Bacterial resistance chloramphenicol

Chloramphenicol, 3 30 13 684 bacterial resistance mechanisms, 3 32t Chlorargyrite, natural occurrence of, 22 668... 

Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a B-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci. The dosage is 50-100 mg/kg/d in four divided doses. 

Of the many mechanisms of bacterial resistance to chloramphenicol and thiamphenicol, the plasmid-mediated transmissible resistance conferred by the presence in resistant bacteria of chloramphenicol-acetyltransferases (CAT) is the most important. 

Bacterial resistance to chloramphenicol occurs from plasmid-mediated bacterial production of acetylase enzymes. Acetylation of hydroxyl groups prevents the drug binding to the 505 ribosomal subunit. There is less bacterial resistance to florfenicol because of the substitution of a fluorine molecule for one of the hydroxyl groups. 

These depend on the fact that bacterial resistance to aminoglycosides (Chapter 13), such as gentamicin, tobramycin, amikacin, netilmicin, streptomycin, spectinomycin, etc. and chloramphenicol is frequently associated with the presence of specific enzymes (often coded for by transmissible plasmids), which either acetylate, adenylylate or phosphory-late the antibiotics, thereby rendering them inactive (Chapter 13). Aminoglycosides may be susceptible to attack by aminoglycoside acetyltransferases... 

Erythromycin. Erythromycin and the other macrolide antibiotics bind to the 508 ribosomal subunit of bacteria near the binding site for chloramphenicol. They prevent the translocation step, the movement of the peptidyl-tRNA from the A to the P site on the ribosome. Because the side effects are less severe and more readily reversible than those of many other antibiotics, the macrolides are often used to treat infections in persons who are allergic to penicillin, an antibiotic that inhibits bacterial cell wall synthesis. However, bacterial resistance to erythromycin is increasing. ThCTefore, its close relative, clarithromycin, is often used. 

Schwarz S, Kehrenberg C, Doublet B, Cloeckaert A, Molecular basis of bacterial resistance to chloramphenicol and florfenicol, FEMS Microbiol. Rev. 2004 28 519-542. 

Florfenicol iahibited 91% of the 399 bacterial isolates at a concentration of 12.5 )J.g/mL (31). At the same concentration, chloramphenicol and thiamphenicol iahibited only 70% and 24% of the isolates, respectively. Other work has also confirmed the superior activity of fiorfenicol against chloramphenicol-resistant strains (32—35). More recendy it has been shown that fiorfenicol is active against E. coli strains that produce type I, II, or III CAT enzymes (36). 

Chloramphenicol is able to inhibit the peptidyl transferase reaction and so bacterial protein synthesis by binding reversibly to the 50s ribosomal subunit. Resistance can occur due to the plasmid-mediated enzyme chloramphenicol acetyltransferase which inactivates the drug by acetylation. Such resistance is often a part of plasmid-mediated multidrug resistance. Resistance can also occur by an altered bacterial permeability. However in most instances resistance to chloramphenicol only develops slowly and remains partial. 

Fluoroquinolones must penetrate bacteria to reach their target, DNA gyrase. The second mechanism of fluoroquinolone resistance is decreased cell wall permeability. The fluoroquinolones diffuse through porin channels in the outer membrane of Gram-negative bacteria. Mutation results in a decrease in porin channel proteins, resulting in decreased uptake of the fluoroquinolones into bacterial cells. Alterations in a wide range of outer membrane proteins in Pseudomonas spp. result in resistance. From these mutations, the increase in MIC of the fluoroquinolones is relatively low (2-to 32-fold). Flowever, there is cross-resistance with unrelated antibiotics, most frequently cefoxitin, chloramphenicol, trimethoprim and tetracycline. 

Reflecting the bacterial ancestry of mitochondria, mitochondrial ribosomes resemble bacterial ribosomes and differ from eukaryotic cytosolic ribosomes in their RNA and protein compositions, their size, and their sensitivity to certain antibiotics (see Figure 4-24). For instance, chloramphenicol blocks protein synthesis by bacterial and mitochondrial ribosomes from most organisms, but cycloheximide does not. This sensitivity of mitochondrial ribosomes to the important aminoglycoside class of antibiotics is the main cause of the toxicity that these antibiotics can cause. Conversely, cytosolic ribosomes are sensitive to cycloheximide and resistant to chloramphenicol. In cultured mammalian cells the only proteins synthesized in the presence of cycloheximide are encoded by mtDNA and produced by mitochondrial ribosomes. I... 

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