Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 47 Inhibitors of Bacterial Ribosomal Actions

MAJOR DRUG CLASSES

Aminoglycosides and related compounds

Ketolides

Macrolides

Oxazolidinones

Streptogramins

Tetracyclines and glycylcyclines

Therapeutic Overview

The antimicrobial agents discussed in this chapter act by binding to bacterial ribosomes and interfering with protein synthesis. Depending on the class, these agents may result in either bactericidal orbacteriostatic effects. A summary of the antimicrobial agents covered in this chapter is in the Therapeutic Overview box.

The aminoglycosides are effective primarily against aerobic gram-negative organisms and, in combination with other classes of antibiotics, are most often used in the treatment of bacteremia and sepsis. They are ineffective against anaerobic organisms, and because of their toxicity they are used less commonly for many gram-negative infections other than bacteremia and sepsis. Because the therapeutic index of the aminoglycosides is narrow and toxicity can be serious, close attention must be paid to the pharmacokinetics of these drugs in individual patients. Renal function must be assessed, and monitoring of plasma concentrations is recommended.

Another ribosome-binding agent, spectinomycin, is related to the aminoglycosides because it is also an aminocyclitol, but it lacks amino sugars, and its actions are different. In addition, the aminoglycosides are bactericidal, whereas spectinomycin is bacteriostatic.

The ribosome-binding sites for macrolides such as erythromycin, azithromycin, clarithromycin, and clindamycin are on the same 50S subunit (S represents the sedimentation parameter), but the structures of the drugs and the spectrum of activities differ considerably. Erythromycin, one of the first macrolides developed, is relatively safe and widely used, especially for the treatment of infections in children (Box 47-1). Because of the success of macrolides in the treatment of pulmonary infections, these drugs continue to be used in the treatment of respiratory tract infections in adults. The primary differences among erythromycin, clarithromycin, and azithromycin are related to relative activities against certain bacterial species such as Mycobacterium, gastrointestinal (GI) tolerability, and pharmacokinetics.Clindamycin displays antimicrobial activity somewhat similar to that

BOX 47–1 Therapeutic Uses of Erythromycin

Drug of Choice

Mycoplasma pneumoniae

Group A streptococcal upper respiratory tract infection (penicillin-allergic patient)

Legionella infection

Bordetella pertussis

Campylobacter jejuni

Ureaplasma urealyticum

Bartonella henselae

Corynebacterium diphtheriae

Alternative Agent

Lyme disease

Chlamydia infection

As Treatment of Syndromes

Bacterial bronchitis

Otitis media (with sulfonamide)

Acne, topical

Prophylaxis

Endocarditis (penicillin-allergic patient)

Large bowel surgery

Oral surgery

Abbreviations

AIDS

Acquired immunodeficiency syndrome

CSF

Cerebrospinal fluid

GI

Gastrointestinal

IM

Intramuscular

IV

Intravenous

MIC

Minimal inhibitory concentration

MLSB

Macrolide-lincosamide-streptogramin B

mRNA

Messenger ribonucleic acid

MRSA

Methicillin-resistant Staphylococcus aureus

tRNA

Transfer ribonucleic acid

VRE

Vancomycin-resistant enterococci

of erythromycin. However, the two differ structurally, and clindamycin displays extensive anaerobic activity while having no activity for atypical respiratory pathogens.

Chloramphenicol is another antibiotic that binds to the 50S ribosomal subunit. Although widely used at one time, its serious side effects and the availability of many other antimicrobial drugs have limited the applications for which this drug is used in the United States.

The ketolides represent a new class of antibiotics within the macrolide-lincosamide-streptogramin B family. Ketolides are semisynthetic derivatives of erythromycin that inhibit protein synthesis via interaction with the 50S ribosomal subunit. Activity against macrolide-resistant respiratory tract pathogens is maintained in ketolides, which also demonstrate excellent activity against atypical respiratory pathogens. Therefore ketolides may provide an additional treatment option for lower respiratory tract infections.

The tetracyclines and synthetic glycylcycline analogs bind to the 30S ribosomal subunit and are effective against aerobic and anaerobic gram-positive and gram-negative organisms. Given their wide spectrum of activity, these agents remain widely used for treatment of bacterial, chlamydial, rickettsial, and mycoplasmal infections, although the development of bacterial resistance has reduced their efficacy against some pathogens (Box 47-2).

BOX 47–2 Therapeutic Uses of Tetracyclines

Drug of Choice

Rickettsial diseases: Rocky Mountain spotted fever, typhus, scrub typhus, Q fever

Ehrlichiosis

Mycoplasma pneumoniae

Chlamydia pneumoniae

Chlamydia trachomatis

Chlamydia psittaci

Lyme disease (Borrelia burgdorferi)

Relapsing fever caused by Borrelia organisms

Brucellosis

Alternative Agent

Plague

Pelvic inflammatory disease

As Treatment of Syndromes

Acne, low-dose oral or topical

Bacterial exacerbations of bronchitis

Malabsorption syndrome resulting from bowel bacterial overgrowth

The streptogramins and oxazolidinones are newer classes of antibiotics that were developed primarily for the treatment of gram-positive organisms and often have activity against organisms that are resistant to β-lactams and glycopeptides. Both classes inhibit protein synthesis, but their structures and mechanisms of action differ.

Therapeutic Overview

Aminoglycosides

Inhibit gram-negative aerobes

Narrow therapeutic index

Renal and otic toxicities can be serious

Pharmacokinetics are important considerations

Plasmid-mediated resistance is a problem

Macrolides

Inhibit Mycoplasma, Chlamydia, Legionella

Inhibit gram-positive organisms

Clindamycin

Inhibits gram-positive cocci and anaerobic species

Active against clostridium difficile-associated diarrhea and colitis

Chloramphenicol

Kills major meningitis pathogens

Serious toxicity

Ketolides

Inhibit respiratory pathogens

Active against penicillin and macrolide-resistant S. pneumoniae

Tetracyclines

Inhibit broad spectrum of organisms

Streptogramins

Inhibit gram-positive organisms

Active against VRE

Oxazolidinones

Inhibit gram-positive organisms

Active against VRE

These drugs represent important agents for the treatment of multidrug-resistant gram-positive infections, but prudent use will be important to prevent the development of resistance to these agents.

Mupirocin, which interferes with transfer ribonucleic acid (tRNA) synthesis, is a topical agent primarily used to treat cutaneous streptococcal and staphylococcal infections.

Mechanisms of Action

The bacterial ribosomal subunit to which each of these drugs binds and the bactericidal or bacteriostatic response of susceptible bacteria to the drugs are in Table 47-1. The principal steps in bacterial ribosomal synthesis of proteins, as carried out by the 70S ribosomes and relevant RNAs, and the points at which the drugs act, are depicted in Figure 47-1.

TABLE 47–1 Bacterial Ribosomal Binding and Resulting Overall Effect on Bacterial Viability

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FIGURE 47–1 Bacterial protein synthesis and points where clinically used antibiotics act. The steps are as follows: (1) Streptomycin and other aminoglycosides freeze initiation, so ribosome does not progress along mRNA and convert from polysome to monosome; oxazolidinones inhibit formation of 70S initiation complex; (2) tetracycline and chloramphenicol prevent tRNA from binding to mRNA codon; (3) chloramphenicol, erythromycin, ketolides, and streptogramins block peptide bond formation; (4) erythromycin, clindamycin, and ketolides block translocation step; and (5) streptomycin and other aminoglycosides cause misreading of mRNA so that the wrong amino acid is added.

Aminoglycosides

Aminoglycosides consist of amino sugars linked through glycosidic bonds to an aminocyclitol. The structures of streptomycin, gentamicin, and other clinically important aminoglycosides are shown inFigure 47-2. The particular amino sugars and specific locations of the amino groups distinguish the compounds and are important for their antimicrobial effects and toxicity. Gentamicin consists of a mixture of three species with little differences in activities.

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FIGURE 47–2 Structures of streptomycin and gentamicin and main components of other clinically used aminoglycosides. D, 2-Deoxystreptamine.

The aminoglycosides exert a concentration-dependent bactericidal action by entering the bacterial cell and inhibiting protein synthesis. The overall process consists of two main steps:

• Transport through the bacterial cell wall and cytoplasmic membrane

• Binding to ribosomal sites, thus inhibiting protein synthesis.

The aminoglycosides can cross the complex cell membrane structure of gram-negative bacteria (see Fig. 46-3) and are more effective against aerobic gram-negative than gram-positive bacteria.

Transport of aminoglycosides into bacterial cells involves several steps. These cationic compounds bind to anionic surfaces and penetrate porin channels of the outer membrane of gram-negative bacteria, or the water-filled areas of the peptidoglycan wall in gram-positive bacteria. The aminoglycoside then binds to a molecule in the electron transport chain in the cytoplasmic membrane. The drug-transporter complex is moved across the cytoplasmic membrane by its potential gradient. The transport is an energy-requiring aerobic step that does not occur in an anaerobic environment or at low pH. After crossing the cytoplasmic membrane, the aminoglycosides bind to ribosomes, maintaining a low concentration of intracellular free drug, which facilitates continued drug transfer accumulation. This results in a loss of membrane integrity and eventual death of the bacteria. Ca++, Mg++, and other divalent ions inhibit the transport of aminoglycosides into bacteria.

Binding to the ribosome leads to inhibition of protein synthesis. This takes place on the ribosomes, where messenger RNA (mRNA) acts as a template for the addition of activated amino acids attached to tRNAs. The 70S ribosomal particles move along the mRNA template, adding the appropriate amino acid (see Fig. 47-1). Aminoglycosides bind to several ribosomal sites (see Table 47-1) of the 30S and 50S subunits of the bacterial ribosome. Streptomycin, the most thoroughly studied, binds to the 30S subunit, although this can be altered by mutation of particular amino acids. Binding of aminoglycosides interferes with protein synthesis in two ways:

• It restricts polysome formation.

• It causes mRNA to be misread.

Disaggregation of polysomes blocks their ability to move along the mRNA and synthesize a new peptide chain. Aminoglycosides also bind to the juncture between the 30S and 50S subunits and cause distortion of codon recognition, resulting in abnormal protein production. However, the presence of miscoded proteins does not necessarily correlate with cell death, as exemplified by other protein synthesis inhibitors that are bacteriostatic, whereas aminoglycosides are bactericidal. The bactericidal activity of aminoglycosides likely results from a combination of impaired protein synthesis and membrane dysfunction.

Aminoglycosides also demonstrate a prolonged postantibiotic effect, in which suppression of bacterial growth continues after the serum concentration falls below the minimal inhibitory concentration (MIC). Higher aminoglycoside concentrations are associated with a longer postantibiotic effect. This postantibiotic effect has allowed for once-daily dosing of aminoglycosides with a lower risk of associated toxicities.

Synergistic killing has been demonstrated when aminoglycosides are combined with cell wall active agents (e.g., β-lactams, glycopeptides). The explanation for synergy is related partly to increased uptake of the aminoglycosides in the presence of cell wall active agents. Clinically, aminoglycosides and cell wall active agents are combined to achieve synergistic killing against enterococci,Staphylococcus aureus, Pseudomonas aeruginosa, and other Enterobacteriaceae.

Bacterial resistance to aminoglycosides results from:

• Enzymatic modification of drug

• Altered ribosomes

• Inadequate transport within the cell

Clinically, enzymatic modification of the aminoglycosides is the most important mechanism of resistance. Although resistance resulting from altered ribosomes does occur in enterococci, it is rarely seen in gram-negative bacteria and is relatively uncommon. Resistance as a consequence of the inadequate transport of drug across the cytoplasmic membrane is uncommon in aerobic or facultative species but is seen in strict anaerobes. Mutants with alterations in the electron transfer chain and in adenosine triphosphatase activity have been identified, but they are very rare. The resistance of some Pseudomonasspecies to aminoglycosides may be related to failure of the drug to distort the lipopolysaccharide of the outer membrane, thus not allowing drug to enter the bacterial cell.

The most common form of resistance stems from modification of the aminoglycoside, which occurs through enzyme-catalyzed phosphorylation, adenylation, or acetylation. The genes for these enzymes are located on plasmids or transposons, which can be spread to many different bacterial species. Many such enzymes have been identified, some of which can inactivate only one or two compounds, whereas others can inactivate multiple compounds. For example, an enzyme that acetylates the amino group at position 6 of the amino hexose can inactivate kanamycin, neomycin, tobramycin, amikacin, and netilmicin but not gentamicin or streptomycin. The altered aminoglycosides do not bind as well to ribosomes, and the modified compounds do not trigger accelerated drug uptake.

Aminoglycoside resistance varies by location and local use patterns. A low resistance to gentamicin may occur in one hospital, whereas high resistance may occur in another hospital. It is not feasible at present to predict precise resistance mechanisms. Over prolonged periods, selective use or substitution of one aminoglycoside may lead to reductions in resistance to other aminoglycosides. This was demonstrated at the Minneapolis Veterans Affairs Medical Center, when the repeated selective use of amikacin reduced resistance to gentamicin and tobramycin among aerobic gram-negative organisms. Amikacin is the most resistant of the aminoglycosides to inactivation by resistant organisms, and netilmicin is the second most resistant.

Spectinomycin

Spectinomycin acts by binding to the 30S ribosome subunit and inhibiting a translocation step, perhaps by interfering with movement of mRNA along the 30S subunit. Resistance to this drug stems from the transfer of a plasmid directing synthesis of an enzyme that acetylates the compound or changes amino acids in the S5 protein of the 30S subunit.

Macrolides, Chloramphenicol, and Clindamycin

The macrolides (erythromycin, clarithromycin, azithromycin, and dirithromycin), chloramphenicol, and clindamycin are discussed as a group because these agents bind to the same site or sites on the ribosomal 50S subunit. They bind to bacterial 70S ribosomes but not to the 80S ribosomes of mammalian cells. Their structures are shown in Figure 47-3. Bacterial resistance is observed for all of these agents.

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FIGURE 47–3 Structures of chloramphenicol, erythromycin, and clindamycin.

Erythromycin and the newer macrolides reversibly bind to 50S ribosomal subunits, causing dissociation of peptidyl-tRNA from the ribosome and interference with peptide elongation. Erythromycin inhibits the binding of chloramphenicol to 50S ribosomes, but chloramphenicol does not inhibit erythromycin binding. The activity of macrolides is primarily bacteriostatic; however, bactericidal activity is observed for certain organisms (see Table 47-1).

Bacterial resistance to macrolides occurs by several mechanisms, some of which also confer resistance to clindamycin and streptogramin type B. The most problematic forms of resistance arise either from alteration of ribosomal binding sites or drug efflux. Alteration of ribosomal binding sites occurs via a plasmid-encoded enzyme that methylates the 50S ribosomal subunit. Methylation likely causes a conformational change of the ribosomal target and decreased binding. This type of resistance is associated with the erm (erythromycin ribosome methylation) gene and is referred to as the macrolide-lincosamide-streptogramin B (MLSB) phenotype, because it confers resistance to macrolides, clindamycin, and streptogramin B. Both erythromycin and clindamycin induce this enzyme, but erythromycin has greater activity. This is clinically important, because an organism resistant to erythromycin and susceptible to clindamycin can become resistant to both drugs during therapy. This applies to the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), which is often resistant to erythromycin but may appear susceptible to clindamycin. This form of resistance is present on plasmids that can pass from enterococci to streptococci and is encountered in strains of macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes.

Efflux systems represent another prominent mechanism of macrolide resistance. This type of resistance is associated with mef genes and does not confer resistance to clindamycin or streptogramin B. For these resistance types, complete cross-resistance exists among erythromycin, clarithromycin, and azithromycin.

Although some gram-negative bacteria possess ribosomes that do not bind erythromycin or clindamycin, the common form of resistance to erythromycin is its failure to pass through the outer membrane of aerobic gram-negative bacteria. For example, 100 times less erythromycin can cross the outer membrane of gram-negative Escherichia coli than that of S. aureus (gram-positive). Gram-negative bacteria may also possess esterases that hydrolyze erythromycin.

Chloramphenicol prevents the addition of new amino acids to growing peptide chains by interfering with binding of the amino acid–acyl–tRNA complex to the 50S subunit, preventing formation of a peptide bond. Chloramphenicol displays primarily bacteriostatic activity but is bactericidal for selected pathogens including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.Macrolides and clindamycin bind to the same ribosomal site, antagonizing the activity of chloramphenicol, and should not be used concurrently. Most resistance to chloramphenicol is caused by chloramphenicol acetyltransferase. This enzyme catalyzes the acetylation of the hydroxy groups of chloramphenicol, which makes it unable to bind to the 50S subunit. Less common mechanisms of resistance arise from alterations in cell wall permeability or ribosomal proteins.

The mechanism of action of clindamycin is similar to that of erythromycin. The ribosomal binding site for clindamycin overlaps with that of macrolides and chloramphenicol, creating the potential for antagonism when used concurrently. Resistance to clindamycin may arise from alterations in ribosomal binding sites as described, with a resultant MLSB phenotype conferring resistance to both clindamycin and macrolides. This form of resistance is often plasmid-mediated and has been observed in clindamycin-resistant strains of Bacteroides fragilis. Intrinsic resistance to clindamycin is seen in Enterobacteriaceae and Pseudomonas, resulting from poor permeability of the cell envelope to clindamycin.

Ketolides

The ketolides are semisynthetic derivatives of erythromycin and are part of the MLSB family of antimicrobials. The currently approved ketolide is telithromycin; its structure is shown in Figure 47-4. Similar to the macrolides, ketolides inhibit protein synthesis at the 50S ribosomal subunit. However, ketolides demonstrate a higher binding affinity. Ketolides are primarily bacteriostatic but demonstrate bactericidal activity against some pathogens, including S. pneumoniae and H. influenzae.

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FIGURE 47–4 Structures of telithromycin, quinupristin, dalfopristin, and linezolid.

In contrast to macrolides, ketolides retain activity against most organisms whose ribosomal binding sites have been modified via methylation (MLSB phenotypes). In addition, ketolides do not appear to induce MLSB resistance in streptococci but may promote constitutive expression of erm genes in staphylococci with an inducible MLSB phenotype. Telithromycin-resistant strains of S. pneumoniae have been described in which both ribosomal modification and mutations in ribosomal proteins were present. Telithromycin has retained activity against streptococci demonstrating mef mediated efflux pumps.

Tetracyclines and Glycylcyclines

The structures of the tetracyclines are shown in Figure 47-5. These compounds bind to 30S ribosomes, thereby preventing attachment of the aminoacyl-tRNA to its acceptor site and preventing the addition of amino acids to the peptide chain being synthesized. Differences in the activities of individual tetracyclines are related to their solubility in lipid membranes of the bacteria. These drugs enter the cytoplasm of gram-positive bacteria by an energy-dependent process, but in gram-negative organisms, they pass through the outer membrane by diffusion through porins. Because minocycline anddoxycycline are more lipophilic, they can enter gram-negative cells through the outer lipid membrane and through the porins. Once in the periplasmic space, the tetracyclines are transported across the inner cytoplasmic membrane by a protein-carrier system.

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FIGURE 47–5 Structures of tetracyclines.

There are several mechanisms of resistance to tetracyclines. The most common, found in both gram-positive and gram-negative bacteria, is plasmid or transposon mediated and involves decreased intracellular accumulation and increased transport of the drug out of the bacterial cell (Fig. 47-6). Drug efflux occurs as a result of the action of a new protein, likely induced by the drug. A second mechanism involves alteration of outer membrane proteins resulting from mutations in chromosomal genes. In a third mechanism the ribosomal binding site is protected as a result of the presence of a plasmid-generated protein that binds to the ribosome. Resistance to one tetracycline usually implies resistance to all tetracyclines. However, some staphylococci and some Bacteroides species are resistant to tetracycline but susceptible to minocycline and doxycycline because of the lipophilicity of these latter agents.

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FIGURE 47–6 Mechanism for bacterial resistance to tetracycline (T) caused by efflux.

The glycylcyclines are newly developed tetracyclines that inhibit bacteria previously resistant to all the commercially available tetracyclines. The first of these clinically approved is tigecycline, which binds to the 30S ribosomal subunit with five times greater affinity than the other tetracyclines. Tigecycline is not expelled by the bacterial macrolide or tetracycline pumps. It has been shown to be effective in the treatment of infections caused by MRSA and vancomycin-resistant enterococci (VRE). However, to reduce the risk of resistance developing to tigecycline, its use is restricted to treat infections resistant to the other tetracyclines.

Streptogramins

Streptogramins are a family of compounds derived from Streptomyces pristinaespiralis whose members are classified into two groups based upon structure. For clinical use, two streptogramins,quinupristin and dalfopristin, whose structures are shown in Figure 47-4, are combined as quinupristin-dalfopristin in a 30:70 mixture. The sequential binding of each component to the 50S ribosomal subunit leaves a stable drug-ribosome complex that interferes with peptide chain elongation and peptidyl transferase. The activity of each component is bacteriostatic, but the combination is bactericidal against some organisms. The spectrum of activity of quinupristin-dalfopristin encompasses many gram-positive organisms, whereas activity against gram-negative organisms is limited.

Resistance to streptogramins occurs by ribosomal modification (erm gene), drug efflux, or drug inactivation, with ribosomal modification being most common. Enterococcus faecalis, in contrast toEnterococcus faecium, is resistant to quinupristin-dalfopristin as the result of an intrinsic efflux pump for dalfopristin present in Enterococcus faecalis. Inherent resistance to quinupristin-dalfopristin also occurs in Enterobacteriaceae and Pseudomonas aeruginosa related to cell wall impermeability.

Oxazolidinones

Oxazolidinones inhibit protein synthesis by binding to the 50S ribosomal subunit and preventing formation of the initiation complex. The oxazolidinone available for use in the United States is linezolid (seeFig. 47-4). Linezolid is bacteriostatic, with activity directed primarily against gram-positive organisms, including those resistant to other antibiotics.

The development of resistance to linezolid in gram-positive organisms has been relatively limited. Although uncommon, resistance has been observed in VRE and MRSA. Resistance in gram-positive organisms occurs by alteration of ribosomal binding sites caused by mutations in the 23S rRNA gene. Cross-resistance with other ribosomal inhibitors has not been demonstrated. Gram-negative organisms become resistant to linezolid via drug efflux.

Mupirocin

Mupirocin is a topical agent, previously known as pseudomonic acid, which inhibits gram-positive and some gram-negative bacteria by binding to isoleucyl-tRNA synthetase, preventing isoleucine incorporation into bacterial proteins. Mupirocin has been shown to eliminate the nasal carriage of methicillin-resistant staphylococci.

Pharmacokinetics

The pharmacokinetic parameters for the antibiotics that inhibit bacterial protein synthesis are given in Table 47-2.

TABLE 47–2 Pharmacokinetic Parameters

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Aminoglycosides

Aminoglycosides are not absorbed to a significant extent after oral or rectal administration and thus are administered by the intramuscular (IM) or intravenous (IV) routes. The exception to this is in newborns with necrotizing enterocolitis, when significant oral absorption can occur. However, if renal impairment is present, even the small amount of drug absorbed by the oral route may accumulate and cause toxicity, even in adults. Peak plasma concentrations occur in 30 to 60 minutes after IM injection, with plasma concentrations comparable to those achieved after a 30-minute infusion. Absorption from the IM site of injection is decreased in patients in shock, and thus the IM route is rarely used to treat life-threatening septic infections.

Topical application of aminoglycosides results in minimal absorption, except in patients with extensive cutaneous damage such as burns or epidermolysis. Intraperitoneal and intrapleural instillation result in such rapid absorption that toxicity may develop; however, irrigation (of bladder), intratracheal, and aerosol delivery do not result in significant absorption. New techniques of aerosolization with correct particle size can produce concentrations of more than 100 µg/mL in the lung but only 4 µg/mL in plasma.

Because of their high polarity, aminoglycosides do not enter phagocytic or other cells, the brain, or the eye. They are distributed into interstitial fluid, with a volume of distribution essentially equal to that of the extracellular fluid. The highest concentrations of aminoglycosides occur in the kidney, where they concentrate in proximal tubular cells. Urine concentrations are generally 20 to 100 times greater than those in plasma and remain so for 24 hours after a single dose. These drugs enter peritoneal, pleural, and synovial fluids relatively slowly but eventually achieve concentrations that are only slightly less than those in plasma.

Concentrations of aminoglycosides in cerebrospinal fluid (CSF) after IM or IV administration are inadequate for treatment of gram-negative meningitis. Intrathecal administration into the lumbar space produces inadequate intraventricular concentrations, whereas intraventricular instillation yields high concentrations in both areas. Subconjunctival injection produces high aqueous fluid concentrations but inadequate intravitreal concentrations.

Elimination of aminoglycosides occurs almost completely by glomerular filtration. A small amount is reabsorbed into proximal renal tubular cells. Renal clearance of aminoglycosides is approximately two thirds that of creatinine. However, these drugs can become trapped in tissue compartments, such that they have tissue half-lives of 25 to 500 hours, and aminoglycosides can be detected in urine for up to 10 days after treatment is discontinued for a week. Dosing schedules must be adjusted in patients who have reduced renal capacity. Because the clearance of aminoglycosides is linearly related to creatinine clearance, the latter can be used to calculate dosing. Aminoglycosides can be removed from the body by hemodialysis but not very well by peritoneal dialysis.

Spectinomycin

Spectinomycin is not absorbed from the GI tract and therefore is administered IM. Elimination is primarily by glomerular filtration, with 85% to 90% removed in 24 hours.

Erythromycin

In its free base form, erythromycin is inactivated by acid. Therefore it is administered orally with an enteric coating that dissolves in the duodenum. Even in the absence of food, which delays absorption, peak plasma concentrations are difficult to predict. Ester forms of erythromycin are available to help overcome this problem. Lactobionate and gluceptate, water-soluble forms of the drug, are available for IV administration.

Erythromycin is well distributed and produces therapeutic concentrations in tonsillar tissue, middle ear fluid, and lung. It enters prostatic fluid, where it reaches concentrations approximately one third those in plasma. It does not diffuse well into brain or CSF. Erythromycin crosses the placenta and is found in breast milk, with high concentrations also observed in liver and bile. It achieves high concentrations in alveolar macrophages and neutrophils.

The main route of elimination of erythromycin is via metabolic demethylation by the liver and biliary excretion. Inactive metabolites are responsible for causing gastric intolerance. Only a small percentage is excreted unchanged. Erythromycin metabolites inhibit cytochrome P450 enzymes and can lead to increased plasma levels of drugs, including theophylline, oral anticoagulants, and digoxin. Care must be taken to monitor patients on other medications if erythromycin is added to their regimen.

Azithromycin

In contrast to erythromycin, azithromycin is acid-stable. Approximately 37% of a dose is absorbed, but this is greatly reduced in the presence of food. Serum concentrations are low because of its rapid distribution to tissues. Therapeutic concentrations are reached in lung, genitalia, and liver. Azithromycin is highly concentrated in phagocytic cells, macrophages, and fibroblasts, from which it is slowly released. Tissue concentrations of azithromycin may be 10 to 100 times greater than plasma concentrations. Release from the tissues is slow and may take from 2 to 4 days; however, the presence of bacteria causes the drug to be released from neutrophils. The prolonged tissue half-life of azithromycin allows for once-daily dosing and shorter durations of therapy.

Azithromycin is eliminated unchanged in feces and to a lesser extent in urine. Concentrations in the elderly and patients with decreased renal function are increased but are not significantly affected by hepatic disease. In contrast to erythromycin and clarithromycin, azithromycin does not inhibit hepatic cytochrome P450 enzymes.

Clarithromycin

Clarithromycin is approximately 55% absorbed by the oral route and is widely distributed to lung, liver, and soft tissues. Concentrations in phagocytic cells are approximately nine fold greater than those in serum. The drug is metabolized to a 14-hydroxy derivative, which has antibacterial activity greater than that of the parent compound. Approximately 30% of the drug is excreted in the urine, and the remainder in feces. The half-lives of clarithromycin and its active metabolite are increased in patients with declining renal function but are not appreciably affected by hepatic disease. Currently, an intravenous preparation of clarithromycin is not available. As with erythromycin, clarithromycin is a hepatic cytochrome P450 inhibitor.

Chloramphenicol

Chloramphenicol is well absorbed from the GI tract, with peak plasma concentrations reached approximately 2 hours after ingestion. It is also available as an inactive palmitate, most of which is hydrolyzed by pancreatic lipases in the duodenum, with subsequent absorption of the active compound. Parenterally administered chloramphenicol is available as a succinate ester, which must be hydrolyzed to the active compound by esterases in the liver, lungs, and kidney. The succinate should not be given IM, because the plasma concentrations are unpredictable.

Because it is highly lipid soluble, chloramphenicol is well distributed throughout the body and enters pleural, ascitic, synovial, eye, and abscess fluids; CSF; and lung, liver, and brain tissues. Approximately 90% of a dose of chloramphenicol is conjugated in the liver to an inactive and nontoxic glucuronide that is filtered by the kidney. The normal plasma half-life is prolonged in patients with hepatic disease but not in patients with renal disease.

High concentrations of free drug may accumulate in infants deficient in forming glucuronides. In addition, hydrolysis of the succinate may be depressed in newborns and infants and requires careful monitoring of serum concentrations when this drug is used in these groups. Because of toxicity, bacterial resistance, and the availability of other antibiotics, chloramphenicol is rarely used.

Clindamycin

Clindamycin is well absorbed from the GI tract. Although absorption is delayed in the presence of food, overall bioavailability is not decreased. Mean peak plasma concentrations occur within 1 hour. Clindamycin is available as a palmitate ester, which is rapidly hydrolyzed to free drug, and is also available as a phosphate ester, with the latter used for IM administration.

Distribution is widespread, with clindamycin entering most body compartments and achieving adequate concentrations in lung, liver, bone, and abscesses. It enters the CSF and brain tissue, but the concentrations are inadequate to treat meningitis and should not be relied on to treat brain infections except toxoplasmosis. This drug enters polymorphonuclear leukocytes and alveolar macrophages and crosses the placenta.

Clindamycin is metabolized to the bacteriologically active N-dimethyl and sulfoxide derivatives, which are excreted in urine and bile. The half-life is prolonged in patients with severe liver disease.

Telithromycin

Telithromycin is well absorbed after oral administration, but 33% of an administered dose undergoes first-pass metabolism in the liver, with 57% reaching the systemic circulation. Absorption is not affected by food. Telithromycin achieves high intracellular concentrations, particularly within neutrophils and alveolar macrophages, and has extensive penetration into respiratory and tonsillar tissues. Metabolism occurs in the liver, with elimination primarily in feces and a smaller portion in urine. Telithromycin inhibits cytochrome P450 activity, which can lead to drug interactions. Dosing does not require modification in patients with hepatic or renal impairment.

Tetracyclines

Some tetracyclines are incompletely absorbed, whereas others are well absorbed when administered orally, but all attain adequate plasma and tissue concentrations. Minocycline and doxycycline are the most completely absorbed and chlortetracycline the least. Absorption is favored during fasting, because tetracyclines form complexes with divalent metals, including Ca++, Mg++, Al++, and Fe++. Absorption of some tetracyclines is decreased when ingested with milk products, antacids, or Fe++ preparations. However, food does not interfere with the absorption of minocycline or doxycycline, and histamine receptor antagonists do not affect absorption.

The tetracyclines are widely distributed in body compartments. High concentrations are found in liver, kidney, bile, bronchial epithelium, and breast milk. These drugs can also enter pleural, peritoneal, synovial, and sinus fluids, cross the placenta, and enter phagocytic cells. Penetration into the CSF is poor and increases only minimally in the setting of meningeal inflammation; however, minocycline does achieve therapeutic concentrations in brain tissue.

Tetracyclines do not bind to formed bone but are incorporated into calcifying tissue and into the dentin and enamel of unerupted teeth. Thus the deposition of tetracyclines in teeth and bones is more problematic in children than adults.

The tetracyclines are eliminated by renal and biliary routes and by metabolism. Although most of the biliary-eliminated drug is reabsorbed by active transport, some is chelated and excreted in feces. This occurs even when these drugs are administered parenterally. Renal clearance of the tetracyclines occurs by glomerular filtration. All tetracyclines, except doxycycline, accumulate in patients with decreased renal function; thus only doxycycline should be given to patients with renal impairment.

Some tetracyclines are also metabolized, an important mechanism for chlortetracycline but less important for doxycycline and minocycline. Metabolism of doxycycline is increased in patients receiving barbiturates, phenytoin, or carbamazepine, because these agents induce the formation of hepatic drug-metabolizing enzymes. The half-life of doxycycline decreases from 16 to 7 hours in such patients. In contrast, decreased hepatic function or common bile duct obstruction will prolong the half-life of the tetracyclines because of the reduction in biliary excretion.

Quinupristin and Dalfopristin

Quinupristin and dalfopristin are water-soluble derivatives of pristinamycin that are available only for parenteral use. After IV administration, quinupristin-dalfopristin rapidly achieves a wide tissue distribution but does not have significant CSF penetration and does not cross the placenta. High concentrations are found in macrophages. Quinupristin-dalfopristin is metabolized in the liver and eliminated primarily through biliary excretion into the feces. In addition, a small fraction is excreted by the urinary system unchanged. Dose adjustment is not required for either hepatic or renal impairment.

Linezolid

Linezolid undergoes rapid and complete absorption after oral administration; food slows absorption, but overall bioavailability is not affected. Linezolid penetrates into muscle, bone, alveolar cells, and CSF. In a small number of patients with gram-positive bone and joint infections, intrabone tissue concentrations of linezolid were below the MIC90 for the tested pathogens, whereas joint and periarticular tissue concentrations were twice the MIC90. Additional studies are needed to fully define the tissue distribution of linezolid.

Metabolism of linezolid occurs by nonenzymatic oxidation throughout the body, with most of the unchanged linezolid and its primary metabolites eliminated by urinary excretion. Dosage adjustment is not required for either mild or moderate hepatic impairment or for renal insufficiency. Accumulation of metabolites does occur in renal insufficiency, but the clinical significance is unknown.

Relationship of Mechanisms of Action to Clinical Response

Aminoglycosides

The aminoglycosides are effective primarily against aerobic gram-negative bacilli such as Enterobacteriaceae or Pseudomonas aeruginosa and have little effect on anaerobic species. Most staphylococci are inhibited.

Aminoglycosides should be reserved for the treatment of serious infections for which other agents such as penicillins or cephalosporins are not suitable. Aminoglycosides have no role in the initial therapy of gram-positive infections. They must be given in combination with penicillins or glycopeptides to treat endocarditis resulting from enterococci, viridans streptococci, or coagulase-negative staphylococci. Gentamicin is the preferred agent, because streptomycin resistance is common.

The initial treatment of suspected sepsis has consisted of an aminoglycoside such as gentamicin or tobramycin in combination with a penicillin or cephalosporin, but newer cephalosporins and other β-lactams such as aztreonam or imipenem have lower toxicity and are being used with increased frequency in this setting (see Chapter 46). Local antimicrobial resistance patterns should be used to help define empiric therapies for sepsis.

Aminoglycosides are particularly effective in the treatment of urinary tract infections, probably because of their elevated concentrations in the kidney. However, many other agents are available for this purpose, particularly orally administered quinolones. Hospital-acquired pneumonia has been treated with aminoglycosides; an aminoglycoside in combination with an antipseudomonal penicillin, cephalosporin, or monobactam is usually selected for the treatment of serious respiratory tract infections resulting from P. aeruginosa.

In the past, aminoglycosides, combined with either clindamycin or metronidazole, were used for the treatment of community-acquired intraabdominal infections. However, given the availability of equally efficacious and less toxic alternatives, aminoglycosides are no longer recommended for routine treatment of these infections. Aminoglycosides may be indicated in combination treatment regimens for intraabdominal infections acquired in the hospital, where the potential for serious Pseudomonas and Enterobacter infections exists. In addition, the combination of an aminoglycoside with clindamycin can be used to treat gynecological infections, including pelvic inflammatory disease.

Although aminoglycosides have been used to treat aerobic gram-negative osteomyelitis and septic arthritis, other agents of the β-lactam or quinolone classes are preferred. Gram-negative meningitis is more appropriately treated with third-generation cephalosporins, although on rare occasions the intraventricular instillation of an aminoglycoside may be necessary for the management of selectedPseudomonas or Acinetobacter meningitis or ventriculitis. Serious endophthalmitis can be treated with gentamicin instilled IV.

Aminoglycosides are used in combination with an antipseudomonal β-lactam to treat suspected sepsis in febrile neutropenic patients. Choice of the particular agent depends on local susceptibility patterns. In general, gentamicin is the first agent used, with tobramycin reserved for Pseudomonas infections, and netilmicin or amikacin used in the event of resistance. Alternatives should be used for the treatment of neutropenic fever when patients have received previous nephrotoxic chemotherapy.

Streptomycin is used primarily to treat uncommon infections such as those caused by Francisella tularensis, Brucella species, Yersinia pestis, and resistant tuberculosis strains or infections in patients allergic to the usual antituberculosis drugs (see Chapter 49). Amikacin is also used to treat multidrug resistant tuberculosis.

Spectinomycin

Although spectinomycin inhibits many gram-negative bacteria, it is used as an alternative agent for gonococcal infections when the drugs of choice (cephalosporin or quinolone) cannot be used. It is ineffective for the treatment of pharyngeal gonorrhea.

Macrolides

The macrolides, erythromycin, azithromycin, clarithromycin, and dirithromycin, are active primarily against gram-positive species such as staphylococci and streptococci but also inhibit some gram-positive bacilli (see Box 47-1). ChlamydiaeM. pneumoniae, Ureaplasma urealyticum, Legionella, Corynebacterium diphtheriae, Bordetella species, Campylobacter jejuni, and most oral anaerobic species are inhibited. Most aerobic gram-negative bacilli are resistant, although azithromycin inhibits Salmonella.

Both azithromycin and clarithromycin inhibit Haemophilus influenzae, but of all the macrolides, azithromycin is the most effective. Azithromycin and clarithromycin both have activity againstMycobacterium avium complex and Mycobacterium chelonae, although clarithromycin is more active against the latter. Both agents also have important activity against Helicobacter pylori. Dirithromycin is generally similar to erythromycin in its spectrum of antibacterial activity.

Erythromycin and other macrolides are used as an alternative to penicillin, particularly in children and especially in those with streptococcal pharyngitis, erysipelas, scarlet fever, cutaneous streptococcal infections, and pneumococcal pneumonia. However, levels of macrolide resistance in S. pneumoniae and S. pyogenes continue to increase; thus therapy with macrolides is increasingly problematic. Despite increasing resistance, macrolides continue to be used widely in combination with β-lactams for the treatment of community-acquired pneumonia because of their excellent activity against atypical respiratory pathogens. Although macrolides can cure S. aureus infections, the high frequency of resistance does not make them an initial choice for therapy. Azithromycin is useful for treating sexually transmitted diseases, including ones caused by Chlamydiae (potential for treatment with a single 1-g dose that significantly increases compliance), and erythromycin can be used to treat chlamydial pneumonia of the newborn. Trachoma can be treated effectively with a single dose of azithromycin. Recent data also support the use of azithromycin for the treatment of traveler’s diarrhea. Erythromycin is also useful for eradicating the carrier state of diphtheria and may shorten the course of pertussis if administered early. Clarithromycin and azithromycin are useful in both preventing and treating M. avium complex infections in patients with acquired immunodeficiency syndrome (AIDS). Bacillary angiomatosis in patients with AIDS has also been successfully treated with erythromycin. Erythromycin can be used to prevent bacterial endocarditis in penicillin-allergic patients with rheumatic fever.

Chloramphenicol

Chloramphenicol has an extremely broad spectrum of antimicrobial activity, inhibiting aerobic and anaerobic gram-positive and gram-negative bacteria, chlamydiae, rickettsiae, and mycoplasmas. It is particularly active against B. fragilis. Although it is bacteriostatic for Enterobacteriaceae, staphylococci, and streptococci, it is bactericidal for Haemophilus influenzae, Neisseria meningitidis, and many S. pneumoniae.

Because of the serious adverse side effects associated with its use, chloramphenicol should be used only when no other drug is suitable. In the United States, chloramphenicol is used mainly as an alternative therapy for patients with bacterial meningitis who have a severe penicillin allergy that precludes treatment with a β-lactam. However, clinical failures have been observed with chloramphenicol when used to treat meningitis caused by penicillin-resistant Streptococcus pneumoniae. Chloramphenicol also represents an alternative therapy for patients with rickettsial diseases who cannot be treated with a tetracycline. In certain parts of the world, chloramphenicol continues to be widely used to treat typhoid fever given its low cost and availability. Unfortunately, chloramphenicol-resistant Salmonella typhi are becoming increasingly problematic.

Clindamycin

Clindamycin inhibits many anaerobes and most gram-positive cocci but not enterococci or the aerobic gram-negative bacteria Haemophilus, Mycoplasma, and Chlamydia. The occurrence of serious diarrhea in patients taking clindamycin, including pseudomembranous colitis from Clostridium difficile, limits its use to specific indications. Clindamycin is useful for anaerobic pleuropulmonary and odontogenic infections. It is appropriate therapy for intraabdominal or gynecological infections in which Bacteroides organisms are likely pathogens, although increased levels of clindamycin resistance inBacteroides species are increasingly common. Clindamycin should not be used for brain abscesses if anaerobic species are anticipated.

Clindamycin is an alternative to penicillin and may be preferable in certain situations in which β-lactamase producing Bacteroides organisms is present. Clindamycin is also an alternative to penicillinase-resistant penicillins in the treatment of staphylococcal infections but is usually not preferred to a cephalosporin or vancomycin and should not be used for treatment of endocarditis. Clindamycin may be useful for some MRSA infections, but inducible clindamycin resistance may occur in isolates resistant to erythromycin. For severe group A streptococcal infections or toxic shock syndrome, clindamycin is often used in combination with penicillin to limit bacterial growth and reduce toxin production.

In AIDS patients with sulfonamide allergy or intolerance, clindamycin represents an important component of alternative combination treatments for central nervous system toxoplasmosis or Pneumocystis carinii pneumonia.

Telithromycin

Telithromycin displays excellent activity against most of the pathogens causing community-acquired pneumonia, including atypical intracellular pathogens. Potent in vitro activity against S. pneumoniae, H. influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila has been demonstrated. As noted, telithromycin retains activity against most penicillin-resistant and macrolide-resistant S. pneumoniae regardless of macrolide resistance phenotype. Clinically, telithromycin represents an additional treatment option for community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute sinusitis. Given its activity against drug-resistant pneumococci, telithromycin may prove to be useful in the treatment of community-acquired pneumonia in areas with high levels of penicillin and macrolide resistance. Efforts to limit overuse will be important to prevent development of telithromycin resistance.

Tetracyclines

Tetracyclines are broad-spectrum agents that inhibit a wide variety of aerobic and anaerobic gram-positive and gram-negative bacteria and other microorganisms such as rickettsiae, Ehrlichia,mycoplasmas, chlamydiae, and some mycobacterial species. The tetracyclines have many clinical uses, but because of increasing bacterial resistance and development of other drugs, they are no longer as widely used. For example, some S. pneumoniae, S. pyogenes, and staphylococci are now resistant to most tetracyclines. Among the Enterobacteriaceae, resistance has increased greatly in recent years, such that many E. coli and Shigella species and virtually all P. aeruginosa are resistant. However, tetracyclines do inhibit Pasteurella multocida, F. tularensis, Yersinia pestis, Vibrio species, and Brucellaorganisms. Doxycycline inhibits Bacteroides fragilis, but most Bacteroides species are resistant to the other tetracyclines. Other anaerobic species such as Fusobacterium and Actinomyces are inhibited, as are Borrelia burgdorferi (the cause of Lyme disease) and others. Mycobacterium marinum is inhibited, and some activity is observed against Plasmodium species.

Tetracyclines are the preferred agents for the treatment of rickettsial diseases such as Rocky Mountain spotted fever, typhus, scrub typhus, rickettsial pox, and Q fever (see Box 47-2), with doxycycline being the preferred agent from this class. Doxycycline is also the drug of choice for the treatment of ehrlichiosis and is used to treat Lyme disease and relapsing fever caused by Borrelia species. Atypical respiratory pathogens including Mycoplasma pneumoniae, Chlamydia pneumoniae, and Chlamydia psittaci respond to tetracyclines, which may be better tolerated by adults than erythromycin. SystemicVibrio infections and peptic ulcer disease associated with Helicobacter pylori may also be treated with tetracyclines. Chlamydial infections of a sexual origin, such as nongonococcal urethritis, salpingitis, cervicitis, and lymphogranuloma venereum, are effectively treated with doxycycline. Tetracyclines are also effective for the treatment of inclusion conjunctivitis and trachoma caused by chlamydiae. For penicillin-allergic patients, tetracycline or doxycycline represent important alternative treatments for some forms of syphilis. In addition, doxycycline is a recommended treatment for granuloma inguinale.

Tetracyclines are no longer used for treating urinary tract infections because of increased resistance and availability of better drugs. They have no role in treatment of pharyngitis, and other drugs are preferred for treatment of staphylococcal infections. In general, other agents should be used to treat osteomyelitis, endocarditis, meningitis, and life-threatening gram-negative infections. Minocycline inhibits some methicillin-resistant staphylococci and has been used to treat these infections; however, vancomycin remains the drug of choice. Doxycycline also represents an important option for prophylaxis against Plasmodium falciparum for travelers to regions where malaria is endemic, particularly those with mefloquine-resistant species.

Quinupristin and Dalfopristin

Quinupristin and dalfopristin primarily inhibit the growth of gram-positive organisms and have limited activity against gram-negative respiratory pathogens; Enterobacteriaceae, Acinetobacter, andPseudomonas are inherently resistant to quinupristin-dalfopristin. Activity has been demonstrated against methicillin-susceptible and methicillin-resistant S. aureus, coagulase-negative staphylococci, vancomycin-susceptible and resistant E. faecium, penicillin-resistant S. pneumoniae, viridans streptococci, and S. pyogenes. Of note, quinupristin-dalfopristin has extremely limited activity against E. faecalis because of an intrinsic efflux pump.

In the United States, quinupristin-dalfopristin is approved for use in the treatment of adults with serious vancomycin-resistant infections and for skin and soft-tissue infections caused by methicillin-susceptible S. aureus or S. pyogenes. It has activity against MRSA and has been used on a limited basis for treatment of MRSA infections that are poorly responsive to glycopeptides; however, treatment of MRSA infections with quinupristin-dalfopristin is not an indication approved by the Food and Drug Administration.

Linezolid

Linezolid displays activity against many gram-positive pathogens, including those resistant to standardly used antibiotics. These include methicillin-susceptible and methicillin-resistant S. aureus;penicillin; macrolide-susceptible or macrolide-resistant S. pneumoniae; S. pyogenes; and vancomycin-susceptible or vancomycin-resistant E. faecium and E. faecalis. Activity against aerobic gram-negative organisms is limited. Linezolid also has activity against mycobacteria, including Mycobacterium tuberculosis, M. avium complex, and rapidly growing mycobacteria.

Clinical indications approved for use in the United States include treatment of vancomycin-resistant enterococcal infections, complicated or uncomplicated skin and soft-tissue infections caused by S. aureus or streptococci, and hospital or community-acquired pneumonia caused by S. aureus or S. pneumoniae. Because linezolid is bacteriostatic, its use for S. aureus infections associated with bacteremia should be avoided unless alternative agents for treatment are not available, or additional data become available to support its use in this setting. Currently, the primary role for linezolid is in the treatment of VRE infections; in step-down to oral therapy for MRSA skin and soft tissue infections; and for treatment of MRSA infections in patients with glycopeptide intolerance or allergy. Linezolid may also be useful for treating S. aureus infections caused by isolates with reduced glycopeptide susceptibility if the isolates are linezolid susceptible. Prudent use of linezolid should be emphasized to avoid development of resistance; routine use for infections caused by pathogens susceptible to other available antibiotics should be avoided.

Given its activity against M. tuberculosis, linezolid may prove effective as an adjunctive therapy in the treatment of multidrug-resistant tuberculosis. However, further study is needed to better define the role and efficacy of linezolid in this setting.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The major problems associated with the use of these antimicrobial gents are summarized in the Clinical Problems Box.

Aminoglycosides

Aminoglycosides can produce serious side effects, with vestibular, cochlear, and renal toxicities the most important and most common.

Renal Toxicity

Reversible renal impairment develops in 5% to 25% of patients receiving an aminoglycoside for more than 3 days. The impairment can progress to severe renal insufficiency in a small number of patients, but it is usually reversible. In the renal cortex, aminoglycosides are transported across the luminal brush border and accumulate in proximal tubular cells. The initial decrease in glomerular filtration that occurs in response to aminoglycosides may result from inhibition of vasodilatory prostaglandins. Aminoglycosides also inhibit several enzymes and alter mitochondria and ribosomes in proximal tubular cells.

The initial manifestation of aminoglycoside renal toxicity is an increased excretion of brush border enzymes such as β-d-glucosaminidase, alanine aminopeptidase, and alkaline phosphatase. However, it is not clinically useful to monitor excretion of these enzymes, because fever and other factors cause similar changes. Of greater clinical significance is the decrease in renal concentrating ability, proteinuria, and the appearance of casts in the urine, followed by a reduction in the glomerular filtration rate and a rise in the serum creatinine concentration.

The risk factors for renal toxicity are not completely understood despite extensive study. Toxicity correlates with the amount of drug given and duration of administration, but older age, female gender, concomitant liver disease, and concomitant hypotension appear to favor the development of toxicity. Coadministration of aminoglycosides with loop diuretics, vancomycin, cisplatin, cyclosporin, or amphotericin B can potentiate renal toxicity and volume depletion. In addition, the risk of nephrotoxicity is higher when aminoglycosides are administered in two or three divided doses compared with a single daily dose.

Aminoglycosides themselves differ in their nephrotoxic potential. Neomycin is the most nephrotoxic, and streptomycin is the least. However, clinical trials comparing the nephrotoxicity of the other agents have yielded contradictory results.

Because tubules can regenerate, renal function usually returns to normal after the drug is cleared. A few patients whose renal function does not return to pretreatment values require dialysis.

Ototoxicity

Aminoglycosides can damage either or both the cochlear and vestibular systems. As compared with renal toxicity, aminoglycoside-induced ototoxicity is usually irreversible. Although the exact frequency is unknown, some damage probably occurs in 5% to 25% of patients, depending on the underlying auditory status and duration of therapy. Cochlear toxicity is a result of the destruction of hair cells of the organ of Corti, particularly the outer hair cells in the basal turn, accompanied by subsequent retrograde degeneration of the auditory nerves. Aminoglycosides also damage hair cells of the ampullar cristae, leading to vestibular dysfunction and vertigo. In addition, aminoglycosides accumulate in perilymph and endolymph and inhibit ionic transport, which is the cause of cochlear cell damage. The drugs accumulate when plasma concentrations are high for prolonged periods, and ototoxicity is probably enhanced by persistently elevated plasma concentrations. Single daily high-dose therapy produces less ototoxicity.

The amount of auditory or vestibular function loss correlates with the amount of hair cell damage. Repeated courses of therapy continue to cause damage to more hair cells. Concomitant use of loop diuretics, such as furosemide, is thought to increase the risk of ototoxicity. The incidence of vestibular toxicity is highest for patients who receive 4 weeks of therapy or longer.

Clinical signs of auditory problems such as tinnitus or a sensation of fullness in the ears are not reliable predictors of this toxicity. The initial hearing loss is of high frequencies outside the voice range; thus toxicity will not be recognized unless hearing tests are performed. Eventually the loss of hearing may progress into the auditory range. For patients receiving prolonged courses of aminoglycosides, serial high-frequency audiometric testing should be undertaken.

Vestibular toxicity is usually preceded by headache, nausea, emesis, and vertigo, so patients who are ill often have difficulty identifying the onset of vestibular toxicity. These patients may go through a series of stages from acute to chronic symptoms that are apparent only on standing, or the patients may achieve a compensatory state in which they use visual cues to adjust for the loss of vestibular function.

Neuromuscular Blockade

Neuromuscular paralysis is rare but appears to result from inhibition of the presynaptic release of acetylcholine and postsynaptic receptor blockade. Aminoglycosides inhibit the influx of Ca++ at the presynaptic nerve terminal, thus blocking acetylcholine release. Presynaptic blockade is more readily caused by neomycin and tobramycin than by streptomycin, whereas the opposite is true for the postsynaptic effects. Neuromuscular paralysis is most likely to occur during surgery when anesthesia and neuromuscular blockers such as succinylcholine are used but can also occur in patients with myasthenia gravis.

Macrolides

Erythromycin is one of the safest antibiotics, with epigastric pain, abdominal cramps, nausea, and emesis representing the most common side effects. Administration by the IV route may be associated with thrombophlebitis. Cholestatic hepatitis may occur in patients receiving estolate preparations of erythromycin, usually beginning 10 to 20 days into treatment and characterized by jaundice, fever, leukocytosis, and eosinophilia. The problem rapidly abates once drug administration is stopped. Erythromycin at high doses can cause reversible transient deafness. Rarely, erythromycin use has been associated with polymorphic ventricular tachycardia (torsades de pointes). Erythromycin stimulates GI motility by acting as a motilin receptor agonist, leading to enhanced gastric emptying. Thus erythromycin can be used to improve gastric motility in patients with gastroparesis.

Erythromycin also inhibits the cytochrome P450 system, which can lead to significant drug-drug interactions. Erythromycin prolongs the half-life of theophylline and can lead to theophylline toxicity. It also inhibits the metabolism of carbamazepine, cyclosporine, corticosteroids, warfarin, and digoxin.

Azithromycin is generally well tolerated and has fewer GI side effects than erythromycin. Because it does not interfere with cytochrome P450 enzymes, it does not have the same drug-drug interactions.

Clarithromycin is similarly well tolerated. It is intermediate between erythromycin and azithromycin with regards to the incidence of intolerance caused by GI side effects. Clarithromycin also inhibits cytochrome P450s, as does erythromycin, and may cause increased serum concentrations of other drugs.

Dirithromycin, like erythromycin, can also cause GI side effects. However, it does not interfere with cytochrome P450 metabolism.

Chloramphenicol

Chloramphenicol produces serious side effects attributed to its action on mitochondrial membrane enzymes, cytochrome oxidases, and adenosine triphosphatases. Because of these adverse effects, chloramphenicol has limited clinical uses, primarily when no alternative treatment is suitable.

Its hematological effects are the most important, and regular monitoring of complete blood count should be performed in patients receiving chloramphenicol. Aplastic anemia occurs in 1:25,000 to 1:40,000 patients, with a high death rate in those in whom an aplastic state develops or who progress to acute leukemia. Aplastic anemia is usually not dose dependent and most often occurs weeks to months after therapy is completed, but it can occur concurrently with therapy.

A second important hematological side effect is reversible bone marrow suppression. This form of toxicity usually develops during therapy, is dose dependent, and is reversible. It is manifest by anemia, thrombocytopenia, or leukopenia, alone or in combination.

A complication known as gray baby syndrome may be encountered in infants receiving chloramphenicol. This syndrome of pallor, cyanosis, abdominal distention, vomiting, and circulatory collapse, resulting in approximately a 50% mortality rate, develops in neonates with excessively high plasma concentrations of drug. High concentrations result from inadequate glucuronidation and failure to excrete the drug by the kidneys. Children less than 1 month of age should receive only low doses of chloramphenicol, though in overdose situations excess drug can be removed by hemoperfusion over a bed of charcoal. Chloramphenicol also can produce optic neuritis in children; GI side effects including nausea, vomiting, and diarrhea; and hypersensitivity rashes.

Chloramphenicol inhibits hepatic cytochrome P450 enzymes, thereby prolonging the half-life of phenytoin, tolbutamide, and other drugs; barbiturates, on the other hand, decrease the half-life of chloramphenicol.

Clindamycin

Diarrhea may occur in up to 20% of patients treated with clindamycin. The most important adverse effect of clindamycin is pseudomembranous enterocolitis produced by Clostridium difficile, estimated to occur in 3% to 5% of patients. This syndrome is characterized by diarrhea, abdominal pain, and fever, with diarrhea beginning either during or after drug therapy. Orally administered vancomycin or metronidazole may be needed for this secondary superinfection if it occurs.

Telithromycin

Overall, telithromycin is well tolerated, with diarrhea and nausea being the most commonly reported side effects. Like erythromycin, telithromycin inhibits cytochrome P450 activity but does not form complexes with cytochrome P450s, which may lead to fewer drug-drug interactions. Concomitant administration of telithromycin with drugs known to prolong the QTc interval, such as midazolam or class IA or IIIA antiarrhythmics, should be avoided. The potential for increased levels of cyclosporine exists, requiring diligent monitoring of cyclosporine levels.

Tetracyclines

Although usually well tolerated, tetracyclines may produce adverse effects ranging from minor to life-threatening. Allergy to a tetracycline precludes its further use. Photosensitization with a rash is a toxic rather than an allergic effect and is most often seen in patients receiving demeclocycline or doxycycline.

Effects on bone and teeth preclude the use of tetracycline in children less than 8 years of age, because a permanent brown-yellow discoloration of teeth will develop in 80% of individuals. The effect is permanent, and the enamel is hypoplastic. The effects on bone and teeth may also result from maternal use of tetracyclines during pregnancy. Thus tetracyclines are contraindicated in this population. Tetracyclines cause dose-dependent GI disturbances, including epigastric burning, nausea, and vomiting. Esophageal ulcers have also been reported. Pancreatitis is rarely observed. Hepatic toxicity is encountered most often in conjunction with parenteral use but can also occur with oral administration. Tetracyclines also aggravate existing renal dysfunction.

Demeclocycline can cause nephrogenic diabetes insipidus, and minocycline may produce vertigo, particularly in women. Superinfection caused by an overgrowth of other bacteria, particularly oral and vaginal candidiasis, frequently occurs after use of tetracyclines.

Quinupristin and Dalfopristin

Local inflammation, pain, edema, and thrombophlebitis at the infusion site may occur with quinupristin-dalfopristin administration, particularly when infused via a peripheral vein. Therefore administration usually requires central venous access. In noncomparative trials myalgia and arthralgia were encountered in up to 13% of patients, but these occurred with lower frequency in comparative trials.

Quinupristin and dalfopristin inhibit cytochrome P450 enzymes, creating the potential for significant drug-drug interactions. Concomitant use of quinupristin-dalfopristin and drugs known to prolong the QTc interval should be avoided.

Linezolid

Linezolid is generally well tolerated, with the most common side effects related to GI complaints, including nausea and diarrhea. Headache, rash, and altered taste may also occur. Thrombocytopenia, often occurring with therapy duration greater than 2 weeks, is the most problematic side effect. The mechanism may be related in part to reversible myelosuppression. Platelet counts usually normalize after linezolid is discontinued. Linezolid use may also be associated with anemia. Complete blood counts should be monitored at least weekly in patients receiving linezolid. In addition, peripheral neuropathy may develop, necessitating discontinuation of therapy.

Linezolid has been known to interact with serotonergic agents, resulting in an increased risk of serotonin syndrome (see Chapter 30). Weak and reversible inhibition of monoamine oxidase occurs with linezolid use. Therefore patients taking linezolid should avoid eating large quantities of food with high tyramine content.

CLINICAL PROBLEMS

Aminoglycosides

Nephrotoxicity

Ototoxicity

Vestibular toxicity

Neuromuscular blockade (infrequent)

Tetracyclines

Binding to bone and teeth: can be serious in infants or children under 8 years of age and during pregnancy

Gastrointestinal tract upsets

Hepatic and renal dysfunction

Vaginal candidiasis

Vertigo (minocycline)

Photosensitivity

Other Drugs

Chloramphenicol: Major hematological effects can be fatal (aplastic anemia, bone marrow suppression); gray baby syndrome if glucuronidation process not well developed (for chloramphenicol elimination); drug interactions with other agents that are metabolized; optic neuritis may result

Erythromycin: Relatively safe; mild gastrointestinal tract disturbances; infrequent hepatotoxicity; drug interaction with theophylline (metabolism); deafness with high doses

Clindamycin: Pseudomembranous colitis; serious rash (rare)

Telithromycin: Well tolerated, inhibits cytochrome P450 with potential for drug interactions

Quinupristin-dalfopristin: Venous irritation when given by peripheral vein, myalgias and arthralgias; inhibits cytochrome P450 with potential for drug interactions

Linezolid: Well tolerated; gastrointestinal complaints; thrombocytopenia; peripheral neuropathy

New Horizons

Emerging antimicrobial resistance continues to be problematic, and the need for agents active against drug-resistant organisms is expanding. Development of new inhibitors of bacterial ribosomes may provide additional options. Currently, the glycylcyclines represent a promising new group of agents within the tetracycline class. With the approval of tigecycline offering treatment for tetracycline- and macrolide-resistant organisms, the glycylcyclines have an expanded spectrum of activity, with in vitro activity against methicillin-resistant S. aureus, vancomycin-resistant enterococci, and penicillin-resistant S. pneumoniae, and may be active against some resistant gram-negative organisms. Furthermore additional ketolides and oxazolidinone derivatives under investigation offer promise for the possibilities to treat infections caused by drug-resistant organisms.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Aminoglycosides

Amikacin sulfate (Amikin)

Gentamicin sulfate (Garamycin, G-Myticin)

Kanamycin sulfate (Kantrex)

Netilmicin sulfate (Netromycin)

Tobramycin sulfate (Nebcin)

Macrolides

Azithromycin (Zithromax)

Clarithromycin (Biaxin)

Dirithromycin (Dynabac)

Erythromycin (ERYC, Erycette, EryDerm, Erygel, Ilotycin)

Erythromycin ethylsuccinate (contains sulfisoxazole) (Pediamycin, Eryzole, Wyamycin)

Erythromycin estolate (Ilosone)

Ketolides

Telithromycin (Keteck)

Tetracyclines and Glycylcyclines

Demeclocycline (Declomycin)

Doxycycline (Doryx)

Doxycycline Ca++ (Vibramycin calcium)

Minocycline HCl (Minocin)

Oxytetracycline or salt (Terramycin, Urobiotic)

Tetracycline (Achromycin, Sumycin)

Tigecycline (Tygacil)

Streptogramins

Quinupristin-dalfopristin (Synercid)

Oxazolidinones

Linezolid (Zyvox)

Others

Spectinomycin (Trobicin)

Chloramphenicol (Chloromycetin)

Clindamycin (Cleocin)

Mupirocin (Bactroban)

FURTHER READING

Ackermann G, Rodloff AC. Drugs of the 21st century: Telithromycin (HMR 3647)—the first ketolide. J Antimicrob Chemother. 2003;51:497-511.

Anonymous. Choice of antibacterial drugs. Treat Guidel Med Lett. 2007;5:33-50.

Anonymous. Tigecycline (tygacil). Med Lett. 2005;47:73-74.

Eliopoulos GM. Quinupristin-dalfopristin and linezolid. Evidence and opinion. Clin Infect Dis. 2003;36:473-481.

Hancock RE. Mechanisms of action of newer antibiotics for gram-positive pathogens. Lancet Infect Dis. 2005;5:209-218.

Noskin GA. Tigecycline: A new glycylcycline for treatment of serious infections. Clin Infect Dis. 2005;41(Suppl):S303-S314.

SELF-ASSESSMENT QUESTIONS

1. A 45-year-old man with a history of a severe penicillin allergy is undergoing treatment for bacterial meningitis. Several days into therapy he reports a severe headache, general malaise, and visual disturbances. Blood tests reveal that he is severely anemic. Which of the following drugs is most likely responsible for these adverse effects?

A. Azithromycin

B. Chloramphenicol

C. Doxycycline

D. Linezolid

E. Tigecline

2. A 27-year-old Asian woman is being treated for a vancomycin-resistant enterococcus infection. Other medications that she is currently taking include a serotonin reuptake inhibitor for depression. Which of the following antibiotics should be avoided in this patient?

A. Chloramphenicol

B. Gentamicin

C. Linezolid

D. Quinupristin-dalfopristin

E. Telithromycin

3. Which of the following classes of drugs acts by binding reversibly to the 50S ribosomal unit, blocks peptidyl transferase, and results in preventing translocation from the aminoacyl site to the peptidyl site?

A. Aminoglycosides

B. Glycylcyclines

C. Ketolides

D. Streptogramins

E. Tetracyclines

4. An antibiotic is administered once daily in the intensive care unit to treat sepsis caused by an abdominal wound. Serum and urine concentrations of the drug are monitored during the course of therapy. Ten days after therapy is discontinued, the drug is still detectable in the urine. Which of the following antibiotics was administered?

A. Azithromycin

B. Chloramphenicol

C. Doxycycline

D. Gentamicin

E. Quinupristin-dalfopristin

5. A macrolide antibiotic is required to treat a streptococcal infection in a 71-year-old penicillin-sensitive man who is also receiving digoxin and warfarin therapy. Which of the following drugs would be best for this patient?

A. Azithromycin

B. Clarithromycin

C. Erythromycin

D. Telithromycin