Goodman and Gilman Manual of Pharmacology and Therapeutics
Chemotherapy of Microbial Diseases
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents
The antimicrobial agents discussed in this chapter may be grouped as:
• Bacteriostatic protein-synthesis inhibitors that target the ribosome, such as tetracyclines and gly-cylcyclines, chloramphenicol, macrolides and ketolides, lincosamides (clindamycin), streptogramins (quinupristin/dalfopristin), oxazolidinones (linezolid), and aminocyclitols (spectinomycin).
• Agents acting on the cell wall or cell membrane such as polymyxins, glycopeptides (vancomycin and teicoplanin), and lipopeptides (daptomycin).
• Miscellaneous compounds acting by diverse mechanisms with limited indications: bacitracin and mupirocin.
TETRACYCLINES AND GLYCYLCYCLINES
The tetracyclines are a series of derivatives of a basic 4-ring structure shown below for doxycycline. Glycylcyclines are tetracycline congers with substituents that confer broad-spectrum activity and activity against bacteria that are resistant to other antibiotics; the available glycylcycline is tigecycline (TYGACIL).
MECHANISM OF ACTION. Tetracyclines and glycylcyclines inhibit bacterial protein synthesis by binding to the 30S bacterial ribosome and preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex (Figure 55–1). These drugs enter gram-negative bacteria by passive diffusion through channels formed by porins in the outer cell membrane and by active transport that pumps tetracyclines across the cytoplasmic membrane.
Figure 55–1 Inhibition of bacterial protein synthesis by tetracyclines. mRNA attaches to the 30S subunit of bacterial ribosomal RNA. The P (peptidyl) site of the 50S ribosomal RNA subunit contains the nascent polypeptide chain; normally, the aminoacyl tRNA charged with the next amino acid (aa) to be added moves into the A (acceptor) site, with complementary base pairing between the anticodon sequence of tRNA and the codon sequence of mRNA. Tetracyclines bind to the 30S subunit, block tRNA binding to the A site, and thereby inhibit protein synthesis.
ANTIMICROBIAL ACTIVITY. Tetracyclines are bacteriostatic antibiotics with activity against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria.
Doxycycline, the most important member of the tetracyclines, is a drug of choice for sexually transmitted diseases, rickettsial infections, plague, brucellosis, tularemia, and spirochetal infections, and is also used for treatment of respiratory tract infections including atypical pneumonia pathogens, and for skin and soft-tissue infections caused by community strains of methicillin-resistant Staphylococcus aureus(MRSA), for which minocycline also is effective. Glycylcyclines have activity against bacteria that resistant to the first- and second-generation tetracyclines.
These agents are effective against some microorganisms, such as Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp., Legionella spp., Ureaplasma, some atypical mycobacteria, andPlasmodium 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. Demeclocycline, tetracycline, minocycline, and doxycycline are available in the U.S. for systemic use. Resistance of a bacterial strain to any 1 member of the class may or may not result in cross-resistance to other tetracyclines. Tigecycline is generally active against organisms that are susceptible to tetracyclines as well as those with acquired resistance to tetracyclines.
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 are displayed in Table 55–1. Bacillus anthracis and Listeria monocytogenes are susceptible. Doxycycline and minocycline can be active against some tetracycline-resistant isolates. Haemophilus 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. The tetracyclines are active against many anaerobic and facultative microorganisms. Tetracycline is a drug of choice for treating actinomycosis.
Activity of Selected Antimicrobials Against Key Gram-Positive Pathogens
In general, tigecycline is equally or more active in vitro against bacteria than the tetracyclines, including 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.
RESISTANCE TO TETRACYCLINES AND GLYCYLCYCLINES. Resistance is primarily plasmid mediated and often inducible. The 3 main resistance mechanisms are:
• Decreased accumulation of tetracycline as a result of either decreased antibiotic influx or acquisition of an energy-dependent efflux pathway
• Production of a ribosomal protection protein that displaces tetracycline from its target
• Enzymatic inactivation of tetracyclines
Cross-resistance, or lack thereof, among tetracyclines depends on which mechanism is operative. 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 glycylcyclines to ribosomes is also enhanced, improving activity against organisms that harbor ribosomal protection proteins that confer resistance to other tetracyclines.
Oral absorption of most tetracyclines is incomplete. The percentage of unabsorbed drug rises as the dose increases. Tigecycline is available only for parenteral administration. Concurrent ingestion of divalent and trivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+, and Zn2+) impairs absorption. Thus, dairy products, antacids, aluminum hydroxide gels; Ca, Mg, and Fe or Zn salts; bismuth subsalicylate (e.g., PEPTO-BISMOL) and dietary Fe and Zn supplements can interfere with absorption of tetracyclines. After a single oral dose, the peak plasma concentration is attained in 2-4 h. These drugs have half-lives in the range of 6-12 h and frequently are administered 2 to 4 times daily. Demeclocycline also is incompletely absorbed but can be administered in lower daily dosages because its t1/2 of 16 h provides effective plasma concentrations for 24-48 h.
Oral doses of doxycycline and minocycline are well absorbed (90-100%) and have half-lives of 16-18 h; they can be administered less frequently and at lower doses than tetracycline or demeclocycline. Plasma concentrations are equivalent whether doxycycline is given orally or parenterally. Food, including dairy products, does not interfere with absorption of doxycycline and minocycline.
Tetracyclines distribute widely throughout the body, 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. Inflammation of the meninges is not required for the passage of tetracyclines into the cerebrospinal fluid. Tetracyclines cross the placenta and enter the fetal circulation and amniotic fluid. Relatively high concentrations are found in breast milk.
Except for doxycycline, most tetracyclines are eliminated primarily by the kidney, although they also are concentrated in the liver, excreted in bile, and partially reabsorbed via enterohepatic recirculation. Comparable amounts of tetracycline (i.e., 20-60%) are excreted in the urine within 24 h 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. Specific dosage adjustment recommendations in hepatic disease are available only for tigecycline. 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.
THERAPEUTIC USES AND DOSAGE
The tetracyclines have been used extensively to treat infectious diseases and as an additive to animal feeds to facilitate growth (a use that likely contributes to the development of bacterial resistance). The drugs remain useful as first-line therapy for infections caused by rickettsiae, mycoplasmas, and chlamydiae. The glycylcyclines have restored much of the antibacterial activity lost to the tetracyclines due to resistance and can be used for a number of infections due to gram-positive and gram-negative organisms.
The oral dose of tetracycline ranges from 1-2 g/day in adults. Children >8 years of age should receive 25-50 mg/kg daily in 4 divided doses. The low pH of tetracycline, but not doxycycline or minocycline, invariably causes phlebitis if infused into a peripheral vein. The oral or intravenous dose of doxycycline for adults is 100 mg every 12 h on the first day and then 50 mg every 12 h, 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/day in 2 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 h; for children, it is 4 mg/kg initially followed by 2 mg/kg every 12 h. Tigecycline is administered intravenously to adults as a 100-mg loading dose, followed by 50 mg every 12 h. For patients with severe hepatic impairment, the loading dose should be followed by a reduced maintenance dose of 25 mg every 12 h. 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 h before or 2 h after coadministration 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 has good activity against Streptococcus pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophilia pneumoniae. Tigecycline has been demonstrated to be effective for use as a single agent for adults hospitalized with community-acquired bacterial pneumonia.
Skin and Soft-Tissue Infections. Tigecycline is approved for the treatment of complicated skin and soft-tissue infections. Low doses of tetracycline have been used to treat acne (250 mg orally twice a day).
Intra-abdominal Infections. 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.
GI Infections. Therapy with the tetracyclines is often ineffective in infections caused by Shigella, Salmonella, or other Enterobacteriaceae because of drug-resistant strains. Resistance limits the usefulness of tetracyclines for travelers’ diarrhea. Doxycycline (300 mg as a single dose) is effective in reducing stool volume and eradicating V. cholerae from the stool within 48 h. Some strains of V. cholerae are resistant to tetracyclines.
Sexually Transmitted Diseases. Doxycycline no longer is recommended for gonococcal infections. Chlamydia trachomatis often is a coexistent pathogen in acute pelvic inflammatory disease. Doxycycline, 100 mg intravenously twice daily, is recommended for at least 48 h after substantial clinical improvement, followed by oral therapy at the same dosage to complete a 14-day course. Acute epididymitis is caused by infection with C. trachomatis or Neisseria 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 also should be treated. Doxycycline (100 mg twice daily for 21 days) is first-line therapy for treatment of lymphogranuloma venereum. Non-pregnant 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 life-saving in rickettsial infections, including Rocky Mountain spotted fever, recrudescent epidemic typhus (Brill disease), murine typhus, scrub typhus, rickettsialpox, and Q fever. Clinical improvement often is evident within 24 h after initiation of therapy. Doxycycline is the drug of choice for treatment of 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.
Anthrax. Doxycycline, 100 mg every 12 h (2.2 mg/kg every 12 h 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 bioterrorism exposures.
Local Application. Except for local use in the eye, topical use of the tetracyclines is not recommended. Minocycline sustained-release microspheres for subgingival administration are used in dentistry.
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. Although streptomycin is preferable, tetracyclines also are effective in tularemia. 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 Mycobacterium marinum.
GI. All tetracyclines can produce GI irritation, most commonly after oral administration. 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. Pseudomembranous colitis caused by overgrowth of Clostridium difficile is a potentially life-threatening complication.
Photosensitivity. Demeclocycline, doxycycline, and other tetracyclines and glycylcyclines to a lesser extent may produce photosensitivity reactions in treated individuals exposed to sunlight.
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. Pregnant women are particularly susceptible.
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 (see Chapter 25). Fanconi syndrome has been observed in patients ingesting outdated tetracycline, presumably due to toxic effects on the proximal renal tubules.
Effects on Teeth. Children treated with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth. The duration of therapy appears to be less important than the total quantity of antibiotic administered. The risk is highest when a tetracycline is given to infants before the first dentition but may develop if the drug is given between the ages of 2 months and 5 years when these teeth are being calcified. Treatment of pregnant patients with tetracyclines may produce discoloration of the teeth in their children.
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. Long-term tetracycline therapy may produce leukocytosis, atypical lymphocytes, toxic granulation of granulocytes, and thrombocytopenic purpura. Tetracyclines may cause increased intracranial pressure (pseudotumor cerebri) in young infants, even when given in the usual therapeutic doses. 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 h after drug cessation. Various skin reactions 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. Other hypersensitivity reactions are burning of the eyes, cheilosis, atrophic or hypertrophic glossitis, pruritus ani or vulvae, and vaginitis. 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.
Chloramphenicol can cause serious and fatal blood dyscrasias; consequently, the drug is now reserved for treatment of life-threatening infections in patients who cannot take safer alternatives because of resistance or allergies.
MECHANISM OF ACTION. Chloramphenicol inhibits protein synthesis in bacteria, and to a lesser extent, in eukaryotic cells. Chloramphenicol acts primarily by binding reversibly to the 50S ribosomal subunit (near the binding site for the macrolide antibiotics and clindamycin). The drug 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).
Figure 55–2 Inhibition of bacterial protein synthesis by chloramphenicol. Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site, inhibiting transpeptidation. Chloramphenicol binds near the site of action of clindamycin and the macrolide antibiotics. These agents interfere with the binding of chloramphenicol and thus may interfere with each other’s actions if given concurrently.See Figure 55–1 for additional information.
Chloramphenicol also can inhibit mitochondrial protein synthesis in mammalian cells, perhaps because mitochondrial ribosomes resemble bacterial ribosomes (both are 70S); erythropoietic cells are particularly sensitive.
ANTIMICROBIAL ACTIVITY. Chloramphenicol is bacteriostatic against most species, although it may be bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae. Many gram-negative bacteria and most anaerobic bacteria are inhibited in vitro. Strains of S. aureus tend to be less susceptible. Chloramphenicol is active against Mycoplasma, Chlamydia, and Rickettsia. Enterobacteriaceae are variably sensitive to chloramphenicol. P. aeruginosa is resistant to even very high concentrations of chloramphenicol. Strains of V. cholerae have remained largely susceptible to chloramphenicol. Prevalent strains of Shigella and Salmonella are resistant to multiple drugs, including chloramphenicol.
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.
ADME. Chloramphenicol is absorbed rapidly from the GI tract. For parenteral use, chloramphenicol succinate is a prodrug that is hydrolyzed by esterases to chloramphenicol 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 h) 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. 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 are excreted in the urine. Patients with impaired hepatic function have decreased metabolic clearance, and dosage should be adjusted. 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. 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 less toxic are available, they should be used instead of chloramphenicol.
Typhoid Fever. Third-generation cephalosporins and quinolones are drugs of choice for the treatment of typhoid fever. The adult dose of chloramphenicol for typhoid fever is 1 g every 6 h for 4 weeks.
Bacterial Meningitis. 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. The total daily dose for children should be 50 mg/kg of body weight, divided into 4 equal doses given intravenously every 6 h.
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-h intervals is recommended. Therapy should be continued until the general condition has improved and is afebrile for 24-48 h.
UNTOWARD EFFECTS. Chloramphenicol inhibits the synthesis of proteins of the inner mitochondrial membrane, probably by inhibiting the ribosomal peptidyltransferase. Much of the toxicity observed with this drug can be attributed to these effects.
Hypersensitivity Reactions. Skin rashes may 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. Chloramphenicol affects the hematopoietic system in 2 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 occurs more commonly in individuals who undergo prolonged therapy and especially in those who are exposed to the drug on more than 1 occasion. 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 proposed mechanism involves 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. 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 without prior dose-related marrow suppression.
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 (e.g., heart, brain) may be particularly susceptible to chloramphenicol’s effects on mitochondrial enzymes.
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 after treatment is started. Within the first 24 h, vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose green stools occur. Over the next 24 h, neonates 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; and (2) inadequate renal excretion of unconjugated drug. At the onset of the clinical syndrome, chloramphenicol concentrations in plasma usually exceed 100 μg/mL, and 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.
Drug Interactions. Chloramphenicol inhibits hepatic CYPs and thereby prolongs the half-lives of drugs that are metabolized by this system. Severe toxicity and death have occurred because of failure to recognize such effects. Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens the t1/2 of the antibiotic and may result in subtherapeutic drug concentrations.
MACROLIDES AND KETOLIDES
Macrolides and ketolides are effective for treatment of respiratory tract infections caused by the common pathogens of community-acquired pneumonia. All except azithromycin have important drug interactions because they inhibit hepatic CYPs.
Chapter 55 of the parent text includes a fuller presentation of the structure-activity data of these compounds. Macrolide antibiotics contain a multi-membered lactone ring to which are attached 1 or more deoxy sugars. Modest structural modifications (e.g., in clarithromycin and azithromycin) improve acid stability and tissue penetration and broaden the spectrum of activity. Ketolides are structurally similar multi-membered ring systems but with different substituents. Telithromycin (KETEK) is the only ketolide currently approved in the U.S. 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.
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 (see 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. Ketolides and macrolides have the same ribosomal target site.
Figure 55–3 Inhibition of bacterial protein synthesis by the erythromycin, clarithromycin, and azithromycin. Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive organisms. Erythromycin appears to inhibit the translocation step such that the nascent peptide chain temporarily residing at the A site fails to move to the P, or donor, site. Alternatively, macrolides may bind and cause a conformational change that terminates protein synthesis by indirectly interfering with transpeptidation and translocation. See Figure 55–1 for additional information.
ANTIMICROBIAL ACTIVITY. Erythromycin usually is bacteriostatic but may be bactericidal in high concentrations against susceptible organisms. The antibiotic is most active in vitro against aerobic gram-positive cocci and bacilli (see Table 55–1). Macrolide resistance among S. pneumoniae often co-exists with penicillin resistance. Staphylococci are not reliably sensitive to erythromycin. Macrolide-resistant strains of S. aureus are potentially cross-resistant to clindamycin and streptogramin B (quinupristin). Gram-positive bacilli also are sensitive to erythromycin, including Clostridium perfringens, Corynebacterium diphtheriae, and L. monocytogenes. Erythromycin is inactive against most aerobic enteric gram-negative bacilli. It has modest activity in vitro against H. influenzae and N. meningitidis, and good activity against most strains of N. gonorrhoeae. Useful antibacterial activity also is observed against P. multocida, Borrelia spp., and Bordetella pertussis. Resistance is common for B. fragilis. Macrolides are usually active against C. jejuni. Erythromycin is active against M. pneumoniae and L. pneumophila. Most strains of C. trachomatis are inhibited by erythromycin. Some of the atypical mycobacteria are sensitive to erythromycin in vitro.
Clarithromycin is slightly more potent than erythromycin against sensitive strains of streptococci and staphylococci, and has modest activity against H. influenzae and N. gonorrhoeae. Clarithromycin and azithromycin have good activity against Moraxella catarrhalis, Chlamydia spp., L. pneumophila, B. burgdorferi, M. pneumoniae, and H. pylori. Azithromycin and clarithromycin have enhanced activity against Mycobacterium avium-intracellulare, as well as against some protozoa (e.g., Toxoplasma gondii, Cryptosporidium, and Plasmodium spp.). Clarithromycin has good activity against Mycobacterium leprae. Telithromycin’s spectrum of activity is similar to those of clarithromycin and azithromycin. Telithromycin’s capacity to withstand many macrolide resistance mechanisms increases its activity against macrolide-resistant S. pneumoniae and S. aureus.
RESISTANCE TO MACROLIDES AND KETOLIDES. Resistance to macrolides usually results from 1 of 4 mechanisms:
• Drug efflux by an active pump mechanism
• Ribosomal protection by inducible or constitutive production of methylase enzymes, that modify the ribosomal target and decrease drug binding
• Macrolide hydrolysis by esterases produced by Enterobacteriaceae
• Chromosomal mutations that alter a 50S ribosomal protein (in Bacillus subtilis, Campylobacter spp., mycobacteria, and gram-positive cocci)
Absorption. Erythromycin base is incompletely but adequately absorbed from the upper small intestine. Because it is inactivated by gastric acid, it is administered as enteric-coated tablets, as capsules containing enteric-coated pellets that dissolve in the duodenum, or as an ester. Food may delay absorption. 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 h.
Clarithromycin is absorbed rapidly from the GI tract after oral administration, but hepatic first-pass metabolism reduces its bioavailability to 50-55%. Peak concentrations occur ~2 h 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. Azithromycin administered orally is absorbed rapidly and distributes widely throughout the body, except to the brain and CSF. Azithromycin should not be administered with food. Azithromycin also can be administered intravenously, producing plasma concentrations of 3-4 μg/mL after a 1-h 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 are achieved within 30 min to 4 h.
Distribution. Erythromycin diffuses readily into intracellular fluids, achieving antibacterial activity in essentially all sites except the brain and CSF. Concentrations in middle ear exudate may be inadequate for the treatment of otitis media caused by H. influenzae. Protein binding is ~70-80% for erythromycin base and even higher 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, achieve high intracellular concentrations throughout the body, including the middle ear. 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. Telithromycin 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 plasma concentration) are maintained 24 h 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. The serum t1/2 of erythromycin is ~1.6 h. Although the t1/2 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 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 h for clarithromycin and 5-9 h for 14-hydroxyclarithromycin. Metabolism is saturable, resulting in nonlinear pharmacokinetics, and longer half-lives with higher dosages. The amount of clarithromycin excreted unchanged in the urine ranges from 20-40%, 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. Dose adjustment is not necessary unless the creatinine clearance is <30 mL/min.
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 t1/2’ 40-68 h, is prolonged because of extensive tissue sequestration and binding. With a t1/2 of 9.8 h, 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.
THERAPEUTIC USES AND DOSAGE. The usual oral dose of erythromycin (erythromycin base) for adults ranges from 1-2 g/day, in divided doses, usually given every 6 h. Daily doses of erythromycin as large as 8 g orally, given for 3 months, have been well tolerated. Food should not be taken concurrently, if possible, with erythromycin base or the stearate formulations, but this is not necessary with erythromycin estolate. The oral dose of erythromycin for children is 30-50 mg/kg/day, divided into 4 portions; this dose may be doubled for severe infections. Intramuscular administration of erythromycin is not recommended because of pain upon injection. Intravenous administration is generally reserved for the therapy of severe infections, such as legionellosis. The usual dose is 0.5-1 g every 6 h; 1 g of erythromycin gluceptate (not available in the U.S.) has been given intravenously every 6 h for as long as 4 weeks with no adverse effects except for local thrombophlebitis. Erythromycin lactobionate is available for intravenous injection. The combination of erythromycin and sulfisoxazole appears to have synergistic antibacterial activity; it is available as a suspension used primarily for treatment of otitis media in children.
Clarithromycin (BIAXIN, others) usually is given twice daily at a dose of 250 mg for children >12 years and adults with mild to moderate infection. Larger doses (e.g., 500 mg twice daily) are indicated for more severe infection such as pneumonia or infections caused by more resistant organisms such as H. influenzae. The 500-mg extended-release formulation is given as 2 tablets once daily. Clarithromycin (500 mg) is also packaged with lansoprazole (30 mg) and amoxicillin (1 g) as a combination regimen (PREVPAC) that is administered twice daily for 10 or 14 days to eradicate H. pylori.
Azithromycin (ZITHROMAX, other) should be given 1 h before or 2 h after meals when administered orally. For outpatient therapy of community-acquired pneumonia, pharyngitis, or skin and skin-structure infections, a loading dose of 500 mg is given on the first day, and then 250 mg per day is given for days 2 through 5. Treatment or prophylaxis of M. avium-intracellulare infection in AIDS patients requires higher doses: 600 mg daily in combination with 1 or more other agents for treatment, or 1200 mg once weekly for primary prevention. Azithromycin is useful in treatment of sexually transmitted diseases, especially during pregnancy when tetracyclines are contraindicated. The treatment of uncomplicated nongonococcal urethritis presumed to be caused by C. trachomatis consists of a single 1-g dose of azithromycin. This dose also is effective for chancroid. Azithromycin (1 g per week for 3 weeks) is an alternative regimen for treatment of granuloma inguinale or lymphogranuloma venereum. In children, the recommended dose of azithromycin oral suspension for acute otitis media and pneumonia is 10 mg/kg on the first day (maximum: 500 mg) and 5 mg/kg (maximum: 250 mg/day) on days 2 through 5. A single 30 mg/kg dose is approved as an alternative for otitis media. The dose for tonsillitis or pharyngitis is 12 mg/kg/day, up to 500 mg total, for 5 days.
Respiratory Tract Infections. Macrolides and ketolides are suitable drugs for the treatment of a number of respiratory tract infections. 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 C. pneumoniae or M. pneumoniae. Erythromycin has been considered as the drug of choice for treatment of pneumonia caused by L. pneumophila, Legionella 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. 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 is effective in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis, and has a potential advantage where macrolide-resistant strains are common. Due to a number of cases of severe hepatotoxicity, the drug’s FDA approval is limited to community-acquired pneumonia; 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. 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.
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 4 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/day in 4 divided doses for 10-14 days). Azithromycin, 1 g/week for 3 weeks, may be effective for lymphogranuloma venereum.
Diphtheria. Erythromycin, 250 mg 4 times daily for 7 days, is very effective for acute infections or for eradicating the carrier state. Other macrolides are not FDA-approved for this indication. Antibiotics do not alter the course of an acute infection with diphtheria or decrease 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/day; maximum: 1 g/day; not available in U.S.) is effective. Clarithromycin and azithromycin also are effective. 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. Nasopharyngeal cultures should be obtained from people with pertussis who do not improve with erythromycin therapy because resistance has been reported.
Campylobacter Infections. Fluoroquinolones have largely has replaced 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.
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. 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. Clarithromycin also has been used with minocycline for the treatment of M. leprae in lepromatous leprosy.
Prophylactic Uses. Erythromycin is an effective alternative for the prophylaxis of recurrences of rheumatic fever in 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.
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. These symptoms are followed shortly thereafter by jaundice, which may be accompanied by fever, leukocytosis, eosinophilia, and elevated transaminases in plasma. Findings usually resolve within a few days after cessation of drug therapy. Hepatotoxicity has also been observed with clarithromycin and azithromycin, although at a lower rate than with erythromycin. Telithromycin may induce severe hepatotoxicity and should only be used in circumstances where it represents a clear advantage over alternative agents.
GI Toxicity. Oral administration of erythromycin, frequently is accompanied by epigastric distress, which may be quite severe. Intravenous administration of erythromycin may cause similar symptoms. Erythromycin stimulates GI motility by acting on motilin receptors (see 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 h or by pretreatment with glycopyrrolate. 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 to a lesser degree than 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 or were receiving anti-arrhythmics or other agents that prolong QTc.
Other Toxic and Irritative Effects. Allergic reactions observed are fever, eosinophilia, and skin eruptions, which disappear shortly after therapy is stopped. Transient auditory impairment with erythromycin has been observed. Visual disturbances due to slowed accommodation have been reported following telithromycin. Telithromycin is contraindicated in patients with myasthenia gravis due to exacerbation of neurological symptoms. Loss of consciousness has been associated with telithromycin.
Drug Interactions. Erythromycin, clarithromycin, and telithromycin inhibit CYP3A4 and cause significant drug interactions. Erythromycin and clarithromycin potentiate the effects of carbamazepine, corticosteroids, cyclosporine, digoxin, ergot alkaloids, theophylline, triazolam, valproate, and warfarin, probably by interfering with CYP-mediated metabolism of these drugs (see Chapter 6). Telithromycin is both a substrate and a strong inhibitor of CYP3A4. Coadministration 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 and dirithromycin appear to be free of these drug interactions; however, caution is advised.
Clindamycin is a congener of lincomycin. Clindamycin principally is used to treat anaerobic infections.
ANTIMICROBIAL ACTIVITY. Clindamycin generally is similar to erythromycin in its in vitro activity against susceptible strains of pneumococci, Streptococcus pyogenes, and viridans streptococci (seeTable 55–1). Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin, but MRSA and coagulase-negative staphylococci frequently are resistant. Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria, especially B. fragilis. From 10-20% of clostridial species other than C.perfringens are resistant. Resistance to clindamycin in Bacteroides spp. increasingly is encountered. Strains of Actinomyces israelii and Nocardia asteroides are sensitive. Essentially all aerobic gram-negative bacilli are resistant. Clindamycin plus primaquine and clindamycin plus pyrimethamine are second-line regimens for Pneumocystis jiroveci pneumonia and T. gondii encephalitis, respectively.
MECHANISM OF ACTION; RESISTANCE. 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 (see Figures 55–2 and 55–3), and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others. Macrolide resistance due to ribosomal methylation also may produce resistance to clindamycin. Because clindamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced constitutively. Clindamycin is not a substrate for macrolide efflux pumps; thus strains that are resistant to macrolides by this mechanism are susceptible to clindamycin.
ADME. Clindamycin is nearly completely absorbed following oral administration. Peak Cp of 2-3 μ/mL are attained within 1 h after the ingestion of 150 mg. Food in the stomach does not reduce absorption significantly. The t1/2 of the antibiotic is ~3 h. Clindamycin palmitate, an oral preparation for pediatric use, is an inactive prodrug that is hydrolyzed rapidly in vivo. The phosphate ester of clindamycin, which is given parenterally, also is rapidly hydrolyzed in vivo to the active parent compound.
Clindamycin is widely distributed in many fluids and tissues, including bone but not to CSF, even when the meninges are inflamed. Concentrations sufficient to treat cerebral toxoplasmosis are achievable. 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.
Clindamycin is inactivated by metabolism to N-demethylclindamycin and clindamycin sulfoxide, which are excreted in the urine and bile. Dosage adjustments may be required in patients with severe hepatic failure. 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 and growth of clindamycin-sensitive microorganisms may be suppressed for up to 2 weeks.
THERAPEUTIC USES AND DOSAGE. The oral dose of clindamycin (clindamycin hydrochloride [CLEOCIN]) for adults is 150-300 mg every 6 h; for severe infections, it is 300-600 mg every 6 h. Children should receive 8-12 mg/kg/day of clindamycin palmitate hydrochloride (CLEOCIN PEDIATRIC) in 3 or 4 divided doses or for severe infections, 13-25 mg/kg/day. However, children weighing ≤10 kg should receive ½ teaspoonful of clindamycin palmitate hydrochloride (37.5 mg) every 8 h as a minimal dose. For serious infections, intravenous or intramuscular administration is recommended in dosages of 1200-2400 mg/day, divided into 3 or 4 equal doses for adults. Children should receive 15-40 mg/kg/day in 3 or 4 divided doses; in severe infections, a minimal daily dose of 300 mg is recommended, regardless of body weight.
Clindamycin is the drug of choice for treatment of lung abscess and anaerobic lung and pleural space infections. Clindamycin (600 mg intravenously every 8 h, or 300-450 mg orally every 6 h 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. Clindamycin 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 (600-1200 mg given intravenously every 6 h) 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.
GI Effects. The reported incidence of diarrhea associated with the administration of clindamycin ranges from 2-20%. A number of patients 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. This syndrome may be lethal. Discontinuation of the drug, combined with administration of metronidazole or oral vancomycin usually is curative, but relapses occur. Agents that inhibit peristalsis (e.g., 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 uncommon reactions 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 may potentiate the effect of a neuromuscular blocking agent administered concurrently.
Quinupristin/dalfopristin (SYNERCID) is a combination of quinupristin (a streptogramin B), with dalfopristin (a streptogramin A), in a 30:70 ratio. These compounds are semisynthetic derivatives of naturally occurring agents produced by Streptomyces pristinaespiralis. Quinupristin and dalfopristin are more soluble derivatives of the congeners, pristinamycin IA and IIA, and therefore are suitable for intravenous administration.
ANTIMICROBIAL ACTIVITY. Quinupristin/dalfopristin is active against gram-positive cocci and organisms responsible for atypical pneumonia (e.g., M. pneumoniae, Legionella spp., and C. pneumoniae), but is inactive against gram-negative organisms. The combination is bactericidal against streptococci and many strains of staphylococci but bacteriostatic against Enterococcus 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. The net result of the cooperative and synergistic binding of these 2 molecules to the ribosome is bactericidal activity.
RESISTANCE TO STREPTOGRAMINS. Resistance to quinupristin is mediated by genes encoding a ribosomal methylase that prevents binding of drug to its target, or genes encoding lactonases that inactivate type B streptogramins. Resistance to dalfopristin is mediated by genes that encode acetyltransferases that inactivate type A streptogramins, or staphylococcal genes that encode ATP-binding efflux proteins that pump type A streptogramins out of the cell. These resistance determinants are located on plasmids. Resistance to quinupristin/dalfopristin always is associated with a resistance gene for type A streptogramins. Methylase-encoding genes can render the combination bacteriostatic instead of bactericidal, making it ineffective in certain infections in which bactericidal activity is necessary (e.g., endocarditis).
ADME. Quinupristin/dalfopristin is administered by intravenous infusion over at least 1 h. It is incompatible with saline and heparin and should be dissolved in 5% dextrose in water. The t1/2 is 0.85 h for quinupristin and 0.7 h 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. Hepatic insufficiency increases the plasma AUC of active component and metabolites by 180% for quinupristin and 50% for dalfopristin.
THERAPEUTIC USES AND DOSAGE. Quinupristin/dalfopristin is approved in the U.S. for treatment of infections caused by vancomycin-resistant strains of E. faecium (dose of 7.5 mg/kg every 8-12 h) and complicated skin and skin-structure infections caused by methicillin-susceptible strains of S. aureus or S. pyogenes. In Europe it also is approved for treatment of nosocomial pneumonia and infections caused by MRSA. 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, more likely to be problematic in patients with hepatic insufficiency are managed by reducing the infusion frequency to every 12 h.
DRUG INTERACTIONS. Quinupristin/dalfopristin inhibits CYP3A4. The concomitant administration of other CYP3A4 substrates with quinupristin/dalfopristin may result in significant toxicity. Caution and monitoring are recommended for drugs in which the toxic therapeutic window is narrow or for drugs that prolong the QTc interval.
Linezolid (ZYVOX) is a synthetic antimicrobial agent of the oxazolidinone class.
ANTIMICROBIAL ACTIVITY. Linezolid is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such asCorynebacterium spp. and L. monocytogenes (see Table 55–1). It has poor activity against most gram-negative aerobic or anaerobic bacteria. It is bacteriostatic against enterococci and staphylococci and bactericidal against streptococci. Mycobacterium tuberculosis is moderately susceptible.
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. Since bacteria have multiple copies of 23S rRNA genes, resistance generally requires mutations in 2 or more copies.
ADME. Linezolid is well absorbed after oral administration and may be administered without regard to food. Dosing for oral and intravenous preparations is the same. The t1/2 is ~4-6 h. Linezolid is 30% protein-bound and distributes widely to well-perfused tissues. Linezolid is nonenzymatically oxidized to aminoethoxyacetic acid and hydroxyethyl glycine derivatives. Approximately 80% of a dose of linezolid appears in the urine, 30% as active compound and 50% as the 2 primary oxidation products. Ten percent of the administered dose appears as oxidation products in feces. No dose adjustment in renal insufficiency is recommended. Linezolid and its breakdown products are eliminated by dialysis; therefore the drug should be administered after hemodialysis.
THERAPEUTIC USES AND DOSAGE. 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 caused by vancomycin-resistant E. faecium. Linezolid is FDA-approved for treatment of skin and skin structure infections (complicated and uncomplicated) caused by streptococci and S. aureus (methicillin-susceptible and MRSA). A 400-mg twice-daily dosage regimen is recommended only for treatment of uncomplicated skin and skin-structure infections. For nosocomial pneumonia caused by MRSA or methicillin-susceptible S. aureus, cure rates with linezolid (~60%) were similar to those with vancomycin. Linezolid also may be an effective alternative for patients with MRSA infections who have reduced susceptibility to vancomycin. Linezolid also is approved for treatment of community-acquired pneumonia caused by penicillin-susceptible strains of S. pneumoniae.
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. Indiscriminant use and overuse will hasten selection of resistant strains and the eventual loss of this valuable newer agent.
UNTOWARD EFFECTS. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been reported in patients receiving linezolid. Platelet counts should be monitored in patients with risk of bleeding, preexisting thrombocytopenia, or intrinsic or acquired disorders of platelet function and in patients receiving courses of therapy lasting beyond 2 weeks. The drug is 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. Linezolid should 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 (palpitations, headache, or hypertensive crisis). Coadministration 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, coadministration with careful monitoring is reasonable. Linezolid is neither a substrate nor an inhibitor of CYPs.
Spectinomycin is indicated only for the treatment of gonococcal infection when β-lactam or fluoroquinolone cannot be given.
ANTIMICROBIAL ACTIVITY, MECHANISM OF ACTION, AND RESISTANCE TO SPECTINOMYCIN. Spectinomycin selectively inhibits protein synthesis in gram-negative bacteria by binding to 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 drug modification by adenylyltransferase.
ADME. Spectinomycin is rapidly absorbed after intramuscular injection. The drug is not significantly bound to plasma protein, and all of an administered dose is recovered in the urine within 48 h.
THERAPEUTIC USES AND DOSAGE. 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 (ceftriaxone, cefixime) or if there are contraindications to these drugs. Spectinomycin is recommended in patients who are intolerant or allergic to β-lactams. The drug is not available in the U.S. The recommended dose for men and women is a single deep intramuscular injection of 2 g. Spectinomycin has no effect on incubating or established syphilis, and is not active against Chlamydia spp. It also is less effective for pharyngeal infections.
UNTOWARD EFFECTS. Local pain, urticaria, chills, fever, dizziness, nausea, and insomnia have been noted. The injection may be painful.
The polymyxins are a group of closely related antibiotics elaborated by strains of Bacillus polymyxa. Colistin (polymyxin E) is produced by Bacillus colistinus. Polymyxin B is a mixture of polymyxins B1 and B2. These drugs, which are cationic detergents, are simple basic peptides with molecular masses of ~1000 Da.
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. Polymyxins are surface-active amphipathic agents. They interact strongly with phospholipids and disrupt the structure of cell membranes. Sensitivity to polymyxin B apparently is related to the phospholipid content of the cell wall–membrane complex. Polymyxin B binds to the lipid A portion of endotoxin (the lipopolysaccharide of the outer membrane of gram-negative bacteria) and inactivates this molecule. The cell walls of certain resistant bacteria may prevent access of the drug to the cell membrane. Although resistance to polymyxins is rare, emergence of resistance while on treatment has been documented.
ADME. 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.
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.
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. 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.
Untoward Effects. Because polymyxins are nephrotoxic when administered via systemically, these drugs are rarely used except topically. 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. Neurological reactions include muscle weakness, apnea, paresthesias, vertigo, and slurred speech.
GLYCOPEPTIDES (VANCOMYCIN AND TEICOPLANIN)
Vancomycin is a tricyclic glycopeptide antibiotic produced by Streptococcus orientalis. Teicoplanin is a mixture of related glycopeptides available as an antibiotic in Europe. It is similar to vancomycin in chemical structure, mechanism of action, spectrum of activity, and route of elimination (i.e., primarily renal).
ANTIMICROBIAL ACTIVITY. Vancomycin possesses activity against a broad spectrum of gram-positive bacteria (see Table 55–1). Essentially all species of gram-negative bacilli and mycobacteria are resistant to vancomycin. Teicoplanin is active against methicillin-susceptible and MRSA. 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.
Figure 55–4 Inhibition of bacterial cell wall synthesis: vancomycin and β-lactam agents. Vancomycin inhibits the polymerization or transglycosylase reaction (A) by binding to the D-alanyl-D-alanine terminus of the cell wall precursor unit attached to its lipid carrier and blocks linkage to the glycopeptide polymer (indicated by the subscript n). These (NAM–NAG)n peptidoglycan polymers are located within the cell wall. Van A-type resistance is due to expression of enzymes that modify cell wall precursor by substituting a terminal D-lactate for D-alanine, reducing affinity for vancomycin by 1000-fold. β-Lactam antibiotics inhibit the cross-linking or transpeptidase reaction (B) that links glycopeptide polymer chains by formation of a cross-bridge with the stem peptide (the 5 glycines in this example) of one chain, displacing the terminal D-alanine of an adjacent chain. See also Figure 53–2.
RESISTANCE TO GLYCOPEPTIDES. Glycopeptide-resistant strains of enterococci, primarily E. faecium, have emerged as major nosocomial pathogens in hospitals in the U.S. Determinants of vancomycin resistance are located on a transposon that is readily transferable among enterococci, and, potentially, other gram-positive bacteria. These strains are typically resistant to multiple antibiotics, including streptomycin, gentamicin, and ampicillin. 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, which bind glycopeptides poorly. Several enzymes within the vangene cluster are required for this target alteration to occur. The Van A phenotype confers inducible resistance to teicoplanin and vancomycin in E. faecium and Enterococcus 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.
S. aureus and coagulase-negative staphylococci may express reduced or “intermediate” susceptibility to vancomycin (MIC, 4-8 μg/mL) or high-level resistance (MIC ≥16 μg/mL). Intermediate resistance is associated with 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. 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. High-level vancomycin-resistant S. aureus strains (MIC ≥32 μg/mL) harbor a conjugative plasmid into which the Van A transposon is integrated by an interspecies horizontal gene transfer from E. faecalis to a MRSA. These isolates have been variably susceptible to teicoplanin and the investigational lipoglycopeptides.
ADME. Vancomycin is poorly absorbed after oral administration. The drug should be administered intravenously, never intramuscularly. 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. About 90% of an injected dose of vancomycin is excreted by glomerular filtration; elimination t1/2 is ~6 h. The drug accumulates if renal function is impaired, and dosage adjustments must be made. The drug can be cleared from plasma with hemodialysis. Teicoplanin can be administered by intramuscular injection as well as intravenous administration. An intravenous dose of 1 g in adults produces plasma concentrations of 15-30 μg/mL 1 h after a 1- to 2-h infusion. Teicoplanin is highly bound by plasma proteins (90-95%) and has an extremely long serum elimination t1/2 (up to 100 h).
THERAPEUTIC USES AND DOSAGE. Vancomycin and teicoplanin have been used to treat a variety of infections, including osteomyelitis and endocarditis caused by methicillin-resistant and methicillin-susceptible staphylococci, streptococci, and enterococci. Teicoplanin is not 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-min period to avoid infusion-related adverse reactions; the recommended dose for adults is 30-45 mg/kg/day in 2-3 divided doses. Current recommendations call for monitoring serum trough concentrations (within 30 min prior to a dose) at steady state, typically before the fourth dose of a given dosage regimen. A trough serum concentration of 10 μg/mL is recommended. For patients with more serious infections (including endocarditis, osteomyelitis, meningitis, and MRSA pneumonia), trough levels of 15-20 μg/mL are recommended. Pediatric doses are: for newborns during the first week of life, 15 mg/kg initially, followed by 10 mg/kg every 12 h; for infants 8-30 days old, 15 mg/kg followed by 10 mg/kg every 8 h; for older infants (>30 days) and children, 10-15 mg/kg every 6 h. Alteration of dosage is required for patients with impaired 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. Blood levels should be monitored to decide on dose adjustments.
Skin/Soft-Tissue and Bone/Joint Infections. Vancomycin is used in the 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. Because vancomycin penetration into lung tissue is relatively low, aggressive dosing is generally recommended.
CNS Infections. Vancomycin is a key component in the initial empirical treatment of community-acquired bacterial meningitis in locations where penicillin-resistant S. pneumoniae is common. Penetration of vancomycin across inflamed meningitis is poor; thus, aggressive dosing is typically warranted. Vancomycin is also used to treat nosocomial meningitis often caused by staphylococci.
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. 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 penicillin-resistant isolates. Vancomycin is used for the treatment of vascular catheter infections due to gram-positive organisms.
Other Infections. Vancomycin can be administered orally to patients with pseudomembranous colitis due to C. difficile. The dose for adults is 125-250 mg every 6 h; the total daily dose for children is 40 mg/kg, given in 3 to 4 divided doses. The standard dose of teicoplanin in adults is 3-6 mg/kg/day, with higher dosages possible for treatment of serious staphylococcal infections. Once-daily dosing is possible due to the prolonged serum t1/2. Teicoplanin doses must be adjusted in patients with renal insufficiency. For functionally anephric patients, administration once weekly is appropriate, but serum drug concentrations should be monitored to determine that the therapeutic range has been maintained.
UNTOWARD EFFECTS. Hypersensitivity reactions produced by vancomycin and teicoplanin include 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 not an allergic reaction but a direct effect of vancomycin on mast cells, causing them to release histamine. This reaction is generally not observed with teicoplanin. Auditory impairment, sometimes permanent, is associated with excessive concentrations of these drugs in plasma (60-100 μg/mL of vancomycin). Nephrotoxicity has become less common with modern formulations at standard dosages. Careful dosing and monitoring of vancomycin is necessary to balance the risks and benefits. Caution should be exercised when ototoxic or nephrotoxic drugs, such as aminoglycosides, are administered concurrently with vancomycin.
Daptomycin (CUBICIN), a cyclic lipopeptide antibiotic derived from Streptomyces roseosporus, has been resurrected in response to increasing need for bactericidal antibiotics effective against vancomycin-resistant gram-positive bacteria.
Antimicrobial Activity. Daptomycin is a bactericidal antibiotic selectively active against aerobic, facultative, and anaerobic gram-positive bacteria (see Table 55–1). Daptomycin may be active against vancomycin-resistant strains, although MICs tend to be higher for these organisms than for their vancomycin-susceptible counterparts.
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. Daptomycin resistance has been reported to emerge while on therapy. The mechanisms of resistance to daptomycin have not been fully characterized.
ADME. Daptomycin is poorly absorbed orally and should be administered only intravenously. Direct toxicity to muscle precludes intramuscular injection. The serum t1/2 is 8-9 h, permitting once-daily dosing. Approximately 80% of the administered dose is recovered in urine; a small amount is excreted in feces. Although the drug penetrates adequately into the lung, the drug is inactivated by pulmonary surfactant. If the creatinine clearance is <30 mL/min; the dose is administered only every 48 h. For hemodialysis patients the dose should be given immediately after dialysis. Daptomycin does not affect CYPs and has no important drug–drug interactions. Caution is recommended when daptomycin is coadministered with aminoglycosides or statins because of potential risks of nephrotoxicity and myopathy, respectively.
Therapeutic Uses and Dosage. Daptomycin is indicated for treatment of complicated skin and soft tissue infections (at 4 mg/kg/day) and complicated bacteremia and right-sided endocarditis (at 6 mg/kg/day). Its efficacy is comparable to that of vancomycin.
Untoward Effects. Elevations of creatine kinase may occur; this does not require discontinuation unless findings suggest an otherwise unexplained myopathy. Rhabdomyolysis has been reported to occur rarely.
Bacitracin is an antibiotic produced by the Tracy-I strain of B. subtilis. The bacitracins are a group of polypeptide antibiotics. The commercial products have multiple components; the major constituent is bacitracin A.
Antimicrobial Activity. Bacitracin inhibits the synthesis of the bacterial cell wall; a variety of gram-positive cocci and bacilli, Neisseria, H. influenzae, and T. pallidum, are sensitive to the drug at ≤0.1 unit/mL. Actinomyces and Fusobacterium are inhibited by concentrations of 0.5-5 units/mL. Enterobacteriaceae, Pseudomonas, Candida spp., and Nocardia are resistant to the drug. A unit of the antibiotic is equivalent to 26 μg of the USP standard.
Therapeutic Uses and Dosage. Current use is restricted to topical application. 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. A number of topical preparations of bacitracin, to which neomycin or polymyxin or both have been added, are available. 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. Bacitracin rarely produces hypersensitivity. Suppurative conjunctivitis and infected corneal ulcer, when caused by susceptible bacteria, respond well to the topical use of bacitracin. 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.
Untoward Effects. Nephrotoxicity results from the parenteral use of bacitracin.
Antimicrobial Activity, Mechanism of Action, and Resistance. Mupirocin (BACTROBAN) is for topical use only. The drug is bactericidal against many gram-positive and selected gram-negative bacteria. It has good activity against S. pyogenes and methicillin-susceptible and MRSA. Mupirocin inhibits bacterial protein synthesis by reversible binding and inhibition of isoleucyl transfer-RNA synthase. There is no cross-resistance with other classes of antibiotics. High-level resistance is mediated by a plasmid, which encodes a “bypass” Ile tRNA synthase that binds mupirocin poorly.
ADME. Systemic absorption through intact skin or skin lesions is minimal. Any absorbed drug 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. The consensus is 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.
Untoward Effects. Mupirocin may cause irritation and sensitization at the site of application. Contact with the eyes causes irritation that may take several days to resolve. 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.