Tetracyclines and Chloramphenicol

CHAPTER 29 Tetracyclines and Chloramphenicol AT A GLANCE Tetracyclines Pseudotumur Cerebri Antimicrobial Spectrum Drug Interactions of Tetracyclines Mechanism of Action (Fig. 29.2) Chloramphenicol Bacterial Resistance Antimicrobial Spectrum Pharmacokinetics Mechanism of Action Classification of Tetracyclines Bacterial Resistance Clinical Uses of Tetracyclines Pharmacokinetics H. pylori Infection Clinical Uses Tigecycline Adverse Effects Adverse Effects of Tetracyclines Drug Interactions The antimicrobial agents that act by inhibiting bacterial OH O OH O protein synthesis are bacteriostatic in their action and OH3 O 10 11 1 12 C include agents such as tetracyclines, chloramphenicol, 9 2 NH macrolides, ketolides, clinda mycin, quinupristin/ 2 dalfopristine, linezolid and spectinomycin. Though 8 3 7 6 5 4 they can be broadly referred to as protein synthesis inhibitors, they have different target sites to elicit their R7 R6 OH HR5 H N(CH32) action. Thus, they can act on 30S or 50S ribosomal R R R subunits to inhibit bacterial protein synthesis and act 7 6 5 as bacteriostatic agents. Chlortetracyline —Cl —CH3 —H Oxytetracycline —H —CH —OH Tetracycline —H 3 —H Demethylchlortetracycline —CH3 —H TETRACYCLINES (Demeclocycline) —Cl —H —OH —OH Methacycline —H —CH2 Doxycycline —H —H Tetracyclines are a class of broad-spectrum antibiotics —CH3 Minocycline — N(CH ) that are used in a wide variety of microbial diseases. In 32 —H 1947, in his study of thousands of microscopic fungi Fig. 29.1 Structural formulae of tetracyclines amongst the Actinomycetes, Duggar in collaboration with discovered a soil Yellapragada Subba Rao Antimicrobial Spectrum organism for which the name Streptomyces29.1 aureofaciens was proposed. When grown in culture broth, a golden Tetracyclines are broad-spectrum antibiotics and yellow antibiotic was elaborated that was named are effective against Gram-positive, Gram-negative Aureomycin (chlortetracycline). In 1950, Finlay and his bacteria, protozoa and many other organisms. associates isolated a new actinomycete, Streptomyces Examples of Gram- positive organisms are rimosus from which tetracycline was isolated. In 1952, Enterococcus faecalis, Enterococcus faecium, the unique chemical structure of these two antibiotics Streptococcus viridans group, Streptococcus was determined and oxytetracycline was developed pneumoniae, Streptococcus pyogenes and staphylococci. from tetracycline. Later, a few other tetracylines were However, the susceptibility of these organisms is developed and named such as demethylchlortetracycline, variable and many of them have shown resistance demeclocycline, methacycline, doxycycline, to tetracyclines. Hence, tetracyclines are not minocycline and tigecycline based on the structures of commonly used to treat clinical conditions caused the originally discovered tetracyclines (Fig. 29.1). by these organisms. Bacillus anthracis and Listeria Site of action of macrolides, 50 S Chloramphenicol, Clindamycin A site aa Nascent polypeptide Aminoacyl tRNA chain Transferase site Site of action of tetracycline x mRNA template 30 S Site of action of 30 S tetracyclines, aminoglycosides 29.2 2 SECTION 7 Chemotherapeutic Agents monocytogenes are also susceptible to tetracyclines. aminoacyl tRNA to the A site on the mRNA ribosome Atypical organisms like Mycoplasma pneumoniaeOH O OH complex.O This action prevents the addition of further are highly susceptible to tetracyclines. amino acids to the nascent peptide thus causing OH3 O 10 11 1 Examples of Gram-negative organisms that 12 inhibitionC of peptide chain growth and subsequent 9 2 are susceptible to tetracyclines include Brucella bacterial proteinNH2 synthesis. species, Campylobacter jejuni, Calymmatobacterium8 Tetracyclines3 enter the cytoplasm of the sensitive granulomatis, Francisella tularensis, Hemophilus7 6 5 Gram-positive4 organisms by an energy-dependent ducreyi, Hemophilus influenzae, Neisseria gonorrhoeaeR R OH ,HR process,H N(CH but) in Gram-negative organisms, they pass Vibrio cholerae, Yersinia pestis and Acinetobacter,7 6 5through 32the outer membrane by diffusion through Klebsiella, E. coli, Shigella, Enterobacter and pores. Because minocycline and doxycycline are R7 R6 R5 Helicobacter pylori. more lipophilic they can enter Gram-negative cells Chlortetracyline —Cl —CH3 —H Tetracyclines are also effectiveOxytetracycline against other—H through the outer—OH lipid membrane and through the —CH3 organisms such as Chlamydia psittaci, C.Tetracycline trachomatis—H , porins. Once in—H the periplasmic area, the tetracyclines Demethylchlortetracycline —CH3 —H Rickettsiae (Rocky mountain spotted(Demeclocycline) fever, Q fever,—Cl are—H transported—OH across the inner cytoplasmic —OH murine typhus, epidemic typhus, rickettMethacyclinesial pox),—H membrane—CH2 to the target site (30S ribosomal unit) Doxycycline —H —H Treponema pallidum, Borrelia recurrentis, Balantidium by—C passiveH3 diffusion or through an active protein Minocycline — N(CH ) coli; anaerobes such as Bacteroides species,32 carrier—H system. Propionibacterium and Peptococcus; and protozoa such as Entameba histolytica and Plasmodium falciparum. Bacterial Resistance The29.1 antimicrobial activities of most tetracyclines are similar There are several mechanisms of developing resistance except that tetracycline resistant strains may be susceptible to tetracyclines; the important mechanisms are: to doxycycline, minocycline and tigecycline all of which are Plasmid-mediated decreased influx and decreased resistant to efflux pump mechanisms responsible for bacterial accumulation of the antibiotic inside the cell, resistance. Plasmid-encoded enhanced efflux of the drug from inside the bacterial cell, Plasmid-mediated production of protein that Mechanism of Action (Fig. 29.2) protects the ribosomal binding site and prevents the Tetracyclines bind reversibly to the 16S rRNA (ribose binding of tetracyclines to the ribosome, RNA) of the 30S subunit and prevent binding of Enzymatic inactivation of tetracyclines. Site of action of macrolides, 50 S Chloramphenicol, Clindamycin A site aa Nascent polypeptide Aminoacyl tRNA chain Transferase site Site of action of tetracycline x mRNA template 30 S Site of action of 30 S tetracyclines, aminoglycosides Fig. 29.2 Mechanism of action of tetracyclines 29.2 3 CHAPTER 29 Tetracyclines and Chloramphenicol Pharmacokinetics into the dentin and enamel of unerupted teeth which explains their adverse effects if they are taken during Tetracyclines are adequately but incompletely absorbed childhood when formation of new bone and new from the gastrointestinal (GI) tract and attain adequate dentition occurs. plasma and tissue concentrations. Minocycline and The disposal of tetracyclines is by renal and biliary doxycycline are the most completely absorbed elimination and by metabolism. Excretion into the bile (95%–100%) and chlortetracycline the least (30%). results in the enterohepatic circulation of tetracyclines Absorption of tetracyclines is fast on an empty stomach which facilitates the maintenance of adequate serum and they are likely to form complexes with divalent levels. This occurs even for drugs administered metals, including calcium, magnesium, aluminum and parenterally. Renal elimination of tetracyclines is by iron. Absorption of some tetracyclines is decreased glomerular filtration and the chelated portion of the when they are ingested with milk products, antacids drug is excreted through feces. All tetracyclines, or iron preparations. However, food does not interfere except doxycycline, accumulate in patients with with absorption of minocycline or doxycycline which decreased renal function. Thus, only doxycycline is rapidly absorbed and detectable in the blood should be given to patients with renal impairment. 15–30 min after administration. Both doxycycline and Some important pharmacokinetic parameters and minocycline have a half-life of 15–25 h. Tigecycline doses are listed in Table 29.1 has a half-life of 36 h. The plasma protein binding of tetracycline is 40%– 80%. Peak plasma levels of 4–6 μg/ml are achieved with Classification of Tetracyclines an oral dose of 500 mg of tetracycline or oxytetracycline Tetracyclines are classified according to their duration given 6 hourly. A 200-mg dose of doxycycline of action. Thus they may be classified as follows: or minocycline produces peak plasma levels of 1. Short acting (6–8 h) such as chlortetracycline, 2–4 μg/ml. Peak serum concentrations of tigecycline tetracycline and oxytetracycline at steady state are 0.6 μg/ml at the usual dose. 2. Intermediate acting (12 h) such as demeclocycline The tetracyclines are widely distributed in the and methacycline body compartments and higher concentrations are 3. Long acting (16–18 h) such as doxycycline and found in the liver, kidneys, bile, bronchial epithelium minocycline. and breast milk. Tetracyclines do not enter the Tigecycline has a half-life of 36 h. cerebrospinal fluid (CSF). Minocycline reaches very high concentrations in tears and saliva which makes Clinical Uses of Tetracyclines it useful for eradication of the meningococcal carrier state. Tetracyclines do not bind to formed bone but are Tetracyclines are useful in a variety of clinical condi- incorporated into calcifying tissue (forming bone) and tions because of their broad spectrum of antimicrobial Table 29.1 Pharmacokinetic parameters and usual therapeutic doses of tetracyclines Plasma Route of Half-life protein Drug Absorption administration (hours) binding (%) Dose Chlortetracycline 30% Oral 6 50 250–500

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