Minireview
Editor's Pick MinireviewIbalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 InfectionLimited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their...
Chemistry; Biosynthesis
Chemistry; BiosynthesisStructure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of MacrolidesAlthough macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsMacrolides Inhibit Capsule Formation of Highly Virulent Cryptococcus gattii and Promote Innate Immune SusceptibilityCryptococcus gattii is a fungal pathogen, endemic in tropical and subtropical regions, the west coast of Canada, and the United States, that causes a potentially fatal infection in otherwise healthy individuals. Because the cryptococcal polysaccharide capsule is a leading virulence factor due to its resistance against innate immunity, the inhibition of capsule...
Mechanisms of Resistance
Mechanisms of ResistanceCharacterization of mcr-5-Harboring Salmonella enterica subsp. enterica Serovar Typhimurium Isolates from Animal and Food Origin in GermanyWe characterized eight mcr-5-positive Salmonella enterica subsp. enterica serovar Typhimurium sequence type 34 (ST34) isolates obtained from pigs and meat in Germany.
Mechanisms of ResistanceZinc Acetate Potentiates the Action of Tosufloxacin against Escherichia coli Biofilm PersistersFormation of bacterial biofilms is a major health threat due to their high levels of tolerance to multiple antibiotics and the presence of persisters responsible for infection relapses. We previously showed that a combination of starvation and induction of SOS response in biofilm led to increased levels of persisters and biofilm tolerance to fluoroquinolones.
Mechanisms of ResistanceA Novel VIM-Type Metallo-β-Lactamase Variant, VIM-60, with Increased Hydrolyzing Activity against Fourth-Generation Cephalosporins in Pseudomonas aeruginosa Clinical Isolates in JapanA novel VIM-type metallo-β-lactamase variant, VIM-60, was identified in multidrug-resistant Pseudomonas aeruginosa clinical isolates in Japan. Compared with VIM-2, VIM-60 had two amino acid substitutions (Arg228Leu and His252Arg) and higher catalytic activities against fourth-generation cephalosporins.
Mechanisms of ResistanceIdentification of a Novel Plasmid Carrying mcr-4.3 in an Acinetobacter baumannii Strain in ChinaHere, we identified mcr-4.3 in Acinetobacter baumannii, which had not been previously observed to carry an mcr gene. The mcr-4.3-harboring A. baumannii strain AB18PR065 was isolated from pig feces from a slaughterhouse in Guangdong Province of China.
Mechanisms of ResistanceOligoribonuclease Contributes to Tolerance to Aminoglycoside and β-Lactam Antibiotics by Regulating KatA in Pseudomonas aeruginosaPseudomonas aeruginosa is an opportunistic bacterial pathogen and is intrinsically resistant to a variety of antibiotics. Oligoribonuclease (Orn) is a 3′-to-5′ exonuclease that degrades nanoRNAs.
Mechanisms of ResistanceIntegron-Derived Aminoglycoside-Sensing Riboswitches Control Aminoglycoside Acetyltransferase Resistance Gene ExpressionClass 1 integrons accumulate antibiotic resistance genes by site-specific recombination at aatI-1 sites. Captured genes are transcribed from a promoter located within the integron; for class 1 integrons, the first gene to be transcribed and translated normally encodes an aminoglycoside antibiotic resistance protein (either an acetyltransferase [AAC] or adenyltransferase [AAD]).
Mechanisms of ResistanceIn Vitro Activity of a Novel Glycopolymer against Biofilms of Burkholderia cepacia Complex Cystic Fibrosis Clinical IsolatesBurkholderia cepacia complex (Bcc) lung infections in cystic fibrosis (CF) patients are often associated with a steady decline in lung function and death. The formation of biofilms and inherent multidrug resistance are virulence factors associated with Bcc infection and contribute to increased risk of mortality in CF patients.
Mechanisms of ResistanceSpecies Distribution and Macrolide Susceptibility of Mycobacterium fortuitum Complex Clinical IsolatesThe understanding of species distribution and inducible macrolide resistance in the Mycobacterium fortuitum complex (MFC) is limited. Of 90 mostly respiratory MFC clinical isolates, half were M. fortuitum, followed by M. peregrinum...
Mechanisms of ResistanceNovel Carbapenemases FLC-1 and IMI-2 Encoded by an Enterobacter cloacae Complex Isolated from Food ProductsFood for human consumption is screened widely for the presence of antibiotic-resistant bacteria to assess the potential for transfer of resistant bacteria to the general population. Here, we describe an Enterobacter cloacae complex isolated from imported seafood that encodes two carbapenemases on two distinct plasmids.
Editor's Pick Mechanisms of ResistanceInactivation of Polymyxin by Hydrolytic MechanismPolymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries.
Editor's Pick Mechanisms of ResistanceA Novel, Widespread qacA Allele Results in Reduced Chlorhexidine Susceptibility in Staphylococcus epidermidisChlorhexidine gluconate (CHG) is a topical antiseptic widely used in health care settings. In Staphylococcus spp., the pump QacA effluxes CHG, while the closely related QacB cannot due to a single amino acid substitution.
Mechanisms of ResistanceCharacterization of β-Lactamase Content of Ceftazidime-Resistant Pathogens Recovered during the Pathogen-Directed Phase 3 REPRISE Trial for Ceftazidime-Avibactam: Correlation of Efficacy against β-Lactamase ProducersREPRISE was a pathogen-directed (ceftazidime-resistant) phase 3 prospective, open-label, randomized, multicenter trial that evaluated the efficacy, safety, and tolerability of ceftazidime-avibactam (CAZ-AVI) and best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). This study characterized the β-lactamase content of...
Mechanisms of ResistanceIntroducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to PyrazinamidePyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive.
Susceptibility
SusceptibilityEUCAST Susceptibility Testing of Isavuconazole: MIC Data for Contemporary Clinical Mold and Yeast IsolatesIsavuconazole is the newest medical azole. We investigated EUCAST MICs for isavuconazole and seven comparators against 1,498 contemporary isolates (2016 to 2017).
SusceptibilityIn Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessusTigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of...
SusceptibilityIndirubin Analogues Inhibit Trypanosoma brucei Glycogen Synthase Kinase 3 Short and T. brucei GrowthThe protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). The disease is fatal if it remains untreated, whereas most drug treatments are inadequate due to high toxicity, difficulties in administration, and low central nervous system penetration.
SusceptibilityAntimicrobial Activity Evaluation of Tebipenem (SPR859), an Orally Available Carbapenem, against a Global Set of Enterobacteriaceae Isolates, Including a Challenge Set of OrganismsThe antimicrobial activity of tebipenem and other carbapenem agents were tested in vitro against a set of recent clinical isolates responsible for urinary tract infection (UTI), as well as against a challenge set. Isolates were tested by reference broth microdilution and included Escherichia coli (101 isolates),...
Analytical Procedures
Analytical ProceduresCandida in the Respiratory Tract Potentially Triggers Galactomannan Positivity in Nonhematological PatientsBAL fluid samples from critically ill patients shared a rate of 29% false-positive galactomannan results. We aimed to determine whether Candida species abundance in BAL fluid causes galactomannan (GM) positivity.
Antiviral Agents
Antiviral AgentsAntiviral Candidates for Treating Hepatitis E Virus InfectionGlobally, hepatitis E virus (HEV) causes significant morbidity and mortality each year. Despite this burden, there are no specific antivirals available to treat HEV patients, and the only licensed vaccine is not available outside China.
Antiviral AgentsHalogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant VariantsWe generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 have meta-monofluorophenyl and para-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50...
Epidemiology and Surveillance
Epidemiology and SurveillanceGeographic Mapping of Escherichia coli Susceptibility To Develop a Novel Clinical Decision Support ToolAntimicrobial resistance (AMR) varies regionally. This study longitudinally maps Escherichia coli susceptibility leveraging Wisconsin antibiograms (n = 202) collected from 2009, 2013, and 2015 to inform the development of a novel clinical decision support tool.
Epidemiology and SurveillanceGenomic Investigation of the Emergence of Invasive Multidrug-Resistant Salmonella enterica Serovar Dublin in Humans and Animals in CanadaSalmonella enterica subsp. enterica serovar Dublin is a zoonotic pathogen that often leads to invasive bloodstream infections in humans that are multidrug resistant.
Epidemiology and SurveillanceRevised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate Mycobacterium canettii and Members of the Mycobacterium tuberculosis ComplexUsing 894 phylogenetically diverse genomes of the Mycobacterium tuberculosis complex (MTBC), we simulated in silico the ability of the Hain Lifescience GenoType MTBC assay to differentiate the causative agents of tuberculosis. Here, we propose a revised interpretation of this assay to reflect its strengths (e.g., it can distinguish some strains of...
Epidemiology and SurveillanceCarbapenem-Susceptible OXA-23-Producing Proteus mirabilis in the French CommunityNineteen Proteus mirabilis isolates producing the carbapenemase OXA-23 were recovered over a 2-year period in 19 French hospitalized patients, of whom 12 had community onset infections. The isolates exhibited a slightly reduced susceptibility to carbapenems.
Epidemiology and SurveillanceGenomic and Functional Analysis of Emerging Virulent and Multidrug-Resistant Escherichia coli Lineage Sequence Type 648The pathogenic extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli lineage ST648 is increasingly reported from multiple origins. Our study of a large and global ST648 collection from various hosts (87 whole-genome sequences) combining core and accessory genomics with functional analyses and in vivo experiments suggests that ST648 is a nascent...
Epidemiology and SurveillanceKlebsiella quasipneumoniae Provides a Window into Carbapenemase Gene Transfer, Plasmid Rearrangements, and Patient Interactions with the Hospital EnvironmentSeveral emerging pathogens have arisen as a result of selection pressures exerted by modern health care. Klebsiella quasipneumoniae was recently defined as a new species, yet its prevalence, niche, and propensity to acquire antimicrobial resistance genes are not fully described.
Epidemiology and SurveillanceCharacterization of Carbapenemase-Producing Klebsiella oxytoca in Spain, 2016–2017There is little information about carbapenemase-producing (CP) Klebsiella oxytoca, an important nosocomial pathogen. We characterized CP K. oxytoca isolates collected from different Spanish hospitals between January 2016 and October 2017.
Epidemiology and SurveillanceNext-Generation-Sequencing-Based Hospital Outbreak Investigation Yields Insight into Klebsiella aerogenes Population Structure and Determinants of Carbapenem Resistance and PathogenicityKlebsiella aerogenes is a nosocomial pathogen associated with drug resistance and outbreaks in intensive care units. In a 5-month period in 2017, we experienced an increased incidence of cultures for carbapenem-resistant K. aerogenes (CR-KA) from an adult cardiothoracic intensive care unit (CICU) involving 15 patients.
Editor's Pick Epidemiology and SurveillanceEscherichia coli Harboring mcr-1 in a Cluster of Liver Transplant Recipients: Detection through Active Surveillance and Whole-Genome Sequencingmcr-1, a plasmid-associated gene for colistin resistance, was first described in China in 2015, but its spread in the United States is unknown. We report detection of mcr-1-carrying Escherichia coli ST117 in a cluster of three liver transplant recipients.
Experimental Therapeutics
Experimental TherapeuticsIn Vitro and In Vivo Activities of Zinc Linolenate, a Selective Antibacterial Agent against Helicobacter pyloriHelicobacter pylori is a major global pathogen, and its infection represents a key factor in the etiology of various gastric diseases, including gastritis, peptic ulcers, and gastric carcinoma. The efficacy of current standard treatment for H. pylori infection including two broad-spectrum...
Experimental TherapeuticsTreatment with the Pseudomonas aeruginosa Glycoside Hydrolase PslG Combats Wound Infection by Improving Antibiotic Efficacy and Host Innate Immune ActivityPseudomonas aeruginosa is an opportunistic, nosocomial bacterial pathogen that forms persistent infections due to the formation of protective communities, known as biofilms. Once the biofilm is formed, the bacteria embedded within it are recalcitrant to antimicrobial treatment and host immune defenses.
Experimental TherapeuticsTridecaptin M, a New Variant Discovered in Mud Bacterium, Shows Activity against Colistin- and Extremely Drug-Resistant EnterobacteriaceaeThe World Health Organization has categorized the Gram-negative superbugs, which are inherently impervious to many antibiotics, as critical priority pathogens due to the lack of effective treatments. The breach in our last-resort antibiotic (i.e., colistin) by extensively drug-resistant and pan-drug-resistant Enterobacteriaceae strains demands the immediate development of new therapies.
Experimental TherapeuticsIn Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicansThe fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including Candida spp. To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 ...
Editor's Pick Experimental TherapeuticsLysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative BacteriaThe prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria.
Experimental TherapeuticsImpact of the Timing of Antibiotic Administration on Digestive Colonization with Carbapenemase-Producing Enterobacteriaceae in a Murine ModelWhile antibiotic use is a risk factor of carbapenemase-producing Enterobacteriaceae (CPE) acquisition, the importance of timing of antibiotic administration relative to CPE exposure remains unclear. In a murine model of gut colonization by New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella...
Experimental TherapeuticsTreatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of TuberculosisClofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure.
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Experimental TherapeuticsSynergic Effect of Allopurinol in Combination with Nitroheterocyclic Compounds against Trypanosoma cruziCombination therapy has gained attention as a possible strategy for overcoming the limitations of the present therapeutic arsenal for Chagas disease. The aim of this study was to evaluate the effect of allopurinol in association with nitroheterocyclic compounds on infection with the Y strain of Trypanosoma cruzi.
Experimental TherapeuticsPostantibiotic and Sub-MIC Effects of Exebacase (Lysin CF-301) Enhance Antimicrobial Activity against Staphylococcus aureusCF-301 (exebacase) is a recombinantly produced bacteriophage-derived lysin (cell wall hydrolase) and is the first agent of this class to enter clinical development in the United States for treating bacteremia including endocarditis due to Staphylococcus aureus. Whereas rapid bactericidal activity is the hallmark in vitro and in vivo response to CF-...
Experimental TherapeuticsNovel MenA Inhibitors Are Bactericidal against Mycobacterium tuberculosis and Synergize with Electron Transport Chain InhibitorsMycobacterium tuberculosis is the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible disease burden, combined with the long course of drug treatment and an increasing incidence of antimicrobial resistance among M. tuberculosis isolates, necessitates...
Experimental TherapeuticsIn Vitro and In Vivo Exposure-Effect Relationship of Liposomal Amphotericin B against Aspergillus fumigatusIn vitro pharmacokinetic/pharmacodynamic data of liposomal amphotericin B (L-AMB) were compared with animal data from neutropenic and nonneutropenic models of azole-susceptible and azole-resistant invasive aspergillosis. L-AMB was equally effective.
Clinical Therapeutics
Clinical TherapeuticsPharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination against Pseudomonas aeruginosa Producing Metallo-β-LactamaseFosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to...
Clinical TherapeuticsPopulation Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy SubjectsVL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397.
Clinical TherapeuticsPharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial PneumoniaErtapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, ...
Clinical TherapeuticsPopulation Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive CandidiasisFluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen.
Clinical TherapeuticsHigh-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole EffectivenessVoriconazole is a triazole antifungal agent recommended as primary treatment for invasive aspergillosis, as well as some other mold infections. However, it presents some pharmacokinetic singularities that lead to a great variability intra- and interindividually, nonlinear pharmacokinetics, and a narrow therapeutic range.
Clinical TherapeuticsAntifungal Drugs Influence Neutrophil Effector FunctionsThere is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN).
Clinical TherapeuticsPharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin LevelsCaspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score.
Clinical TherapeuticsA Phase 1, Randomized, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S, an Anti-Staphylococcus aureus Thiomab Antibody-Antibiotic Conjugate, in Healthy VolunteersStaphylococcus aureus causes serious bacterial infections with high morbidity and mortality, necessitating the discovery of new antibiotics. DSTA4637S is a novel antibody-antibiotic conjugate designed to target intracellular S. aureus that is not adequately eliminated by current standard-of-care...
Pharmacology
PharmacologyPopulation Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological MalignanciesImipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking.
PharmacologyPulmonary Pharmacokinetics of Oseltamivir Carboxylate in Rats after Nebulization or Intravenous Administration of Its Prodrug, Oseltamivir PhosphateThe aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure...
PharmacologyPreclinical Development of Inhalable d-Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosisWe compared the pharmacokinetics and efficacy of a combination of d-cycloserine (DCS) and ethionamide (ETO) via oral and inhalation routes in mice. The plasma half-life (t1/2) of oral ETO at a human-equivalent dose decreased from 4.63 ± 0.61 h to 1.64 ± 0.40 h when DCS was coadministered.
PharmacologyEfficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous DiseaseThe emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals.
PharmacologyRifampin Pharmacokinetics and Safety in Preterm and Term InfantsRifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA).
PharmacologyDaptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis/oralis in an Ex Vivo Simulated Endocarditis Vegetation ModelThe viridans group streptococci (VGS) are a heterogeneous group of organisms which are important components of the normal human oral flora. Among the VGS, the Streptococcus mitis/oralis subgroup is one of the most common causes of infective endocarditis (IE).
PharmacologyTissue Distribution and Penetration of Isavuconazole at the Site of Infection in Experimental Invasive Aspergillosis in Mice with Underlying Chronic Granulomatous DiseaseIsavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis...
PharmacologyLow Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations.
PharmacologyCeftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose RegimensCeftriaxone has a higher biliary elimination than cefotaxime (40% versus 10%), which may result in a more pronounced impact on the intestinal microbiota. We performed a monocenter, randomized open-label clinical trial in 22 healthy volunteers treated by intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for 3 days.
PharmacologyCeftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal InfectionsCeftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-...
PharmacologyNo Dose Adjustment for Isavuconazole Based on Age or Sex...This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females).
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Antimicrobial Agents and Chemotherapy® (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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Commentary
This year marks the 70th anniversary since Parke-Davis and Company announced the synthesis of chloramphenicol, the first naturally occurring antibiotic to be chemically generated in vitro for large-scale production. The effort was led by the chemist Mildred Rebstock, Ph.D., (1919 to 2011), who would turn 100 years old this year.