AntibioticsProtein Synthesis Inhibitors:

phenicols
Pharmacology L3 PHCL-L3-AntiMicroOct 2011
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Classification of Antibiotics that act by inhibiting the synthesis of proteins

Protein Synthesis Inhibitors
Macrolides Tetracyclines Aminoglycosides & Spectinomycin

phenicols
Lincosamides Streptogramins and Oxazoladinones

Ribosomal Targets

Phenicoles

Chloramphenicol
O N O
+

OH O Cl Cl

OH

N H

after screening thousands of isolates from forest soils Used for treatment of a typhus epidemic in Bolivia 1950 first awareness of fatal bone marrow aplasia

Newer analogues with reduced side effects:

O S O OH O Cl N H O S OH O F O Cl N H OH Cl Cl

Thiamphenicol, 1968

Florphenicol, 1986
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M.O.A of C.A.F
Inhibits protein biosynthesis
binds to 50S subunit (1 molecule/unit at MIC) inhibits the peptidyl transferase activity competes with other drugs binding to same site => antagonism

Spectrum of C.A.F
Generally BACTERIOSTATIC May be bactericidal against Haemophilus Broad spectrum
Gram-postive cocci (Staphylococci, streptococci) Gram-negative aerobes (E. coli, Klebsiella, Pasturella, Salmonella, Shigella, Vibrio) Gram-negative anaerobes (Bacteroides) Actinomycetes (A. israelii) Rickettsia Mycoplasma
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P.K of C.A.F
absorbed orally. Wide distribution in body including CSF. Bound to serum albumin. Eliminated by glomerular filtration (kidney)

Adverse Effects of Chloramphenicol

Hypersensitivity skin rash, fever, glossitis, black tongue Hematological anemia (inhibition of ferrochelatase for heme formation) dose dependent bone marrow aplasia: covalent reaction with bone marrow. related to exposure duration. Results in pancytopenia, granulocytopenia, thrombocytopenia Incidence 1 in 20,000 or less. Children most affected High incidence of mortality Gray syndrome (Fatal toxicity in neonates) abdominal distension, lethargy, hypotension, temperature drop, coma. Dose related (>50 mg/L body fluid) Interfwerence with mitochondrial respiration

Use of Chloramphenicol
Chloramphenicol is regarded as one of the more toxic antibiotics Use reserved for diseases where it is drug of choice and there is no alternative due to resistance or intolerance Salmonella typhi (typhoid fever) Brain abscess (Bacteroides spp.) Meningitis where etiology is undetermined Rickettsia (patients with renal dysfunction or teracycline allergy)

Guidelines: Do not use indiscriminately Contraindicated in undefined illness Avoid repeated exposure Short treatment duration Monitor blood cell counts Avoid outpatient use Avoid prophylactic use
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Resistance to Chloramphenicol
Chloramphenicol-acetyl transferase Transfers acetyl group from acetyl CoA to 2-hydroxyl of CAP Acetyl group migrates through internal reaction, Further acetylation Hyperproduction of CAT leads to cross resistance to fusidic which binds to CAT acid,

Efflux proteins (Acr {alpha-crystallin protein} multi-drug protein of Gramnegative bacteria, MFS (major facilitator superfamily) proteins (Pseudomonas aeruginosa)
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