Dr Khulood Alsaraf

Aminoglycosides
-Hydrophilic, polycationic, amine containing carbohydrates, composed of three five rings.
-They are bactericidal antibiotics, sharing chemical, antimicrobial, pharmacological & toxic characteristics. -The major clinically important Aminoglycosides are :-

Amikacin, Gentamicin, Neomycin, Streptomycin, & Tobramycin.

Mechanism of action
-The antibacterial action of Aminoglycosides involved 2 possibly synergistic effects:-First : the positively charged Aminoglycosides binds to negatively charged sites on the outer bac. memb., there by disrupting memb. integrity. -Second : Aminoglycosides bind to various sites on bac. 30S ribosomal subunits, disrupting the initiation of protein syn. & inducing errors in the translation of messenger RNA to peptides.

Susceptible organisms have an oxygen dependent system that transport the antibiotic across the cell memb. & Aminoglycosides are active against aerobic organisms only. -It is active against gm-ve bacilli, including pseudomonas aeruginosa.

Mechanism of resistance
1- The M.O produces a transferase enzyme or enzymes that inactivate the Aminoglycosides 2- Impaired entry of Aminoglycosides into the cell
3- The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation

1- Serious gm-ve bacillary infection Aminoglycosides & -lactam combination used in the initial empirical therapy for sepsis & fever in immunocompromised patients Aminoglycosides also used in the treatment of pneumonia. 2- Gentamycin and clindamycin combination is useful in patients with intra-abdominal infection 3- Cystic fibrosis : large doses of Tobramycin 4- Enterococcus species : Gentamycin + ampicillin 5- Meningitis : In combination with lactam 6- Tuberculosis : Streptomycin 7- Ophthalmological infection : Gentamycin & Tobramycin 8- Brucella species: Gentamycin + Doxycucline 9- pseudomonas aeruginosa: Tobramycin + antipseudomonal penicillin such as Piperacillin or Ticarcillin. 10- skin infection: Neomycin

Clinical uses

Toxicity
1- Nephrotoxicity : ranging from mild renal impairment to sever acute tubular necrosis which can be irreversible 2- Ototoxicity : Aminoglycosides accumulate in otolymph & cause both vestibular & auditory ototoxicity, both of which can be irreversible. 3- Neuromuscular paralysis

4- Allergic reaction

Chloramphenicol
-It is a nitrobenzene derivative that affect protein

syn. By binding to the 50S ribosomal subunit & preventing peptide bond formation -It prevents the attachment of the amino acid end of aminoacyl-tRNA to A site.

-Resistance due to production of Chlorampenicol acetyltransferase, a plasmide-encoded enzyme that inactivate the drug. -The drug induced inhibition of mitochondrial protein syn. is probably responsible for the associated toxicity. -Its a broad spectrum antibiotic that is effective against gm+ve & gm-ve bacteria, including Reckettsia, Mycoplasma & Chlamydia spp. -Its also effective against most anaerobic bacteria, including Bacteroides fragilis.

-Because of its toxicity, its use is restricted to life threatening infection in which there are no alternatives.

Clinical uses
-Because of potential toxicity, bacterial resistance and the availability of many other effective alternatives, Chloramphenicol used only for: 1- for treatment of serious rickettsial infections such as typhus fever. 2- alternative to a lactam antibiotic for treatment of bacterial meningitis in patient who have major hypersensitivity reaction to penicillin. 3- Chloramphenicol also is widely used for topical treatment of eye infection [ can penetrate ocular tissue ]
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Adverse effects
1- Gray baby syndrome Abdominal distention, vomiting, progressive cyanosis, irregular respiration, hypothermia & vasomotor collapse. The mortality rate is high. 2- Hematopoietic S.E Toxic bone marrow depression [ a plastic anemia ] 3- Nausea, vomiting and diarrhea. 4- Oral or vaginal candidiasis occur as a result of alteration of normal flora.

Clindamycin
-Inhibit protein synthesis by binding to 50S ribosomal subunit at a binding site close to or overlapping the binding site for erythromycin. -Active against streptococci, staphylococci, and pneumococci. -Bacteriodes sp and other anaerobes, both gm-ve and gm+ve are susceptable.
-Resistance to Clindamycin due to: 1- mutation of ribosomal receptor site 2- modification of the receptor 3- enzymatic inactivation of Clindamycin

Clinical uses
1- In the treatment of skin and soft tissue infection caused by Staph. & Strep. 2- Active against community-acquired strains of methicillin-resistant S aureus. 3- Clindamycin has shown excellent activity topically against Corynebacterium acnes. 4- Clindamycin have excellent activity against anaerobic bac. 5- Used in combination with aminoglycosides or cephalosporin in the treatment of pelvic abscesses, or pelvic inflammatory disease, and lung abscesses. 6- Prophylaxis of endocarditis in patient with valvular heart disease who under go certain dental procedures and have allergies to pencillin.

Adverse effects
1- GIT irritation such as nausea, vomiting and rashes. 2- The most serious adverse effect is potentially fatal pseudomembranous colitis caused by overgrowth of C. Difficile which elaborates necrotizing toxins that caused mucosal ulceration and bleeding and infrequently may necessitate colectomy. Oral administration of either metronidazole or vancomycin is usually effective in controlling this serious problem. 3- Impaired liver function and neutropenia.

Linezolid
New class of synthetic antimicrobials Active against gm+ve organisms including staphylococci, streptococci, enterococci, gm+ve anaerobic cocci, and gm+ve rodes such as corynebacteria. It inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23s ribosomal RNA of the 50s subunit, results in no cross-resistance with other drug classes. Resistance is caused by mutation of the linezolid site on 23s ribosomal RNA.

1- linezolid approved for vancomycin resistant E faecium infection 2- for treatment of community-acquired pneumonia. 3- complicated and uncomplicated skin and soft tissue infections caused by gm+ve bacteria. 4- treatment of multidrug resistant tuberculosis and Nocardia infection.

Clinical uses

Adverse effects
1- Thrombocytopenia 2- Anemia and neutropenia 3- Optic and peripheral neuropathy and lactic acidosis with prolonged courses of linezolid. 4- Headache, rash, nausea, and diarrhea. 5- Serotonin syndrome occurring when linezolid is co-administered with selective serotonin reuptake inhibitor antidepressant.