Overview of Aminoglycosides and other protein synthesis inhibitors

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Welcome
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Overview of Aminoglycosides and other protein
synthesis inhibitors
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Presented By

• Maruf Kamal (2008-3-70-006)
• Sabbir Ahmed (2008-3-70-007)
• Md. Tanvir Rahman (2009-1-70-018)

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Introducton

• An aminoglycoside is a molecule or a portion of a
  molecule composed of amino-modified sugars.
• Several aminoglycosides function as antibiotics
  that are effective against certain types of
  bacteria. They include amikacin, arbekacin,
  gentamicin, kanamycin, neomycin, netilmicin,
  paromomycin, rhodostreptomycin, streptomycin,
  tobramycin, and apramycin.

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History
  Aminoglycoside   Year   Source organism
streptomycin 1944 Streptomyces griseus
neomycin 1949 Streptomyces fradiae
kanamycin 1957 Streptomyces kanamyceticus
paromomycin 1959 Streptomyces rimosus
spectinomycin 1962 Streptomyces spectabilis
gentamicin 1963 Micromonospora purpurea
tobramycin 1968 Streptomyces tenebrarius
sisomicin 1972 Micromonospora inyoensis
amikacin 1972 semisynthetic derivative of kanamycin
netilmicin 1975 semisynthetic derivative of sisomicin
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History

• The first aminoglycoside, streptomycin, was
  isolated from Streptomyces griseus in 1943.
  Neomycin, isolated from Streptomyces fradiae, had
  better activity than streptomycin against aerobic
  gram-negative bacilli but, because of its
  formidable toxicity, could not safely be used
  systemically. Gentamicin, isolated from
  Micromonospora in 1963, was a breakthrough in the
  treatment of gram-negative bacillary infections,
  including those caused by Pseudomonas aeruginosa.
  Other aminoglycosides were subsequently
  developed, including amikacin (Amikin),
  netilmicin (Netromycin) and tobramycin (Nebcin),
  which are all currently available for systemic
  use

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Nomenclature

• Aminoglycosides that are derived from bacteria of
  the Streptomyces genus are named with the suffix
  -mycin, whereas those that are derived from
  Micromonospora are named with the suffix -micin.
• This nomenclature system is not specific for
  aminoglycosides. For example, vancomycin is a
  glycopeptide antibiotic and erythromycin, which
  is produced from the species Saccharopolyspora
  erythraea (previously misclassified as
  Streptomyces) along with its synthetic
  derivatives clarithromycin and azithromycin, is a
  macrolide. All differ in their mechanisms of
  action, however.

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Physical and chemical properties

• They are water-soluble due to their polar groups
  (hydroxyl and amine groups), stable in solution
  and more active at alkaline than at acid PH.
• Aminoglycosides frequently exhibit synergism
  with ß-lactams or vancomycin.
• However, aminoglycosides may complex with
  ß-lactam drugs, resulting in loss of activity and
  they should not be mixed together for
  administration.

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Specific Agents

• Amikacin (Amikin),
• Gentamicin (Garamycin),
• Kanamycin (Kantrex),
• Neomycin, Netilmicin (Netromycin),
• Streptomycin, Tobramycin (Nebcin)

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Structure of Aminoglycosides
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Mechanism of action

• bactericidal aminoglycosides bind to the 30S
  subunit of the bacterial ribosome, interfering
  with the binding of fMet-tRNA and therefore the
  formation of the initiation complex. Binding to
  the 30S subunit may also cause misreading of mRNA
  codons
• ß-lactams, vancomycin facilitate uptake by
  Gram-positive organisms
• resistance via plasmid-mediated
  aminoglycoside-modifying enzymes

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Mechanism of action
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Pharmacokinetics

• poor oral absorption
• volume of distribution approximates the
  extracellular space (about 0.26 L/kg)
• (larger in cystic fibrosis patients, about 0.35
  L/kg)
• tissue distribution variable (poor CNS
  penetration)
• negligible metabolism
• renally eliminated (filtered, with a small amount
  of proximal reabsorption)
• elimination half-life 2-3 hours (if renal
  function normal)

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Pharmacodynamics

• concentration-dependent killing
• postantibiotic effect (concentration-dependent)

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SARs of Aminoglycosides

• Crucial for broad spectrum activity
• Primary target for inactivating enzymes
• Congeners with amino groups at 2' and 6' are
  especially active

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SARs of Aminoglycosides

• Methylation of these amines does not alter
  activity,decreases inactivation
• Hydroxyls at the 3' or 4 position are not
  critically important

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SARs of Aminoglycosides

• Modifications compromise antibacterial activity
• One exception is amikacin with its
  aminohydroxybutyrate

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SARs of Aminoglycosides

• Substitution pattern is somewhat more flexible
• Only real requirement is the amine at the 3"
  position.

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Spectrum of activity

• Aminoglycosides are classified as broad-spectrum
  antibiotics, they used for treatment of serious
  systemic infections caused by
• Aerobic Gm ve bacilli.
• Aerobic Gm ve and Gm ve cocci (with the
  exception of Staphylococci) tend to be less
  sensitive to aminoglycosides and thus the
  ß-lactam and other antibiotics tend to be
  preferred for the treatment of infections caused
  by these organisms.

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Spectrum of activity

• broad gram-negative spectrum including P.
  aeruginosa
• gram-positive synergistic in combination with
  ß-lactams, glycopeptides
• anaerobes negligible activity
• amikacin Nocardia, MAI, certain rapid-growing
  mycobacteria, gentamicin-resistant gram-negative
  bacilli
• streptomycin multidrug-resistant tuberculosis,
  tularemia, plague

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Adverse reactions

• nephrotoxicity
• proximal acute tubular necrosis (ATN) ? ? GFR
• likely related to inhibition of intracellular
  phospholipases in the proximal tubule
• tends to be reversible
• associated factors hypotension, dehydration,
  duration of therapy, concomitant liver disease,
  advanced age, other nephrotoxins (vancomycin)
• nephrotoxicity correlates with drug accumulation
  in the renal cortex

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Aminoglycoside accumulation in critically ill
surgical patients
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Toxicity

• 1- Nephrotoxicity
• 2- Ototoxicity
• 3- Neurotoxicity
• 4- Neuromuscular blockade
• Additional adverse reactions with
  administration of aminoglycosides may include
  nausea, vomiting, anorexia, rash, and urticaria.

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Toxicity

• ototoxicity
• vestibulotoxic and cochleotoxic
• generally irreversible
• difficult to assess
• high tone frequencies affected first
• neuromuscular blockade
• rare but potentially serious
• enhanced by conditions or drugs affecting the NM
  junction (e.g., myasthenia gravis,
  succinylcholine)
• can be treated with calcium

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Contraindications

• Aminoglycosides should not be given to patients
  requiring long term therapy because of the
  potential for ototoxicity and nephrotoxicity.
• These drugs are contraindicated in patients
  with
• - Preexisting hearing loss -
  Myasthenia gravis
• - Parkinsonism
• - During lactation or pregnancy.
• The aminoglycosides are used cautiously in
  patients with renal failure, in the elderly and
  in patients with neuromuscular disorders.

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Drug interactions

• Administration of aminoglycosides with the
  cephalosporins may increase the risk of
  nephrotoxicity.
• When the aminoglycosides are administered with
  loop diuretics there is an increase the risk of
  ototoxicity (irreversible hearing loss).
• There is an increased risk of neuromuscular
  blockage (paralysis of the respiratory muscles)
  if the aminoglycosides are given shortly after
  general anesthetic (neuromuscular junction
  blockers).

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Drug interactions

• Increased risk of nephrotoxicity and ototoxicity
  when aminoglycosides given with vancomycin.
• Increased risk of nephrotoxicity when
  aminoglycosides given with colistin.
• Aminoglycosides antagonize effects of
  neostigmine.

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• Streptomycin sulfate

• Neomycin sulfate

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• Kanamycin sulfate

Amikacin
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• Gentamicin sulfate

Netilmicin sulfate
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Other Protein Synthesis Inhibitors

• Tetracycline
• Chloramphenicol
• Macrolides
• Mupirocin
• Quinolones

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• Mechanisms action of tetracycline

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Commercially available tetracyclines

• First generation (Dose intervals shorter)
• Chlorotetracycline
• Oxytetracycline
• Tetracycline
• Dmeclocycline
• Second Generation (Dose interval longer)
• Minocycline
• Methacycline
• Doxycycline
• Third Generation
• Glycylcycline

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• Mechanism action of chloramphenicol

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Structure of cloramphenicol
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• MUPIROCIN
• Mupirocin is active against many gram-positive
  and selected gram-negative bacteria. It has good
  activity against S. pyogenes and
  methicillin-susceptible and methicillin-resistant
  strains of S. aureus. It is bactericidal at
  concentrations achieved with topical application.
  
• Mupirocin inhibits bacterial protein synthesis by
  reversible inhibition of Ile tRNA synthase. There
  is no cross-resistance with other antibiotic
  classes. Clinically insignificant, low-level
  resistance results from mutations of the gene
  encoding Ile tRNA synthase or an extra
  chromosomal copy of a gene encoding a modified
  Ile tRNA synthase. High-level resistance is
  mediated by a plasmid or chromosomal copy of a
  gene encoding a bypass synthetase that binds
  Mupirocin poorly.

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• Mechanism action of chloramphenicol

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Structure of chloramphenicol
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• Mode of action of Macrolides

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Examples of Macrolides

• Erythromycin
• Clarithromycin
• Roxithromycin
• Azithromycin

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• Mupirocin is available as a 2 cream or ointment
  for dermatologic use and as a 2 ointment for
  intranasal use. The dermatological preparations
  are indicated for treatment of traumatic skin
  lesions and impetigo secondarily infected with S.
  aureus or S. pyogenes. Systemic absorption
  through intact skin or skin lesions is minimal.
  Any Mupirocin absorbed is rapidly metabolized to
  inactive monic acid.
• Mupirocin is effective in eradicating S. aureus
  carriage. The consensus is that patients who may
  benefit from Mupirocin prophylaxis are those with
  proven S. aureus nasal colonization plus risk
  factors for distant infection or a history of
  skin or soft tissue infections.
• Mupirocin may cause irritation and sensitization
  and contact with the eyes should be avoided.
• Systemic reactions to Mupirocin occur rarely, if
  at all. Application of the ointment to large
  surface areas should be avoided in patients with
  renal failure to avoid accumulation of
  polyethylene glycol from the ointment.

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Examples of Quinolones

• Nalidixic acid
• Ciprofloxacin
• Levofloxacin
• Glatifloxacin
• Norfloxacin
• Sparfloxacin
• Fluroquinolone

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