Table of Contents
Perspective
Editor's Pick PerspectiveNew Perspectives on Antimicrobial Agents: Remdesivir Treatment for COVID-19Remdesivir was recently approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Remdesivir is the prodrug of an adenosine analogue that inhibits viral replication of several RNA virus families, including Coronaviridae. Preclinical data in animal models of coronavirus diseases, including COVID-19, have demonstrated that early treatment with remdesivir...
Meeting Review
Editor's Pick Meeting ReviewFDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug DevelopmentThe U.S. Food and Drug Administration (FDA) hosted a public workshop entitled “Advancing Animal Models for Antibacterial Drug Development” on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii. The program included...
Challenging Clinical Case in Antimicrobial Resistance
Editor's Pick Challenging Clinical Case in Antimicrobial ResistanceImipenem plus Fosfomycin as Salvage Therapy for Vertebral OsteomyelitisWe applied combination antibiotic therapy to treat vertebral osteomyelitis and a psoas abscess caused by glycopeptide-intermediate (MIC, 2 μg/ml) and daptomycin-nonsusceptible (>2 μg/ml) methicillin-resistant Staphylococcus aureus. The Etest synergy test showed the largest synergistic effects for imipenem/cilastatin and fosfomycin. Whole-gene sequencing showed...
Editor's Pick Challenging Clinical Case in Antimicrobial ResistanceCase Commentary: Imipenem/Cilastatin and Fosfomycin for Refractory Methicillin-Resistant Staphylococcus aureus Infection: a Novel Combination TherapyGiven that it is unlikely that randomized clinical trials will yield answers for treating the most challenging bacteremic infections caused by methicillin-resistant Staphylococcus aureus, clinicians, microbiologists, and pharmacists will have to cooperate to discover novel ways to select successful individualized antimicrobial therapy for these patients. An example of...
Chemistry; Biosynthesis
Chemistry; BiosynthesisNew Amides Containing Selenium as Potent Leishmanicidal Agents Targeting Trypanothione ReductaseTwo new series of 28 selenocyanate and diselenide derivatives containing amide moieties were designed, synthesized, and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the...
Chemistry; BiosynthesisRegioisomerization of Antimalarial Drug WR99210 Explains the Inactivity of a Commercial StockWR99210, a former antimalarial drug candidate now widely used for the selection of Plasmodium transfectants, selectively targets the parasite’s dihydrofolate reductase thymidine synthase bifunctional enzyme (DHFR-TS) but not human DHFR, which is not fused with TS. Accordingly, WR99210 and plasmids expressing the human dhfr gene have become valued tools for the genetic modification of parasites in the laboratory....
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsInhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and SurvivalOne of the major barriers in the prevention and control of malaria programs worldwide is the growing emergence of multidrug resistance in Plasmodium parasites, and this necessitates continued efforts to discover and develop effective drug molecules targeting novel proteins essential for parasite survival. In recent years, epigenetic regulators have evolved as an attractive drug target option owing to their crucial role in...
Mechanisms of Action: Physiological EffectsComparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action ElucidationNew antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of...
Mechanisms of Action: Physiological EffectsLack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II SystemPhenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance...
Mechanisms of Resistance
Mechanisms of ResistanceERG11 Polymorphism in Voriconazole-Resistant Candida tropicalis: Weak Role of ERG11 Expression, Ergosterol Content, and Membrane PermeabilityMutations in ERG11 were detected by gene sequencing and amino acid alignment in 18 Candida tropicalis strains with different degrees of sensitivity to voriconazole (VRC). ERG11 expression, sterol content, and membrane permeability were also evaluated. We report three missense mutations in ERG11 that resulted in resistance to VRC. The...
Mechanisms of ResistanceAcetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosisIsoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis. The activated drug hinders cell wall biosynthesis by inhibiting the InhA protein. INH-resistant strains of M. tuberculosis...
Mechanisms of ResistanceIdentification and Characterization of a Novel FosA7 Member from Fosfomycin-Resistant Escherichia coli Clinical Isolates from Canadian HospitalsHere, we characterize the fosA genes from three Escherichia coli clinical isolates recovered from Canadian patients. Each fosA sequence was individually overexpressed in E. coli BW25113, and antimicrobial susceptibility testing was performed to assess their role in fosfomycin...
Mechanisms of ResistanceTransmission of Artemisinin-Resistant Malaria Parasites to Mosquitoes under Antimalarial Drug PressureResistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. While resistance manifests as delayed parasite clearance in patients, the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual...
Mechanisms of ResistanceDe Novo Resistance to Arg10-Teixobactin Occurs Slowly and Is CostlyBacterial pathogens are rapidly evolving resistance to all clinically available antibiotics. One part of the solution to this complex issue is to better understand the resistance mechanisms to new and existing antibiotics. Here, we focus on two antibiotics. Teixobactin is a recently discovered promising antibiotic that is claimed to “kill pathogens without detectable resistance” (L. L. Ling, T. Schneider, A. J. Peoples, A. L. Spoering,...
Mechanisms of ResistanceExpression of the MexXY Aminoglycoside Efflux Pump and Presence of an Aminoglycoside-Modifying Enzyme in Clinical Pseudomonas aeruginosa Isolates Are Highly CorrelatedThe impact of MexXY efflux pump expression on aminoglycoside resistance in clinical Pseudomonas aeruginosa isolates has been debated. In this study, we found that, in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in...
Editor's Pick Mechanisms of ResistanceSystematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human PathogensAs drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism’s collateral response to a wide variety of antibiotics. The results of these studies have...
Mechanisms of ResistanceNovel Mechanisms of Efflux-Mediated Levofloxacin Resistance and Reduced Amikacin Susceptibility in Stenotrophomonas maltophiliaFluoroquinolone resistance in Stenotrophomonas maltophilia is multifactorial, but the most significant factor is overproduction of efflux pumps, particularly SmeDEF, following mutation. Here, we report that mutations in the glycosyl transferase gene smlt0622 in S. maltophilia K279a mutant K...
Mechanisms of ResistanceKPC-53, a KPC-3 Variant of Clinical Origin Associated with Reduced Susceptibility to Ceftazidime-AvibactamThis study reports on the characterization of a Klebsiella pneumoniae clinical isolate showing high-level resistance to ceftazidime-avibactam associated with the production of KPC-53, a KPC-3 variant exhibiting a Leu167Glu168 duplication in the Ω-loop and a loss of carbapenemase activity. Whole-genome sequencing (WGS) revealed the presence of two copies of bla...
Mechanisms of ResistanceExperimental Evolution Identifies Adaptive Aneuploidy as a Mechanism of Fluconazole Resistance in Candida aurisCandida auris is a newly emerging fungal pathogen of humans and has attracted considerable attention from both the clinical and basic research communities. Clinical isolates of C. auris are often resistant to one or more antifungal agents. To explore how antifungal resistance develops, we performed...
Mechanisms of ResistanceEmergence of a Novel tet(L) Variant in Campylobacter spp. of Chicken Origin in ChinaTetracyclines are widely used in veterinary medicine and food animal production. Campylobacter members are major foodborne pathogens, and their resistance to tetracycline has been widely reported in different countries. To date, Tet(O), a ribosomal protection protein, is the only confirmed Tet resistance determinant in Campylobacter spp. Here, we reported the detection and characterization of a novel Tet resistance...
Mechanisms of ResistanceMolecular Evaluation of Fluoroquinolone Resistance in Serial Mycobacterium tuberculosis Isolates from Individuals Diagnosed with Multidrug-Resistant TuberculosisFluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Differing levels of resistance are associated with specific mutations within the quinolone-resistance-determining region (QRDR) of gyrA. We sequenced the QRDR from serial isolates of MDR TB patients in the...
Mechanisms of ResistanceSecretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensisLugdunin is the first reported nonribosomally synthesized antibiotic from human microbiomes. Its production by the commensal Staphylococcus lugdunensis eliminates the pathogen Staphylococcus aureus from human nasal microbiomes. The cycloheptapeptide lugdunin is the founding member of the new class...
Editor's Pick Mechanisms of ResistanceMutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosisThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant...
Mechanisms of ResistanceEvolution of Colistin Resistance in the Klebsiella pneumoniae Complex Follows Multiple Evolutionary Trajectories with Variable Effects on Fitness and Virulence CharacteristicsThe increasing prevalence of multidrug-resistant Klebsiella pneumoniae has led to a resurgence in the use of colistin as a last-resort drug. Colistin is a cationic antibiotic that selectively acts on Gram-negative bacteria through electrostatic interactions with anionic phosphate groups of the lipid A moiety of lipopolysaccharides (LPSs). Colistin resistance in...
Susceptibility
SusceptibilityTolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate AssayMonitoring of Plasmodium falciparum sensitivity to antimalarial drugs in Africa is vital for malaria elimination. However, the commonly used ex vivo/in vitro 50% inhibitory concentration (IC50) test gives inconsistent results for several antimalarials, while the alternative ring-stage survival assay (RSA) for artemisinin derivatives has...
SusceptibilityIn Vitro Activity Analysis of a New Polymyxin, SPR741, Tested in Combination with Antimicrobial Agents against a Challenge Set of Enterobacteriaceae, Including Molecularly Characterized StrainsThe activities of azithromycin, fusidic acid, vancomycin, doxycycline, and minocycline were evaluated alone and in combination with SPR741. A total of 202 Escherichia coli and 221 Klebsiella pneumoniae isolates were selected, and they included a genome-sequenced subset (n = 267), which was...
SusceptibilityOlorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum ActivityOlorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus. Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates...
SusceptibilityAzole and Amphotericin B MIC Values against Aspergillus fumigatus: High Agreement between Spectrophotometric and Visual Readings Using the EUCAST EDef 9.3.2 ProcedureThe EUCAST EDef 9.3.2 procedure recommends visual readings of azole and amphotericin B MICs against Aspergillus spp. Visual determination of MICs may be challenging. In this work, we aim to obtain and compare visual and spectrophotometric MIC readings of azoles and amphotericin B against Aspergillus fumigatus sensu lato isolates. A total of 847...
SusceptibilityIn Vitro Activity of Cefepime-Zidebactam, Ceftazidime-Avibactam, and Other Comparators against Clinical Isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii: Results from China Antimicrobial Surveillance Network (CHINET) in 2018This study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228),...
Analytical Procedures
Analytical ProceduresPrediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical EquationThe pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were...
Antiviral Agents
Antiviral AgentsThe Dihydroquinolizinone Compound RG7834 Inhibits the Polyadenylase Function of PAPD5 and PAPD7 and Accelerates the Degradation of Matured Hepatitis B Virus Surface Protein mRNAHepatitis B virus (HBV) mRNA metabolism is dependent upon host proteins PAPD5 and PAPD7 (PAPD5/7). PAPD5/7 are cellular, noncanonical, poly(A) polymerases (PAPs) whose main function is to oligoadenylate the 3′ end of noncoding RNA (ncRNA) for exosome degradation. HBV seems to exploit these two ncRNA quality-control factors for viral mRNA stabilization, rather than degradation. RG7834 is a small-molecule compound that binds PAPD5/7 and...
Antiviral AgentsEffect of a Neuropilin-1-Derived Virus Receptor Trap on Enterovirus A71 Infection In VitroWe discovered that neuropilin 1 (NRP1) is a new receptor candidate to mediate enterovirus A71 (EVA71) into cells. In the engineered form as a decoy receptor, NRP1 was able to recognize and neutralize EVA71 but not enterovirus D68 or coxsackievirus B3 (CVB3). NRP1 recognizes EVA71 through a novel domain on the VP3 capsid protein. The principle in the design, engineering, and refinement of the NRP1-based decoy receptor described in this...
Antiviral AgentsPharmacological Characterization of TP0591816, a Novel Macrocyclic Respiratory Syncytial Virus Fusion Inhibitor with Antiviral Activity against F Protein MutantsHuman respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early childhood. However, no vaccines have yet been approved for prevention of RSV infection, and the treatment options are limited. Therefore, development of effective and safe anti-RSV drugs is needed. In this study, we evaluated the antiviral activity and mechanism of action of a novel macrocyclic anti-RSV compound, TP0591816. TP0591816...
Antiviral AgentsDevelopment of a Simple In Vitro Assay To Identify and Evaluate Nucleotide Analogs against SARS-CoV-2 RNA-Dependent RNA PolymeraseNucleotide analogs targeting viral RNA polymerase have been proved to be an effective strategy for antiviral treatment and are promising antiviral drugs to combat the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In this study, we developed a robust in vitro nonradioactive primer extension assay to quantitatively evaluate the efficiency of incorporation of nucleotide analogs by SARS-CoV-2 RNA-...
Antiviral AgentsInvestigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during PregnancyCongenital cytomegalovirus (HCMV) infection may cause significant fetal malformation, lifelong disease, and, in severe cases, fetal or neonatal death. Placental infection with HCMV is the major mechanism of mother-to-child transmission (MTCT) and fetal injury. Thus, any pharmaceutical antiviral interference to reduce viral load may reduce placental damage, MTCT, and fetal disease. However, there is currently no licensed HCMV antiviral...
Antiviral AgentsRepurposing Nucleoside Analogs for Human CoronavirusesCoronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated...
Antiviral AgentsIn Vitro Exposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression ProfilesThe use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine...
Antiviral AgentsEpigenetic Compound Screening Uncovers Small Molecules for Reactivation of Latent HIV-1During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established that circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically indistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of...
Antiviral AgentsLow Tenofovir Plasma Exposure in HIV Oral Pre-exposure Prophylaxis Recipients with Gastrointestinal DisordersFour pre-exposure prophylaxis (PrEP) users with gastrointestinal disorders (sleeve gastrectomy, terminal ileitis, celiac disease, or chronic diarrhea) and receiving oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) were included. Despite self-reported high adherence, trough plasma tenofovir concentrations (after supervised intake) were significantly lower in these patients than in PrEP recipients without gastrointestinal...
Epidemiology and Surveillance
Epidemiology and SurveillanceCarbapenemase-Producing Gram-Negative Bacteria from American Crows in the United StatesWild corvids were examined for the presence of carbapenemase-producing Gram-negative bacteria in the United States. A total of 13 isolates were detected among 590 fecal samples of American crow; 11 Providencia rettgeri isolates harboring blaIMP-27 on the chromosome as a class 2 integron gene cassette within the Tn7 transposon, 1...
Epidemiology and SurveillanceEscherichia coli Sequence Type 457 Is an Emerging Extended-Spectrum-β-Lactam-Resistant Lineage with Reservoirs in Wildlife and Food-Producing AnimalsSilver gulls carry phylogenetically diverse Escherichia coli, including globally dominant extraintestinal pathogenic E. coli (ExPEC) sequence types and pandemic ExPEC-ST131 clades; however, our large-scale study (504 samples) on silver gulls nesting off the coast of New South Wales identified...
Epidemiology and SurveillanceHeterogeneity and Diversity of mcr-8 Genetic Context in Chicken-Associated Klebsiella pneumoniaeIncreasing mobile colistin resistance, mediated by the mcr gene family, in Enterobacteriaceae has become a global concern. Among the 10 reported mcr genes, mcr-8 was first identified in Klebsiella pneumoniae, which could cause severe infections with high mortality. Information about the prevalence and genetic context of mcr-8...
Experimental Therapeutics
Experimental TherapeuticsPotent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida aurisThe limited therapeutic options and the recent emergence of multidrug-resistant Candida species present a significant challenge to human medicine and underscore the need for novel therapeutic approaches. Drug repurposing appears as a promising tool to augment the activity of current azole antifungals, especially against multidrug-resistant Candida auris. In...
Experimental TherapeuticsEfficacy of Telavancin in Comparison to Linezolid in a Porcine Model of Severe Methicillin-Resistant Staphylococcus aureus PneumoniaCurrent guidelines recommend vancomycin and linezolid as first-line agents against methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Telavancin is a potential new therapeutic alternative, specifically in monomicrobial MRSA pneumonia. This study compared the efficacies of telavancin versus linezolid in a porcine model of severe MRSA pneumonia. In...
Experimental TherapeuticsThe Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal InfectionInvasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern recognition receptors (e.g., Toll-like receptors, C-type lectins, or scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a nonredundant...
Experimental TherapeuticsActivity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring tet(X) and mcr-1Alternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against...
Editor's Pick Experimental TherapeuticsOptimization of a Noncanonical Anti-infective: Interrogation of the Target Binding Pocket for a Small-Molecule Inhibitor of Escherichia coli Polysaccharide Capsule ExpressionWe previously identified a small-molecule inhibitor of capsule biogenesis (designated DU011) and identified its target as MprA, a MarR family transcriptional repressor of multidrug efflux pumps. Unlike other proposed MprA ligands, such as salicylate and 2,4-dinitrophenol (DNP), DU011 does not alter Escherichia coli antibiotic resistance and has significantly enhanced...
Experimental TherapeuticsSmall-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive BacteriaBacterial infections and the rise of antibiotic resistance, especially multidrug resistance, have generated a clear need for discovery of novel therapeutics. We demonstrated that a small-molecule drug, PKZ18, targets the T-box mechanism and inhibits bacterial growth. The T-box is a structurally conserved riboswitch-like gene regulator in the 5′ untranslated region (UTR) of numerous essential genes of Gram-positive bacteria. T-boxes are...
Experimental TherapeuticsChloroquine Potentiates Primaquine Activity against Active and Latent Hepatic Plasmodia Ex Vivo: Potentials and PitfallsFor a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of...
Experimental TherapeuticsDisparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic MiceComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly...
Experimental TherapeuticsPharmacokinetics and Time-Kill Study of Inhaled Antipseudomonal Bacteriophage Therapy in MiceInhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different from antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study...
Experimental TherapeuticsCiprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in MiceThe mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationships of the effect of ciprofloxacin in subcutaneous treatment for 3 days with varying doses and dosing intervals against a susceptible Escherichia coli strain (MIC, 0.032 mg/liter). Further, a humanized dose of ciprofloxacin was administered for 3...
Experimental TherapeuticsBacteriophage AB-SA01 Cocktail in Combination with Antibiotics against MRSA-VISA Strain in an In Vitro Pharmacokinetic/Pharmacodynamic ModelThis study aimed to test the efficacy of bacteriophage-antibiotic combinations (BACs) in vitro in 24-h time-kill settings and in ex vivo simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic models for 96 h. BACs prevented the development of bacteriophage resistance, while some bacteriophage resistance emerged in bacteriophage-alone treatments. In addition, BACs resulted in an enhancement of bacterial...
Experimental TherapeuticsIs Once-Daily High-Dose Ceftriaxone plus Ampicillin an Alternative for Enterococcus faecalis Infective Endocarditis in Outpatient Parenteral Antibiotic Therapy Programs?Ceftriaxone administered as once-daily high-dose short infusion combined with ampicillin has been proposed for the treatment of Enterococcus faecalis infective endocarditis in outpatient parenteral antibiotic therapy programs (OPAT). This combination requires synergistic activity, but the attainment of ceftriaxone synergic concentration (Cs) with the regimen proposed...
Clinical Therapeutics
Clinical TherapeuticsTreatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South AfricaTreatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine...
Clinical TherapeuticsIs Ceftazidime/Avibactam an Option for Serious Infections Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacterales?: a Systematic Review and Meta-analysisCarbapenem-sparing regimens are needed for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)- and AmpC-producing members of the Enterobacterales. We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL- and AmpC-producing Enterobacterales species. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with...
Clinical TherapeuticsAn Exposure-Response Perspective on the Clinical Dose of PretomanidPretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this...
Clinical TherapeuticsClinical Pharmacokinetics of Fosfomycin after Continuous Infusion Compared with Intermittent Infusion: a Randomized Crossover Study in Healthy VolunteersContinuous infusion (CON) of fosfomycin has been proposed as potentially advantageous in certain clinical scenarios. However, no clinical data on the pharmacokinetics (PK) of fosfomycin after CON are available to date. This study aimed to investigate the PK of fosfomycin after CON and compare it with intermittent infusion (INT) of fosfomycin. A randomized two-way crossover study including 8 healthy male volunteers was performed. Each...
Clinical TherapeuticsOptimization of an Assay To Determine Colonization Resistance to Clostridioides difficile in Fecal Samples from Healthy Subjects and Those Treated with AntibioticsA healthy, intact gut microbiota is often resistant to colonization by gastrointestinal pathogens. During periods of dysbiosis, however, organisms such as Clostridioides difficile can thrive. We describe an optimized in vitro colonization resistance assay for C. difficile in stool (CRACS)...
Clinical TherapeuticsPrediction of Vancomycin Levels Using Cystatin C in Overweight and Obese Patients: a Retrospective Cohort Study of Hospitalized PatientsThe use of the kidney function biomarker cystatin C (cysC) can improve the accuracy of vancomycin dosing for target trough attainment in nonobese patients. It is unknown whether cysC can also improve vancomycin target trough attainment in overweight and obese patients. We conducted a retrospective observational study of overweight or obese hospitalized adults with stable renal function administered intravenous vancomycin between January...
Clinical TherapeuticsDecreased Overall and Inappropriate Antibiotic Prescribing in a Veterans Affairs Hospital Emergency Department following a Peer Comparison-Based Stewardship InterventionAntibiotic prescribing is very common in emergency departments (EDs). Optimal stewardship intervention strategies in EDs are not well defined. We conducted a prospective, observational cohort study in a Veterans Affairs ED in which clinician education and monthly e-mail-based peer comparisons were directed against all oral antibiotic prescribing for discharged patients. Oral antibiotic prescriptions were compared in baseline (June 2016...
Clinical TherapeuticsCerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular DrainThe aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and...
Clinical TherapeuticsSingle-Arm Open-Label Clinical Trial of Two Grams of Aztreonam for the Treatment of Neisseria gonorrhoeaeThe threat of ceftriaxone-resistant Neisseria gonorrhoeae necessitates new gonorrhea treatment regimens. Repurposing older antibiotics not routinely used for N. gonorrhoeae may expeditiously identify new therapies. Ideally, all recommended therapies should eradicate gonorrhea at the pharynx. Between...
Clinical TherapeuticsPatients with Erythema Migrans: Characterizing the Impact of Initiation of Antibiotic Therapy Prior to Study EnrollmentErythema migrans is the most common clinical manifestation of Lyme disease, with concomitant subjective symptoms occurring in ∼65% of cases in the United States. We evaluated the impact of having been started on antibiotic treatment before study enrollment on 12 particular symptoms for 38 subjects with erythema migrans versus 52 untreated subjects. There were no significant differences in the frequency of having at least one symptom or...
Clinical TherapeuticsA Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed MeningesVentriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically...
Pharmacology
PharmacologyPopulation Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous MeningitisOptimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of...
PharmacologyPopulation Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant TuberculosisA population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model...
PharmacologyCumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant TuberculosisPharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under...
PharmacologyIntrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial PneumoniaCefepime-enmetazobactam is a novel β-lactam–β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae. This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of β-lactam–β-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime...
PharmacologyIsavuconazole Therapeutic Drug Monitoring during Long-Term Treatment for Chronic Pulmonary AspergillosisIsavuconazole is the newest triazole antifungal, and it displays a favorable pharmacokinetic and safety profile. Less is known about its long-term use in immunocompetent hosts. We performed a retrospective service evaluation of isavuconazole therapeutic drug monitoring in patients with chronic pulmonary aspergillosis. Adverse events (AEs) and dose adjustments made during routine clinical practice were recorded, and AEs were classified...
PharmacologyFirst Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessusMycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates...
Letters to the Editor
Letter to the EditorRisk of Serotonin Syndrome with Isoniazid
Letter to the EditorImprobable Results of Urine Isolate Antimicrobial Susceptibility Testing
Author Correction
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