Chloramphenicol

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Chapter: Essential pharmacology : Tetracyclines And Chloramphenicol (Broadspectrum Antibiotics)

Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. It was soon synthesized chemically and the commercial product now is all synthetic.


CHLORAMPHENICOL

 

Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. It was soon synthesized chemically and the commercial product now is all synthetic.

 

It is a yellowish white crystalline solid, aqueous solution is quite stable, stands boiling, but needs protection from light. It has a nitrobenzene substitution, which is probably responsible for the antibacterial activity and its intensely bitter taste.

 


 

Mechanism Of Action

 

Chloramphenicol inhibits bacterial protein synthesis by interferring with ‘transfer’ of the elongating peptide chain to the newly attached aminoacylt-RNA at the ribosomem-RNA complex. It specifically attaches to the 50S ribosome and thus may hinder the access of aminoacylt-RNA to the acceptor site for amino acid incorporation (see Fig. 52.1). Probably by acting as a peptide analogue, it prevents formation of peptide bonds.

 


 

At high doses, it can inhibit mammalian mitochondrial protein synthesis as well. Bone marrow cells are especially susceptible.

 

Antimicrobial Spectrum

 

Chloramphenicol is primarily bacteriostatic, though high concentrations have been shown to exert cidal effect on some bacteria, e.g. H. influenzae. It is a broad-spectrum antibiotic, active against nearly the same range of organisms (gram-positive and negative bacteria, rickettsiae, mycoplasma) as tetracyclines. Notable differences between these two are:

 

·     Chloramphenicol was highly active against Salmonella including S. typhi, but resistant strains are now rampant.

 

·  It is more active than tetracyclines against H. influenzae (though many have now developed resistance), B. pertussis, Klebsiella, N. meningitidis and anaerobes including Bact. fragilis.

 

·      It is less active against gram-positive cocci, spirochetes, certain Enterobacteriaceae and Chlamydia. Entamoeba and Plasmodia are not inhibited.

 

Like tetracyclines, it is ineffective against Mycobacteria, Pseudomonas, many Proteus, viruses and fungi.

 

Resistance

 

Most bacteria are capable of developing resistance to chloramphenicol, which generally emerges in a graded manner, as with tetracyclines. Being orally active, broad-spectrum and relatively cheap, chloramphenicol was extensively and often indiscriminately used, especially in developing countries, resulting in high incidence of resistance among many gram-positive and gram-negative bacteria.

 

In many areas, highly chloramphenicol resistant S. typhi have emerged due to transfer of R factor by conjugation. Resistance among gram-negative bacteria is generally due to acquisition of R plasmid encoded for an acetyl transferase— an enzyme which inactivates chloramphenicol. Acetyl-chloramphenicol does not bind to the bacterial ribosome. In many cases, this plasmid has also carried resistance to ampicillin and tetracycline. Multi-drugresistant S. typhi have arisen.

 

 

Decreased permeability into the resistant bacterial cells (chloramphenicol appears to enter bacterial cell both by passive as well as facilitated diffusion) and lowered affinity of bacterial ribosome for chloramphenicol are the other mechanisms of resistance. Partial cross resistance between chloramphenicol and erythromycin/ clindamycin has been noted, because all these antibiotics bind to 50S ribosome at adjacent sites. Some cross resistance with tetracyclines also occurs, though the latter binds to 30S ribosome.

 

Pharmacokinetics

 

Chloramphenicol is rapidly and completely absorbed after oral ingestion. It is 50–60% bound to plasma proteins and very widely distributed: volume of distribution 1 L/kg. It freely penetrates serous cavities and blood-brain barrier: CSF concentration is nearly equal to that of unbound drug in plasma. It crosses placenta and is secreted in bile and milk.

 

 

Chloramphenicol is primarily conjugated with glucuronic acid in the liver and little is excreted unchanged in urine. Cirrhotics and neonates, who have low conjugating ability, require lower doses. The metabolite is excreted mainly in urine. Plasma t½ of chloramphenicol is 3–5 hours in adults. It is increased only marginally in renal failure: dose need not be modified.

 

Preparations And Administration

 

 

The commonest route of administration of chloramphenicol is oral—as capsules; 250–500 mg 6 hourly (max. total dose 28 g), children 25–50 mg/kg/day. Significant bioavailability differences among different market preparations have been shown. It is also available for application to eye/ear, but topical use at other sites is not recommended.

 

CHLOROMYCETIN, ENTEROMYCETIN, PARAXIN, 250 mg, 500 mg cap, 1% eye oint, 0.5% eye drops, 5% ear drops, 1% applicaps.

 

Chloramphenicol Palmitate (CHLOROMYCETIN PALMITATE, ENTEROMYCETIN, PARAXIN 125 mg/5 ml oral susp) is an insoluble tasteless ester of chloramphenicol, which is inactive as suCh. No. It is nearly completely hydrolysed in the intestine by pancreatic lipase and absorbed as free chloramphenicol, but produces lower plasma concentration.

 

Chloramphenicol Succinate (ENTEROMYCETIN, CHLOROMYCETIN SUCCINATE, KEMICETINE 1 g/ vial inj, PHENIMYCIN 0.25, 0.5, 1.0 g inj. is the soluble but inactive ester which is used in the parenteral preparations. Intramuscular injection is painful and produces lower blood levels. It is hydrolysed in tissues to the free active form. However, bioavailability even on i.v. injection is only 70% due to renal excretion of the ester before hydrolysis. also VANMYCETIN 0.4% eye drops, 250 mg opticaps, LYKACETIN 1% skin cream, 10% otic solution.

 

Adverse Effects

 

1. Bone Marrow Depression: Of all drugs, chloramphenicol is the most important cause of aplastic anaemia, agranulocytosis, thrombocytopenia or pancytopenia. Two forms are recognized:

 

a) Nondose related idiosyncratic reaction: This is rare (1 in 40,000), unpredictable, but serious, often fatal, probably has a genetic basis and is more common after repeated courses. Aplastic anaemia is the most common manifestation. Apparently, a longer latent period of onset of marrow aplasia is associated with higher mortality. Many victims, even if they survive, develop leukaemias later.

 

b) Dose and duration of therapy related myelosuppression: a direct toxic effect, predictable and probably due to inhibition of mitochondrial enzyme synthesis. This is often reversible without long-term sequelae. Liver and kidney disease predisposes to such toxicity.

 

2. Hypersensitivity Reactions: Rashes, fever, atrophic glossitis, angioedema are infrequent.

 

3. Irritative Effects: Nausea, vomiting, diarrhoea, pain on injection.

 

4. Superinfections: These are similar to tetracyclines, but less common.

 

5. Gray Baby Syndrome: It occurred when high doses (~100 mg/kg) were given prophylactically to neonates, especially premature. The baby stopped feeding, vomited, became hypotonic and hypothermic, abdomen distended, respiration became irregular; an ashen gray cyanosis developed in many, followed by cardiovascular collapse and death. Blood lactic acid was raised.

 

It occurs because of inability of the newborn to adequately metabolize and excrete chloramphenicol. At higher concentration, chloramphenicol blocks electron transport in the liver, myocardium and skeletal muscle, resulting in the above symptoms. It should be avoided in neonates, and even if given, dose should be ~ 25 mg/kg/day.

 

Interactions Chloramphenicol inhibits metabolism of tolbutamide, chlorpropamide, warfarin, cyclophosphamide and phenytoin. Toxicity can occur if dose adjustments are not done. Phenobarbitone, phenytoin, rifampin enhance chloramphenicol metabolism reduce its concentration failure of therapy may occur.

 

Being bacteriostatic, chloramphenicol can antagonize the cidal action of βlactams/ aminoglycosides on certain bacteria.

 

Uses

 

Because of serious (though rare) bone marrow toxicity:

 

1.   Never use chloramphenicol for minor infections or those of undefined etiology.

 

2.   Do not use chloramphenicol for infections treatable by other safer antimicrobials.

 

3.   Avoid repeated courses.

 

4. Daily dose not to exceed 2–3 g; duration of therapy to be < 2 weeks, total dose in a course < 28 g.

 

5. Regular blood counts (especially reticulocyte count) may detect dose-related bone marrow toxicity but not the idiosyncratic type.

 

6. Combined formulation of chloramphenicol with any drug meant for internal use is banned in India.

 

Indications Of Chloramphenicol Are:

 

1. Enteric Fever: Chloramphenicol was the first antibiotic and the drug of choice for typhoid fever till the 1980s when resistant S. typhi emerged and spread globally, including most parts of India. As a result, it became clinically unreliable; 50–80% isolates showed in vitro resistance. Many of these are multidrug resistant—not responsive to ampicillin and cotrimoxazole as well. However, few recent reports from certain parts of India indicate return of sensitivity to chloramphenicol. Being orally active and inexpensive, it may be used only if the local strain is known to be sensitive. The dose is 0.5 g 6 hourly (children 50 mg/kg/day) till fever subsides, then 0.25 g 6 hourly for another 5–7 days, because bacteriological cure takes longer.

 

Being bacteriostatic, relapses occur in ~ 10% chloramphenicol treated patients. Also, it does not prevent or cure the carrier state. Bactericidal action is required to eradicate carrier state, because in this state, host defence mechanisms do not operate against the pathogenic bacteria; body treats them as commensals.

 

2. Pyogenic Meningitis: Third generation cephalosporins (± vancomycin) are presently the first line drugs for empirical therapy of bacterial meningitis (see Ch. No. 51). Chloramphenicol in a dose of 50–75 mg/kg/day may be used as a second line drug for H. influenzae and meningococcal meningitis, especially in young children and cephalosporin allergic patients, because it has excellent penetration into CSF and clinical efficacy has been demonstrated.

 

3. Anaerobic Infections: caused by Bact. fragilis and others (wound infections, pelvic and brain abscesses, etc.) respond well to chloramphenicol. However, clindamycin or metronidazole are preferred for these. Chloramphenicol may be used in addition or as an alternative in patients not tolerating these drugs. A penicillin/cephalosporin is generally combined since most of these are mixed infections.

 

4. Intraocular Infections: Chloramphenicol given systemically attains high concentration in ocular fluid. It is the preferred drug for endophthalmitis caused by sensitive organisms.

 

5. As Second Choice Drug

a) to tetracyclines for brucellosis and rickettsial infections, especially in young children and pregnant women in whom tetracyclines are contraindicated.

b) to erythromycin for whooping cough.

 

6. Urinary Tract Infections Use of chloramphenicol is improper when safer drugs are available. It should be used only when kidney substance is involved and the organism is found to be sensitive only to this drug.

 

7. Topically  In  conjunctivitis,  external  ear infections—chloramphenicol 0.5–5.0% is highly effective. Topical use on skin or other areas is not recommended because of risk of sensitization.


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