Amphenicols

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The Amphenicols are a group of broad spectrum, bacteriostatic drugs that include Chloramphenicol (the parent compound), Thiamphenicol and Florfenicol. Chloramphenicol was initially obtained from streptomyces venezuelae in 1947, but now it is manufactured synthetically. Chloramphenicol is used in a variety of infections in veterinary and human medicine, particularly those caused by anaerobic bacteria.

 

Chemical structure: Chloramphenicol is unique among natural compounds due to possession of a nitro-benzene moity in its structure. The para-nitrophenyl group is not important for antibacterial activity and it may be changed to ortho or meta positions or even it can be replaced by halogens without significant loss of antibacterial activity. The nitrophenyl group has been implicated in the irreversible suppression of bone marrow. Thiamphenicol is a semi-synthetic derivative of Chloramphenicol in which the p-nitrophenyl group has been replaced by a sulphomethyl group (CH₃SO₂). This structural modification preserves the antibacterial activity but makes the drug less lipophillic and potent. Florfenicol is fluorinated analogue of Thiamphenicol in which the hydroxyl group has been substituted by fluorine. This structural alteration makes the drug less susceptible to microbial inactivation and also abolishes the occurrence of irreversible aplastic anemia.

 

Mode of action: Chloramphenicol inhibits protein synthesis in susceptible micro-organisms and to a lesser extent in mammalian cells. It readily penetrates into bacterial cells, probably both by passive and facilitated diffusions. Once inside the bacterial cell, it binds reversibly to 50S-ribosomal subunit and prevents the action of peptidyl transferase enzyme. This interferes with transfer of elongating polypeptide chain in the nearly attached amino-acyl tRNA at ribosome-mRNA complex. Although host ribosomes do not bind to Chloramphenicol as effectively as do bacterial ribosomes, some host ribosomal protein synthesis is impaired. The mode of action and antibacterial spectrum of  Thiamphenicol and Florfenicol resemble that of Chloramphenicol but their pharmacokinetic profile is different from that of Chloramphenicol.

Bacterial resistance: Resistance against Chloramphenicol occurs mainly due to production of Chloramphenicol-acetytransferase enzyme in bacteria that inactivates the drug. In resistant gram negative bacteria, Chloramphenicol-acetytransferase is a constitutive enzyme, while in gram positive bacteria it is inducible. Non-enzymatic resistance like decreased penetration of antibiotic into bacterial cells and lower affinity of bacterial ribosomes to Chloramphenicol are other less important mechanisms for the acquisition of bacterial resistance.

 

Pharmacokinetics: Chloramphenicol is a highly lipid soluble drug so it is very rapidly and efficiently absorbed after oral administration. It is freely soluble in alcohol, acetone, and ether, less soluble in water and insoluble in benzene. Aqueous solution of Chloramphenicol is neutral and quite stable but needs protection from light.  In ruminants, Chloramphenicol is not available for absorption after oral administration because ruminal microflora readily reduce the p-nitrophenyl group that results in inactivation of the drug. Chloramphenicol readily crosses cellular barriers and achieves high levels in most body tissues and fluids including CSF, brain, aqueous humor, placenta and synovial fluid. The peak concentration in CSF is almost half of the plasma concentration. Chloramphenicol is primarily eliminated by hepatic metabolism via glucoronide conjugation. The inactive metabolites as well some unmetabolised drug are excreted mainly in urine. Cats are deficient in glucoronide conjugatory mechanism so elimination of Chloramphenicol is slower in cats as compared to that in dogs. Elimination half life of Chloramphenicol in dogs, cats and ponnies is 1-5 hours, 4-8 hours and <1 hour respectively. The short half life of Chloramphenicol in ponnies and horses makes it unsuitable for use in these animals.

 

Antimicrobial spectrum: Chloramphenicol is a broad spectrum antimicrobial agent that is active against many gram positive and gram negative bacteria (including both aerobes and anaerobes). Staphylococcus, Streptococcus, Salmonella, Brucella, Shigella, Haemophilus, anaerobes (Clostridium and Fusobacterium), Nocardia, Rickettsiae, Chlamydiae and Mycoplasma are susceptible to Chloramphenicol. It has no or less activity against many strains of Pseudomonas and Proteus. Whereas the Mycobacteria, protozoa, fungi and viruses are resistant to Chloramphenicol.

 

Clinical uses: Chloramphenicol has been used in the treatment of a wide range of susceptible microbial infections in animals (such as chronic respiratory infections and otitis externa). In human medicine, Chloramphenicol is mainly used to treat typhoid, brucellosis and bacterial meningitis. It is also used in the form of eye drops to treat ocular infections caused by susceptible bacteria. But its use in human medicine is gradually declining due to emergence of new antibacterial agents such as Fluoroquinolones that are more potent and less toxic. Florfenicol has been developed for use in animals and is recommended mainly in cattle for the treatment of bovine respiratory diseases associated with Pasteurella hemolytica, Pasteurella multocida (e.g., hemorrhagic septicemia) and Haemophilus somnus.

 

Adverse effects: Chloramphenicol has a low order of toxicity in domestic animals when used in recommended doses. However the following adverse effects may be possibly observed in treated animals.

 

Ø  Bone marrow suppression (mylosuppression): Chloramphenicol may cause dose-dependent (reversible) and dose-independent (irreversible) mylosuppression. The reversible mylosuppression may occur in all animal species, particularly with prolonged use of Chloramphenicol. It occurs due to inhibition of mammalian mitochondrial protein synthesis in the bone marrow. The irreversible mylosuppression is a serious problem in humans but does not occur in animals. It mainly results from the formation of toxic metabolites associated with p-nitrophenyl group, which irreversibly damages the stem cell of bone marrow. The reversible form of bone marrow suppression is not dependent on the dose and occurs in some individuals (1 out of 40000) after the drug has been discontinued. The signs of mylosuppression include vacuolation of myloid and erythroid stem cells, lymphophenia, neutrophenia. In irreversible mylosuppression, aplastic anemia may develop and peripheral blood shows pancytopenia. Bone marrow is often hypolplastic or aplastic. Thiamphenicol and Florfenicol do not cause irreversible mylosuppression (due to lack of p-nitrophenyl group in their chemical structures). However the incidence of reversible mylosuppression is possible.

Ø  Malabsorption syndrome: Use of Chloramphenicol in neonatal calves may lead to malabsorption syndrome associated with disruption of small intestine enterocytes (thereby causing enteritis that leads to diarrhea and progressive dehydration).

 

Ø  Gray-baby syndrome: In human neonates and pre-mature infants, Chloramphenicol produces gray-baby syndrome that is characterized by vomiting, hypothermia, cynosis, cardiovascular collapse and death. It occurs due to accumulation of unconjugated drug that blocks electron transport system in liver, myocardium and skeletal muscles. The human neonates are deficient in microsomal enzymes and inadequately metabolize and excrete the Chloramphenicol.

 

Contraindications: Chloramphenicol is contraindicated in patients with pre-existing hematological disorders, human neonates (and infants) and young calves in order to avoid the possible toxic reactions.

 

Drug interactions: Chloramphenicol inhibits hepatic microsomal enzymes and thus can prolong the half lives of many anticonvulsant drugs like Phenytoin, Primidone and Phenobarbitone. Cyclophosphamide (cytotoxic/anticancer drug) and Chloramphenicol combination can severely depress the bone marrow. Macrolides and Lincosamides (which also bind to 50S-ribosomal subunit) if co-administered with Chloramphenicol may compete for binding site and thus can interfere with the antibacterial action of Chloramphenicol. Chloramphenicol should not be concurrently administered with β-lactams and Aminoglycosides as being bacteriostatic the Chloramphenicol may inhibit the bactericidal action of these drugs.

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