Aminoglycosides

Jackson, Justin; Chen, Caroline; Buising, Kirsty

doi:10.1097/qco.0000000000000012

Cited by 66 publications

(40 citation statements)

References 114 publications

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“…This change has also being applied to the establishment of gentamicin dosing in pediatrics (1,5,13,14). However, its pharmacokinetics in infants exhibits large inter-and intraindividual variability, mainly due to the developmental changes occurring from the first month of life (15).…”

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confidence: 99%

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Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

Medellín‐Garibay

Rueda-Naharro

Peña-Cabia

et al. 2015

Antimicrob Agents Chemother

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The aim of this study was to characterize and validate the population pharmacokinetics of gentamicin in infants and to determine the influences of clinically relevant covariates to explain the inter-and intraindividual variabilities associated with this drug. Infants receiving intravenous gentamicin and with routine therapeutic drug monitoring were consecutively enrolled in the study. Plasma concentration and time data were retrospectively collected from 208 infants (1 to 24 months old) of the Hospital Universitario Severo Ochoa (Spain), of whom 44% were males (mean age [؎ standard deviation], 5.8 ؎ 4.8 months; mean body weight, 6.4 ؎ 2.2 kg). Data analysis was performed with NONMEM 7.2. One-and two-compartment open models were analyzed to estimate the gentamicin population parameters and the influences of several covariates. External validation was carried out in another population of 55 infants. The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics, with total body weight being the covariate that mainly influences central volume (V c ) and clearance (CL); this parameter was also related to creatinine clearance. Both parameters are age related and different from those reported for neonatal populations. On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 mg/kg of body weight every 24 h is proposed for intravenous gentamicin, followed by therapeutic drug monitoring in order to avoid toxicity and ensure efficacy with minimal blood sampling. Gentamicin pharmacokinetics and disposition were accurately characterized in this pediatric population (infants), with the parameters obtained being different from those reported for neonates and children. These differences should be considered in the dosing and therapeutic monitoring of this antibiotic.

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confidence: 99%

“…A minoglycosides are among the most commonly used broadspectrum antibiotics used in anti-infective therapy (1,2). Despite their potential for renal toxicity, ototoxicity, and bacterial resistance, several aminoglycosides continue to play an important role in the treatment of infections (3,4).…”

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confidence: 99%

Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

Medellín‐Garibay

Rueda-Naharro

Peña-Cabia

et al. 2015

Antimicrob Agents Chemother

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“…The ease of their spread among pathogens within mobile genetic elements and the broad, high-level resistance conferred by these rRNA modification enzymes make them a profound threat to the future usefulness of aminoglycosides (34,35). The recent reevaluation of potential applications of aminoglycosides in the clinic, particularly against multidrug-resistant organisms (36,37), thus warrants a more complete understanding of the origins and modes of action of these emerging resistance determinants.…”

Section: Discussionmentioning

confidence: 99%

30S Subunit-Dependent Activation of the Sorangium cellulosum So ce56 Aminoglycoside Resistance-Conferring 16S rRNA Methyltransferase Kmr

Savic

Sunita

Zelinskaya

et al. 2015

Antimicrob Agents Chemother

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bMethylation of bacterial 16S rRNA within the ribosomal decoding center confers exceptionally high resistance to aminoglycoside antibiotics. This resistance mechanism is exploited by aminoglycoside producers for self-protection while functionally equivalent methyltransferases have been acquired by human and animal pathogenic bacteria. Here, we report structural and functional analyses of the Sorangium cellulosum So ce56 aminoglycoside resistance-conferring methyltransferase Kmr. Our results demonstrate that Kmr is a 16S rRNA methyltransferase acting at residue A1408 to confer a canonical aminoglycoside resistance spectrum in Escherichia coli. Kmr possesses a class I methyltransferase core fold but with dramatic differences in the regions which augment this structure to confer substrate specificity in functionally related enzymes. Most strikingly, the region linking core ␤-strands 6 and 7, which forms part of the S-adenosyl-L-methionine (SAM) binding pocket and contributes to base flipping by the m 1 A1408 methyltransferase NpmA, is disordered in Kmr, correlating with an exceptionally weak affinity for SAM. Kmr is unexpectedly insensitive to substitutions of residues critical for activity of other 16S rRNA (A1408) methyltransferases and also to the effects of by-product inhibition by S-adenosylhomocysteine (SAH). Collectively, our results indicate that adoption of a catalytically competent Kmr conformation and binding of the obligatory cosubstrate SAM must be induced by interaction with the 30S subunit substrate. Gene pools in soil and aquatic microbial communities represent largely unexplored reservoirs of antibiotic resistance (1, 2). An analysis of the resistance mechanisms present in these communities may reveal new insights into the origins, activities, and potential for mobilization of antibiotic resistance determinants to pathogenic bacterial populations. In particular, myxobacteria of the genus Sorangium have become a major source of secondary metabolites over the last several decades alongside the actinobacteria and fungi (3, 4). The model strain Sorangium cellulosum So ce56 possesses a 13.1-Mb genome with 17 gene clusters for secondary metabolites (5). Associated with this tremendous biosynthetic power is a high resistance potential against multiple antibiotics. For example, all Sorangium strains can grow in the presence of exceptionally high concentrations of kanamycin through the action of a single, specific aminoglycoside resistance-conferring 16S rRNA methyltransferase, Kmr (6).In common with most aminoglycosides, kanamycin binds within helix (h) 44 of the 16S rRNA in the bacterial small (30S) ribosomal subunit and induces errors in mRNA decoding (7-9). Aminoglycoside-producing bacteria typically protect themselves from self-intoxication by expression of aminoglycoside resistance-conferring methyltransferases that modify the drug binding site. Two subfamilies of 16S rRNA methyltransferases introduce distinct 16S rRNA modifications at N7 of guanosine 1405 (m 7 G1405) or N1 of adenosine 1408 (m 1 A140...

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“…But, with the increasing threat of MDR bacteria [3][4][5][6][7] and the decline in new antibiotics approved to help combat this global challenge [8], aminoglycosides are being revisited [9][10][11][12][13][14][15][16][17]. Because aminoglycosides have been able to largely evade bacterial resistance due to their waned use, it has made them a safer choice [9][10][11][12][13][14][15][16][17]. In particular, approaches in which aminoglycosides are used in combination therapy with other antibiotics is an emerging strategy [9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…However, with the emergence of equally potent but less toxic antibiotics, the use of aminoglycosides as antibiotics fell out of favor. But, with the increasing threat of MDR bacteria [3][4][5][6][7] and the decline in new antibiotics approved to help combat this global challenge [8], aminoglycosides are being revisited [9][10][11][12][13][14][15][16][17]. Because aminoglycosides have been able to largely evade bacterial resistance due to their waned use, it has made them a safer choice [9][10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D)

Joshi

Voo

Graham

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The rapid increase in multi-drug resistant bacteria has resulted in previously discontinued treatments being revisited. Aminoglycosides are effective "old" antibacterial agents that fall within this category. Despite extensive usage and understanding of their intracellular targets, there is limited mechanistic knowledge regarding how aminoglycosides penetrate bacterial membranes. Thus, the activity of two well-known aminoglycosides, kanamycin A and neomycin B, towards a bacterial mimetic membrane (DMPC:DMPG (4:1)) was examined using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). The macroscopic effect of increasing the aminoglycoside concentration showed that kanamycin A exerts a threshold response, switching from binding to the membrane to disruption of the surface. Neomycin B, however, disrupted the membrane at all concentrations examined. At concentrations above the threshold value observed for kanamycin A, both aminoglycosides revealed similar mechanistic details. That is, they both inserted into the bacterial mimetic lipid bilayer, prior to disruption via loss of materials, presumably aminoglycoside-membrane composites. Depth profile analysis of this membrane interaction was achieved using the overtones of the quartz crystal sensor. The measured data is consistent with a two-stage process in which insertion of the aminoglycoside precedes the 'detergent-like' removal of membranes from the sensor. The results of this study contribute to the insight required for aminoglycosides to be reconsidered as active antimicrobial agents/co-agents by providing details of activity at the bacterial membrane. Kanamycin and neomycin still offer potential as antimicrobial therapeutics for the future and the QCM-D method illustrates great promise for screening new antibacterial or antiviral drug candidates.

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Aminoglycosides

Cited by 66 publications

References 114 publications

Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

30S Subunit-Dependent Activation of the Sorangium cellulosum So ce56 Aminoglycoside Resistance-Conferring 16S rRNA Methyltransferase Kmr

Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D)

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