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Nov 26, 2014
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OVERVIEW OF AMINOGLYCOSIDES AND
OTHER PROTEIN SYNTHESIS INHIBITORS
Presented By
Maruf Kamal (2008-3-70-006)Sabbir Ahmed (2008-3-70-007)Md. Tanvir Rahman (2009-1-70-018)
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.
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
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
NomenclatureAminoglycosides 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.
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 β-lactams or vancomycin.
However, aminoglycosides may complex with
β-lactam drugs, resulting in loss of activity and they should not be mixed together for administration.
Specific AgentsAmikacin (Amikin®), Gentamicin (Garamycin®), Kanamycin (Kantrex®), Neomycin, Netilmicin (Netromycin®),Streptomycin, Tobramycin (Nebcin®)
Structure of Aminoglycosides
Mechanism of actionbactericidal; 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
β-lactams, vancomycin facilitate uptake by Gram-positive organisms
resistance: via plasmid-mediated aminoglycoside-modifying enzymes
Mechanism of action
Pharmacokineticspoor oral absorptionvolume 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 metabolismrenally eliminated (filtered, with a small amount of
proximal reabsorption)elimination half-life: 2-3 hours (if renal function
normal)
Pharmacodynamicsconcentration-dependent killingpostantibiotic effect (concentration-
dependent)
SARs of AminoglycosidesCrucial for broad
spectrum activityPrimary target for
inactivating enzymes
Congeners with amino groups at 2' and 6' are especially active
SARs of AminoglycosidesMethylation of
these amines does not alter activity,decreases inactivation
Hydroxyls at the 3' or 4‘ position are not critically important
SARs of AminoglycosidesModifications
compromise antibacterial activity
One exception is amikacin with its aminohydroxybutyrate
SARs of AminoglycosidesSubstitution
pattern is somewhat more flexible
Only real requirement is the amine at the 3" position.
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 β-lactam and other antibiotics tend to be preferred for the treatment of infections caused by these organisms.
Spectrum of activitybroad gram-negative spectrum including
P. aeruginosagram-positive: synergistic in combination
with ß-lactams, glycopeptidesanaerobes: negligible activityamikacin: Nocardia, MAI, certain rapid-
growing mycobacteria, gentamicin-resistant gram-negative bacilli
streptomycin: multidrug-resistant tuberculosis, tularemia, plague
Adverse reactionsnephrotoxicityproximal acute tubular necrosis (ATN) → ↓ GFRlikely related to inhibition of intracellular
phospholipases in the proximal tubuletends to be reversibleassociated factors: hypotension, dehydration,
duration of therapy, concomitant liver disease, advanced age, other nephrotoxins (vancomycin)
nephrotoxicity correlates with drug accumulation in the renal cortex
Aminoglycoside accumulation in critically ill surgical patients
Toxicity1- Nephrotoxicity 2- Ototoxicity3- Neurotoxicity4- Neuromuscular blockade
Additional adverse reactions with administration of aminoglycosides may include: nausea, vomiting, anorexia, rash, and urticaria.
Toxicityototoxicityvestibulotoxic and cochleotoxicgenerally irreversibledifficult to assesshigh tone frequencies affected firstneuromuscular blockaderare but potentially seriousenhanced by conditions or drugs affecting the NM
junction (e.g., myasthenia gravis, succinylcholine)can be treated with calcium
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.
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).
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.
Streptomycin sulfate
O
CH3
OH O
N-Methyl-L- Glucosamine
Streptomycin
L-Streptose
OH
OH
NH
HO
NH O
H2N
NH
H2N
NH CHO
ONHCH3
OH
HO
HO
Streptidine
Neomycin sulfate
Neosamine C
OCH2NH2
HO
HO NH2 ONH2
NH2
OH
Neomycin C
DeoxystreptamineOO
CH2OH
OHO
O
CH2NH2
HO
HONH2
D-Ribose
13
5
4 13 2
56
5
13
26
54
31
Neosamine C
6
Kanamycin sulfate
O
CH2R1
HO
HO R2 ONH2
NH2
O
1`3`
5`6`
26
5
43
1
HO
O OHHO
HOCH2
H2N
1``
2``4``
5``
Ring I
Ring II
Ring III
Kanamycin A
Kanamycin C
Kanamycin B
R1=NH2, R2=OH
R1=NH2, R2=NH2
R1=OH, R2=NH2
Amikacin
O
CH2NH2
HO
HO OH ONH-C-C-CH2CH2NH2
NH2
O
1`3`
5`6`
26
5
43
1
HO
O OHHO
HOCH2
H2N
1``
2``4``
5``
Ring I
Ring II
Ring III
Amikacin
O OH
H
Gentamicin sulfate
Netilmicin sulfate
26
5
4 1
HO
O OHCH3
OH
NHCH3
1``
2``4``
5``
Ring I
Ring II
Ring III
3``
ONHR
O
NH2
O
CH2OH
H2N 3
6`
5`
4`
3`2`
1`
Sisomicin R= HNetilmicin R= C2H5
Other Protein Synthesis Inhibitors
TetracyclineChloramphenicolMacrolides Mupirocin Quinolones
Mechanisms action of tetracycline
Commercially available tetracyclinesFirst generation (Dose intervals shorter) ChlorotetracyclineOxytetracyclineTetracyclineDmeclocycline• Second Generation (Dose interval longer)Minocycline Methacycline Doxycycline • Third Generation Glycylcycline
Mechanism action of chloramphenicol
Structure of cloramphenicol
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.
Mechanism action of chloramphenicol
Structure of chloramphenicol
Mode of action of Macrolides
Examples of Macrolides
ErythromycinClarithromycin Roxithromycin Azithromycin
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.
Examples of Quinolones Nalidixic acid Ciprofloxacin Levofloxacin Glatifloxacin Norfloxacin Sparfloxacin Fluroquinolone
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