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The Journal of the Association of... Dec 2018Increasing resistance to currently available antimicrobials has led to the development of new agents. Arbekacin is aminoglycoside antibiotic currently used in Japan and... (Randomized Controlled Trial)
Randomized Controlled Trial
A Multicentre, Open label, Randomized, Comparative, Parallel Group, Active-controlled, Phase III Clinical Trial to Evaluate Safety and Efficacy of Arbekacin Sulphate Injection versus Vancomycin Injection in Patients Diagnosed with MRSA Infection.
BACKGROUND
Increasing resistance to currently available antimicrobials has led to the development of new agents. Arbekacin is aminoglycoside antibiotic currently used in Japan and Korea for the treatment of infections caused by multi-resistant bacteria including MRSA. Currently there is no published data available for use of Arbekacin in Indian patient population, thus the present study was conducted to evaluate the safety and efficacy of Arbekacin in Indian population.
MATERIAL AND METHODS
The study was a phase III, multi-centre, open-label, randomised comparative, active control study. Subjects with microbiologically confirmed MRSA infection were randomized in the study to receive either Arbekacin sulphate 200 mg OD or Vancomycin hydrochloride 1000 mg BD for a period of 7 to 14 days. The primary endpoint was to evaluate the overall cure rate i.e. Clinical and microbiological cure during the study.
RESULTS
A total of 162 patients were randomized in 2 treatment groups (i.e. 81 patients in each group). Out of these microbiologically confirmed MRSA patients, 153 patients were admitted for SSTI while 9 patients were admitted for CAP. Overall cure rate of MRSA infection (clinical as well as microbiological cure) was comparable in both the treatment groups i.e. 97.5% (79/81) in Arbekacin group and 100 % (79/79) in Vancomycin group (p value: 0.159). Both Arbekacin and Vancomycin were well tolerated by the patients during the study period.
CONCLUSION
Arbekacin can be considered as safe and effective alternative to vancomycin in the management of MRSA infections.
Topics: Anti-Bacterial Agents; Dibekacin; Humans; Japan; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Vancomycin
PubMed: 31313549
DOI: No ID Found -
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 -
Die Pharmazie Jun 2019Four potential process related impurities were detected during the impurity profiling study of a semi-synthetic aminoglycoside antibiotic, arbekacin. The current...
Four potential process related impurities were detected during the impurity profiling study of a semi-synthetic aminoglycoside antibiotic, arbekacin. The current preparation process from 3',4'-didehydro-dibekacin easily generates the specific impurities with similar structures to arbekacin that makes hard to separate and identify the residues. HPLC-ELSD and column chromatography loading weakly acidic cation exchange resin were used for the detection and isolation of these process impurities. Based on the synthesis and spectral data (ESI-MS/MS, H NMR, C NMR and 2D-NMR), the structures of these impurities were characterized as dibekacin, 3-N-γ-aminohydroxybutyric (AHB)-dibekacin, 3''-N-AHB-dibekacin and 1,3-N,N-di-AHB-dibekacin. The characterization of these impurities is discussed in detail and our current efforts may help to develop a general strategy for isolation and identification of aminoglycoside products.
Topics: Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Dibekacin; Drug Contamination
PubMed: 31138373
DOI: 10.1691/ph.2019.8242 -
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 Antibiotics Mar 2018On the occasion of the 60th anniversary of the discovery (1957) of kanamycin (KM), a series of research achievements on KM and its semisynthetic derivative Arbekacin... (Review)
Review
On the occasion of the 60th anniversary of the discovery (1957) of kanamycin (KM), a series of research achievements on KM and its semisynthetic derivative Arbekacin (ABK) are outlined. KM was first used clinically in 1958 and was appreciated for its remarkable curing effect on various bacterial infections, especially tuberculosis. ABK is a KM derivative rationally semisynthesized to overcome KM resistance due to enzymatic phosphorylation and acetylation. Since its approval in 1990 as an anti-MRSA drug, ABK has been and still is effectively used in chemotherapy because MRSA rarely develops high ABK-resistance. Research that illuminated the unique features of ABK enabling it to resist the development of resistance by MRSA are also described.
Topics: Animals; Anti-Bacterial Agents; Dibekacin; Humans; Kanamycin; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections
PubMed: 29402999
DOI: 10.1038/s41429-017-0017-8 -
The Journal of Antibiotics Mar 2018To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel...
To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC and MIC of TS2037 against clinical isolates of MRSA (n = 54) were both 0.25 µg/mL, and no resistant strain was observed. The MIC and MIC of TS2037 against clinical isolates of P. aeruginosa (n = 54) were 1 and 4 µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6')-APH(2″), aminoglycoside-6'-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6')-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-β-D-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0 μM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.
Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cell Line; Dibekacin; Drug Resistance, Bacterial; Epithelial Cells; Kanamycin Kinase; Kidney Diseases; Methicillin-Resistant Staphylococcus aureus; Mice; Pseudomonas Infections; Pseudomonas aeruginosa; Staphylococcal Infections
PubMed: 29348522
DOI: 10.1038/s41429-017-0002-2 -
European Journal of Orthopaedic Surgery... May 2018Antibiotic-loaded acrylic cement (ALAC) spacers are useful for treatment of infected prostheses in the course of a two-stage revision. Spacers are handmade or are made...
PURPOSE
Antibiotic-loaded acrylic cement (ALAC) spacers are useful for treatment of infected prostheses in the course of a two-stage revision. Spacers are handmade or are made using a commercial template, with reportedly good treatment outcomes. This study aimed to confirm the usefulness of custom-made ALAC spacers shaped like bipolar hip prostheses using a dental silicone template for treatment of infected hip prostheses, and described their manufacture.
METHODS
This study evaluated 10 patients who underwent two-stage revision for treatment of infected hip prostheses. Custom-made ALAC spacers were used in all patients. Templates were made with dental silicone. We investigated the following in treatment of the infected hip prostheses: bacterial pathogens; antibiotic-cement mixtures; waiting time to revision; dislocation, breakage, and migration of custom-made ALAC spacers; current hip status; progress during follow-up; presence or absence of recurrence; and walking ability.
RESULTS
Dislocation, breakage, and migration were not observed in custom-made ALAC spacers. All patients recovered after two-stage revision without additional surgery and showed no recurrence during the follow-up period.
CONCLUSION
Custom-made ALAC spacers shaped like bipolar hip prostheses using a template made of dental silicone may be useful for treatment of infected hip prostheses.
Topics: Adult; Aged; Anti-Bacterial Agents; Arthroplasty, Replacement, Hip; Bone Cements; Dibekacin; Equipment Design; Female; Hip Prosthesis; Humans; Male; Methicillin Resistance; Middle Aged; Polymethyl Methacrylate; Prosthesis-Related Infections; Reoperation; Silicone Elastomers; Staphylococcal Infections; Surgical Instruments; Time-to-Treatment; Treatment Outcome; Vancomycin
PubMed: 29332203
DOI: 10.1007/s00590-017-2117-3 -
Journal of Infection and Chemotherapy :... Jan 2018This study describes highly aminoglycoside-resistant Klebsiella pneumoniae and Klebsiella oxytoca clinical isolates obtained from an inpatient in Okinawa, Japan, with no...
This study describes highly aminoglycoside-resistant Klebsiella pneumoniae and Klebsiella oxytoca clinical isolates obtained from an inpatient in Okinawa, Japan, with no known record of traveling overseas. The minimum inhibitory concentrations of amikacin and arbekacin against these strains were >1024 μg/ml. Whole-genome sequencing analysis revealed that these isolates harbored armA, which encodes a 16S rRNA methylase, ArmA, that confers pan-aminoglycoside resistance. This is the second report of K. pneumoniae harboring armA and the first report of K. oxytoca harboring a 16S rRNA methylase encoding gene in Japan.
Topics: Aged; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Dibekacin; Drug Resistance, Bacterial; Female; Humans; Japan; Klebsiella Infections; Klebsiella oxytoca; Klebsiella pneumoniae; Methyltransferases; Microbial Sensitivity Tests; Whole Genome Sequencing
PubMed: 29066218
DOI: 10.1016/j.jiac.2017.09.006 -
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