Chloramphenicol antimicrobial activity

In 1939 the isolation of a mixture of microbial products named tyrotbricin from a soil bacillus was described. Further investigation showed this material to be a mixture of gramicidin and tyrocidine. In rapid succession the isolation of actinomycin (1940), streptothricin (1942), streptomycin (1943), and neomycin (1949), produced by Streptomjces were reported and in 1942 the word antibiotic was introduced. Chloramphenicol, the first of the so-called broad spectmm antibiotics having a wide range of antimicrobial activity, was discovered in 1947. Aureomycin, the first member of the commercially important tetracycline antibiotics, was discovered in 1948. 

Chloramphenicol has a broad spectrum of antimicrobial activity, including Gram-positive, Gram-negative, aerobic, and anaerobic bacteria, spirochaeta, mycoplasma, chlamydia, and so on however, it can cause pronounced suppression of blood flow, which is accompanied by reticulocytopenia, granulocytopenia, and in severe cases, aplastic anemia. 

Chloramphenicol is one of the older broad-spectrum antibiotics. It was introduced in 1948 and grew in popularity because of its high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, Rickettsiae, Chlamydia, and Mycoplasma species. It is particularly useful in infections caused by Salmonella typhi and Haemophilus influenzae. It is mainly bacteriostatic. It readily crosses tissue barriers and diffuses rapidly into nearly all tissues and body fluids. 

Polyoxyethylene stearates are unstable in hot alkaline solutions owing to hydrolysis, and will also saponify with strong acids or bases. Discoloration or precipitation can occur with salicylates, phenolic substances, iodine salts, and salts of bismuth, silver, and tannins.Complex formation with preservatives may also occur. The antimicrobial activity of some materials such as bacitracin, chloramphenicol, phenoxymethylpenicillin, sodium penicillin, and tetracycline may be reduced in the presence of polyoxyethylene stearate concentrations greater than 5% w/w. ... 

Macrolides bind to the SOS ribosomal subunit, in a manner similar to chloramphenicol and flor-fenicol, and interfere with bacterial protein synthesis. They are usually considered bacteriostatic but may be bactericidal at high concentrations. The antimicrobial activity of erythromycin is pH dependent. Optimum activity occurs at a pH of 8.8 activity is reduced in acidic environments such as abscesses. 

Antimicrobial agents most likely to be affected by the first-pass effect include trimethoprim, sulphonamides, fluoroquinolones, chloramphenicol, metronidazole and rifampin. The metabolites of trimethoprim, sulphonamides, most fluoroquinolones and chloramphenicol are inactive, while ciprofloxacin and sarafloxacin formed by N-dealkylation of enrofloxacin and difloxacin, respectively, and desacetylrifampin have antimicrobial activity similar to or greater than (ciprofloxacin) the parent drug. Certain antimicrobial agents (chloramphenicol and erythromycin) inhibit hepatic microsomal enzyme activity, whereas rifampin is a potent inducer of hepatic microsomal enzymes. 

Chloramphenicol Analogs. — Microbial kinetics have permitted a more precise quantification of substituent effect on antimicrobial activity in a series of chloramphenicol analogs. 

Asker, A., M. el-Nakeeb, M. Motawi, and N. el-Gindy. 1973. Effect of certain tablet formulation factors on the antimicrobial activity of tetracycline hydrochloride and chloramphenicol. 3. Effect of lubricants. Pharmazie. 28 476M78. 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

There are also a large number of antibiotics structurally unrelated to penicillins and cephalosporins. These compounds exert their antimicrobial activity by inhibiting protein biosynthesis. In 1947 chloramphenicol (see Figure 3) was isolated from cultures of Streptomyces venezuelae. It is a broad-spectrum bacteriostatic agent that interferes with protein synthesis by binding to bacterial ribosomes. The use of chloramphenicol in humans is hmited because of the drug s toxicity. It inhibits liver enzymes and suppresses red blood cell formation. 

B. Antimicrobial Activity Chloramphenicol has a wide spectrum of antimicrobial activity and is usually bacteriostatic. Some strains of H influenzae, N meningitidis, and bacteroides are highly susceptible, and for these organisms chloramphenicol may be bactericidal. It is not active against chlamydia. Resistance to chloramphenicol, which is plasmid-mediated, occurs through the formation of acetyltransferases that inactivate the drug. 

The essential oil of T. patula and its major components (piperitone, piperitenone, and terpinolene) have antifungal activity/ The total leaf extract of T. minuta and its major flavonoid (quercetagetin-7-arabinoga-lactoside) possess considerable antimicrobial activity against Gram-positive and Gramnegative bacteria in comparison to chloramphenicol/ ... 

The high level resistance of certain bacteria to Cm is due to the enzyme chloramphenicol acetyltransferase (CAT) which modifies the Cm to a biologically inactive derivative. CAT is an intracellular, trimeric enzyme with an average monomer size of 25 kDa. CAT catalyzes the transfer of an acetyl group from donor acetyl-CoA to the primary (C-3) hydroxyl of Cm, generating chloramphenicol 3-acetate and CoA-SH as products (Fig. 8.7). The acetylated Cm is incapable of binding to bacterial ribosome and is devoid of antimicrobial activity. 

An attempt to correlate the antimicrobial activity of chloraophenicol analogs with electronic polarizability led to the idea that the high potency shown by chloramphenicol and its methylthio analog may be bestowed in part by intramolecular charge transfer. 

Concurrent administration with phenylbutazone increases plasma concentrations, but lowers tissue concentrations, of penicillin G. Bacteriostatic antimicrobial agents, such as chloramphenicol and the tetracyclines, antagonize the antibacterial activity of penicillin G. 

Syriopoulou, V.P., Harding, A.L., Goldman, D.A. Smith, A.L. (1981) In vitro antibacterial activity of fluorinated analogs of chloramphenicol and thiamphenicol. Antimicrobial Agents and Chemotherapy, 19, 294-297. 

In an attempt to suppress the toxic side effects of the antimicrobial drug, but retain or enhance the activity, the deacylated chloramphenicole amine D-(—)-/, rift>-2-amino-l-(4-nitrophenyl)-l,3-diol (o-amine, 247-d) and its enantiomer, the L-(- -)-/,4ri o-form (L-amine, 247-L) are introduced into a tetrahydro-2//-l,3,5-thiadiazine-2-thione skeleton (Scheme 49). Coupling between the D-amine and the diol 248 affords tetrahydro-2//-l,3,5-thiadiazine-2-thione derivatives 249 of moderate to good antibacterial activity <2000MI281>. 

Tested with a variety of antimicrobial drugs, reishi showed antagonistic activity with ampicillin and cefazo-lin against Proteus vulgaris, but no antagonistic effects were observed with the drugs oxytetracycline or chloramphenicol, or in tested species of Bacillus, Staphylococcus, Escherichia, Klebsiella, or Salmonella (Yoon et al. 1994). 

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