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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 -
MicrobiologyOpen Jun 2019Kanamycin B as the secondary metabolite of wild-type Streptomyces kanamyceticus (S. kanamyceticus) ATCC12853 is often used for the synthesis of dibekacin and arbekacin....
Kanamycin B as the secondary metabolite of wild-type Streptomyces kanamyceticus (S. kanamyceticus) ATCC12853 is often used for the synthesis of dibekacin and arbekacin. To construct the strain has the ability for kanamycin B production; the pSET152 derivatives from Escherichia coli ET12567 were introduced to S. kanamyceticus by intergeneric conjugal transfer. In this study, we established a reliable genetic manipulation system for S. kanamyceticus. The key factors of conjugal transfer were evaluated, including donor-to-recipient ratio, heat-shock, and the overlaying time of antibiotics. When spores were used as recipient, the optimal conjugation frequency was up to 6.7 × 10 . And mycelia were used as an alternative recipient for conjugation instead of spores; the most suitable donor-to-recipient ratio is 1:1 (10 :10 ). After incubated for only 10-12 hr and overlaid with antibiotics subsequently, the conjugation frequency can reach to 6.2 × 10 which is sufficient for gene knockout and other genetic operation. Based on the optimized conjugal transfer condition, kanJ was knocked out successfully. The kanamycin B yield of kanJ-disruption strain can reach to 543.18 ± 42 mg/L while the kanamycin B yield of wild-type strain was only 46.57 ± 12 mg/L. The current work helps improve the content of kanamycin B in the fermentation broth of S. kanamyceticus effectively to ensure the supply for the synthesis of several critical semisynthetic antibiotics.
Topics: Anti-Bacterial Agents; Conjugation, Genetic; Escherichia coli; Fermentation; Gene Transfer Techniques; Kanamycin; Plasmids; Streptomyces
PubMed: 30449069
DOI: 10.1002/mbo3.747 -
Experimental and Therapeutic Medicine Oct 2018The present study aimed to investigate the bacterial distribution, changes in drug susceptibility and clinical characteristics in patients with diabetic foot infection...
The present study aimed to investigate the bacterial distribution, changes in drug susceptibility and clinical characteristics in patients with diabetic foot infection (DFI). A retrospective analysis of 216 patients with DFI treated at Xinxiang Central Hospital between 2013 and 2016 was carried out to analyze the bacterial distribution, changes of susceptibility and clinical characteristics. A total of 262 pathogenic strains were isolated from 216 patients with DFI. Among them, 43.13% exhibited Gram-positive (G) bacteria, 45.04% exhibited Gram-negative (G) bacteria and 11.83% was other. Between 2013 and 2016, the susceptibility of pathogenic bacteria to common antibacterial drugs showed a declining trend year by year. G bacteria had high susceptibility to vancomycin and acetazolamide; while G bacteria showed high susceptibility to dibekacin, panipenem and biapenem. The main clinical symptoms of the 216 patients included edema (98.61%), purulent secretions (62.96%) and lower extremity sepsis (58.80%). The top three complications of the 216 cases were lower extremity vascular disease (58.80%), peripheral neuropathy (39.81%) and kidney disease (26.39%). Logistic regression analysis showed that age [odds ratio (OR), 2.708; P=0.005], previous use of antibacterial drugs (OR, 3.816; P=0.007) and application of the third generation cephalosporins (OR, 3.014; P=0.008) were the independent risk factors of drug resistance in patients with DFI (P<0.05). There were numerous types of pathogens in patients with DFI, and all of them had certain drug resistance. The drug susceptibility was decreasing year by year. The pathogens and drug resistance in patients with DFI should be monitored to reduce the incidence of related complications and improve the prognosis of patients.
PubMed: 30214532
DOI: 10.3892/etm.2018.6530 -
The Journal of Antimicrobial... Aug 2017Mycobacterium abscessus is innately resistant to a variety of drugs thereby limiting therapeutic options. Bacterial resistance to aminoglycosides (AGs) is conferred...
OBJECTIVES
Mycobacterium abscessus is innately resistant to a variety of drugs thereby limiting therapeutic options. Bacterial resistance to aminoglycosides (AGs) is conferred mainly by AG-modifying enzymes, which often have overlapping activities. Several putative AG-modifying enzymes are encoded in the genome of M. abscessus . The aim of this study was to investigate the molecular basis underlying AG resistance in M. abscessus .
METHODS
M. abscessus deletion mutants deficient in one of three genes potentially involved in AG resistance, aac(2 ' ) , eis1 and eis2 , were generated by targeted gene inactivation, as were combinatorial double and triple deletion mutants. MICs were determined to study susceptibility to a variety of AG drugs and to capreomycin.
RESULTS
Deletion of aac(2 ' ) increased susceptibility of M. abscessus to kanamycin B, tobramycin, dibekacin and gentamicin C. Deletion of eis2 increased susceptibility to capreomycin, hygromycin B, amikacin and kanamycin B. Deletion of eis1 did not affect drug susceptibility. Equally low MICs of apramycin, arbekacin, isepamicin and kanamycin A for WT and mutant strains indicate that these drugs are not inactivated by either AAC(2 ' ) or Eis enzymes.
CONCLUSIONS
M. abscessus expresses two distinct AG resistance determinants, AAC(2 ' ) and Eis2, which confer clinically relevant drug resistance.
Topics: Aminoglycosides; Antibiotics, Antitubercular; Capreomycin; Drug Resistance, Bacterial; Gene Deletion; Genes, Bacterial; Microbial Sensitivity Tests; Mycobacterium abscessus
PubMed: 28486671
DOI: 10.1093/jac/dkx125 -
Annals of Laboratory Medicine Jul 2017
Topics: Adolescent; Anti-Bacterial Agents; DNA, Bacterial; Dibekacin; Female; Graft vs Host Disease; Humans; Immunocompromised Host; Mycoplasma Infections; Mycoplasma hominis; Polymerase Chain Reaction; Soft Tissue Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tigecycline; Transplantation, Homologous
PubMed: 28445018
DOI: 10.3343/alm.2017.37.4.346