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The Journal of Antibiotics Jan 1988The genetic and biochemical basis of a 200-fold increase in kanamycin (KM)-resistance shown in Streptomyces griseus SS-1198PR generated by protoplast regeneration was...
Mechanism of increased kanamycin-resistance generated by protoplast regeneration of Streptomyces griseus. I. Cloning of a gene segment directing a high level of an aminoglycoside 3-N-acetyltransferase activity.
The genetic and biochemical basis of a 200-fold increase in kanamycin (KM)-resistance shown in Streptomyces griseus SS-1198PR generated by protoplast regeneration was investigated. A 15-kb Bcl I-DNA segment responsible for the KM-resistance was cloned into pIJ61 with Streptomyces lividans TK21 as host. The KM-resistance segment was then subcloned into pIJ702 as a 1.8-kb BamH I-Bgl II fragment with a BamH I site essential for the KM-resistance. Both S. lividans TK21 containing the cloned segments and S. griseus SS-1198PR showed multiple resistance to KM, dibekacin and gentamicin C complex. Cell free extracts from these strains inactivated the antibiotics in the presence of acetyl CoA in agreement with their resistance pattern. The structure of the inactivated KM-A was determined as 3-N-acetyl-KM-A indicating acetylation by an aminoglycoside acetyltransferase, AAC(3). The substrate range of the enzyme was unique and was designated AAC(3)-V. No genetic linkage was found between the cloned 15 kb Bcl I segment and the separately cloned streptomycin resistance gene (str) segment (3.8 kb Sph I fragment). The str genes cloned from both the parent (SS-1198) and the strain SS-1198PR were identical in their size, restriction site and function. In addition, these strains showed no significant difference in the total DNA digestion pattern. These results indicate that protoplast regeneration may cause a critical change in a specific region of DNA resulting in a high activity of an AAC(3) with a novel substrate range.
Topics: Acetylation; Acetyltransferases; Cloning, Molecular; Drug Resistance, Microbial; Genes, Bacterial; Kanamycin; Protoplasts; Regeneration; Streptomyces griseus; Streptomycin
PubMed: 3126171
DOI: 10.7164/antibiotics.41.94 -
European Journal of Clinical... Jul 2012The bacteriological efficacy response (improved, arbekacin vs. vancomycin; 71.2% vs. 79.5%) and clinical efficacy response (improved, arbekacin vs. vancomycin; 65.3% vs.... (Comparative Study)
Comparative Study
The bacteriological efficacy response (improved, arbekacin vs. vancomycin; 71.2% vs. 79.5%) and clinical efficacy response (improved, arbekacin vs. vancomycin; 65.3% vs. 76.1%) were not statistically different between the two groups. The complication rate was significantly higher in the vancomycin group (32.9%) compared to the arbekacin group (15.1%) (p=0.019). Arbekacin was not inferior to vancomycin, and it could be a good alternative drug for vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) treatment.
Topics: Adult; Anti-Bacterial Agents; Case-Control Studies; Dibekacin; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Staphylococcal Infections; Treatment Outcome; Vancomycin
PubMed: 22124537
DOI: 10.1007/s10096-011-1490-9 -
Antimicrobial Agents and Chemotherapy Nov 2006Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the... (Clinical Trial)
Clinical Trial
Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (C(max)), AUC/MIC, C(max)/MIC, and trough concentration (C(min)) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The C(max), C(min), and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the C(max) of arbekacin was increased, with an odds ratio of 6.7 for a change in C(max) from 7.9 to 12.5 microg/ml (P = 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed C(min) and AUC as risk factors of nephrotoxicity (P < 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the C(min) values were 1, 2, and 5 microg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Child; Dibekacin; Drug Monitoring; Female; Humans; Kidney Diseases; Kidney Function Tests; Logistic Models; Male; Methicillin Resistance; Microbial Sensitivity Tests; Middle Aged; Risk; Staphylococcal Infections; Staphylococcus aureus
PubMed: 17065622
DOI: 10.1128/AAC.00480-05 -
Journal of Infection and Chemotherapy :... Jan 2014Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of...
Clinical practice guidelines for therapeutic drug monitoring of arbekacin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.
Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200 mg was approved in Japan, recent PK-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (Cmax) was generally adopted, the serum concentration at 1 h after initiation of administration [peak serum concentration (Cpeak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies.
Topics: Anti-Infective Agents; Consensus; Dibekacin; Drug Monitoring; Humans; Japan; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections
PubMed: 24486168
DOI: 10.1016/j.jiac.2013.08.008 -
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 -
The Journal of Antibiotics Feb 1993Only a limited number of strains of methicillin-resistant Staphylococcus aureus (MRSA) moderately resistant to arbekacin (ABK) have been isolated clinically. Three...
Only a limited number of strains of methicillin-resistant Staphylococcus aureus (MRSA) moderately resistant to arbekacin (ABK) have been isolated clinically. Three inactivated products of ABK have been obtained by reaction with excess amounts of a crude enzyme preparation extracted from an ABK-resistant MRSA strain (MIC, 25 micrograms/ml). The 2"-O-phosphate was the major product together with small amounts of the 6'-N-acetate and the double modification product. The structures of these modification products were determined by MS and NMR spectral analyses.
Topics: Aminoglycosides; Anti-Bacterial Agents; Dibekacin; Inactivation, Metabolic; Magnetic Resonance Spectroscopy; Methicillin Resistance; Staphylococcus aureus
PubMed: 8468247
DOI: 10.7164/antibiotics.46.310 -
Antimicrobial Agents and Chemotherapy Oct 1996A novel gene encoding an aminoglycoside 2'-N-acetyltransferase (AAC) was cloned from Mycobacterium fortuitum. DNA sequencing results identified an open reading frame...
A novel gene encoding an aminoglycoside 2'-N-acetyltransferase (AAC) was cloned from Mycobacterium fortuitum. DNA sequencing results identified an open reading frame that we have called aac(2')-Ib encoding a putative protein with a predicted molecular mass of 24,800 Da. The deduced AAC(2')-Ib protein showed homology to the AAC(2')-Ia from Providencia stuartii. This is the second member of a subfamily of AAC(2')-I enzymes to be identified. No homology was found with other acetyltransferases, including all of the AAC(3) and AAC(6') proteins. The aac(2')-Ib gene cloned in a mycobacterial plasmid and introduced in Mycobacterium smegmatis conferred resistance to gentamicin, tobramycin, dibekacin, netilmicin, and 6'-N-ethylnetilmicin. DNA hybridization with an intragenic probe of aac(2')-Ib showed that this gene was present in all 34 strains of M. fortuitum tested. The universal presence of the aac(2')-Ib gene in M. fortuitum was not correlated with any aminoglycoside resistance phenotype, suggesting that this gene may play a role in the secondary metabolism of the bacterium.
Topics: Acetyltransferases; Amino Acid Sequence; Aminoglycosides; Anti-Bacterial Agents; Base Sequence; Chromosomes, Bacterial; DNA, Bacterial; Drug Resistance, Microbial; Escherichia coli; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Mycobacterium; Nucleic Acid Hybridization; Plasmids; Providencia
PubMed: 8891143
DOI: 10.1128/AAC.40.10.2350 -
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 -
The Journal of Antibiotics Oct 1978A pair of new butirosin analogs was isolated from the fermentation broth obtained by cultivating a neamine-negative mutant of the butirosin-producing organism Bacillus...
A pair of new butirosin analogs was isolated from the fermentation broth obtained by cultivating a neamine-negative mutant of the butirosin-producing organism Bacillus circulans in the medium supplemented with 6'-N-methylgentamine C1a. These antibiotics were characterized and elucidated as 3', 4'-dideoxy-6'-N-methylbutirosins A and B (DMB-A & DMB-B), by chemical and spectroscopic studies. DMB-A and DMB-B exhibited broad-spectrum antibacterial activities with in vitro potency similar to or slightly less than that for the butirosin A, with the exception of strains of Pseudomonas aeruginosa and Serratia marcescens against which they exhibited activities equal to or slightly greater than that for butirosin A. As expected, they exhibited stronger activities against butirosin-resistant organisms which contain acetylating enzymes AAC(6')-I and AAC(6')-IV, and phosphorylating enzyme APH(3')-II. They were also active against some of the clinical isolates resistant to butirosins, dibekacin and/or gentamicin. The acute intravenous toxicity in mice of the DMB complex (B:70 APPROXIMATELY 80%) was somewhat less than that of the butirosin A.
Topics: Animals; Anti-Bacterial Agents; Bacillus; Bacteria; Butirosin Sulfate; Chemical Phenomena; Chemistry; Mice; Molecular Conformation; Mutation
PubMed: 81823
DOI: 10.7164/antibiotics.31.1031 -
Antimicrobial Agents and Chemotherapy Apr 1987The pharmacokinetics of habekacin, a new semisynthetic aminoglycoside antibiotic, were investigated in six healthy subjects and 25 uremic patients (six of whom were on... (Comparative Study)
Comparative Study
The pharmacokinetics of habekacin, a new semisynthetic aminoglycoside antibiotic, were investigated in six healthy subjects and 25 uremic patients (six of whom were on hemodialysis) after administration of a single 3-mg/kg dose. Six healthy subjects received the 3-mg/kg dose both intramuscularly (i.m.) and intravenously (i.v.) (1-h infusion). Uremic patients were given the 3-mg/kg dose as an i.m. injection, except for the hemodialysis patients, who received the dose as a 1-h i.v. infusion. After the i.m. injection, the peak concentrations in serum were higher and the times to peak levels were longer in patients with renal impairment than in healthy subjects. The elimination half-life in serum increased in relation to the degree of renal impairment, from 2 h in normal subjects to 32 h in patients with creatinine clearances of less than 10 ml/min. Renal impairment did not significantly modify the apparent volume of distribution. After the same 3-mg/kg dose as a 1-h i.v. infusion in six hemodialysis patients, the elimination half-life averaged 48 and 5 h off and on a 4- to 5-h hemodialysis session, respectively. The habekacin pharmacokinetic data appeared to be similar to those of the other available aminoglycoside antibiotics.
Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Dibekacin; Half-Life; Humans; Injections, Intramuscular; Injections, Intravenous; Kanamycin; Kidney Failure, Chronic; Kinetics; Metabolic Clearance Rate; Middle Aged; Renal Dialysis; Uremia
PubMed: 3606062
DOI: 10.1128/AAC.31.4.575