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Microbiology Spectrum Aug 2022Seven drug-resistant strains of Stenotrophomonas maltophilia were isolated from patients at two university hospitals in Nepal. S. maltophilia JUNP497 was found to encode...
Stenotrophomonas maltophilia from Nepal Producing Two Novel Antibiotic Inactivating Enzymes, a Class A β-Lactamase KBL-1 and an Aminoglycoside 6'--Acetyltransferase AAC(6')-Iap.
Seven drug-resistant strains of Stenotrophomonas maltophilia were isolated from patients at two university hospitals in Nepal. S. maltophilia JUNP497 was found to encode a novel class A β-lactamase, KBL-1 (Kathmandu β-lactamase), consisting of 286 amino acids with 52.98% identity to PSV-1. Escherichia coli transformants expressing were less susceptible to penicillins. The recombinant KBL-1 protein efficiently hydrolyzed penicillins. The genomic environment surrounding was a unique structure, with the upstream region derived from strains in China and the downstream region from strains in India. S. maltophilia JUNP350 was found to encode a novel 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap, consisting of 155 amino acids with 85.0% identity to AAC(6')-Iz. E. coli transformants expressing were less susceptible to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin and tobramycin. The recombinant AAC(6')-Iap protein acetylated all aminoglycosides tested, except for apramycin and paromomycin. The genomic environment surrounding was 90.99% identical to that of S. maltophilia JV3 obtained from a rhizosphere in Brazil. Phylogenetic analysis based on whole genome sequences showed that most S. maltophilia isolates in Nepal were similar to those isolates in European countries, including Germany and Spain. The emergence of drug-resistant S. maltophilia has become a serious problem in medical settings worldwide. The present study demonstrated that drug-resistant S. maltophilia strains in Nepal harbored novel genes encoding a class A β-lactamase, KBL-1, or a 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap. Genetic backgrounds of most S. maltophilia strains in Nepal were similar to those in European countries. Surveillance of drug-resistant S. maltophilia in medical settings in Nepal is necessary.
Topics: Acetyltransferases; Amino Acids; Anti-Bacterial Agents; Escherichia coli; Humans; Microbial Sensitivity Tests; Nepal; Penicillins; Phylogeny; Stenotrophomonas maltophilia; beta-Lactamases
PubMed: 35862995
DOI: 10.1128/spectrum.01143-22 -
Journal of Infection and Chemotherapy :... Sep 2022Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis...
INTRODUCTION
Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database.
METHODS
Data of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis.
RESULTS
The proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation.
CONCLUSIONS
From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.
Topics: Aminoglycosides; Anti-Bacterial Agents; Dibekacin; Drug Monitoring; Humans; Japan; Methicillin-Resistant Staphylococcus aureus
PubMed: 35606308
DOI: 10.1016/j.jiac.2022.05.007 -
Nucleic Acids Research Jul 2021How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action...
How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from ∼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome. Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by ∼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.
Topics: Anti-Bacterial Agents; Dibekacin; Kinetics; Peptide Elongation Factor G; Peptide Termination Factors; Peptides; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA, Messenger; RNA, Transfer, Amino Acyl; Ribosomes
PubMed: 34125898
DOI: 10.1093/nar/gkab495 -
Journal of Microbiology, Immunology,... Dec 2021Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
BACKGROUND
Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
METHODS
Arbekacin minimum inhibitory concentration (MIC) values were determined for 296 drug-resistant Gram-negative bacilli, and compared to previously determined plazomicin, amikacin, gentamicin, and tobramycin MIC values.
RESULTS
The MIC values required to inhibit 50% and 90% of isolates (MIC and MIC, respectively) were 16 and >128 μg/ml, respectively.
CONCLUSIONS
Arbekacin showed similar MIC values to amikacin and gentamicin, a lower MIC value than tobramycin, and a higher MIC value than plazomicin.
Topics: Anti-Bacterial Agents; Dibekacin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests
PubMed: 32962921
DOI: 10.1016/j.jmii.2020.08.018 -
Antimicrobial Agents and Chemotherapy Sep 2020ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial...
ME1100 (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 model with 1st-order elimination, nonclinical PK-PD targets from one-compartment and/or infection models, and surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log CFU reductions from baseline for , , and Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log CFU reduction from baseline at MIC values above the MIC value for (8 μg/ml), (4 μg/ml), and (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.
Topics: Anti-Bacterial Agents; Dibekacin; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus
PubMed: 32661000
DOI: 10.1128/AAC.02367-19 -
Antimicrobial Agents and Chemotherapy Aug 2019ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia....
ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)·[(CLcrn-77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data ( of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.
Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Dibekacin; Female; Humans; Male; Middle Aged; Models, Biological; Nebulizers and Vaporizers; Pharmaceutical Solutions; Young Adult
PubMed: 31182524
DOI: 10.1128/AAC.00267-19