aminoglycosides
Clinical TherapeuticsOptimizing Aminoglycoside Dosing Regimens for Critically Ill Pediatric Patients with Augmented Renal Clearance: a Convergence of Parametric and Nonparametric Population ApproachesAugmented renal clearance (ARC) can occur in critically ill pediatric patients receiving aminoglycosides such as gentamicin and tobramycin, yet optimal dosing strategies for ARC are undefined. We evaluated the probability of achieving efficacious or toxic exposures in pediatrics. Parallel population modeling of concentration strategies were pursued using Pmetrics v1.5.2 (nonparametric) and Monolix v2019R2 (parametric).
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Mechanisms of ResistanceA GC-Rich Prophage-Like Genomic Region of Mycoplasma bovirhinis HAZ141_2 Carries a Gene Cluster Encoding Resistance to Kanamycin and NeomycinRecently, a complete genome sequence of Mycoplasma bovirhinis HAZ141_2 was published showing the presence of a 54-kB prophage-like region. Bioinformatic analysis revealed that this region has a more than 40% GC content and a chimeric organization with three structural elements—a prophage continuous region, a restriction-modification cassette, and a highly...
Mechanisms of ResistancePseudomonas aeruginosa Polynucleotide Phosphorylase Controls Tolerance to Aminoglycoside Antibiotics by Regulating the MexXY Multidrug Efflux PumpPseudomonas aeruginosa is an opportunistic pathogen that shows high intrinsic resistance to a variety of antibiotics. The MexX-MexY-OprM efflux pump plays an important role in bacterial resistance to aminoglycoside antibiotics.
Clinical TherapeuticsA Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed MeningesVentriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically...
PharmacologyPharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation SolutionME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment...
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...
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...
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 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...
SusceptibilityActivity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals in 2016–2017: Effect of Different Breakpoint Criteria on Susceptibility Rates among AminoglycosidesPlazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and...