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Home , Chloramphenicol, Demeclocycline

Chapter 29 and

AT A GLANCE

Tetracyclines Pseudotumur Cerebri Antimicrobial Spectrum Drug Interactions of Tetracyclines (Fig. 29.2) Chloramphenicol Bacterial Resistance Antimicrobial Spectrum Mechanism of Action Classification of Tetracyclines Bacterial Resistance Clinical Uses of Tetracyclines Pharmacokinetics H. pylori Clinical Uses 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 , , clinda­mycin, quinupristin/ 2 dalfopristine, and . 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 —H —CH —OH —H 3 —H Demethylchlortetracycline —CH3 —H TETRACYCLINES () —Cl —H —OH —OH Methacycline —H —CH2 —H —H Tetracyclines are a class of broad-spectrum —CH3 — 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 was elaborated that was named are effective against Gram-positive, Gram-negative Aureomycin (). In 1950, Finlay and his , protozoa and many other organisms. associates isolated a new actinomycete, Examples of Gram-positive­ organisms are rimosus from which tetracycline was isolated. In 1952, Enterococcus faecalis, , 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,

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,

29.2 2 SECTION 7 Chemotherapeutic Agents monocytogenes are also susceptible to tetracyclines. aminoacyl tRNA to the A site on the mRNA 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 , Yersinia pestis and ,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, ,—Cl are—H transported—OH across the inner cytoplasmic —OH murine , , 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 ŠŠ Plasmid-mediated decreased influx and decreased resistant to efflux pump mechanisms responsible for bacterial accumulation of the antibiotic inside the cell, resistance. ŠŠ Plasmid-encoded enhanced efflux of the drug from inside the bacterial cell, ŠŠ 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 ŠŠ 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 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. 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 , , 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, 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 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 , kidneys, bile, bronchial epithelium minocycline. and . Tetracyclines do not enter the Tigecycline has a half-life of 36 h. (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 mg 6 hourly Tetracycline 75% Oral, 8 55 250–500 mg (oral) 6 hourly IM, IV 100 mg IM/IV 6 hourly Oxytetracycline 30%–40% Oral, 9 85 250–500 mg (oral) 6 hourly IM, IV 100 mg IM/IV 6 hourly Demethyl 80% Oral 12 85 150–300 mg 8 hourly chlortetracycline Doxycycline 93% Oral, IV 16 85 200 mg on the first day and 100 mg on subsequent days. Minocycline 95% Oral 16 75 200 mg on the first day and 100 mg on subsequent days Tigecycline ------IV 36 71%–89% 100 mg infusion initially on day one followed by 50 mg infusion twice daily for 5–14 days 5 CHAPTER 29 Tetracyclines and Chloramphenicol meningococci from the nasopharynx. It is given in wit multidrug resistant Gram-negative doses of 100 mg every 12 h for 5 days to eradicate organisms. It is one of the most effective drug to treat the carrier state. It is not useful in treating the acute community-acquired pneumonia. It is also found to . Because of the existence of resistant strains be effective in Donovanosis though is the and adverse effects; rifampicin is advocated for such first line drug to treat the condition. indication. Dose and route of administration Tigecycline is administered intravenously only. The usual dose is 100 mg as a loading dose followed by 50 mg over Tetracyclines along with topically applied antibiotics like a period of 30–60 min every 12 h for a duration of clindamycin, base and and 14 days. sulfacetamide are found to be effective in the treatment of acne. All the antibiotics including tetracyclines are useful against the acne caused by propionibacteria Adverse Effects of Tetracyclines (Propianibacterium acnes, Acne rosacea). Either Tetracyclines produce moderate to severe adverse minocycline or doxycycline 100 mg/day is highly effective effects which are reversible. Therefore, therapy need in reducing the inflammatory lesions more rapidly than not be discontinued if the prescribed doses are used for the other tetracyclines given for the condition. appropriate duration.

Mycobacterium marinum infections Gastrointestinal Minocycline has been successfully used in the treatment The common GI adverse effects of tetracyclines of infections caused by Mycobacterium marinum. include GI irritation, abdominal discomfort, nausea, vomiting and diarrhea. Tetracyclines modify the normal H. Pylori Infection intestinal flora and cause overgrowth of Pseudomonas, Tetracyclines are effective to treat H. pylori infection Proteus, staphylococci, resistant coliforms, Candida as a part of rescue therapy or third-line therapy in and Clostridia. Pseudomembranous colitis is the result combination with lansoprazole –30 mg BID (proton of a toxin produced by difficile. Because pump inhibitor), bismuth potassium citrate –220 mg of overgrowth of Candida, there may be oral or vaginal BID and metronidazole –400 mg QID. candidiasis. Effects on and teeth Tigecycline The use of tetracyclines during tooth development It is a compound and a derivative of (last half of pregnancy, infancy and childhood up to 8 minocycline and has wider antimicrobial effects and years) may cause permanent discoloration of the teeth clinical uses in comparison to older tetracyclines. The (yellow-gray-brown). The discoloration usually occurs organisms sensitive to it include coagulase-negative on long-term use but has been observed following staphylococci, and S. aureus including methicillin repeated short-term courses also and is often associated resistant and vancomycin resistant strains; streptococci with use of higher doses than prescribed. Enamel both sensitive and resistant strains; gram- hypoplasia has also been reported. The deposition of positive rods; Enterobacteriaceae; multidrug resistant the drug in the teeth and bones is due to its chelating strains of Acinetobacter spp.; anaerobes; mycoplasma; property and formation of a tetracycline–calcium rickettsiae; ; E. coli; Chlamydia; orthophosphate complex. Hence, tetracyclines are Legionella; rapidly growing Mycobacteria and contraindicated during this period. Bacteroides spp. However it is not effective against Pseudomonas, Proteus and Gonococci. Retardation of bone growth As a stable tetracycline–calcium orthophosphate Clinical uses complex is formed in the developing bones, bone Tigecycline is used for the treatment of skin and skin growth is retarded if tetracyclines are given in early structure infections and intra-abdominal infections childhood up to 8 years. (appendictis with perforation, diverticulitis and cholycystitis with perforation, empyema, gastric/ Photosensitivity duodenal perforation and purulent peritonitis). Demethylchlortetracycline (demeclocycline), doxycycline It is used in combination with colistin to treat serious and minocycline may produce photosensitivity manifested 6 SECTION 7 Chemotherapeutic Agents as an exaggerated sunburn reaction. Onycholysis and CHLORAMPHENICOL pigmentation of the nails may also appear with or without photosensitivity reaction. Chloramphenicol is a bacteriostatic antibiotic obtained from Streptomyces venezuelae and Hepatotoxicity introduced into clinical practice in 1948. It was It has been reported with the use of minocycline and the drug of first choice to treat for therefore, tetracycline should be used with caution in many years but has been replaced by cotrimoxazole, patients with hepatic dysfunction. Hepatotoxicity is aminopenicillins and later because more likely to occur during pregnancy and when large of the fatal blood dyscrasias produced by it. Now, doses of tetracyclines are administered. the use of chloramphenicol is confined to life- threatening infections (such as meningitis and Renal toxicity rickettsial infections) and for topical use in treating Tetracyclines can cause renal tubular necrosis and ocular and middle ear infections. interstitial nephritis resulting in nitrogen retention in patients with renal disease. Nephrogenic diabetes Antimicrobial Spectrum insipidus has been observed in some patients receiving demeclocycline. However, the renal changes do not The organisms sensitive to chloramphenicol are necessarily occur with regular tetracycline use in other H. influenzae, N. meningitidis, N. gonorrhoeae, clinical conditions. Fanconi syndrome, characterized Brucella spp. and Bordetella pertussis. Similarly, by nausea, vomiting, polyuria, polydipsia, acidosis, most anaerobic bacteria, including Gram-negative glycosuria and aminoaciduria has been observed in cocci and Clostridium spp. and Gram-negative rods patients ingesting outdated and degraded tetracycline including Bacteroides fragilis are also sensitive. preparations. Chloramphenicol is also active against aerobic Gram- positive cocci such as S. pyogenes, Streptococcus Pseudotumur Cerebri agalactiae (Group B streptococci) and S. pneumoniae. Most strains of E. coli, K. pneumoniae, (Benign intracranial hypertension) has been associated Proteus mirabilis and indole-positive Proteus spp. with the use of tetracyclines. The usual clinical are also sensitive. The other organisms sensitive to manifestations are headache and blurred vision. chloramphenicol include , Shigella, V. Bulging fontanelles have been associated with the use cholerae and Rickettsia. However, P. aeruginosa is not of tetracyclines in infants. sensitive to chloramphenicol. Drug Interactions of Tetracyclines Mechanism of Action Tetracyclines can produce the following drug Chloramphenicol inhibits protein synthesis in bacteria interactions which are both pharmacokinetic and by binding to the 50S ribosomal subunit which is in pharmacodynamic in nature. close proximity to the binding sites of macrolides and clindamycin. The common binding of the three drugs Pharmacokinetic or Drug interactions pharmacodynamic effect may result in the inhibition of activity of any two by the Antacids and iron preparations Tetracycylines chelate other drug binding at the same site. aluminum, calcium, magnesium and iron salts, produce insoluble salts and reduce their Bacterial Resistance absorption Most resistance to chloramphenicol is caused by Reduced half-life of . This (carbamazepine, phenytoin) tetracyclines chlorampenicol acetyl transferase Barbiturates catalyzes the acetylation of the hydroxyl group of Alcohol chlorampenicol, which makes it unable to bind to the Oral contraceptives Reduced conjugate estrogen 50S subunit. levels The less common mechanism of resistance is due to Interference with bactericidal inadequate cell permeability or alteration of ribosomal action of penicillin proteins. 8 SECTION 7 Chemotherapeutic Agents more than 25 μg/ml. The idiosyncratic response occurs to excrete the drug by the kidneys. Neonates lack an on prolonged therapy or on repeated administration of effective metabolism for the metabolic the drug. degradation and detoxification of chloramphenicol. In neonates, the dose of chloramphenicol should not GI Effects exceed 25 mg/kg body weight which may be increased Chloramphenicol may produce gastric irritation and to 50 mg/kg for full-term infants. cause nausea and vomiting. Toxicity in Newborn Infants Drug Interactions A complication known as the is Chloramphenicol inhibits hepatic CYP450 encountered in infants given chloramphenicol. This and thereby prolongs the half-lives of many drugs that syndrome of pallor, cyanosis, abdominal distension, are metabolized by this system which include warfarin, vomiting and circulatory collapse with 50% dicoumarol, phenytoin, chlorpropamide, antiretroviral mortality, develops in neonates with exceedingly protease inhibitors, rifabutin and tolbutamide. high plasma concentrations of the drug which Barbiturates, on the other hand, decrease the half-life result from inadequate glucuronidation and failure of chloramphenicol.

Clinical Case Study A male patient aged 36 years reports to the venereology department with the features of tender inguinal lymphadenopathy. The patient had a history of having sexual exposure 20 days earlier after which he had initially noticed a genital ulcer. 1. What could be the clinical condition called? 2. What could be course of the disease usually before an effective treatment is initiated? 3. What could be the symptoms seen in women with a possibility of similar disease? 4. How do you treat the condition?

R ECAP  Tetracyclines are a group of broad spectrum antibiotics pneumoniae, Brucella spp, Campylobacter jejuni, having wide range of clinical uses. Calymmatobacterium granulomatis, Hemophilus ducreyi,  The commonly used tetracyclines include Hemophilus influenza, Vibrio , Yersinia pestis, tetracycline, chlortetracycline, oxytetracycline, Klebsiella pneumoniae, Chlamydiae, E. coli, Shigella, demethylchlortetracycline, methacycline, doxycycline, Treponema pallidum, Rickettsiae, Enterobacter spp, minocycline and tigecycline. H. pylori, Protozoa (malarial parasites and amoebae),  Tetracyclines are classified according to their B. coli, and Bacteroides spp. duration of action. Thus, they may be short acting  Tetracyclines are bacteriostatic and bind reversibly to (chlortetracycline, tetracycline, oxytetracycline) of 16S rRNA of 30S ribosomal subunit of the microbial 6-8 hours duration of action; intermediate acting organisms and inhibit protein synthesis. They enter the (demethylchlortetracycline, methacycline) of 12 hours bacteria either through an energy dependent process duration of action and long acting (minocycline, in Gram-positive organisms or through transmembrane doxycycline and tigecycline) of 16–36 hours of duration porins by diffusion in Gram-negative organisms. action.  Bacterial resistance to tetracyclines develops through  Tetracyclines are effective against most species of decreased plasmid mediated influx or a plasmid encoded Gram-positive and Gram-negative organisms such as efflux from inside the bacteria or the production ofa Sreptococci, Staphylococci and enterococci. However protein that prevents the binding of the tetracycline bacterial resistance has developed to most of these to the ribosome. Inactivation may also result from the strains and they are generally not effective in treating production of an inactivating enzyme. infections caused by these organisms. The other  Tetracyclines are widely distributed in the body, but organisms that are sensitive to tetracyclines include higher levels are found in the liver, kidneys, bile, bronchial Bacillus anthracis, Listeria monocytogenes, Mycoplasma epithelium and breast milk. However they do not enter CSF.