1. Antimicrobials acting on ribosomeBy
Dr.Mohamed Abd Almoneim Attia

2. 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.

3. 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.

4. 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 penicillin-G, or (metronidazole) if anaerobes are thought to be present (e.g. peritonitis)

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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).

18. Interactions 1-Combination of the therapeutic dose of erythromycin with penicillin antagonizes the bactericidal effect of penicillin. 2-Erythromycin decreases P450 enzymes.

19. 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.

20. 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.

21. QUINUPRISTINE / DALFOPRISTIN
 LINEZOLID
Mechanism of action
It binds to 50S bacterial ribosome to interrupt protein synthesis (bactericidal).

22. Thank you