Transcript Antimicrobials acting on ribosome

Antimicrobials acting on
ribosome
By
Dr.Mohamed Abd Almoneim Attia
AMINOGLYCOSIDES
The aminoglycoside grou are antibiotics.
*Mechanism of action
Aminoglycosides have been shown to inhibit protein synthesis
through binding to the 30 S of the bacterial ribosome.
*Antimicrobial spectrum
1-All aminoglycosides have a similar spectrum of antimicrobial
action. They are most active against aerobic gram negative
bacilli.
2-Mycobacterium tuberculosis is susceptible to streptomycin,
kanamycin.
Pharmacokinetic properties
1-They are water-soluble and do not readily cross any
lipoprotein tissue barrier , thus intestinal absorption is
poor, and penetration to CSF is very limited.
2-They can cross the placental barrier and may
accumulate in fetal plasma causing congenital deafness.
Plasma binding is low (30%)
3-They are eliminated by glomerular filtration. Dosage
adjustment must be made in patients with renal
insufficiency. They are more active in alkaline medium
in cases of urinary tract infection.
Therapeutic uses
Streptomycin was the first aminoglycoside to become
available for clinical use:
1-Treatment of tuberculosis) and TB meningitis
(intrathecal) (never alone .
2-With penicillin-G or ampicillin, in the treatment of
Streptococcal viridans and Enterococcal endocarditis
infections and as prophylaxis in persons with known
valvular disease undergoing surgery.
3- used in septicemia, usually combined with penicillinG, or (metronidazole) if anaerobes are thought to be
present (e.g. peritonitis)
4-It is used in meningitis, urinary tract infections,
pneumonia, endocarditis and bone and joint
infections (osteomyelitis).
5-Orally in hepatic coma, but neomycin is better.
6-Acute intestinal infections either alone or with
other agents e.g. in bacillary dysentery and summer
diarrhea.
7-treatment of plague, tularemia and brucellosis.
Neomycin and gentamycin
1-is included in a wide variety of topical
preparations (skin, eye, ear) often in combination
with other antibiotics (polymyxin B and bacitracin)
and adrenal corticosteroids to increase antibacterial
spectrum and reduce bacterial resistance.
2-Orally for sterilization of intestine before surgery,
bacillary dysentery and summer diarrhea.
3- as other indications for streptomycin include the
treatment of plague, tularemia and brucellosis.
Tobramycin :
Similar to the spectrum of gentamicin but :
-More effective against Pseudomonas, less active
against other organisms.
-Used for gentamicin resistant cases.
-It is less nephrotoxic than gentamicin.
Amikacin and Netilmicin :
Less potent than gentamicin (2-4 times less potent),
but has broader spectrum than other
aminoglycosides.
Resistant to inactivating enzymes so it is used for
gentamicin resistant cases.
Paromomycin:
Similar to neomycin in use and toxicity.
Paromomycin may be used for intestinal
amoebiasis.
It is very ototoxic and enough concentration may be
absorbed from raw surfaces to produce Adverse
effects.
Spectinomycin :
It is active against most strains of N. gonorrhoea in
patients who are allergic to penicillin or those
infected with penicillinase-producing organisms.
Adverse effects : narrow therapeutic index
1-Nephrotoxicity:
In form of reversible renal tubular damage.
2-Ototoxicity:
It may be either cochleotoxic or vestibulotoxic.
The risk of drug toxicity increases with age, renal
disease, preexisting hearing defect, or prior
administration of aminoglycosides and diuretics.
3-Neuromuscular blockade: may result in weakness of
skeletal muscles and respiratory depression after
intraperitoneal or interpleural injection especially if
given with anesthetics or muscle relaxants.
4-Malabsorption
observed following oral administration of neomycin,
kanamycin and paromomycin. It is due to:
*Neomycin binds with bile salts and inhibits pancreatic
lipase with failure of fat digestion and absorption leading
to steatorrhoea and diarrhoea.
*Decreased intestinal lactase activity lead to
malabsorption of lactose, which by osmotic action
makes gut content more fluid and more easily
eliminated.
5-Other toxic reactions
are uncommon, but they include skin rashes, fever,
parathesia, nausea and vomiting.
Drug interactions
1-With antibiotics:
-With cephalosporins nephrotoxicity increases.
-Anti-pseudomonal penicillins, and cephalosporins decrease the
antibacterial effect of gentamicin if combined together in the same syringe
because penicillins are acidic and aminoglycosides are alkaline.
2=Skeletal muscle relaxants:
Aminoglycosides increase the effect of non-depolarizing NMB agents .It
could be reversed by neostigmine and calcium gluconate.
Aminoglycosides should be administered with great caution during surgery
or in the post-operative period.
3-Anticoagulants:
With oral anticoagulants: oral aminoglycosides impair vitamin K production
by intestinal bacteria potentiating the effect of anticoagulants.
Heparin precipitate aminoglycosides (avoid their mixing in the same
syringe).
4-Diuretics and antihistamines:
Diuretics e.g. frusemide, mannitol and antihistamines (e.g. dimenhydrinate)
potentiate ototoxicity of aminoglycosides.
MACROLIDES
Source and members
The macrolide antibiotics consist of a large
macrocyclic lactone ring to which sugars are
attached. Antibiotics in this group include
erythromycin (the prototype ), clarithromycin,
azithromycin, spiramycin and roxithromycin.
Mechanism of action
Macrolides bind to the 50S ribosomal subunit of
bacteria with a resultant inhibition of protein
synthesis. Its activity is enhanced at alkaline pH.
Antibacterial spectrum
The macrolids are effective against a number of
organisms, including gram-positive bacteria
some gram-negative bacteria, e.g. Neisseria, H.
influenza, Mycoplasma species and Chlamydia.
Erythromycin is bacteriostatic in low
concentration, but becomes bacteriocidal in
higher concentration.
Pharmacokinetic properties
Absorption:
Food interferes with absorption and part of the dose is
destroyed because of the acid liability of these antimicrobials.
To, minimize destruction and enhance absorption, erythromycin
is administered as esters (a stearate, ethylsuccinate or estolate
salt) or as enteric coated.
Distribution:
The macrolides widely distributed in body fluids.
Metabolism and excretion:
Macrolides are concentrated in liver and excreted primarily in
active form via bile with only low levels found in urine.
Therapeutic uses
1-Treatment and prevention of infections caused by staphylococci,
streptococci and pneumococci in penicillin-hypersensitive
individuals
2-Eradication of C. diphtheriae from pharyngeal carriers (1st
choice).
3-Treatment of Mycoplasma pneumonia infections in infants
4-Chlamydial infections in pregnancy and infants.
5-It is a second line drug for the treatment of gonorrhea and
syphilis.
6-Treatment of middle ear and sinus infections, since the causative
agents, H. influenza and Strep. pneumonia are usually sensitive.
* Clarithromycin has activity against Toxoplasma. It is also effective
against helicobacter pylori in peptic ulcer.
*Azithromycin is effective in pelvic infections, urethritis and
cervicitis caused by chlamydia and gonococci.
Adverse effects
1-Mild gastrointestinal upset
with nausea, diarrhoea and abdominal pain (more
commonly when the propionate and estolate salts
are used).
2-Hypersensitivity reactions: fever, rashes
3-Thrombophlebitis
may follow intravenous administrations.
4-Transient impairment of hearing may also occur.
5-Inhibition of hepatic microsomal enzymes leading to
increased serum concentration of various drugs with
potentiation of their activity or toxicity.
6-Cholestatic hepatitis
may occur when drug therapy lasts longer than 10 days
or repeated courses are prescribed. The hepatitis is
believed to be the result of both a hepatoxic effect and
hypersensitivity reaction. This latter effect is reversible
on withdrawal of the drug.
7-Bacterial resistance
if it is used more than one week (so erythromycin should
be combined with another antibiotic if used more than
one week).
Interactions
1-Combination of the therapeutic dose of
erythromycin with penicillin antagonizes the
bactericidal effect of penicillin.
2-Erythromycin decreases P450 enzymes.
LINCOSAMIDES
Examples : clindamycin and lincomycin
Mechanism of action
They bind to the 50s ribosomal subunit of bacteria.
Antibacterial spectrum
active against staphylococci, streptococci (excluding enterococci) and
most anaerobic bacteria.
Pharmacokinetic properties
Absorption:
Food in the stomach does not interfere with the absorption of
clindamycin or lincomycin. So it is completely absorbed after oral
administration.
Distribution:
Approximately 90 % of the antibiotic are plasma protein bound.
Lincomycin and clindamycin penetrate most tissues well, including
bone. Therefore, bone and joint infections caused by susceptible
organisms respond well to treatment with clindamycin.
Therapeutic uses
Treatment of severe anaerobic bacterial infections
caused by bacteroids especially B. fragilis e.g. mixed
infections and female genital system infection e.g.
missed or septic abortion, pelvic abscess
Adverse effects
1-Like erythromycin.
2-Pseudomembranous colitis.
QUINUPRISTINE / DALFOPRISTIN
LINEZOLID
Mechanism of action
It binds to 50S bacterial ribosome to interrupt protein
synthesis (bactericidal).
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