Chapter 55: Protein Synthesis Inhibitorsand Miscellaneous Antibacterial Agents

Chlortetracycline, the prototype of this class, was introduced in 1948 but is no longer marketed in the U.S. Oxytetracycline is a natural product elaborated by Streptomyces rimosus. Tetracycline is a semisynthetic derivative of chlortetracycline. Demeclocycline is the product of a mutant strain of S. aureofaciens, and methacycline (not available in the U.S.), doxycycline, and minocycline all are semisynthetic derivatives.

Because of their activity against Rickettsia, aerobic and anaerobic gram-positive and gram-negative bacteria, and Chlamydia, tetracyclines became known as "broad-spectrum" antibiotics. The spread of antimicrobial resistance has eroded the activity of tetracyclines against many gram-positive and gram-negative organisms. A new group of tetracycline derivatives, the glycyclines, have regained much of this activity. The glycylcyclines are synthetic analogs of the tetracyclines; the glycycline currently approved is tigecycline, the 9-tert-butyl-glycylamido derivative of minocycline.

They also are effective against some microorganisms, such as Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp., Legionella spp., Ureaplasma, some atypical mycobacteria, and Plasmodium spp., that are resistant to cell-wall-active antimicrobial agents. The tetracyclines are active against many spirochetes, including Borrelia recurrentis, Borrelia burgdorferi (Lyme disease), Treponema pallidum (syphilis), and Treponema pertenue. Tetracyclines are active against Chlamydia and Mycoplasma. Some nontuberculosis strains of mycobacteria (e.g., M. marinum) also are susceptible. They are not active against fungi. Demeclocycline, tetracycline, minocycline, and doxycycline are available in the U.S. for systemic use. Other derivatives are available in other countries. The more lipophilic drugs, minocycline and doxycycline, usually are the most active by weight, followed by tetracycline. Resistance of a bacterial strain to any one member of the class may or may not result in cross-resistance to other tetracyclines. Tigecycline is generally, although not universally, active against organisms that are susceptible to tetracyclines as well as those with acquired resistance to tetracyclines (Gales et al., 2008).

Bacterial strains with tetracycline minimum inhibitory concentrations (MICs) ≤4 μg/mL are considered susceptible except for Haemophilus influenzae and Streptococcus pneumoniae, whose susceptibility breakpoints (defined as the upper limit of the concentration at which bacteria are still considered susceptible to a given drug) are ≤2 μg/mL, and Neisseria gonorrhoeae, with a breakpoint of ≤0.25 μg/mL. The MIC breakpoint for susceptible anaerobic bacteria is 8 μg/mL. Tetracyclines intrinsically are more active against gram-positive than gram-negative microorganisms, but acquired resistance is common. Recent data from the U.S. on the activity of tetracycline and other agents discussed in this chapter against selected gram-positive aerobes are displayed in Table 55–2. However, prevalence of resistant strains varies in different regions. For example, ~10% of S. pneumoniae isolates in the U.S. are resistant to tetracycline versus 40% in the Asia-Pacific region (Hoban et al., 2001). Bacillus anthracis and Listeria monocytogenes are susceptible. Of note, the tetracyclines, doxycycline and minocycline in particular, have generally retained excellent levels of activity against staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA). Doxycycline and minocycline can be active against some tetracycline-resistant isolates.

H. influenzae is generally susceptible, but many Enterobacteriaceae have acquired resistance. Although all strains of Pseudomonas aeruginosa are resistant, 90% of strains of Burkholderia pseudomallei (the cause of melioidosis) are sensitive. Most strains of Brucella also are susceptible. Tetracyclines remain useful for infections caused by Haemophilus ducreyi (chancroid), Vibrio cholerae and V. vulnificus, and inhibit the growth of Legionella pneumophila, Campylobacter jejuni, Helicobacter pylori, Yersinia pestis, Yersinia enterocolitica, Francisella tularensis, and Pasteurella multocida. Strains of Neisseria gonorrhoeae no longer are predictably susceptible to tetracycline, which is not recommended for treatment of gonococcal infections. The tetracyclines are active against many anaerobic and facultative microorganisms. A variable number of anaerobes (e.g., Bacteroides spp., Propionibacterium, Peptococcus) are sensitive to doxycycline, but other antibiotics (e.g., chloramphenicol, clindamycin, metronidazole, and certain β-lactam antibiotics) have better activity. Tetracycline is active against Actinomyces and is a drug of choice for treating actinomycosis.

Currently established breakpoints for tigecycline susceptibility vary by organism: for S. aureus ≤0.5 μg/mL; for Streptococcus, Haemophilus, and Enterococcus species, ≤0.25 μg/mL; for S. pneumoniae, ≤0.06 μg/mL; for Enterobacteriaceae ≤2 μg/mL; and for anaerobic organisms ≤4 μg/mL. In general, tigecycline is equally or more active in vitro against bacteria than the tetracyclines (Table 55–1), including activity against tetracycline-resistant organisms, especially gram-negative organisms. There are a few exceptions where other tetracyclines may be more active against certain organisms, such as Stenotrophomonas and Ureaplasma. There is currently a lack of clinical experience with tigecycline for infections caused by organisms such as Burkholderia, Brucella, Yersinia, Francisella, and Pasteurella. Notable holes in the spectrum of activity of tigecycline (as with the tetracyclines) include Pseudomonas, Proteus, and Providencia spp.

Resistance to Tetracyclines and Glycylcyclines. Resistance is primarily plasmid mediated and often inducible. The three main resistance mechanisms are (1) decreased accumulation of tetracycline as a result of either decreased antibiotic influx or acquisition of an energy-dependent efflux pathway; (2) production of a ribosomal protection protein that displaces tetracycline from its target, a "protection" that also may occur by mutation; and (3) enzymatic inactivation of tetracyclines. Cross-resistance, or lack thereof, among tetracyclines depends on which mechanism is operative. For example, S. aureus strains that are tetracycline resistant on the basis of efflux mediated by tetK still may be susceptible to minocycline. Tetracycline resistance due to a ribosomal protection mechanism (tetM) produces cross-resistance to doxycycline and minocycline because the target site protected is the same for all tetracyclines.

The glycylamido moiety characteristic of tigecycline reduces its affinity for most efflux pumps, restoring activity against many organisms displaying tetracycline resistance due to this mechanism. Binding of glycyclines to ribosomes is also enhanced, improving activity against organisms that harbor ribosomal protection proteins that confer resistance to other tetracyclines (Petersen et al., 1999).

Absorption, Distribution, and Excretion

Absorption. Oral absorption of most tetracyclines is incomplete. The percentage of an oral dose that is absorbed with an empty stomach is modest for demeclocycline and tetracycline (60-80%) and high for doxycycline (95%) and minocycline (100%). The percentage of unabsorbed drug rises as the dose increases. Tigecycline is not appreciably absorbed from the gastrointestinal (GI) tract and is only available for parenteral administration. Absorption of orally administered tetracyclines mostly takes place in the stomach and upper small intestine and is greater in the fasting state. Absorption may be impaired by the concurrent ingestion of divalent and trivalent cations (e.g., Ca²⁺, Mg ²⁺, Al³⁺, Fe^2+/3+, and Zn²⁺). Thus, dairy products, antacids, aluminum hydroxide gels; calcium, magnesium, and iron or zinc salts; bismuth subsalicylate (e.g., pepto-bismol), and dietary Fe and Zn supplements can interfere with absorption of tetracyclines. The decreased absorption apparently results from chelation with these cations and formation of complexes with poor solubility. Doxycycline and minocycline are less affected than tetracyclines and administration with milk or calcium-containing foods is unlikely to impair absorption substantially, but co-administration of antacids or mineral supplements should be avoided.

Variable absorption of orally administered tetracyclines leads to a wide range of plasma concentrations in different individuals. Tetracycline is incompletely absorbed. After a single oral dose, the peak plasma concentration is attained in 2-4 hours. These drugs have half-lives in the range of 6-12 hours and frequently are administered two to four times daily. The administration of 250 mg tetracycline every 6 hours produces peak plasma concentrations of 2-2.5 μg/mL. Increasing the dosage above 1 g every 6 hours does not further increase plasma concentrations. Demeclocycline, which also is incompletely absorbed, can be administered in lower daily dosages than the congeners just mentioned because its t_1/2 of 16 hours provides effective plasma concentrations for 24-48 hours.

Oral doses of doxycycline and minocycline are well absorbed (90-100%) and have half-lives of 16-18 hours; they therefore can be administered less frequently and at lower doses than tetracycline or demeclocycline. After an oral dose of 200 mg of doxycycline, a maximum plasma concentration of 3 μg/mL is achieved at 2 hours, and the plasma concentration remains above 1 μg/mL for 8-12 hours. Plasma concentrations are equivalent whether doxycycline is given orally or parenterally.

Distribution. Tetracyclines distribute widely throughout the body and into tissues and secretions, including urine and prostate. They accumulate in reticuloendothelial cells of the liver, spleen, and bone marrow, and in bone, dentine, and enamel of unerupted teeth. Tigecycline distributes rapidly and extensively into tissues, with an estimated apparent volume of 7-10 L/kg. Because of this extensive distribution, peak serum levels of tigecycline are relatively low (~1 μg/mL).

Inflammation of the meninges is not required for the passage of tetracyclines into the cerebrospinal fluid (CSF). Penetration of these drugs into most other fluids and tissues is excellent. Concentrations in synovial fluid and the mucosa of the maxillary sinus approach that in plasma. Tetracyclines cross the placenta and enter the fetal circulation and amniotic fluid. Relative to the maternal circulation, tetracycline concentrations in umbilical cord plasma and amniotic fluid are 60% and 20%, respectively. Relatively high concentrations of these drugs also are found in breast milk.

Excretion. The primary route of elimination of most older tetracyclines (e.g., demeclocycline, tetracycline) is the kidney, although they also are concentrated in the liver and excreted in bile. After biliary excretion, they are partially reabsorbed via enterohepatic recirculation. Elimination via the intestinal tract occurs even when the drugs are given parenterally. Comparable amounts of tetracycline (i.e., 20-60%) are excreted in the urine within 24 hours following oral or intravenous administration.

Doxycycline is largely excreted unchanged both in the bile and urine, tigecycline is mostly excreted unchanged along with a small amount of glucuronidated metabolites, and minocycline is extensively metabolized by the liver before excretion. Doses of these agents do not require adjustment in patients with renal dysfunction. Decreased hepatic function or obstruction of the common bile duct reduces the biliary excretion of these agents, resulting in longer half-lives and higher plasma concentrations. Specific dosage adjustment recommendations in hepatic disease are available only for tigecycline. Because of their enterohepatic circulation, these drugs may remain in the body for a long time after cessation of therapy. There is some evidence for drug interactions between doxycycline and hepatic enzyme-inducing agents such as phenytoin and rifampin, but not for minocycline or tigecycline.

Children >8 years of age should receive 25-50 mg/kg daily in four divided doses. The total daily dose of intravenous tetracycline (no longer available in the U.S.) for most acute infections is 1 g (or 2 g for severe infection), divided into equal doses and administered at 6- or 12-hour intervals. The low pH of tetracycline, but not doxycycline or minocycline, invariably causes phlebitis if infused into a peripheral vein. The recommended dose of demeclocycline is 150 mg every 6 hours or 300 mg every 12 hours for adults and 6.6-13.2 mg/kg in two to four divided doses for children >8 years of age. Demeclocycline is used rarely as an antimicrobial agent because of its higher risks of photosensitivity reactions and nephrogenic diabetes insipidus. The oral or intravenous dose of doxycycline for adults is 100 mg every 12 hours on the first day and then 50 mg every 12 hours, 100 mg once a day, or 100 mg twice daily when severe infection is present; for children >8 years of age, the dose is 4-5 mg/kg per day in two divided doses the first day, then 2-2.5 mg/kg given once or twice daily. The dose of minocycline for adults is 200 mg orally or intravenously initially, followed by 100 mg every 12 hours; for children, it is 4 mg/kg initially followed by 2 mg/kg every 12 hours. Tigecycline is administered intravenously to adults as a 100-mg loading dose, followed by 50 mg every 12 hours. For patients with severe hepatic impairment, the loading dose should be followed by a reduced maintenance dose of 25 mg every 12 hours. Dosage data are not available for tigecycline in pediatrics.

Tetracyclines should not be administered intramuscularly because of local irritation and poor absorption. GI distress, nausea, and vomiting can be minimized by administration of tetracyclines with food. Generally, oral administration of tetracyclines should occur 2 hours before or 2 hours after co-administration with any of the agents listed. Cholestyramine and colestipol also bind orally administered tetracyclines and interfere with the absorption of the antibiotic.

Respiratory Tract Infections. Doxycycline's good activity against S. pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophilia pneumoniae make it an effective single agent for empirical therapy of community-acquired pneumonia in the outpatient setting or as an adjunct to cephalosporin-based therapy for inpatients (Mandell et al., 2007). Tigecycline has been demonstrated to be effective for use as a single agent for adults hospitalized with community-acquired bacterial pneumonia (Bergallo et al., 2009).

Skin and Soft-Tissue Infections. Community strains of methicillin-resistant S. aureus often are susceptible to tetracycline, doxycycline, or minocycline, which appear to be effective for uncomplicated skin and soft-tissue infections, although published data are limited (Cenizal et al., 2007). Tigecycline is approved by the Food and Drug Administration (FDA) for the treatment of complicated skin and soft-tissue infections.

Tetracyclines have been used to treat acne. They may act by inhibiting propionibacteria, which reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The relatively low doses of tetracycline used for acne (e.g., 250 mg orally twice a day) are associated with few side effects.

Intra-abdominal Infections. Increasing resistance among Enterobacteriaceae and gram-negative anaerobes limit the utility of the tetracyclines for intra-abdominal infections. However, tigecycline possesses excellent activity against these pathogens as well as Enterococcus and has demonstrated effectiveness in clinical trials for complicated intra-abdominal infections (Oliva et al., 2005).

GI Infections. Therapy with the tetracyclines is often ineffective in infections caused by Shigella, Salmonella, or other Enterobacteriaceae because of a high prevalence of drug-resistant strains in many areas. Resistance limits the usefulness of tetracyclines for travelers' diarrhea. Doxycycline (300 mg as a single dose) is effective in reducing stool volume and eradicating Vibrio cholerae from the stool within 48 hours. Antimicrobial agents, however, are not substitutes for fluid and electrolyte replacement in this disease. In addition, some strains of V. cholerae are resistant to tetracyclines.

Urinary Tract Infections. Tetracyclines are no longer recommended for routine treatment of urinary tract infections because many enteric organisms that cause these infections, including E. coli, are resistant. There is little experience in using tigecycline for urinary tract infections; based on its in vitro activity, it should be adequate.

Sexually Transmitted Diseases. Because of resistance, doxycycline no longer is recommended for gonococcal infections. If coinfection with C. trachomatis has not been excluded, then either doxycycline or azithromycin should be administered in addition to an agent effective for gonococcal urethritis (Workowski and Berman, 2006).

C. trachomatis often is a coexistent pathogen in acute pelvic inflammatory disease, including endometritis, salpingitis, parametritis, and/or peritonitis. Doxycycline, 100 mg intravenously twice daily, is recommended for at least 48 hours after substantial clinical improvement, followed by oral therapy at the same dosage to complete a 14-day course. Doxycycline usually is combined with cefoxitin or cefotetan (Chapter 53) to cover anaerobes and facultative aerobes.

Acute epididymitis is caused by infection with C. trachomatis or N. gonorrhoeae in men <35 years of age. Effective regimens include a single injection of ceftriaxone (250 mg) plus doxycycline, 100 mg orally twice daily for 10 days. Sexual partners of patients with any of these conditions also should be treated.

Nonspecific urethritis is often due to Chlamydia trachomatis. Doxycycline, 100 mg every 12 hours for 7 days, is effective; however, azithromycin is usually preferred because it can be given as a single 1-g dose. Doxycycline (100 mg twice daily for 21 days) is first-line therapy for treatment of lymphogranuloma venereum. The size of buboes decreases within 4 days, and inclusion and elementary bodies entirely disappear from the lymph nodes within 1 week. Rectal pain, discharge, and bleeding of lymphogranulomatous proctitis are decreased markedly. When relapses occur, treatment is resumed with full doses and is continued for longer periods.

Nonpregnant penicillin-allergic patients who have primary, secondary, or latent syphilis can be treated with a tetracycline regimen such as doxycycline, 100 mg orally twice daily for 2 weeks. Tetracyclines should not be used for treatment of neurosyphilis.

Rickettsial Infections. Tetracyclines are effective and may be lifesaving in rickettsial infections, including Rocky Mountain spotted fever, recrudescent epidemic typhus (Brill's disease), murine typhus, scrub typhus, rickettsialpox, and Q fever. Clinical improvement often is evident within 24 hours after initiation of therapy. Doxycycline is the drug of choice for treatment of suspected or proven Rocky Mountain spotted fever in adults and in children, including those <9 years of age, in whom the risk of staining of permanent teeth is outweighed by the seriousness of this potentially fatal infection (Masters et al., 2003).

Anthrax. Doxycycline, 100 mg every 12 hours (2.2 mg/kg every 12 hours for children weighing <45 kg), is indicated for prevention or treatment of anthrax. It should be used in combination with another agent when treating inhalational or GI infection. The recommended duration of therapy is 60 days for exposures occurring as an act of bioterrorism.

Local Application. Except for local use in the eye, topical use of the tetracyclines is not recommended. Their use in ophthalmic therapy is discussed in previous versions of this text. Minocycline sustained-release microspheres for subgingival administration are used in dentistry as an adjunct to scaling and root planing procedures to reduce pocket depth in patients with adult periodontitis.

Other Infections. Tetracyclines in combination with rifampin or streptomycin are effective for acute and chronic infections caused by Brucella melitensis, Brucella suis, and Brucella abortus. Effective regimens are doxycycline, 200 mg per day, plus rifampin, 600-900 mg daily for 6 weeks, or the usual dose of doxycycline plus streptomycin 1 g daily, intramuscularly. Relapses usually respond to a second course of therapy. Although streptomycin is preferable, tetracyclines also are effective in tularemia (Ellis et al., 2002). Both the ulceroglandular and typhoidal types of the disease respond well. Actinomycosis, although most responsive to penicillin G, may be successfully treated with a tetracycline. Minocycline is an alternative for the treatment of nocardiosis, but a sulfonamide should be used concurrently. Yaws and relapsing fever respond favorably to the tetracyclines. Tetracyclines are useful in the acute treatment and for prophylaxis of leptospirosis (Leptospira spp.). Borrelia spp., including B. recurrentis (relapsing fever) and B. burgdorferi (Lyme disease), respond to therapy with a tetracycline. The tetracyclines have been used to treat susceptible atypical mycobacterial pathogens, including M. marinum.

Untoward Effects

Gastrointestinal. All tetracyclines can produce GI irritation, most commonly after oral administration. GI distress is also characteristic of tigecycline administration. Epigastric burning and distress, abdominal discomfort, nausea, vomiting, and diarrhea may occur. Tolerability can be improved by administering these drugs with food, but tetracyclines should not be taken with dairy products or antacids. Tetracycline has been associated with esophagitis, esophageal ulcers, and pancreatitis.

Many of the tetracyclines are incompletely absorbed from the GI tract, and high concentrations in the bowel can markedly alter enteric flora. Sensitive aerobic and anaerobic coliform microorganisms and gram-positive spore-forming bacteria are suppressed markedly during long-term tetracycline regimens. As the fecal coliform count declines, overgrowth of tetracycline-resistant microorganisms occurs, particularly of yeasts (Candida spp.), enterococci, Proteus, and Pseudomonas. Moniliasis, thrush, or Candida-associated esophagitis may arise during therapy with tetracyclines. Tetracyclines and glycylcyclines may occasionally produce pseudomembranous colitis caused by Clostridium difficile; pseudomembranous colitis caused by overgrowth of C. difficile is a potentially life-threatening complication.

Photosensitivity. Demeclocycline, doxycycline, and other tetracyclines and glycylcyclines to a lesser extent may produce mild-to-severe photosensitivity reactions in the skin of treated individuals exposed to sunlight. Onycholysis and pigmentation of the nails may develop with or without accompanying photosensitivity.

Hepatic Toxicity. Hepatic toxicity has developed in patients with renal failure receiving ≥2 g of drug per day parenterally, but this effect also may occur when large quantities are administered orally. Cases of hepatotoxicity have been reported rarely with doxycycline, minocycline, and tigecycline administration. Pregnant women are particularly susceptible to tetracycline-induced hepatic damage.

Renal Toxicity. Tetracyclines may aggravate azotemia in patients with renal disease because of their catabolic effects. Doxycycline, minocycline, and tigecycline have fewer renal side effects than other tetracyclines. Nephrogenic diabetes insipidus has been observed in some patients receiving demeclocycline, and this phenomenon has been exploited for the treatment of the syndrome of inappropriate secretion of antidiuretic hormone (Chapter 25).

Fanconi syndrome, characterized by nausea, vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria, and aminoaciduria, has been observed in patients ingesting outdated and degraded tetracycline. These symptoms presumably result from a toxic effect of the degradation products on proximal renal tubules. Under no circumstances should outdated tetracyclines be administered.

Effects on Teeth. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth. The larger the drug dose relative to body weight, the more intense the enamel discoloration. The duration of therapy appears to be less important than the total quantity of antibiotic administered. The risk of this untoward effect is highest when a tetracycline is given to neonates and infants before the first dentition. However, pigmentation of the permanent teeth may develop if the drug is given between the ages of 2 months and 5 years when these teeth are being calcified. The deposition of the drug in the teeth and bones probably is due to its chelating property and the formation of a tetracycline–calcium orthophosphate complex.

Treatment of pregnant patients with tetracyclines may produce discoloration of the teeth in their children. The period of greatest danger to the teeth is from midpregnancy to ~4-6 months of the postnatal period for the deciduous anterior teeth, and from a few months to 5 years of age for the permanent anterior teeth when the crowns are being formed. However, children up to 8 years old may be susceptible to this complication of tetracycline therapy.

Other Toxic and Irritative Effects. Tetracyclines are deposited in the skeleton during gestation and throughout childhood and may depress bone growth in premature infants. This is readily reversible if the period of exposure to the drug is short.

Thrombophlebitis frequently follows intravenous administration. This irritative effect of tetracyclines has been used therapeutically in patients with malignant pleural effusions, where drug is instilled into the pleural space in a procedure called pleurodesis.

Long-term tetracycline therapy may produce leukocytosis, atypical lymphocytes, toxic granulation of granulocytes, and thrombocytopenic purpura.

The tetracyclines may cause increased intracranial pressure (pseudotumor cerebri) in young infants, even when given in the usual therapeutic doses. Except for the elevated pressure, the spinal fluid is normal. The pressure promptly returns to normal when therapy is discontinued, and this complication rarely occurs in older individuals.

Patients receiving minocycline may experience vestibular toxicity, manifested by dizziness, ataxia, nausea, and vomiting. The symptoms occur soon after the initial dose and generally disappear within 24-48 hours after drug administration is stopped. Long-term use of minocycline can pigment the skin, producing a brownish discoloration. Various skin reactions, including morbilliform rashes, urticaria, fixed drug eruptions, and generalized exfoliative dermatitis, rarely may follow the use of any of the tetracyclines. Among the more severe allergic responses are angioedema and anaphylaxis; anaphylactoid reactions can occur even after the oral use of these agents. Other hypersensitivity reactions are burning of the eyes, cheilosis, atrophic or hypertrophic glossitis, pruritus ani or vulvae, and vaginitis. Although the exact cause of these reactions is unknown, they can persist for weeks or months after cessation of tetracycline therapy. Fever of varying degrees and eosinophilia may occur when these agents are administered. Asthma also has been observed. Cross-sensitization among the various tetracyclines is common.

Tetracyclines have a variety of effects on mammalian cells unrelated to their capacity to inhibit bacterial protein synthesis. Doxycycline is being studied as an inhibitor of matrix metalloproteinases (Villareal et al., 2003).

The antibiotic is unique among natural compounds in that it contains a nitrobenzene moiety and is a derivative of dichloroacetic acid. The biologically active form is levorotatory.

Antimicrobial Activity. Chloramphenicol possesses a broad spectrum of antimicrobial activity. Strains are considered sensitive if they are inhibited by concentrations of ≤8 μg/mL, except S. pneumoniae where the breakpoint is 4 μg/mL, and H. influenzae, which has a breakpoint of 2 μg/mL. Chloramphenicol is bacteriostatic against most species, although it may be bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae. More than 95% of strains of the following gram-negative bacteria are inhibited in vitro by 8 μg/mL or less of chloramphenicol: H. influenzae, N. meningitidis, N. gonorrhoeae, Brucella spp., and Bordetella pertussis. Likewise, most anaerobic bacteria, including gram-positive cocci and Clostridium spp., and gram-negative rods including B. fragilis, are inhibited by this concentration of the drug. Strains of S. aureus tend to be less susceptible, with MICs >8 μg/mL. Chloramphenicol is active against Mycoplasma, Chlamydia, and Rickettsia.

The Enterobacteriaceae are variably sensitive to chloramphenicol. Most strains of Escherichia coli (≥75%) and Klebsiella pneumoniae are susceptible. Proteus mirabilis and indole-positive Proteus spp. are susceptible. P. aeruginosa is resistant to even very high concentrations of chloramphenicol. Strains of V. cholerae have remained largely susceptible to chloramphenicol. Strains of Shigella and Salmonella resistant to multiple drugs, including chloramphenicol, are prevalent. Of special concern is the increasing prevalence of multiple-drug-resistant strains of Salmonella serotype typhi, particularly for strains acquired outside the U.S.

Mechanism of Action. Chloramphenicol inhibits protein synthesis in bacteria, and to a lesser extent, in eukaryotic cells. The drug readily penetrates bacterial cells, probably by facilitated diffusion. Chloramphenicol acts primarily by binding reversibly to the 50S ribosomal subunit (near the binding site for the macrolide antibiotics and clindamycin, which chloramphenicol inhibits competitively). Although binding of tRNA at the codon recognition site on the 30S ribosomal subunit is undisturbed, the drug apparently prevents the binding of the amino acid–containing end of the aminoacyl tRNA to the acceptor site on the 50S ribosomal subunit. The interaction between peptidyltransferase and its amino acid substrate cannot occur, and peptide bond formation is inhibited (Figure 55–2).

Chloramphenicol also can inhibit mitochondrial protein synthesis in mammalian cells, perhaps because mitochondrial ribosomes resemble bacterial ribosomes (both are 70S) more than they do the 80S cytoplasmic ribosomes of mammalian cells. The peptidyltransferase of mitochondrial ribosomes, but not of cytoplasmic ribosomes, is inhibited by chloramphenicol. Mammalian erythropoietic cells are particularly sensitive to the drug.

Resistance to Chloramphenicol. Resistance to chloramphenicol usually is caused by a plasmid-encoded acetyltransferase that inactivates the drug. Resistance also can result from decreased permeability and from ribosomal mutation. Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes.

Absorption, Distribution, Fate, and Excretion. Chloramphenicol is absorbed rapidly from the GI tract, and peak concentrations of 10-13 μg/mL occur within 2-3 hours after the administration of a 1-g dose. The product for oral administration is no longer available in the U.S. The preparation of chloramphenicol for parenteral use is the water-soluble, inactive prodrug sodium succinate. Similar concentrations of chloramphenicol succinate in plasma are achieved after intravenous and intramuscular administration. Hydrolysis of chloramphenicol succinate by esterases occurs in vivo. Chloramphenicol succinate is rapidly cleared from plasma by the kidneys; this may reduce overall bioavailability of the drug because as much as 30% of the dose may be excreted before hydrolysis. Poor renal function in the neonate and other states of renal insufficiency result in increased plasma concentrations of chloramphenicol succinate. Decreased esterase activity has been observed in the plasma of neonates and infants, prolonging time to peak concentrations of active chloramphenicol (up to 4 hours) and extending the period over which renal clearance of chloramphenicol succinate can occur.

Chloramphenicol is widely distributed in body fluids and readily reaches therapeutic concentrations in CSF, where values are ~60% of those in plasma (range, 45-99%) in the presence or absence of meningitis. The drug actually may accumulate in the brain. Chloramphenicol is present in bile, milk, and placental fluid. It also is found in the aqueous humor after subconjunctival injection.

Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol itself are excreted in the urine following filtration and secretion. Patients with cirrhosis or otherwise impaired hepatic function have decreased metabolic clearance, and dosage should be adjusted in these individuals. The t_1/2 of chloramphenicol correlates with plasma bilirubin concentrations. About 50% of chloramphenicol is bound to plasma proteins; such binding is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dosage adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. This effect can be minimized by administering the drug at the end of hemodialysis. Significant variability in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of drug concentrations in plasma.

Therapeutic Uses and Dosage. Therapy with chloramphenicol must be limited to infections for which the benefits of the drug outweigh the risks of the potential toxicities. When other antimicrobial drugs that are equally effective and potentially less toxic are available, they should be used instead of chloramphenicol (Wareham and Wilson, 2002).

Typhoid Fever. Third-generation cephalosporins and quinolones are drugs of choice for the treatment of typhoid fever because they are less toxic and because strains of Salmonella typhi often are resistant to chloramphenicol (Parry, 2003).

The adult dose of chloramphenicol for typhoid fever is 1 g every 6 hours for 4 weeks. Although intravenous and oral routes have been used, the response is more rapid with oral administration. Provided that the primary isolate is sensitive, relapses respond satisfactorily to retreatment.

Bacterial Meningitis. Third-generation cephalosporins have replaced chloramphenicol in the therapy of bacterial meningitis (Quagliarello and Scheld, 1997). Chloramphenicol remains an alternative drug for the treatment of meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae in patients who have severe allergy to β-lactams and in developing countries (Fuller et al., 2003). The total daily dose for children should be 50 mg/kg of body weight, divided into four equal doses given intravenously every 6 hours. Results with chloramphenicol used for pneumococcal meningitis may be unsatisfactory because some strains are inhibited but not killed. Moreover, penicillin-resistant strains frequently also are resistant to chloramphenicol (Hoban et al., 2001). In the rare situation in which chloramphenicol must be used to treat pneumococcal meningitis, lumbar puncture should be repeated 2-3 days after treatment is initiated to ensure that an adequate response has occurred.

Rickettsial Diseases. The tetracyclines usually are the preferred agents for the treatment of rickettsial diseases. However, in patients allergic to these drugs, in those with reduced renal function, in pregnant women, and in children <8 years of age who require prolonged or repeated courses of therapy, chloramphenicol may be the drug of choice. Rocky Mountain spotted fever, epidemic, murine, scrub, and recrudescent typhus, and Q fever respond well to chloramphenicol. For adults and children with these diseases, a dosage of 50 mg/kg/day divided into 6-hour intervals is recommended. For severe or resistant infections, doses up to 100 mg/kg/day may be used for short intervals, but the dose be reduced to 50 mg/kg/day as soon as possible. Therapy should be continued until the general condition has improved and the patient is afebrile for 24-48 hours.

Untoward Effects. Chloramphenicol inhibits the synthesis of proteins of the inner mitochondrial membrane, probably by inhibiting the ribosomal peptidyltransferase. These include subunits of cytochrome c oxidase, ubiquinone-cytochrome c reductase, and the proton-translocating ATPase critical for aerobic metabolism. Much of the toxicity observed with this drug can be attributed to these effects.

Hypersensitivity Reactions. Although relatively uncommon, macular or vesicular skin rashes result from hypersensitivity to chloramphenicol. Fever may appear simultaneously or be the sole manifestation. Angioedema is a rare complication. Jarisch-Herxheimer reactions may occur after institution of chloramphenicol therapy for syphilis, brucellosis, and typhoid fever.

Hematological Toxicity. The most important adverse effect of chloramphenicol is on the bone marrow. Chloramphenicol affects the hematopoietic system in two ways: a dose-related toxicity that presents as anemia, leukopenia, or thrombocytopenia, and an idiosyncratic response manifested by aplastic anemia, leading in many cases to fatal pancytopenia. Pancytopenia seems to occur more commonly in individuals who undergo prolonged therapy and especially in those who are exposed to the drug on more than one occasion. A genetic predisposition is suggested by the occurrence of pancytopenia in identical twins. Although the incidence of the reaction is low, ~1 in ≥30,000 courses of therapy, the fatality rate is high when bone marrow aplasia is complete, and there is an increased incidence of acute leukemia in those who recover. Aplastic anemia accounts for ~70% of cases of blood dyscrasias due to chloramphenicol; hypoplastic anemia, agranulocytosis, and thrombocytopenia make up the remainder. The exact biochemical mechanism has not yet been elucidated but is hypothesized to involve conversion of the nitro group to a toxic intermediate by intestinal bacteria.

The risk of aplastic anemia does not contraindicate the use of chloramphenicol in situations in which it may be lifesaving. The drug should never be used, however, in undefined situations or in diseases readily, safely, and effectively treatable with other antimicrobial agents.

Dose-related, reversible erythroid suppression probably reflects an inhibitory action of chloramphenicol on mitochondrial protein synthesis in erythroid precursors, which in turn impairs iron incorporation into heme. Leukopenia and thrombocytopenia also may occur. Bone marrow suppression occurs regularly when plasma concentrations are ≥25 μg/mL and is observed with the use of large doses of chloramphenicol, prolonged treatment, or both. Dose-related suppression of the bone marrow may progress to fatal aplasia if treatment is continued, but most cases of bone marrow aplasia develop suddenly, without prior dose-related marrow suppression. Some patients who developed chronic bone marrow hypoplasia after chloramphenicol treatment subsequently developed acute myeloblastic leukemia. The administration of chloramphenicol in the presence of hepatic disease frequently depresses erythropoiesis. About one-third of patients with severe renal insufficiency exhibit the same reaction.

Other Toxic and Irritative Effects. Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation may follow the oral administration of chloramphenicol. Blurring of vision and digital paresthesias may rarely occur. Tissues that have a high rate of oxygen consumption may be particularly susceptible to chloramphenicol effects on mitochondrial enzyme systems; encephalopathy and cardiomyopathy have been reported.

Neonates, especially if premature, may develop a serious illness termed gray baby syndrome if exposed to excessive doses of chloramphenicol. This syndrome usually begins 2-9 days (average of 4 days) after treatment is started. Within the first 24 hours, vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose green stools occur. The children all are severely ill by the end of the first day, and in the next 24 hours turn an ashen-gray color and become flaccid and hypothermic. A similar "gray syndrome" has been reported in adults who were accidentally overdosed with the drug. Death occurs in ~40% of patients within 2 days of initial symptoms. Those who recover usually exhibit no sequelae.

Two mechanisms apparently are responsible for chloramphenicol toxicity in neonates: (1) a developmental deficiency of glucuronyl transferase, the hepatic enzyme that metabolizes chloramphenicol, in the first 3-4 weeks of life; and (2) inadequate renal excretion of unconjugated drug. At the onset of the clinical syndrome, chloramphenicol concentrations in plasma usually exceed 100 μg/mL, although they may be as low as 75 μg/mL. Children ≤2 weeks of age should receive chloramphenicol in a daily dose no larger than 25 mg/kg of body weight; after this age, full-term infants may be given daily quantities up to 50 mg/kg. Toxic effects have not been observed in the newborns when as much as 1 g of the antibiotic has been given every 2 hours to the mothers during labor.

Drug Interactions. Chloramphenicol inhibits hepatic CYPs and thereby prolongs the half-lives of drugs that are metabolized by this system, including warfarin, dicumarol, phenytoin, chlorpropamide, antiretroviral protease inhibitors, rifabutin, and tolbutamide. Severe toxicity and death have occurred because of failure to recognize such effects. Conversely, other drugs may alter the elimination of chloramphenicol. Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens the t_1/2 of the antibiotic and may result in subtherapeutic drug concentrations.

Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin and clarithromycin and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural modifications improve acid stability and tissue penetration and broaden the spectrum of activity.

Telithromycin differs from erythromycin in that a 3-keto group replaces the α-L-cladinose of the 14-member macrolide ring, and there is a substituted carbamate at C11-C12. These modifications render ketolides less susceptible to methylase-mediated (erm) and efflux-mediated (mef or msr) mechanisms of resistance. Ketolides therefore are active against many macrolide-resistant gram-positive strains. The structural formula of telithromycin is:

Erythromycin is inactive against most aerobic enteric gram-negative bacilli. It has modest activity in vitro against other gram-negative organisms, including H. influenzae (MIC, 1-32 μg/mL) and N. meningitidis (MIC, 0.4-1.6 μg/mL), and good activity against most strains of N. gonorrhoeae (MIC, 0.12-2 μg/mL). Useful antibacterial activity also is observed against Pasteurella multocida, Borrelia spp., and Bordetella pertussis. Resistance is common for B. fragilis (the MIC ranging from 2-32 μg/mL). Macrolides are usually active against Campylobacter jejuni (MIC, 0.5-4 μg/mL). Erythromycin is active against M. pneumoniae (MIC, 0.004-0.02 μg/mL) and Legionella pneumophila (MIC, 0.01-2 μg/mL). Most strains of C. trachomatis are inhibited by 0.06-2 μg/mL of erythromycin. Some of the atypical mycobacteria, including M. scrofulaceum, are sensitive to erythromycin in vitro; M. kansasii and M. avium-intracellulare vary in sensitivity. M. fortuitum is resistant. Macrolides have no effect on viruses, yeasts, or fungi.

Clarithromycin and azithromycin have some activity against H. influenzae, with MIC breakpoints of ≤8 μg/mL and ≤4 μg/mL, respectively. However, these agents are not drugs of choice for documented H. influenzae infections because of their lesser activity compared to β-lactams or fluoroquinolones. Clarithromycin is slightly more potent than erythromycin against sensitive strains of streptococci and staphylococci, and has modest activity against H. influenzae and N. gonorrhoeae. Azithromycin generally is less active than erythromycin against gram-positive organisms and slightly more active than either erythromycin or clarithromycin against H. influenzae and Campylobacter spp. Clarithromycin and azithromycin have good activity against M. catarrhalis, Chlamydia spp., L. pneumophila, B. burgdorferi, Mycoplasma pneumoniae, and H. pylori. Azithromycin and clarithromycin have enhanced activity against M. avium-intracellulare, as well as against some protozoa (e.g., Toxoplasma gondii, Cryptosporidium, and Plasmodium spp.). Clarithromycin has good activity against Mycobacterium leprae.

Mechanism of Action. Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to 50S ribosomal subunits of sensitive microorganisms (Figure 55–3), at or very near the site that binds chloramphenicol (Figure 55–2). Erythromycin does not inhibit peptide bond formation per se but rather inhibits the translocation step wherein a newly synthesized peptidyl tRNA molecule moves from the acceptor site on the ribosome to the peptidyl donor site. Gram-positive bacteria accumulate ~100 times more erythromycin than do gram-negative bacteria. Cells are considerably more permeable to the unionized form of the drug, which probably explains the increased antimicrobial activity at alkaline pH. Ketolides and macrolides have the same ribosomal target site. The principal difference between the two is that structural modifications within ketolides neutralize the common resistance mechanisms that make macrolides ineffective (Nilius and Ma, 2002).

The MLS_B (macrolide-lincosamide-streptogramin B) phenotype is conferred by erm genes, which encode methylases that modify the macrolide binding of the ribosome. Because macrolides, lincosamides, and type B streptogramins share the same ribosomal binding site, constitutive expression of erm confers cross-resistance to all three drug classes. If resistance is due to inducible expression of erm, there is resistance to the macrolides, which are inducers of erm, but not to lincosamides and streptogramin B, which are not inducers. Cross-resistance can still occur if constitutive mutants are selected by exposure to lincosamides or streptogramin B. Efflux-mediated resistance to macrolides may not result in cross-resistance to lincosamides or streptogramin B because they are structurally dissimilar to macrolides and are not substrates of the macrolide pump.

Introduction of the 3-keto function converts a methylase-inducing macrolide into a noninducing ketolide. This moiety also prevents drug efflux, probably because it generates a less-desirable substrate. The carbamate substitution at C11-C12 enhances binding to the ribosomal target site, even when the site is methylated, by introducing an extra interaction of the ketolide with the ribosome. Inducible and constitutive methylase-producing strains of S. pneumoniae are therefore susceptible to telithromycin. However, constitutive methylase-producing strains of S. aureus and S. pyogenes are telithromycin resistant because the strength of the ketolide interaction with the fully methylated ribosomal binding site is insufficient to overcome resistance. Constitutive methylase producers can be selected from strains with the inducible erm phenotype.

Absorption, Distribution, and Excretion.

Absorption. Erythromycin base is incompletely but adequately absorbed from the upper small intestine. Because it is inactivated by gastric acid, the drug is administered as enteric-coated tablets, as capsules containing enteric-coated pellets that dissolve in the duodenum, or as an ester. Food, which increases gastric acidity, may delay absorption.

Peak serum concentrations are 0.3-0.5 μg/mL, 4 hours after oral administration of 250 mg of the base, and 0.3-1.9 μg/mL after a single dose of 500 mg. Esters of erythromycin base (e.g., stearate, estolate, and ethylsuccinate) have improved acid stability, and their absorption is less altered by food. A single oral 250-mg dose of erythromycin estolate produces peak serum concentrations of ~1.5 μg/mL after 2 hours, and a 500-mg dose produces peak concentrations of 4 μg/mL. Peak serum concentrations of erythromycin ethylsuccinate are 1.5 μg/mL (0.5 μg/mL of base) 1-2 hours after administration of a 500-mg dose. These peak values include the inactive ester and the free base, the latter of which comprises 20-35% of the total. The concentration of microbiologically active erythromycin base in serum therefore is similar for the various preparations. Higher concentrations of erythromycin can be achieved by intravenous administration. Values are ~10 μg/mL 1 hour after intravenous administration of 500-1000 mg of erythromycin lactobionate.

Clarithromycin is absorbed rapidly from the GI tract after oral administration, but first-pass metabolism reduces its bioavailability to 50-55%. Peak concentrations occur ~2 hours after drug administration. Clarithromycin may be given with or without food, but the extended-release form, typically given once daily as a 1-g dose, should be administered with food to improve bioavailability. Steady-state peak concentrations in plasma of 2-3 μg/mL are achieved after 2 hours with a regimen of 500 mg every 12 hours, or after 2-4 hours with two 500-mg extended-release tablets given once daily.

Azithromycin administered orally is absorbed rapidly and distributes widely throughout the body, except to the brain and CSF. Concomitant administration of aluminum and magnesium hydroxide antacids decreases the peak serum drug concentrations but not overall bioavailability. Azithromycin should not be administered with food. A 500-mg loading dose will produce a peak plasma drug concentration of ~0.4 μg/mL. When this loading dose is followed by 250 mg once daily for 4 days, the steady-state peak drug concentration is 0.24 μg/mL. Azithromycin also can be administered intravenously, producing plasma concentrations of 3-4 μg/mL after a 1-hour infusion of 500 mg.

Telithromycin is formulated as a 400-mg tablet for oral administration. There is no parenteral form. It is well absorbed with ~60% bioavailability. Peak serum concentrations, averaging 2 μg/mL following a single 800-mg oral dose, are achieved within 30 minutes to 4 hours.

Distribution. Erythromycin diffuses readily into intracellular fluids, achieving antibacterial activity in essentially all sites except the brain and CSF. Erythromycin penetrates into prostatic fluid, achieving concentrations ~40% of those in plasma. Concentrations in middle ear exudate reach only 50% of serum concentrations and thus may be inadequate for the treatment of otitis media caused by H. influenzae. Protein binding is ~70-80% for erythromycin base and even higher, 96%, for the estolate. Erythromycin traverses the placenta, and drug concentrations in fetal plasma are ~5-20% of those in the maternal circulation. Concentrations in breast milk are 50% of those in serum.

Clarithromycin and its active metabolite, 14-hydroxyclarithromycin, distribute widely and achieve high intracellular concentrations throughout the body. Tissue concentrations generally exceed serum concentrations. Concentrations in middle-ear fluid are 50% higher than simultaneous serum concentrations for clarithromycin and the active metabolite. Protein binding of clarithromycin ranges from 40% to 70% and is concentration dependent.

Azithromycin's unique pharmacokinetic properties include extensive tissue distribution and high drug concentrations within cells (including phagocytes), resulting in much greater concentrations of drugs in tissue or secretions compared to simultaneous serum concentrations. Tissue fibroblasts act as the natural reservoir for the drug in vivo. Protein binding is 50% at very low plasma concentrations and less at higher concentrations.

Telithromycin is 60-70% bound by serum protein, principally albumin. It penetrates well into most tissues, exceeding plasma concentrations by ~2-fold to ≥10-fold. Telithromycin is concentrated into macrophages and white blood cells, where concentrations of 40 μg/mL (500 times the simultaneous plasma concentration) are maintained 24 hours after dosing.

Elimination. Only 2-5% of orally administered erythromycin is excreted in active form in the urine; this value is from 12-15% after intravenous infusion. The antibiotic is concentrated in the liver and excreted in the bile, which may contain as much as 250 μg/mL when serum concentrations are very high. The serum elimination t_1/2 of erythromycin is ~1.6 hours. Although the t_1/2 may be prolonged in patients with anuria, dosage reduction is not routinely recommended in renal failure patients. The drug is not removed significantly by either peritoneal dialysis or hemodialysis.

Clarithromycin is eliminated by renal and nonrenal mechanisms. It is metabolized in the liver to several metabolites; the active 14-hydroxy metabolite is the most significant. Primary metabolic pathways are oxidative N-demethylation and hydroxylation at the 14 position. The elimination half-lives are 3-7 hours for clarithromycin and 5-9 hours for 14-hydroxyclarithromycin. Metabolism is saturable, resulting in nonlinear pharmacokinetics with higher dosages; longer half-lives are observed after larger doses. The amount of clarithromycin excreted unchanged in the urine ranges from 20% to 40%, depending on the dose administered and the formulation (tablet versus oral suspension). An additional 10-15% of a dose is excreted in the urine as 14-hydroxyclarithromycin. Although the pharmacokinetics of clarithromycin are altered in patients with either hepatic or renal dysfunction, dose adjustment is not necessary unless the creatinine clearance is <30 mL/minute.

Azithromycin undergoes some hepatic metabolism to inactive metabolites, but biliary excretion is the major route of elimination. Only 12% of drug is excreted unchanged in the urine. The elimination t_1/2, 40-68 hours, is prolonged because of extensive tissue sequestration and binding.

With a t_1/2 of 9.8 hours, telithromycin can be given once daily. The drug is cleared primarily by hepatic metabolism, 50% by CYP3A4 and 50% by CYP-independent metabolism. No adjustment of the dose is required for hepatic failure or mild-to-moderate renal failure. No dose has been established for patients in whom creatinine clearance is <30 mL/minute, although a reduction in dosage probably is advisable (Shi et al., 2004).

Respiratory Tract Infections. Macrolides and ketolides are suitable drugs for the treatment of a number of respiratory tract infections due to their activity against Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens (Mycoplasma, Chlamydophilia, Legionella). Azithromycin and clarithromycin are suitable choices for treatment of mild to moderate community-acquired pneumonia among ambulatory patients. In hospitalized patients, a macrolide is commonly added to a cephalosporin for coverage of atypical respiratory pathogens. Macrolides, fluoroquinolones, and tetracyclines are drugs of choice for treatment of pneumonia caused by Chlamydia pneumoniae or Mycoplasma pneumoniae. Erythromycin has been considered as the drug of choice for treatment of pneumonia caused by L. pneumophila, L. micdadei, or other Legionella spp. Because of excellent in vitro activity, superior tissue concentration, the ease of administration as a single daily dose, and better tolerability compared to erythromycin, azithromycin (or a fluoroquinolone) has supplanted erythromycin as the first-line agent for treatment of legionellosis (Garey and Amsden, 1999). The recommended dose is 500 mg daily, intravenously or orally, for a total of 10-14 days.

Macrolides are also appropriate alternative agents for the treatment of acute exacerbations of chronic bronchitis, acute otitis media, acute streptococcal pharyngitis, and acute bacterial sinusitis. Azithromycin or clarithromycin are generally preferred to erythromycin for these indications due to their broader spectrum and superior tolerability.

Telithromycin has shown to be effective in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis, and has a potential advantage over macrolides in regions where macrolide-resistant strains are common. However, due to a number of cases of severe hepatotoxicity due to telithromycin, telithromycin's U.S. FDA approval for treatment of acute exacerbations of chronic bronchitis and sinusitis have been rescinded, leaving only its indication for community-acquired pneumonia. Because of the substantial risk of serious hepatotoxicity, telithromycin should be used only in circumstances where it provides a substantial advantage over less toxic therapies.

Skin and Soft-Tissue Infections. Macrolides are alternatives for treatment of erysipelas and cellulitis among patients who have a serious allergy to penicillin. Unfortunately, macrolide-resistant strains of staphylococci and streptococci are increasingly encountered. Erythromycin has been an alternative agent for the treatment of relatively minor skin and soft-tissue infections caused by either penicillin-sensitive or penicillin-resistant S. aureus. However, many strains of S. aureus are resistant to macrolides, and they no longer can be relied on unless in vitro susceptibility has been documented.

Chlamydial Infections. Chlamydial infections can be treated effectively with any of the macrolides. A single 1-g dose of azithromycin is recommended for patients with uncomplicated urethral, endocervical, rectal, or epididymal infections because of the ease of compliance. During pregnancy, erythromycin base, 500 mg four times daily for 7 days, is recommended as first-line therapy for chlamydial urogenital infections. Azithromycin, 1 g orally as a single dose, is a suitable alternative. Erythromycin base is preferred for chlamydial pneumonia of infancy and ophthalmia neonatorum (50 mg/kg per day in four divided doses for 10-14 days). Azithromycin, 1 g/week for 3 weeks, may be effective for lymphogranuloma venereum.

Diphtheria. Erythromycin, 250 mg four times daily for 7 days, is very effective for acute infections or for eradicating the carrier state. The other macrolides also are likely to be effective; because clinical experience with them is lacking, they are not FDA-approved for this indication. The presence of an antibiotic does not alter the course of an acute infection with the diphtheria bacillus or the risk of complications. Antitoxin is indicated in the treatment of acute infection.

Pertussis. Erythromycin is the drug of choice for treating persons with B. pertussis disease and for postexposure prophylaxis of household members and close contacts. A 7-day regimen of erythromycin estolate (40 mg/kg per day; maximum: 1 g/day; not available in U.S) is as effective as the 14-day regimens traditionally recommended (Halperin et al., 1997). Clarithromycin and azithromycin also are effective (Bace et al., 1999). If administered early in the course of whooping cough, erythromycin may shorten the duration of illness; it has little influence on the disease once the paroxysmal stage is reached, although it may eliminate the microorganisms from the nasopharynx. Nasopharyngeal cultures should be obtained from people with pertussis who do not improve with erythromycin therapy because resistance has been reported.

Campylobacter Infections. The treatment of gastroenteritis caused by C. jejuni with erythromycin (250-500 mg orally four times a day for 7 days) hastens eradication of the microorganism from the stools and reduces the duration of symptoms. Availability of fluoroquinolones, which are highly active against Campylobacter species and other enteric pathogens, largely has replaced the use of erythromycin for this disease in adults. Erythromycin remains useful for treatment of Campylobacter gastroenteritis in children.

Helicobacter pylori Infection. Clarithromycin, 500 mg, in combination with omeprazole, 20 mg, and amoxicillin, 1 g (prevpac), each administered twice daily for 10-14 days, is effective for treatment of peptic ulcer disease caused by H. pylori (Peterson et al., 2000). Numerous other regimens, some effective as 7-day treatments, have been studied and also are effective. The more effective regimens generally include three agents, one of which usually is clarithromycin (Chapter 45).

Mycobacterial Infections. Clarithromycin or azithromycin is recommended as first-line therapy for prophylaxis and treatment of disseminated infection caused by M. avium-intracellulare in AIDS patients and for treatment of pulmonary disease in patients not infected with HIV (Kovacs and Masur, 2000). Azithromycin (1.2 g once weekly) or clarithromycin (500 mg twice daily) is recommended for primary prevention for AIDS patients with <50 CD4 cells/mm³. Single-agent therapy should not be used for treatment of active disease or for secondary prevention in AIDS patients. Clarithromycin (500 mg twice daily) plus ethambutol (15 mg/kg once daily) with or without rifabutin is an effective combination regimen. Azithromycin (500 mg once daily) may be used instead of clarithromycin, but clarithromycin appears to be slightly more efficacious (Ward et al., 1998). Clarithromycin also has been used with minocycline for the treatment of Mycobacterium leprae in lepromatous leprosy.

Prophylactic Uses. Penicillin is the drug of choice for the prophylaxis of recurrences of rheumatic fever. Erythromycin is an effective alternative for individuals who are allergic to penicillin. Clarithromycin or azithromycin (or clindamycin) are recommended alternatives for the prevention of bacterial endocarditis in patients undergoing dental procedures who are at high risk for endocarditis (Wilson et al., 2007).

Untoward Effects.

Hepatoxicity. Cholestatic hepatitis is the most striking side effect. It is caused primarily by erythromycin estolate and rarely by the ethylsuccinate or the stearate. The illness starts after 10-20 days of treatment and is characterized initially by nausea, vomiting, and abdominal cramps. The pain often mimics that of acute cholecystitis. These symptoms are followed shortly thereafter by jaundice, which may be accompanied by fever, leukocytosis, eosinophilia, and elevated transaminases in plasma. Biopsy of the liver reveals cholestasis, periportal infiltration by neutrophils, lymphocytes, and eosinophils, and occasionally, necrosis of neighboring parenchymal cells. Findings usually resolve within a few days after cessation of drug therapy and rarely are prolonged. The syndrome may represent a hypersensitivity reaction to the estolate ester.

Hepatotoxicity has also been observed with clarithromycin and azithromycin, although at a lower rate than with erythromycin. After its regulatory approval and widespread use, a number of postmarketing reports of severe telithromycin-induced hepatotoxicity emerged. These cases tended to have a short latency between drug initiation and manifestation of hepatotoxicity, with some leading to death or liver transplantation (Brinker et al., 2009). Because of this toxicity, telithromycin should only be used in circumstances where it represents a clear advantage over alternative agents.

GI Toxicity. Oral administration of erythromycin, especially of large doses, frequently is accompanied by epigastric distress, which may be quite severe. Intravenous administration of erythromycin may cause similar symptoms, with abdominal cramps, nausea, vomiting, and diarrhea. Erythromycin stimulates GI motility by acting on motilin receptors. Because of this property, erythromycin is used postoperatively to promote peristalsis; it has been exploited to speed gastric emptying in patients with gastroparesis (Chapter 46). The GI symptoms are dose related and occur more commonly in children and young adults; they may be reduced by prolonging the infusion time to 1 hour or by pretreatment with glycopyrrolate (Bowler et al., 1992). Intravenous infusion of 1-g doses, even when dissolved in a large volume, often is followed by thrombophlebitis. This can be minimized by slow rates of infusion. Clarithromycin, azithromycin, and telithromycin also may cause GI distress, but typically to a lesser degree than that seen with erythromycin.

Cardiac toxicity. Erythromycin, clarithromycin, and telithromycin have been reported to cause cardiac arrhythmias, including QT prolongation with ventricular tachycardia. Most patients have had underlying risk factors, such as prolonged QT syndrome, uncorrected hypokalemia or hypomagnesemia, profound bradycardia, or in patients receiving certain antiarrhythmics (e.g., quinidine, procainamide, amiodarone) or other agents that prolong QTc (e.g., cisapride, pimozide).

Other Toxic and Irritative Effects. Among the allergic reactions observed are fever, eosinophilia, and skin eruptions, which may occur alone or in combination; each disappears shortly after therapy is stopped. Transient auditory impairment is a potential complication of treatment with erythromycin; it has been observed to follow intravenous administration of large doses of the gluceptate or lactobionate (4 g per day) or oral ingestion of large doses of the estolate. Visual disturbances due to slowed accommodation have been reported to occur in ~1% of treatment courses with telithromycin, and they include blurred vision, difficulty focusing, and diplopia. Telithromycin is contraindicated in patients with myasthenia gravis due to reports of exacerbation of neurological symptoms by the antibiotic in these patients. Loss of consciousness and visual disturbances are associated with telithromycin.

Drug Interactions. Erythromycin, clarithromycin, and telithromycin inhibit CYP3A4 and are associated with clinically significant drug interactions (Periti et al., 1992). Erythromycin potentiates the effects of carbamazepine, corticosteroids, cyclosporine, digoxin, ergot alkaloids, theophylline, triazolam, valproate, and warfarin, probably by interfering with CYP-mediated metabolism of these drugs (Chapter 6). Clarithromycin, which is structurally related to erythromycin, has a similar drug interaction profile. Telithromycin is both a substrate and a strong inhibitor of CYP3A4. Co-administration of rifampin, a potent inducer of CYP, decreases the serum concentrations of telithromycin by 80%. CYP3A4 inhibitors (e.g., itraconazole) increase peak serum concentrations of telithromycin. Azithromycin, which differs from erythromycin and clarithromycin because of its 15-membered lactone ring structure, and dirithromycin, which is a longer-acting 14-membered lactone ring analog of erythromycin, appear to be free of these drug interactions. Caution is advised, nevertheless, when using azithromycin in conjunction with drugs known to interact with erythromycin.

Antimicrobial Activity. Bacterial strains are susceptible to clindamycin at MICs of ≤0.5 μg/mL. Clindamycin generally is similar to erythromycin in its in vitro activity against susceptible strains of pneumococci, S. pyogenes, and viridans streptococci (Table 55–2). Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin, but methicillin-resistant strains of S. aureus and coagulase-negative staphylococci frequently are resistant.

Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria, especially B. fragilis; some strains are inhibited by <0.1 μg/mL, and most are inhibited by 2 μg/mL. The MICs for other anaerobes are as follows: Bacteroides melaninogenicus, 0.1 to 1 μg/mL; Fusobacterium, <0.5 μg/mL (although most strains of Fusobacterium varium are resistant); Peptostreptococcus, <0.1-0.5 μg/mL; Peptococcus, 1-100 μg/mL (with 10% of strains resistant); and C. perfringens, <0.1-8 μg/mL. From 10-20% of clostridial species other than C. perfringens are resistant. Resistance to clindamycin in Bacteroides spp. increasingly is encountered (Hedberg and Nord, 2003). Strains of Actinomyces israelii and Nocardia asteroides are sensitive. Essentially all aerobic gram-negative bacilli are resistant.

With regard to atypical organisms and parasites, M. pneumoniae is resistant. Chlamydia spp. are variably sensitive, although the clinical relevance is not established. Clindamycin plus primaquine and clindamycin plus pyrimethamine are second-line regimens for Pneumocystis jiroveci pneumonia and T. gondii encephalitis, respectively. Clindamycin has been used for treatment of babesiosis.

Mechanism of Action. Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Although clindamycin, erythromycin, and chloramphenicol are not structurally related, they act at sites in close proximity (Figures 55–2 and 55–3), and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others. There are no clinical indications for the concurrent use of these antibiotics.

Resistance to Clindamycin. Macrolide resistance due to ribosomal methylation by erm-encoded enzymes also may produce resistance to clindamycin. Because clindamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced constitutively. However, strains with inducible resistance may develop constitutive production of the methylase during therapy. Thus, many clinicians avoid use of clindamycin in the treatment of deep-seated infections due to organisms displaying an inducible resistance phenotype. Detection of this phenotype can be accomplished by approximating erythromycin and clindamycin on an agar plate with a lawn of the organism; a blunting of the zone of inhibition between clindamycin and erythromycin suggests inducible resistance (this is known as the "D-test") (Lewis & Jorgensen, 2005). Clindamycin is not a substrate for macrolide efflux pumps; thus strains that are resistant to macrolides by this mechanism are susceptible to clindamycin. These strains would not display a blunting of inhibition on a D-test, and clindamycin use would be appropriate. Altered metabolism occasionally causes clindamycin resistance (Bozdogan et al., 1999).

Absorption, Distribution, and Excretion

Absorption. Clindamycin is nearly completely absorbed following oral administration. Peak plasma concentrations of 2-3 μg/mL are attained within 1 hour after the ingestion of 150 mg. The presence of food in the stomach does not reduce absorption significantly. The t_1/2 of the antibiotic is ~2.9 hours, and modest accumulation of drug is thus expected if it is given every 6 hours.

Clindamycin palmitate, an oral preparation for pediatric use, is an inactive prodrug that is hydrolyzed rapidly in vivo. Its rate and extent of absorption are similar to those of clindamycin. After several oral doses at 6-hour intervals, children attain plasma concentrations of 2-4 μg/mL with the administration of 8-16 μg/kg.

The phosphate ester of clindamycin, which is given parenterally, also is rapidly hydrolyzed in vivo to the active parent compound. After intramuscular injection, peak concentrations in plasma are not attained until 3 hours in adults and 1 hour in children; these values approximate 6 μg/mL after a 300-mg dose and 9 μg/mL after a 600-mg dose in adults.

Distribution. Clindamycin is widely distributed in many fluids and tissues, including bone. Significant concentrations are not attained in CSF, even when the meninges are inflamed. Concentrations sufficient to treat cerebral toxoplasmosis are achievable (Gatti et al., 1998). The drug readily crosses the placental barrier. Ninety percent or more of clindamycin is bound to plasma proteins. Clindamycin accumulates in polymorphonuclear leukocytes, alveolar macrophages, and in abscesses.

Excretion. Only ~10% of the clindamycin administered is excreted unaltered in the urine, and small quantities are found in the feces. However, antimicrobial activity persists in feces for ≥5 days after parenteral therapy with clindamycin is stopped; growth of clindamycin-sensitive microorganisms in colonic contents may be suppressed for up to 2 weeks.

Clindamycin is inactivated by metabolism to N-demethylclindamycin and clindamycin sulfoxide, which are excreted in the urine and bile. Accumulation of clindamycin can occur in patients with severe hepatic failure, and dosage adjustments thus may be required.

Therapeutic Uses and Dosage. The oral dose of clindamycin (clindamycin hydrochloride; cleocin, others) for adults is 150-300 mg every 6 hours; for severe infections, it is 300-600 mg every 6 hours. Children should receive 8-12 mg/kg per day of clindamycin palmitate hydrochloride (cleocin pediatric) in three or four divided doses (some physicians recommend 10-30 mg/kg per day in six divided doses) or for severe infections, 13-25 mg/kg per day. However, children weighing ≤10 kg should receive ¹/₂ teaspoonful of clindamycin palmitate hydrochloride (37.5 mg) every 8 hours as a minimal dose. Clindamycin phosphate (cleocin phosphate, others) is available for intramuscular or intravenous use. For serious infections, intravenous or intramuscular administration is recommended in dosages of 1200-2400 mg per day, divided into three or four equal doses for adults. Daily doses as high as 4.8 g have been given intravenously to adults. Children should receive 15-40 mg/kg per day in three or four divided doses; in severe infections, a minimal daily dose of 300 mg is recommended, regardless of body weight.

Skin and Soft-Tissue Infections. Because of clindamycin's good activity against aerobic and anaerobic gram-positive cocci and good oral bioavailability, it is an alternative agent for the treatment of skin and soft-tissue infections, especially in patients with β-lactam allergies. However, the high incidence of diarrhea and the occurrence of pseudomembranous colitis should limit its use to infections where it represents a clear therapeutic advantage. Clindamycin has been employed in the treatment of necrotizing skin and soft-tissue infections based on its potential to reduce toxin expression.

Respiratory Tract Infections. On the basis of one clinical trial which found that clindamycin (600 mg intravenously every 8 hours) was superior to penicillin (1 million units intravenously every 4 hours; Levison et al., 1983), clindamycin has replaced penicillin as the drug of choice for treatment of lung abscess and anaerobic lung and pleural space infections. Clindamycin (600 mg intravenously every 8 hours, or 300-450 mg orally every 6 hours for less severe disease) in combination with primaquine (15 mg of base once daily) is useful for the treatment of mild to moderate cases of P. jiroveci pneumonia in AIDS patients.

Other Infections. Clindamycin (600-1200 mg given intravenously every 6 hours) in combination with pyrimethamine (a 200-mg loading dose followed by 75 mg orally each day) and leucovorin (folinic acid, 10 mg/day) is effective for acute treatment of encephalitis caused by T. gondii in patients with AIDS. Clindamycin also is available as a topical solution, gel, or lotion (cleocin t, others) and as a vaginal cream (cleocin, others). It is effective topically (or orally) for acne vulgaris and bacterial vaginosis. Clindamycin is not predictably useful for the treatment of bacterial brain abscesses because penetration into the CSF is poor; metronidazole, in combination with penicillin or a third-generation cephalosporin, is preferred.

Untoward Effects.

Gastrointestinal Effects. The reported incidence of diarrhea associated with the administration of clindamycin ranges from 2% to 20%. A number of patients (variously reported as 0.01-10%) have developed pseudomembranous colitis caused by the toxin from the organism C. difficile. This colitis is characterized by watery diarrhea, fever, and elevated peripheral white blood cell counts. Proctoscopic examination reveals white to yellow plaques on the mucosa of the colon. This syndrome may be lethal. Discontinuation of the drug, combined with administration of metronidazole or oral vancomycin usually is curative, but relapses occur in up to 20% of cases. Agents that inhibit peristalsis, such as opioids, may prolong and worsen the condition.

Other Toxic and Irritative Effects. Skin rashes occur in ~10% of patients treated with clindamycin and may be more common in patients with HIV infection. Other reactions, which are uncommon, include exudative erythema multiforme (Stevens-Johnson syndrome), reversible elevation of aspartate aminotransferase and alanine aminotransferase, granulocytopenia, thrombocytopenia, and anaphylactic reactions. Local thrombophlebitis may follow intravenous administration of the drug. Clindamycin can inhibit neuromuscular transmission and may potentiate the effect of a neuromuscular blocking agent administered concurrently.

Antimicrobial Activity. Quinupristin/dalfopristin is active against gram-positive cocci, including S. pneumoniae, beta- and alpha-hemolytic strains of streptococci, E. faecium (but not E. faecalis), and coagulase-positive and coagulase-negative strains of staphylococci (Table 55–2). Strains are considered sensitive if they are inhibited by concentrations of ≤1 μg/mL. The combination is largely inactive against gram-negative organisms, although Moraxella catarrhalis and Neisseria spp. are susceptible. It also is active against organisms responsible for atypical pneumonia, M. pneumoniae, Legionella spp., and Chlamydia pneumoniae. The combination is bactericidal against streptococci and many strains of staphylococci but bacteriostatic against E. faecium.

Mechanism of Action. Quinupristin and dalfopristin are protein synthesis inhibitors that bind the 50S ribosomal subunit. Quinupristin binds at the same site as macrolides and has a similar effect, with inhibition of polypeptide elongation and early termination of protein synthesis. Dalfopristin binds at a site nearby, resulting in a conformational change in the 50S ribosome, synergistically enhancing the binding of quinupristin at its target site. Dalfopristin directly interferes with polypeptide-chain formation. In many bacterial species, the net result of the cooperative and synergistic binding of these two molecules to the ribosome is bactericidal activity.

Resistance to Streptogramins. Resistance to quinupristin is mediated by MLS type B resistance determinants (e.g., ermA and ermC in staphylococci and ermB in enterococci), encoding a ribosomal methylase that prevents binding of drug to its target; or vgb or vgbB, which encode lactonases that inactivate type B streptogramins (Allignet et al., 1998; Bozdogan and Leclercq, 1999). Resistance to dalfopristin is mediated by vat, vatB, vatC, vatD, and satA, which encode acetyltransferases that inactivate type A streptogramins (Soltani et al., 2000); or staphylococcal genes vga and vgaB, which encode ATP-binding efflux proteins that pump type A streptogramins out of the cell (Bozdogan and Leclercq, 1999). These resistance determinants are located on plasmids that may be transferable by conjugative mobilization. Resistance to quinupristin/dalfopristin always is associated with a resistance gene for type A streptogramins. Genes encoding resistance to type B streptogramins also may be present but are not sufficient by themselves to produce resistance. Methylase-encoding erm genes, however, can render the combination bacteriostatic instead of bactericidal, making it ineffective in certain infections in which bactericidal activity is necessary for cure, such as endocarditis.

Absorption, Distribution, and Excretion. The combination of quinupristin/dalfopristin is administered only by intravenous infusion over at least 1 hour. It is incompatible with saline and heparin and should be dissolved in 5% dextrose in water. Steady-state peak serum concentrations in healthy male volunteers are ~3 μg/mL of quinupristin and 7 μg/mL of dalfopristin with a 7.5-mg/kg dose administered every 8 hours. The t_1/2 is 0.85 hour for quinupristin and 0.7 hour for dalfopristin. The volume of distribution is 0.87 L/kg for quinupristin and 0.71 L/kg for dalfopristin. Hepatic metabolism by conjugation is the principal means of clearance for both compounds, with 80% of an administered dose eliminated by biliary excretion. Renal elimination of active compound accounts for most of the remainder. No dosage adjustment is necessary for renal insufficiency. Pharmacokinetics are not significantly altered by peritoneal dialysis or hemodialysis. The area under the plasma concentration curve of active component and its metabolites is increased by 180% for quinupristin and 50% for dalfopristin by hepatic insufficiency. No adjustment is recommended unless the patient is unable to tolerate the drug, in which case the dosing frequency should be reduced from 8 to 12 hours.

Therapeutic Uses and Dosage. Quinupristin/dalfopristin is approved in the U.S. for treatment of infections caused by vancomycin-resistant strains of E. faecium and complicated skin and skin-structure infections caused by methicillin-susceptible strains of S. aureus or S. pyogenes (Nichols et al., 1999). In Europe it also is approved for treatment of nosocomial pneumonia and infections caused by methicillin-resistant strains of S. aureus (Fagon et al., 2000). In open-label, nonrandomized studies, clinical and microbiological cure rates for a variety of infections caused by vancomycin-resistant E. faecium were ~70% with quinupristin/dalfopristin at a dose of 7.5 mg/kg every 8-12 hours (Moellering et al., 1999). Quinupristin/dalfopristin should be reserved for treatment of serious infections caused by multiple-drug-resistant gram-positive organisms such as vancomycin-resistant E. faecium.

Untoward Effects. The most common side effects are infusion-related events, such as pain and phlebitis at the infusion site and arthralgias and myalgias. Phlebitis and pain can be minimized by infusion of drug through a central venous catheter. Arthralgias and myalgias, which are more likely to be a problem in patients with hepatic insufficiency and may be due to accumulation of metabolites, are managed by reducing the infusion frequency to every 12 hours.

Drug Interactions. Quinupristin/dalfopristin inhibits CYP3A4. The concomitant administration of other CYP3A4 substrates (Chapter 6) with quinupristin/dalfopristin may raise blood pressure and/or result in significant toxicity. Examples include antihistamines (e.g., azelastine and clemastine); some anticonvulsants (e.g., fosphenytoin and felbamate), macrolide antibiotics; some fluoroquinolones (e.g., moxifloxacin) and ketoconazole; some antimalarials (e.g., chloroquine, mefloquine, and quinine); some antidepressants (e.g., fluoxetine, imipramine, venlafaxine); some antipsychotics (e.g., haloperidol, risperidone, and quetiapine); tacrolimus; and doxepin. Appropriate caution and monitoring are recommended for drugs in which the toxic therapeutic window is narrow or for drugs that prolong the QTc interval.

Antimicrobial Activity. Linezolid is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as Corynebacterium spp. and Listeria monocytogenes (Table 55–2). It has poor activity against most gram-negative aerobic or anaerobic bacteria. It is bacteriostatic against enterococci and staphylococci and bactericidal against streptococci. Breakpoints for susceptibility are ≤4 μg/mL for staphylococci and ≤2 μg/mL for enterococci and streptococci. Mycobacterium tuberculosis is moderately susceptible, with MICs of 2 μg/mL.

Mechanism of Action and Resistance to Oxazolidinones. Linezolid inhibits protein synthesis by binding to the P site of the 50S ribosomal subunit and preventing formation of the larger ribosomal-fMet-tRNA complex that initiates protein synthesis. Because of its unique mechanism of action, linezolid is active against strains that are resistant to multiple other agents, including penicillin-resistant strains of S. pneumoniae; methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant strains of staphylococci; and vancomycin-resistant strains of enterococci. Resistance in enterococci and staphylococci is due to point mutations of the 23S rRNA (Wilson et al., 2003). Because multiple copies of 23S rRNA genes are present in bacteria, resistance generally requires mutations in two or more copies.

Absorption, Distribution, and Excretion. Linezolid is well absorbed after oral administration and may be administered without regard to food. With oral bioavailability approaching 100%, dosing for oral and intravenous preparations is the same. Peak serum concentrations average 13 μg/mL 1-2 hours after a single 600-mg dose in adults and ~20 μg/mL at steady state with dosing every 12 hours. The t_1/2 is ~4-6 hours. Linezolid is 30% protein-bound and distributes widely to well-perfused tissues, with a 0.6-0.7 L/kg volume of distribution.

Linezolid is broken down by nonenzymatic oxidation to aminoethoxyacetic acid and hydroxyethyl glycine derivatives. Approximately 80% of the dose of linezolid appears in the urine, 30% as active compound and 50% as the two primary oxidation products. Ten percent of the administered dose appears as oxidation products in feces. Although serum concentrations and t_1/2 of the parent compound are not appreciably altered by renal insufficiency, oxidation products accumulate in renal insufficiency, with half-lives increasing by ~50-100%. The clinical significance of this is unknown, and no dose adjustment in renal insufficiency is currently recommended. Linezolid and its breakdown products are eliminated by dialysis; therefore the drug should be administered after hemodialysis. One case report noted sustained therapeutic concentrations of linezolid in peritoneal dialysis fluid with oral administration of 600 mg of linezolid twice daily (DePestel et al., 2003).

Therapeutic Uses and Dosage. Linezolid is FDA approved for treatment of infections caused by vancomycin-resistant E. faecium; nosocomial pneumonia caused by methicillin-susceptible and resistant strains of S. aureus; community-acquired pneumonia caused by penicillin-susceptible strains of S. pneumoniae; complicated skin and skin structure infections caused by streptococci and methicillin-susceptible and -resistant strains of S. aureus; and uncomplicated skin and skin-structure infections (Clemett and Markham, 2000). Linezolid is bacteriostatic for staphylococci and enterococci; it should not be first-line therapy for treatment of suspected endocarditis, although there are reports of cure of endocarditis with linezolid in salvage situations (Falagas et al., 2006).

Infections Due to Vancomycin-resistant E. faecium. In noncomparative studies, linezolid (600 mg twice daily) has had clinical and microbiological cure rates in the range of 85-90% in treatment of a variety of infections (soft tissue, urinary tract, and bacteremia) caused by vancomycin-resistant E. faecium.

Skin and Soft-Tissue Infections. Efficacy of linezolid was similar to that of either oxacillin or vancomycin for complicated and uncomplicated skin and skin-structure infections, most microbiologically documented cases are caused by S. aureus. Linezolid, 600 mg twice daily (with or without aztreonam), was as effective as ampicillin/ sulbactam (with or without vancomycin or aztreonam) for the management of diabetic foot infections. A 400-mg twice-daily dosage regimen is recommended only for treatment of uncomplicated skin and skin-structure infections.

Respiratory Tract Infections. In randomized, comparative studies, cure rates with linezolid (~60%) were similar to those with vancomycin for nosocomial pneumonia caused by methicillin-resistant or methicillin-susceptible S. aureus (Rubinstein et al., 2001; Wunderink et al., 2003a). A post hoc analysis suggested that linezolid may be superior to vancomycin for nosocomial pneumonia caused by methicillin-resistant S. aureus, but this needs to be confirmed in a prospective randomized trial (Wunderink et al., 2003b). Linezolid also may be an effective alternative for patients with MRSA infections who are failing vancomycin therapy or whose isolates have reduced susceptibility to vancomycin (Howden et al., 2004).

Linezolid should be reserved as an alternative agent for treatment of infections caused by multiple-drug-resistant strains. It should not be used when other agents are likely to be effective (e.g., community-acquired pneumonia, even though it has the indication). Indiscriminant use and overuse will hasten selection of resistant strains and the eventual loss of this valuable newer agent.

Untoward Effects

Hematological Toxicity. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been reported in patients receiving linezolid. Thrombocytopenia or a significant reduction in platelet count has been associated with linezolid in 2.4% of treated patients, and its occurrence is related to duration of therapy. Platelet counts should be monitored in patients with risk of bleeding, preexisting thrombocytopenia, or intrinsic or acquired disorders of platelet function (including those potentially caused by concomitant medication) and in patients receiving courses of therapy lasting beyond 2 weeks.

Other Toxic and Irritative Effects. The drug seems to be well tolerated, with generally minor side effects (e.g., GI complaints, headache, rash). Patients receiving long-term (e.g., >8 weeks) treatment with linezolid have developed peripheral neuropathy, optic neuritis, and lactic acidosis (Narita et al., 2007). It is believed that these toxicities may originate from effects of linezolid on the mitochondria. Because these effects have not always been reversible, linezolid should be generally not be used for long-term therapy if there are alternative agents.

Drug Interactions. Linezolid is a weak nonspecific inhibitor of monoamine oxidase. Patients receiving concomitant therapy with an adrenergic or serotonergic agent (including selective serotonin reuptake inhibitors [SSRIs]) or consuming >100 mg of tyramine a day may experience serotonin syndrome, characterized by palpitations, headache, or hypertensive crisis. Co-administration of these agents is best avoided if possible. However, in patients receiving SSRIs who acutely require linezolid therapy for short-term (10-14 days) treatment, co-administration with careful monitoring is reasonable because SSRIs generally require tapering to avoid discontinuation syndrome. Linezolid is neither a substrate nor an inhibitor of CYPs.

Antimicrobial Activity, Mechanism of Action, and Resistance to Spectinomycin. Spectinomycin is active against a number of gram-negative bacterial species, but it is inferior to other drugs to which such microorganisms are susceptible. Its only therapeutic use is in the treatment of gonorrhea caused by strains resistant to first-line drugs or if there are contraindications to the use of these drugs. Spectinomycin selectively inhibits protein synthesis in gram-negative bacteria. The antibiotic binds to and acts on the 30S ribosomal subunit. Its action is similar to that of the aminoglycosides, but spectinomycin is not bactericidal and does not cause misreading of messenger RNA. Bacterial resistance may be mediated by mutations in the 16S ribosomal RNA or by modification of the drug by adenylyltransferase (Clark et al., 1999).

Absorption, Distribution, and Excretion. Spectinomycin is rapidly absorbed after intramuscular injection. A single dose of 2 g produces peak serum concentrations of 100 μg/mL at 1 hour. Eight hours after injection, the concentration is ~15 μg/mL. The drug is not significantly bound to plasma protein, and all of an administered dose is recovered in the urine within 48 hours.

Therapeutic Uses and Dosage. The Centers for Disease Control and Prevention recommends ceftriaxone or cefixime for the treatment of uncomplicated gonococcal infection (Workowski and Berman, 2006). Fluoroquinolones are no longer recommended because of increasing resistance. Spectinomycin is recommended as an alternative regimen in patients who are intolerant or allergic to β-lactam antibiotics; however, the drug is not currently available in the U.S. Spectinomycin also is useful in pregnancy when patients are intolerant to β-lactams. The recommended dose for men and women is a single deep intramuscular injection of 2 g. One of the disadvantages of this regimen is that spectinomycin has no effect on incubating or established syphilis, and it is not active against Chlamydia spp. It also is less effective for pharyngeal infections, and follow-up cultures to document cure should be obtained.

Untoward Effects. Spectinomycin, when given as a single intramuscular injection, produces few significant untoward effects. Urticaria, chills, and fever have been noted after single doses, as have dizziness, nausea, and insomnia. The injection may be painful.

Antimicrobial Activity, Mechanism of Action, and Resistance to Polymyxins. The antimicrobial activities of polymyxin B and colistin are similar and restricted to gram-negative bacteria, including Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella, which usually are sensitive to concentrations of 0.05-2 μg/mL. Most strains of P. aeruginosa and Acinetobacter are inhibited by <8 μg/mL in vitro. Proteus and Serratia spp. are intrinsically resistant.

Polymyxins are surface-active amphipathic agents. They interact strongly with phospholipids and disrupt the structure of cell membranes. The permeability of the bacterial membrane changes immediately on contact with the drug. Sensitivity to polymyxin B apparently is related to the phospholipid content of the cell wall–membrane complex. The cell walls of certain resistant bacteria may prevent access of the drug to the cell membrane. Polymyxin B binds to the lipid A portion of endotoxin (the lipopolysaccharide of the outer membrane of gram-negative bacteria) and inactivates this molecule. Polymyxin B attenuates pathophysiological consequences of the release of endotoxin in several experimental systems, but the clinical utility of polymyxin B for this indication has not yet been established.

Although resistance to polymyxins among normally susceptible species is rare (likely owing to the minimal systemic use of this agent for many years), emergence of resistance while on treatment has been documented. Dosing regimens, including combination therapies, able to suppress the emergence of resistance are currently being studied.

Absorption, Distribution, and Excretion. Polymyxin B and colistin are not absorbed when given orally and are poorly absorbed from mucous membranes and the surfaces of large burns. They are cleared renally, and modification of the dose is required in patients with impaired renal function.

Therapeutic Uses and Dosage

Topical Uses. Polymyxin B sulfate is available for ophthalmic, otic, and topical use in combination with a variety of other compounds. Colistin is available as otic drops. Infections of the skin, mucous membranes, eye, and ear due to polymyxin B–sensitive microorganisms respond to local application of the antibiotic in solution or ointment. External otitis, frequently due to Pseudomonas, may be cured by the topical use of the drug. P. aeruginosa is a common cause of infection of corneal ulcers; local application or subconjunctival injection of polymyxin B often is curative. Polymyxin B, in combination with neomycin (neosporin g.u. irrigant), is administered as a urinary bladder irrigant in conjunction with the use of indwelling catheters.

Systemic Uses. Colistin is available as colistin sulfate for oral use and as colistimethate sodium for parenteral administration. Due to the emergence of multidrug-resistant gram-negative organisms (especially Stenotrophomonas maltophilia, Acinetobacter spp., P. aeruginosa, and Klebsiella spp), there has been a resurgence in the systemic use of polymyxins, despite their toxicity when administered via this route. There are no prospective clinical trials of polymyxin use for systemic infections; however, a number of studies have described their use as salvage therapy for treatment of infections caused by multidrug-resistant organisms (Linden et al., 2003; San Gabriel et al., 2004). Because dosing of these agents varies by drug (polymyxin B or colistin), by the particular commercial preparation, and by the patient's degree of renal dysfunction, expert consultation is recommended before using these agents.

Untoward Effects. Polymyxin B applied to intact or denuded skin or mucous membranes produces no systemic reactions because of its almost complete lack of absorption from these sites. Hypersensitization is uncommon with topical application. Polymyxins are nephrotoxic, and administration with aminoglycosides or other nephrotoxins should be avoided if possible. Polymyxins interfere with neurotransmission at the neuromuscular junction, resulting in muscle weakness and apnea. Other neurological reactions include paresthesias, vertigo, and slurred speech.

Antimicrobial Activity. Vancomycin possesses activity against a broad spectrum of gram-positive bacteria (Table 55–2). Strains are considered susceptible at MICs of ≤2 μg/mL for S. aureus, ≤4 μg/mL for S. epidermidis, and ≤1 μg/mL for streptococci. Bacillus spp., including B. anthracis, are inhibited by ≤2 μg/mL. Corynebacterium spp. (diphtheroids) are inhibited by <0.04-3.1 μg/mL of vancomycin; most species of Actinomyces, by 5-10 μg/mL; and Clostridium spp., by 0.39-6 μg/mL. Essentially all species of gram-negative bacilli and mycobacteria are resistant to vancomycin.

Teicoplanin is active against methicillin-susceptible and methicillin-resistant staphylococci, which typically have MICs of <4 μg/mL. The MICs for Listeria monocytogenes, Corynebacterium spp., Clostridium spp., and anaerobic gram-positive cocci range from 0.25-2 μg/mL. Nonviridans and viridans streptococci, S. pneumoniae, and enterococci are inhibited by concentrations ranging from 0.01-1 μg/mL. Some strains of staphylococci, coagulase positive and coagulase negative, as well as enterococci and other organisms that are intrinsically resistant to vancomycin (i.e., Lactobacillus spp. and Leuconostoc spp.), are resistant to teicoplanin.

Mechanism of Action. Vancomycin and teicoplanin inhibit the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units (Figure 55–4). Because of their large molecular size, they are unable to penetrate the outer membrane of gram-negative bacteria.

Glycopeptides are generally bactericidal against susceptible strains, except for enterococci. The activity of glycopeptides is best predicted by the ratio of the total drug exposure (area under the curve [AUC]) of glycopeptide to minimum inhibitory concentration (MIC) of the infecting organism. This AUC-to-MIC ratio is established as being predictive of organism killing and cure in in vitro and animal models, and in some limited clinical data (Rybak, 2006). An AUC-to-MIC ratio of 400 was predictive of efficacy in patients with MRSA pneumonia (Moise-Broder et al., 2004). One implication of the potential importance of this parameter is that increases in organism MIC, even below the cutoff for susceptibility, can make achieving this target ratio difficult without substantial dosage increases. Thus, although an isolate of S. aureus with an MIC of 2 μg/mL would be considered susceptible, it would be difficult to achieve an AUC-to-MIC ratio of 400 at standard doses. The validity and target value of this parameter requires confirmation in further clinical studies with a variety of organisms and infections. The potential contribution to toxicity of using higher doses to achieve these target values also requires consideration (see later in the chapter).

Resistance to Glycopeptides. Strains of enterococci once were uniformly susceptible to glycopeptides. Glycopeptide-resistant strains of enterococci, primarily Enterococcus faecium, have emerged as major nosocomial pathogens in hospitals in the U.S. Vancomycin resistance determinants in E. faecium and E. faecalis are located on a transposon that is part of a conjugative plasmid, rendering it readily transferable among enterococci and, potentially, other gram-positive bacteria. These strains typically are resistant to multiple antibiotics, including streptomycin, gentamicin, and ampicillin, effectively eliminating these as alternative therapeutic agents. Resistance to streptomycin and gentamicin is of special concern because the combination of an aminoglycoside with a cell-wall-synthesis inhibitor is the only reliably bactericidal regimen for treatment of enterococcal endocarditis.

Enterococcal resistance to glycopeptides is the result of alteration of the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine (Arias et al., 2000), which bind glycopeptides poorly, due to the lack of a critical site for hydrogen bonding. Several enzymes within the van gene cluster are required for this target alteration to occur. Several phenotypes of resistance to glycopeptides have been described. The Van A phenotype confers inducible resistance to teicoplanin and vancomycin in E. faecium and E. faecalis. The Van B phenotype, which tends to be a lower level of resistance, also has been identified in E. faecium and E. faecalis. The trait is inducible by vancomycin but not teicoplanin, and consequently, many strains remain susceptible to teicoplanin. The Van C phenotype, the least important clinically and least well characterized, confers resistance only to vancomycin, is constitutive, and is present in no species of enterococci other than E. faecalis and E. faecium. Van D and Van E gene clusters also have been identified, and presumably others will follow.

S. aureus and coagulase-negative staphylococci may express reduced or "intermediate" susceptibility to vancomycin (MIC, 4-8 μg/mL) (Garrett et al., 1999; Hiramatsu et al., 1997; Smith et al., 1999) or high-level resistance (MIC ≥16 μg/mL). Intermediate resistance is associated with (and may be preceded by) a heterogeneous phenotype in which a small proportion of cells within the population (1 in 10⁵ to 1 in 10⁶) will grow in the presence of vancomycin concentrations >4 μg/mL. The genetic and biochemical basis of the intermediate phenotype is unknown. Intermediate strains produce an abnormally thick cell wall, and resistance may be due to false targets for vancomycin. Several genetic elements and multiple mutations are involved, and many of the genes that have been implicated encode enzymes of the cell-wall biosynthetic pathway (Sieradzki and Tomasz, 1999; Sieradzki et al., 1999). Infections caused by vancomycin-intermediate strains have failed to respond to vancomycin clinically and in animal models (Climo et al., 1999; Moore et al., 2003). Prior treatment courses and low vancomycin levels may predispose patients to infection and treatment failure with vancomycin-intermediate strains. These strains typically are resistant to methicillin and multiple other antibiotics; their emergence is a major concern because until recently vancomycin has been the only antibiotic to which staphylococci were reliably susceptible.

The first high-level vancomycin-resistant S. aureus strain (MIC ≥32 μg/mL) was isolated in June 2002 (Weigel et al., 2003). This strain, like others that have subsequently been isolated, harbored a conjugative plasmid into which the Van A transposon, Tn1546, was integrated as a consequence of an interspecies horizontal gene transfer from E. faecalis to a methicillin-resistant strain of S. aureus. These isolates have been variably susceptible to teicoplanin and the investigational lipoglycopeptides.

Absorption, Distribution, and Excretion

Absorption. Vancomycin is poorly absorbed after oral administration. For parenteral therapy, the drug should be administered intravenously, never intramuscularly. Teicoplanin can be administered safely by intramuscular injection as well as intravenous administration.

Distribution. A single intravenous dose of 1 g in adults produces plasma concentrations of 15-30 μg/mL 1 hour after a 1- to 2-hour infusion. Approximately 30% of vancomycin is bound to plasma protein. Vancomycin appears in various body fluids, including the CSF when the meninges are inflamed (7-30%); bile; and pleural, pericardial, synovial, and ascitic fluids. Teicoplanin is highly bound by plasma proteins (90-95%).

Elimination. About 90% of an injected dose of vancomycin is excreted by glomerular filtration. The drug has a serum elimination t_1/2 of ~6 hours. The drug accumulates if renal function is impaired, and dosage adjustments must be made under these circumstances. The drug can be cleared rapidly from plasma with high-flux methods of hemodialysis. In contrast to vancomycin, teicoplanin has an extremely long serum elimination t_1/2 (up to 100 hours in patients with normal renal function).

Therapeutic Uses and Dosage. Vancomycin and teicoplanin have been used to treat a wide variety of infections, including osteomyelitis and endocarditis, caused by methicillin-resistant and methicillin-susceptible staphylococci, streptococci, and enterococci. Teicoplanin has been found to be comparable to vancomycin in efficacy, except for treatment failures from low doses used for such serious infections as endocarditis. In general, recommendations for teicoplanin follow those of vancomycin, except where noted later. Although extensively studied for >10 years, teicoplanin has not yet been licensed for use in the U.S.

Vancomycin hydrochloride (vancocin, others) is marketed for intravenous use as a sterile powder for solution. It should be diluted and infused over at least a 60-minute period to avoid infusion-related adverse reactions. The recommended dose of vancomycin for adults is 30-45 mg/kg per day in 2-3 divided doses. The "therapeutic range" for this agent is somewhat controversial. Current recommendations call for monitoring serum trough concentrations (within 30 minutes prior to a dose) at steady state, typically before the fourth dose of a given dosage regimen. A minimum target trough serum concentration of 10 μg/mL is recommended in the most recent consensus guidelines (Rybak et al., 2009). For patients with more serious infections (including endocarditis, osteomyelitis, meningitis, and MRSA pneumonia), trough levels of 15-20 μg/mL are recommended. General pediatric dosage ranges for vancomycin are as follows: for newborns during the first week of life, 15 mg/kg initially, followed by 10 mg/kg every 12 hours; for infants 8-30 days old, 15 mg/kg followed by 10 mg/kg every 8 hours; for older infants (>30 days) and children, 10-15 mg/kg every 6 hours (Frymoyer et al, 2009).

Alteration of dosage is required for patients with impaired renal function. Serum drug concentrations may help guide dose adjustment, but caution should be used in interpreting concentrations in patients with rapidly changing renal function. In functionally anephric patients and patients receiving dialysis with non-high-flux membranes, administration of 1 g (~15 mg/kg) every 5-7 days typically achieves adequate serum levels. In patients receiving intermittent high-efficiency or high-flux dialysis, maintenance doses administered after each dialysis session are typically required because these modalities clear vancomycin efficiently. Because there is so much variation in how well vancomycin is dialyzed with different membranes, it is recommended that blood levels be monitored to decide how frequently the drug needs to be administered to maintain therapeutic concentrations.

Skin/Soft-Tissue and Bone/Joint Infections. Vancomycin is frequently used in the empirical and definitive treatment of skin/soft-tissue and bone/joint infections, where gram-positive organisms including MRSA are the leading pathogens.

Respiratory Tract Infections. Vancomycin is employed for the treatment of pneumonia when MRSA is suspected, either because of healthcare-associated acquisition or in patients with community-acquired pneumonia with risk factors for staphylococcal infection (e.g., influenza). Because vancomycin penetration into lung tissue is relatively low, aggressive dosing (targeting trough levels of 15-20 μg/mL) is generally recommended.

CNS Infections. Because of vancomycin's excellent activity against Streptococcus pneumoniae, it is a key component in the initial empirical treatment of community-acquired bacterial meningitis in locations where penicillin-resistant Streptococcus pneumoniae is common (Tunkel et al., 2004). Penetration of vancomycin across inflamed meningitis is modest to poor; thus aggressive dosing is typically warranted. Vancomycin is also used to treat nosocomial meningitis, usually associated with neurosurgical procedures and often caused by staphylococci. Intraventricular administration of vancomycin (via a shunt or reservoir) has been necessary in a few cases of CNS infections due to susceptible microorganisms that did not respond to intravenous therapy alone.

Endocarditis and Vascular Catheter Infections. Vancomycin is standard therapy for staphylococcal endocarditis when the isolate is methicillin resistant or patients have a severe penicillin allergy (Baddour et al., 2005). Administration of an adjunctive aminoglycoside is no longer recommended unless there is a prosthetic valve. Vancomycin is an effective alternative for the treatment of endocarditis caused by viridans streptococci in patients who are allergic to penicillin. In combination with an aminoglycoside, it may be used for enterococcal endocarditis in patients with serious penicillin allergy or for isolates that are not susceptible to penicillins.

Vancomycin is commonly used for the treatment of vascular catheter infections due to gram-positive organisms, such as staphylococci, viridans streptococci, Corynebacterium spp, and Bacillus spp. In situations when removal of the catheter is not desired, adjunctive treatment with vancomycin as an "antibiotic lock" may aid in salvaging the catheter. In this procedure, a concentrated solution of vancomycin is instilled into the catheter hub and allowed to dwell for variable amounts of time when the catheter is not in use (Carratala, 2002).

Other Infections. Vancomycin can be administered orally to patients with pseudomembranous colitis due to C. difficile, and it may be more efficacious than metronidazole in patients with severe disease. The dose for adults is 125-250 mg every 6 hours; the total daily dose for children is 40 mg/kg, given in three to four divided doses. Commercially available capsules can be used for this purpose, or the intravenous formulation can be administered orally with or without compounding into a more palatable oral solution.

The standard dose of teicoplanin in adults is 3-6 mg/kg per day, with higher dosages possible for treatment of serious staphylococcal infections. Once-daily dosing is possible for the treatment of most infections because of the prolonged serum elimination half-life. As with vancomycin, teicoplanin doses must be adjusted in patients with renal insufficiency. For functionally anephric patients, administration once weekly has been appropriate, but serum drug concentrations should be monitored to determine that the therapeutic range has been maintained (e.g., trough concentration of 15-20 μg/mL). Oral teicoplanin has also been studied for the treatment of C. difficile disease, at a dose of 100 mg twice daily.

Untoward Effects. Among the hypersensitivity reactions produced by vancomycin and teicoplanin are macular skin rashes and anaphylaxis. Phlebitis and pain at the site of intravenous injection are relatively uncommon. Chills, rash, and fever may occur. Rapid intravenous infusion of vancomycin may cause erythematous or urticarial reactions, flushing, tachycardia, and hypotension. The extreme flushing that can occur is sometimes called "red-neck" or "red-man" syndrome. This is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine. This reaction is generally not observed with teicoplanin.

Auditory impairment, sometimes permanent, may follow the use of vancomycin or teicoplanin. Ototoxicity is associated with excessively high concentrations of these drugs in plasma (60-100 μg/mL of vancomycin). Nephrotoxicity, formerly very problematic due to the impurities in earlier formulations of vancomycin, has become less common with modern formulations at standard dosages. However, the more aggressive dosing regimens recently advocated have been demonstrated to increase nephrotoxicity risk. In a recent observational study, nephrotoxicity occurred in 33% of patients with initial vancomycin trough concentrations of >20 μg/mL, compared to 5% among patients with trough concentrations of <10 μg/mL (Lodise et al., 2009). Thus, careful dosing and monitoring of vancomycin is necessary to balance the risks and benefits. Additionally, caution should be exercised when ototoxic or nephrotoxic drugs, such as aminoglycosides, are administered concurrently with vancomycin.

Antimicrobial Activity. Daptomycin is a bactericidal antibiotic selectively active against aerobic, facultative, and anaerobic gram-positive bacteria (Table 55–2) (Jevitt et al., 2003; Streit et al., 2004). The MIC susceptibility breakpoint for staphylococci and streptococci is ≤1 μg/mL; for enterococci it is ≤4 μg/mL. Daptomycin may be active against vancomycin-resistant strains, although MICs tend to be higher for these organisms than for their vancomycin-susceptible counterparts. MICs of Corynebacterium spp., Peptostreptococcus, propionibacteria, and Clostridium perfringens are generally inhibited by ≤0.5-1 μg/mL (Goldstein et al., 2004). Actinomyces spp. are inhibited over the concentration range of 4-32 μg/mL. In vitro activity of daptomycin is Ca²⁺ dependent, and MIC tests should be performed in medium containing 50 mg/L calcium.

Mechanisms of Action and Resistance to Daptomycin. Daptomycin binds to bacterial membranes resulting in depolarization, loss of membrane potential, and cell death. It has concentration-dependent bactericidal activity. During initial clinical trials for treatment of skin and soft-tissue infections, resistance was rarely observed. Subsequently, during clinical use, daptomycin resistance has been reported to emerge while on therapy, typically during treatment of deep-seated infections (e.g., osteomyelitis, endocarditis, infections of prosthetic material). In a trial of vancomycin for staphylococcal bacteremia and right-sided endocarditis, increases in daptomycin MIC associated with microbiological treatment failure were seen in 6 of 120 patients (5%) (Fowler et al., 2006). The mechanisms of resistance to daptomycin have not been fully characterized, although genetic changes in the mprF gene (regulating cell membrane charge) correlating to daptomycin resistance have been described (Yang et al., 2009). Staphylococci with decreased susceptibility to vancomycin have higher daptomycin MICs than fully susceptible strains (Jevitt et al., 2003).

Absorption, Fate, and Excretion. Daptomycin is poorly absorbed orally and should only be administered intravenously. Direct toxicity to muscle precludes intramuscular injection. The steady-state peak serum concentration following intravenous administration of 4 mg/kg in healthy volunteers is ~58 μg/mL. Daptomycin displays linear pharmacokinetics at doses up to 8 mg/kg. It is reversibly bound to albumin; protein binding is 92%. The serum t_1/2 is 8-9 hours in normal subjects, permitting once-daily dosing. Although the drug penetrates adequately into the lung, the drug is inactivated by pulmonary surfactant (Silverman et al., 2005). Approximately 80% of the administered dose is recovered in urine; a small amount is excreted in feces. Dosage adjustment is required for creatinine clearance <30 mL/minute; this is accomplished by administering the recommended dose every 48 hours. For hemodialysis patients the dose should be administered immediately after dialysis.

Therapeutic Uses and Dosage. Daptomycin is indicated for treatment of complicated skin and soft tissue infections (at 4 mg/kg per day) and complicated bacteremia and right-sided endocarditis (at 6 mg/kg per day) (Carpenter and Chambers, 2004). Its efficacy was comparable to that of vancomycin or semisynthetic penicillins. Higher doses (up to 10-12 mg/kg per day) appear to be well tolerated and may be incorporated into future recommendations (Figueroa et al., 2009). Daptomycin was inferior to comparators for treatment of community-acquired pneumonia, likely due to its inactivation in pulmonary surfactant, and it should not be used for this indication (Pertel et al., 2008).

Untoward Effects. The primary toxicity of daptomycin is damage to the musculoskeletal system. In humans, elevations of creatine kinase may occur; this does not require discontinuation of the drug unless there are findings of an otherwise unexplained myopathy. Rhabdomyolysis has been reported to occur rarely. In phase 1 and 2 clinical trials, a few patients had evidence of possible neuropathy, although this was not observed in phase 3 studies.

Drug Interactions. Daptomycin neither inhibits nor induces CYPs, and there are no important drug–drug interactions. However, caution is recommended when administering daptomycin in conjunction with aminoglycosides or statins because of potential risks of nephrotoxicity and myopathy, respectively.

A unit of the antibiotic is equivalent to 26 μg of the USP standard.

Antimicrobial Activity, Mechanism of Action, and Resistance to Bacitracin. Bacitracin inhibits the synthesis of the bacterial cell wall. A variety of gram-positive cocci and bacilli, Neisseria, H. influenzae, and Treponema pallidum, are sensitive to ≤0.1 unit of bacitracin per milliliter. Actinomyces and Fusobacterium are inhibited by concentrations of 0.5-5 units/mL. Enterobacteriaceae, Pseudomonas, Candida spp., and Nocardia are resistant to the drug.

Therapeutic Uses and Dosage. Although bacitracin previously has been employed parenterally, current use is restricted to topical application because of the toxicity of intravenous administration. Bacitracin is available in ophthalmic and dermatologic ointments; the antibiotic also is available as a powder (baci-rx) for the extemporaneous compounding of topical solutions. The ointments are applied directly to the involved surface one or more times daily. A number of topical preparations of bacitracin, to which neomycin or polymyxin or both have been added, are available, and some contain the three antibiotics plus hydrocortisone.

Topical bacitracin alone or in combination with other antimicrobial agents has no established value in the treatment of furunculosis, pyoderma, carbuncle, impetigo, and superficial and deep abscesses. For open infections such as infected eczema and infected dermal ulcers, the local application of the antibiotic may be of some help in eradicating sensitive bacteria. Unlike several other antibiotics used topically, bacitracin rarely produces hypersensitivity. Suppurative conjunctivitis and infected corneal ulcer respond well to the topical use of bacitracin when caused by susceptible bacteria. Bacitracin has been used with limited success for eradication of nasal carriage of staphylococci. Oral bacitracin has been used with some success for the treatment of antibiotic-associated diarrhea caused by C. difficile. Bacitracin is used by neurosurgeons to irrigate the meninges intraoperatively as an alternative to vancomycin. It has no direct toxicity on neurons.

Untoward Effects. Serious nephrotoxicity results from the parenteral use of this antibiotic. Hypersensitivity reactions rarely result from topical application.

Antimicrobial Activity. Mupirocin is active against many gram-positive and selected gram-negative bacteria. It has good activity with MICs ≤1 μg/mL against Streptococcus pyogenes and methicillin-susceptible and methicillin-resistant strains of S. aureus. It is bactericidal at concentrations achieved with topical application.

Mechanism of Action and Mupirocin Resistance. Mupirocin inhibits bacterial protein synthesis by reversible binding and inhibition of isoleucyl transfer-RNA synthetase. There is no cross-resistance with other classes of antibiotics. Low-level resistance, which is not clinically significant, is due to mutations of the host gene encoding isoleucyl transfer-RNA synthetase or an extra chromosomal copy of a gene encoding a modified isoleucyl transfer-RNA synthetase (Ramsey et al., 1996; Udo et al., 2001). High-level resistance (MIC >1 mg/mL) is mediated by a plasmid or chromosomal copy of mupA, which encodes a "bypass" synthetase that binds mupirocin poorly (Udo et al., 2001).

Absorption, Fate, and Excretion. Systemic absorption through intact skin or skin lesions is minimal. Any mupirocin that is absorbed is rapidly metabolized to inactive monic acid.

Therapeutic Uses and Dosage. Mupirocin is available as a 2% cream and a 2% ointment for dermatologic use and as a 2% ointment for intranasal use. The dermatologic preparations are indicated for treatment of traumatic skin lesions and impetigo secondarily infected with S. aureus or S. pyogenes.

The nasal ointment is approved for eradication of S. aureus nasal carriage. Mupirocin is highly effective in eradicating S. aureus carriage (Laupland and Conly, 2003). Because S. aureus colonization often precedes infection, eradication of carriage by intranasal application of mupirocin might reduce the risk of later infection. However, two clinical trials failed to demonstrate that mupirocin prophylaxis reduces nosocomial S. aureus infections (Kalmeijer et al., 2002; Wertheim et al., 2004). A third large study found that S. aureus nasal carriers had fewer S. aureus nosocomial infections of any site, but it failed to show a reduction in S. aureus surgical site infections, the primary end point of the study (Perl et al., 2002). The accumulated evidence indicates that patients who stand to benefit from mupirocin prophylaxis are those with proven S. aureus nasal colonization plus risk factors for distant infection or a history of skin or soft-tissue infections. General inpatient populations and individuals lacking specific risk factors for S. aureus infection are not likely to benefit from mupirocin prophylaxis.

Untoward Effects. Mupirocin may cause irritation and sensitization at the site of application. Contact with the eyes should be avoided because mupirocin causes tearing, burning, and irritation that may take several days to resolve. Systemic reactions to mupirocin occur rarely, if at all. Polyethylene glycol present in the ointment can be absorbed from damaged skin. Application of the ointment to large surface areas should be avoided in patients with moderate to severe renal failure to avoid accumulation of polyethylene glycol.