Basic and Clinical Pharmacology, 13th Ed.

Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones

Daniel H. Deck, PharmD, & Lisa G. Winston, MD

CASE STUDY

A 19-year-old woman with no significant past medical history presents to her college medical clinic complaining of a 2-week history of vaginal discharge. She denies any fever or abdominal pain but does report vaginal bleeding after sexual intercourse. When questioned about her sexual activity, she reports having vaginal intercourse, at times unprotected, with two men in the last 6 months. A pelvic examination is performed and is positive for mucopurulent discharge from the endocervical canal. No cervical motion tenderness is present. A first-catch urine specimen is obtained to be tested for chlamydia and gonorrhea. A pregnancy test is also ordered as the patient reports she “missed her last period.” Pending these results, the decision is made to treat her empirically for gonococcal and chlamydial cervicitis. What are two potential treatment options for her possible chlamydial infection? How does her potential pregnancy affect the treatment decision?

The drugs described in this chapter inhibit bacterial protein synthesis by binding to and interfering with ribosomes. Most are bacteriostatic, but a few are bactericidal against certain organisms. Because of overuse, tetracycline and macrolide resistance is common. Except for tigecycline and the streptogramins, these antibiotics are usually administered orally.

image TETRACYCLINES

All of the tetracyclines have the basic structure shown at right:

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Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity. A newer tetracycline analog, tigecycline, is a glycylcycline and a semisynthetic derivative of minocycline.

Mechanism of Action & Antimicrobial Activity

Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible organisms concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex (Figure 44–1). This prevents addition of amino acids to the growing peptide.

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FIGURE 44–1 Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit (step 1).

Tetracyclines are active against many gram-positive and gram-negative bacteria, including certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump, if that is the mechanism of resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs.

Resistance

Three mechanisms of resistance to tetracycline analogs have been described: (1) impaired influx or increased efflux by an active transport protein pump; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and (3) enzymatic inactivation. The most important of these are production of an efflux pump and ribosomal protection. Tet(AE) efflux pump-expressing gram-negative species are resistant to the older tetracyclines, doxycycline, and minocycline. They are susceptible, however, to tigecycline, which is not a substrate of these pumps. Similarly, the Tet(K) efflux pump of staphylococci confers resistance to tetracycline, but not to doxycycline, minocycline, or tigecycline, none of which are pump substrates. The Tet(M) ribosomal protection protein expressed by gram-positives produces resistance to tetracycline, doxycycline, and minocycline, but not to tigecycline, which, because of its bulky t-butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome. Tigecycline is a substrate of the chromosomally encoded multidrug efflux pumps of Proteus sp and Pseudomonas aeruginosa, accounting for their intrinsic resistance to all tetracyclines including tigecycline.

Pharmacokinetics

Tetracyclines differ in their absorption after oral administration and in their elimination. Absorption after oral administration is approximately 30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline and minocycline. Tigecycline is poorly absorbed orally and must be administered intravenously. A portion of an orally administered dose of tetracycline remains in the gut lumen, alters intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which contain multivalent cations; and by alkaline pH. Specially buffered tetracycline solutions are formulated for intravenous administration.

Tetracyclines are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4–6 mcg/mL. Intravenously injected tetracyclines give somewhat higher levels, but only temporarily. Peak levels of 2–4 mcg/mL are achieved with a 200 mg dose of doxycycline or minocycline. Steady-state peak serum concentrations of tigecycline are 0.6 mcg/mL at the standard dosage. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid, where concentrations are 10–25% of those in serum. Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state. Tetracyclines cross the placenta to reach the fetus and are also excreted in breast milk. As a result of chelation with calcium, tetracyclines are bound to—and damage—growing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline by 50% due to induction of hepatic enzymes that metabolize the drug.

Tetracyclines are excreted mainly in bile and urine. Concentrations in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels. Ten to fifty percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to forty percent of the drug is excreted in feces. Doxycycline and tigecycline, in contrast to other tetracyclines, are eliminated by nonrenal mechanisms, do not accumulate significantly, and require no dosage adjustment in renal failure.

Tetracyclines are classified as short-acting (chlortetracycline, tetracycline, oxytetracycline), intermediate-acting (demeclocycline and methacycline), or long-acting (doxycycline and minocycline) based on serum half-lives of 6–8 hours, 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life of 36 hours. The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing for certain indications, but, by convention, these two drugs are usually dosed twice daily.

Clinical Uses

A tetracycline is the drug of choice in the treatment of infections caused by rickettsiae. Tetracyclines are also excellent drugs for the treatment of Mycoplasma pneumonia, chlamydiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be used in various gram-positive and gram-negative bacterial infections, including vibrio infections, provided the organism is not resistant. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance has appeared during epidemics. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted infections. Doxycycline, in combination with ceftriaxone, is an alternative treatment for gonococcal disease. A tetracycline—in combination with other antibiotics—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes used in the treatment or prophylaxis of protozoal infections, eg, those due to Plasmodium falciparum (see Chapter 52). Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis and urinary tract infections. However, many strains of bacteria causing these infections are now resistant, and other agents have largely supplanted tetracyclines.

Minocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state, but because of side effects and resistance of many meningococcal strains, ciprofloxacin or rifampin is preferred. Demeclocyclineinhibits the action of antidiuretic hormone in the renal tubule and has been used in the treatment of inappropriate secretion of antidiuretic hormone or similar peptides by certain tumors (see Chapter 15).

Tigecycline, the first glycylcycline to reach clinical practice, has several unique features that warrant its consideration apart from the older tetracyclines. Many tetracycline-resistant strains are susceptible to tigecycline because it is not affected by the common resistance determinants. Its spectrum is very broad. Coagulase-negative staphylococci and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant strains; streptococci, penicillin-susceptible and resistant; enterococci, including vancomycin-resistant strains; gram-positive rods; Enterobacteriaceae; multidrug-resistant strains of Acinetobacter sp; anaerobes, both gram-positive and gramnegative; rickettsiae, Chlamydia sp, and Legionella pneumophila; and rapidly growing mycobacteria all are susceptible. Proteus sp and P aeruginosa, however, are intrinsically resistant.

Tigecycline, formulated for intravenous administration only, is given as a 100 mg loading dose, then 50 mg every 12 hours. As with all tetracyclines, tissue and intracellular penetration is excellent; consequently, the volume of distribution is quite large and peak serum concentrations are low. Elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency. In addition to the tetracycline class effects, the chief adverse effect of tigecycline is nausea, which occurs in up to one third of patients, and occasionally vomiting. Neither nausea nor vomiting usually requires discontinuation of the drug.

Tigecycline is approved for treatment of skin and skin-structure infection, intra-abdominal infections, and community-acquired pneumonia. However, in a meta-analysis of clinical trials, tigecycline was associated with a small but significant increase in the risk of death compared with other antibiotics used to treat these infections. This has led the FDA to issue a black box warning that tigecycline should be reserved for situations where alternative treatments are not suitable. Because active drug concentrations in the urine are relatively low, tigecycline may not be effective for urinary tract infections and has no indication for this use. Tigecycline has in vitro activity against a wide variety of multidrug-resistant nosocomial pathogens (eg, methicillin-resistant S aureus, extended-spectrum β-lactamase-producing gram-negatives, and Acinetobacter sp); however, its clinical efficacy in infections with multidrug-resistant organisms, compared with other agents, is unproven.

A. Oral Dosage

The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is 0.25–0.5 g four times daily for adults and 20–40 mg/kg/d for children (8 years of age and older). For severe systemic infections, the higher dosage is indicated, at least for the first few days. The daily dose is 600 mg for demeclocycline or methacycline, 100 mg once or twice daily for doxycycline, and 100 mg twice daily for minocycline. Doxycycline is the oral tetracycline of choice because it can be given twice daily, and its absorption is not significantly affected by food. All tetracyclines chelate with metals, and none should be orally administered with milk, antacids, or ferrous sulfate. To avoid deposition in growing bones or teeth, tetracyclines should be avoided in pregnant women and children younger than 8 years.

B. Parenteral Dosage

Several tetracyclines are available for intravenous injection in doses of 0.1–0.5 g every 6–12 hours (similar to oral doses) but doxycycline is the usual preferred agent, at a dosage of 100 mg every 12–24 hours. Intramuscular injection is not recommended because of pain and inflammation at the injection site.

Adverse Reactions

Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse effects are due to direct toxicity of the drug or to alteration of microbial flora.

A. Gastrointestinal Adverse Effects

Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracyclines. These effects are attributable to direct local irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose, reducing drug dosage, or discontinuing the drug.

Tetracyclines alter the normal gastrointestinal flora, with suppression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or Clostridium difficile-associated colitis. However, the risk of C difficile colitis may be lower with tetracyclines than with other antibiotics.

B. Bony Structures and Teeth

Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia. It can also be deposited in bone, where it may cause deformity or growth inhibition. Because of these effects, tetracyclines are generally avoided in pregnancy. If the drug is given for long periods to children younger than 8 years, similar changes can result.

C. Other Toxicities

Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously.

Renal tubular acidosis and Fanconi syndrome have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may cause nephrotoxicity. Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function.

Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided.

Systemically administered tetracycline, especially demeclocycline, can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons.

Dizziness, vertigo, nausea, and vomiting have been noted, particularly with minocycline. With dosages of 200–400 mg/d of minocycline, 35–70% of patients will have these reactions. These symptoms may also occur with higher doses of doxycycline.

image MACROLIDES

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin.

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ERYTHROMYCIN

Chemistry

The general structure of erythromycin is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts.

Mechanism of Action & Antimicrobial Activity

The antibacterial action of erythromycin and other macrolides may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. The binding site is near the peptidyltrans-ferase center, and peptide chain elongation (ie, transpeptidation) is prevented by blocking of the polypeptide exit tunnel. As a result, peptidyl-tRNA is dissociated from the ribosome. Erythromycin also inhibits the formation of the 50S ribosomal subunit (Figure 44–1).

Erythromycin is active against susceptible strains of gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma pneumoniaeL pneumophilaChlamydia trachomatisChlamydia psittaci, Chlamydia pneumoniaeH pyloriListeria monocytogenes, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) are also susceptible. Gram-negative organisms such as Neisseria sp, Bordetella pertussis, Bartonella henselae, and Bartonella quintana as well as some Rickettsia species, Treponema pallidum, and Campylobacter species are susceptible. Haemophilus influenzae is somewhat less susceptible.

Resistance to erythromycin is usually plasmid-encoded. Three mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. Efflux and methylase production are the most important resistance mechanisms in gram-positive organisms. Cross-resistance is complete between erythromycin and the other macrolides. Constitutive methylase production also confers resistance to structurally unrelated but mechanistically similar compounds such as clindamycin and streptogramin B (so-called macrolide-lincosamide-streptogramin, or MLS-type B, resistance), which share the same ribosomal binding site. Because nonmacrolides are poor inducers of the methylase, strains expressing an inducible methylase will appear susceptible in vitro. However, constitutive mutants that are resistant can be selected out and emerge during therapy with clindamycin.

Pharmacokinetics

Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Food interferes with absorption. Stearates and esters are fairly acid-resistant and somewhat better absorbed. The lauryl salt of the propionyl ester of erythromycin (erythromycin estolate) is the best-absorbed oral preparation. Oral dosage of 2 g/d results in serum erythromycin base and ester concentrations of approximately 2 mcg/mL. However, only the base is microbiologically active, and its concentration tends to be similar regardless of the formulation. A 500 mg intravenous dose of erythromycin lactobionate produces serum concentrations of 10 mcg/mL 1 hour after dosing. The serum half-life is approximately 1.5 hours normally and 5 hours in patients with anuria. Adjustment for renal failure is not necessary. Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile and lost in feces, and only 5% is excreted in the urine. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus.

Clinical Uses

Erythromycin is a traditional drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma) and in respiratory, neonatal, ocular, or genital chlamydial infections. While it was used in treatment of community-acquired pneumonia because its spectrum of activity includes pneumococcus, M pneumoniae, and L pneumophila, newer macrolides are now more commonly selected. Macrolide resistance is also increasing in pneumococci and M pneumoniae. Erythromycin had also been useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci. Emergence of erythromycin resistance in staphylococci and in strains of group A streptococci has made macrolides less attractive as first-line agents for treatment of pharyngitis and skin and soft tissue infections. Erythromycin has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, but clindamycin, which is better tolerated, has largely replaced it. Although erythromycin estolate is the best-absorbed salt, it imposes the greatest risk of adverse reactions. Therefore, the stearate or succinate salt may be preferred.

The oral dosage of erythromycin base, stearate, or estolate is 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage of erythromycin ethylsuccinate is 0.4–0.6 g every 6 hours. Oral erythromycin base (1 g) is sometimes combined with oral neomycin or kanamycin for preoperative preparation of the colon. The intravenous dosage of erythromycin gluceptate or lactobionate is 0.5–1.0 g every 6 hours for adults and 20–40 mg/kg/d for children. The higher dosage is recommended when treating pneumonia caused by L pneumophila.

Adverse Reactions

Anorexia, nausea, vomiting, and diarrhea are common. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason for discontinuing erythromycin and substituting another antibiotic.

Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes.

Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus, increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability.

CLARITHROMYCIN

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are similar with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against Mycobacterium lepraeToxoplasma gondii, and H influenzae. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin.

A 500 mg dose of clarithromycin produces serum concentrations of 2–3 mcg/mL. The longer half-life of clarithromycin (6 hours) compared with erythromycin permits twice-daily dosing. The recommended dosage is 250–500 mg twice daily or 1000 mg of the extended-release formulation once daily. Clarithromycin penetrates most tissues well, with concentrations equal to or exceeding serum concentrations.

Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. Portions of active drug and this major metabolite are eliminated in the urine, and dosage reduction (eg, a 500 mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin.

The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing.

AZITHROMYCIN

Azithromycin, a 15-atom lactone macrolide ring compound, is derived from erythromycin by addition of a methylated nitrogen into the lactone ring. Its spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin. Azithromycin is active against M avium complex and T gondii. Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against H influenzae. Azithromycin is highly active against Chlamydia sp.

Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic properties. A 500 mg dose of azithromycin produces relatively low serum concentrations of approximately 0.4 mcg/mL. However, azithromycin penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold. The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases. For example, a single 1-g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days.

Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and, therefore, is free of the drug interactions that occur with erythromycin and clarithromycin.

Macrolide antibiotics prolong the QT interval due to an effect on potassium ion channels. Prolongation of the QT interval can lead to the torsades de pointes arrhythmia. Recent studies have suggested that azithromycin may be associated with a small increased risk of cardiac death.

KETOLIDES

Ketolides are semisynthetic 14-membered-ring macrolides, differing from erythromycin by substitution of a 3-keto group for the neutral sugar L-cladinose. Telithromycin is approved for limited clinical use. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalisMycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria gonorrhoeae, B fragilis, T gondii, and certain nontuberculosis mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance, and they bind to ribosomes of some bacterial species with higher affinity than macrolides.

Oral bioavailability of telithromycin is 57%, and tissue and intracellular penetration is generally good. Telithromycin is metabolized in the liver and eliminated by a combination of biliary and urinary routes of excretion. It is administered as a once-daily dose of 800 mg, which results in peak serum concentrations of approximately 2 mcg/mL. It is a reversible inhibitor of the CYP3A4 enzyme system and may slightly prolong the QTc interval. In the USA, telithromycin is now indicated only for treatment of community-acquired bacterial pneumonia. Other respiratory tract infections were removed as indications when it was recognized that use of telithromycin can result in hepatitis and liver failure. Telithromycin is also contraindicated in patients with myasthenia gravis because it may exacerbate this condition.

image CLINDAMYCIN

Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic that is elaborated by Streptomyces lincolnensis.

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Mechanism of Action & Antibacterial Activity

Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin. Streptococci, staphylococci, and pneumococci are inhibited by clindamycin, 0.5–5 mcg/mL. Enterococci and gram-negative aerobic organisms are resistant. Bacteroides sp and other anaerobes, both gram-positive and gram-negative, are usually susceptible. Resistance to clindamycin, which generally confers cross-resistance to macrolides, is due to (1) mutation of the ribosomal receptor site; (2) modification of the receptor by a constitutively expressed methylase (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane.

Pharmacokinetics

Oral dosages of clindamycin, 0.15–0.3 g every 8 hours (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL. When administered intravenously, 600 mg of clindamycin every 8 hours gives levels of 5–15 mcg/mL. The drug is about 90% protein-bound. Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure.

Clinical Use

Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It is often active against community-acquired strains of methicillin-resistant S aureus, an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of infections caused by Bacteroides sp and other anaerobes. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung abscesses. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with specific valvular heart disease who are undergoing certain dental procedures and have significant penicillin allergies. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.

Adverse Effects

Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Administration of clindamycin is a risk factor for diarrhea and colitis due to C difficile.

image STREPTOGRAMINS

MECHANISM OF ACTION & ANTIBACTERIAL ACTIVITY

Quinupristin-dalfopristin is a combination of two streptogramins—quinupristin, a streptogramin B, and dalfopristin, a streptogramin A—in a 30:70 ratio. The streptogramins share the same ribosomal binding site as the macrolides and clindamycin and thus inhibit protein synthesis in an identical manner. Quinupristin-dalfopristin is rapidly bactericidal for most susceptible organisms except Enterococcus faecium, which is killed slowly. Quinupristin-dalfopristin is active against gram-positive cocci, including multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium (but not Enterococcus faecalis). Resistance is due to modification of the quinupristin binding site (MLS-B type resistance), enzymatic inactivation of dalfopristin, or efflux.

Pharmacokinetics

Quinupristin-dalfopristin is administered intravenously at a dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentrations following an infusion of 7.5 mg/kg over 60 minutes are 3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin. Quinupristin and dalfopristin are rapidly metabolized, with half-lives of 0.85 and 0.7 hours, respectively. Elimination is principally by the fecal route. Dose adjustment is not necessary for renal failure, peritoneal dialysis, or hemodialysis. Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours. Quinupristin and dalfopristin significantly inhibit CYP3A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, non-nucleoside reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary.

Clinical Uses & Adverse Effects

Quinupristin-dalfopristin is approved for treatment of infections caused by staphylococci or by vancomycin-resistant strains of E faecium, but not E faecalis, which is intrinsically resistant, probably because of an efflux-type resistance mechanism. The principal toxicities are infusion-related events, such as pain at the infusion site, and an arthralgia-myalgia syndrome.

image CHLORAMPHENICOL

Crystalline chloramphenicol is a neutral, stable compound with the following structure:

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It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate, which is used for parenteral administration, is highly water-soluble. It is hydrolyzed in vivo with liberation of free chloramphenicol.

Mechanism of Action & Antimicrobial Activity

Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome (Figure 44–1) and inhibits peptide bond formation (step 2). Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against Rickettsiae but not Chlamydiae. Most gram-positive bacteria are inhibited at concentrations of 1–10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some strains of bacteroides are highly susceptible, and for these organisms, chloramphenicol may be bactericidal.

Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug.

Pharmacokinetics

The usual dosage of chloramphenicol is 50–100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1 g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which is hydrolyzed to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily.

Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol, about 10% of the total dose administered, and its inactive degradation products are eliminated in the urine. A small amount of active drug is excreted into bile and feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.

Clinical Uses

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

Chloramphenicol is used topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor. It is not effective for chlamydial infections.

Adverse Reactions

Adults occasionally develop gastrointestinal disturbances, including nausea, vomiting, and diarrhea. These symptoms are rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.

Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. The anemia tends to be irreversible and can be fatal, although it may respond to bone marrow transplantation or immunosuppressive therapy.

Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d (or less during the first week of life) in full-term infants more than 1 week old and 25 mg/kg/d in premature infants.

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives of these drugs are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased.

image OXAZOLIDINONES

MECHANISM OF ACTION & ANTIMICROBIAL ACTIVITY

Linezolid is a member of the oxazolidinones, a newer class of synthetic antimicrobials. It is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic agent but is bactericidal against streptococci. It is also active against Mycobacterium tuberculosis.

Linezolid inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA.

Pharmacokinetics

Linezolid is 100% bioavailable after oral administration and has a half-life of 4–6 hours. It is metabolized by oxidative metabolism, yielding two inactive metabolites. It is neither an inducer nor an inhibitor of cytochrome P450 enzymes. Peak serum concentrations average 18 mcg/mL following a 600 mg oral dose. The recommended dosage for most indications is 600 mg twice daily, either orally or intravenously.

Clinical Uses

Linezolid is approved for vancomycin-resistant E faecium infections, health care-associated pneumonia, community-acquired pneumonia, and both complicated and uncomplicated skin and soft tissue infections caused by susceptible gram-positive bacteria. Off-label uses of linezolid include treatment of multidrug-resistant tuberculosis and Nocardia infections.

Adverse Effects

The principal toxicity of linezolid is hematologic; the effects are reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. There are case reports of serotonin syndrome (see Chapter 16) occurring when linezolid is co-administered with serotonergic drugs, most frequently selective serotonin reuptake inhibitor antidepressants. The FDA has issued a warning regarding the use of the drug with serotonergic agents.

Tedizolid is the active moiety of the prodrug tedizolid phosphate, a next-generation oxazolidinone, with high potency against gram-positive bacteria, including methicillin-resistant S aureus. It is currently in the late stages of clinical development for the treatment of skin and soft tissue infection and health care-associated pneumonia. Potential advantages over linezolid include increased potency against staphylococci and once-daily dosing.

SUMMARY Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones

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PREPARATIONS AVAILABLE

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REFERENCES

Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232.

De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006;42:1111.

Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. 2011;66(Suppl 4):S7.

Hancock RE: Mechanisms of action of newer antibiotics for gram-positive pathogens. Lancet Infect Dis 2005;5:209.

Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clin Infect Dis 2002;34:482.

Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012;367:1508.

Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob Chemother 2005;56:611.

Moran GJ et al: Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med 2006;355:666.

Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. JAMA 2013;309:559.

Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious diseases: A meta-analysis. Lancet Infect Dis 2011;11:834.

Wayne RA et al: Azithromycin and risk of cardiovascular death. N Engl J Med 2012;366:1881.

Woytowish MR, Rowe AS: Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother 2013;47:388.

Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18:621.

CASE STUDY ANSWER

A tetracycline or a macrolide is effective in the treatment of chlamydial cervicitis. Doxycycline at a dose of 100 mg PO bid for 7 days is the preferred tetracycline, while azithromycin as a single 1 g dose is the preferred macrolide. If the patient is pregnant, then tetracyclines would be contraindicated and she should receive azithromycin, which is safe in pregnancy.