    The treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype...

    Daiana Macedo, Tomás Brito Devoto, Santiago Pola, Jorge L. Finquelievich, María L. Cuestas, Guillermo Garcia-Effron
  • <span class="named-content genus-species" id="named-content-1">Plasmodium falciparum</span> Isolates Carrying <em>pf</em>k13 Polymorphisms Harbor the SVMNT Allele of <em>pfcrt</em> in Northwestern Indonesia
    Mechanisms of Resistance
    Plasmodium falciparum Isolates Carrying pfk13 Polymorphisms Harbor the SVMNT Allele of pfcrt in Northwestern Indonesia

    Artemisinin-based combination therapy (ACT) is the first-line antimalarial regimen in Indonesia. Susceptibility of Plasmodium falciparum to artemisinin is falling in the Greater Mekong subregion, but it is not known whether the efficacy of current combinations is also threatened in nearby Sumatera. We evaluated the genetic loci pfcrt, pfmdr1, and pfk13...

    Inke N. D. Lubis, Hendri Wijaya, Munar Lubis, Chairuddin P. Lubis, Khalid B. Beshir, Colin J. Sutherland

Susceptibility

  • Open Access
    AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward <em>Mycobacterium abscessus</em>
    Susceptibility
    AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus

    Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo. Antimicrobial...

    Shaoyan Zhang, Yuzhen Zou, Qi Guo, Jianhui Chen, Liyun Xu, Xiaoyu Wan, Zhemin Zhang, Bing Li, Haiqing Chu
  • <em>In Vitro</em> Activities of Eravacycline and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas
    Susceptibility
    In Vitro Activities of Eravacycline and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas

    We performed in vitro susceptibility testing for eravacycline in comparison to 4 other antimicrobials against 10 Mycoplasma genitalium, 40 Mycoplasma hominis, 44 Mycoplasma pneumoniae, 20...

    Ken B. Waites, Donna M. Crabb, Li Xiao, Lynn B. Duffy, Sixto M. Leal
  • <em>In Vitro</em> Activity of Manogepix (APX001A) and Comparators against Contemporary Molds: MEC Comparison and Preliminary Experience with Colorimetric MIC Determination
    Editor's Pick Susceptibility
    In Vitro Activity of Manogepix (APX001A) and Comparators against Contemporary Molds: MEC Comparison and Preliminary Experience with Colorimetric MIC Determination

    Manogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections. We compared manogepix EUCAST minimum effective concentrations (MECs) to MICs of five comparators and CLSI MECs and MICs by a colorimetric method against contemporary molds. EUCAST susceptibility testing was performed for 161 isolates. Interlaboratory and intermethod...

    Karin Meinike Jørgensen, Karen M. T. Astvad, Maiken Cavling Arendrup

Antiviral Agents

  • Filovirus Antiviral Activity of Cationic Amphiphilic Drugs Is Associated with Lipophilicity and Ability To Induce Phospholipidosis
    Antiviral Agents
    Filovirus Antiviral Activity of Cationic Amphiphilic Drugs Is Associated with Lipophilicity and Ability To Induce Phospholipidosis

    Several cationic amphiphilic drugs (CADs) have been found to inhibit cell entry of filoviruses and other enveloped viruses. Structurally unrelated CADs may have antiviral activity, yet the underlying common mechanism and structure-activity relationship are incompletely understood. We aimed to understand how widespread antiviral activity is among CADs and which structural and physico-chemical properties are linked to entry inhibition. We...

    Antonia P. Gunesch, Francisco J. Zapatero-Belinchón, Lukas Pinkert, Eike Steinmann, Michael P. Manns, Gisbert Schneider, Thomas Pietschmann, Mark Brönstrup, Thomas von Hahn
  • Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection
    Antiviral Agents
    Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection

    Flaviviruses such as Zika virus (ZIKV), dengue virus (DENV), and West Nile virus (WNV) are major global pathogens for which safe and effective antiviral therapies are not currently available. To identify antiviral small molecules with well-characterized safety and bioavailability profiles, we screened a library of 2,907 approved drugs and pharmacologically active compounds for inhibitors of ZIKV infection using a high-throughput cell-...

    Nicholas S. Eyre, Emily N. Kirby, Daniel R. Anfiteatro, Gustavo Bracho, Alice G. Russo, Peter A. White, Amanda L. Aloia, Michael R. Beard
  • Open Access
    Structure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents
    Antiviral Agents
    Structure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents

    “Shock and kill” therapeutic strategies toward HIV eradication are based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) and the consequent killing of the reactivated cell by either the cytopathic effect of HIV or an arm of the immune system. We have recently found several benzotriazole and benzotriazine analogues that have the ability to reactivate latent HIV by inhibiting signal transducer and...

    Eric S. Sorensen, Amanda B. Macedo, Rachel S. Resop, J. Natalie Howard, Racheal Nell, Indra Sarabia, Daniel Newman, Yanqin Ren, R. Brad Jones, Vicente Planelles, Adam M. Spivak, Alberto Bosque
  • Open Access
    Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle
    Antiviral Agents
    Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle

    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that originated in Wuhan, China, in December 2019 has impacted public health, society, the global economy, and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary...

    Clarisse Salgado-Benvindo, Melissa Thaler, Ali Tas, Natacha S. Ogando, Peter J. Bredenbeek, Dennis K. Ninaber, Ying Wang, Pieter S. Hiemstra, Eric J. Snijder, Martijn J. van Hemert

Epidemiology and Surveillance

  • A Propensity Score Matched Study of the Positive Impact of Infectious Diseases Consultation on Antimicrobial Appropriateness in Hospitalized Patients with Antimicrobial Stewardship Oversight
    Editor's Pick Epidemiology and Surveillance
    A Propensity Score Matched Study of the Positive Impact of Infectious Diseases Consultation on Antimicrobial Appropriateness in Hospitalized Patients with Antimicrobial Stewardship Oversight

    Hospital-based antibiotic stewardship (AS) programs provide oversight and guidance for appropriate antimicrobial use in acute care settings. Infectious disease expertise is beneficial in the care of hospitalized patients with infections. The impact of infectious diseases consultation (IDC) on antimicrobial appropriateness in a large tertiary hospital with an established AS program was investigated. This was a cross-sectional study from...

    Jacqueline T. Bork, Kimberly C. Claeys, Emily L. Heil, Mary Banoub, Surbhi Leekha, John D. Sorkin, Michael Kleinberg
  • Antimicrobial Susceptibility and Cross-Resistance Patterns among Common Complicated Urinary Tract Infections in U.S. Hospitals, 2013 to 2018
    Epidemiology and Surveillance
    Antimicrobial Susceptibility and Cross-Resistance Patterns among Common Complicated Urinary Tract Infections in U.S. Hospitals, 2013 to 2018

    In the face of increasing rates of antimicrobial resistance in complicated urinary tract infections (cUTIs), clinicians need to understand cross-resistance patterns among commonly encountered pathogens. We performed a multicenter, retrospective cohort study in the Premier database of approximately 180 hospitals, from 2013 to 2018. Using an ICD-9/10-based algorithm, we identified all adult patients hospitalized with cUTIs and included...

    Marya D. Zilberberg, Brian H. Nathanson, Kate Sulham, Andrew F. Shorr
  • Genomic Study of <em>bla</em><sub>IMI</sub>-Positive <span class="named-content genus-species" id="named-content-1">Enterobacter cloacae</span> Complex in Singapore over a Five-Year Study Period
    Epidemiology and Surveillance
    Genomic Study of blaIMI-Positive Enterobacter cloacae Complex in Singapore over a Five-Year Study Period

    The blaIMI gene is rarely detected outside the Enterobacter genus. Genomic characterization of 87 blaIMI-positive Enterobacter cloacae complex members revealed that the largest phylogenomic clade was made up of E. cloacae subsp. cloacae (71.3...

    Sophie Octavia, Tse Hsien Koh, Oon Tek Ng, Kalisvar Marimuthu, Indumathi Venkatachalam, Raymond T. P. Lin, Jeanette W. P. Teo
  • Open Access
    <em>In Vitro</em> Activity of Omadacycline, a New Tetracycline Analog, and Comparators against <span class="named-content genus-species" id="named-content-1">Clostridioides difficile</span>
    Epidemiology and Surveillance
    In Vitro Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficile

    Omadacycline is a potent aminomethylcycline with in vitro activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has in vitro activity against Clostridioides difficile; however, large-scale in vitro studies have not been done. The purpose of this study was to assess the in...

    Khurshida Begum, Eugénie Bassères, Julie Miranda, Chris Lancaster, Anne J. Gonzales-Luna, Travis J. Carlson, Tasnuva Rashid, David W. Eyre, Mark H. Wilcox, M. Jahangir Alam, Kevin W. Garey
  • The <em>mcr-9</em> Gene of <em>Salmonella</em> and <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> Is Not Associated with Colistin Resistance in the United States
    Epidemiology and Surveillance
    The mcr-9 Gene of Salmonella and Escherichia coli Is Not Associated with Colistin Resistance in the United States

    Reports of transmissible colistin resistance show the importance of comprehensive colistin resistance surveillance. Recently, a new allele of the mobile colistin resistance (mcr) gene family designated mcr-9, which shows variation in genetic context and colistin susceptibility, was reported. We tested over 100 Salmonella enterica and...

    Gregory H. Tyson, Cong Li, Chih-Hao Hsu, Sherry Ayers, Stacey Borenstein, Sampa Mukherjee, Thu-Thuy Tran, Patrick F. McDermott, Shaohua Zhao
  • Extended-Spectrum-β-Lactamase- and Plasmid AmpC-Producing <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> Causing Community-Onset Bloodstream Infection: Association of Bacterial Clones and Virulence Genes with Septic Shock, Source of Infection, and Recurrence
    Epidemiology and Surveillance
    Extended-Spectrum-β-Lactamase- and Plasmid AmpC-Producing Escherichia coli Causing Community-Onset Bloodstream Infection: Association of Bacterial Clones and Virulence Genes with Septic Shock, Source of Infection, and Recurrence

    Invasive infections due to extended-spectrum-β-lactamase- and pAmpC-producing Escherichia coli (ESBL/pAmpC-EC) are an important cause of morbidity, often caused by the high-risk clone sequence type (ST131) and isolates classified as extraintestinal pathogenic E. coli (ExPEC). The relative influence...

    Inga Fröding, Badrul Hasan, Isak Sylvin, Maarten Coorens, Pontus Nauclér, Christian G. Giske

Experimental Therapeutics

  • Novel Antiparasitic Activity of the Antifungal Lead Occidiofungin
    Experimental Therapeutics
    Novel Antiparasitic Activity of the Antifungal Lead Occidiofungin

    Novel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite Cryptosporidium parvum in vitro with limited cytotoxicity (50% effective concentration [EC50] = 120 nM versus 50% cytotoxic concentration [TC50] = 988 nM), and its application disrupted the...

    Jingbo Ma, Fengguang Guo, Zi Jin, Mengxin Geng, Min Ju, Akshaya Ravichandran, Ravi Orugunty, Leif Smith, Guan Zhu, Haili Zhang
  • Preserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial Infection
    Editor's Pick Experimental Therapeutics
    Preserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial Infection

    The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii,...

    Teclegiorgis Gebremariam, Lina Zhang, Sondus Alkhazraji, Yiyou Gu, Eman G. Youssef, Zongzhong Tong, Erik Kish-Trier, Ashok Bajji, Claudia V. de Araujo, Bianca Rich, Samuel W. French, Dean Y. Li, Alan L. Mueller, Shannon J. Odelberg, Weiquan Zhu, Ashraf S. Ibrahim
  • Open Access
    <em>In Vitro</em> and <em>In Vivo</em> Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis
    Experimental Therapeutics
    In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis

    Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor...

    Zhe Cheng, Zhijian Xu, Huimin Tian, Fan Liu, Xiu Li, Damin Luo, Yanhai Wang
  • Open Access
    Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis
    Experimental Therapeutics
    Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

    Primary amoebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The amoeba migrates along the olfactory nerve to the brain, resulting in seizures, coma, and, eventually, death. Previous research has shown that Naegleria gruberi, a close...

    Maarten J. Sarink, Aloysius G. M. Tielens, Annelies Verbon, Robert Sutak, Jaap J. van Hellemond
  • Open Access
    Chitosan Ameliorates <span class="named-content genus-species" id="named-content-1">Candida auris</span> Virulence in a <span class="named-content genus-species" id="named-content-2">Galleria mellonella</span> Infection Model
    Experimental Therapeutics
    Chitosan Ameliorates Candida auris Virulence in a Galleria mellonella Infection Model

    Candida auris has emerged as a multidrug-resistant nosocomial pathogen over the last decade. Outbreaks of the organism in health care facilities have resulted in life-threatening invasive candidiasis in over 40 countries worldwide. Resistance by C. auris to conventional antifungal drugs such as...

    Laís Salomão Arias, Mark C. Butcher, Bryn Short, Emily McKloud, Chris Delaney, Ryan Kean, Douglas Roberto Monteiro, Craig Williams, Gordon Ramage, Jason L. Brown
  • TCP1γ Subunit Is Indispensable for Growth and Infectivity of <span class="named-content genus-species" id="named-content-1">Leishmania donovani</span>
    Experimental Therapeutics
    TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani

    T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In Leishmania donovani, the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the...

    Shailendra Yadav, Jitendra Kuldeep, Mohammad I. Siddiqi, Neena Goyal
  • Analysis of Paradoxical Efficacy of Carbapenems against Carbapenemase-Producing <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> in a Murine Model of Lethal Peritonitis
    Experimental Therapeutics
    Analysis of Paradoxical Efficacy of Carbapenems against Carbapenemase-Producing Escherichia coli in a Murine Model of Lethal Peritonitis

    The clinical benefit of carbapenems against carbapenemase-producing Enterobacteriaceae (CPE) remains in question. MICs of imipenem (IMP) and ertapenem (ERT) against isogenic derivatives of the wild-type strain Escherichia coli CFT073 producing KPC-3, OXA-48, or NDM-1 were 0.25, 2, 16, and 64 mg/liter for IMP and 0.008, 0.5, 8, and 64 mg/liter for ERT,...

    Ariane Roujansky, Victoire de Lastours, François Guérin, Françoise Chau, Geoffrey Cheminet, Laurent Massias, Vincent Cattoir, Bruno Fantin
  • Open Access
    Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas Cardiomyopathy
    Experimental Therapeutics
    Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas Cardiomyopathy

    Chagas disease, caused by the protozoan Trypanosoma cruzi, endemic in Latin America but distributed worldwide because of migration. Without appropriate treatment, the disease progresses from an acute asymptomatic phase to a chronic, progressive inflammatory cardiomyopathy causing heart failure and death. Despite specific trypanocidal therapy, heart damage progression...

    Daniela Guzmán-Rivera, Ana Liempi, Fabiola González-Herrera, Sebastián Fuentes-Retamal, Ileana Carrillo, Patricio Abarca, Christian Castillo, Ulrike Kemmerling, Barbara Pesce, Juan Diego Maya
  • Amlodipine Increases the Therapeutic Potential of Ravuconazole upon <span class="named-content genus-species" id="named-content-1">Trypanosoma cruzi</span> Infection
    Experimental Therapeutics
    Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

    Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed...

    Yara Almeida Machado, Maria Terezinha Bahia, Ivo Santana Caldas, Ana Lia Mazzeti, Rômulo Dias Novaes, Breno Raimundo Vilas Boas, Lorena Júnia de Souza Santos, Olindo Assis Martins-Filho, Marcos José Marques, Lívia de Figueiredo Diniz

Clinical Therapeutics

  • Open Access
    Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults
    Clinical Therapeutics
    Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults

    Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two...

    George R. Thompson, Phoebe Lewis, Stuart Mudge, Thomas F. Patterson, Bruce P. Burnett
  • <em>In Vitro</em> and <em>In Vivo</em> Characterization of Tebipenem, an Oral Carbapenem
    Clinical Therapeutics
    In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

    The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability...

    Nicole Cotroneo, Aileen Rubio, Ian A. Critchley, Chris Pillar, Michael J. Pucci

Pharmacology

  • Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling
    Pharmacology
    Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling

    Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-...

    Rajith K. R. Rajoli, Zach R. Demkovich, Charles Flexner, Andrew Owen, Marco Siccardi
  • Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span>
    Pharmacology
    Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae

    Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae. Monotherapies and double- and triple-combination...

    Su Mon Aye, Irene Galani, Heidi Yu, Jiping Wang, Ke Chen, Hasini Wickremasinghe, Ilias Karaiskos, Phillip J. Bergen, Jinxin Zhao, Tony Velkov, Helen Giamarellou, Yu-Wei Lin, Brian T. Tsuji, Jian Li
  • Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative
    Pharmacology
    Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative

    Animal infection models are invaluable in optimizing antimicrobial dosage in humans. Utilization of human-simulated regimens (HSRs) in animal models helps to evaluate antimicrobial efficacy at clinically achievable drug concentrations. To that end, pharmacokinetic studies in infected animals and confirmation of the HSR pharmacokinetic profile are essential in evaluating observed versus expected drug concentrations. We present and...

    Christian M. Gill, Tomefa E. Asempa, David P. Nicolau
  • Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis
    Pharmacology
    Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis

    Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for...

    Ze-Ming Wang, Xiao-Yu Chen, Jing Bi, Mei-Ying Wang, Bao-Ping Xu, Bo-Hao Tang, Cen Li, Wei Zhao, A-Dong Shen
  • Sequential Time-Kill, a Simple Experimental Trick To Discriminate between Pharmacokinetics/Pharmacodynamics Models with Distinct Heterogeneous Subpopulations versus Homogenous Population with Adaptive Resistance
    Pharmacology
    Sequential Time-Kill, a Simple Experimental Trick To Discriminate between Pharmacokinetics/Pharmacodynamics Models with Distinct Heterogeneous Subpopulations versus Homogenous Population with Adaptive Resistance

    Experiments were conducted with polymyxin B and two Klebsiella pneumonia isogenic strains (the wild type, KP_WT, and its transconjugant carrying the mobile colistin resistance gene, KP_MCR-1) to demonstrate that conducting two consecutive time-kill experiments (sequential TK) represents a simple approach to discriminate between pharmacokinetics/pharmacodynamics models...

    A. Chauzy, H. Ih, M. Jacobs, S. Marchand, N. Grégoire, W. Couet, J. M. Buyck
  • Time above the MIC of Piperacillin-Tazobactam as a Predictor of Outcome in <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> Bacteremia
    Pharmacology
    Time above the MIC of Piperacillin-Tazobactam as a Predictor of Outcome in Pseudomonas aeruginosa Bacteremia

    Pseudomonas aeruginosa bacteremia is an infection associated with a high mortality rate. Piperacillin-tazobactam is a β-lactam–β-lactamase inhibitor combination that is frequently used for the management of Pseudomonas aeruginosa infections. The pharmacokinetic-pharmacodynamic index associated with...

    Elias Tannous, Shelly Lipman, Antonella Tonna, Emma Hector, Ziad Hussein, Michal Stein, Sharon Reisfeld

Letters to the Editor

  • Open Access
    Reduced Susceptibility to Carbapenems in a <span class="named-content genus-species" id="named-content-1">Klebsiella pneumoniae</span> Clinical Isolate Producing SCO-1 and CTX-M-15 β-Lactamases Together with OmpK35 and OmpK36 Porin Deficiency
    Letter to the Editor
    Reduced Susceptibility to Carbapenems in a Klebsiella pneumoniae Clinical Isolate Producing SCO-1 and CTX-M-15 β-Lactamases Together with OmpK35 and OmpK36 Porin Deficiency
    Carolina Venditti, Ornella Butera, Anna Proia, Luigi Rigacci, Bruno Mariani, Gabriella Parisi, Francesco Messina, Alessandro Capone, Carla Nisii, Antonino Di Caro
  • Emergence of Novel Mutations in Extensively Drug-Resistant <span class="named-content genus-species" id="named-content-1">Salmonella enterica</span> Serovar Typhi from Pakistan
    Letter to the Editor
    Emergence of Novel Mutations in Extensively Drug-Resistant Salmonella enterica Serovar Typhi from Pakistan
    Afreenish Amir, Aamer Ikram, Muhammad Salman
  • Accelerating Drug Development through Repurposed FDA-Approved Drugs for COVID-19: Speed Is Important, Not Haste
    Letter to the Editor
    Accelerating Drug Development through Repurposed FDA-Approved Drugs for COVID-19: Speed Is Important, Not Haste
    James T. Gordy, Kaushiki Mazumdar, Noton K. Dutta
  • Free
    The Good, the Bad, and the Hoax: When Publication Instantaneously Impacts Treatment Strategies for COVID-19
    Letter to the Editor
    The Good, the Bad, and the Hoax: When Publication Instantaneously Impacts Treatment Strategies for COVID-19
    François Danion, Yvon Ruch, Marion Fourtage, Charlotte Kaeuffer, Valentin Greigert, Nicolas Lefebvre, Joris Muller, Thierry Nai, Yves Hansmann

Author Correction

  • Free
    Correction for Klotz et al., “Inhibition of Adherence and Killing of <span class="named-content genus-species" id="named-content-1">Candida albicans</span> with a 23-Mer Peptide (Fn/23) with Dual Antifungal Properties”
    Author Correction
    Correction for Klotz et al., “Inhibition of Adherence and Killing of Candida albicans with a 23-Mer Peptide (Fn/23) with Dual Antifungal Properties”
    Stephen A. Klotz, Nand K. Gaur, Jason Rauceo, Douglas F. Lake, Y. Park, K. S. Hahm, Peter N. Lipke

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    Editorial Board
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Antimicrobial Agents and Chemotherapy: 64 (8)

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volume 64, issue 8
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  • Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling
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  • New Perspectives on Antimicrobial Agents: Remdesivir Treatment for COVID-19
  • Updated Approaches against SARS-CoV-2
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