Minireview
MinireviewPast and Present Perspectives on β-Lactamasesβ-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years ago. These well-studied enzymes, currently numbering almost 2,800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally occurring β-lactams.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsStudies on Aminoglycoside Susceptibility Identify a Novel Function of KsgA To Secure Translational Fidelity during Antibiotic StressAntibiotic resistance has become a global crisis. Studies on the mechanism of bacterial tolerance to antibiotics will not only increase our conceptual understanding of bacterial death but also provide potential targets for novel inhibitors.
Mechanisms of Action: Physiological EffectsAntibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile InfectionAntibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis and quantified the link between this intensity and mortality.
Mechanisms of Resistance
Mechanisms of ResistanceSulfide Protects Staphylococcus aureus from Aminoglycoside Antibiotics but Cannot Be Regarded as a General Defense Mechanism against AntibioticsSulfide production has been proposed to be a universal defense mechanism against antibiotics in bacteria (K. Shatalin, E.
Mechanisms of ResistanceCoidentification of mcr-4.3 and blaNDM-1 in a Clinical Enterobacter cloacae Isolate from China...We describe the first report of a clinical colistin-resistant ST84 Enterobacter cloacae isolate coharboring mcr-4.3 (previously named mcr-4.2) and blaNDM-1 from a patient in China. The blaNDM-1-harboring IncX3 plasmid and the novel mcr-4.3-harboring ColE plasmid were completely sequenced.
Mechanisms of ResistanceLoss-of-Function Mutations in epaR Confer Resistance to ϕNPV1 Infection in Enterococcus faecalis OG1RFEnterococcus faecalis is a Gram-positive opportunistic pathogen that inhabits the human gastrointestinal tract. Because of the high frequency of antibiotic resistance among Enterococcus clinical isolates, interest in using phage to treat enterococcal infections and to decolonize high-risk patients...
Mechanisms of ResistanceIn Silico Typing and Comparative Genomic Analysis of IncFIIK Plasmids and Insights into the Evolution of Replicons, Plasmid Backbones, and Resistance Determinant ProfilesIncFIIK plasmids are associated with the acquisition and dissemination of multiple-antimicrobial resistance in Klebsiella pneumoniae and often encountered in clinical isolates of this species. Since the phylogeny and evolution of IncFIIK plasmids remain unclear, here we performed large-scale in silico typing and comparative analysis of...
Mechanisms of ResistanceFirst Clinical Isolation of an Azole-Resistant Aspergillus fumigatus Isolate Harboring a TR46 Y121F T289A Mutation in South AmericaOne of the most recently described Aspergillus fumigatus CYP51A-mediated azole resistance mechanisms is TR46 Y121F T289A. Clinical A. fumigatus strains harboring these substitutions have been reported worldwide, with the exception of South America.
Mechanisms of ResistanceValidation of Novel Mycobacterium tuberculosis Isoniazid Resistance Mutations Not Detectable by Common Molecular TestsResistance to the first-line antituberculosis (TB) drug isoniazid (INH) is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole-genome sequencing (WGS) to analyze 52 phenotypically INH-R Mycobacterium tuberculosis complex (MTBC) clinical isolates that...
Mechanisms of ResistanceThe PA3177 Gene Encodes an Active Diguanylate Cyclase That Contributes to Biofilm Antimicrobial Tolerance but Not Biofilm Formation by Pseudomonas aeruginosaA hallmark of biofilms is their heightened resistance to antimicrobial agents. Recent findings suggested a role for bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) in the susceptibility of bacteria to antimicrobial agents; however, no c-di-GMP modulating enzyme(s) contributing to the drug tolerance phenotype of biofilms has been identified.
Mechanisms of ResistanceRelative Contribution of the ABC Transporters Cdr1, Pdh1, and Snq2 to Azole Resistance in Candida glabrata...The utility of the azole antifungals for the treatment of invasive candidiasis is severely hampered by azole resistance in Candida glabrata. This resistance is mediated almost exclusively by activating mutations in the zinc cluster transcription factor Pdr1, which controls the genes encoding the multidrug resistance transporters Cdr1, Pdh1, and Snq2.
Mechanisms of ResistanceCharacterization of Mutations Conferring Resistance to Rifampin in Mycobacterium tuberculosis Clinical StrainsResistance of Mycobacterium tuberculosis to rifampin (RMP), mediated by mutations in the rpoB gene coding for the beta-subunit of RNA polymerase, poses a serious threat to the efficacy of clinical management and, thus, control programs for tuberculosis (TB). The contribution of many individual rpoB mutations to the development and level of RMP...
Mechanisms of ResistanceCharacterization of the AmpC β-Lactamase from Burkholderia multivoransBurkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from cystic fibrosis. β-Lactam antibiotics are recommended as therapy for infections due to B.
Mechanisms of ResistanceGenetic and Biochemical Characterization of OXA-535, a Distantly Related OXA-48-Like β-LactamaseOXA-535 is a chromosome-encoded carbapenemase of Shewanella bicestrii JAB-1 that shares only 91.3% amino acid sequence identity with OXA-48. Catalytic efficiencies are similar to those of OXA-48 for most β-lactams, except for ertapenem, where a 2,000-fold-higher efficiency was observed with OXA-535.
Mechanisms of ResistanceMode of Action of the Monobactam LYS228 and Mechanisms Decreasing In Vitro Susceptibility in Escherichia coli and Klebsiella pneumoniaeThe monobactam scaffold is attractive for the development of new agents to treat infections caused by drug-resistant Gram-negative bacteria because it is stable to metallo-β-lactamases (MBLs). However, the clinically used monobactam aztreonam lacks stability to serine β-lactamases (SBLs) that are often coexpressed with MBLs.
Mechanisms of ResistanceImpact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 ExpressionTwenty-three Klebsiella pneumoniae (blaDHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/ml for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected from representative isolates.
Mechanisms of ResistanceGenetic Determinants of Penicillin Tolerance in Vibrio choleraeMany bacteria are resistant to killing (tolerant) by typically bactericidal antibiotics due to their ability to counteract drug-induced cell damage. Vibrio cholerae, the cholera agent, displays an unusually high tolerance to diverse inhibitors of cell wall synthesis.
Mechanisms of ResistanceMutation-Driven Evolution of Pseudomonas aeruginosa in the Presence of either Ceftazidime or Ceftazidime-AvibactamCeftazidime-avibactam is a combination of β-lactam/β-lactamase inhibitor, the use of which is restricted to some clinical cases, including cystic fibrosis patients infected with multidrug-resistant Pseudomonas aeruginosa, in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for...
Mechanisms of ResistanceLimited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole SusceptibilityMultiple Erg11 amino acid substitutions were identified in clinical isolates of Candida auris originating from India and Colombia. Elevated azole MICs were detected in Saccharomyces cerevisiae upon heterologous expression of C. auris...
Susceptibility
SusceptibilityNovel Approaches To Kill Toxoplasma gondii by Exploiting the Uncontrolled Uptake of Unsaturated Fatty Acids and Vulnerability to Lipid Storage Inhibition of the ParasiteToxoplasma gondii, an obligate intracellular parasite replicating in mammalian cells within a parasitophorous vacuole (PV), is an avid scavenger of lipids retrieved from the host cell. Following lipid uptake, this parasite stores excess lipids in lipid droplets (LD).
SusceptibilityIn Vitro Activity of LYS228, a Novel Monobactam Antibiotic, against Multidrug-Resistant EnterobacteriaceaeLYS228 is a novel monobactam with potent activity against Enterobacteriaceae. LYS228 is stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency against the majority of extended-spectrum β-lactamase (ESBL)-producing...
SusceptibilitySynergistic Activity of Colistin-Containing Combinations against Colistin-Resistant EnterobacteriaceaeResistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We...
SusceptibilityScreening a Repurposing Library for Inhibitors of Multidrug-Resistant Candida auris Identifies Ebselen as a Repositionable Candidate for Antifungal Drug DevelopmentSince its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris is typically intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B.
SusceptibilityMinocycline Has No Clear Role in the Treatment of Mycobacterium abscessus DiseaseMycobacterium abscessus causes a difficult-to-treat pulmonary disease (MAb-PD). After initial intravenous treatment, minocycline is recommended in the oral continuation phase of treatment.
SusceptibilityAPX001A In Vitro Activity against Contemporary Blood Isolates and Candida auris Determined by the EUCAST Reference MethodAPX001A is the active moiety of the first-in-class drug candidate APX001. So far, most susceptibility testing studies have examined ≤30 isolates/species, and only one used the EUCAST method.
Biologic Response Modifiers
Biologic Response ModifiersEffect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile InfectionClostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and the high incidence of recurrence. We previously reported protection of mice from CDI using the antigerminant bile salt analog CamSA.
Antiviral Agents
Antiviral AgentsSensitivity of the C-Terminal Nuclease Domain of Kaposi's Sarcoma-Associated Herpesvirus ORF29 to Two Classes of Active-Site LigandsKaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, belongs to the Herpesviridae family, whose members employ a multicomponent terminase to resolve nonparametric viral DNA into genome-length units prior to their packaging. Homology modeling of the ORF29 C-terminal nuclease domain (pORF29C) and bacteriophage Sf6 gp2 have suggested...
Antiviral AgentsDevelopment and Validation of a Phenotypic High-Content Imaging Assay for Assessing the Antiviral Activity of Small-Molecule Inhibitors Targeting Zika VirusZika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat ZIKV infection, and accordingly, there is an unmet medical need for the discovery of new therapies.
Antiviral AgentsNovel Potent Capsid Assembly Modulators Regulate Multiple Steps of the Hepatitis B Virus Life CycleThe assembly of hepatitis B virus (HBV) core protein (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies.
Antiviral AgentsExtended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and PreventionRegimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses.
Antiviral AgentsNo Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B InfectionTenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles.
Antiviral AgentsPooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical TrialsOver 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF)...
Antiviral AgentsIn Vitro Antiviral Activity of Cabotegravir against HIV-2We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naive individuals. HIV-2 was sensitive to cabotegravir in single-cycle and spreading-infection assays, with 50% effective concentrations (EC50s) in the low to subnanomolar range; comparable results were obtained for HIV-1 in both assay formats.
Epidemiology and Surveillance
Epidemiology and SurveillanceAbsence of K13 Polymorphism in Plasmodium falciparum from Brazilian Areas Where the Parasite Is EndemicPlasmodium falciparum artemisinin-resistant parasites can be evaluated by examining polymorphisms in the kelch (PfK13) domain. A total of 69 samples from patients with falciparum malaria were analyzed.
Epidemiology and SurveillanceExtensive Genetic Commonality among Wildlife, Wastewater, Community, and Nosocomial Isolates of Escherichia coli Sequence Type 131 (H30R1 and H30Rx Subclones) That Carry blaCTX-M-27 or blaCTX-M-15Escherichia coli sequence type 131 (ST131) is currently one of the leading causes of multidrug-resistant extraintestinal infections globally. Here, we analyzed the phenotypic and genotypic characteristics of 169 ST131 isolates from various sources (wildlife, wastewater, companion animals, community, and hospitals) to determine whether wildlife and the environment...
Epidemiology and SurveillanceVarious Sequence Types of Enterobacteriaceae Isolated from Commercial Chicken Farms in China and Carrying the blaNDM-5 GeneA total of 108 meropenem-resistant Enterobacteriaceae isolates were obtained from 1,658 rectal swabs collected from 15 unrelated commercial chicken farms in China between 2014 and 2016. These samples yielded 16 Escherichia coli and 2 ...
Epidemiology and SurveillanceTrend and Pattern of Antimicrobial Resistance in Molluscan Vibrio Species Sourced to Canadian EstuariesThe emergence of antimicrobial resistance (AMR) in foodborne bacteria is a growing concern worldwide. AMR surveillance is a key element in understanding the implications resulting from the use of antibiotics for therapeutic as well as prophylactic needs.
Epidemiology and SurveillanceClinical and Molecular Correlates of Escherichia coli Bloodstream Infection from Two Geographically Diverse Centers in Rochester, Minnesota, and SingaporeEscherichia coli bacteremia is caused mainly by sequence type complex 131 (STc131) and two clades within its fluoroquinolone-resistance-associated H30 subclone, H30R1 and H30Rx. We examined clinical and molecular correlates of E. coli bacteremia in two geographically...
Epidemiology and SurveillanceIn Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference LaboratoriesMonitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of isavuconazole against 4,856 invasive yeasts and molds collected worldwide.
Experimental Therapeutics
Experimental TherapeuticsSignificantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive CandidiasisAPX001 is a first-in-class, intravenous and orally available, broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 to 2.75 h in mice versus 2 to 2.5 days in humans), making the exploration of efficacy in mouse models difficult.
Experimental TherapeuticsEffective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal CiprofloxacinNontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging.
Experimental TherapeuticsCyclic Nucleotide-Specific Phosphodiesterases as Potential Drug Targets for Anti-Leishmania TherapyThe available treatments for leishmaniasis are less than optimal due to inadequate efficacy, toxic side effects, and the emergence of resistant strains, clearly endorsing the urgent need for discovery and development of novel drug candidates. Ideally, these should act via an alternative mechanism of action to avoid cross-resistance with the current drugs.
Experimental TherapeuticsBroad Spectrum and Safety of Oral Treatment with a Promising Nitrosylated Chalcone in Murine LeishmaniasisThe oral efficacy and safety of a leishmanicidal nitrochalcone (CH8) were studied in BALB/c mouse infections with Leishmania amazonensis and Leishmania infantum. Although 10-fold-higher doses of CH8 were needed to produce the same antiparasitic effect as that seen with the reference drug miltefosine...
Experimental TherapeuticsAssessing the Effectiveness of Curative Benznidazole Treatment in Preventing Chronic Cardiac Pathology in Experimental Models of Chagas DiseaseChagasic heart disease develops in 30% of those infected with the protozoan parasite Trypanosoma cruzi, but can take decades to become symptomatic. Because of this, it has been difficult to assess the extent to which antiparasitic therapy can prevent the development of pathology.
Experimental TherapeuticsEvaluation of Oritavancin Combinations with Rifampin, Gentamicin, or Linezolid against Prosthetic Joint Infection-Associated Methicillin-Resistant Staphylococcus aureus Biofilms by Time-Kill AssaysThe antibiofilm activity of oritavancin in combination with rifampin, gentamicin, or linezolid was evaluated against 10 prosthetic joint infection (PJI)-related methicillin-resistant Staphylococcus aureus (MRSA) isolates by time-kill assays. Oritavancin combined with rifampin demonstrated statistically significant bacterial reductions compared with those of either...
Experimental TherapeuticsLysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine ModelThe cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response that results primarily in low-affinity IgM antibodies.
Clinical Therapeutics
Clinical TherapeuticsProspective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial TherapyThe empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known.
Clinical TherapeuticsA Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine SettingThere has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to health care systems. An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice-monthly multidisciplinary team meetings, and a dedicated weekly...
Clinical TherapeuticsIn Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung DiseaseAlthough it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD....
Clinical TherapeuticsSingle-Center Pharmacokinetic Study and Simulation of a Low Meropenem Concentration in Brain-Dead Organ DonorsMeropenem is an ultrabroad-spectrum antibiotic of the carbapenem family. In brain-dead organ donors, administration of standard meropenem dosages does not reach therapeutic levels.
Clinical TherapeuticsEffects of Phage Endolysin SAL200 Combined with Antibiotics on Staphylococcus aureus InfectionPhages and their derivatives are increasingly being reconsidered for use in the treatment of bacterial infections due to the rising rates of antibiotic resistance. We assessed the antistaphylococcal effect of the endolysin SAL200 in combination with standard-of-care (SOC) antibiotics.
Clinical TherapeuticsPopulation Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body SizesDespite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese,...
Clinical TherapeuticsClinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal InfectionsPosaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole.
Clinical TherapeuticsNontuberculous Mycobacterial Lung Diseases Caused by Mixed Infection with Mycobacterium avium Complex and Mycobacterium abscessus ComplexMycobacterium avium complex (MAC) and M. abscessus complex (MABC) comprise the two most important human pathogen groups causing nontuberculous mycobacterial lung disease (NTM-LD). However, there are limited data regarding NTM-LD caused by mixed NTM infections.
Pharmacology
PharmacologyPharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection ModelThe Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures.
PharmacologyPopulation Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum MalariaThe artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies.
PharmacologyImpact of Antibiotic Treatment on the Burden of Nasal Staphylococcus aureus among Hospitalized PatientsWe examined the impact of systemic antibiotics on the burden of nasal Staphylococcus aureus in hospitalized patients. Of 1,482 patients, 237 (16%) had nasal methicillin-susceptible S. aureus (MSSA) and 92 (6%) had nasal methicillin-resistant...
PharmacologyLocal Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin BDisfiguring skin lesions caused by several species of the Leishmania parasite characterize cutaneous leishmaniasis (CL). Successful treatment of CL with intravenous (i.v.) liposomal amphotericin B (LAmB) relies on the presence of adequate antibiotic concentrations at the dermal site of infection within the inflamed skin.
PharmacologyStructure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosisMacozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-...
PharmacologyIncreased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of TuberculosisPatients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses.
PharmacologyPopulation Pharmacokinetics of Amikacin in Adult Patients with Cystic FibrosisPractitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy.
PharmacologyValidation of a Dried Blood Spot Ceftriaxone Assay in Papua New Guinean Children with Severe Bacterial InfectionsDried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study, we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children with severe illness from Papua New Guinea (PNG), a setting in which health care resources are limited and anemia is common.
PharmacologyValidation of Heel Stick Microsampling To Optimize Micafungin Doses in Neonates and Young InfantsMajor gaps exist in our knowledge of antimicrobial pharmacokinetics in critically ill neonates and infants that require validated microsampling and bioanalysis methods to support therapeutic drug monitoring. We compared serially collected intravenous (i.v.) and heel stick capillary (HSC)-sampled plasma concentrations of micafungin (8 mg/kg) in eight infants born preterm with systemic candidiasis.
PharmacologyMicrodialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental PeritonitisThe purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular veins, hind leg muscles, and peritoneal cavities of control rats (n = 5) and rats...
PharmacologyEffect of Pregnancy on the Pharmacokinetic Interaction between Efavirenz and Lumefantrine in HIV-Malaria CoinfectionArtemether-lumefantrine is often coadministered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in nonpregnant adults.
PharmacologyBiopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. AminoglycosidesAmikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively.
PharmacologyEx Vivo Characterization of Effects of Renal Replacement Therapy Modalities and Settings on Pharmacokinetics of Meropenem and VaborbactamThe combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH).
PharmacologyPopulation Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize DosingAmodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses.
Letters to the Editor
Erratum
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