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 foul-smelling 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 gonococcus. 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 the potential treatment options? How does her potential pregnancy affect the treatment decision?

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

The drugs described in this chapter inhibit bacterial protein synthesis by binding to and interfering with ribosomes. They are active against a wide variety of organisms (broad spectrum). Most are bacteriostatic but a few are bactericidal against certain organisms. Because of overuse, resistance is common. Except for tigecycline and the streptogramins, they are usually given orally.

Tetracyclines

All of the tetracyclines have the basic structure shown below:

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 newly approved tetracycline analog, tigecycline, is a glycylcycline and a semisynthetic derivative of minocycline.

Antimicrobial Activity

Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa (eg, amebas). 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 that mediates resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs.

Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible cells 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.

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 species, and Pseudomonas aeruginosa, accounting for their intrinsic resistance to all tetracyclines including tigecycline.

Pharmacokinetics

Tetracyclines mainly differ in their absorption after oral administration and 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, modifies 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 divalent cations (Ca²⁺, Mg²⁺, Fe²⁺) or 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 usual 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 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 50% by 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 50 percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to 40 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.

Clinical Uses

A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, 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 diseases. Tetracyclines are no longer recommended for treatment of gonococcal disease because of resistance. A tetracycline—usually in combination with an aminoglycoside—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes used in the treatment of protozoal infections, eg, those due to Entamoeba histolytica or 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, pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinary tract infections. However, many strains of bacteria causing these infections now are 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, rifampin is preferred. Demeclocycline inhibits 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 the clinic, has several unique features that warrant its consideration apart from the older tetracyclines. Many tetracycline-resistant strains are susceptible to tigecycline because the common resistance determinants have no activity against it. 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; multi-drug-resistant strains of Acinetobacter sp; anaerobes, both gram-positive and gram-negative; atypical agents, rickettsiae, chlamydia, and legionella; and rapidly growing mycobacteria all are susceptible. Proteus 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 somewhat blunted. 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 FDA-approved for treatment of skin and skin-structure infection and intra-abdominal infections. 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. Because it is active against a wide variety of multidrug-resistant nosocomial pathogens (eg, methicillin-resistant S aureus, extended-spectrum -lactamase-producing gram-negatives, and Acinetobacter species), tigecycline is a welcome addition to the antimicrobial drug group.

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 as a once-daily dose 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 less than 8 years of age.

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.

Gastrointestinal Adverse Effects

Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracycline medication. 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 modify the normal 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 enterocolitis with shock and death.

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 under 8 years of age, similar changes can result.

Liver Toxicity

Tetracyclines can probably 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.

Kidney Toxicity

Renal tubular acidosis and other renal injury resulting in nitrogen retention have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may produce nitrogen retention. Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function.

Local Tissue Toxicity

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

Photosensitization

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

Vestibular Reactions

Dizziness, vertigo, nausea, and vomiting have been noted particularly with doxycycline at doses above 100 mg. With dosages of 200–400 mg/d of minocycline, 35–70% of patients will have these reactions.

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.

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.

Antimicrobial Activity

Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria, in plasma concentrations of 0.02–2 mcg/mL. Mycoplasma, legionella, Chlamydia trachomatis, C psittaci, C pneumoniae, helicobacter, listeria, and certain mycobacteria (Mycobacterium kansasii, M scrofulaceum) are also susceptible. Gram-negative organisms such as Neisseria, Bordetella pertussis, Bartonella henselae, and B quintana (etiologic agents of cat-scratch disease and bacillary angiomatosis), some Rickettsia species, Treponema pallidum, and Campylobacter species are susceptible. Haemophilus influenzae is somewhat less susceptible.

The antibacterial action of erythromycin 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, which blocks the aminoacyl translocation reaction and formation of initiation complexes (Figure 44–1).

Resistance

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 by far 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

An erythromycin is a drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment of community-acquired pneumonia because its spectrum of activity includes pneumococcus, mycoplasma, and legionella. Erythromycin is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci. Emergence of erythromycin resistance in strains of group A streptococci and pneumococci (penicillin-resistant pneumococci in particular) has made macrolides less attractive as first-line agents for treatment of pharyngitis, skin and soft tissue infections, and pneumonia. Erythromycin has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, although 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 Legionella species.

Adverse Reactions

Gastrointestinal Effects

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

Liver Toxicity

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.

Drug Interactions

Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, 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 virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. 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. A portion of active drug and this major metabolite is 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. Except for the specific organisms noted above, the two drugs are otherwise therapeutically very similar, and the choice of one over the other usually turns out to be cost and tolerability.

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 and clinical uses are virtually identical 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.

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.

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 clinical use. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, B fragilis, T gondii, and 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. Telithromycin is indicated for treatment of respiratory tract infections, including community-acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and streptococcal pharyngitis. It is a reversible inhibitor of the CYP3A4 enzyme system and may slightly prolong the QT_c interval. Rare cases of hepatitis and liver failure have been reported.

Clindamycin

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

Antibacterial Activity

Streptococci, staphylococci, and pneumococci are inhibited by clindamycin, 0.5–5 mcg/mL. Enterococci and gram-negative aerobic organisms are resistant. Bacteroides species and other anaerobes, both gram-positive and gram-negative, are usually susceptible. 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. 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 Uses

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 anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. 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 and pelvic abscesses; and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. 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. Severe diarrhea and enterocolitis have followed clindamycin administration. Administration of clindamycin is a risk factor for diarrhea and colitis due to Clostridium difficile.

Chloramphenicol

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

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.

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 the peptidyl transferase step of protein synthesis. 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, N meningitidis, and some strains of bacteroides are highly susceptible, and for them 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 hydrolyzes 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 (about 90% of the total) 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. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a -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.

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 ineffective for chlamydial infections.

Adverse Reactions

Gastrointestinal Disturbances

Adults occasionally develop nausea, vomiting, and diarrhea. This is rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.

Bone Marrow Disturbances

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. It tends to be irreversible and can be fatal.

Toxicity for Newborn Infants

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 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.

Interaction with Other Drugs

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.

Streptogramins

Quinupristin-dalfopristin  is a combination of two streptogramins—quinupristin, a streptogramin B, and dalfopristin, a streptogramin A—in a 30:70 ratio. It is rapidly bactericidal for most 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 E faecalis). Resistance is due to modification of the quinupristin binding site (MLS-B type), enzymatic inactivation of dalfopristin, or efflux.

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, nonnucleoside reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary.

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.

Oxazolidinones

Linezolid  is a member of the oxazolidinones, a new 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 and Listeria monocytogenes. It is primarily a bacteriostatic agent except for streptococci, for which it is bactericidal. It is active in vitro 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.

The principal toxicity of linezolid is hematologic—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.

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. Linezolid is a weak, reversible monoamine oxidation inhibitor. There are case reports of serotonin syndrome occurring when linezolid is co-administered with serotonergic drugs, most frequently selective serotonin reuptake inhibitor antidepressants. 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. Linezolid is approved for vancomycin-resistant E faecium infections; nosocomial pneumonia; community-acquired pneumonia; and skin infections, complicated or uncomplicated. It should be reserved for treatment of infections caused by multidrug-resistant gram-positive bacteria.

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

Preparations Available

Chloramphenicol

Tetracyclines

Macrolides

Ketolides

Lincomycin

Streptogramins

Oxazolidinone

References