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[PMID]:28316100
[Au] Autor:Kumar P; Serpersu EH
[Ad] Endereço:Graduate School of Genome Science and Technology, The University of Tennessee and Oak Ridge National Laboratory, Knoxville, Tennessee, 37996.
[Ti] Título:Thermodynamics of an aminoglycoside modifying enzyme with low substrate promiscuity: The aminoglycoside N3 acetyltransferase-VIa.
[So] Source:Proteins;85(7):1258-1265, 2017 Jul.
[Is] ISSN:1097-0134
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kinetic, thermodynamic, and structural properties of the aminoglycoside N3-acetyltransferase-VIa (AAC-VIa) are determined. Among the aminoglycoside N3-acetyltransferases, AAC-VIa has one of the most limited substrate profiles. Kinetic studies showed that only five aminoglycosides are substrates for this enzyme with a range of fourfold difference in k values. Larger differences in K (∼40-fold) resulted in ∼30-fold variation in k /K . Binding of aminoglycosides to AAC-VIa was enthalpically favored and entropically disfavored with a net result of favorable Gibbs energy (ΔG < 0). A net deprotonation of the enzyme, ligand, or both accompanied the formation of binary and ternary complexes. This is opposite of what was observed with several other aminoglycoside N3-acetyltransferases, where ligand binding causes more protonation. The change in heat capacity (ΔCp) was different in H O and D O for the binary enzyme-sisomicin complex but remained the same in both solvents for the ternary enzyme-CoASH-sisomicin complex. Unlike, most other aminoglycoside-modifying enzymes, the values of ΔCp were within the expected range of protein-carbohydrate interactions. Solution behavior of AAC-VIa was also different from the more promiscuous aminoglycoside N3-acetyltransferases and showed a monomer-dimer equilibrium as detected by analytical ultracentrifugation (AUC). Binding of ligands shifted the enzyme to monomeric state. Data also showed that polar interactions were the most dominant factor in dimer formation. Overall, thermodynamics of ligand-protein interactions and differences in protein behavior in solution provide few clues on the limited substrate profile of this enzyme despite its >55% sequence similarity to the highly promiscuous aminoglycoside N3-acetyltransferase. Proteins 2017; 85:1258-1265. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Acetiltransferases/química
Antibacterianos/química
Proteínas de Bactérias/química
Enterobacter cloacae/química
Prótons
Sisomicina/química
[Mh] Termos MeSH secundário: Acetiltransferases/genética
Acetiltransferases/metabolismo
Motivos de Aminoácidos
Antibacterianos/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Clonagem Molecular
Óxido de Deutério/química
Enterobacter cloacae/enzimologia
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Gentamicinas/química
Gentamicinas/metabolismo
Canamicina/química
Canamicina/metabolismo
Cinética
Ligantes
Modelos Moleculares
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Sisomicina/metabolismo
Homologia Estrutural de Proteína
Especificidade por Substrato
Termodinâmica
Tobramicina/química
Tobramicina/metabolismo
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Gentamicins); 0 (Ligands); 0 (Protons); 0 (Recombinant Proteins); 059QF0KO0R (Water); 59-01-8 (Kanamycin); EC 2.3.1.- (Acetyltransferases); EC 2.3.1.81 (aminoglycoside N(3')-acetyltransferase); J65BV539M3 (Deuterium Oxide); VZ8RRZ51VK (Tobramycin); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE
[do] DOI:10.1002/prot.25286


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[PMID]:27919895
[Au] Autor:López-Diaz MD; Culebras E; Rodríguez-Avial I; Rios E; Viñuela-Prieto JM; Picazo JJ; Rodríguez-Avial C
[Ad] Endereço:Servicio de Microbiología, Hospital Clínico San Carlos, Madrid, Spain.
[Ti] Título:Plazomicin Activity against 346 Extended-Spectrum-ß-Lactamase/AmpC-Producing Escherichia coli Urinary Isolates in Relation to Aminoglycoside-Modifying Enzymes.
[So] Source:Antimicrob Agents Chemother;61(2), 2017 Feb.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The activity of plazomicin and clinically relevant aminoglycosides was tested against 346 extended-spectrum-ß-lactamase/AmpC-producing Escherichia coli urinary isolates, and the results were correlated with the presence of aminoglycoside-modifying enzymes (AMEs). Data showed that plazomicin was very active against all ESBL/AmpC-producing E. coli urinary isolates. Its activity was not related to the AME genes studied.
[Mh] Termos MeSH primário: Aminoglicosídeos/farmacologia
Escherichia coli/efeitos dos fármacos
Escherichia coli/enzimologia
Sisomicina/análogos & derivados
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/farmacologia
Escherichia coli/genética
Testes de Sensibilidade Microbiana
Sisomicina/farmacologia
Sistema Urinário/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Aminoglycosides); 0 (Anti-Bacterial Agents); EC 3.5.2.6 (beta-Lactamases); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161207
[St] Status:MEDLINE


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[PMID]:27614915
[Au] Autor:Mega WM; Doyle-Eisele M; Cass RT; Kostrub CF; Sherwood RL; Metz MA; Cirz RT
[Ad] Endereço:Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108, United States.
[Ti] Título:Plazomicin is effective in a non-human primate pneumonic plague model.
[So] Source:Bioorg Med Chem;24(24):6429-6439, 2016 Dec 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The efficacy of plazomicin for pneumonic plague was evaluated in a non-human primate model. African Green monkeys challenged with a lethal aerosol of Yersinia pestis [median (range) of 98 (15-331) LD ] received placebo (n=12) or 'humanized' dose regimens (6.25, 12.5 or 25mg/kg every 24h) of plazomicin (n=52) after the onset of fever for a duration of 5 or 10days. All animals treated with placebo died, while 36 plazomicin-treated animals survived through study end. The majority (33/36) were either in the 10-day (high-/mid-/low-dose) or 5-day high-dose groups. The findings suggest an exposure range of plazomicin for treatment of pneumonic/bacteremic Y. pestis infection in humans.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Peste/tratamento farmacológico
Sisomicina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Cercopithecus aethiops
Relação Dose-Resposta a Droga
Conformação Molecular
Sisomicina/química
Sisomicina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160912
[St] Status:MEDLINE


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[PMID]:27297487
[Au] Autor:Haidar G; Alkroud A; Cheng S; Churilla TM; Churilla BM; Shields RK; Doi Y; Clancy CJ; Nguyen MH
[Ad] Endereço:University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
[Ti] Título:Association between the Presence of Aminoglycoside-Modifying Enzymes and In Vitro Activity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-ß-Lactamase-Producing Enterobacter Species.
[So] Source:Antimicrob Agents Chemother;60(9):5208-14, 2016 Sep.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We compared the in vitro activities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13 Enterobacter isolates possessing both Klebsiella pneumoniae carbapenemase and extended-spectrum ß-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL-, 6 KPC-/ESBL+, and 38 KPC-/ESBL- isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL- (25% and 38%, respectively), KPC-/ESBL+ (50% and 17%, respectively), and KPC-/ESBL- (0% and 3%, respectively) isolates. KPC+/ESBL+ isolates were more likely than others to possess an aminoglycoside-modifying enzyme (AME) (100% versus 38%, 67%, and 5%; P = 0.007, 0.06, and <0.0001, respectively) or multiple AMEs (100% versus 13%, 33%, and 0%, respectively; P < 0.01 for all). KPC+/ESBL+ isolates also had a greater number of AMEs (mean of 4.6 versus 1.5, 0.9, and 0.05, respectively; P < 0.01 for all). GEN and TOB MICs were higher against isolates with >1 AME than with ≤1 AME. The presence of at least 2/3 of KPC, SHV, and TEM predicted the presence of AMEs. PLZ MICs against all isolates were ≤4 µg/ml, regardless of KPC/ESBL pattern or the presence of AMEs. In conclusion, GEN and TOB are limited as treatment options against KPC+ and ESBL+ Enterobacter PLZ may represent a valuable addition to the antimicrobial armamentarium. A full understanding of AMEs and other aminoglycoside resistance mechanisms will allow clinicians to incorporate PLZ rationally into treatment regimens. The development of molecular assays that accurately and rapidly predict antimicrobial responses among KPC- and ESBL-producing Enterobacter spp. should be a top research priority.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Proteínas de Bactérias/genética
Farmacorresistência Bacteriana Múltipla/genética
Enterobacter/efeitos dos fármacos
Sisomicina/análogos & derivados
beta-Lactamases/genética
[Mh] Termos MeSH secundário: Amicacina/metabolismo
Amicacina/farmacologia
Antibacterianos/metabolismo
Proteínas de Bactérias/metabolismo
Biotransformação
Enterobacter/enzimologia
Enterobacter/genética
Enterobacter/crescimento & desenvolvimento
Escherichia coli/química
Escherichia coli/enzimologia
Expressão Gênica
Gentamicinas/metabolismo
Gentamicinas/farmacologia
Klebsiella pneumoniae/química
Klebsiella pneumoniae/enzimologia
Testes de Sensibilidade Microbiana
Sisomicina/metabolismo
Sisomicina/farmacologia
Tobramicina/metabolismo
Tobramicina/farmacologia
beta-Lactamases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Gentamicins); 84319SGC3C (Amikacin); EC 3.5.2.6 (beta-Lactamases); VZ8RRZ51VK (Tobramycin); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160615
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00869-16


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[PMID]:26866778
[Au] Autor:Cerceo E; Deitelzweig SB; Sherman BM; Amin AN
[Ad] Endereço:1 Division of Hospital Medicine, Cooper Medical School of Rowan University , Camden, New Jersey.
[Ti] Título:Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options.
[So] Source:Microb Drug Resist;22(5):412-31, 2016 Jul.
[Is] ISSN:1931-8448
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The increasing prevalence of infections due to multidrug-resistant (MDR) gram-negative bacteria constitutes a serious threat to global public health due to the limited treatment options available and the historically slow pace of development of new antimicrobial agents. Infections due to MDR strains are associated with increased morbidity and mortality and prolonged hospitalization, which translates to a significant burden on healthcare systems. In particular, MDR strains of Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii have emerged as particularly serious concerns. In the United States, MDR strains of these organisms have been reported from hospitals throughout the country and are not limited to a small subset of hospitals. Factors that have contributed to the persistence and spread of MDR gram-negative bacteria include the following: overuse of existing antimicrobial agents, which has led to the development of adaptive resistance mechanisms by bacteria; a lack of good antimicrobial stewardship such that use of multiple broad-spectrum agents has helped perpetuate the cycle of increasing resistance; and a lack of good infection control practices. The rising prevalence of infections due to MDR gram-negative bacteria presents a significant dilemma in selecting empiric antimicrobial therapy in seriously ill hospitalized patients. A prudent initial strategy is to initiate treatment with a broad-spectrum regimen pending the availability of microbiological results allowing for targeted or narrowing of therapy. Empiric therapy with newer agents that exhibit good activity against MDR gram-negative bacterial strains such as tigecycline, ceftolozane-tazobactam, ceftazidime-avibactam, and others in the development pipeline offer promising alternatives to existing agents.
[Mh] Termos MeSH primário: Acinetobacter baumannii/efeitos dos fármacos
Antibacterianos/uso terapêutico
Infecções por Enterobacteriaceae/tratamento farmacológico
Escherichia coli/efeitos dos fármacos
Klebsiella pneumoniae/efeitos dos fármacos
Pseudomonas aeruginosa/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acinetobacter baumannii/crescimento & desenvolvimento
Acinetobacter baumannii/patogenicidade
Ácidos Borônicos/uso terapêutico
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Farmacorresistência Bacteriana Múltipla/fisiologia
Quimioterapia Combinada
Infecções por Enterobacteriaceae/microbiologia
Infecções por Enterobacteriaceae/patologia
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/patogenicidade
Compostos Heterocíclicos com 1 Anel/uso terapêutico
Hospitais
Seres Humanos
Klebsiella pneumoniae/crescimento & desenvolvimento
Klebsiella pneumoniae/patogenicidade
Pseudomonas aeruginosa/crescimento & desenvolvimento
Pseudomonas aeruginosa/patogenicidade
Sisomicina/análogos & derivados
Sisomicina/uso terapêutico
Tetraciclinas/uso terapêutico
Tienamicinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline); 0 (Anti-Bacterial Agents); 0 (Boronic Acids); 0 (Heterocyclic Compounds, 1-Ring); 0 (RPX7009); 0 (Tetracyclines); 0 (Thienamycins); FV9J3JU8B1 (meropenem); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170419
[Lr] Data última revisão:
170419
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160212
[St] Status:MEDLINE
[do] DOI:10.1089/mdr.2015.0220


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[PMID]:26419762
[Au] Autor:Karaiskos I; Souli M; Giamarellou H
[Ad] Endereço:a 1 Hygeia General Hospital, 6th Department of Internal Medicine , 4, Erythrou Stavrou street & Kifisias avenue, Athens 15123, Greece.
[Ti] Título:Plazomicin: an investigational therapy for the treatment of urinary tract infections.
[So] Source:Expert Opin Investig Drugs;24(11):1501-11, 2015.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Living in the ever-expanding era of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the approaching fear of the "End of Antibiotics." Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance. A newer aminoglycoside active against several MDR-XDR microorganisms is herein presented and discussed. AREAS COVERED: Herein, the authors present the currently available information on plazomicin. This includes the current knowledge concerning plazomicin's: mechanisms of action, in vitro activity and interactions, its pharmacokinetics, its clinical efficacy in complicated urinary tract infections (cUTIs) and acute pyelonephritis, and its toxicity issues. EXPERT OPINION: Plazomicin was developed to evade all clinically relevant aminoglycoside-modifying enzymes. Unfortunately, ribosomal enzymatic modification by ribosomal 16S-rRNA methyltransferases confers broad-spectrum high-level aminoglycoside resistance. Still, plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related. However, the authors believe that the real position of plazomicin in the MDR-XDR world will be revealed once pending Phase III studies are completed.
[Mh] Termos MeSH primário: Antibacterianos/uso terapêutico
Sisomicina/análogos & derivados
Infecções Urinárias/tratamento farmacológico
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Antibacterianos/efeitos adversos
Antibacterianos/farmacologia
Farmacorresistência Bacteriana Múltipla
Seres Humanos
Pielonefrite/tratamento farmacológico
Sisomicina/efeitos adversos
Sisomicina/farmacologia
Sisomicina/uso terapêutico
Infecções Urinárias/imunologia
Infecções Urinárias/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Anti-Bacterial Agents); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:151031
[Lr] Data última revisão:
151031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151001
[St] Status:MEDLINE
[do] DOI:10.1517/13543784.2015.1095180


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[PMID]:26391381
[Au] Autor:Rodríguez-Avial I; Pena I; Picazo JJ; Rodríguez-Avial C; Culebras E
[Ad] Endereço:Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Plaza de Cristo Rey s/n, 28040 Madrid, Spain. Electronic address: iciaravial@hotmail.com.
[Ti] Título:In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains.
[So] Source:Int J Antimicrob Agents;46(6):616-21, 2015 Dec.
[Is] ISSN:1872-7913
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n=125; KPC-2, n=34; OXA-48, n=4; and IMP-22, n=1). MIC90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12-4 mg/L with MIC50 and MIC90 values of 0.25 and 1 mg/L. The MICs of plazomicin did not correlate with the other aminoglycoside MICs, with the resistance phenotype or with the carbapenemase harboured. Chequerboard experiments against 10 carbapenemase-producing Klebsiella pneumoniae isolates showed that combinations of plazomicin with colistin yielded synergy against 60% of the strains. Synergy of plazomicin with meropenem or fosfomycin was detected against 20% and 25% of the isolates, respectively. Using time-kill methodology, the interactions of plazomicin at 2×, 1× and 0.5× MIC with meropenem, colistin, fosfomycin or tigecycline at steady-state concentrations against two K. pneumoniae carrying the VIM-1 enzyme were investigated. Bactericidal activity was evident for both isolates at 2× MIC of plazomicin. Synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin against both isolates, whilst the combination with tigecycline resulted in indifference. Antagonism was not observed for any of the combinations tested. The results of this study suggest that plazomicin may address the need for new therapeutic options for the treatment of infections due to CPE.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Proteínas de Bactérias/metabolismo
Colistina/farmacologia
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Infecções por Enterobacteriaceae/tratamento farmacológico
Fosfomicina/farmacologia
Klebsiella pneumoniae/efeitos dos fármacos
Minociclina/análogos & derivados
Sisomicina/análogos & derivados
Tienamicinas/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Sinergismo Farmacológico
Quimioterapia Combinada
Enterobacter/efeitos dos fármacos
Enterobacter/isolamento & purificação
Seres Humanos
Klebsiella oxytoca/efeitos dos fármacos
Klebsiella oxytoca/isolamento & purificação
Klebsiella pneumoniae/isolamento & purificação
Testes de Sensibilidade Microbiana
Minociclina/farmacologia
Serratia marcescens/efeitos dos fármacos
Serratia marcescens/isolamento & purificação
Sisomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Thienamycins); 2N81MY12TE (Fosfomycin); 70JE2N95KR (tigecycline); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (carbapenemase); FV9J3JU8B1 (meropenem); FYY3R43WGO (Minocycline); X55XSL74YQ (Sisomicin); Z67X93HJG1 (Colistin)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151224
[Lr] Data última revisão:
151224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150923
[St] Status:MEDLINE


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[PMID]:26169398
[Au] Autor:García-Salguero C; Rodríguez-Avial I; Picazo JJ; Culebras E
[Ad] Endereço:Microbiology Department, Hospital Clínico San Carlos, Madrid, Spain.
[Ti] Título:Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii?
[So] Source:Antimicrob Agents Chemother;59(10):5959-66, 2015 Oct.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nosocomial pathogens can be associated with a variety of infections, particularly in intensive care units (ICUs) and in immunocompromised patients. Usually these pathogens are resistant to multiple drugs and pose therapeutic challenges. Among these organisms, Acinetobacter baumannii is one of the most frequent being encountered in the clinical setting. Carbapenems are very useful to treat infections caused by these drug-resistant Gram-negative bacilli, but carbapenem resistance is increasing globally. Combination therapy is frequently given empirically for hospital-acquired infections in critically ill patients and is usually composed of an adequate beta-lactam and an aminoglycoside. The purpose of this study was to evaluate the in vitro activity of plazomicin against carbapenem-resistant Acinetobacter baumannii. Amikacin was used as a comparator. The activity of plazomicin in combination with several different antibiotics was tested by disk diffusion, the checkerboard method, and time-kill studies. Synergy was consistently observed with carbapenems (meropenem and/or imipenem) along with plazomicin or amikacin. When the aminoglycosides were combined with other classes of antibiotics, synergy was observed in some cases, depending on the strain and the antibiotic combination; importantly, there was no antagonism observed in any case. These findings indicate the potential utility of plazomicin in combination with other antibiotics (mainly carbapenems) for the treatment of A. baumannii infections, including those caused by carbapenem-resistant isolates.
[Mh] Termos MeSH primário: Acinetobacter baumannii/efeitos dos fármacos
Antibacterianos/farmacologia
Imipenem/farmacologia
Sisomicina/análogos & derivados
Tienamicinas/farmacologia
[Mh] Termos MeSH secundário: Infecções por Acinetobacter/tratamento farmacológico
Infecções por Acinetobacter/microbiologia
Acinetobacter baumannii/crescimento & desenvolvimento
Acinetobacter baumannii/isolamento & purificação
Amicacina/farmacologia
Infecção Hospitalar/tratamento farmacológico
Infecção Hospitalar/microbiologia
Sinergismo Farmacológico
Quimioterapia Combinada
Seres Humanos
Testes de Sensibilidade Microbiana
Sisomicina/farmacologia
Resistência beta-Lactâmica/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Anti-Bacterial Agents); 0 (Thienamycins); 71OTZ9ZE0A (Imipenem); 84319SGC3C (Amikacin); FV9J3JU8B1 (meropenem); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160401
[Lr] Data última revisão:
160401
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150715
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00873-15


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[PMID]:25880243
[Au] Autor:Wlasichuk KB; Tan L; Guo Y; Hildebrandt DJ; Zhang H; Karr DE; Schmidt DE
[Ad] Endereço:Achaogen, Inc., 7000 Shoreline Court, Suite 371, South San Francisco, CA 94080, USA.
[Ti] Título:Determination of equilibrium constant of amino carbamate adduct formation in sisomicin by a high pH based high performance liquid chromatography.
[So] Source:J Pharm Biomed Anal;111:126-30, 2015.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amino carbamate adduct formation from the amino group of an aminoglycoside and carbon dioxide has been postulated as a mechanism for reducing nephrotoxicity in the aminoglycoside class compounds. In this study, sisomicin was used as a model compound for amino carbamate analysis. A high pH based reversed-phase high performance liquid chromatography (RP-HPLC) method is used to separate the amino carbamate from sisomicin. The carbamate is stable as the breakdown is inhibited at high pH and any reactive carbon dioxide is removed as the carbonate. The amino carbamate was quantified and the molar fraction of amine as the carbamate of sisomicin was obtained from the HPLC peak areas. The equilibrium constant of carbamate formation, Kc, was determined to be 3.3 × 10(-6) and it was used to predict the fraction of carbamate over the pH range in a typical biological systems. Based on these results, the fraction of amino carbamate at physiological pH values is less than 13%, and the postulated mechanism for nephrotoxicity protection is not valid. The same methodology is applicable for other aminoglycosides.
[Mh] Termos MeSH primário: Carbamatos/química
Sisomicina/química
[Mh] Termos MeSH secundário: Aminoglicosídeos/química
Dióxido de Carbono/química
Cromatografia Líquida de Alta Pressão/métodos
Cromatografia de Fase Reversa/métodos
Concentração de Íons de Hidrogênio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Carbamates); 142M471B3J (Carbon Dioxide); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150521
[Lr] Data última revisão:
150521
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150417
[St] Status:MEDLINE


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[PMID]:25459738
[Au] Autor:Olsen SC; Carlson SA
[Ad] Endereço:Bacterial Diseases of Livestock Research Unit, National Animal Disease Center, Ames, IA 50010, USA.
[Ti] Título:In vitro bactericidal activity of aminoglycosides, including the next-generation drug plazomicin, against Brucella spp.
[So] Source:Int J Antimicrob Agents;45(1):76-8, 2015 Jan.
[Is] ISSN:1872-7913
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Plazomicin is a next-generation aminoglycoside with a potentially unique set of clinical characteristics compared with other aminoglycosides. This study assessed the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of plazomicin against 15 clinical isolates as well as three reference strains representing Brucella abortus, Brucella melitensis and Brucella suis. These data were compared with those obtained for six other aminoglycosides and two aminocyclitols. Plazomicin and gentamicin were the only drugs demonstrating bactericidal activity towards two of the three Brucella spp., whilst plazomicin was the only drug exhibiting bactericidal activity against B. suis. This is the first study to assess the bactericidal nature of plazomicin against Brucella spp. in vitro.
[Mh] Termos MeSH primário: Aminoglicosídeos/farmacologia
Antibacterianos/farmacologia
Brucella abortus/efeitos dos fármacos
Brucella melitensis/efeitos dos fármacos
Brucella suis/efeitos dos fármacos
Viabilidade Microbiana/efeitos dos fármacos
Sisomicina/análogos & derivados
[Mh] Termos MeSH secundário: Brucella abortus/isolamento & purificação
Brucella melitensis/isolamento & purificação
Brucella suis/isolamento & purificação
Brucelose/microbiologia
Seres Humanos
Testes de Sensibilidade Microbiana
Sisomicina/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (6'-(hydroxylethyl)-1-(haba)-sisomicin); 0 (Aminoglycosides); 0 (Anti-Bacterial Agents); X55XSL74YQ (Sisomicin)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:150105
[Lr] Data última revisão:
150105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE



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