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  • The Future of Antifungal Drug Therapy: Novel Compounds and Targets
    The Future of Antifungal Drug Therapy: Novel Compounds and Targets
  • Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia
    Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia
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Minireview

  • The Future of Antifungal Drug Therapy: Novel Compounds and Targets
    Minireview
    The Future of Antifungal Drug Therapy: Novel Compounds and Targets

    Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans.

    Caroline Mota Fernandes, Deveney Dasilva, Krupanandan Haranahalli, J. Brian McCarthy, John Mallamo, Iwao Ojima, Maurizio Del Poeta

Mechanisms of Action: Physiological Effects

  • Open Access
    Cefiderocol Retains Antibiofilm Activity in Multidrug-Resistant Gram-Negative Pathogens
    Mechanisms of Action: Physiological Effects
    Cefiderocol Retains Antibiofilm Activity in Multidrug-Resistant Gram-Negative Pathogens

    Cefiderocol is a siderophore cephalosporin with potent antibacterial activity against a broad range of Gram-negative pathogens, including multidrug-resistant strains. Siderophore antibiotics bind ferric iron and utilize iron transporters to cross the cell membrane.

    Christine A. Pybus, Christina Felder-Scott, Victor Obuekwe, David E. Greenberg
  • Efg1 and Cas5 Orchestrate Cell Wall Damage Response to Caspofungin in <span class="named-content genus-species" id="named-content-1">Candida albicans</span>
    Mechanisms of Action: Physiological Effects
    Efg1 and Cas5 Orchestrate Cell Wall Damage Response to Caspofungin in Candida albicans

    Echinocandins are recommended as the first-line drugs for the treatment of systemic candidiasis. Cas5 is a key transcription factor involved in the response to cell wall damage induced by echinocandins.

    Kang Xiong, Chang Su, Qiangqiang Sun, Yang Lu
  • Structural and Cellular Insights into the <span class="sc">l</span>,<span class="sc">d</span>-Transpeptidase YcbB as a Therapeutic Target in <span class="named-content genus-species" id="named-content-1">Citrobacter rodentium</span>, <em>Salmonella</em> Typhimurium, and <em>Salmonella</em> Typhi Infections
    Mechanisms of Action: Physiological Effects
    Structural and Cellular Insights into the l,d-Transpeptidase YcbB as a Therapeutic Target in Citrobacter rodentium, Salmonella Typhimurium, and Salmonella Typhi Infections

    The bacterial cell wall plays a key role in viability and is an important drug target. The cell wall is made of elongated polymers that are cross-linked to one another to form a load-bearing mesh. An alternative cell wall cross-linking mechanism used by the l,d-transpeptidase YcbB has been implicated in the stress-regulated roles of β-lactam resistance, outer membrane defect rescue, and...

    N. A. Caveney, A. Serapio-Palacios, S. E. Woodward, T. Bozorgmehr, G. Caballero, M. Vuckovic, W. Deng, B. B. Finlay, N. C. J. Strynadka

Mechanisms of Resistance

  • Open Access
    Atypical Mutation in <span class="named-content genus-species" id="named-content-1">Neisseria gonorrhoeae</span> 23S rRNA Associated with High-Level Azithromycin Resistance
    Mechanisms of Resistance
    Atypical Mutation in Neisseria gonorrhoeae 23S rRNA Associated with High-Level Azithromycin Resistance

    A2059G mutation in the 23S rRNA gene is the only reported mechanism conferring high-level azithromycin resistance (HL-AZMR) in Neisseria gonorrhoeae. Through U.S. gonococcal antimicrobial resistance surveillance projects, we identified four HL-AZMR gonococcal isolates lacking this mutational genotype. Genetic analysis revealed an A2058G mutation of 23S rRNA alleles in...

    Cau D. Pham, Evelyn Nash, Hsi Liu, Matthew W. Schmerer, Samera Sharpe, Grace Woods, Brad Roland, Karen Schlanger, Sancta B. St. Cyr, Jonathan Carlson, Kevin Sellers, Aaron Olsen, Ruth Sanon, Henrietta Hardin, Olusegun O. Soge, Brian H. Raphael, Ellen N. Kersh
    and on behalf of the AR Lab Network Workgroup for GC
  • A GC-Rich Prophage-Like Genomic Region of <span class="named-content genus-species" id="named-content-1">Mycoplasma bovirhinis</span> HAZ141_2 Carries a Gene Cluster Encoding Resistance to Kanamycin and Neomycin
    Mechanisms of Resistance
    A GC-Rich Prophage-Like Genomic Region of Mycoplasma bovirhinis HAZ141_2 Carries a Gene Cluster Encoding Resistance to Kanamycin and Neomycin

    Recently, a complete genome sequence of Mycoplasma bovirhinis HAZ141_2 was published showing the presence of a 54-kB prophage-like region. Bioinformatic analysis revealed that this region has a more than 40% GC content and a chimeric organization with three structural elements—a prophage continuous region, a restriction-modification cassette, and a highly...

    Inna Lysnyansky, Ilya Borovok
  • Mechanisms of Resistance to Ceftolozane/Tazobactam in <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span>: Results of the GERPA Multicenter Study
    Mechanisms of Resistance
    Mechanisms of Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa: Results of the GERPA Multicenter Study

    Resistance mechanisms of Pseudomonas aeruginosa to ceftolozane/tazobactam (C/T) were assessed on a collection of 420 nonredundant strains nonsusceptible to ceftazidime (MIC > 8 μg/ml) and/or imipenem (>4 μg/ml), collected by 36 French hospital laboratories over a one-month period (the GERPA study). Rates of C/T resistance (MIC > 4/4 μg/ml) were equal to 10%...

    Damien Fournier, Romain Carrière, Maxime Bour, Emilie Grisot, Pauline Triponney, Cédric Muller, Jérôme Lemoine, Katy Jeannot, Patrick Plésiat, the GERPA Study Group
  • Fungal Zn(II)<sub>2</sub>Cys<sub>6</sub> Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress
    Mechanisms of Resistance
    Fungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress

    Antifungal azoles are the most widely used antifungal drugs in clinical and agricultural practice. Fungi can mount adaptive responses to azole stress by modifying the transcript levels of many genes, and the responsive mechanisms to azoles are the basis for fungi to develop azole resistance.

    Yajing Yin, Hanxing Zhang, Yu Zhang, Chengcheng Hu, Xianyun Sun, Wei Liu, Shaojie Li
  • <em>fosM</em>, a New Family of Fosfomycin Resistance Genes Identified in Bacterial Species Isolated from Human Microbiota
    Mechanisms of Resistance
    fosM, a New Family of Fosfomycin Resistance Genes Identified in Bacterial Species Isolated from Human Microbiota

    Fosfomycin is a decades-old antibiotic, currently reused because of its activity against multidrug-resistant bacteria. Here, we used a combined in vitro/in silico approach to search for fosfomycin resistance determinants in 25 new bacterial species isolated from the human microbiota.

    Sami Khabthani, Mouna Hamel, Sophie Alexandra Baron, Seydina M. Diene, Jean-Marc Rolain, Vicky Merhej
  • Potential Mobilization of <em>mcr-10</em> by an Integrative Mobile Element via Site-Specific Recombination in <span class="named-content genus-species" id="named-content-1">Cronobacter sakazakii</span>
    Mechanisms of Resistance
    Potential Mobilization of mcr-10 by an Integrative Mobile Element via Site-Specific Recombination in Cronobacter sakazakii

    mcr-10 is a newly identified plasmid-borne colistin resistance gene, but its mobilization mechanism remains unclear. In this study, mcr-10 was found on an IncFIB plasmid carrying virulence genes mrkABCDFJ, iucABCD/iutA, and eitCBAD in a Cronobacter sakazakii isolate.

    Jing Yang, Lina Liu, Yu Feng, Da He, Chengcheng Wang, Zhiyong Zong
  • New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> upon <em>tolC</em> Inactivation and Differentiating Their Efflux Pump Substrate Nature
    Mechanisms of Resistance
    New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

    Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the...

    Sabine Schuster, Martina Vavra, Raphael Köser, John W. A. Rossen, Winfried V. Kern
  • <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span> Polynucleotide Phosphorylase Controls Tolerance to Aminoglycoside Antibiotics by Regulating the MexXY Multidrug Efflux Pump
    Mechanisms of Resistance
    Pseudomonas aeruginosa Polynucleotide Phosphorylase Controls Tolerance to Aminoglycoside Antibiotics by Regulating the MexXY Multidrug Efflux Pump

    Pseudomonas aeruginosa is an opportunistic pathogen that shows high intrinsic resistance to a variety of antibiotics. The MexX-MexY-OprM efflux pump plays an important role in bacterial resistance to aminoglycoside antibiotics.

    Zheng Fan, Xiaolei Pan, Dan Wang, Ronghao Chen, Tongtong Fu, Baopeng Yang, Yongxin Jin, Fang Bai, Zhihui Cheng, Weihui Wu
  • Open Access
    Structural Investigations of the Inhibition of <span class="named-content genus-species" id="named-content-1">Escherichia coli</span> AmpC β-Lactamase by Diazabicyclooctanes
    Mechanisms of Resistance
    Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes

    β-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli, but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with...

    Pauline A. Lang, Thomas M. Leissing, Malcolm G. P. Page, Christopher J. Schofield, Jürgen Brem

Susceptibility

  • <span class="named-content genus-species" id="named-content-1">Burkholderia pseudomallei</span> Clinical Isolates Are Highly Susceptible <em>In Vitro</em> to Cefiderocol, a Siderophore Cephalosporin
    Susceptibility
    Burkholderia pseudomallei Clinical Isolates Are Highly Susceptible In Vitro to Cefiderocol, a Siderophore Cephalosporin

    Cefiderocol is a cephalosporin designed to treat multidrug-resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative...

    Delaney Burnard, Gemma Robertson, Andrew Henderson, Caitlin Falconer, Michelle J. Bauer, Kyra Cottrell, Ian Gassiep, Robert Norton, David L. Paterson, Patrick N. A. Harris
  • Emergence of Resistance in <em>Klebsiella aerogenes</em> to Piperacillin-Tazobactam and Ceftriaxone
    Susceptibility
    Emergence of Resistance in Klebsiella aerogenes to Piperacillin-Tazobactam and Ceftriaxone

    We examined the effects of piperacillin-tazobactam (TZP) concentration and bacterial inoculum on in vitro killing and the emergence of resistance in Klebsiella aerogenes. The MICs for 15 clinical respiratory isolates were determined by broth microdilution for TZP and by Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistance in TZP-...

    Marco M. Custodio, Daniel Sanchez, Beverly Anderson, Keenan L. Ryan, Carla Walraven, Renee-Claude Mercier
  • Rifampin, Rifapentine, and Rifabutin Are Active against Intracellular Periprosthetic Joint Infection-Associated <span class="named-content genus-species" id="named-content-1">Staphylococcus epidermidis</span>
    Susceptibility
    Rifampin, Rifapentine, and Rifabutin Are Active against Intracellular Periprosthetic Joint Infection-Associated Staphylococcus epidermidis

    Staphylococcus epidermidis is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant...

    Cody Fisher, Robin Patel

Antiviral Agents

  • Broad-Spectrum Antiviral Activity of 3′-Deoxy-3′-Fluoroadenosine against Emerging Flaviviruses
    Antiviral Agents
    Broad-Spectrum Antiviral Activity of 3′-Deoxy-3′-Fluoroadenosine against Emerging Flaviviruses

    Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties.

    Luděk Eyer, Pavel Svoboda, Jan Balvan, Tomáš Vičar, Matina Raudenská, Michal Štefánik, Jan Haviernik, Ivana Huvarová, Petra Straková, Ivo Rudolf, Zdeněk Hubálek, Katherine Seley-Radtke, Erik de Clercq, Daniel Růžek
  • Open Access
    Off-Target <em>In Vitro</em> Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent
    Antiviral Agents
    Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent

    Remdesivir (RDV, GS-5734), the first FDA-approved antiviral for the treatment of COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. It is intracellularly metabolized into the active triphosphate form, which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases.

    Yili Xu, Ona Barauskas, Cynthia Kim, Darius Babusis, Eisuke Murakami, Dmytro Kornyeyev, Gary Lee, George Stepan, Michel Perron, Roy Bannister, Brian E. Schultz, Roman Sakowicz, Danielle Porter, Tomas Cihlar, Joy Y. Feng
  • Free
    A Valid Warning or Clinical Lore: an Evaluation of Safety Outcomes of Remdesivir in Patients with Impaired Renal Function from a Multicenter Matched Cohort
    Antiviral Agents
    A Valid Warning or Clinical Lore: an Evaluation of Safety Outcomes of Remdesivir in Patients with Impaired Renal Function from a Multicenter Matched Cohort

    Per prescribing guidance, remdesivir is not recommended for SARS-CoV-2 in patients with renal disease given the absence of safety data in this patient population. This study was a multicenter, retrospective chart review of hospitalized patients with SARS-CoV-2 who received remdesivir.

    Tyler W. Ackley, Dayna McManus, Jeffrey E. Topal, Brian Cicali, Sunish Shah

Epidemiology and Surveillance

  • ICEHpsaHPS7, a Novel Multiple Drug Resistance Integrative Conjugative Element in <em>Glaesserella parasuis</em>
    Epidemiology and Surveillance
    ICEHpsaHPS7, a Novel Multiple Drug Resistance Integrative Conjugative Element in Glaesserella parasuis

    Integrative conjugative elements (ICEs) are a kind of novel self-transmissible mobile genetic element. In this study, a novel ICE was identified in Glaesserella (Haemophilus) parasuis.

    Jiahui An, Genglin Guo, Dong Yu, Kexin Zhu, Chao Zhang, Yufeng Li
  • Open Access
    Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019
    Epidemiology and Surveillance
    Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019

    Biennial therapeutic efficacy monitoring is a crucial activity for ensuring the efficacy of currently used artemisinin-based combination therapy in Angola. Children with acute uncomplicated Plasmodium falciparum infection in sentinel sites in the Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate-amodiaquine (ASAQ)...

    Pedro Rafael Dimbu, Roberta Horth, Ana Luísa M. Cândido, Carolina Miguel Ferreira, Felismina Caquece, Luzala Elisabeth Armando Garcia, Kialanda André, Garcia Pembele, Domingos Jandondo, Belmira José Bondo, Benjamin Nieto Andrade, Sarah Labuda, Gabriel Ponce de León, Julia Kelley, Dhruviben Patel, Samaly S. Svigel, Eldin Talundzic, Naomi Lucchi, Joana F. M. Morais, Filomeno Fortes, José Franco Martins, Mateusz M. Pluciński
  • Characterization of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump in <em>Klebsiella pneumoniae</em> and <em>Klebsiella quasipneumoniae</em> from Patients in China
    Epidemiology and Surveillance
    Characterization of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump in Klebsiella pneumoniae and Klebsiella quasipneumoniae from Patients in China

    Two multidrug-resistant (MDR) mcr-1-harboring Klebsiella pneumoniae isolates from patients with urinary tract infections and one MDR Klebsiella quasipneumoniae isolate from a patient with bloodstream infection were identified to carry tmexCD1-toprJ1. The addition of the efflux pump...

    Ruowen He, Yongqiang Yang, Yiping Wu, Lan-Lan Zhong, Yanxian Yang, Guanping Chen, Mingyang Qin, Xiaoxue Liang, Mohamed Abd El-Gawad El-Sayed Ahmed, Minmin Lin, Bin Yan, Yong Xia, Min Dai, Hongtao Chen, Guo-Bao Tian

Experimental Therapeutics

  • Open Access
    Sodium Tetraphenylborate Displays Selective Bactericidal Activity against <span class="named-content genus-species" id="named-content-1">Neisseria meningitidis</span> and <span class="named-content genus-species" id="named-content-2">N. gonorrhoeae</span> and Is Effective at Reducing Bacterial Infection Load
    Experimental Therapeutics
    Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

    Neisseria meningitidis and Neisseria gonorrhoeae, two highly related species that might have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection,...

    Eve Bernet, Marthe Lebughe, Antony T. Vincent, Mohammad Mehdi Haghdoost, Golara Golbaghi, Steven Laplante, Annie Castonguay, Frederic J. Veyrier
  • Pharmacokinetics of Benznidazole in Experimental Chronic Chagas Disease Using the Swiss Mouse–Berenice-78 <span class="named-content genus-species" id="named-content-1">Trypanosoma cruzi</span> Strain Model
    Experimental Therapeutics
    Pharmacokinetics of Benznidazole in Experimental Chronic Chagas Disease Using the Swiss Mouse–Berenice-78 Trypanosoma cruzi Strain Model

    Chronic Chagas disease might have an impact on benznidazole pharmacokinetics with potential alterations in the therapeutic dosing regimen. This study aims to investigate the influence of chronic Trypanosoma cruzi infection on the pharmacokinetics and biodistribution of benznidazole in mice.

    Suzana Marques de Jesus, Leonardo Pinto, Fernanda de Lima Moreira, Glauco Henrique Balthazar Nardotto, Rodrigo Cristofoletti, Luísa Perin, Kátia da Silva Fonseca, Pauliana Barbêdo, Lorena Cera Bandeira, Paula Melo de Abreu Vieira, Claudia Martins Carneiro
  • Discovery of Amoebicidal Compounds by Combining Computational and Experimental Approaches
    Experimental Therapeutics
    Discovery of Amoebicidal Compounds by Combining Computational and Experimental Approaches

    Pathogenic and opportunistic free-living amoebae such as Acanthamoeba spp. can cause keratitis (Acanthamoeba keratitis [AK]), which may ultimately lead to permanent visual impairment or blindness. Acanthamoeba can also cause rare but usually fatal granulomatous amoebic encephalitis (GAE). Current therapeutic options for AK require a lengthy treatment with nonspecific drugs that are often associated with...

    Víctor Sebastián-Pérez, Ines Sifaoui, María Reyes-Batlle, Angélica Domínguez-De Barros, Atteneri López-Arencibia, Nuria E. Campillo, José E. Piñero, Jacob Lorenzo-Morales, Carmen Gil
  • The Antifungal and Synergistic Effect of Bisphosphonates in <em>Cryptococcus</em>
    Experimental Therapeutics
    The Antifungal and Synergistic Effect of Bisphosphonates in Cryptococcus

    New treatment strategies are required for cryptococcosis, a leading mycosis in HIV-AIDS patients. Following the identification of Cryptococcus proteins differentially expressed in response to fluconazole, we targeted farnesyl pryrophosphate synthetase (FPPS), an enzyme in the squalene biosynthesis pathway, using nitrogenous bisphosphonates. We hypothesized that these would disrupt squalene synthesis and thereby produce synergy...

    Aidan Kane, Leona Campbell, Diana Ky, David Hibbs, Dee Carter
  • Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia
    Experimental Therapeutics
    Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia

    The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in...

    Ana Motos, Gianluigi Li Bassi, Francesco Pagliara, Laia Fernandez-Barat, Hua Yang, Eli Aguilera Xiol, Tarek Senussi, Francesco A. Idone, Chiara Travierso, Chiara Chiurazzi, Rosanel Amaro, Minlan Yang, Joaquim Bobi, Montserrat Rigol, David P. Nicolau, Gerard Frigola, Roberto Cabrera, Jose Ramirez, Paolo Pelosi, Francesco Blasi, Massimo Antonelli, Antonio Artigas, Jordi Vila, Marin Kollef, Antoni Torres
  • Differential <em>In Vitro</em> Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span>
    Experimental Therapeutics
    Differential In Vitro Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessus

    Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net nonreplicating...

    Jin Lee, Nicole Ammerman, Anusha Agarwal, Maram Naji, Si-Yang Li, Eric Nuermberger

Clinical Therapeutics

  • Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections
    Clinical Therapeutics
    Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections

    In the treatment of hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine’s metabolites in adolescents receiving tribendimidine monotherapy or in combination with ivermectin or...

    Janneke M. Brussee, Anna Neodo, Jessica D. Schulz, Jean T. Coulibaly, Marc Pfister, Jennifer Keiser
  • Liquid Chromatography Mass Spectrometry Detection of Antibiotic Agents in Sputum from Persons with Cystic Fibrosis
    Clinical Therapeutics
    Liquid Chromatography Mass Spectrometry Detection of Antibiotic Agents in Sputum from Persons with Cystic Fibrosis

    Antibiotic therapy is expected to impact host microbial communities considerably, yet many studies focused on microbiome and health are often confounded by limited information about antibiotic exposure. Given that antibiotics have diverse pharmacokinetic and antimicrobial properties, investigating the type and concentration of these agents in specific host specimens would provide much needed insight into their impact on the microbes...

    Tara Gallagher, Stefan Riedel, Joseph Kapcia, Lindsay J. Caverly, Lisa Carmody, Linda M. Kalikin, Junnan Lu, Joann Phan, Matthew Gargus, Miki Kagawa, Simon W. Leemans, Jason A. Rothman, Felix Grun, John J. LiPuma, Katrine L. Whiteson
  • Adverse Events Associated with Nifurtimox Treatment for Chagas Disease in Children and Adults
    Clinical Therapeutics
    Adverse Events Associated with Nifurtimox Treatment for Chagas Disease in Children and Adults

    Nifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, data on NF safety are scarce, and many physicians defer or refuse NF treatment because of concerns about drug tolerance.

    A. J. Berenstein, N. Falk, G. Moscatelli, S. Moroni, N. González, F. Garcia-Bournissen, G. Ballering, H. Freilij, J. Altcheh
  • Open Access
    Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage <span class="named-content genus-species" id="named-content-1">Plasmodium falciparum</span>
    Clinical Therapeutics
    Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum

    The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum.

    James S. McCarthy, Azrin N. Abd-Rahman, Katharine A. Collins, Louise Marquart, Paul Griffin, Anne Kümmel, Aline Fuchs, Cornelis Winnips, Vishal Mishra, Katalin Csermak-Renner, J. Prakash Jain, Preetam Gandhi
  • Validation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical Center
    Clinical Therapeutics
    Validation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical Center

    The 2019 American Thoracic Society and the Infectious Diseases Society of America community-acquired pneumonia (CAP) guidelines recommend that drug-resistant pathogens (DRP) be empirically covered if locally validated risk factors are present. This retrospective case-control validation study evaluated the performance of the drug resistance in pneumonia (DRIP) clinical prediction score.

    Meredith B. Oliver, Karen Fong, Laura Certain, Emily S. Spivak, Tristan T. Timbrook
  • Effects of Antibiotic Treatment with Piperacillin/Tazobactam versus Ceftriaxone on the Composition of the Murine Gut Microbiota
    Clinical Therapeutics
    Effects of Antibiotic Treatment with Piperacillin/Tazobactam versus Ceftriaxone on the Composition of the Murine Gut Microbiota

    Effective antimicrobial stewardship requires a better understanding of the impact of different antibiotics on the gut microflora. Studies with humans are confounded by large interindividual variability and difficulty in identifying control cohorts.

    Carola Venturini, Bethany Bowring, Alicia Fajardo-Lubian, Carol Devine, Jonathan Iredell
  • Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy
    Clinical Therapeutics
    Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy

    Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of...

    Silke Gastine, William Hope, Georg Hempel, Ruta Petraitiene, Vidmantas Petraitis, Diana Mickiene, John Bacher, Thomas J. Walsh, Andreas H. Groll
  • Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections
    Clinical Therapeutics
    Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections

    Linezolid standard dosing is fixed at 600 mg every 12 h (q12h) for adults. Literature suggests critically ill, obese patients require higher doses.

    Alison L. Blackman, Praneeth Jarugula, David P. Nicolau, Sai Ho Chui, Manjari Joshi, Emily L. Heil, Mathangi Gopalakrishnan
  • Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection
    Clinical Therapeutics
    Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection

    Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine’s primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii)...

    Janneke M. Brussee, Noemi Hiroshige, Anna Neodo, Jean T. Coulibaly, Marc Pfister, Jennifer Keiser
  • Comparing the Population Pharmacokinetics of and Acute Kidney Injury Due to Polymyxin B in Chinese Patients with or without Renal Insufficiency
    Clinical Therapeutics
    Comparing the Population Pharmacokinetics of and Acute Kidney Injury Due to Polymyxin B in Chinese Patients with or without Renal Insufficiency

    Despite excellent bactericidal effect, dosing adjustment of polymyxin B for patients with renal insufficiency and polymyxin B-related nephrotoxicity is still a major concern to clinicians. The aim of this study was to compare the population pharmacokinetics (PK) properties of polymyxin B in Chinese patients with different renal functions and to investigate the relationship between PK parameters and polymyxin B-related acute kidney...

    Peile Wang, Qiwen Zhang, Zhenfeng Zhu, Hui Pei, Min Feng, Tongwen Sun, Jing Yang, Xiaojian Zhang
  • Prospective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation
    Clinical Therapeutics
    Prospective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation

    The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment (TA) in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000-mg dose of vancomycin, samples were collected 9 times per patient prospectively.

    Younghee Jung, Dong-Hwan Lee, Hyoung Soo Kim

Pharmacology

  • Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis
    Pharmacology
    Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis

    Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid.

    Elisa H. Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Lubbe Wiesner, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti
    and on behalf of the Assessing Pretomanid for Tuberculosis Study Team
  • Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Pediatric Patients
    Pharmacology
    Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Pediatric Patients

    This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM.

    Jumpei Saito, Kensuke Shoji, Yusuke Oho, Hiroki Kato, Shotaro Matsumoto, Satoshi Aoki, Hidefumi Nakamura, Takanori Ogawa, Mayumi Hasegawa, Akimasa Yamatani, Isao Miyairi
  • Open Access
    <em>In Vivo</em> Efficacy and Metabolism of the Antimalarial Cycleanine and Improved <em>In Vitro</em> Antiplasmodial Activity of Semisynthetic Analogues
    Pharmacology
    In Vivo Efficacy and Metabolism of the Antimalarial Cycleanine and Improved In Vitro Antiplasmodial Activity of Semisynthetic Analogues

    Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine [compound 1], isochondodendrine [compound 2], and 2′-norcocsuline [compound 3]) isolated from the Triclisia subcordata Oliv. medicinal plant...

    Fidelia Ijeoma Uche, Xiaozhen Guo, Jude Okokon, Imran Ullah, Paul Horrocks, Joshua Boateng, Chenggang Huang, Wen-Wu Li
  • The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens
    Pharmacology
    The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens

    The Mycobacterium tuberculosis drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged.

    G. L. Drusano, Sarah Kim, Mohammed Almoslem, Stephan Schmidt, D. Z. D’Argenio, Jenny Myrick, Brandon Duncanson, Jocelyn Nole, David Brown, C. A. Peloquin, Michael Neely, Walter Yamada, Arnold Louie

Letters to the Editor

  • Whole-Genome and Targeted-Amplicon Sequencing of Fluconazole-Susceptible and -Resistant <span class="named-content genus-species" id="named-content-1">Candida parapsilosis</span> Isolates from Kuwait Reveals a Previously Undescribed N1132D Polymorphism in <em>CDR1</em>
    Letter to the Editor
    Whole-Genome and Targeted-Amplicon Sequencing of Fluconazole-Susceptible and -Resistant Candida parapsilosis Isolates from Kuwait Reveals a Previously Undescribed N1132D Polymorphism in CDR1
    Mohammad Asadzadeh, Mohammed Dashti, Suhail Ahmad, Wadha Alfouzan, Abbas Alameer
  • Might Confounding Factors Have an Effect on Suboptimal Dosing of Fluconazole in Critically Ill Patients?
    Letter to the Editor
    Might Confounding Factors Have an Effect on Suboptimal Dosing of Fluconazole in Critically Ill Patients?
    Emre Kara, Aygin Bayraktar Ekincioglu, Gokhan Metan
  • Reply to Kara et al., “Might Confounding Factors Have an Effect on Suboptimal Dosing of Fluconazole in Critically Ill Patients?”
    Letter to the Editor
    Reply to Kara et al., “Might Confounding Factors Have an Effect on Suboptimal Dosing of Fluconazole in Critically Ill Patients?”
    E. W. Muilwijk, R. J. M. Brüggemann
  • The Ongoing Challenge with NDM-Harboring <em>Enterobacteriaceae</em> in Murine Infection Models
    Letter to the Editor
    The Ongoing Challenge with NDM-Harboring Enterobacteriaceae in Murine Infection Models
    Tomefa E. Asempa, Kamilia Abdelraouf, David P. Nicolau
  • Reply to Asempa et al., “The Ongoing Challenge with NDM-Harboring <em>Enterobacteriaceae</em> in Murine Infection Models”
    Letter to the Editor
    Reply to Asempa et al., “The Ongoing Challenge with NDM-Harboring Enterobacteriaceae in Murine Infection Models”
    Shampa Das, Martin Everett, Magdalena Zalacain, William Hope

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