Journal articles on the topic 'Aminoglycosides'
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1
Caldwell, Shane J., and Albert M. Berghuis. "Plasticity of Aminoglycoside Binding to Antibiotic Kinase APH(2″)-Ia." Antimicrobial Agents and Chemotherapy 62, no. 7 (April 16, 2018): e00202-18. http://dx.doi.org/10.1128/aac.00202-18.
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ABSTRACTThe APH(2″)-Ia aminoglycoside resistance enzyme forms the C-terminal domain of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme and confers high-level resistance to natural 4,6-disubstituted aminoglycosides. In addition, reports have suggested that the enzyme can phosphorylate 4,5-disubstituted compounds and aminoglycosides with substitutions at the N1 position. Previously determined structures of the enzyme with bound aminoglycosides have not indicated how these noncanonical substrates may bind and be modified by the enzyme. We carried out crystallographic studies to directly observe the interactions of these compounds with the aminoglycoside binding site and to probe the means by which these noncanonical substrates interact with the enzyme. We find that APH(2″)-Ia maintains a preferred mode of binding aminoglycosides by using the conserved neamine rings when possible, with flexibility that allows it to accommodate additional rings. However, if this binding mode is made impossible because of additional substitutions to the standard 4,5- or 4,6-disubstituted aminoglycoside architecture, as in lividomycin A or the N1-substituted aminoglycosides, it is still possible for these aminoglycosides to bind to the antibiotic binding site by using alternate binding modes, which explains the low rates of noncanonical phosphorylation activities seen in enzyme assays. Furthermore, structural studies of a clinically observed arbekacin-resistant mutant of APH(2″)-Ia revealed an altered aminoglycoside binding site that can stabilize an alternative binding mode for N1-substituted aminoglycosides. This mutation may alter and expand the aminoglycoside resistance spectrum of the wild-type enzyme in response to newly developed aminoglycosides.
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Zieliński, Michał, Jonathan Blanchet, Sophia Hailemariam, and Albert M. Berghuis. "Structural elucidation of substrate-bound aminoglycoside acetyltransferase (3)-IIIa." PLOS ONE 17, no. 8 (August 3, 2022): e0269684. http://dx.doi.org/10.1371/journal.pone.0269684.
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Canonical aminoglycosides are a large group of antibiotics, where the part of chemical diversity stems from the substitution of the neamine ring system on positions 5 and 6. Certain aminoglycoside modifying enzymes can modify a broad range of 4,5- and 4,6-disubstituted aminoglycosides, with some as many as 15. This study presents the structural and kinetic results describing a promiscuous aminoglycoside acetyltransferase AAC(3)-IIIa. This enzyme has been crystallized in ternary complex with coenzyme A and 4,5- and 4,6-disubstituted aminoglycosides. We have followed up this work with kinetic characterization utilizing a panel of diverse aminoglycosides, including a next-generation aminoglycoside, plazomicin. Lastly, we observed an alternative binding mode of gentamicin in the aminoglycoside binding site, which was proven to be a crystallographic artifact based on mutagenesis.
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Childs-Kean, Lindsey M., Kristy M. Shaeer, Sheeba Varghese Gupta, and Jonathan C. Cho. "Aminoglycoside Allergic Reactions." Pharmacy 7, no. 3 (August 29, 2019): 124. http://dx.doi.org/10.3390/pharmacy7030124.
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Aminoglycosides are antimicrobial agents that are primarily used for infections caused by Gram-negative pathogens. The purpose of this article is to review the allergic reactions reported in the published literature to aminoglycoside antibiotics. A thorough PubMed search was conducted and excluded non-allergic adverse reactions to aminoglycosides. Allergic reactions to aminoglycosides occur infrequently, but can include cutaneous reactions as well as systemic reactions, including anaphylaxis. Of the evaluated aminoglycosides, gentamicin had the most reported allergic reactions, including the most reports of anaphylaxis, followed by tobramycin, and then amikacin. Most reports of allergic reactions occurred in patients who had a prior exposure to some dosage form of an aminoglycoside. Cross-reactivity among aminoglycosides is common and occurs due to the similarities in their chemical structures. Desensitization protocols to tobramycin have been described in the literature.
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Rivetti, Serena, Alberto Romano, Stefano Mastrangelo, Giorgio Attinà, Palma Maurizi, and Antonio Ruggiero. "Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients." Pharmaceuticals 16, no. 10 (September 25, 2023): 1353. http://dx.doi.org/10.3390/ph16101353.
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Aminoglycosides are broad-spectrum antibiotics largely used in children, but they have potential toxic side effects, including ototoxicity. Ototoxicity from aminoglycosides is permanent and is a consequence of its action on the inner ear cells via multiple mechanisms. Both uncontrollable risk factors and controllable risk factors are involved in the pathogenesis of aminoglycoside-related ototoxicity and, because of the irreversibility of ototoxicity, an important undertaking for preventing ototoxicity includes antibiotic stewardship to limit the use of aminoglycosides. Aminoglycosides are fundamental in the treatment of numerous infectious conditions at neonatal and pediatric age. In childhood, normal auditory function ensures adequate neurocognitive and social development. Hearing damage from aminoglycosides can therefore strongly affect the normal growth of the child. This review describes the molecular mechanisms of aminoglycoside-related ototoxicity and analyzes the risk factors and the potential otoprotective strategies in pediatric patients.
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Uneme, Mio, Kazuya Ishikawa, Kazuyuki Furuta, Atsuko Yamashita, and Chikara Kaito. "Overexpression of the flagellar motor protein MotB sensitizes Bacillus subtilis to aminoglycosides in a motility-independent manner." PLOS ONE 19, no. 4 (April 26, 2024): e0300634. http://dx.doi.org/10.1371/journal.pone.0300634.
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The flagellar motor proteins, MotA and MotB, form a complex that rotates the flagella by utilizing the proton motive force (PMF) at the bacterial cell membrane. Although PMF affects the susceptibility to aminoglycosides, the effect of flagellar motor proteins on the susceptibility to aminoglycosides has not been investigated. Here, we found that MotB overexpression increased susceptibility to aminoglycosides, such as kanamycin and gentamicin, in Bacillus subtilis without affecting swimming motility. MotB overexpression did not affect susceptibility to ribosome-targeting antibiotics other than aminoglycosides, cell wall-targeting antibiotics, DNA synthesis-inhibiting antibiotics, or antibiotics inhibiting RNA synthesis. Meanwhile, MotB overexpression increased the susceptibility to aminoglycosides even in the motA-deletion mutant, which lacks swimming motility. Overexpression of the MotB mutant protein carrying an amino acid substitution at the proton-binding site (D24A) resulted in the loss of the enhanced aminoglycoside-sensitive phenotype. These results suggested that MotB overexpression sensitizes B. subtilis to aminoglycosides in a motility-independent manner. Notably, the aminoglycoside-sensitive phenotype induced by MotB requires the proton-binding site but not the MotA/MotB complex formation.
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Chiang, Wen-Chi, Martin Nilsson, Peter Østrup Jensen, Niels Høiby, Thomas E. Nielsen, Michael Givskov, and Tim Tolker-Nielsen. "Extracellular DNA Shields against Aminoglycosides in Pseudomonas aeruginosa Biofilms." Antimicrobial Agents and Chemotherapy 57, no. 5 (March 11, 2013): 2352–61. http://dx.doi.org/10.1128/aac.00001-13.
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ABSTRACTWithin recent years, it has been established that extracellular DNA is a key constituent of the matrix of microbial biofilms. In addition, it has recently been demonstrated that DNA binds positively charged antimicrobials such as aminoglycosides and antimicrobial peptides. In the present study, we provide evidence that extracellular DNA shields against aminoglycosides inPseudomonas aeruginosabiofilms. We show that exogenously supplemented DNA integrates intoP. aeruginosabiofilms and increases their tolerance toward aminoglycosides. We provide evidence that biofilms formed by a DNA release-deficientP. aeruginosaquorum-sensing mutant are more susceptible to aminoglycoside treatment than wild-type biofilms but become rescued from the detrimental action of aminoglycosides upon supplementation with exogenous DNA. Furthermore, we demonstrate that exposure to lysed polymorphonuclear leukocytes, which are thought to be a source of extracellular DNA at sites of infections, increases the tolerance ofP. aeruginosabiofilms toward aminoglycosides. Although biofilm-associated aminoglycoside tolerance recently has been linked to extracellular DNA-mediated activation of thepmrgenes, we demonstrate that the aminoglycoside tolerance mediated by the presence of extracellular DNA is not caused by activation of thepmrgenes in ourP. aeruginosabiofilms but rather by a protective shield effect of the extracellular DNA.
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Ban, Yeon Hee, Myoung Chong Song, Je Won Park, and Yeo Joon Yoon. "Minor components of aminoglycosides: recent advances in their biosynthesis and therapeutic potential." Natural Product Reports 37, no. 3 (2020): 301–11. http://dx.doi.org/10.1039/c9np00041k.
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This Highlight covers the recent advances in the biosynthetic pathways of aminoglycosides including their minor components, together with the therapeutic potential for minor aminoglycoside components and semi-synthetic aminoglycosides.
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Kim, Ock-Hwa, Byoung Soo Kwon, Minkyu Han, Younsuck Koh, Woo-Sung Kim, Jin-Woo Song, Yeon-Mok Oh, et al. "Association Between Duration of Aminoglycoside Treatment and Outcome of Cavitary Mycobacterium avium Complex Lung Disease." Clinical Infectious Diseases 68, no. 11 (September 15, 2018): 1870–76. http://dx.doi.org/10.1093/cid/ciy804.
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Abstract Background Although aminoglycosides are recommended for cavitary Mycobacterium avium complex lung disease (MAC-LD), the optimal duration of treatment is unclear. We investigated the association between duration of aminoglycoside treatment and outcomes in cavitary MAC-LD. Methods Among patients diagnosed with macrolide-susceptible cavitary MAC-LD between 2000 and 2013, 101 who received treatment up to August 2017 with a regimen containing aminoglycosides were enrolled at a tertiary referral center in South Korea. Their medical records were retrospectively reviewed. The duration of aminoglycoside treatment was at the discretion of the attending physician. Results A total of 75 patients (74.3%) were administered aminoglycosides for ≥3 months (median 164 days), whereas the remaining 26 patients (25.7%) received treatment for <3 months (median 59 days). The overall treatment success rate was 63.4% (64/101). Patients treated with aminoglycosides for ≥3 months had a significantly higher success rate than those treated for <3 months (69.3% vs 46.2%; P = .035). Multivariate analysis revealed that aminoglycoside treatment for ≥3 months was a significant factor for treatment success (adjusted odds ratio, 3.602; 95% confidence interval, 1.249–10.390; P = .018). Recurrence occurred in 8 (22.9%) of 35 patients who were followed up for at least 3 years after the end of treatment; all 8 patients received aminoglycosides for ≥3 months. Conclusions Patients with cavitary MAC-LD treated with aminoglycosides for ≥3 months showed higher treatment success rate than those treated for <3 months. However, treatment for ≥3 months was not associated with the development of recurrence.
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Fong, Desiree H., and Albert M. Berghuis. "Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics." Antimicrobial Agents and Chemotherapy 53, no. 7 (May 11, 2009): 3049–55. http://dx.doi.org/10.1128/aac.00062-09.
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ABSTRACT Butirosin is unique among the naturally occurring aminoglycosides, having a substituted amino group at position 1 (N1) of the 2-deoxystreptamine ring with an (S)-4-amino-2-hydroxybutyrate (AHB) group. While bacterial resistance to aminoglycosides can be ascribed chiefly to drug inactivation by plasmid-encoded aminoglycoside-modifying enzymes, the presence of an AHB group protects the aminoglycoside from binding to many resistance enzymes, and hence, the antibiotic retains its bactericidal properties. Consequently, several semisynthetic N1-substituted aminoglycosides, such as amikacin, isepamicin, and netilmicin, were developed. Unfortunately, butirosin, amikacin, and isepamicin are not resistant to inactivation by 3′-aminoglycoside O-phosphotransferase type IIIa [APH(3′)-IIIa]. We report here the crystal structure of APH(3′)-IIIa in complex with an ATP analog, AMPPNP [adenosine 5′-(β,γ-imido)triphosphate], and butirosin A to 2.4-Å resolution. The structure shows that butirosin A binds to the enzyme in a manner analogous to other 4,5-disubstituted aminoglycosides, and the flexible antibiotic-binding loop is key to the accommodation of structurally diverse substrates. Based on the crystal structure, we have also constructed a model of APH(3′)-IIIa in complex with amikacin, a commonly used semisynthetic N1-substituted 4,6-disubstituted aminoglycoside. Together, these results suggest a strategy to further derivatize the AHB group in order to generate new aminoglycoside derivatives that can elude inactivation by resistance enzymes while maintaining their ability to bind to the ribosomal A site.
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Trylska, Joanna, and Marta Kulik. "Interactions of aminoglycoside antibiotics with rRNA." Biochemical Society Transactions 44, no. 4 (August 15, 2016): 987–93. http://dx.doi.org/10.1042/bst20160087.
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Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-negative bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics containing a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on molecular dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodynamics of interactions of these aminoglycosides with their 16S RNA target.
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Rybak, Michael J., Betty J. Abate, S. Lena Kang, Michael J. Ruffing, Stephen A. Lerner, and George L. Drusano. "Prospective Evaluation of the Effect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity." Antimicrobial Agents and Chemotherapy 43, no. 7 (July 1, 1999): 1549–55. http://dx.doi.org/10.1128/aac.43.7.1549.
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ABSTRACT The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for ≥72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P ≤ 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (P ≤ 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.
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Henley, Charles M. "Kanamycin Depletes Cochlear Polyamines in the Developing Rat." Otolaryngology–Head and Neck Surgery 110, no. 1 (January 1994): 103–9. http://dx.doi.org/10.1177/019459989411000112.
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Developing mammals are more sensitive to aminoglycoside antibiotics and other ototoxic agents than adults, with maximum sensitivity occurring during the period of anatomic and functional maturation of the cochlea. For the aminoglycoside antibiotics, the hypersensitive period in rats occurs during the second and third postnatal weeks. Toxicity is initially expressed as outer hair cell (OHC) damage in the high-frequency, basal region of the cochlea. Distortion-product otoacoustic emissions (DPOAEs), physiologic measures of OHC function, are particularly sensitive to aminoglycoside exposure during the period of rapid cochlear physiologic development. Toxicity is characterized by increased DPOAE thresholds and decreased amplitudes. The mechanism of developmental sensitivity to aminoglycosides is unknown. A potential biochemical target of aminoglycosides is the ornithine decarboxylase (ODC)-polyamine pathway. ODC activity is elevated in the developing rat cochlea, aminoglycosides inhibit cochlear ODC in developing rats, and α-difluoromethylornithine (a specific ODC inhibitor) impairs development of cochlear function. In the present study we demonstrate an incomplete polyamnine response to aminoglycoside damage, characterized by inhibition of the polyamines spermidine and spermine and accumulation of putrescine in the organ of Corti. Aminoglycoside inhibition of polyamine synthesis may mediate developmental ototoxic hypersensitivity by interfering with developmental and repair processes.
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Ahmadian, Leila, Zahra Norouzi Bazgir, Mohammad Ahanjan, Reza Valadan, and Hamid Reza Goli. "Role of Aminoglycoside-Modifying Enzymes (AMEs) in Resistance to Aminoglycosides among Clinical Isolates of Pseudomonas aeruginosa in the North of Iran." BioMed Research International 2021 (August 21, 2021): 1–10. http://dx.doi.org/10.1155/2021/7077344.
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In recent years, the prevalence of resistance to aminoglycosides among clinical isolates of Pseudomonas aeruginosa is increasing. The aim of this study was to investigate the role of aminoglycoside-modifying enzymes (AMEs) in resistance to aminoglycosides in clinical isolates of P. aeruginosa. The clinical isolates were collected from different hospitals. Disk agar diffusion test was used to determine the antimicrobial resistance pattern of the clinical isolates, and the minimum inhibitory concentration of aminoglycosides was detected by microbroth dilution method. The PCR was performed for discovery of aminoglycoside-modifying enzyme-encoding genes. Among 100 screened isolates, 43 (43%) isolates were resistant to at least one tested aminoglycosides. However, 13 (13%) isolates were resistant to all tested aminoglycosides and 37 isolates were detected as multidrug resistant (MDR). The resistance rates of P. aeruginosa isolates against tested antibiotics were as follows: ciprofloxacin (41%), piperacillin-tazobactam (12%), cefepime (32%), piperacillin (26%), and imipenem (31%). However, according to the MIC method, 13%, 32%, 33%, and 37% of the isolates were resistant to amikacin, gentamicin, tobramycin, and netilmicin, respectively. The PCR results showed that AAC(6 ′ )-Ib was the most commonly (26/43, 60.4%) identified AME-encoding gene followed by AAC(6 ′ )-IIa (41.86%), APH(3 ′ )-IIb (34.8%), ANT(3 ″ )-Ia (18.6), ANT(2 ″ )-Ia (13.95%), and APH(3 ″ )-Ib (2.32%). However, APH(3 ′ )-Ib was not found in any of the studied isolates. The high prevalence of AME-encoding genes among aminoglycoside-resistant P. aeruginosa isolates in this area indicated the important role of AMEs in resistance to these antibiotics similar to most studies worldwide. Due to the transmission possibility of these genes between the Gram-negative bacteria, we need to control the prescription of aminoglycosides in hospitals.
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Wargo, Kurt A., and Jonathan D. Edwards. "Aminoglycoside-Induced Nephrotoxicity." Journal of Pharmacy Practice 27, no. 6 (September 7, 2014): 573–77. http://dx.doi.org/10.1177/0897190014546836.
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Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.
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Farook, Saika, Md Shariful Alam Jilani, Alpona Akhter, and J. Ashraful Haq. "Melioidosis by aminoglycoside susceptible Burkholderia pseudomallei: First case in Bangladesh." IMC Journal of Medical Science 14, no. 2 (April 5, 2021): 55–59. http://dx.doi.org/10.3329/imcjms.v14i2.52830.
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Burkholderia pseudomallei is the etiological agent of melioidosis. It is a gram-negative bacillus present in environment and intrinsically resistant to many antibiotics including aminoglycosides. However, recently aminoglycoside susceptible B. pseudomallei has been isolated from melioidosis cases and reported from some countries of the world. But, such aminoglycoside susceptible B. pseudomallei has never been detected in Bangladesh either from melioidosis cases or from environment. All the B. pseudomallei isolated so far in Bangladesh were resistant to gentamicin and other aminoglycosides. Here, we describe a disseminated case of melioidosis caused by aminoglycoside susceptible B. pseudomallei in a 55 years old Bengali male patient. This is the first case of melioidosis due to aminoglycoside susceptible B. pseudomallei in Bangladesh.
Ibrahim Med. Coll. J. 2020; 14(2): 55-59
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Rodriguez, Mônica B., and Sérgio O. P. Costa. "Spontaneous kanamycin-resistant Escherichia coli mutant with altered periplasmic oligopeptide permease protein (OppA) and impermeability to aminoglycosides." Revista de Microbiologia 30, no. 2 (April 1999): 153–56. http://dx.doi.org/10.1590/s0001-37141999000200013.
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A spontaneous kanamycin-resistant Escherichia coli mutant, showing cross resistance to five other aminoglycosides and absence of the OppA protein was isolated. [3H]-dihydrostreptomycin uptake is reduced in this mutant, implying that the oligopeptide transport system is involved in accumulation of aminoglycosides, although apparently not related with aminoglycoside permeability alteration due to bacterial adaptation to osmotic changes.
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Jassem, Agatha N., James E. A. Zlosnik, Deborah A. Henry, Robert E. W. Hancock, Robert K. Ernst, and David P. Speert. "In VitroSusceptibility of Burkholderia vietnamiensis to Aminoglycosides." Antimicrobial Agents and Chemotherapy 55, no. 5 (February 14, 2011): 2256–64. http://dx.doi.org/10.1128/aac.01434-10.
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ABSTRACTBurkholderia cepaciacomplex (BCC) bacteria are opportunistic pathogens that can cause severe disease in cystic fibrosis (CF) patients and other immunocompromised individuals and are typically multidrug resistant. Here we observed that unlike other BCC species, most environmental and clinicalBurkholderia vietnamiensisisolates were intrinsically susceptible to aminoglycosides but not to cationic antimicrobial peptides or polymyxin B. Furthermore, strains acquired aminoglycoside resistance during chronic CF infection, a phenomenon that could be induced under tobramycin or azithromycin pressurein vitro. In comparing susceptible and resistantB. vietnamiensisisolates, no gross differences in lipopolysaccharide structure were observed, all had lipid A-associated 4-amino-4-deoxy-l-arabinose residues, and all were resistant to the permeabilizing effects of aminoglycosides, a measure of drug entry via self-promoted uptake. However, susceptible isolates accumulated 5 to 6 times more gentamicin than a resistant isolate, and aminoglycoside susceptibility increased in the presence of an efflux pump inhibitor.B. vietnamiensisis therefore unusual among BCC bacteria in its susceptibility to aminoglycosides and capacity to acquire resistance. Aminoglycoside resistance appears to be due to decreased cellular accumulation as a result of active efflux.
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Menashe, Ofir, Elena Kaganskaya, Timor Baasov, and Sima Yaron. "Aminoglycosides Affect Intracellular Salmonella enterica Serovars Typhimurium and Virchow." Antimicrobial Agents and Chemotherapy 52, no. 3 (January 2, 2008): 920–26. http://dx.doi.org/10.1128/aac.00382-07.
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ABSTRACT The high antibacterial activity and selectivity of aminoglycosides and their low activity against intracellular bacteria associated with eukaryotic cells make them the antibiotics of choice for the elimination of extracellular bacteria during intracellular studies. Given the evidence that aminoglycosides can penetrate the eukaryotic cell membrane, the goal of this study was to examine the influence of aminoglycosides on macrophage-associated Salmonella. Herein, we show that gentamicin, kanamycin, and tobramycin at concentrations between 15 to 150 μg ml−1 do not kill intracellular Salmonella but have other effects on the bacterial physiology. By using Salmonella enterica serovars Typhimurium and Virchow harboring luciferase reporter plasmid, we observed that the light produced by intracellular Salmonella declined immediately upon exposure to aminoglycosides, indicating that the bacteria were under stress. The extent of this effect was dependent on the macrophage host, on the identity of the aminoglycoside and its concentration, on the exposure time, and on the Salmonella serovar. Salmonella associated with Nramp1-negative macrophages, in which the phagosomal pH is higher, were more susceptible to aminoglycosides than Salmonella associated with Nramp1-expressing macrophages. These results verify that aminoglycosides affect intracellular bacteria and that the extent of this effect is dependent on the acidity level within the phagosome, suggesting that for the study of intracellular bacteria, the aminoglycoside concentration should be limited to two to five times the MIC for the bacterial strain studied. This precaution should guarantee the complete execution of extracellular bacteria with minimal effects on the intracellular bacteria and the host cells.
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Gutierrez, Belen, Jose A. Escudero, Alvaro San Millan, Laura Hidalgo, Laura Carrilero, Cristina M. Ovejero, Alfonso Santos-Lopez, Daniel Thomas-Lopez, and Bruno Gonzalez-Zorn. "Fitness Cost and Interference of Arm/Rmt Aminoglycoside Resistance with the RsmF Housekeeping Methyltransferases." Antimicrobial Agents and Chemotherapy 56, no. 5 (February 13, 2012): 2335–41. http://dx.doi.org/10.1128/aac.06066-11.
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ABSTRACTArm/Rmt methyltransferases have emerged recently in pathogenic bacteria as enzymes that confer high-level resistance to 4,6-disubstituted aminoglycosides through methylation of the G1405 residue in the 16S rRNA (like ArmA and RmtA to -E). In prokaryotes, nucleotide methylations are the most common type of rRNA modification, and they are introduced posttranscriptionally by a variety of site-specific housekeeping enzymes to optimize ribosomal function. Here we show that while the aminoglycoside resistance methyltransferase RmtC methylates G1405, it impedes methylation of the housekeeping methyltransferase RsmF at position C1407, a nucleotide that, like G1405, forms part of the aminoglycoside binding pocket of the 16S rRNA. To understand the origin and consequences of this phenomenon, we constructed a series of in-frame knockout and knock-in mutants ofEscherichia coli, corresponding to the genotypesrsmF+, ΔrsmF,rsmF+rmtC+, and ΔrsmF rmtC+. When analyzed for the antimicrobial resistance pattern, the ΔrsmFbacteria had a decreased susceptibility to aminoglycosides, including 4,6- and 4,5-deoxystreptamine aminoglycosides, showing that the housekeeping methylation at C1407 is involved in intrinsic aminoglycoside susceptibility inE. coli. Competition experiments between the isogenicE. colistrains showed that, contrary to expectation, acquisition ofrmtCdoes not entail a fitness cost for the bacterium. Finally, matrix-assisted laser desorption ionization (MALDI) mass spectrometry allowed us to determine that RmtC methylates the G1405 residue not only in presence but also in the absence of aminoglycoside antibiotics. Thus, the coupling between housekeeping and acquired methyltransferases subverts the methylation architecture of the 16S rRNA but elicits Arm/Rmt methyltransferases to be selected and retained, posing an important threat to the usefulness of aminoglycosides worldwide.
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Huth, M. E., A. J. Ricci, and A. G. Cheng. "Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection." International Journal of Otolaryngology 2011 (2011): 1–19. http://dx.doi.org/10.1155/2011/937861.
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Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection.
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Qian, Yaping, and Min-Xin Guan. "Interaction of Aminoglycosides with Human Mitochondrial 12S rRNA Carrying the Deafness-Associated Mutation." Antimicrobial Agents and Chemotherapy 53, no. 11 (August 17, 2009): 4612–18. http://dx.doi.org/10.1128/aac.00965-08.
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ABSTRACT The mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we employed an RNA-directed chemical-modification approach to understanding the pathogenesis of aminoglycoside-induced hearing loss. The patterns of chemical modification of RNA oligonucleotides carrying the A1555G mutation by dimethyl sulfate (DMS) were distinct from those of the RNA oligonucleotides carrying wild-type sequence in the presence of aminoglycosides. In the RNA analogue carrying the A1555G mutation, reduced reactivity to DMS occurred in base G1555 as well as in bases C1556 and A1553 in the presence of paromomycin, neomycin, gentamicin, kanamycin, tobramycin, or streptomycin. In particular, base G1555 exhibited marked but similar levels of protection in the presence of 0.1 μM to 100 μM neomycin, gentamicin, or kanamycin. In contrast, the levels of protection in base G1555 appeared to be correlated with the concentration of paromycin, tobramycin, or steptomycin. Furthermore, increasing reactivities to DMS in the presence of these aminoglycosides were observed for bases A1492, C1493, C1494, and A1557 in the RNA analogue carrying the A1555G mutation. These data suggested that the A1555G mutation altered the binding properties of aminoglycosides at the A site of 12S rRNA and led to local conformational changes in 12S rRNA carrying the A1555G mutation. The interaction between aminoglycosides and 12S rRNA carrying the A1555G mutation provides new insight into the pathogenesis of aminoglycoside ototoxicity.
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Dager, William E. "Aminoglycoside Pharmacokinetics: Volume of Distribution in Specific Adult Patient Subgroups." Annals of Pharmacotherapy 28, no. 7-8 (July 1994): 944–51. http://dx.doi.org/10.1177/106002809402800719.
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OBJECTIVE: To review the published clinical studies reporting volume of distribution for aminoglycosides in patient population subgroups. Controversies in methods used are discussed. DATA SOURCES: National Library of Medicine Medlars, searched using MEDLINE. STUDY SELECTION: Published articles primarily relating to pharmacokinetic properties of aminoglycosides in specific adult patient subgroups published within the past 20 years were included. Pediatric studies were excluded. DATA EXTRACTION: The methodology, assay technique, and results from clinical studies reporting aminoglycoside volume of distribution were evaluated. DATA SYNTHESIS: Clinical studies reporting aminoglycoside volume of distribution subgroups, including the methods by which their results were derived, are tabulated. CONCLUSIONS: The expected aminoglycoside volume of distribution can vary, depending on a patient's clinical presentation. Data presented will allow a more refined initial estimation of volumes of distribution, which may facilitate the achievement of desired aminoglycoside serum concentrations.
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Prokhorova, Irina, Roger B. Altman, Muminjon Djumagulov, Jaya P. Shrestha, Alexandre Urzhumtsev, Angelica Ferguson, Cheng-Wei Tom Chang, Marat Yusupov, Scott C. Blanchard, and Gulnara Yusupova. "Aminoglycoside interactions and impacts on the eukaryotic ribosome." Proceedings of the National Academy of Sciences 114, no. 51 (December 5, 2017): E10899—E10908. http://dx.doi.org/10.1073/pnas.1715501114.
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Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored. Here, we use the combination of X-ray crystallography and single-molecule FRET analysis to reveal the interactions of distinct classes of aminoglycosides with the 80S eukaryotic ribosome. Crystal structures of the 80S ribosome in complex with paromomycin, geneticin (G418), gentamicin, and TC007, solved at 3.3- to 3.7-Å resolution, reveal multiple aminoglycoside-binding sites within the large and small subunits, wherein the 6′-hydroxyl substituent in ring I serves as a key determinant of binding to the canonical eukaryotic ribosomal decoding center. Multivalent binding interactions with the human ribosome are also evidenced through their capacity to affect large-scale conformational dynamics within the pretranslocation complex that contribute to multiple aspects of the translation mechanism. The distinct impacts of the aminoglycosides examined suggest that their chemical composition and distinct modes of interaction with the ribosome influence PTC read-through efficiency. These findings provide structural and functional insights into aminoglycoside-induced impacts on the eukaryotic ribosome and implicate pleiotropic mechanisms of action beyond decoding.
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McCollister, Bruce D., Matthew Hoffman, Maroof Husain, and Andrés Vázquez-Torres. "Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake." Antimicrobial Agents and Chemotherapy 55, no. 5 (February 22, 2011): 2189–96. http://dx.doi.org/10.1128/aac.01203-10.
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ABSTRACTOur investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protectSalmonellaspp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellularSalmonellaagainst the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressedSalmonellarespiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen inSalmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogensPseudomonas aeruginosaandStaphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria.
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Tada, Tatsuya, Tohru Miyoshi-Akiyama, Kayo Shimada, Masahiro Shimojima, and Teruo Kirikae. "Novel 6′-N-Aminoglycoside Acetyltransferase AAC(6′)-Iaj from a Clinical Isolate of Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 57, no. 1 (October 15, 2012): 96–100. http://dx.doi.org/10.1128/aac.01105-12.
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ABSTRACTPseudomonas aeruginosaNCGM1588 has a novel chromosomal class 1 integron, In151, which includes theaac(6′)-Iajgene. The encoded protein, AAC(6′)-Iaj, was found to consist of 184 amino acids, with 70% identity to AAC(6′)-Ia.Escherichia colitransformed with a plasmid containing theaac(6′)-Iajgene acquired resistance to all aminoglycosides tested except gentamicin. Of note,aac(6′)-Iajcontributed to the resistance to arbekacin. Thin-layer chromatography revealed that AAC(6′)-Iaj acetylated all aminoglycosides tested except gentamicin. These findings indicated that AAC(6′)-Iaj is a functional acetyltransferase that modifies the amino groups at the 6′ positions of aminoglycosides and contributes to aminoglycoside resistance ofP. aeruginosaNCGM1588, including arbekacin.
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Vetting, M., S. L. Roderick, S. Hegde, S. Magnet, and J. S. Blanchard. "What can structure tell us about in vivo function? The case of aminoglycoside-resistance genes." Biochemical Society Transactions 31, no. 3 (June 1, 2003): 520–22. http://dx.doi.org/10.1042/bst0310520.
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Resistance to antibiotics used in the treatment of bacterial infections is an expanding clinical problem. Aminoglycosides, one of the oldest classes of natural product antibiotics, exert their bactericidal effect as the result of inhibiting bacterial protein synthesis by binding to the acceptor site of the 30 S ribosomal subunit. The most common mechanism of clinical resistance to aminoglycosides results from the expression of enzymes that covalently modify the aminoglycoside. We will discuss the enzymology and structure of two representative chromosomally encoded aminoglycoside N-acetyltransferases, Mycobacterium tuberculosis AAC(2´)-Ic and Salmonella enterica AAC(6´)-Iy, and speculate about their possible physiological function and substrates.
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Bellucci, Maria Cristina, and Alessandro Volonterio. "Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles." Antibiotics 9, no. 8 (August 11, 2020): 504. http://dx.doi.org/10.3390/antibiotics9080504.
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Aminoglycosides are a class of naturally occurring and semi synthetic antibiotics that have been used for a long time in fighting bacterial infections. Due to acquired antibiotic resistance and inherent toxicity, aminoglycosides have experienced a decrease in interest over time. However, in the last decade, we are seeing a renaissance of aminoglycosides thanks to a better understanding of their chemistry and mode of action, which had led to new trends of application. The purpose of this comprehensive review is to highlight one of these new fields of application: the use of aminoglycosides as building blocks for the development of liposomal and polymeric vectors for gene delivery. The design, synthetic strategies, ability to condensate the genetic material, the efficiency in transfection, and cytotoxicity as well as when available, the antibacterial activity of aminoglycoside-based cationic lipids and polymers are covered and critically analyzed.
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Mao, Weimin, Mark S. Warren, Angela Lee, Anita Mistry, and Olga Lomovskaya. "MexXY-OprM Efflux Pump Is Required for Antagonism of Aminoglycosides by Divalent Cations inPseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 45, no. 7 (July 1, 2001): 2001–7. http://dx.doi.org/10.1128/aac.45.7.2001-2007.2001.
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ABSTRACT Antagonism of aminoglycosides by divalent cations is well documented for Pseudomonas aeruginosa and is regarded as one of the problems in aminoglycoside therapy. It is generally considered that divalent cations interfere with uptake of aminoglycosides at both the outer and inner membranes. It has been demonstrated recently that aminoglycosides can be removed from cells ofP. aeruginosa by the three-component multidrug resistance efflux pump MexXY-OprM. We sought to investigate the interplay between efflux and uptake in resistance to aminoglycosides inP. aeruginosa. To do so, we studied the effects of the divalent cations Mg2+ and Ca2+ on susceptibility to aminoglycosides in a wild-type strain of P. aeruginosa and in mutants either overexpressing or lacking the MexXY-OprM efflux pump. MICs of gentamicin, streptomycin, amikacin, apramycin, netilmicin, and arbekacin were determined in Mueller-Hinton broth in the presence of cations added at concentrations that varied from 0.125 to 8 mM. We found, unexpectedly, that while both Mg2+ and Ca2+ antagonized aminoglycosides (up to a 64-fold decrease in susceptibility at 8 mM), antagonism was seen only in the strains of P. aeruginosa that contained the functional MexXY-OprM efflux pump. Our results indicate that inhibition of the MexXY-OprM efflux pump should abolish the antagonism of aminoglycosides by divalent cations, regardless of its precise mechanism. This may significantly increase the therapeutic index of aminoglycosides and improve the clinical utility of this important class of antibiotics.
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Hao, Guo-Xiang, Sophie Teng, Evelyne Jacqz-Aigrain, and Wei Zhao. "DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS." Archives of Disease in Childhood 101, no. 1 (December 14, 2015): e1.51-e1. http://dx.doi.org/10.1136/archdischild-2015-310148.55.
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Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.
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Heintz, Brett H., George R. Thompson, and William E. Dager. "Clinical Experience with Aminoglycosides in Dialysis-Dependent Patients: Risk Factors for Mortality and Reassessment of Current Dosing Practices." Annals of Pharmacotherapy 45, no. 11 (October 18, 2011): 1338–45. http://dx.doi.org/10.1345/aph.1q403.
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Background:: A resurgence of aminoglycoside use has followed the recent increase of multidrug-resistant gram-negative pathogens and is often needed even in the treatment of dialysis-dependent patients; however, studies evaluating the treatment of gram-negative infections with aminoglycosides, including the optimal dose, in the setting of dialysis are limited. Objective: To evaluate the current patterns of aminoglycoside use, including microbiologic and clinical indications, and identify risk factors associated with mortality in dialysis-dependent patients receiving aminoglycosides. Methods: Utilization, clinical, and microbiologic data were collected retrospectively over a 2-year period (July 2008-June 2010) for adults with a diagnosis of renal failure requiring dialysis and aminoglycoside therapy. Binary logistic and multivariate regression analyses were performed to identify risk factors for alt-cause 30-day mortality. Results: Ninety-five consecutive aminoglycoside courses in 88 patients met inclusion criteria for evaluation. A wide variety of clinical and microbiologic indications were documented. The average duration of aminoglycoside therapy was 5.2 days (range 1-42), the average duration of antimicrobial therapy was 13.5 days (1-60), and the all-cause 30-day mortality rate was 36.5%. Factors associated with all-cause 30-day mortality were gram-negative rod (GNR) bacteremia (OR 28.6; p = 0.035), advanced age (OR 8.5; p = 0.030), recent admission (OR 33.4; p = 0.038). and inadequate empiric therapy (OR 14.9; p = 0.024). Intravenous catheter removal was protective of all-cause 30-day mortality (OR 0.01; p = 0.005). A first pre-dialysis plasma concentration relative to the minimum inhibitory concentration (Cp:MIC) <6 mg/L (gentamicin/tobramycin) was associated with an increased risk of mortality (p = 0.026) upon subgroup analysis of dialysis-dependent patients with GNR bloodstream infections. Conclusions: Outcomes among dialysis-dependent patients who received aminoglycosides were below expectations. Various risk factors for mortality were identified, including retention of the catheter, inadequate empiric therapy, and a Cp:MIC <6 mg/L. Improved approaches to dosing of aminoglycosides in dialysis-dependent patients, including more aggressive dosing practices, should be urgently explored in attempts to maximize favorable patient outcomes.
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Xia, Wan Qiu, Lei Zhang, and Jian Ping Wang. "Development of a Fluorescence Polarization Assay for Multi-Determination of 10 Aminoglycosides in Pork Muscle Sample Based on Ribosomal Protein S12 and Studying Its Recognition Mechanism." Foods 11, no. 20 (October 13, 2022): 3196. http://dx.doi.org/10.3390/foods11203196.
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The residues of aminoglycosides in foods of animal origin are a potential risk to consumers. There have been some immunoassays reported for the screening of aminoglycoside residues, but the method showing the broadest detection spectrum can only be used to detect two drugs. This is because a broad specific recognition reagent is not available. In the present study, the receptor of aminoglycosides (ribosomal protein S12 of Lysinibacillus sphaericus) was expressed, and its affinities and recognition mechanisms for 10 aminoglycosides were studied by using surface plasmon resonance and molecular docking, respectively. Then the receptor was used as a recognition reagent to develop a fluorescence polarization assay on a 96-well microplate for the detection of the 10 drugs in pork muscle samples. The limits of detection for the 10 drugs ranged from 5.25 to 30.25 ng/g. The sensitivities for the 10 drugs were generally consistent with their respective receptor affinities and binding energies. After comprehensive comparison, the method performances were better than all the previously reported immunoassays for aminoglycosides. This is the first study reporting the recognition mechanisms of ribosomal protein S12 of Lysinibacillus sphaericus for 10 aminoglycosides and the use of it as a recognition reagent to develop a pseudo-immunoassay for the multi-determination of aminoglycosides in food samples.
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Moore, Richard A., David DeShazer, Shauna Reckseidler, Ania Weissman, and Donald E. Woods. "Efflux-Mediated Aminoglycoside and Macrolide Resistance in Burkholderia pseudomallei." Antimicrobial Agents and Chemotherapy 43, no. 3 (March 1, 1999): 465–70. http://dx.doi.org/10.1128/aac.43.3.465.
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Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to a wide range of antimicrobial agents including β-lactams, aminoglycosides, macrolides, and polymyxins. We used Tn5-OT182 to mutagenizeB. pseudomallei to identify the genes involved in aminoglycoside resistance. We report here on the identification of AmrAB-OprA, a multidrug efflux system inB. pseudomallei which is specific for both aminoglycoside and macrolide antibiotics. We isolated two transposon mutants, RM101 and RM102, which had 8- to 128-fold increases in their susceptibilities to the aminoglycosides streptomycin, gentamicin, neomycin, tobramycin, kanamycin, and spectinomycin. In addition, both mutants, in contrast to the parent, were susceptible to the macrolides erythromycin and clarithromycin but not to the lincosamide clindamycin. Sequencing of the DNA flanking the transposon insertions revealed a putative operon consisting of a resistance, nodulation, division-type transporter, a membrane fusion protein, an outer membrane protein, and a divergently transcribed regulator protein. Consistent with the presence of an efflux system, both mutants accumulated [3H]dihydrostreptomycin, whereas the parent strain did not. We constructed an amr deletion strain,B. pseudomallei DD503, which was hypersusceptible to aminoglycosides and macrolides and which was used successfully in allelic exchange experiments. These results suggest that an efflux system is a major contributor to the inherent high-level aminoglycoside and macrolide resistance found inB. pseudomallei.
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Yadav, Rajbharan, Cornelia B. Landersdorfer, Roger L. Nation, John D. Boyce, and Jürgen B. Bulitta. "Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii." Antimicrobial Agents and Chemotherapy 59, no. 4 (February 2, 2015): 2286–98. http://dx.doi.org/10.1128/aac.04379-14.
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ABSTRACTAcinetobacter baumanniiis among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize β-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistantA. baumannii. We studied combinations of 10 β-lactams and three aminoglycosides against fourA. baumanniistrains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance ofA. baumanniiusing Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (≤2.3 log10) ofA. baumanniiATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other β-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/liter combined with an aminoglycoside yielded synergistic killing (>5 log10) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistantA. baumannii(MIC, 32 mg/liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log10killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.
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Vucovich, Megan M., Robert B. Cotton, Elaine L. Shelton, Jeremy A. Goettel, Noah J. Ehinger, Stanley D. Poole, Naoko Brown, et al. "Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 5 (September 1, 2014): H732—H740. http://dx.doi.org/10.1152/ajpheart.00838.2013.
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Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA; 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation; and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, <25 wk and >32 wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.
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Kashef, Mona T., and Omneya M. Helmy. "Genetic Characterization of a Novel Composite Transposon Carrying armA and aac(6)-Ib Genes in an Escherichia coli Isolate from Egypt." Polish Journal of Microbiology 66, no. 2 (June 28, 2017): 163–69. http://dx.doi.org/10.5604/01.3001.0010.7835.
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Aminoglycosides are used in treating a wide range of infections caused by Gram-positive and Gram-negative bacteria; however, aminoglycoside resistance is common and occurs by several mechanisms. Among these mechanisms is bacterial rRNA methylation by the 16S rRNA methyl transferase (16S-RMTase) enzymes; but data about the spread of this mechanism in Egypt are scarce. Cephalosporins are the most commonly used antimicrobial agents in Egypt; therefore, this study was conducted to determine the frequency of 16S-RMTase among third generation cephalosporin-resistant clinical isolates in Egypt. One hundred and twenty three cephalosporin resistant Gram-negative clinical isolates were screened for aminoglycosides resistance by the Kirby Bauer disk diffusion method and tested for possible production of 16S-RMTase. PCR testing and sequencing were used to confirm the presence of 16S-RMTase and the associated antimicrobial resistance determinants, as well as the genetic region surrounding the armA gene. Out of 123 isolates, 66 (53.66%) were resistant to at least one aminoglycoside antibiotic. Only one Escherichia coli isolate (E9ECMO) which was totally resistant to all tested aminoglycosides, was confirmed to have the armA gene in association with blaTEM-1, blaCTX-M-15, blaCTX-M-14 and aac(6)-Ib genes. The armA gene was found to be carried on a large A/C plasmid. Genetic mapping of the armA surrounding region revealed, for the first time, the association of armA with aac(6)-Ib on the same transposon. In conclusion, the isolation frequency of 16S-RMTase was low among the tested aminoglycoside-resistant clinical samples. However, a novel composite transposon has been detected conferring high-level aminoglycosides resistance.
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McGann, Patrick, Sarah Chahine, Darius Okafor, Ana C. Ong, Rosslyn Maybank, Yoon I. Kwak, Kerry Wilson, Michael Zapor, Emil Lesho, and Mary Hinkle. "Detecting 16S rRNA Methyltransferases in Enterobacteriaceae by Use of Arbekacin." Journal of Clinical Microbiology 54, no. 1 (November 4, 2015): 208–11. http://dx.doi.org/10.1128/jcm.02642-15.
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16S rRNA methyltransferases confer resistance to most aminoglycosides, but discriminating their activity from that of aminoglycoside-modifying enzymes (AMEs) is challenging using phenotypic methods. We demonstrate that arbekacin, an aminoglycoside refractory to most AMEs, can rapidly detect 16S methyltransferase activity inEnterobacteriaceaewith high specificity using the standard disk susceptibility test.
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Bulitta, Jürgen B., Neang S. Ly, Cornelia B. Landersdorfer, Nicholin A. Wanigaratne, Tony Velkov, Rajbharan Yadav, Antonio Oliver, et al. "Two Mechanisms of Killing of Pseudomonas aeruginosa by Tobramycin Assessed at Multiple Inocula via Mechanism-Based Modeling." Antimicrobial Agents and Chemotherapy 59, no. 4 (February 2, 2015): 2315–27. http://dx.doi.org/10.1128/aac.04099-14.
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ABSTRACTBacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against threePseudomonas aeruginosastrains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 108.9CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.
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Recht, Michael I., and Joseph D. Puglisi. "Aminoglycoside Resistance with Homogeneous and Heterogeneous Populations of Antibiotic-Resistant Ribosomes." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2414–19. http://dx.doi.org/10.1128/aac.45.9.2414-2419.2001.
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ABSTRACT Aminoglycosides bind to rRNA in the small subunit of the bacterial ribosome. Mutations in the decoding region of 16S rRNA confer resistance to specific subsets of aminoglycoside antibiotics. The two major classes of 2-deoxystreptamine aminoglycosides are the 4,5- and the 4,6-disubstituted antibiotics. Antibiotics of the 4,5-disubstituted class include neomycin, paromomycin, and ribostamycin. Gentamicins and kanamycins belong to the 4,6-disubstituted class of aminoglycosides. Structural studies indicated the potential importance of position 1406 (Escherichia coli numbering) in the binding of ring III of the 4,6-disubstituted class of aminoglycosides to 16S rRNA. We have introduced a U1406-to-A mutation in a plasmid-encoded copy of E. coli 16S rRNA which has been expressed either in a mixture with wild-type ribosomes or in a strain in which all rRNA is transcribed from the plasmid-encoded rrn operon. High-level resistance to many of the 4,6-disubstituted aminoglycosides is observed only when all the rRNA contains the U1406-to-A mutation. In contrast to the partial dominance of resistance observed with other mutations in the decoding region, there is a dominance of sensitivity with the 1406A mutation. Chemical footprinting experiments indicate that resistance arises from a reduced affinity of the antibiotic for the rRNA target. These results demonstrate that although position 1406 is an important determinant in the binding and action of the 4,6-disubstituted aminoglycosides, other rRNA mutations that perturb the binding of ring I of both classes of 2-deoxystreptamine aminoglycosides confer higher levels of resistance as well as a partial dominance of resistance.
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Rougier, Florent, Daniel Claude, Michel Maurin, Alexandre Sedoglavic, Michel Ducher, Stéphane Corvaisier, Roger Jelliffe, and Pascal Maire. "Aminoglycoside Nephrotoxicity: Modeling, Simulation, and Control." Antimicrobial Agents and Chemotherapy 47, no. 3 (March 2003): 1010–16. http://dx.doi.org/10.1128/aac.47.3.1010-1016.2003.
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ABSTRACT The main constraints on the administration of aminoglycosides are the risks of nephrotoxicity and ototoxicity, which can lead to acute, renal, vestibular, and auditory toxicities. In the present study we focused on nephrotoxicity. No reliable predictor of nephrotoxicity has been found to date. We have developed a deterministic model which describes the pharmacokinetic behavior of aminoglycosides (with a two-compartment model), the kinetics of aminoglycoside accumulation in the renal cortex, the effects of aminoglycosides on renal cells, the resulting effects on renal function by tubuloglomerular feedback, and the resulting effects on serum creatinine concentrations. The pharmacokinetic parameter values were estimated by use of the NPEM program. The estimated pharmacodynamic parameter values were obtained after minimization of the least-squares objective function between the measured and the calculated serum creatinine concentrations. A simulation program assessed the influences of the dosage regimens on the occurrence of nephrotoxicity. We have also demonstrated the relevancy of modeling of the circadian rhythm of the renal function. We have shown the ability of the model to fit with 49 observed serum creatinine concentrations for a group of eight patients treated for endocarditis by comparison with 49 calculated serum creatinine concentrations (r 2 = 0.988; P < 0.001). We have found that for the same daily dose, the nephrotoxicity observed with a thrice-daily administration schedule appears more rapidly, induces a greater decrease in renal function, and is more prolonged than those that occur with less frequent administration schedules (for example, once-daily administration). Moreover, for once-daily administration, we have demonstrated that the time of day of administration can influence the incidence of aminoglycoside nephrotoxicity. The lowest level of nephrotoxicity was observed when aminoglycosides were administered at 1:30 p.m. Clinical application of this model might make it possible to adjust aminoglycoside dosage regimens by taking into account both the efficacies and toxicities of the drugs.
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Chiem, Kevin, Saumya Jani, Brooke Fuentes, David L. Lin, Madeline E. Rasche, and Marcelo E. Tolmasky. "Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking." MedChemComm 7, no. 1 (2016): 184–89. http://dx.doi.org/10.1039/c5md00316d.
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The aminoglycoside 6′-N-acetyltransferase type Ib, AAC(6′)-Ib, confers resistance to clinically relevant aminoglycosides and is the most widely distributed enzyme among AAC(6′)-I-producing Gram-negative pathogens.
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&NA;. "Aminoglycosides see Penicillins + aminoglycosides." Reactions Weekly &NA;, no. 350 (May 1991): 3. http://dx.doi.org/10.2165/00128415-199103500-00005.
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Ezraty, Benjamin, Alexandra Vergnes, Manuel Banzhaf, Yohann Duverger, Allison Huguenot, Ana Rita Brochado, Shu-Yi Su, et al. "Fe-S Cluster Biosynthesis Controls Uptake of Aminoglycosides in a ROS-Less Death Pathway." Science 340, no. 6140 (June 27, 2013): 1583–87. http://dx.doi.org/10.1126/science.1238328.
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All bactericidal antibiotics were recently proposed to kill by inducing reactive oxygen species (ROS) production, causing destabilization of iron-sulfur (Fe-S) clusters and generating Fenton chemistry. We find that the ROS response is dispensable upon treatment with bactericidal antibiotics. Furthermore, we demonstrate that Fe-S clusters are required for killing only by aminoglycosides. In contrast to cells, using the major Fe-S cluster biosynthesis machinery, ISC, cells using the alternative machinery, SUF, cannot efficiently mature respiratory complexes I and II, resulting in impendence of the proton motive force (PMF), which is required for bactericidal aminoglycoside uptake. Similarly, during iron limitation, cells become intrinsically resistant to aminoglycosides by switching from ISC to SUF and down-regulating both respiratory complexes. We conclude that Fe-S proteins promote aminoglycoside killing by enabling their uptake.
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Liscovitch, M., V. Chalifa, M. Danin, and Y. Eli. "Inhibition of neural phospholipase D activity by aminoglycoside antibiotics." Biochemical Journal 279, no. 1 (October 1, 1991): 319–21. http://dx.doi.org/10.1042/bj2790319.
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The effects of aminoglycoside antibiotics on phospholipase D (PLD) activity were investigated in permeabilized NG108-15 cells and in isolated rat brain membranes. Neomycin inhibited guanosine 5′-[gamma-thio]triphosphate-stimulated PLD activity in digitonin-permeabilized NG108-15 cells in a concentration-dependent manner (50% inhibition at 100 microM). Neomycin similarly inhibited PLD activity present in rat brain membranes and assayed in vitro with [3H]phosphatidylcholine as substrate (50% inhibition at 65 microM). Other aminoglycosides tested (kanamycin, geneticin and streptomycin) were nearly equipotent inhibitors of rat brain PLD. These results indicate that aminoglycoside antibiotics inhibit phosphatidylcholine-PLD activity with comparable and sometimes greater potency than their well known inhibition of phosphoinositide-phospholipase C. The possibility that PLD inhibition could mediate some of the toxic side effects of aminoglycosides is suggested.
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McKay, G. A., J. Roestamadji, S. Mobashery, and G. D. Wright. "Recognition of aminoglycoside antibiotics by enterococcal-staphylococcal aminoglycoside 3'-phosphotransferase type IIIa: role of substrate amino groups." Antimicrobial Agents and Chemotherapy 40, no. 11 (November 1996): 2648–50. http://dx.doi.org/10.1128/aac.40.11.2648.
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The interactions of the aminoglycoside 3'-phosphotransferase IIIa with aminoglycoside antibiotics lacking specific amino groups were examined by steady-state kinetic analyses. The results demonstrate that an amino group on C-1 and either an amino or a hydroxyl group at the 2' and 6' positions are important for detoxification of aminoglycosides by this enzyme.
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Abdul-Wahid, Ali A., and Ali M. Almohana. "Dissemination of Aminoglycosides Resistance in Pseudomonas Aeruginosa Isolates in Al-Nasiriya Hospitals Pseudomonas Aeruginosa." Kufa Journal for Nursing Sciences 5, no. 1 (April 15, 2015): 118–27. http://dx.doi.org/10.36321/kjns.vi20151.3158.
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Background: Pseudomonas Aeruginosa is one of the primary opportunistic pathogens responsible for nosocomial infections. Aminoglycosides are an important component of antipseudomonal chemotherapy. The inactivation of drugs by modifying enzymes and 16S rRNA methylase are the most common mechanisms of aminoglycoside resistance. Aim of the study: Investigate the occurrence of aminoglycoside resistance and the incidence of the 16S rRNA methylase and resistance-modifying enzyme genes in P. Aeruginosa isolated of several hospitals in Al-Nasiriya province. Methodology: A total of 355 clinical isolates were collected of three main hospitals in Al-Nasiriya city. The isolates were classified according the source of collection to three groups (160 ear swab, 105 burn swab and 90 urine samples). The results of culture and biochemical tests showed that 65 isolate was Pseudomonas Aeruginosa, which then confirmed by API-20E. Antibiotic susceptibility test (by using the Kirby-pour technique) was performed to all these isolates by using 18 type of antibiotics. The isolates that resistance to at least one type of aminoglycosides were screened for the presence of modifying enzyme genes (AACs, APHs, ANTs) and 16S rRNA methylase genes by polymerase chain reaction. Results: 65 (18.3%) isolates of P. Aeruginosa were identified. The results of antibiotic susceptibility test showed that 29 isolate (44.6%) resistance to at least one type of aminoglycosides which represented by gentamicin the highest (44.6%) and amikacin (18.5%) the lowest. Four genes of AAC were found in 21 (72.4%) aminoglycosides resistant isolates, aac(6')-Ib (69%), aac(6')-I (24.1%), aac(3)-II and aac(3)-I (10.3% each). The most repeated combinations, aac(6')-Ib+aac(6')-I and aac(6')-Ib+aac(3)-II, were detected in 12.7% and 6.9% of isolates, respectively. Negative results for the presence 16rRNA methylase (armA, rmtA, rmtD, and npmA), aph (3')-VI and ant (4')-IIb genes. Conclusions: The aminoglycosides resistance rates in P. Aeruginosa were roughly high in Al-Nasiriya, and most of the resistance isolates harbored aac (6')-Ib gene. Recommendations: In order to overcome the worrisome development of increased resistance to antibiotics in general and aminoglycoside in particular, continued national surveillance programs are crucial.
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Chittapragada, Maruthi, Sarah Roberts, and Young Wan Ham. "Aminoglycosides: Molecular Insights on the Recognition of RNA and Aminoglycoside Mimics." Perspectives in Medicinal Chemistry 3 (January 2009): PMC.S2381. http://dx.doi.org/10.4137/pmc.s2381.
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RNA is increasingly recognized for its significant functions in biological systems and has recently become an important molecular target for therapeutics development. Aminoglycosides, a large class of clinically significant antibiotics, exert their biological functions by binding to prokaryotic ribosomal RNA (rRNA) and interfering with protein translation, resulting in bacterial cell death. They are also known to bind to viral mRNAs such as HIV-1 RRE and TAR. Consequently, aminoglycosides are accepted as the single most important model in understanding the principles that govern small molecule-RNA recognition, which is essential for the development of novel antibacterial, antiviral or even anti-oncogenic agents. This review outlines the chemical structures and mechanisms of molecular recognition and antibacterial activity of aminoglycosides and various aminoglycoside mimics that have recently been devised to improve biological efficacy, binding affinity and selectivity, or to circumvent bacterial resistance.
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Yao, Cheng-Jiao, Yi-lin Li, Meng-Jun Pu, Li-Hong Luo, Qin Xiong, Feng-Jiao Xie, Ting-Lin Li, and Pei-Min Feng. "Aminoglycosides with Anti-MRSA Activity: A Concise Review." Current Topics in Medicinal Chemistry 21, no. 27 (December 8, 2021): 2483–99. http://dx.doi.org/10.2174/1568026621666211004093647.
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Methicillin-resistant Staphylococcus aureus (MRSA), a leading cause of infections in human being and is usually associated with a multidrug-resistant profile, represents a significant health threat and public burden globally. The limited options of effective antibiotics motivate the search for novel anti-MRSA agents. Aminoglycoside antibiotics have been extensively applied in the medical field due to their desirable broad-spectrum antibacterial activity, especially for systemic infections caused by Gram-negative organisms. Recent studies demonstrated that aminoglycosides also possessed potential activity against MRSA, so aminoglycosides may be useful weapons to fight against MRSA. The present work aims to summarize the current scenario of aminoglycosides with anti- MRSA potential, covering articles published between 2010 and 2020. The structure-activity relationship and the mechanism of action are also discussed for the further rational design of novel potential drug candidates.
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Yao, Cheng-Jiao, Yi-lin Li, Meng-Jun Pu, Li-Hong Luo, Qin Xiong, Feng-Jiao Xie, Ting-Lin Li, and Pei-Min Feng. "Aminoglycosides with Anti-MRSA Activity: A Concise Review." Current Topics in Medicinal Chemistry 21, no. 27 (December 8, 2021): 2483–99. http://dx.doi.org/10.2174/1568026621666211004093647.
Full textAbstract:
Methicillin-resistant Staphylococcus aureus (MRSA), a leading cause of infections in human being and is usually associated with a multidrug-resistant profile, represents a significant health threat and public burden globally. The limited options of effective antibiotics motivate the search for novel anti-MRSA agents. Aminoglycoside antibiotics have been extensively applied in the medical field due to their desirable broad-spectrum antibacterial activity, especially for systemic infections caused by Gram-negative organisms. Recent studies demonstrated that aminoglycosides also possessed potential activity against MRSA, so aminoglycosides may be useful weapons to fight against MRSA. The present work aims to summarize the current scenario of aminoglycosides with anti- MRSA potential, covering articles published between 2010 and 2020. The structure-activity relationship and the mechanism of action are also discussed for the further rational design of novel potential drug candidates.
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Kumar, Mukesh, Manish Parakh, D. R. Dabi, and B. D. Gupta. "A study of effect of aminoglycoside therapy on auditory brainstem evoked responses in preterm and term neonates." International Journal of Contemporary Pediatrics 7, no. 8 (July 22, 2020): 1741. http://dx.doi.org/10.18203/2349-3291.ijcp20203168.
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Background: Aminoglycosides are widely used drugs in neonates with associated ototoxic side effects, that can be diagnosed with auditory brainstem evoked responses, which is the recommended screening technique in neonatal intensive care unit infants. This study was conducted to evaluate the effect of aminoglycoside therapy on auditory brainstem evoked responses in term and preterm neonates.Methods: A cross-sectional case control study. Two groups of 26 term and 22 preterm neonates who received aminoglycosides, with no other known risk factors for ototoxicity, were compared with suitable matched control group of 10 neonates in each. ABER was done after at least 5 days of aminoglycoside therapy and results were compared to suitable matched controls.Results: Mean latency of wave I in term neonates at 90 dB and 60 dB and mean interwave latencies of I-V waves in preterm neonates at 30 dB was higher in study group and statistically significant. No statistically significant difference in any of ABER parameters was observed in any group, at all other intensities.Conclusions: Wave I latency was prolonged in study group of term neonates at two intensities which indicates effect of aminoglycoside therapy on distal portion of acoustic nerve. But as there were no such findings at other intensities in term study group and in preterm study group and moreover no other ABER abnormalities were observed, it was concluded that the aminoglycoside therapy has low potential for ototoxicity. Authors support the ABER screening for early detection of hearing abnormalities, and recommend study on larger group of neonates and meta-analysis for final conclusion for evidence-based recommendations to use aminoglycosides in neonates, in view of audiometric and neurological abnormalities.
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Pai, Manjunath P., Anne N. Nafziger, and Joseph S. Bertino. "Simplified Estimation of Aminoglycoside Pharmacokinetics in Underweight and Obese Adult Patients." Antimicrobial Agents and Chemotherapy 55, no. 9 (June 13, 2011): 4006–11. http://dx.doi.org/10.1128/aac.00174-11.
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ABSTRACTAminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m2, respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051–1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance.