Figure 6.16 Several classes of antibiotics inhibit bacterial protein synthesis.
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Table 6-15. Aminoglycosides currently available in the US, their route of administration and use
Agent Routes Comment Streptomycin i.m.
(i.v.) For tuberculosis, plague, tularemia, severe brucellosis, some gentamicin-resistant enterococci
Neomycin p.o. Used to reduce the load of Enterobacteriaceae in the bowel and to treat hepatic encephalopathy, or with erythromycin as prophylaxis in elective colorectal surgery Paromomycin p.o. For certain intestinal protozoa
Kanamycin i.v./i.m. Rarely used, owing to bacterial resistance
Gentamicin i.v./i.m. The 'workhorse' aminoglycoside; used for Enterobacteriaceae, Pseudomonas aeruginosa, enterococci
Netilmicin i.v./i.m. Similar to effect of gentamicin against Enterobacteriaceae and P. aeruginosa; poor synergistic activity against enterococci
Tobramycin i.v./i.m. Similar to effect of gentamicin against Enterobacteriaceae; more active than gentamicin against P. aeruginosa; poor synergistic activity against enterococci
Amikacin i.v./i.m. Aminoglycoside least affected by aminoglycoside-modifying enzymes; good activity against Enterobacteriaceae and P. aeruginosa; the most active against
mycobacteria; poor synergistic activity against enterococci; the most expensive aminoglycoside
i.m., intramuscular; i.v., intravenous; p.o., oral.
Several major classes of antibiotic act principally by inhibiting bacterial protein synthesis (Fig. 6.16). These drugs exhibit selective toxicity by inhibiting bacterial protein synthesis to a much greater extent than host cell protein
synthesis. This is a result of binding to specific bacterial targets. Most of these drugs are predominantly bacteriostatic, except for the aminoglycosides and oxazolidinones, which are bactericidal.
Aminoglycosides
Aminoglycosides have structures in which two or more amino sugars are linked by glycosidic bonds to an aminocyclitol ring. The aminoglycosides currently available in the US are listed in Table 6.15.
Aminoglycosides enter bacteria via an oxygen-dependent transport system, which is not present in anaerobic bacteria, or streptococci. Accordingly, anaerobes and streptococci are innately resistant to aminoglycosides. Once inside bacteria, aminoglycosides bind irreversibly to sites on the ribosome to inhibit protein synthesis. There is also at least one other ill-understood mechanism, which probably contributes to their bactericidal activity.
Aminoglycosides are active against aerobic Gram-negative bacilli, staphylococci and mycobacteria. Although they are not active against enterococci or L. monocytogenes, the addition of an aminoglycoside to penicillin G, ampicillin, or vancomycin is often synergistic and usually results in bactericidal activity.
There are two principal mechanisms of acquired bacterial resistance to aminoglycosides:
Reduced bacterial aminoglycoside permeability caused by alterations in the bacterial cell membrane.
Production of a variety of enzymes that act on aminoglycosides.
Nonhydrolytic aminoglycoside-modifying enzymes add acetyl, adenyl, or phosphoryl groups to the aminoglycoside thereby rendering them incapable of reaching their target sites on the bacterial ribosome. Each of the aminoglycoside-modifying enzymes has different substrate specificity and may modify only some aminoglycosides. Accordingly, bacteria may be resistant to one aminoglycoside and not to another.
In view of their toxicity, aminoglycosides are used primarily for serious infections due to Enterobacteriaceae and P.
aeruginosa, usually in a hospital setting. Aminoglycosides are also used in conjunction with penicillin, ampicillin, or vancomycin in the treatment of serious infections due to enterococci and L. monocytogenes.
▪ Gentamicin is the most frequently used aminoglycoside
Gentamicin is the most active aminoglycoside against enterococci. Tobramycin is usually more active than gentamicin against P. aeruginosa, but is not more active against Enterobacteriaceae, and unlikely to be effective against
enterococci. Ophthalmic preparations of gentamicin and tobramycin are available for treatment of eye infections.
▪ Streptomycin can be used as part of a multidrug regimen for tuberculosis
Streptomycin is also the drug of choice in plague and tularemia, although recent evidence suggests that gentamicin is equally effective for these two infections. Streptomycin demonstrates synergy with penicillin, ampicillin, or vancomycin in the treatment of a few enterococcal strains whereas gentamicin does not. Streptomycin plus doxycycline is used to treat brucellosis.
Amikacin is the aminoglycoside least susceptible to aminoglycoside-modifying enzymes and is sometimes active against bacteria that are resistant to other aminoglycosides.
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Neomycin is not used parenterally because of its lower efficacy and greater adverse effects than other
aminoglycosides. It can be used orally (without systemic effects) to reduce the intestinal Enterobacteriaceae in the treatment of hepatic encephalopathy, or, in combination with erythromycin, as a prophylactic regimen to reduce the incidence of wound infection following elective colorectal surgery. Kanamycin is rarely used, owing to acquired resistance.
Paromomycin, which is related to neomycin, is used only orally to treat intestinal protozoal infections.
Aminoglycosides are not absorbed from the digestive tract and must be used parenterally. They are excreted
unchanged by the kidney and are suitable for treating urinary tract infections. They do not enter the cerebrospinal fluid
to reach adequate therapeutic concentrations, except in neonates.
▪ Aminoglycosides have two major adverse effects
Aminoglycosides can elicit nephrotoxicity and ototoxicity (auditory and vestibular). The risk of these adverse effects is both dose- and duration-dependent. Nephrotoxicity is more common, but is usually mild and reversible. Ototoxicity is often permanent (see Ch. 20). Aminoglycosides elicit more adverse effects than most other antibiotics and must be given parenterally. Owing to their adverse effects, serum aminoglycoside concentrations are often monitored, but adverse effects can occur even with 'ideal' serum concentrations.
Aminoglycosides
Are not absorbed orally
Are active against aerobic Gram-negative bacilli
Demonstrate concentration-dependent killing
Cause nephrotoxicity and ototoxicity (their major adverse effects)
Macrolides, lincosamides and streptogramins (MLS antibiotics)
Macrolides, lincosamides and streptogramins (MLS drugs) are chemically unrelated antibiotics that possess similar mechanisms of action, and antimicrobial activity with a similar profile of resistance. They reversibly bind to the 50S ribosomal subunit to block translocation. Although conventionally considered as bacteriostatic antibiotics, they are bactericidal against specific isolates. The principal mechanism of acquired resistance is a specific mutation in the ribosomal ribonucleic acid (RNA) of the 50S ribosomal subunit. Resistance to one member of the MLS class does not necessarily imply resistance to others.
▪ Macrolides have a macrocyclic lactone ring
The prototype macrolide is erythromycin, which is available in different salts. In recent years, newer macrolides have been introduced in the US, including clarithromycin, azithromycin and dirithromycin. Other macrolides are available in Europe and Asia. Macrolides are usually given orally although i.v. forms of erythromycin and azithromycin are
available, and erythromycin lotion can be used in the treatment of acne vulgaris. Macrolides are metabolized in the liver and do not penetrate the cerebrospinal fluid sufficiently to achieve therapeutically relevant concentrations.
Erythromycin is active against streptococci, staphylococci, Bordetella pertussis, Corynebacterium diphtheriae,
Campylobacter jejuni, Mycoplasma pneumoniae, Ureaplasma urealyticum, Legionella species and Chlamydia species.
Erythromycin and dirithromycin have limited activity against H. influenzae, but both clarithromycin and azithromycin are considerably more effective against this organism. Macrolides are not active against Enterobacteriaceae, P.
aeruginosa, or Mycoplasma hominis.
Macrolides are used primarily to treat respiratory tract infections. They are the alternative to penicillin for treating streptococcal pharyngitis, especially in patients allergic to penicillin.
Marcrolides are the drugs of choice for community-acquired pneumonia as they are active against pneumococci, M.
pneumoniae, C. pneumoniae and Legionella species. In cases where infection may be due to H. influenzae, clarithromycin or azithromycin are preferred.
Erythromycin is the drug of choice for the treatment of pertussis, legionnaires' disease, Chlamydia trachomatis (in pregnancy where tetracyclines are contraindicated) and are equivalent to penicillin in eradicating the carrier state in diphtheria. Erythromycin is equivalent to tetracycline in the treatment of M. pneumoniae infections, is used for C. jejuni enteritis and is an alternative to β lactams for mild skin and soft tissue infections due to S. pyogenes and S. aureus.
▪ Clarithromycin and azithromycin are more active than erythromycin against some pathogens
Clarithromycin and azithromycin, but not dirithromycin, are more active than erythromycin against H. influenzae and are more appropriate choices for the empiric treatment of respiratory tract infections if H. influenzae is a possible pathogen.
Both clarithromycin and azithromycin are active against Mycobacterium avium complex, an important pathogen in patients with AIDS. Clarithromycin is useful in the treatment of most other nontuberculous mycobacteria. It is also very active against Helicobacter pylori and is routinely used in a multidrug regimen to treat duodenal ulcers caused by H.
pylori. Azithromycin is active against C. trachomatis and is the only drug that can cure C. trachomatis urethritis and cervicitis when given in a single dose.
▪ Erythromycin and clarithromycin have a number of interactions with other drugs
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Erythromycin elevates serum theophylline concentrations when given concomitantly. In combination with the non-sedating histamine-H1 antagonists astemizole or terfenadine, or the promotility drug cisapride, erythromycin and
clarithromycin is contraindicated as it results in significant prolongation of the QT interval in the electrocardiogram (see Ch. 13). This can result in the torsades de pointes variant of ventricular tachycardia, which can be fatal.
▪ Erythromycin causes gastrointestinal adverse effects
Erythromycin is probably the single most poorly tolerated oral antibiotic, owing to dyspepsia, nausea and vomiting.
Independently of its antibiotic activity, it interacts with motilin receptors to increase gastrointestinal motility for the treatment of diabetic gastroparesis. The newer macrolides clarithromycin and azithromycin produce less severe gastrointestinal adverse effects than erythromycin, and may be suitable for individuals who have demonstrated gastrointestinal intolerance to erythromycin.
The routes of administration of macrolides as well as their pharmacokinetic profiles are summarized in Table 6.16.
KETOLIDES (MODIFIED MACROLIDES)
Recently, a series of modified macrolides have been synthesized in which the cladinose at position 3 of the
macrolactone ring has been replaced by a keto group. These modified macrolides are also known as ketolides. The first agent in this class was telithromycin. The major difference between ketolides and macrolides is that ketolides are much more resistant to the principal mechanism of MLS resistance in Streptococcus pneumoniae, so that the majority of macrolide-resistant pneumococci remain susceptible to ketolides. Otherwise, ketolides are similar to the newer macrolides clarithromycin and azithromycin.
LINCOSAMIDES
Lincomycin and clindamycin are the two available lincosamides. Lincomycin is named after Lincoln, Nebraska, where it was first isolated from the mold Streptomyces lincolnensis. The replacement of a hydroxyl group in lincomycin with a chloride results in clindamycin. Since clindamycin has greater activity and superior oral bioavailability, it has
supplanted lincomycin in clinical use.
Table 6-16. Route of administration and pharmacokinetics of macrolides, lincosamides and streptogramins
Erythromycin i.v., p.o., topical 25 Hepatic 1.8 Phlebitic i.v.
formulation
Clarithromycin p.o. 5 Hepatic 6 Active metabolite
Azithromycin i.v., p.o. 35 GI and
hepatic
68 Highly concentrated
intracellularly
Quinupristin-dalfopristin i.v. Not used Hepatic 8.5 Active against
Gram-positive cocci, including phlebitic VRE
i.v., intravenous; p.o., by mouth; GI, gastrointestinal; VRE, vancomycin-resistant enterococci.
Clindamycin is active against streptococci, staphylococci and anaerobic bacteria, including B. fragilis. It is also active against Mycoplasma hominis, but not M. pneumoniae or U. urealyticum. It has no useful activity against enterococci or aerobic Gram-negative bacilli. Clindamycin is also active against several protozoa. Clindamycin is an important antibiotic in the treatment of anaerobic infections, particularly in mixed aerobic-anaerobic infections where it is usually used in combination with other antibiotics. It can also be used as an alternative to β lactams in people who are allergic to β lactams, particularly if the oral route is appropriate.
Clindamycin can be given either orally or intravenously. There is also a topical solution for the treatment of acne vulgaris and a vaginal cream for the treatment of bacterial vaginosis. Clindamycin is metabolized by the liver and does not penetrate the cerebrospinal fluid.
Clindamycin is associated with a higher risk of Clostridium difficile enteritis than other antibiotics.
Streptogramins
Streptogramins consist of a combination of two naturally occurring chemically unrelated groups of molecules, referred to as groups A and B. Pristinamycin is such a combination, which has been available in Europe for many years as an oral antistaphylococcal agent, but it is not available in the US.
Quinupristin-dalfopristin is an i.v. streptogramin consisting of a 30:70 ratio of quinupristin to dalfopristin, which was introduced into clinical use in the late 1990s. This combination is active against staphylococci (including methicillin-resistant staphylococci), streptococci (including penicillin-methicillin-resistant pneumococci), and Enterococcus faecium (but not most Enterococcus faecalis). The major clinical indication for quinupristin-dalfopristin is the treatment of infections due to vancomycin-resistant E. faecium, and as an alternative to vancomycin in the treatment of infections due to
methicillin-resistant staphylococci.
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Quinupristin-dalfopristin is rapidly cleared by nonrenal mechanisms, but there is a long postantibiotic effect against Staphylococcus aureus, Streptococcus pneumoniae and E. faecium, so that twice-daily dosing is clinically effective. Its major adverse effect is an infusion-related phlebitis, which can be avoided if the drug is administered via a central venous catheter.
Clearance is primarily the result of hepatic metabolism and the serum half-life is about 8.5 hours.
Tetracyclines
Tetracyclines are moderately broad-spectrum, primarily bacteriostatic antibiotics that have a nucleus of four fused cyclic rings (Fig. 6.17), hence the name tetracyclines. Different tetracyclines are derived by different substitutions at positions 5, 6 and 7 of the tetracycline nucleus. Tetracyclines reversibly bind to the bacterial 30S ribosomal subunit in such a manner that they block the binding of transfer RNA to the messenger RNA-ribosome complex, preventing the addition of new amino acids to the growing peptide chain (see Fig. 6.16). Acquired tetracycline resistance is usually due to changes in the transport mechanism, resulting in a lack of tetracycline accumulation with bacteria. Since tetracyclines are concentrated intracellularly, they are useful for intracellular infections. Although tetracyclines are active against a wide variety of bacteria, the important organisms against which they are consistently active include chlamydiae, mycoplasmas, spirochetes (including those that cause leptospirosis, Lyme disease and relapsing fever), rickettsial infections, Legionella species and Brucella species. Tetracyclines, particularly minocycline, are also effective in the treatment of acne vulgaris.
Of the six tetracyclines available in the US, only three are used with any frequency: tetracycline, doxycycline and minocycline.
Tetracycline is a short-acting drug that is usually administered four times daily, whereas both doxycycline and minocycline have longer half-lifes, allowing once- or twice-daily administration.
Figure 6.17 Chemical structure of tetracyclines. Substitutions at positions five, six and seven result in different drugs, including the three common agents: tetracycline, doxycycline and minocycline.
They are excreted mainly by the kidneys and do not achieve adequate therapeutic concentrations in cerebrospinal fluid. They are usually used orally but i.v. preparations are available, as well as topical formulations for acne vulgaris
▪ Tetracyclines are chelated by divalent and trivalent cations
Absorption of tetracyclines is markedly decreased when taken orally in conjunction with calcium-, magnesium-, and aluminum-containing antacids, dairy products, calcium supplements, or sucralfate. They have a strong affinity for developing bone and teeth, to which they give a permanent yellow-brown color. They are therefore contraindicated in pregnant and breastfeeding women, as well as in children less than 8 years of age.
The routes of administration of tetracyclines well as their pharmacokinetic profiles are summarized in Table 6.17.
Amphenicols
Chloramphenicol is the only amphenicol available in the US. The related drug, thiamphenicol, is available in parts of
Europe. Chloramphenicol is a relatively broad-spectrum, predominantly bacteriostatic antibiotic that reversibly binds to the bacterial 50S ribosomal subunit to prevent the attachment of the amino acid-containing end of transfer RNA to the peptide chain (i.e. it blocks peptidyl transferase) (see Fig. 6.16).
Acquired chloramphenicol resistance results from:
Reduced bacterial permeability.
Production of the chloramphenicol-modifying enzyme, chloramphenicol acetyltransferase.
Chloramphenicol is available orally and parenterally and as a topical ophthalmic formulation.
Chloramphenicol enters the cerebrospinal fluid to achieve therapeutically effective concentrations against the three principal bacterial meningeal pathogens (i.e. S. pneumoniae, N. meningitidis and H. influenzae), but not for
Enterobacteriaceae. Chloramphenicol accumulates in the brain parenchyma at concentrations useful in the treatment of brain abscess.
Chloramphenicol is seldom used in developed countries, but:
Is an acceptable alternative for the treatment of bacterial meningitis, particularly in patients with cephalosporin allergies.
May be used in the treatment of brain abscess or enteric fever, although a variety of Salmonella strains around the world are resistant to chloramphenicol.
Is an alternative to tetracycline in the treatment of Rocky Mountain spotted fever.
▪ Chloramphenicol's main adverse effect is myelosuppression
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Table 6-17. Route of administration and pharmacokinetics of tetracycline antibiotics
Drug Routes of
Tetracycline p.o. 75 Renal 9 Contraindicated in
pregnancy and children
<8 years
Doxycycline i.v., p.o. 95 GI tract 18 Contraindicated in
pregnancy and children
i.v., intravenous; p.o., by mouth; GI, gastrointestinal.
Choramphenicol exerts a dose-dependent myelosuppression, which is common and reversible. Approximately 1 in 30 000 patients given chloramphenicol develop irreversible aplastic anemia. Although this idiosyncratic reaction is rare it is the major reason why chloramphenicol is seldom used. However, chloramphenicol is more widely used in
developing countries because of its low price, broad spectrum of activity and efficacy in enteric fevers.
▪ Chloramphenicol is conjugated in the liver to its inactive glucuronide
Neonates have a reduced ability to conjugate chloramphenicol; this sometimes results in high serum chloramphenicol concentrations with resultant toxicity. Such toxicity is manifest as the gray baby syndrome, which is characterized by abdominal distention, vomiting, cyanosis and circulatory collapse. If chloramphenicol must be used in neonates, serum concentrations need to be monitored closely. It is given by oral, i.v. and topical routes. The oral route is associated with 80% bioavailability and clearance is primarily through hepatic metabolism resulting in a half-life of 3 hours.
Oxazolidinones
Oxazolidinones are the newest class of synthetic antibiotics. In 2000, linezolid became the first oxazolidinone to be approved in the USA. It acts by binding to the bacterial 23S ribosomal RNA of the 50S subunit, thus preventing the formation of the 70S initiation complex required for protein synthesis. This inhibition of bacterial protein synthesis is at a very early step, preceding the interaction of transfer RNA and the 30S ribosome with the initiator codon. Currently only linezolid is available for oral or i.v. administration. As a result of its unique mechanism of action, there is no cross-resistance with other classes of antibiotics.
Linezolid is active against most important aerobic Gram-positive cocci, including staphylococci (including methicillin-resistant staphylococci), streptococci (including penicillin-methicillin-resistant pneumococci) and enterococci - both E. faecalis and E. faecium, including vancomycin-resistant enterococci. It is bacteriostatic against staphylococci and enterococci, but bactericidal against most streptococci. The spectrum includes most aerobic Gram-positive cocci whereas enteric Gram-negative bacilli and Pseudomonas species are not.
In view of its high cost and usefulness, linezolid is best reserved for the treatment of infection due to susceptible Gram-positive cocci, which cannot be treated by other agents. Its principal use in the treatment of vancomycin-resistant enterococci, and as an alternative to vancomycin for methicillin-vancomycin-resistant staphylococci.
The most frequent side effects of linezolid are nausea, vomiting and headaches. A reversible bone marrow suppression can occur; therefore, blood concentrations of linezolid are monitored during prolonged treatment.
Linezolid is a reversible inhibitor of monoamine oxidase enzyme (an MAOI); therefore, the usual precautions for this class of drugs apply. Linezolid is rapidly and completely orally bioavailable and has a long serum half-life. The usual dose is 600 mg every 12 hours whether i.v. or oral (serum half-life 5.5 hours). Clearance involves both hepatic and some renal mechanisms.