Table of Contents
Minireviews
MinireviewPovidone Iodine: Properties, Mechanisms of Action, and Role in Infection Control and Staphylococcus aureus DecolonizationNasal decolonization is an integral part of the strategies used to control and prevent the spread of methicillin-resistant Staphylococcus aureus (MRSA) infections. The two most commonly used agents for decolonization are intranasal mupirocin 2% ointment and chlorhexidine wash, but the increasing emergence of resistance and treatment failure has underscored the need...
MinireviewScreening Repurposing Libraries for Identification of Drugs with Novel Antifungal ActivityFungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsNADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission YeastInvasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal...
Mechanisms of Action: Physiological EffectsA Roadblock-and-Kill Mechanism of Action Model for the DNA-Targeting Antibiotic CiprofloxacinFluoroquinolones, antibiotics that cause DNA damage by inhibiting DNA topoisomerases, are clinically important, but their mechanism of action is not yet fully understood. In particular, the dynamical response of bacterial cells to fluoroquinolone exposure has hardly been investigated, although the SOS response, triggered by DNA damage, is often thought to play a key role. Here, we investigated the growth inhibition of the bacterium...
Mechanisms of Resistance
Mechanisms of ResistancePlausible Minimal Substrate for Erm ProteinErm proteins methylate a specific adenine residue (A2058, Escherichia coli coordinates) conferring macrolide-lincosamide-streptogramin B (MLSB) antibiotic resistance on a variety of microorganisms, ranging from antibiotic producers to pathogens. To identify the minimal motif required to be recognized and methylated by the Erm protein, various RNA substrates...
Mechanisms of ResistanceMutational Effects on Carbapenem Hydrolysis of YEM-1, a New Subclass B2 Metallo-β-Lactamase from Yersinia mollaretiiAnalysis of the genome sequence of Yersinia mollaretii ATCC 43969 identified the blaYEM gene, encoding YEM-1, a putative subclass B2 metallo-β-lactamase. The objectives of our work were to produce and purify YEM-1 and to complete its kinetic characterization. YEM-1 displayed the narrowest substrate range among known subclass B2 metallo-β-lactamases...
Mechanisms of ResistanceAntileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug ResistanceCurrent antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple...
Editor's Pick Mechanisms of ResistanceRapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant MorphologyWe have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (...
Mechanisms of ResistanceCandida glabrata Transcription Factor Rpn4 Mediates Fluconazole Resistance through Regulation of Ergosterol Biosynthesis and Plasma Membrane PermeabilityThe ability to acquire azole resistance is an emblematic trait of the fungal pathogen Candida glabrata. Understanding the molecular basis of azole resistance in this pathogen is crucial for designing more suitable therapeutic strategies. This study shows that the C. glabrata transcription factor (TF...
Mechanisms of ResistanceNovel Aminoglycoside-Tolerant Phoenix Colony Variants of Pseudomonas aeruginosaPseudomonas aeruginosa is an opportunistic bacterial pathogen and is known to produce biofilms. We previously showed the emergence of colony variants in the presence of tobramycin-loaded calcium sulfate beads. In this study, we characterized the variant colonies, which survived the antibiotic treatment, and identified three distinct phenotypes—classically resistant...
Mechanisms of ResistanceRadial Expansion Facilitates the Maintenance of Double Antibiotic ResistancesMost microbes live in spatially confined subpopulations. Under spatial structure conditions, the efficacy of natural selection is often reduced (relative to homogeneous conditions) due to the increased importance of genetic drift and local competition. Additionally, under spatial structure conditions, the fittest genotype may not always be the one with better access to the heterogeneous distribution of nutrients. The effect of radial...
Mechanisms of ResistanceRole of Whole-Genome Sequencing in Characterizing the Mechanism of Action of para-Aminosalicylic Acid and Its Resistancepara-Aminosalicylic acid (PAS) remains one of the drugs of last resort for the treatment of tuberculosis, but its mechanism of action is still not completely understood. The main aim of this project was to identify new potential mechanisms of action and resistance to PAS by performing whole-genome sequencing on PAS-resistant laboratory mutants. A new variant in the folC gene was identified, as well as some other...
Mechanisms of ResistanceGenetic Basis of Azole and Echinocandin Resistance in Clinical Candida glabrata in JapanInfections caused by Candida glabrata have caused worldwide concern, especially when they are associated with increasing echinocandin and azole resistance. In this study, we analyzed the molecular mechanisms of azole and echinocandin resistance in C. glabrata isolates obtained from hospitalized...
Mechanisms of ResistanceCharacterization of Large Deletion Mutants of Mycobacterium tuberculosis Selected for Isoniazid ResistanceLarge genomic deletions (LGDs) (6 to 63 kbp) were observed in isoniazid-resistant Mycobacterium tuberculosis mutants derived from four M. tuberculosis strains. These LGDs had no growth defect in vitro but could be defective in intracellular growth and showed various sensitivities toward...
Mechanisms of ResistanceCRISPR-Cas9-Mediated Carbapenemase Gene and Plasmid Curing in Carbapenem-Resistant EnterobacteriaceaeCombating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here, we conducted a proof-of-concept study to demonstrate that CRISPR-Cas9-mediated resistance gene and plasmid curing can effectively resensitize CRE to carbapenems. A novel CRISPR-Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into...
Mechanisms of ResistancePrevalence of Aminoglycoside Resistance Genes and Molecular Characterization of a Novel Gene, aac(3)-IIg, among Clinical Isolates of the Enterobacter cloacae Complex from a Chinese Teaching HospitalMembers of the Enterobacter cloacae complex are important opportunistic human pathogens capable of causing a wide variety of infections. During recent decades, aminoglycoside-resistant E. cloacae complex isolates have increasingly been reported and have become a major concern. Here, we employed high...
Mechanisms of ResistanceEvidence for Expanding the Role of Streptomycin in the Management of Drug-Resistant Mycobacterium tuberculosisIn 2019, the WHO tuberculosis (TB) treatment guidelines were updated to recommend only limited use of streptomycin, in favor of newer agents or amikacin as the preferred aminoglycoside for drug-resistant Mycobacterium tuberculosis. However, the emergence of resistance to newer drugs, such as bedaquiline, has prompted a reanalysis of antitubercular drugs in search of...
Mechanisms of ResistanceProlonged Exposure to β-Lactam Antibiotics Reestablishes Susceptibility of Daptomycin-Nonsusceptible Staphylococcus aureus to DaptomycinDaptomycin-nonsusceptible (DAP-NS) Staphylococcus aureus often exhibits gain-in-function mutations in the mprF gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against methicillin-resistant S. aureus (MRSA), may prevent the emergence...
Editor's Pick Mechanisms of ResistanceAdding Insult to Injury: Mechanistic Basis for How AmpC Mutations Allow Pseudomonas aeruginosa To Accelerate Cephalosporin Hydrolysis and Evade AvibactamPseudomonas aeruginosa is a leading cause of nosocomial infections worldwide and notorious for its broad-spectrum resistance to antibiotics. A key mechanism that provides extensive resistance to β-lactam antibiotics is the inducible expression of AmpC β-lactamase. Recently, a number of clinical isolates expressing mutated forms of AmpC have been found to be clinically...
Mechanisms of ResistanceHow To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for PyrazinamideFalse-susceptible phenotypic drug-susceptibility testing (DST) results for pyrazinamide due to mutations with MICs close to the critical concentration (CC) confound the classification of pncA resistance mutations, leading to an underestimate of the specificity of genotypic DST. This could be minimized by basing treatment decisions on well-understood mutations and by adopting an area of technical uncertainty for phenotypic DST...
Susceptibility
SusceptibilityAntibacterial Effect of Caffeic Acid Phenethyl Ester on Cariogenic Bacteria and Streptococcus mutans BiofilmsDental caries is the most common disease in the human mouth. Streptococcus mutans is the primary cariogenic bacterium. Propolis is a nontoxic natural product with a strong inhibitory effect on oral cariogenic bacteria. The polyphenol-rich extract from propolis inhibits S. mutans growth and biofilm...
SusceptibilityFrom Etest to Vitek 2: Impact of Enterococcal Linezolid Susceptibility Testing Methodology on Time to Active TherapyDifferent linezolid antimicrobial susceptibility testing (AST) methodologies yield various results. In 2018, we transitioned our linezolid AST methodology from the Etest to Vitek 2. We sought to evaluate the impact of this change on antibiotic use among 181 inpatients with vancomycin-resistant enterococcal (VRE) infections. The transition from Etest to Vitek 2 resulted in an increase in linezolid susceptibility (38% versus 96%; P...
SusceptibilityAntibiotic Susceptibility of NDM-Producing Enterobacterales Collected in the United States in 2017 and 2018The treatment of infections caused by carbapenem-resistant Enterobacterales, especially New Delhi metallo-β-lactamase (NDM)-producing bacteria, is challenging. Although less common in the United States than some other carbapenemase producers, NDM-producing bacteria are a public health threat due to the limited treatment options available. Here, we report on the antibiotic susceptibility of 275 contemporary NDM-producing ...
SusceptibilityIn Vitro Activities of Ravuconazole and Isavuconazole against Dematiaceous FungiThe in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as...
SusceptibilityIn Vitro Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including Bacteroides fragilis Group, Prevotella, Porphyromonas, and Veillonella SpeciesTedizolid’s anaerobic activity is unappreciated. In this study, it was active against all 332 anaerobic isolates tested at ≤2 μg/ml except Bilophila wadsworthia and was more active than linezolid against Bacteroides fragilis group species (MIC90, 1 μg/ml versus 2 to 4 μg/ml). Tedizolid...
Analytical Procedures
Analytical ProceduresUse of a Fluorescence-Based Assay To Measure Escherichia coli Membrane Potential Changes in High ThroughputBacterial membrane potential is difficult to measure using classical electrophysiology techniques due to the small cell size and the presence of the peptidoglycan cell wall. Instead, chemical probes are often used to study membrane potential changes under conditions of interest. Many of these probes are fluorescent molecules that accumulate in a charge-dependent manner, and the resulting fluorescence change can be analyzed via flow...
Antiviral Agents
Antiviral AgentsIn Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital InfectionHerpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule...
Antiviral AgentsMonoclonal Antibody Therapy Protects Pharmacologically Immunosuppressed Mice from Lethal Infection with Influenza B VirusHuman influenza A and B viruses are highly contagious and cause similar illnesses and seasonal epidemics. Currently available antiviral drugs have limited efficacy in humans with compromised immune systems; therefore, alternative strategies for protection are needed. Here, we investigated whether monoclonal antibodies (MAbs) targeting hemagglutinin (HA) and/or neuraminidase (NA) proteins would protect immunosuppressed mice from severe...
Antiviral AgentsHIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase MutantsThe currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in...
Antiviral AgentsModulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C VirusThe activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (...
Antiviral AgentsATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure RegimensATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of...
Antiviral AgentsDiscovery of M Protease Inhibitors Encoded by SARS-CoV-2The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C‐like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the M...
Antiviral AgentsThe FDA-Approved Drug Nelfinavir Inhibits Lytic Cell-Free but Not Cell-Associated Nonlytic Transmission of Human AdenovirusAdenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. Human AdV (HAdV) species B and C, such as HAdV-C2, -C5, and -B14, cause respiratory disease and constitute a health threat for immunocompromised individuals. HAdV-Cs are well known for lysing cells owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening framework and identified an...
Editor's Pick Antiviral AgentsA Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19To the best of our knowledge, there is no published study on the use of interferon β-1a (IFN β-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN β-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN β-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir)....
Editor's Pick Antiviral AgentsA Retrospective Controlled Cohort Study of the Impact of Glucocorticoid Treatment in SARS-CoV-2 Infection MortalityEvidence to support the use of steroids in coronavirus disease 2019 (COVID-19) pneumonia is lacking. We aim to determine the impact of steroid use for COVID-19 pneumonia on hospital mortality. We performed a single-center retrospective cohort study in a university hospital in Madrid, Spain, during March of 2020. To determine the role of steroids in in-hospital mortality, patients admitted with severe acute respiratory syndrome...
Antiviral AgentsAssessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial VirusThis study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific...
Epidemiology and Surveillance
Epidemiology and SurveillanceAntifungal Susceptibility of Clinical Yeast Isolates from a Large Canadian Reference Laboratory and Application of Whole-Genome Sequence Analysis To Elucidate Mechanisms of Acquired ResistanceTo understand the epidemiology and susceptibility patterns of yeast infections in Ontario, Canada, we examined 4,715 clinical yeast isolates submitted to our laboratory for antifungal susceptibility testing from 2014 to 2018. Candida albicans was the most frequently submitted species (43.0%), followed by C...
Epidemiology and SurveillanceCefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in ChildrenSelect methicillin-susceptible Staphylococcus aureus (MSSA) strains may produce β-lactamases with affinity for first-generation cephalosporins (1GCs). In the setting of a high inoculum, these β-lactamases may promote the cleavage of 1GCs, a phenomenon known as the cefazolin inoculum effect (CzIE). We evaluated the prevalence and impact of CzIE on clinical outcomes...
Epidemiology and SurveillanceGenomic Analysis Reveals Antibiotic-Susceptible Clones and Emerging Resistance in Neisseria gonorrhoeae in Saskatchewan, CanadaWhole-genome sequencing was used to identify mutations in antibiotic resistance-conferring genes to compare susceptibility predictions with MICs and to ascertain strain types in 99 isolates of Neisseria gonorrhoeae. Genotypes associated with susceptibility, as well as MIC creep or emerging resistance, were noted. Phylogenomic analysis revealed three distinctive clades...
Experimental Therapeutics
Experimental TherapeuticsEfficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruziPyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a...
Experimental TherapeuticsTherapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in RatsAntimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP...
Experimental TherapeuticsOrally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain CystsToxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute...
Experimental TherapeuticsIn Vitro Pharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacae and Klebsiella aerogenesThe increase of carbapenem-resistant Enterobacterales (CRE) and lack of therapeutic options due to the scarcity of new antibiotics has sparked interest toward the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the in vitro pharmacodynamics of fosfomycin against carbapenem-resistant Enterobacter cloacae and...
Editor's Pick Experimental TherapeuticsEfficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse StrainsToxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we...
Experimental TherapeuticsActivity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophiliaThe production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia,...
Experimental TherapeuticsCharacterization of Amikacin Drug Exposure and Nephrotoxicity in an Animal ModelDespite excellent in vitro activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically...
Experimental TherapeuticsPreclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal AgentThe incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low...
Experimental TherapeuticsMetformin Suppresses Development of the Echinococcus multilocularis Larval Stage by Targeting the TOR PathwayAlveolar echinococcosis (AE) is a severe disease caused by the larval stage of the tapeworm Echinococcus multilocularis. Current chemotherapeutic treatment options based on benzimidazoles are of limited effectiveness, which underlines the need to find new antiechinococcosis drugs. Metformin is an antihyperglycemic and antiproliferative agent that shows activity...
Experimental TherapeuticsComputational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivaxWidespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select...
Clinical Therapeutics
Clinical TherapeuticsNew Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: Clinical, Parasitological, and Serological Assessment after Three Years of Follow-UpIn a pilot study, we showed that the intermittent administration of benznidazole in chronic Chagas disease patients resulted in a low rate of treatment suspension and therapeutic failure, as assessed by quantitative PCR (qPCR) at the end of treatment. Here, a 3-year posttreatment follow-up study of the same cohort of patients is presented. The treatment scheme consisted of 12 doses of benznidazole at 5 mg/kg of body weight/day in two...
Clinical TherapeuticsA Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance DeterminationCriteria defining bedaquiline resistance for tuberculosis have been proposed addressing an emerging concern. We evaluated bedaquiline phenotypic drug susceptibility testing (pDST) criteria using drug-resistant tuberculosis clinical isolates tested at five reference laboratories. Isolates were tested at the proposed bedaquiline MGIT960 and 7H11 agar proportion (AP) critical concentrations and also at higher dilutions. The epidemiological...
Clinical TherapeuticsPharmacist-Driven Implementation of Fast Identification and Antimicrobial Susceptibility Testing Improves Outcomes for Patients with Gram-Negative Bacteremia and CandidemiaBloodstream infections (BSI) are associated with increased morbidity and mortality, especially when caused by Gram-negative or fungal pathogens. The objective of this study was to assess the impact of fast identification-antimicrobial susceptibility testing (ID/AST) with the Accelerate Pheno system (AXDX) from May 2018 to December 2018 on antibiotic therapy and patient outcomes. A pre-post quasiexperimental study of 200 patients (100...
Clinical TherapeuticsEthionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant TuberculosisEthionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy...
Clinical TherapeuticsRisk Factors Associated with Antibiotic Treatment Failure of Buruli UlcerCombination antibiotic therapy is highly effective in curing Buruli ulcer (BU) caused by Mycobacterium ulcerans. Treatment failures have been uncommonly reported with the recommended 56 days of antibiotics, and little is known about risk factors for treatment failure. We analyzed treatment failures among BU patients treated with ≥56 days of antibiotics from a...
Editor's Pick Clinical TherapeuticsToward a Single-Dose Cure for Buruli UlcerA single dose of Q203 (Telacebec), a phase 2 clinical candidate for tuberculosis, eradicates Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 weeks posttreatment. Clinical use of Q203 may dramatically simplify the clinical management of Buruli ulcer, a neglected mycobacterial disease.
Clinical TherapeuticsPopulation Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial DosingCefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC (fT>MIC) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a...
Clinical TherapeuticsBacteriophage-Antibiotic Combinations for Enterococcus faecium with Varying Bacteriophage and Daptomycin SusceptibilitiesConcerns regarding increased prevalence of daptomycin (DAP)-resistant strains necessitate novel therapies for Enterococcus faecium infections. Obligately lytic bacteriophages are viruses that target, infect, and kill bacterial cells. Limited studies have evaluated phage-antibiotic combinations against E....
Clinical TherapeuticsEffectiveness of Vancomycin Dosing Guided by Therapeutic Drug Monitoring in Adult Patients Receiving Extracorporeal Membrane OxygenationThe clinical situation for patients receiving extracorporeal membrane oxygenation (ECMO) is complex, and drug dosing is complicated by significant pharmacokinetic alterations. We sought to describe the frequency of achievement of therapeutic vancomycin concentrations in critically ill patients receiving ECMO with therapeutic drug monitoring (TDM). In this retrospective observational study, we included all critically ill patients...
Pharmacology
PharmacologyPolymyxin-Induced Cell Death of Human Macrophage-Like THP-1 and Neutrophil-Like HL-60 Cells Associated with the Activation of Apoptotic PathwaysInnate immunity is crucial for the host to defend against infections, and understanding the effect of polymyxins on innate immunity is important for optimizing their clinical use. In this study, we investigated the potential toxicity of polymyxins on human macrophage-like THP-1 and neutrophil-like HL-60 cells. Differentiated THP-1 human macrophages (THP-1-dMs) and HL-60 human neutrophils (HL-60-dNs) were employed. Flow cytometry was...
PharmacologyIntracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/EmtricitabineThe altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment...
PharmacologyNonstationary Pharmacokinetics of Caspofungin in ICU PatientsStandard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0–24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring...
PharmacologyUnraveling the Gentamicin Drug Product Complexity Reveals Variation in Microbiological Activities and NephrotoxicityThe gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture. A liquid...
PharmacologyPopulation Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicumAn estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and...
PharmacologySafety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus MacaquesPreviously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50...
PharmacologyPharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection ModelGiven that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P....
PharmacologyCaspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill PatientsThe objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of...
PharmacologyInterspecies Differences in Tenofovir Alafenamide Fumarate Stability in PlasmaTenofovir (TFV) alafenamide fumarate (TAF) is an antiretroviral that has been evaluated in alternative drug delivery systems in several species. The ex vivo stability of TAF was evaluated, and TAF was stable in dog-, sheep-, and macaque-spiked plasma. A negative bias was observed in TAF recovery in rabbit-spiked plasma; there was complete loss of TAF and corresponding overestimation of TFV in rodent-spiked plasma. These data...
PharmacologyEffect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma ConcentrationsCoronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at...
PharmacologySemimechanistic Modeling of Eravacycline Pharmacodynamics Using In Vitro Time-Kill Data with MIC Incorporated in an Adaptive Resistance FunctionEffective bacterial infection eradication requires not only potent antibacterial agents but also proper dosing strategies. Current practices generally utilize point estimates of the effects of therapeutic agents, even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed in vitro effects to develop a semimechanistic pharmacokinetic-pharmacodynamic model for...
Letters to the Editor
Errata
Masthead
Commentary
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir-...