Aminoglycosides

Distribution by Scientific Domains

Terms modified by Aminoglycosides

  • aminoglycoside antibiotics

  • Selected Abstracts


    Aminoglycoside dosing in diabetes

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2000
    Axworthy
    Studies have evaluated the comparative efficacy, toxicity and costs associated with extended-interval vs. standard multiple daily dosing of aminoglycosides. In this case, an elderly man with diabetes and good renal function at baseline was switched from standard to extended-interval dosing. During the course of therapy there was evidence of decreased renal function. Pertinent literature was searched for, uncovered and critically evaluated to determine if and what evidence supports using extended dosing of aminoglycosides in this population. No data were found specifically evaluating the different dosing strategies in diabetic patients. However, there were many trials and several meta-analysis located that compared the two dosing strategies, most suggesting at least a cost advantage and possibly less toxicity with extended-interval dosing. Further information is needed to determine whether there is a differential risk for toxicity between these dosing regimens in patient with diabetes. [source]


    Secondary Apoptosis of Spiral Ganglion Cells Induced by Aminoglycoside: Fas,Fas Ligand Signaling Pathway,

    THE LARYNGOSCOPE, Issue 9 2008
    Woo Yong Bae MD
    Abstract Objectives/Hypothesis: Hair cell loss results in the secondary loss of spiral ganglion neurons (SGNs), over a period of several weeks. The death of the SGNs themselves results from apoptosis. Previous studies have shown that several molecules are involved in the apoptosis of SGNs that occurred secondary to hair cell loss. However, the precise mechanism of apoptosis of the SGNs remains unclear. The aim of this study was to ascertain the secondary apoptosis of spiral ganglion cells induced by aminoglycoside and to investigate the role of the Fas,FasL signaling pathway using guinea pigs as an experimental animal model. Study Design: Laboratory study using experimental animals. Methods: Guinea pigs weighing 250 to 300 g (n = 21) from 3 to 4 weeks of age were used. Gentamicin (60 ,L) was injected through a cochleostomy site on their left side. At 1 (n = 7), 2 (n = 7), and 3 (n = 7) weeks after gentamicin treatment, their cochleas were obtained from their temporal bone. Hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining were performed to observe apoptosis. To investigate the involvement of the Fas,FasL signaling pathway in the secondary apoptosis of SGNs, we performed reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Results: A progressive loss of spiral ganglion cells with increasing time after gentamicin treatment was observed on light microscopic examination. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining demonstrated induction of apoptotic cell death in SGNs after gentamicin treatment. Expression of FasL increased over time after gentamicin treatment as determined by RT-PCR and western blotting. On immunohistochemical staining, we observed the localization of FasL in the SGNs. The proapoptotic molecules Bax and Bad were increased, but levels of the antiapoptotic molecule Bcl-2 were decreased at increasing survival times after gentamicin treatment on RT-PCR. The gentamicin-treated group displayed initial activation of caspase-8 and increased the cleavage of caspase-3, caspase-8, and PARP protein in a time-dependent manner. Conclusions: The secondary apoptosis of SGNs could be a result of the apoptotic Fas,FasL signaling pathway. Blocking the Fas,FasL signaling pathway could be considered as a method for preventing secondary degeneration of SGNs, and further studies are needed to confirm this. [source]


    Deafness Due to A1555G Mitochondrial Mutation Without Use of Aminoglycoside,

    THE LARYNGOSCOPE, Issue 6 2004
    Tatsuo Matsunaga MD
    Abstract Objectives/Hypothesis: The objective was to clarify the characteristics of deafness associated with the A1555G mutation within mitochondrial 12S ribosomal RNA gene in the absence of aminoglycoside exposure. Study Design: Clinical and genetic studies in family members with the A1555G mitochondrial mutation were performed. Methods: The subjects were 123 maternally related members of a large Japanese family with the A1555G mutation. All subjects had no previous history of exposure to aminoglycosides. Hearing disability and handicap, tinnitus, and medical histories were analyzed by interviews in all of the subjects, genetic testing was performed in 41 subjects, and pure-tone audiometry was conducted in 26 subjects with hearing disability and handicap. Results: The A1555G mutation was detected in a homoplasmic form (meaning that all the mitochondrial DNA carries the mutation) in all 41 subjects who were screened. The risk for developing postlingual hearing loss was likely to be much higher in the present subjects than in the general population. Both the severity and age at onset of the phenotype were similar in affected subjects within the same sibling group. Pure-tone averages were significantly worse in subjects who developed hearing loss before age 10 years than in those who developed hearing loss later. Conclusion: The present study demonstrated that the prevalence of deafness in individuals with the A1555G mitochondrial mutation was likely to be high even in the absence of aminoglycoside exposure and clearly showed the association of severe to profound hearing loss with the onset of hearing loss before age 10 years. [source]


    A Tale of Two Targets: Differential RNA Selectivity of Nucleobase,Aminoglycoside Conjugates

    CHEMBIOCHEM, Issue 10 2006
    Kenneth F. Blount Dr.
    Aminoglycoside antibiotics are RNA-binding polyamines that can bind with similar affinities to structurally diverse RNA targets. To design new semisynthetic aminoglycosides with improved target selectivity, it is important to understand the energetic and structural basis by which diverse RNA targets recognize similar ligands. It is also imperative to discover how novel aminoglycosides could be rationally designed to have enhanced selectivity for a given target. Two RNA drug targets, the prokaryotic ribosomal A-site and the HIV-1 TAR, provide an excellent model system in which to dissect the issue of target selectivity, in that they each have distinctive interactions with aminoglycosides. We report herein the design, synthesis, and binding activity of novel nucleobase,aminoglycoside conjugates that were engineered to be more selective for the A-site binding pocket. Contrary to the structural design, the conjugates bind the A-site more weakly than does the parent compound and bind the TAR more tightly than the parent compound. This result implies that the two RNA targets differ in their ability to adapt to structurally diverse ligands and thus have inherently different selectivities. This work emphasizes the importance of considering the inherent selectivity traits of the RNA target when engineering new ligands. [source]


    Aminoglycoside,Quinacridine Conjugates: Towards Recognition of the P6.1 Element of Telomerase RNA

    CHEMBIOCHEM, Issue 2 2006
    Markus Kaiser Dr.
    Abstract A modular synthesis has been developed which allows easy and rapid attachment of one or two aminoglycoside units to a quinacridine intercalator, thereby leading to monomeric and dimeric conjugates. Melting temperature (Tm) experiments show that the tobramycin dimeric conjugate TD1 exhibits strong binding to the P6.1 element of human telomerase RNA. By contrast, tobramycin alone is much less efficient and the monomeric compound TM1 elicits a poor binding ability. Monitoring of the interaction by an electrophoretic mobility shift assay shows a 1:1 stoichiometry for the binding of the dimeric compound to the hairpin structure and confirms the lower affinity for a control duplex. Protection experiments with RNase T1 indicate interaction of the drug both in the stem and in the loop of the hairpin. Taken together, the data suggest a binding of TD1 inside the hairpin at the stem-loop junction. The same trends are observed with paromomycin and kanamycin analogues but with a lower affinity. [source]


    Determination of aminoglycoside and macrolide antibiotics in meat by pressurized liquid extraction and LC-ESI-MS

    JOURNAL OF SEPARATION SCIENCE, JSS, Issue 4-5 2010
    Houda Berrada
    Abstract A simple method for the simultaneous determination of dihydrostreptomycin, spectinomycin, spiramycin, streptomycin, tilmicosin, and tylosin in meat has been developed using pressurized liquid extraction and LC-triple quadrupole MS (LC-ESI-MS/MS). The pressurized liquid extraction operational parameters were optimized and no protein precipitating and fat removing steps were required. A gradient HPLC separation was developed with ion-pair mobile phases consisting of aqueous 1,mM heptafluorobutyric acid water and methanol. Protonated molecules were used as precursor ions for CID. Data acquisition under MS/MS was achieved by applying multiple reaction monitoring of three fragment ion transitions to provide a high degree of sensitivity and specificity. Dirithromycin and sisomycin were selected as internal standards. A validation study was conducted for these antibiotics in poultry meat samples. All selected compounds could be detected (monitoring ions by multiple reaction monitoring) in meat samples at amounts below the regulatory level of concern. Using the internal standards, pressurized liquid extraction recovery rates were from 70 to 96% (RSD 12,25%). LC-ESI-MS/MS method detection limits of the selected antibiotics were 1,6,,g/kg. Good method reproducibility was found by intra- and inter-day precisions at maximum residue level, yielding the RSDs less than 15 and 16%, respectively. [source]


    Intracellular readthrough of nonsense mutations by aminoglycosides in coagulation factor VII

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2006
    M. PINOTTI
    Summary.,Background: Nonsense mutations in coagulation factor (F) VII potentially cause a lethal hemorrhagic diathesis. Readthrough of nonsense mutations by aminoglycosides has been studied in a few human disease models with variable results. Objectives: We investigated the K316X and W364X FVII mutations, associated with intracranial hemorrhage, and their correction by aminoglycosides. The rare nonsense mutations in FVII represent favorite models to test this strategy, because even tiny increases in the amount of functional full-length protein in patients could ameliorate hemorrhagic phenotypes. Results: A FVII,green fluorescent protein (GFP) chimaera provided us with a fluorescent model of FVII expression in living cells. Appreciable fluorescence in cells transfected with nonsense FVII,GFP mutants was detected upon geneticin treatment, thus demonstrating suppression of premature translation termination. To investigate the rescue of FVII function, nonsense variants of the native FVII without GFP (p316X,FVII and p364X,FVII) were transfected and found to secrete low amounts of FVII (,1% of Wt,FVII activity), thus suggesting a spontaneous stop codon readthrough. Geneticin treatment of cells resulted in a significant and dose-dependent increase of secreted FVII molecules (p316X,FVII, 24 ± 12 ng mL,1, 3.6 ± 0.8% of Wt,FVII activity; p364X,FVII, 26 ± 10 ng mL,1, 3.7±0.6%) characterized by reduced specific activity, thus indicating the synthesis of dysfunctional proteins. Similar results were observed with gentamicin, a commonly used aminoglycoside of potential interest for patient treatment. Conclusions: Our approach, extendable to other coagulation factors, represents an effective tool for a systematic study of the effects of aminoglycosides and neighboring sequences on nonsense codon readthrough. These results provide the rationale for a mutation-specific therapeutic approach in FVII deficiency. [source]


    Crystal structure and kinetic mechanism of aminoglycoside phosphotransferase-2,-IVa

    PROTEIN SCIENCE, Issue 8 2010
    Marta Toth
    Abstract Acquired resistance to aminoglycoside antibiotics primarily results from deactivation by three families of aminoglycoside-modifying enzymes. Here, we report the kinetic mechanism and structure of the aminoglycoside phosphotransferase 2,-IVa (APH(2,)-IVa), an enzyme responsible for resistance to aminoglycoside antibiotics in clinical enterococcal and staphylococcal isolates. The enzyme operates via a Bi-Bi sequential mechanism in which the two substrates (ATP or GTP and an aminoglycoside) bind in a random manner. The APH(2,)-IVa enzyme phosphorylates various 4,6-disubstituted aminoglycoside antibiotics with catalytic efficiencies (kcat/Km) of 1.5 × 103 to 1.2 × 106 (M,1 s,1). The enzyme uses both ATP and GTP as the phosphate source, an extremely rare occurrence in the phosphotransferase and protein kinase enzymes. Based on an analysis of the APH(2,)-IVa structure, two overlapping binding templates specifically tuned for hydrogen bonding to either ATP or GTP have been identified and described. A detailed understanding of the structure and mechanism of the GTP-utilizing phosphotransferases is crucial for the development of either novel aminoglycosides or, more importantly, GTP-based enzyme inhibitors which would not be expected to interfere with crucial ATP-dependent enzymes. [source]


    Secondary Apoptosis of Spiral Ganglion Cells Induced by Aminoglycoside: Fas,Fas Ligand Signaling Pathway,

    THE LARYNGOSCOPE, Issue 9 2008
    Woo Yong Bae MD
    Abstract Objectives/Hypothesis: Hair cell loss results in the secondary loss of spiral ganglion neurons (SGNs), over a period of several weeks. The death of the SGNs themselves results from apoptosis. Previous studies have shown that several molecules are involved in the apoptosis of SGNs that occurred secondary to hair cell loss. However, the precise mechanism of apoptosis of the SGNs remains unclear. The aim of this study was to ascertain the secondary apoptosis of spiral ganglion cells induced by aminoglycoside and to investigate the role of the Fas,FasL signaling pathway using guinea pigs as an experimental animal model. Study Design: Laboratory study using experimental animals. Methods: Guinea pigs weighing 250 to 300 g (n = 21) from 3 to 4 weeks of age were used. Gentamicin (60 ,L) was injected through a cochleostomy site on their left side. At 1 (n = 7), 2 (n = 7), and 3 (n = 7) weeks after gentamicin treatment, their cochleas were obtained from their temporal bone. Hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining were performed to observe apoptosis. To investigate the involvement of the Fas,FasL signaling pathway in the secondary apoptosis of SGNs, we performed reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Results: A progressive loss of spiral ganglion cells with increasing time after gentamicin treatment was observed on light microscopic examination. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining demonstrated induction of apoptotic cell death in SGNs after gentamicin treatment. Expression of FasL increased over time after gentamicin treatment as determined by RT-PCR and western blotting. On immunohistochemical staining, we observed the localization of FasL in the SGNs. The proapoptotic molecules Bax and Bad were increased, but levels of the antiapoptotic molecule Bcl-2 were decreased at increasing survival times after gentamicin treatment on RT-PCR. The gentamicin-treated group displayed initial activation of caspase-8 and increased the cleavage of caspase-3, caspase-8, and PARP protein in a time-dependent manner. Conclusions: The secondary apoptosis of SGNs could be a result of the apoptotic Fas,FasL signaling pathway. Blocking the Fas,FasL signaling pathway could be considered as a method for preventing secondary degeneration of SGNs, and further studies are needed to confirm this. [source]


    Deciphering interactions of the aminoglycoside phosphotransferase(3,)-IIIa with its ligands

    BIOPOLYMERS, Issue 9 2009
    Lingzhi Wu
    Abstract Aminoglycoside phosphotransferase(3,)-IIIa (APH) is the enzyme with broadest substrate range among the phosphotransferases that cause resistance to aminoglycoside antibiotics. In this study, the thermodynamic characterization of interactions of APH with its ligands are done by determining dissociation constants of enzyme,substrate complexes using electron paramagnetic resonance and fluorescence spectroscopy. Metal binding studies showed that three divalent cations bind to the apo-enzyme with low affinity. In the presence of AMPPCP, binding of the divalent cations occurs with 7-to-37-fold higher affinity to three additional sites dependent on the presence and absence of different aminoglycosides. Surprisingly, when both ligands, AMPPCP and aminoglycoside, are present, the number of high affinity metal binding sites is reduced to two with a 2-fold increase in binding affinity. The presence of divalent cations, with or without aminoglycoside present, shows only a small effect (<3-fold) on binding affinity of the nucleotide to the enzyme. The presence of metal,nucleotide, but not nucleotide alone, increases the binding affinity of aminoglycosides to APH. Replacement of magnesium (II) with manganese (II) lowered the catalytic rates significantly while affecting the substrate selectivity of the enzyme such that the aminoglycosides with 2,-NH2 become better substrates (higher Vmax) than those with 2,-OH. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 801,809, 2009. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source]


    Evidence-based prescription of antibiotics in urology: a 5-year review of microbiology

    BJU INTERNATIONAL, Issue 6 2009
    Ranan DasGupta
    OBJECTIVE To analyse the results of positive urine cultures over a 5-year period in a large hospital and urology department (amongst both inpatients and outpatients), assess the prevalence of different organisms and the resistance profiles of a range of antibiotics, and thus provide information on which organisms are likely to cause urosepsis. METHODS The use of antibiotics should be based on knowledge of which pathogens are present and what resistance patterns are emerging, particularly relevant in surgical disciplines like urology, as antibiotics are now routinely administered peri-operatively, whereby evidence-based prescription is preferable to generic guidelines. We therefore examined almost 25 000 positive urine cultures in our hospital over a 5-year period, and focused on the infections encountered amongst urology patients during this time. RESULTS A significant proportion of inpatient urinary infection (40%) is caused by Gram-positive bacteria such as Streptococcus faecalis, underlining the need for including Gram-positive cover during urological prophylaxis. The commonest pathogen remains Escherichia coli among both inpatients and outpatients. The ineffectiveness of common antibiotics such as ciprofloxacin and trimethoprim was identified, as was the increase in gentamicin resistance. CONCLUSION We propose using an aminoglycoside with a penicillin for high-risk cases (e.g. endoscopic stone surgery) while low-risk cases (e.g. flexible cystoscopy with no risk factors) might be managed without such prophylaxis. Pathogenic patterns and resistance rates should be monitored regularly. [source]


    A Tale of Two Targets: Differential RNA Selectivity of Nucleobase,Aminoglycoside Conjugates

    CHEMBIOCHEM, Issue 10 2006
    Kenneth F. Blount Dr.
    Aminoglycoside antibiotics are RNA-binding polyamines that can bind with similar affinities to structurally diverse RNA targets. To design new semisynthetic aminoglycosides with improved target selectivity, it is important to understand the energetic and structural basis by which diverse RNA targets recognize similar ligands. It is also imperative to discover how novel aminoglycosides could be rationally designed to have enhanced selectivity for a given target. Two RNA drug targets, the prokaryotic ribosomal A-site and the HIV-1 TAR, provide an excellent model system in which to dissect the issue of target selectivity, in that they each have distinctive interactions with aminoglycosides. We report herein the design, synthesis, and binding activity of novel nucleobase,aminoglycoside conjugates that were engineered to be more selective for the A-site binding pocket. Contrary to the structural design, the conjugates bind the A-site more weakly than does the parent compound and bind the TAR more tightly than the parent compound. This result implies that the two RNA targets differ in their ability to adapt to structurally diverse ligands and thus have inherently different selectivities. This work emphasizes the importance of considering the inherent selectivity traits of the RNA target when engineering new ligands. [source]


    Bacteria commonly isolated from keratitis specimens retain antibiotic susceptibility to fluoroquinolones and gentamicin plus cephalothin

    CLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 1 2006
    Cameron N Ly MB BS
    Abstract Purpose:, Patients presenting with presumed infective keratitis were studied to determine predisposing factors, the current susceptibilities of the bacterial isolates to a range of relevant antibiotics, the success rate of topical antibiotic treatment of keratitis and predictors of failure of topical therapy. Methods:, Corneal scrapings taken from patients who presented between January 2002 and December 2003 to the Sydney Eye Hospital Emergency Department with keratitis were cultured. The minimum inhibitory concentration of selected antibiotics was determined for each bacterial isolate using an agar dilution technique. Results:, One hundred and twelve consecutive patients presented with corneal ulcers. Forty-seven of the 112 (42%) patients had a growth from the corneal scraping. Potential predisposing factors were identified in 64% of patients, most frequently contact lens wear (36% of patients). Coagulase-negative staphylococci were the most common species isolated. Other common organisms isolated include Pseudomonas aeruginosa, Corynebacterium spp., Staphylococcus aureus and Streptococcus spp. Conclusions:, Most microorganisms isolated from patients with bacterial keratitis showed susceptibility to ciprofloxacin and aminoglycosides. Cephalothin plus aminoglycoside constituted an effective initial broad-spectrum antibiotic combination. The success rate of topical antibiotic treatment of corneal abscess is 89%. Predictors of failure include older age group, medium or large ulcer, culture-negative keratitis, hypopyon and poor visual acuity. [source]


    Problems associated with potential massive use of antimicrobial agents as prophylaxis or therapy of a bioterrorist attack

    CLINICAL MICROBIOLOGY AND INFECTION, Issue 8 2002
    E. Navas
    In addition to the direct sanitary damage of a terrorist attack caused by biological weapons, the consequences of the massive stockpiling and consumption of antimicrobial agents in order to treat or prevent the disease under a potential epidemic due to pathogenic bacteria must also be considered. Bacillus anthracis, Francisella tularensis and Yersinia pestis are the bacteria most likely to be used as terrorist weapons. Tetracyclines, quinolones and aminoglycoside are the antibiotics of choice against these microorganisms. The recent terrorist attack with anthrax spores in the USA caused a substantial increase in the sales of ciprofloxacin, as thousands of citizens received antibiotic prophylaxis for either confirmed or suspected exposure to anthrax, and many others stockpiled antibiotic supplies at their homes under a panic scenario. The massive consumption of antimicrobial drugs may lead to the selection of antibiotic resistant strains, and to the appearance of undesirable side effects, such as anaphylaxis or teratogenesis. National health authorities must develop realistic protocols in order to detect, treat and prevent mass casualties caused by biological weapons. An antibiotic stockpile has to be planned and implemented, and home stockpiling of antibiotics must be strongly discouraged. [source]


    Combined Chemical-Enzymatic Assembly of Aminoglycoside Derivatives with N-1-AHB Side Chain

    ADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2008
    Igor Nudelman
    Abstract A series of unprotected pseudo-disaccharides and pseudo-trisaccharides of 2-deoxystreptamine-containing aminoglycosides have been selectively acylated at the N-1 position with the valuable (S)-4-amino-2-hydroxybutanoyl (AHB) pharmacophore by using the recombinant BtrH and BtrG enzymes from butirosin biosynthesis in combination with a synthetic acyl donor. The process was optimized by performing two enzymatic steps in a sequential manner without purification of the intermediate product. [source]


    Biosynthesis of spectinomycin: heterologous production of spectinomycin and spectinamine in an aminoglycoside-deficient host, Streptomyces venezuelae YJ003

    JOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2008
    L.P. Thapa
    Abstract Aims:, To obtain spectinomycin and spectinamine by heterologous expression into the biosynthetic deoxysugar (desosamine) gene-deleted host Streptomyces venezuelae YJ003. Methods and Results:, The 17-kb spectinomycin biosynthetic gene cluster from Streptomyces spectabilis ATCC 27741 was heterologously expressed into Streptomyces venezuelae YJ003. Furthermore, the speA, speB and spcS2 encoded in the spectinomycin biosynthetic gene cluster of cosmid pSPC8 were also heterologously characterized to be responsible for the production of spectinamine. Conclusions:, The results of this study indicated that pSPC8 contains all the genes necessary for the biosynthesis of spectinomycin. We also concluded that SpeA, SpeB and SpcS2 are sufficient for the biosynthesis of spectinamine. We also verified that SpeB and SpcS2 show dual character in the biosynthetic pathway of spectinomycin in Streptomyces spectabilis. Significance and Impact of the Study:, This is the report regarding the expression of a biosynthetic gene cluster that gives rise to the production of aminoglycoside antibiotics in Streptomyces venezuelae YJ003. Therefore, this work may serve as a foundation for further research on spectinomycin biosynthesis and other aminoglycosides. [source]


    Application of artificial neural network modelling to identify severely ill patients whose aminoglycoside concentrations are likely to fall below therapeutic concentrations

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2003
    S. Yamamura PhD
    Summary Objective:, Identification of ICU patients whose concentrations are likely to fall below therapeutic concentrations using artificial neural network (ANN) modelling and individual patient physiologic data. Method:, Data on indicators of disease severity and some physiologic data were collected from 89 ICU patients who received arbekacin (ABK) and 61 who received amikacin (AMK). Three-layer ANN modelling and multivariate logistic regression analysis were used to predict the plasma concentrations of the aminoglycosides (ABK and AMK) in the severely ill patients. Results:, Predictive performance analysis showed that the sensitivity and specificity of ANN modelling was superior to multivariate logistic regression analysis. For accurate modelling, a predictable range should be inferred from the data structure before the analysis. Restriction of the predictable region, based on the data structure, increased predictive performance. Conclusion:, ANN analysis was superior to multivariate logistic regression analysis in predicting which patients would have plasma concentrations lower than the minimum therapeutic concentration. To improve predictive performance, the predictable range should be inferred from the data structure before prediction. When applying ANN modelling in clinical settings, the predictive performance and predictable region should be investigated in detail to avoid the risk of harm to severely ill patients. [source]


    Aminoglycoside dosing in diabetes

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2000
    Axworthy
    Studies have evaluated the comparative efficacy, toxicity and costs associated with extended-interval vs. standard multiple daily dosing of aminoglycosides. In this case, an elderly man with diabetes and good renal function at baseline was switched from standard to extended-interval dosing. During the course of therapy there was evidence of decreased renal function. Pertinent literature was searched for, uncovered and critically evaluated to determine if and what evidence supports using extended dosing of aminoglycosides in this population. No data were found specifically evaluating the different dosing strategies in diabetic patients. However, there were many trials and several meta-analysis located that compared the two dosing strategies, most suggesting at least a cost advantage and possibly less toxicity with extended-interval dosing. Further information is needed to determine whether there is a differential risk for toxicity between these dosing regimens in patient with diabetes. [source]


    A molecular dynamics study on binding recognition between several 4,5 and 4,6-linked aminoglycosides with A-site RNA

    JOURNAL OF MOLECULAR RECOGNITION, Issue 5 2010
    Shih-Yuan Chen
    Abstract A molecular dynamics (MD) simulation has been performed for two sets of aminoglycoside antibiotics bound with an RNA duplex corresponding to the aminoacyl-tRNA decoding site of the 16S rRNA to characterize the energetics and dynamics of binding for several aminoglycosides. The binding free energy, essential dynamics and hydration analysis have been conducted to characterize the dynamics' properties associated with the binding recognition between each set of antibiotics and the RNA duplex. We have built several dynamic models with reasonable binding free energies showing good correlation with the experimental data. We have also conducted a hydration analysis on some long residency water molecules detected as W8 and W49 sites around the U1406,·,U1495 pair and which are found to be important in binding recognition and in causing some apparent stretch variations of this pair during the dynamic studies. In addition, we also find that the hydration sites with long residence time identified between the ring III of two 4,6-linked antibiotics (tobramycin and kanamycin) and phosphate oxygen atoms of G1405/U1406 may be worthy of further exploration for rational drug design. Copyright © 2009 John Wiley & Sons, Ltd. [source]


    Aminoglycoside-mediated partial suppression of MECP2 nonsense mutations responsible for Rett syndrome in vitro

    JOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2010
    Andreea C. Popescu
    Abstract Rett syndrome is a pediatric neurological condition that affects primarily girls. Approximately 30% of Rett syndrome cases arise from point mutations that introduce a premature stop codon into the MECP2 gene. Several studies have now shown that certain aminoglycosides can facilitate read-through of some types of nonsense mutations in a context-dependent manner and allow the generation of a full-length protein. It remains mostly unclear whether different nonsense mutations of MECP2 will be responsive to aminoglycoside treatment. In this study, we tested whether the common premature terminating mutations of MECP2 seen in Rett syndrome cases can be partially suppressed by aminoglycoside administration. Our results show that aminoglycosides allow different mutant forms of MECP2 to be overcome in transiently transfected HEK293 cells, but with differing levels of efficiency. In addition, we also show that aminoglycosides increased the prevalence of full-length MeCP2 protein in a dose-dependent manner in a lymphocyte cell line derived from a Rett syndrome girl with the R255X mutation. This study helps to establish the "proof of principle" that some nonsense mutations causing Rett syndrome can be at least partially suppressed by drug treatment. © 2010 Wiley-Liss, Inc. [source]


    Intracellular readthrough of nonsense mutations by aminoglycosides in coagulation factor VII

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2006
    M. PINOTTI
    Summary.,Background: Nonsense mutations in coagulation factor (F) VII potentially cause a lethal hemorrhagic diathesis. Readthrough of nonsense mutations by aminoglycosides has been studied in a few human disease models with variable results. Objectives: We investigated the K316X and W364X FVII mutations, associated with intracranial hemorrhage, and their correction by aminoglycosides. The rare nonsense mutations in FVII represent favorite models to test this strategy, because even tiny increases in the amount of functional full-length protein in patients could ameliorate hemorrhagic phenotypes. Results: A FVII,green fluorescent protein (GFP) chimaera provided us with a fluorescent model of FVII expression in living cells. Appreciable fluorescence in cells transfected with nonsense FVII,GFP mutants was detected upon geneticin treatment, thus demonstrating suppression of premature translation termination. To investigate the rescue of FVII function, nonsense variants of the native FVII without GFP (p316X,FVII and p364X,FVII) were transfected and found to secrete low amounts of FVII (,1% of Wt,FVII activity), thus suggesting a spontaneous stop codon readthrough. Geneticin treatment of cells resulted in a significant and dose-dependent increase of secreted FVII molecules (p316X,FVII, 24 ± 12 ng mL,1, 3.6 ± 0.8% of Wt,FVII activity; p364X,FVII, 26 ± 10 ng mL,1, 3.7±0.6%) characterized by reduced specific activity, thus indicating the synthesis of dysfunctional proteins. Similar results were observed with gentamicin, a commonly used aminoglycoside of potential interest for patient treatment. Conclusions: Our approach, extendable to other coagulation factors, represents an effective tool for a systematic study of the effects of aminoglycosides and neighboring sequences on nonsense codon readthrough. These results provide the rationale for a mutation-specific therapeutic approach in FVII deficiency. [source]


    Methicillin-Resistant Staphylococcus aureus in Horses at a Veterinary Teaching Hospital: Frequency, Characterization, and Association with Clinical Disease

    JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2006
    J.S. Weese
    Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging equine pathogen. To attempt to control nosocomial and zoonotic transmission, an MRSA screening program was established for all horses admitted to the Ontario Veterinary College Veterinary Teaching Hospital, whereby nasal screening swabs were collected at admission, weekly during hospitalization, and at discharge. MRSA was isolated from 120 (5.3%) of 2,283 horses: 61 (50.8%) at the time of admission, 53 (44.2%) during hospitalization, and 6 from which the origin was unclear because an admission swab had not been collected. Clinical infections attributable to MRSA were present or developed in 14 (11.7%) of 120 horses. The overall rate of community-associated colonization was 27 per 1,000 admissions. Horses colonized at admission were more likely to develop clinical MRSA infection than those not colonized at admission (OR 38.9, 95% CI 9.49,160, P < 0.0001). The overall nosocomial MRSA colonization incidence rate was 23 per 1,000 admissions. The incidence rate of nosocomial MRSA infection was at the rate of 1.8 per 1,000 admissions, with an incidence density of 0.88 per 1,000 patient days. Administration of ceftiofur or aminoglycosides during hospitalization was the only risk factor associated with nosocomial MRSA colonization. MRSA screening of horses admitted to a veterinary hospital was useful for identification of community-associated and nosocomial colonization and infection, and for monitoring of infection control practices. [source]


    Cationic antimicrobial peptides activate a two-component regulatory system, PmrA-PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa

    MOLECULAR MICROBIOLOGY, Issue 1 2003
    Joseph B. McPhee
    Summary The two-component regulatory system PhoP-PhoQ of Pseudomonas aeruginosa regulates resistance to cationic antimicrobial peptides, polymyxin B and aminoglycosides in response to low Mg2+ conditions. We have identified a second two-component regulatory system, PmrA-PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides. This system responds to limiting Mg2+, and is affected by a phoQ, but not a phoP mutation. Inactivation of the pmrB sensor kinase and pmrA response regulator greatly decreased the expression of the operon encoding pmrA-pmrB while expression of the response regulator pmrA in trans resulted in increased activation suggesting that the pmrA-pmrB operon is autoregulated. Interposon mutants in pmrB, pmrA, or in an intergenic region upstream of pmrA-pmrB exhibited two to 16-fold increased susceptibility to polymyxin B and cationic antimicrobial peptides. The pmrA-pmrB operon was also found to be activated by a number of cationic peptides including polymyxins B and E, cattle indolicidin and synthetic variants as well as LL-37, a component of human innate immunity, whereas peptides with the lowest minimum inhibitory concentrations tended to be the weakest inducers. Additionally, we showed that the putative LPS modification operon, PA3552-PA3559, was also induced by cationic peptides, but its expression was only partially dependent on the PmrA-PmrB system. The discovery that the PmrA-PmrB two-component system regulates resistance to cationic peptides and that both it and the putative LPS modification system are induced by cationic antimicrobial peptides has major implications for the development of these antibiotics as a therapy for P. aeruginosa infections. [source]


    Renoprotective effect of Hemidesmus indicus, a herbal drug used in gentamicin-induced renal toxicity

    NEPHROLOGY, Issue 3 2004
    MANGALA S KOTNIS
    SUMMARY: Background and Aims: Owing to the global trend towards improved ,quality of life', there is considerable evidence of an increase in demand for medicinal plants. The WHO guidelines define basic criteria for the standardization of herbal medicines. The present work is an effort in this direction to prove the safety and efficacy of Hemidesmus indicus Linn. in the management of nephrotoxicity induced by aminoglycosides such as gentamicin. Methods and Results: Simple, quality control methods using high performance thin layer chromatographic (HPTLC) phytochemical fingerprint, proximate analysis, and the stability of the H. indicus root powder were developed. From the toxicity study using albino Swiss mice, it was observed that the drug (H. indicus) was relatively safe up to 7 g/kg bodyweight dose. Efficacy was evaluated against gentamicin-induced nephrotoxicity in albino Wister rats. The study examined animals from the following groups: no treatment, gentamicin treated, gentamicin treated recovery, and gentamicin and plant treated. Animals from all groups were killed on day 13 of the study; those from gentamicin treated group were killed on the seventh day. Assessment of the drug efficacy drug was conducted by using haematological and histological examination. Conclusion: The treatment with H. indicus helped in the management of renal impairment, which was induced by gentamicin in rats. This is evident from the results obtained for various kidney function tests for gentamicin, along with the results from the plant treated group, and is in comparison with the results found for the gentamicin recovery group. A histological examination of kidneys also supports the findings from haematological evaluations. The plant shows promise as an adjunct therapy along side aminoglycosides as it reduces nephrotoxicity caused by aminoglycosides. [source]


    Production of ,-globin and adult hemoglobin following G418 treatment of erythroid precursor cells from homozygous ,039 thalassemia patients,

    AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2009
    Francesca Salvatori
    In several types of thalassemia (including ,039-thalassemia), stop codon mutations lead to premature translation termination and to mRNA destabilization through nonsense-mediated decay. Drugs (for instance aminoglycosides) can be designed to suppress premature termination, inducing a ribosomal readthrough. These findings have introduced new hopes for the development of a pharmacologic approach to the cure of this disease. However, the effects of aminoglycosides on globin mRNA carrying ,-thalassemia stop mutations have not yet been investigated. In this study, we have used a lentiviral construct containing the ,039-thalassemia globin gene under control of the ,-globin promoter and a LCR cassette. We demonstrated by fluorescence-activated cell sorting (FACS) analysis the production of ,-globin by K562 cell clones expressing the ,039-thalassemia globin gene and treated with G418. More importantly, after FACS and high-performance liquid chromatography (HPLC) analyses, erythroid precursor cells from ,039-thalassemia patients were demonstrated to be able to produce ,-globin and adult hemoglobin after treatment with G418. This study strongly suggests that ribosomal readthrough should be considered a strategy for developing experimental strategies for the treatment of ,0 -thalassemia caused by stop codon mutations. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source]


    Renal dysfunction in cystic fibrosis: Is there cause for concern?,

    PEDIATRIC PULMONOLOGY, Issue 10 2009
    Natalie Soulsby
    Abstract Most people associate cystic fibrosis (CF) with lung disease. Although this is the major cause of morbidity and mortality, CF is in fact a multi-organ disease. Patients with CF are living longer. Accompanying their increased life expectancy are complications not previously encountered. One of the less obvious concerns is that of renal dysfunction associated with long-term exposure to aminoglycosides as well as renally toxic immunosuppressants in lung transplant recipients. This article reviews what is known about the extent of the problem, summarizes what the current practices of measuring and monitoring renal function in patients with CF, and makes suggestions for alternative approaches. In particular, the potential role of cystatin C will be discussed. Pediatr Pulmonol. 2009; 44:947,953. ©2009 Wiley-Liss, Inc. [source]


    Normal volume of distribution of tobramycin in a mother and daughter with a CFTR splice mutation (1717,,,1G,,,A)

    PEDIATRIC PULMONOLOGY, Issue 4 2002
    Dawn Simon MD
    Abstract A mother and daughter pair with CF who shared a splice mutation (1717,,,1G,,,A) had a normal volume of distribution of tobramycin. The literature on tobramycin pharmacokinetics, which was published before the genetic defect was identified, is discussed. The authors speculate on the role of CFTR in the distribution of aminoglycosides and recommend that CFTR mutations should be clarified in all future studies of tobramycin pharmacokinetics in patients with CF. Pediatr Pulmonol. 2002; 33:315-317. © 2002 Wiley-Liss, Inc. [source]


    Risk of drug-related problems for various antibiotics in hospital: assessment by use of a novel method,

    PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2008
    Hege Salvesen Blix MSc
    Abstract Purpose To investigate the use of antibiotics in hospitals, to explore drug-related problems (DRPs) linked to antibiotics and to introduce a novel way of expressing the risks accompanying use of various antibiotics. Methods Patients from internal medicine departments in four Norwegian hospitals were prospectively included in 2002. Demographics, drugs used, medical history, laboratory data and clinical/pharmacological risk factors were recorded. DRPs were identified by clinical pharmacists and assessed in multidisciplinary hospital teams. A new term, the drug risk ratio, was established and defined as the number of times the antibiotic was associated with DRPs in relation to the number of times it was used. Results Out of the 668 patients included, 283 patients (42%) used antibiotics (AB users). AB users were older (76.2 vs. 73.9), used more drugs on admission (5.1 vs. 4.4) and had more DRPs (3.0 vs. 2.2) than non-users. The DRP categories no further need for drug, non-optimal drug and non-optimal dose were most frequently observed. The drug risk ratio, calculated for 12 antibiotic groups, was highest for aminoglycosides (0.77), , -lactamase-resistant penicillins (0.56), macrolides (0.54) and quinolones (0.48) and lowest for first- and third-generation cephalosporins, 0.17 and 0.13, respectively. Conclusions Nearly half of the hospitalised patients were prescribed antibiotics and antibiotic associated DRPs occurred frequently. The drug risk ratio for the different antibiotic groups varied with a factor of six from the lowest to the highest. A high drug risk ratio would alert of antibiotics which require heightened awareness when going to be used in clinical practice. Copyright © 2008 John Wiley & Sons, Ltd. [source]


    Trends in antimicrobial utilization at a Spanish general hospital during a 5-year period

    PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 3 2003
    Lorena Hermosilla Nájera
    Abstract Purpose Antimicrobials are a major part of hospital pharmacy budgets and must be considered in resource planning and spending projections. This study describes the profile of antibiotic use at a medium-sized hospital (by examining the ICU separately) and analyses its evolution over the period 1996,2000. Methods Descriptive and retrospective study. Pharmacy records were reviewed to identify oral and parenteral antimicrobial agents administered to inpatients. Results were expressed in Daily Defined Doses (DDD) per 100 stays and day. Results During the 5-year study period 176.162 DDD/100 s-d of antibiotics were consumed in the ICU, whereas in the rest of the hospital usage was much lower (54.438 DDD/100 s-d). Aminoglycosides, cephalosporins, penicillins, glycopeptides and carbapenems were the most commonly used groups of antimicrobials in the ICU, and penicillins, cephalosporins, trimethoprim/sulfonamide combinations, aminoglycosides and quinolones in the rest of the hospital. Conclusions ICUs have some special features which make them different to the other inpatient areas. Because of that fact we consider it important to study this specific patient-care area separately. Copyright © 2003 John Wiley & Sons, Ltd. [source]


    Construction of the Korea Elderly Pharmacoepidemiologic Cohort: drug utilization review of cephalosporins in geriatric inpatients

    PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2001
    Byung Joo Park MD
    Abstract We performed a cohort-based pharmacoepidemiologic study in order to evaluate the pattern of cephalosporin prescriptions in elderly inpatients in Korea. The Korea Elderly Pharmacoepidemiologic Cohort was composed of a geriatric population of beneficiaries of the Korea Medical Insurance Corporation residing in Busan in 1993. The cohort consisted of 23,649 members, comprising 15,221 women (64.4%) and 8428 men (35.6%). The study population for drug utilization review consisted of those cohort members who were admitted into hospitals during the period January 1993 through December 1994. The number of hospitalized patients was 4262, comprising 2631 women (61.7%) and 1681 men (38.3%). The trend of cephalosporin prescriptions over the 2-year period showed that the use of second and third generation cephalosporins increased relative to the use of first generation. The use of cephalosporins combined with other antibiotics was found to occur in 22.8% aminoglycosides (76.7%) and quinolones (17.1%) being the most common antibiotics combined with cephalosporins. Our result demonstrates an increase in the prescription of second and third generation cephalosporins in Korea, which has implications not only for the elderly population but also for the total population because of the impact on health care costs and the potential for the emergence of antimicrobial resistance. Copyright © 2001 John Wiley & Sons, Ltd. [source]