Aminoglycoside


Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside sugar;12 the term can also refer more generally to any organic molecule that contains aminosugar substructures Aminoglycoside antibiotics display bactericidal activity against gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen, but generally not against Gram-positive and anaerobic Gram-negative bacteria3 They include the first-in-class aminoglycoside antibiotic streptomycin images at right derived from Streptomyces griseus, the earliest modern agent used against tuberculosis, and an example that lacks the common 2-deoxystreptamine moiety image right, below present in many other class members Other examples include the deoxystreptamine-containing agents kanamycin, tobramycin, gentamicin, and neomycin see below

2-deoxystrept-amine, 2D representation, oxygens, nitrogens with attached hydrogens in red, blue

Contents

  • 1 Nomenclature
  • 2 Mechanisms of action
    • 21 Pharmacokinetics and pharmacodynamics
    • 22 Indications
    • 23 Nonsense suppression
  • 3 Routes of administration
  • 4 Clinical use
  • 5 Contraindication for specific diseases
  • 6 References
  • 7 External links

Nomenclatureedit

Aminoglycosides that are derived from bacteria of the Streptomyces genus are named with the suffix mycin, whereas those that are derived from Micromonospora4 are named with the suffix micin5 However, this nomenclature system is not specific for aminoglycosides, and so appearance of this set of suffixes does not imply common mechanism of action For instance, vancomycin, a glycopeptide antibiotic,6 and erythromycin,7 a macrolide antibiotic produced by Saccharopolyspora erythraea, along with its synthetic derivatives clarithromycin and azithromycin, all share the suffixes but have notably different mechanisms of action

In the following gallery, kanamycin A through netilmicin are examples of the 4,6-disubstituted deoxystreptamine sub-class of aminoglycosides, the neomycins are examples of the 4,5-disubstituted sub-class, and streptomycin is an example of a non-deoxystreptamine aminoglycoside2

Mechanisms of actionedit

Streptomycin in complex with a bacterial ribosome X-ray crystallographic structure of the 30S ribosomal subunit with bound drug purple, Space-filling model, at center protein secondary structure elements such as alpha-helices in bright green, and the RNA phosphodiester backbone shown in orange and the ladder of base pairs in dark green and blue

Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" but not against gram-negative anaerobes and most gram-positive bacteria3 They require only short contact time, and are most effective against susceptible bacterial populations that are rapidly multiplying8 These activities are attributed to a primary mode of action as protein synthesis inhibitors, though additional mechanisms are implicated for some specific agents, and/or thorough mechanistic descriptions are as yet unavailable238

The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to the cytosolic, membrane-associated bacterial ribosome image at right2 Aminoglycosides first cross bacterial cell walls—lipopolysaccharide in gram-negative bacteria—and cell membranes, where they are actively transported8 While specific steps in protein synthesis affected may vary somewhat between specific aminoglycoside agents, as can their affinity and degree of binding,8 aminoglycoside presence in the cytosol generally disturbs peptide elongation at the 30S ribosomal subunit, giving rise to inaccurate mRNA translation and therefore biosynthesis of proteins that are truncated, or bear altered amino acid compositions at particular points2 Specifically, binding impairs translational proofreading leading to misreading of the RNA message, premature termination, or both, and so to inaccuracy of the translated protein product The subset of aberrant proteins that are incorporated into the bacterial cell membrane may then lead to changes in its permeability and then to "further stimulation of aminoglycoside transport"2 The amino-sugar portion of this class of molecules eg, the 2-deoxystreptamine in kanamycins, gentamicins, and tobramycin, see above are implicated in the association of the small molecule with ribosomal structures that lead to the infidelities in translation ibid Inhibition of ribosomal translocation—ie, movement of the peptidyl-tRNA from the A- to the P-site—has also been suggestedcitation needed Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal8

Finally, a further "cell-membrane effect" also occurs with aminoglycosides; "functional integrity of the bacterial cell membrane" can be lost, later in time courses of aminoglycoside exposure and transport9

Pharmacokinetics and pharmacodynamicsedit

There is a significant variability in the relationship between the dose administered and the resultant plasma level in bloodcitation needed Therapeutic drug monitoring TDM is necessary to obtain the correct dose These agents exhibit a post-antibiotic effect in which there is no or very little drug level detectable in blood, but there still seems to be inhibition of bacterial re-growth This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop, and allows a prolonged dosage intervalcitation needed Depending on their concentration, they act as bacteriostatic or bactericidal agentscitation needed

Indicationsedit

Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter In addition, some Mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed because of their toxicity and inconvenient route of administration except for multiple-drug-resistant strainscitation needed The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibioticscitation needed

As noted, aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses2 Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host In the past, the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, in particular in endocarditis One of the most frequent combinations is ampicillin a beta-lactam, or penicillin-related antibiotic and gentamicin Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamicincitation needed

Nonsense suppressionedit

The interference with mRNA proofreading has been exploited to treat genetic diseases that result from premature stop codons leading to early termination of protein synthesis and truncated proteins Aminoglycosides can cause the cell to overcome the stop codons, insert a random amino acid, and express a full-length protein10 The aminoglycoside gentamicin has been used to treat cystic fibrosis CF cells in the laboratory to induce them to grow full-length proteins CF is caused by a mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator CFTR protein In approximately 10% of CF cases, the mutation in this gene causes its early termination during translation, leading to the formation of is truncated and non-functional CFTR protein It is believed that gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the termination codon, causing the ribosome to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein11

Routes of administrationedit

Since they are not absorbed from the gut, they are administered intravenously and intramuscularly Some are used in topical preparations for wounds Oral administration can be used for gut decontamination eg, in hepatic encephalopathy Tobramycin may be administered in a nebulized form12

Clinical useedit

The recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reevaluate the use of these antibacterial agents13 This revived interest in the use of aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity Current evidence shows that aminoglycosides do retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world Still, the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment makes physicians reluctant to use these compounds in everyday practice Recent advances in the understanding of the effect of various dosage schedules of aminoglycosides on toxicity have provided a partial solution to this problem, although more research still needs to be done in order to overcome this problem entirely14

Aminoglycosides are in pregnancy category D,15 that is, there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Contraindication for specific diseasesedit

Aminoglycosides can exacerbate weakness in patients with myasthenia gravis, and use is therefore avoided in these patients16

Aminoglycosides are contraindicated in patients with mitochondrial diseases as they may result in impaired mtDNA translation, which can lead to irreversible hearing loss, tinnitus, cardiac toxicity, and renal toxicity However, hearing loss and tinnitus have also been observed in some patients without mitochondrial diseases17

Referencesedit

  1. ^ Eg, see wwwmerriam-webstercom/medical/aminoglycoside: "any of a group of antibiotics as streptomycin and neomycin that inhibit bacterial protein synthesis and are active especially against gram-negative bacteria"
  2. ^ a b c d e f g Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM 1999 "Aminoglycosides: activity and resistance" Antimicrob Agents Chemother 43 4: 727–37 PMC 89199  PMID 10103173 
  3. ^ a b c ME Levison, MD, 2012, Aminoglycosides, The Merck Manual 1, accessed 22 February 2014
  4. ^ Kroppenstedt RM, Mayilraj S, Wink JM Jun 2005 "Eight new species of the genus Micromonospora, Micromonospora citrea sp nov, Micromonospora echinaurantiaca sp nov, Micromonospora echinofusca sp nov Micromonospora fulviviridis sp nov, Micromonospora inyonensis sp nov, Micromonospora peucetia sp nov, Micromonospora sagamiensis sp nov, and Micromonospora viridifaciens sp nov" Syst Appl Microbiol 28 4: 328–39 PMID 15997706 doi:101016/jsyapm200412011 
  5. ^ Paul M Dewick 2009 Medicinal Natural Products: A Biosynthetic Approach 3rd ed Wiley ISBN 0-470-74167-8 
  6. ^ Walter P Hammes1 and Francis C Neuhaus 1974 "On the Mechanism of Action of Vancomycin: Inhibition of Peptidoglycan Synthesis in Gaffkya homari" Antimicrobial Agents and Chemotherapy 6 6: 722–728 PMC 444726  PMID 4451345 doi:101128/AAC66722 
  7. ^ The Mechanism of Action of Macrolides, Lincosamides and Streptogramin B Reveals the Nascent Peptide Exit Path in the Ribosome Martin Lovmar and Måns Ehrenberg
  8. ^ a b c d e DVM Boothe, DVM, PhD, 2012, Aminoglycosides Aminocyclitols, The Merck Veterinary Manual "Archived copy" Archived from the original on 2014-03-01 Retrieved 2014-02-22 , accessed 22 February 2014
  9. ^ As Boothe notes, "high concentrations of aminoglycosides may cause nonspecific membrane toxicity, even to the point of bacterial cell lysis", though the physiologic relevance of these concentrations to specific clinical situations is unclear DVM Boothe, DVM, PhD, 2012, Aminoglycosides Aminocyclitols, The Merck Veterinary Manual "Archived copy" Archived from the original on 2014-03-01 Retrieved 2014-02-22 , accessed 22 February 2014
  10. ^ Feero, W Gregory; Guttmacher, Alan E; Dietz, Harry C 2010 "New Therapeutic Approaches to Mendelian Disorders" New England Journal of Medicine 363 9: 852–63 PMID 20818846 doi:101056/NEJMra0907180 
  11. ^ Wilschanski, Michael; Yahav, Yaacov; Yaacov, Yasmin; Blau, Hannah; Bentur, Lea; Rivlin, Joseph; Aviram, Micha; Bdolah-Abram, Tali; et al 2003 "Gentamicin-Induced Correction of CFTR Function in Patients with Cystic Fibrosis andCFTRStop Mutations" New England Journal of Medicine 349 15: 1433–41 PMID 14534336 doi:101056/NEJMoa022170 
  12. ^ Pai VB, Nahata MC October 2001 "Efficacy and safety of aerosolized tobramycin in cystic fibrosis" Pediatr Pulmonol 32 4: 314–27 PMID 11568993 doi:101002/ppul1125 
  13. ^ Falagas, Matthew E; Grammatikos, Alexandros P; Michalopoulos, Argyris 2008 "Potential of old-generation antibiotics to address current need for new antibiotics" Expert Review of Anti-infective Therapy 6 5: 593–600 PMID 18847400 doi:101586/1478721065593 
  14. ^ Durante-Mangoni, Emanuele; Grammatikos, Alexandros; Utili, Riccardo; Falagas, Matthew E 2009 "Do we still need the aminoglycosides" International Journal of Antimicrobial Agents 33 3: 201–5 PMID 18976888 doi:101016/jijantimicag200809001 
  15. ^ Merck Manual > Bacteria and Antibacterial Drugs Last full review/revision July 2009 by Matthew E Levison, MD
  16. ^ Gautam Mehta and Bilal Iqbal Clinical Medicine for the MRCP PACES Volume 1 Core Clinical Skills Oxford University Press 2010
  17. ^ referenced in Treatment of Mitochodrial Disease: Bindu LH, Reddy PP Genetics of aminoglycoside-induced and prelingual non-syndromic mitochondrial hearing impairment: a review Int J Audiol 2008; 47:702–707 PubMed: 19031229 See Also Fischel-Ghodsian N Genetic factors in aminoglycoside toxicity Ann NY Acad Sci 1999; 884:99– 109 PubMed: 10842587

External linksedit

  • MedlinePlus drug information - Aminoglycosides Systemic
  • Science Daily Bacterial 'Battle for Survival' - Rhodostreptomycin


Aminoglycoside Information about


Aminoglycoside
Aminoglycoside

Aminoglycoside Information Video


Aminoglycoside viewing the topic.
Aminoglycoside what, Aminoglycoside who, Aminoglycoside explanation

There are excerpts from wikipedia on this article and video