-
Antimicrobial Agents and Chemotherapy Nov 2006Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant...
Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CL(CR)), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CL(CR) + (26.5/age) (CL(CR) < 80 ml/min) and CL (liter/h) = 0.0130 CL(CR) + 0.0342WT + (26.5/age) (CL(CR) >/= 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Aminoglycosides; Anti-Bacterial Agents; Child; Dibekacin; Dose-Response Relationship, Drug; Female; Humans; Male; Methicillin Resistance; Middle Aged; Models, Statistical; Population; Reproducibility of Results; Sepsis; Staphylococcal Infections
PubMed: 17065621
DOI: 10.1128/AAC.00420-05 -
Journal of Korean Medical Science Apr 2006This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus...
This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinupristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillin-sulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.
Topics: Aminoglycosides; Ampicillin; Anti-Bacterial Agents; Dibekacin; Drug Resistance, Bacterial; Drug Synergism; Humans; In Vitro Techniques; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Sulbactam; Teicoplanin; Vancomycin; Virginiamycin
PubMed: 16614499
DOI: 10.3346/jkms.2006.21.2.188 -
Antimicrobial Agents and Chemotherapy Apr 2006We inoculated an in vitro pharmacodynamic model simultaneously with clinical isolates of methicillin-resistant Staphylococcus aureus and an enterocin-producing...
Impact of Enterococcus faecalis on the bactericidal activities of arbekacin, daptomycin, linezolid, and tigecycline against methicillin-resistant Staphylococcus aureus in a mixed-pathogen pharmacodynamic model.
We inoculated an in vitro pharmacodynamic model simultaneously with clinical isolates of methicillin-resistant Staphylococcus aureus and an enterocin-producing enterococcus (vancomycin-resistant Enterococcus faecalis, ampicillin susceptible) at 7 log10 CFU/ml to examine enterocin effects and antimicrobial activity on staphylococci. The investigated antimicrobial regimens were 100 mg arbekacin every 12 h (q12h), 6 mg daptomycin per kg of body weight/day, 600 mg linezolid q12h, and 100 mg tigecycline q24h alone and in combination (daptomycin, linezolid, and tigecycline) with arbekacin. Simulations were performed in triplicate; bacterial quantification occurred over 48 h, and development of resistance was evaluated throughout. When we evaluated the impact of antimicrobial activity against S. aureus alone, daptomycin demonstrated bactericidal activity (>or=3 log10 CFU/ml kill), whereas arbekacin, linezolid, and tigecycline displayed bacteriostatic activities (<3 log10 CFU/ml kill). In the mixed-pathogen model, early and distinctive stunting of S. aureus growth was noted (1.5 log CFU/ml difference) in the presence of enterocin-producing E. faecalis compared to growth controls run individually (P=0.02). Most noteworthy was that in the presence of enterocin-producing E. faecalis, bactericidal activity was observed with arbekacin and tigecycline and with the addition of arbekacin to linezolid. Antagonism was noted for the combination of tigecycline and arbekacin against S. aureus in the presence of enterocin-producing E. faecalis. Our research demonstrates that the inhibitory effect of E. faecalis contributed significantly to its overall antimicrobial impact on S. aureus. This contribution was enhanced or improved compared to the activity of each antimicrobial alone. Further research is warranted to determine the impact of polymicrobial infections on antimicrobial activity.
Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Dibekacin; Enterococcus faecalis; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Staphylococcus aureus; Tigecycline
PubMed: 16569844
DOI: 10.1128/AAC.50.4.1298-1303.2006 -
Biological & Pharmaceutical Bulletin Mar 2006An extract from ginger (root of Zingiber officinale) reduced the minimum inhibitory concentrations (MICs) of aminoglycosides in vancomycin-resistant enterococci (VRE)....
An extract from ginger (root of Zingiber officinale) reduced the minimum inhibitory concentrations (MICs) of aminoglycosides in vancomycin-resistant enterococci (VRE). The effective compound was isolated and identified as [10]-gingerol. In the presence of [10]-gingerol at 1/10 concentration of its own MIC, the MIC of arbekacin was lowered by 1/32 to 1/16. [10]-Gingerol also reduced the MICs of other aminoglycosides, and of bacitracin and polymixin B, but not of other antimicrobial agents tested. Because [10]-gingerol reduced the MICs of several aminoglycosides both in strains possessing or lacking aminoglycoside-modification enzymes, it seems that the effect of [10]-gingerol is not related to these enzymes, which mainly confer bacterial resistance against aminoglycosides. It seemed that a detergent-like effect of [10]-gingerol potentiated the antimicrobial activity of the aminoglycosides. In fact, some detergents such as sodium dodecyl sulfate (SDS) and Triton X-100 reduced the MICs of aminoglycosides, bacitracin and polymixin B in VRE. Since the intrinsic resistance to aminoglycosides in enterococci is due to low level of entry of the drugs into the cells, increase in the membrane permeability caused by [10]-gingerol will enhance the influx of aminoglycosides into enterococcal cells.
Topics: Acetyltransferases; Aminoglycosides; Anti-Bacterial Agents; Catechols; Cell Count; Colony Count, Microbial; Detergents; Dibekacin; Drug Synergism; Enterococcus faecalis; Fatty Alcohols; Microbial Sensitivity Tests; Mutagens; Phosphotransferases (Alcohol Group Acceptor); Sodium Dodecyl Sulfate; Structure-Activity Relationship; Surface-Active Agents; Vancomycin Resistance
PubMed: 16508142
DOI: 10.1248/bpb.29.443 -
Antimicrobial Agents and Chemotherapy Sep 2005We characterized multidrug-resistant Pseudomonas aeruginosa strains isolated from patients involved in an outbreak of catheter-associated urinary tract infections that...
Multidrug-resistant Pseudomonas aeruginosa strain that caused an outbreak in a neurosurgery ward and its aac(6')-Iae gene cassette encoding a novel aminoglycoside acetyltransferase.
We characterized multidrug-resistant Pseudomonas aeruginosa strains isolated from patients involved in an outbreak of catheter-associated urinary tract infections that occurred in a neurosurgery ward of a hospital in Sendai, Japan. Pulsed-field gel electrophoresis of SpeI-, XbaI-, or HpaI-digested genomic DNAs from the isolates revealed that clonal expansion of a P. aeruginosa strain designated IMCJ2.S1 had occurred in the ward. This strain possessed broad-spectrum resistance to aminoglycosides, beta-lactams, fluoroquinolones, tetracyclines, sulfonamides, and chlorhexidine. Strain IMCJ2.S1 showed a level of resistance to some kinds of disinfectants similar to that of a control strain of P. aeruginosa, ATCC 27853. IMCJ2.S1 contained a novel class 1 integron, In113, in the chromosome but not on a plasmid. In113 contains an array of three gene cassettes of bla(IMP-1), a novel aminoglycoside resistance gene, and the aadA1 gene. The aminoglycoside resistance gene, designated aac(6')-Iae, encoded a 183-amino-acid protein that shared 57.1% identity with AAC(6')-Iq. Recombinant AAC(6')-Iae protein showed aminoglycoside 6'-N-acetyltransferase activity by thin-layer chromatography. Escherichia coli expressing exogenous aac(6')-Iae showed resistance to amikacin, dibekacin, isepamicin, kanamycin, netilmicin, sisomicin, and tobramycin but not to arbekacin, gentamicins, or streptomycin. Alterations of gyrA and parC at the amino acid sequence level were detected in IMCJ2.S1, suggesting that such mutations confer the resistance to fluoroquinolones observed for this strain. These results indicate that P. aeruginosa IMCJ2.S1 has developed multidrug resistance by acquiring resistance determinants, including a novel member of the aac(6')-I family and mutations in drug resistance genes.
Topics: Acetyltransferases; Amino Acid Sequence; Anti-Bacterial Agents; Cross Infection; DNA, Bacterial; Disinfectants; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Gene Transfer, Horizontal; Genes, Bacterial; Genotype; Hospital Units; Humans; Integrons; Microbial Sensitivity Tests; Molecular Sequence Data; Neurosurgery; Phenotype; Pseudomonas Infections; Pseudomonas aeruginosa; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 16127047
DOI: 10.1128/AAC.49.9.3734-3742.2005 -
Emerging Infectious Diseases Jun 2005Emergence of the newly identified 16S rRNA methylases RmtA, RmtB, and ArmA in pathogenic gram-negative bacilli has been a growing concern. ArmA, which had been...
Emergence of the newly identified 16S rRNA methylases RmtA, RmtB, and ArmA in pathogenic gram-negative bacilli has been a growing concern. ArmA, which had been identified exclusively in Europe, was also found in several gram-negative pathogenic bacilli isolated in Japan, suggesting global dissemination of hazardous multiple aminoglycoside resistance genes.
Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Dibekacin; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Global Health; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Methyltransferases; Microbial Sensitivity Tests; RNA, Ribosomal, 16S
PubMed: 15963295
DOI: 10.3201/eid1106.040924 -
The Journal of Antibiotics Oct 2004A clinical isolate (designated PRC104) of methicillin-resistant Staphylococcus aureus was discovered with a novel aminoglycoside resistance profile, including unusually...
Characterization of a bifunctional aminoglycoside-modifying enzyme with novel substrate specificity and its gene from a clinical isolate of methicillin-resistant Staphylococcus aureus with high arbekacin resistance.
A clinical isolate (designated PRC104) of methicillin-resistant Staphylococcus aureus was discovered with a novel aminoglycoside resistance profile, including unusually high resistance (MIC 128 microg/ml) to arbekacin (an effective anti-MRSA drug in Japan). We characterized the activity and gene of its bifunctional aminoglycoside-modifying enzyme, AAC(6')/APH(2"), in comparison with those of a regular one that has been known as the critical resistance basis to both gentamicin and arbekacin in methicillin-resistant Staphylococcus aureus. The aac(6')/aph(2") gene of strain PRC104 contained a single base alteration at a novel site (G1126A) resulting in one amino acid substitution (S376N) in the phosphorylation catalytic motif. The phosphorylation activity of the PRC104 enzyme was enhanced for arbekacin and reduced for gentamicin. Both strain PRC104 and S. aureus RN4220 containing the cloned gene were identical in terms of the substrate specificity of the enzyme as well as the aminoglycoside resistance profile, although both mRNA and aminoglycoside resistance levels were markedly high in strain PRC104. Therefore, the cloned aac(6')/aph(2") gene may represent the molecular basis for the novel aminoglycoside modification capability as well as novel aminoglycoside resistance profile of S. aureus PRC104.
Topics: Amino Acid Sequence; Aminoglycosides; Dibekacin; Drug Resistance, Bacterial; Humans; Methicillin Resistance; Molecular Sequence Data; Phosphorylation; RNA, Messenger; Staphylococcus aureus; Substrate Specificity
PubMed: 15638329
DOI: 10.7164/antibiotics.57.679 -
Antimicrobial Agents and Chemotherapy Apr 2004Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for... (Clinical Trial)
Clinical Trial Comparative Study
Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.
Topics: Aminoglycosides; Anti-Bacterial Agents; Bayes Theorem; Body Weight; Creatinine; Dibekacin; Female; Gestational Age; Glomerular Filtration Rate; Humans; Infant, Newborn; Male; Models, Biological; Population; Thienamycins; Vancomycin
PubMed: 15047516
DOI: 10.1128/AAC.48.4.1159-1167.2004 -
Antimicrobial Agents and Chemotherapy Feb 2004Serratia marcescens S-95, which displayed an unusually high degree of resistance to aminoglycosides, including kanamycins and gentamicins, was isolated in 2002 from a...
Serratia marcescens S-95, which displayed an unusually high degree of resistance to aminoglycosides, including kanamycins and gentamicins, was isolated in 2002 from a patient in Japan. The resistance was mediated by a large plasmid which was nonconjugative but transferable to an Escherichia coli recipient by transformation. The gene responsible for the aminoglycoside resistance was cloned and sequenced. The deduced amino acid sequence of the resistance gene shared 82% identity with RmtA, which was recently identified as 16S rRNA methylase conferring high-level aminoglycoside resistance in Pseudomonas aeruginosa. Histidine-tagged recombinant protein showed methylation activity against E. coli 16S rRNA. The novel aminoglycoside resistance gene was therefore designated rmtB. The genetic environment of rmtB was further investigated. The sequence immediately upstream of rmtB contained the right end of transposon Tn3, including bla(TEM), while an open reading frame possibly encoding a transposase was identified downstream of the gene. This is the first report describing 16S rRNA methylase production in S. marcescens. The aminoglycoside resistance mechanism mediated by production of 16S rRNA methylase and subsequent ribosomal protection used to be confined to aminoglycoside-producing actinomycetes. However, it is now identified among pathogenic bacteria, including Enterobacteriaceae and P. aeruginosa in Japan. This is a cause for concern since other treatment options are often limited in patients requiring highly potent aminoglycosides such as amikacin and tobramycin.
Topics: Aged; Amino Acid Sequence; Aminoglycosides; Anti-Bacterial Agents; Cloning, Molecular; DNA, Bacterial; Dibekacin; Drug Resistance, Bacterial; Escherichia coli; Histidine; Humans; Male; Methylation; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; RNA, Ribosomal, 16S; Ribosomes; Serratia Infections; Serratia marcescens; tRNA Methyltransferases
PubMed: 14742200
DOI: 10.1128/AAC.48.2.491-496.2004 -
Antimicrobial Agents and Chemotherapy Dec 2003We adopted an in vitro infective endocarditis model (IVIEM) to compare the efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN) alone or in combination....
Efficacies of vancomycin, arbekacin, and gentamicin alone or in combination against methicillin-resistant Staphylococcus aureus in an in vitro infective endocarditis model.
We adopted an in vitro infective endocarditis model (IVIEM) to compare the efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN) alone or in combination. Using two strains of clinically isolated methicillin-resistant Staphylococcus aureus, one GEN susceptible (GS171) and one GEN resistant (GR153), fibrin clots were prepared and suspended in the IVIEM. Antibiotics were given as boluses every 6 h (q6h), q12h, or q24h or by continuous infusion with VAN, q12h or q24h with ABK, and q8h or q24h with GEN. For combination treatment, VAN q12h plus ABK q24h and VAN q12h plus GEN q24h were given. Fibrin clots were removed from each model at 0, 8, 24, 32, 48, and 72 h, and the bacterial densities were determined. The number of colonies within the fibrin clot was significantly decreased in all study groups compared with control groups (P<0.001). When VAN and ABK were administered alone, the number of colonies was significantly lower in GS171 than in GR153 by 8 h after administration (P=0.02) and was lowest in GS171 when ABK was administered q12h (P=0.01). At 72 h, ABK or VAN alone produced equivalent bacterial reductions regardless of dosing frequency and GEN resistance. In GR153, VAN plus ABK showed an additive effect till 24 h, although VAN plus GEN showed indifference. Our data suggest that ABK could be used as an alternative to VAN in GEN-resistant staphylococcal endocarditis. An additive effect was seen when VAN and ABK were used together in GEN-resistant strains until 24 h; however, further studies are warranted for the clinical application of this combination.
Topics: Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Blood Coagulation; Colony Count, Microbial; Dibekacin; Drug Therapy, Combination; Endocarditis, Bacterial; Fibrin; Gentamicins; Methicillin Resistance; Microbial Sensitivity Tests; Models, Biological; Staphylococcal Infections; Staphylococcus aureus; Vancomycin
PubMed: 14638480
DOI: 10.1128/AAC.47.12.3768-3773.2003