Minireview
MinireviewDose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-abdominal Infections, Complicated Urinary Tract Infections, and Nosocomial PneumoniaAvibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options.
Chemistry; Biosynthesis
Chemistry; BiosynthesisNegative Impact of Carbapenem Methylation on the Reactivity of β-Lactams for Cysteine Acylation as Revealed by Quantum Calculations and Kinetic AnalysesThe Enterococcus faecium l,d-transpeptidase (Ldtfm) mediates resistance to most β-lactam antibiotics in this bacterium by replacing classical peptidoglycan polymerases. The catalytic Cys of Ldtfm is rapidly acylated by β-lactams belonging to the carbapenem class but not by penams or cephems.
...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsInhibition of Yeast-to-Hypha Transition and Virulence of Candida albicans by 2-Alkylaminoquinoline Derivatives...A rapid increase in Candida albicans infection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives against C. albicans isolates.
Mechanisms of Action: Physiological EffectsIn Vitro and Intracellular Activity of Imipenem Combined with Tedizolid, Rifabutin, and Avibactam against Mycobacterium abscessusMycobacterium abscessus infections are difficult to treat because of their resistance to many antibiotics. In vitro, tedizolid combined with imipenem displayed a moderate synergistic effect (fractional inhibitory concentration index, 0.41) but no bactericidal activity.
Mechanisms of Action: Physiological EffectsA FASII Inhibitor Prevents Staphylococcal Evasion of Daptomycin by Inhibiting Phospholipid Decoy ProductionDaptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus. We have shown recently that S. aureus can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the...
Editor's Pick Mechanisms of Action: Physiological EffectsThe Novel β-Lactam Enhancer Zidebactam Augments the In Vivo Pharmacodynamic Activity of Cefepime in a Neutropenic Mouse Lung Acinetobacter baumannii Infection ModelWCK 5222 is a combination of cefepime and the high-affinity PBP2-binding β-lactam enhancer zidebactam. The cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including carbapenemase-expressing Acinetobacter baumannii.
Mechanisms of Action: Physiological EffectsIn Vitro Activity of Tebipenem (SPR859) against Penicillin-Binding Proteins of Gram-Negative and Gram-Positive BacteriaTebipenem (SPR859) is the microbiologically active form of SPR994 (tebipenem-pivoxil), an orally available carbapenem with activity against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Measurement of the relative binding of SPR859 to the bacterial cell targets revealed that it is a potent inhibitor of multiple penicillin-binding proteins (PBPs) but primarily a Gram-negative PBP 2 inhibitor, similar to...
Mechanisms of Resistance
Mechanisms of ResistanceAbrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida aurisCandida auris has rapidly emerged as a health care-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four C. auris genes with the highest degree of homology to Candida...
Mechanisms of ResistanceUncoupled Quorum Sensing Modulates the Interplay of Virulence and Resistance in a Multidrug-Resistant Clinical Pseudomonas aeruginosa Isolate Belonging to the MLST550 Clonal ComplexPseudomonas aeruginosa is a prevalent and pernicious pathogen equipped with extraordinary capabilities both to infect the host and to develop antimicrobial resistance (AMR). Monitoring the emergence of AMR high-risk clones and understanding the interplay of their pathogenicity and antibiotic resistance is of paramount importance to avoid resistance dissemination and...
Mechanisms of ResistanceRole of Viscoelasticity in Bacterial Killing by Antimicrobials in Differently Grown Pseudomonas aeruginosa BiofilmsPseudomonas aeruginosa colonizes the sputum of most adult cystic fibrosis patients, forming difficult-to-eradicate biofilms in which bacteria are protected in their self-produced extracellular polymeric substance (EPS) matrices. EPS provide biofilms with viscoelastic properties, causing time-dependent relaxation after stress-induced deformation, according to multiple...
Mechanisms of ResistanceVarious Evolutionary Trajectories Lead to Loss of the Tobramycin-Potentiating Activity of the Quorum-Sensing Inhibitor Baicalin Hydrate in Burkholderia cenocepacia BiofilmsCombining antibiotics with potentiators that increase their activity is a promising strategy to tackle infections caused by antibiotic-resistant bacteria. As potentiators do not interfere with essential processes, it has been hypothesized that they are less likely to induce resistance.
Mechanisms of ResistanceMolecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by AvibactamIn 2016, we identified a new class A carbapenemase, VCC-1, in a nontoxigenic Vibrio cholerae strain that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1-producing V. cholerae isolates were recovered along the German...
Mechanisms of ResistanceLow Prevalence of Gram-Positive Isolates Showing Elevated Lefamulin MIC Results during the SENTRY Surveillance Program for 2015–2016 and Characterization of Resistance MechanismsThis study investigated the molecular mechanisms possibly associated with non-wild-type MICs for lefamulin among staphylococci and streptococci included in the lefamulin surveillance program from 2015 to 2016. A total of 2,919 Staphylococcus aureus, 276 coagulase-negative staphylococci (CoNS), 3,923 ...
Mechanisms of ResistanceWhole-Genome Sequencing for Drug Resistance Profile Prediction in Mycobacterium tuberculosisWhole-genome sequencing allows rapid detection of drug-resistant Mycobacterium tuberculosis isolates. However, the availability of high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data have thus far been limited.
Mechanisms of ResistanceKinetic Profile and Molecular Dynamic Studies Show that Y229W Substitution in an NDM-1/L209F Variant Restores the Hydrolytic Activity of the Enzyme toward Penicillins, Cephalosporins, and CarbapenemsThe New Delhi metallo-β-lactamase-1 (NDM-1) enzyme is the most common metallo-β-lactamase identified in many Gram-negative bacteria causing severe nosocomial infections. The aim of this study was to focus the attention on non-active-site residues L209 and Y229 of NDM-1 and to investigate their role in the catalytic mechanism.
Mechanisms of ResistanceResurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-Resistant Burkholderia Species Isolates from the United StatesBurkholderia spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised.
Mechanisms of ResistancePredicting Antibiotic Resistance in Gram-Negative Bacilli from Resistance GenesWe developed a rapid high-throughput PCR test and evaluated highly antibiotic-resistant clinical isolates of Escherichia coli (n = 2,919), Klebsiella pneumoniae (n = 1,974), Proteus mirabilis (n = 1,150...
Mechanisms of ResistanceAmpI Functions as an Iron Exporter To Alleviate β-Lactam-Mediated Reactive Oxygen Species Stress in Stenotrophomonas maltophiliaStenotrophomonas maltophilia is an organism with a remarkable capacity for drug resistance with several antibiotic resistance determinants in its genome. S. maltophilia genome codes for L1 and L2, responsible for intrinsic β-lactam resistance.
Mechanisms of ResistanceLarge-Scale Identification of AbaR-Type Genomic Islands in Acinetobacter baumannii Reveals Diverse Insertion Sites and Clonal Lineage-Specific Antimicrobial Resistance Gene ProfilesAbaR-type genomic islands (AbaRs) are important elements responsible for antimicrobial resistance in Acinetobacter baumannii. This study performed a large-scale identification of AbaRs to understand their distribution and compositions of antimicrobial resistance genes.
Mechanisms of ResistanceCharacterization of Hypermutator Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis in AustraliaHypermutable Pseudomonas aeruginosa isolates (hypermutators) have been identified in patients with cystic fibrosis (CF) and are associated with reduced lung function. Hypermutators display a greatly increased mutation rate and an enhanced ability to become resistant to antibiotics during treatment.
Mechanisms of ResistanceCirculation of Plasmids Harboring Resistance Genes to Quinolones and/or Extended-Spectrum Cephalosporins in Multiple Salmonella enterica Serotypes from Swine in the United StatesNontyphoidal Salmonella enterica (NTS) poses a major public health risk worldwide that is amplified by the existence of antimicrobial-resistant strains, especially those resistant to quinolones and extended-spectrum cephalosporins (ESC). Little is known on the dissemination of plasmids harboring the acquired genetic determinants that confer resistance to these...
Susceptibility
SusceptibilityEarly Detection of Emergent Extensively Drug-Resistant Tuberculosis by Flow Cytometry-Based Phenotyping and Whole-Genome SequencingA critical gap in tuberculosis (TB) treatment is detection of emergent drug resistance. We hypothesized that advanced phenotyping with whole-genome sequencing (WGS) will detect low-frequency Mycobacterium tuberculosis drug resistance.
SusceptibilityIn Vitro Activity of Tedizolid against Mycobacterium tuberculosisTedizolid is a novel oxazolidinone with activities against Gram-positive microorganisms, including mycobacteria. We studied the in vitro activity of tedizolid against 120 Mycobacterium tuberculosis strains, including susceptible, first-line-resistant, and multidrug-resistant isolates.
SusceptibilityAntibacterial Activity of Lefamulin against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016)Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for in vitro activity against a global collection of pathogens commonly causing CABP (n = 8595) from the 2015 and 2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against the pathogens...
SusceptibilityIn Vitro Synergism of Rifabutin with Clarithromycin, Imipenem, and Tigecycline against the Mycobacterium abscessus ComplexInfections caused by the difficult-to-treat bacterium Mycobacterium abscessus are increasing in frequency. Rifabutin, in contrast to rifampin, appears to be active in vitro against M. abscessus, especially against clarithromycin-resistant strains.
SusceptibilityIn Vitro Activity of Iclaprim against Isolates in Two Phase 3 Clinical Trials (REVIVE-1 and -2) for Acute Bacterial Skin and Skin Structure InfectionsIclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, β-hemolytic streptococci, and...
SusceptibilityBacterial Cytological Profiling as a Tool To Study Mechanisms of Action of Antibiotics That Are Active against Acinetobacter baumanniiAn increasing number of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections have been reported worldwide, posing a threat to public health. The establishment of methods to elucidate the mechanism of action (MOA) of A. baumannii-specific antibiotics is needed to develop novel...
SusceptibilityEmergence of Neisseria gonorrhoeae Strains Harboring a Novel Combination of Azithromycin-Attenuating MutationsThe nimbleness of Neisseria gonorrhoeae to evade the effect of antibiotics has perpetuated the fight against antibiotic-resistant gonorrhea for more than 80 years. The ability to develop resistance to antibiotics is attributable to its indiscriminate nature in accepting and integrating exogenous DNA into its genome.
SusceptibilityResults from a Prospective In Vitro Study on the Mecillinam (Amdinocillin) Susceptibility of EnterobacteralesThe activity of mecillinam (amdinocillin) was assessed in Enterobacterales (n = 420) isolated from urine samples between 2016 and 2017. Mecillinam susceptibilities were 97.4% in Escherichia coli isolates (294/302), 89.7% in Klebsiella spp.
SusceptibilityResults from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosaThe in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed...
SusceptibilityA Combination Antibiogram Evaluation for Pseudomonas aeruginosa in Respiratory and Blood Sources from Intensive Care Unit (ICU) and Non-ICU Settings in U.S. HospitalsPseudomonas aeruginosa is an important pathogen associated with significant morbidity and mortality. U.S.
SusceptibilityThe Anthelmintic Drug Niclosamide Synergizes with Colistin and Reverses Colistin Resistance in Gram-Negative BacilliThere is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S.
SusceptibilitySelect β-Lactam Combinations Exhibit Synergy against Mycobacterium abscessus In VitroMycobacterium abscessus is a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease. M. abscessus is intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to...
Antiviral Agents
Antiviral AgentsPharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy VolunteersThe combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three...
Editor's Pick Antiviral AgentsCMCdG, a Novel Nucleoside Analog with Favorable Safety Features, Exerts Potent Activity against Wild-Type and Entecavir-Resistant Hepatitis B VirusWe designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxymethyl)-2-methylene-cyclopentanecarbonitrile, or 4′-cyano-methylenecarbocyclic-2′-deoxyguanosine (CMCdG), and evaluated its anti-hepatitis B virus (anti-HBV) activity, safety, and related features. CMCdG’s in vitro activity was determined using quantitative...
Antiviral AgentsImpact of Preexisting Hepatitis C Virus Genotype 6 NS3, NS5A, and NS5B Polymorphisms on the In Vitro Potency of Direct-Acting Antiviral AgentsHCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved.
Antiviral AgentsSrc Family Kinase Inhibitors Block Translation of Alphavirus Subgenomic mRNAsAlphaviruses are arthropod-transmitted RNA viruses that can cause arthralgia, myalgia, and encephalitis in humans. Since the role of cellular kinases in alphavirus replication is unknown, we profiled kinetic changes in host kinase abundance and phosphorylation following chikungunya virus (CHIKV) infection of fibroblasts.
Antiviral AgentsIn Vitro Evaluation of the Drug Interaction Potential of DoravirineDoravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters.
Antiviral AgentsPopulation Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine...
Epidemiology and Surveillance
Epidemiology and SurveillanceIn Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin American Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015The International Network for Optimal Resistance Monitoring (INFORM) global surveillance program collected clinical isolates of Enterobacteriaceae (n = 7,665) and Pseudomonas aeruginosa (n = 1,794) from 26 medical centers in six Latin American countries from 2012 to 2015. The ...
Epidemiology and SurveillanceMolecular Epidemiology of Emerging Carbapenem Resistance in Acinetobacter nosocomialis and Acinetobacter pittii in Taiwan, 2010 to 2014This study investigated the molecular epidemiology of carbapenem-resistant Acinetobacter nosocomialis and Acinetobacter pittii (ANAP). Clinical isolates of Acinetobacter spp.
Epidemiology and SurveillanceClinical and Molecular Characteristics of qacA- and qacB-Positive Methicillin-Resistant Staphylococcus aureus Causing Bloodstream InfectionsThe increasing use of chlorhexidine for methicillin-resistant Staphylococcus aureus (MRSA) decolonization has raised concerns about the emergence of resistance to these agents. However, the clinical significance of MRSA positive for the qacA and qacB chlorhexidine tolerance genes has not been established.
Epidemiology and SurveillanceDynamics of Resistance Plasmids in Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae during Postinfection ColonizationExtended-spectrum β-lactamase-producing Enterobacteriaceae (EPE) are a major cause of bloodstream infections, and the colonization rate of EPE in the gut microbiota of individuals lacking prior hospitalization or comorbidities is increasing. In this study, we performed an in-depth investigation of the temporal dynamics of EPE and their plasmids during one year by...
Epidemiology and SurveillanceConjugal Transfer, Whole-Genome Sequencing, and Plasmid Analysis of Four mcr-1-Bearing Isolates from U.S. Patients...Four Enterobacteriaceae clinical isolates bearing mcr-1 gene-harboring plasmids were characterized. All isolates demonstrated the ability to transfer colistin resistance to Escherichia coli; plasmids were stable in conjugants after multiple passages on nonselective media.
Experimental Therapeutics
Experimental TherapeuticsActivity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis InfectionThe potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI.
Experimental TherapeuticsDalbavancin Alone and in Combination with Ceftaroline against Four Different Phenotypes of Staphylococcus aureus in a Simulated Pharmacodynamic/Pharmacokinetic ModelGlycopeptides such as vancomycin have been used as the first-line therapy against MRSA infections for over half a century. Reduced susceptibility and emergence of resistance to first-generation glycopeptides has led to development of second-generation lipoglycopeptide derivatives such as dalbavancin which hold broader ranges of activity and enhanced pharmacokinetic properties.
Experimental TherapeuticsIn Vitro Antimicrobial Activity of Diacerein on 76 Isolates of Gram-Positive Cocci from Bacterial Keratitis Patients and In Vivo Study of Diacerein Eye Drops on Staphylococcus aureus Keratitis in MiceBacterial keratitis is an aggressive infectious corneal disease. With the continuing rise in antibiotic resistance and a decline in the discovery of new antibiotics, new antimicrobial drugs are now required.
Experimental TherapeuticsPharmacological, Toxicological, and Dose Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile-Associated InfectionLantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of Clostridium difficile infection.
Experimental TherapeuticsA Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of RifapentineRifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response.
Experimental TherapeuticsIn Vitro Activity of a Novel Antifungal Compound, MYC-053, against Clinically Significant Antifungal-Resistant Strains of Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp.An urgent need exists for new antifungal compounds to treat fungal infections in immunocompromised patients. The aim of the current study was to investigate the potency of a novel antifungal compound, MYC-053, against the emerging yeast and yeast-like pathogens Candida glabrata, Candida auris,...
Experimental TherapeuticsEfficacy of Intranasal Administration of the Recombinant Endolysin SAL200 in a Lethal Murine Staphylococcus aureus Pneumonia ModelSAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model.
Experimental TherapeuticsSynergistic Antifungal Effect of Amphotericin B-Loaded Poly(Lactic-Co-Glycolic Acid) Nanoparticles and Ultrasound against Candida albicans BiofilmsCandida albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices.
Experimental TherapeuticsClyJ Is a Novel Pneumococcal Chimeric Lysin with a Cysteine- and Histidine-Dependent Amidohydrolase/Peptidase Catalytic Domain...Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae, new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed.
Editor's Pick Experimental TherapeuticsOptimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Cryptosporidium InfectionCryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons.
Editor's Pick Experimental TherapeuticsEfficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse ModelAN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid.
Experimental TherapeuticsDS86760016, a Leucyl-tRNA Synthetase Inhibitor with Activity against Pseudomonas aeruginosaDS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms.
Experimental TherapeuticsIron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal CandidiasisCandida albicans, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy.
Experimental TherapeuticsImidazole Derivatives as Promising Agents for the Treatment of Chagas DiseaseMore than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continents but has become a global health threat.
Experimental TherapeuticsThe Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-Resistant Staphylococcus aureus BacteriolysisBacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and...
Experimental TherapeuticsA Small-Molecule Inhibitor of trans-Translation Synergistically Interacts with Cathelicidin Antimicrobial Peptides To Impair Survival of Staphylococcus aureus...Staphylococcus aureus is a leading cause of infection in the United States, and due to the rapid development of resistance, new antibiotics are constantly needed. trans-Translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical for bacterial survival, and is unique among prokaryotes.
Experimental TherapeuticsAPX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an In Vivo Model of Invasive Pulmonary AspergillosisAPX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against Aspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A...
Experimental TherapeuticsEfficacy of Human-Simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine β-Lactamase-Producing Enterobacteriaceae in the Neutropenic Murine Lung Infection ModelNacubactam is a novel, broad-spectrum, β-lactamase inhibitor that is currently under development as combination therapy with meropenem. This study evaluated the efficacy of human-simulated epithelial lining fluid (ELF) exposures of meropenem, nacubactam, and the combination of meropenem and nacubactam against class A serine carbapenemase-producing ...
Experimental TherapeuticsViability Screen of LOPAC1280 Reveals Tyrosine Kinase Inhibitor Tyrphostin A9 as a Novel Partner Drug for Artesunate Combinations To Target the Plasmodium falciparum Ring StageThe emergence of artemisinin-resistant Plasmodium falciparum poses a major threat to current frontline artemisinin combination therapies. Artemisinin resistance is widely associated with mutations in the P. falciparum Kelch13 (PfKelch13) propeller region, leading to delayed parasite clearance and...
Editor's Pick Experimental TherapeuticsEfficacy of Tedizolid against Enterococci and Staphylococci, Including cfr+ Strains, in a Mouse Peritonitis ModelIn a mouse peritonitis model, tedizolid was comparable to linezolid and daptomycin against an Enterococcus faecium strain (VANr, AMPr), an Enterococcus faecalis strain, and a methicillin-resistant Staphylococcus...
Experimental TherapeuticsIron/Heme Metabolism-Targeted Gallium(III) Nanoparticles Are Active against Extracellular and Intracellular Pseudomonas aeruginosa and Acinetobacter baumanniiIron/heme acquisition systems are critical for microorganisms to acquire iron from the human host, where iron sources are limited due to the nutritional immune system and insolubility of the ferric form of iron. Prior work has shown that a variety of gallium compounds can interfere with bacterial iron acquisition.
Clinical Therapeutics
Clinical TherapeuticsPooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini InfectionsOpisthorchiasis, caused by the foodborne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People’s Democratic Republic, pharmacokinetic samples were obtained from 125 adult and adolescent O. viverrini...
Clinical TherapeuticsImpact of an Antimicrobial Stewardship Intervention on Within- and Between-Patient Daptomycin Resistance Evolution in Vancomycin-Resistant Enterococcus faeciumVancomycin-resistant Enterococcus (VRE) is a leading cause of hospital-acquired infection, with limited treatment options. Resistance to one of the few remaining drugs, daptomycin, is a growing clinical problem and has previously been described in this hospital.
Editor's Pick Clinical TherapeuticsDSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparumDSM265 is a novel antimalarial drug in clinical development that acts as a selective inhibitor of Plasmodium dihydroorotate dehydrogenase. In a previous phase 1b study, a single 150-mg dose of DSM265 showed partial efficacy against experimentally induced blood-stage Plasmodium falciparum malaria (IBSM).
Clinical TherapeuticsPharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation StudyCysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an...
Clinical TherapeuticsSoftware for Dosage Individualization of Voriconazole: a Prospective Clinical StudyVoriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care.
Clinical TherapeuticsPopulation Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric PatientsLinezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited.
Clinical TherapeuticsPharmacokinetics of Albendazole, Albendazole Sulfoxide, and Albendazole Sulfone Determined from Plasma, Blood, Dried-Blood Spots, and Mitra Samples of Hookworm-Infected AdolescentsAlbendazole is an effective anthelmintic intensively used for decades. However, profound pharmacokinetic (PK) characterization is missing in children, the population mostly affected by helminth infections.
Pharmacology
PharmacologyRace/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of...
PharmacologyPharmacokinetics, Safety, and Dosing of Novel Pediatric Levofloxacin Dispersible Tablets in Children with Multidrug-Resistant Tuberculosis ExposureThis study characterized the pharmacokinetics of novel 100-mg levofloxacin dispersible tablets in 24 children aged <5 years who had household multidrug-resistant tuberculosus (MDR-TB) exposure. The current data were pooled with previously published data from children (n = 109) with MDR-TB receiving adult (250-mg) levofloxacin tablets, using nonlinear mixed-effects modelling.
PharmacologyDose Optimization of Colistin Combinations against Carbapenem-Resistant Acinetobacter baumannii from Patients with Hospital-Acquired Pneumonia in China by Using an In Vitro Pharmacokinetic/Pharmacodynamic ModelColistin-based combination therapy has become an important strategy to combat the carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal dosage regimen selection for the combination with maximum efficacy is challenging.
PharmacologyCefepime Pharmacokinetics in Critically Ill Pediatric Patients Receiving Continuous Renal Replacement TherapyThis retrospective study included pediatric intensive care unit patients receiving continuous veno-venous hemodiafiltration (CVVHDF) being treated with cefepime. The free drug concentration above one time the MIC (fT>1×MIC) and four times a presumed MIC (fT>4×MIC) of 8 μg/ml were calculated.
PharmacologyNovel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniaePolymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae. However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility.
PharmacologyIn Vitro Mechanistic Study of the Distribution of Lascufloxacin into Epithelial Lining FluidThe present study aimed to clarify the mechanism underlying the high distribution of lascufloxacin in epithelial lining fluid (ELF). Involvement of transporters was examined by transcellular transport across Calu-3 and transporter-overexpressing cells; the binding of lascufloxacin to ELF components was examined by an organic solvent-water partitioning system that employed pulmonary surfactant and phospholipids.
PharmacologyIn Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae InfectionLYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of...
PharmacologyPopulation Pharmacokinetics with Monte Carlo Simulations of Gentamicin in a Population of Severely Ill Adult Patients from Sub-Saharan Africa...In sub-Saharan Africa (SSA), gentamicin is commonly used for severe infections in non-intensive-care-unit (ICU) settings, but pharmacokinetic and pharmacodynamic data for this specific population are lacking. We performed a population pharmacokinetic study in an adult Mozambican non-ICU hospital population treated with gentamicin (n = 48) and developed a pharmacokinetic model using nonlinear mixed-effects modeling.
PharmacologyPopulation Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical StudiesPlazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae. Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW.
PharmacologyPopulation Pharmacokinetic Assessment of Vancomycin Dosing in the Large Pediatric PatientThe most appropriate vancomycin dosing strategy in pediatric patients weighing ≥70 kg (weight based versus non-weight based) to achieve an area under the concentration-time curve (AUC) of ≥400 mg·liter/h and a trough concentration of <20 mg/liter is not known. Population pharmacokinetic analysis determined that dosing of vancomycin should be weight based using fat-free mass, with appropriate adjustment for kidney dysfunction.
...
PharmacologyPharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside FexinidazoleFexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease.
Letter to the Editor
Errata
Masthead
Current Issue
About AAC
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.
For Authors
Dr. Louis B. Rice, Editor in Chief