9
`
`GOODMAN & GILMAN S I 1"’I(
`P
`JA%K1i1i
`
`Tenth Edition
`
`McGraw-Hill
`MEDIC AL PUBLISHING Divisio
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`McGraw-Hill
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`Goodman and Gilman’s THE I’HAE M:\COI CGIfCL B SIE OE[H K (cid:9)
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`ICE, 10/c
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`1955, 1941 by The McGraw-Hill
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`Library of Congress Cataloging-in-Publication Data
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`Goodman and Gilman’s the pharmacological basis of therapeutics.(cid:151)IOth ed. / [edited by]
`Joel G. Hardman, Lee E. Limbird, Alfred Goodman Gilman.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 0-07-135469-7
`I. Title: Pharmacological basis of therapeutics.
`1. Pharmacology. (cid:9)
`2. Chemotherapy. (cid:9)
`II. Goodman, Louis Sanford III. Gilman, Alfred IV. Hardman, Joel G.
`V. Limbird, Lee E. VI. Gilman, Alfred Goodman
`[DNLM: 1. Pharmacology. 2. Drug Therapy. QV 4 G6532 20021
`RM300 G644 2001
`615’.7(cid:151)dc2l
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`2001030728
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`INTERNATIONAL EDITION ISBN 0-07-112432-2
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`2
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`(cid:9)
`

`

`C H A P T E R 4 7
`
`ANTIMICROBIAL AGENTS
`(Continued)
`Protein Synthesis Inhibitors and
`Miscellaneous Antibacterial Agents
`
`Henry F Chambers
`
`The antimicrobial agents discussed in this chapter are: (1) bacteriostatic, protein-synthesis
`inhibitors that act principally by binding to ribosomes; (2) non-3-lactam inhibitors of
`cell-wall synthesis; or (3) a miscellaneous group of compounds acting by diverse mech-
`anisms that have limited indications. Included within the first group are tetracyclines,
`chloramphenicol, macrolides, clindamycin, streptogramins, and linezolid. The tetracy-
`clines are broad-spectrum antibiotics with activity against aerobic and anaerobic gram-
`positive and gram-negative organisms, rickettsiae, mycoplasmas, and chlamydiae. How-
`ever; resistance to tetracyclines has reduced their clinical usejidness over the last decade.
`Chloramphenicol is recommended only for treatment of life-threatening infections (for
`example, bacterial meningitis when alternative drugs cannot be used, or rickettsial infec-
`tions) because of its potential for causing aplastic anemia. The macrolides, erythromycin,
`clarithromycin, and azithromycin, are used primarily for treatment of respiratory tract
`infections because of their activity against Streptococcus pneumoniae and agents of
`atypical pneumonia. Clarithromycin and azithromycin are effective for prophylaxis and
`treatment of nontuberculous mycobacterial infections. Clindamycin, a lincosamide an-
`tibiotic, exerts a potent bacteriostatic effect against streptococci, staphylococci, and
`anaerobic organisms, including Bacteroides fragilis. Clindamycin also has been found
`to be useful in the treatment of Pneumocystis carinii and Toxoplasma gondii infec-
`tions. Quinupristin-dalfopristin is a streptogramin combination. It is a parenteral agent
`indicated for treatment of infections caused by multiple-drug- resistant gram-positive bac-
`teria, particularly vancomycin- resistant strains of Enterococcus faecium. Linezolid is a
`member of the oxazolidinone class of compounds. It acts at an earlier step in protein
`synthesis than other inhibitors, and there is no cross resistance between it and other
`agents. It is active against vancomycin- resistant strains of enterococci and methicillin-
`resistant strains of Staphylococcus aureus. Vancomycin, the only glycopeptide antibiotic
`currently approved for use in the United States, is active against staphylococci (including
`all strains of Staphylococcus aureus(cid:151)except those rare strains that exhibit intermedi-
`ate susceptibility(cid:151)and virtually all strains of coagulase-negative staphylococci), strep-
`tococci, and enterococci. Teicoplanin is available in Europe, but offers little advantage
`over vancomycin, except that it can be administered intramuscularly. Bacitracin is active
`against aerobic gram-positive bacteria and is used only in topical preparations because
`of nephrotoxicity with parenteral use. Spectinomycin, an aminocyclitol, is used exclu-
`sively for treatment of Neisseria gonorrhoeae in patients who have contra indications to
`first-line therapies. Polymyxin B, which is active against aerobic gram-negative bacilli,
`including Pseudomonas aeruginosa,
`is limited to use in ointments and irrigation solu-
`tions because of its extreme nephrotoxicity when administered systemically. These agents
`and issues related to their appropriate selection for therapy represent the focus of this
`chapter.
`
`1239
`
`3
`
`

`

`1240 (cid:9)
`
`SECTION VIII CHEMOTHERAPY OF MICROBIAL DISEASES
`
`TETRACYCLINES
`History. Tetracycline antibiotics were discovered by system-
`atic screening of soil specimens collected from many parts of
`the world for antibiotic-producing microorganisms. The first of
`these compounds, chlortetracycline, was introduced in 1948.
`Tetracyclines were found to be highly effective against rick-
`ettsiae, a number of gram-positive and gram-negative bacteria,
`and Chlamydia, and hence became known as "broad-spectrum"
`in vitro antimicrobial
`antibiotics. With establishment of their
`activity, effectiveness in experimental infections, and pharma-
`cological properties, the tetracyclines rapidly became widely
`used in therapy.
`Although there are specific and useful differences among
`the tetracyclines currently available in the United States, they
`are sufficiently similar to permit discussion as a group.
`
`Source and Chemistry. Chlortetracycline and oxytetracycline
`are elaborated by Streptomyces aureofaciens and Streptomyces
`rimosus, respectively. Tetracycline is produced semisynthetically
`from chlortetracycline. Demeclocycline is the product of a mu-
`tant strain of Strep. aureofaciens, and methacycline, doxycycline,
`and minocycline are all semisynthetic derivatives.
`The tetracyclines are close congeners of polycyclic naph-
`thacenecarboxamide. Their structural formulas are shown in
`Table 47-1.
`
`Effects on Microorganisms. The tetracyclines are active
`against a wide range of aerobic and anaerobic gram-positive
`and gram-negative bacteria. They also are effective against
`some microorganisms that are resistant to cell-wall-active
`antimicrobial agents, such as Rickettsia, Coxiella burnetii,
`Mycoplasmapneumoniae, Chiamydia spp., Legionella spp.,
`Ureaplasma, some atypical mycobacteria, and Plasmo-
`dium spp. They are not active against fungi. Demeclocy-
`dine, tetracycline, oxytetracycline, minocycline, and doxy-
`
`cycline are available in the United States for syste1
`use. Chlortetracycline and oxytetracycline are used in
`thalmic preparations. Methacycline is not available. Other
`derivatives are available in other countries.
`The more lipophilic drugs, minocycline and doxy
`dine, usually are the most active by weight, followed by
`tetracycline. Resistance of a bacterial strain to any 0fle
`member of the class usually results in cross-resistance to
`other tetracyclines. Most bacterial strains that are
`inhibited by 4[kg/ml of tetracycline are considered s en-
`sitive. Exceptions to this minimal inhibitory concentr a
`tion (MIC) are Haemophilus influenzae and Streptoc 0
`cus pneumoniae, both of which are considered sensitive at
`-_2 /xg/ml, and Neisseria gonorrhoeae, considered sensj
`tive at 0.25 xg/ml. Tetracyclines are bacteriostatic agents.
`In general, tetracyclines are more active again st
`Bacteria.
`gram-positive than gram-negative microorganisms. Prob-
`lems of resistance and the availability of superior antimi
`crobial agents limit the use of tetracyclines for treatment
`of infections caused by many gram-positive bacteria. Most
`strains of enterococci are resistant to tetracycline; group
`B streptococci are 50% susceptible, and only 65% or less
`of Staphylococcus aureus remain susceptible (Standiford,
`2000). Both tetracycline and doxycycline are quite active
`against most strains of S. pneumoniae, although penicillin-
`resistant strains also are often resistant to tetracyclines
`(Doern et at., 1998).
`Although the tetracyclines initially were useful for
`treatment of infections with aerobic gram-negative organ-
`isms, many Enterobacteriaceae are now relatively resis-
`tant. However, more than 90% of strains of H. influen-
`zae still may be sensitive to doxycycline (Doern et at.,
`
` *,,o
`
`Table 47-1
`Structural Formulas of the Tetracyclines
`
`:H 0 OH 0
`
`0
`
`H
`
`67 OH 3 OH (cid:9)
`
`N(OH3)2
`TETRACYCLINE
`
`CONGENER
`
`Chlortetracycline
`Oxytetracycline
`Demeclocycline
`Methacycline
`Doxycycline
`Minocycline
`
`SUB STITUENT(S)
`
`POSITION(S)
`
`(cid:151)Cl
`(cid:151)OH,--H
`(cid:151)Cl
`(cid:151)OH,--H;
`(cid:151)OH,--H; =CH2
`(cid:151)OH,--H;
`(cid:151)CH3, (cid:151)H
`(cid:151)N(CH3)2
`(cid:151)H,(cid:151)H;
`
`(7)
`(5)
`(6; 7)
`(5; 6)
`(5; 6)
`(6; 7)
`
`4
`
`

`

`i97 Although all strains of Pseudomonas aeruginosa
`re resistant, 90% of strains of Pseudomonas pseudomallei
`(the cause of melioidosis) are sensitive. Most strains of
`gracella also are susceptible. Tetracyclines are particu-
`larly useful for infections caused by 1-laemophilus ducreyi
`(chafl0d) Brucella, and Vibrio cholerae. These drugs
`also inhibit the growth of Legionella pneumophila, Campy-
`jobacter jejuni, Helicobacter pylon, Yersinia pestis,
`yerSi"" enterocolitica, Francisella tularensis, and Pas-
`teure11c multocida. Strains of N. gonorrhoeae and Neis-
`seria meningitidis, once uniformly susceptible to tetracy-
`cline, generally are resistant (Harnett et al., 1997).
`The tetracyclines are active against many anaerobic
`and facultative microorganisms, and their activity against
`ActinomYces is particularly relevant. The MIC breakpoint
`for susceptible anaerobic bacteria is 8 jig/ml. A variable
`number of anaerobes (i.e., Bacteroides spp.) are sensitive
`to doxycyclifle, the most active congener of tetracycline.
`However, doxycycline is much less active against Bac-
`tero ides fragilis than are chloramphenicol, clindamycin,
`metronidazole, and certain -lactam antibiotics. Gram-
`positive anaerobes also vary in sensitivity, with Propioni-
`bacterium the most susceptible and Peptococcus the least
`susceptible.
`Rickettsiae. Like chioramphenicol, all of the tetracy-
`clines are highly effective against the rickettsiae respon-
`sible for Rocky Mountain spotted fever, murine typhus,
`epidemic typhus, scrub typhus, rickettsialpox, and Q fever
`(C. burnetii).
`Miscellaneous Microorganisms. The tetracyclines are
`active against many spirochetes, including Borrelia recur-
`rentis, Borrelia burgdorfeni (Lyme disease), Treponema
`pallidum (syphilis), and Treponema pertenue. The activity
`of tetracyclines against Chlamydia and Mycoplasma has
`become particularly important. Strains of Mycobacterium
`inarinum also are susceptible.
`Effects on Intestinal Flora. Many of the tetracyclines
`are incompletely absorbed from the gastrointestinal tract,
`such that high concentrations are reached in the bowel,
`and therefore the enteric flora is markedly altered. Many
`aerobic and anaerobic coliform microorganisms and gram-
`Positive spore-forming bacteria are sensitive and may be
`Suppressed markedly during long-term tetracycline regi-
`mens before resistant strains reappear. The stools become
`Softer and odorless and acquire a yellow-green color. How -
`ever, as the fecal coliform count declines, overgrowth
`Of tetracycline-resistant microorganisms occurs, particu-
`larly of yeasts (Candida spp.), enterococci, Proteus, and
`Pseudomonas Tetracycline occasionally produces pseu-
`domembranous colitis caused by toxin from Clostridium
`d(fJjc
`
`5Lgg nFni 3
`
`direction of
`mRNA translation
`
` ribosomal
`(990
`subunits
`
`nascent polypeptide chain
`P site A site
`
`’l
`
`site
`
`mRNA
`
` (V acid
`
`£tRNA
`
`amino
`
`Figure 47-1. Inhibition of bacterial protein synthesis
`by tetracyclines.
`
`Messenger RNA (mRNA) becomes attached to the 30 S
`subunit of bacterial ribosomal RNA. The P (peptidyl)
`site of the 50 S ribosomal RNA subunit contains the
`nascent polypeptide chain; normally, the aminoacyl tRNA
`charged with the next amino acid (aa) to be added to
`the chain moves into the A (acceptor) site, with comple-
`mentary base pairing between the anticodon sequence of
`tRNA and the codon sequence of mRNA. Additional de-
`tails of bacterial protein synthesis are given in Chapter
`46. Tetracyclines inhibit bacterial protein synthesis by
`binding to the 30 S subunit, which blocks tRNA binding
`to the A site.
`
`Mechanism of Action. Tetracyclines inhibit bacterial
`protein synthesis by binding to the 30 S bacterial ribo-
`some and preventing access of aminoacyl tRNA to the
`acceptor (A) site on the mRNA-ribosome complex
`(see
`Figure 47-1). They enter gram-negative bacteria by pas-
`sive diffusion through the hydrophilic channels formed by
`the porin proteins of the outer cell membrane, and active
`transport by an energy-dependent system that pumps all
`tetracyclines across cytoplasmic membrane. Although per-
`meation of these drugs into gram-positive bacteria is less
`well understood, it also is energy requiring.
`At high concentrations, these compounds impair pro-
`tein synthesis in mammalian cells. However, because mam-
`malian cells lack the active transport system found in
`bacteria, and the ribosomal target is less sensitive, tetra-
`cyclines are selectively active against bacteria.
`
`Resistance to the Tetracyclines. Microorganisms that
`have become resistant to one tetracycline frequently are
`resistant to the others. Resistance to the tetracyclines in
`Eschenichia coli and probably in other bacterial species
`is primarily plasmid-mediated and is an inducible trait.
`The three main resistance mechanisms are: (1) decreased
`
`5
`
`(cid:9)
`

`

`1242
`
`accumulation of tetracycline as a result of either decreased
`antibiotic influx or acquisition of an energy-dependent ef -
`flux pathway; (2) decreased access of tetracycline to the
`ribosome because of the presence of ribosome protection
`proteins; and (3) enzymatic inactivation of tetracyclines
`(Speer et at., 1992).
`
`Absorption, Distribution, and Excretion. Absorption.
`Absorption of most tetracyclines from the gastrointestinal
`tract is incomplete. The percentage of an oral dose that
`is absorbed (when the stomach is empty) is lowest for
`chlortetracycline (30%); intermediate for oxytetracycline,
`demeclocycline, and tetracycline (60% to 80%); and high
`for doxycycline (95%) and minocycline (100%) (Barza
`and Scheife, 1977). The percentage of unabsorbed drug
`rises as the dose increases. Most absorption takes place
`from the stomach and upper small intestine and is greater
`in the fasting state. Absorption of tetracyclines is impaired
`by the concurrent ingestion of dairy products; aluminum
`hydroxide gels; calcium, magnesium, and iron or zinc
`salts; and bismuth subsalicylate. The mechanism respon-
`sible for the decreased absorption appears to be chelation
`of divalent and trivalent cations.
`
`The wide range of plasma concentrations present in differ-
`ent individuals following the oral administration of the various
`tetracyclines is related to the variability of their absorption.
`These drugs can be divided into three groups based on the
`dosage and frequency of oral administration required to pro-
`duce effective plasma concentrations.
`Oxytetracycline and tetracycline are incompletely absorbed.
`After a single oral dose, the peak plasma concentration is at-
`tained in 2 to 4 hours. These drugs have half-lives in the range of
`6 to 12 hours and are frequently administered two to four times
`daily. The administration of 250 mg every 6 hours produces
`peak plasma concentrations of 2 to 2.5 Lg/ml. Increasing the
`dosage above I g every 6 hours does not produce significantly
`higher plasma concentrations.
`Demeclocycline, which also is incompletely absorbed, usu-
`ally is administered in lower daily dosages than are the above-
`mentioned congeners, because its half-life of about 16 hours per-
`mits effective plasma concentrations lasting for 24 to 48 hours.
`Doxycycline and minocycline should be administered in
`even lower daily dosages by the oral route, since their half-lives
`are long (16 to 18 hours) and they are better absorbed (90%
`to 100%) than tetracycline, oxytetracycline, or demeclocycline.
`After an oral dose of 200 mg of doxycycline, a maximum
`plasma concentration of 3 fLg/ml is achieved at 2 hours, and the
`plasma concentration is maintained above 1 gg/ml for
`8 to 12
`hours. Plasma concentrations are equivalent when doxycycline
`is given by the oral or parenteral route. Food does not interfere
`with the absorption of doxycycline or minocycline.
`
`Distribution. Tetracyclines distribute widely throughout
`the body and into tissues and secretions, including the
`urine and prostate. They accumulate in the reticuloen-
`
`(
`
`dothelial cells of the liver, spleen, and bone marrow and
`in bone, dentine, and the enamel of unerupted teeth ’
`below).
`Inflammation of the meninges is not a prerequisite
`
`for the passage of tetracyclines into the cerebrospinal
`Uld
`CSF). Penetration of these drugs into most other flj
`and tissues is excellent. Concentrations in synovial flu
`and the mucosa of the maxillary sinus approach that in
`plasma. Tetracyclines cross the placenta and enter the f etol
`
`circulation and amniotic fluid. Concentrations of tetracy
`dine in umbilical-cord plasma reach 60%, and in amniotic
`fluid 20%, of those in the circulation of the mother. Rel_
`atively high concentrations of these drugs also are found
`in breast milk.
`Excretion. The primary route of elimination for most
`tetracyclines is the kidney (doxycycline being an impo r
`tant exception), although they are also concentrated in the
`liver and excreted by way of the bile into the intestine s
`where they are partially reabsorbed via enterohepatic recir-
`culation. Elimination via the intestinal tract occurs even
`when the drugs are given parenterally, as a result of ex-
`cretion into the bile. Minocycline is an exception and is
`significantly metabolized by the liver.
`Since renal clearance of these drugs is by glorneru
`lar filtration, their excretion is significantly affected by the
`renal function status of the patient (see below). From 20%
`to 60% of an intravenous 0.5-g dose of tetracycline is ex-
`creted in the urine during the first 24 hours; from 20% to
`55% of an oral dose is excreted by this route. Approxi-
`mately 10% to 35% of a dose of oxytetracycline is ex-
`creted in active form in the urine, in which it is detectable
`within 30 minutes and reaches a peak concentration about
`5 hours after it is administered. The rate of renal clearance
`of demeclocycline is less than half that of tetracycline.
`About 50% of methacycline is excreted unchanged in the
`urine. Decreased hepatic function or obstruction of the
`common bile duct reduces the biliary excretion of these
`agents, resulting in longer half-lives and higher plasma
`concentrations. Because of their enterohepatic circulation,
`the tetracyclines may be present in the body for a long
`time after cessation of therapy.
`Minocycline is recoverable from both urine and feces
`in significantly lower amounts than are the other tetracy-
`clines, and it appears to be metabolized to a considerable
`extent. Renal clearance of minocycline is low. The drug
`persists in the body after its administration is stopped;
`this may be due to retention in fatty tissues. The half-life
`of minocycline is not prolonged in patients with hepatic
`failure.
`With conventional doses, doxycycline is not elimi -
`nated via the same pathways as are other tetracyclines ,
`and it does not accumulate significantly in patients with
`
`6
`
`

`

`k L{ (cid:9)
`
`o( (cid:9)
`
`t. k (cid:9)
`
`ilufflnn)I (cid:9)
`
`,id \mcou A ~~iOb acierhd Aac k iis 1243
`
`re
`
`al failure. It is thus one of the safest of the tetracyclines
`the treatment of extrarenal infections in such individu-
`The drug is excreted in the feces, largely as an inactive
`.011jugate or perhaps as a chelate; for this reason it has less
`iinpact on the intestinal microflora (Nord and Heimdahl,
`988). The half-life of doxycycline may be shortened from
`,P,roximately 16 to 7 hours in patients who are receiving
`100g-term treatment with barbiturates or phenytoin.
`
`goutes of Administration and Dosage. The tetracy-
`clines are available in a wide variety of forms for oral,
`parentemi and topical administration. As indicated earlier,
`only tetracycline (ACHROMYCIN, others), oxytetracycline
`(TERRAMYCIN others), demeclocycline
`(DECLOMYCIN),
`(MINOC1N, others), doxycycline (VIBRAMYCIN,
`niinocycli1
`others), and chlortetracycline (AUREOMYCIN) are available
`in the United States.
`Oral Administration. The appropriate oral dose of the
`tetracyclines varies with the nature and the severity of the
`infection being treated. For tetracycline, it ranges from 1 to
`2 g per day in adults. Children over 8 years of age should
`receive 25 to 50 mg/kg daily in two to four divided doses.
`The recommended dose of demeclocycline is somewhat
`lower, being 150 mg every 6 hours or 300 mg every 12
`hours for adults. The daily dose for children over 8 years
`of age is 6 to 12 mg/kg in two to four divided portions.
`Demeclocycline, however, is rarely used as an antimicro-
`bial agent because of its higher risks of photosensitivity
`reactions and diabetes insipidus syndrome (see below).
`The dose of doxycycline for adults is 100 mg every 12
`hours during the first 24 hours, followed by 100 mg once
`a day, or twice daily when severe infection is present.
`Children over 8 years of age should receive doxycycline,
`4 to 5 mg/kg per day, divided into two equal doses given
`every 12 hours the first day, after which half this amount
`(2 to 2.5 mg/kg) should be given as a single daily dose. In
`serious disease, the 2 to 2.5 mg/kg dose is given every 12
`hours. The dose of minocycline for adults is 200 mg ini-
`tially, followed by 100 mg every 12 hours; for children it
`is 4 mg/kg initially, followed by 2 mg/kg every 12 hours.
`Gastrointestinal distress, nausea, and vomiting can be
`minimized by administration of the tetracyclines with food
`(but not dairy products). Dairy products; antacids contain-
`ing calcium, aluminum, zinc, magnesium, or silicate; vi-
`tamins with iron; sulcralfate (which contains aluminum);
`and bismuth subsalicylate will chelate and therefore inter-
`fere with the absorption of tetracyclines and should not be
`ingested at the same time. Cholestyramine and colestipol
`also bind orally administered tetracyclines and interfere
`With their absorption.
`Parenteral Administration. Doxycycline is the preferred
`Parenteral tetracycline in the United States. It is used in
`
`severe illness, in patients unable to ingest medication, or
`when the drug causes significant nausea and vomiting if
`given orally. Because of local irritation and poor absorp-
`tion, intramuscular administration of these tetracyclines is
`generally unsatisfactory and is not recommended.
`The usual intravenous dose of doxycycline is 200 mg
`in one or two infusions on the first day and 100 to 200 mg
`on subsequent days. The dose for children who weigh less
`than 45 kg is 4.4 mg/kg on the first day, after which it is re-
`duced correspondingly. The total daily dose of intravenous
`tetracycline (where available) for most acute infections is
`500 mg to 1 g, usually administered in equally divided
`doses at 6-hour or 12-hour intervals. Up to 2 g per day
`may be given in severe infections. This dose should not be
`exceeded and may cause difficulty in some patients (see
`"Toxic Effects," below). Parenteral preparations of tetra-
`cycline no longer are available in the United States. The
`intravenous dose of minocycline for adults is 200 mg, fol-
`lowed by 100 mg every 12 hours. Children over 8 years
`of age should receive an initial dose of 4 mg/kg, followed
`by 2 mg/kg every 12 hours. Each 100 mg of minocy-
`dine must be diluted with 500 ml to 1 liter of compatible
`fluid and is slowly administered over 6 hours to minimize
`toxicity.
`Local Application. Except for local use in the eye,
`topical use of the tetracyclines is not recommended. Oph-
`thalmic preparations include chlortetracycline hydrochlo-
`ride, tetracycline hydrochloride, and oxytetracycline hy-
`drochloride; they are available as ophthalmic ointments
`or suspensions. Their use in ophthalmic therapy is dis-
`cussed in Chapter 66.
`
`Therapeutic Uses. The tetracyclines have been used ex-
`tensively both for the treatment of infectious diseases and
`as an additive to animal feeds to facilitate growth. Both
`uses have resulted in dramatically increased bacterial re-
`sistance to these drugs, and their use has declined. Tetra-
`cyclines are especially useful in diseases caused by rick-
`ettsiae, mycoplasmas, and chlamydiae. The status of the
`tetracyclines for the therapy of various infections is given
`in Table 43-1.
`Rickettsial Infections. The tetracyclines and chloram-
`phenicol are effective and may be life-saving in rickettsial
`infections, including Rocky Mountain spotted fever, re-
`crudescent epidemic typhus (Brill’s disease), murine ty-
`phus, scrub typhus, rickettsialpox, and Q fever. Clinical
`improvement often is evident within 24 hours after initiation
`of therapy.
`is
`Mycoplasma Infections. Mycoplasma pneumoniae
`sensitive to the tetracyclines. Treatment of pneumonia with
`either tetracycline or erythromycin results in a shorter
`duration of fever, cough, malaise, fatigue, pulmonary rales,
`
`7
`
`

`

`1244 (cid:9)
`
`SECTION VIII CHEMOTHERAPY OF MICROBIAL DISEASES
`
`and radiological changes in the lungs. Mycoplasma may
`persist in the sputum following cessation of therapy,
`despite rapid resolution of the active infection.
`Lymphogranuloma Venereum. Doxycycline
`Chiamydia.
`(100 mg twice daily for 21 days) is first-line therapy for
`treatment of this infection (Prevention, 1998). Decided re-
`duction in the size of buboes occurs within 4 days, and
`inclusion and elementary bodies entirely disappear from
`the lymph nodes within 1 week. Lymphogranulomatous
`proctitis is improved promptly. Rectal pain, discharge, and
`bleeding are decreased markedly. When relapses occur,
`treatment is resumed with full doses and is continued for
`longer periods.
`Pneumonia, bronchitis, or sinusitis caused by Chlamy-
`dia pneumoniae responds to tetracycline therapy. The tetra-
`cyclines also are of value in cases of psittacosis. Drug
`therapy for 10 to 14 days usually is adequate.
`Trachoma. Doxycycline (100 mg twice daily for 14
`days) or tetracycline (250 mg four times daily for 14 days)
`is effective for this infection. However, this disease is
`important in early childhood, and tetracyclines therefore
`often are contraindicated (see "Untoward Effects," below).
`Azithromycin (see section on macrolides), which is effec-
`tive as a single dose, is preferred.
`Nonspecific Urethritis. Nonspecific urethritis is of -
`ten due to Chiamydia trachomatis. One hundred mg of
`doxycycline every 12 hours for 7 days is effective, al-
`though azithromycin, which can be given as a single 1-g
`dose, is preferred because of improved compliance.
`Tetracyclines have been
`Sexually Transmitted Diseases.
`effective for uncomplicated gonococcal infections. Doxy-
`cycline (100 mg twice daily for 7 days) is still recom-
`mended for treatment of gonorrhea, although cefixime,
`ceftriaxone (see Chapter 45), or a fluoroquinolone
`(see
`Chapter 44), each of which is effective as a single dose,
`is preferred (Centers for Disease Control and Prevention,
`1998). Because coinfection with N. gonorrhoeae and
`C. trachomatis is common, doxycycline or azithromycin
`should be administered empirically in addition to one of
`these other agents when treating gonorrhea.
`C. trachomatis often is a coexistent pathogen in acute
`pelvic inflammatory disease, including endometritis, sal-
`pingitis, parametritis, and/or peritonitis (Walker
`et al.,
`1993). Doxycycline, 100 mg intravenously twice daily, is
`recommended for at least 48 hours after substantial clin-
`ical improvement, followed by oral therapy at the same
`dosage to complete a 14-day course. Doxycycline usually
`is combined with cefoxitin or cefotetan (see Chapter 45)
`to cover anaerobes and facultative aerobes.
`Acute epididymitis is caused by infection with C. tra-
`chomatis or N. gonorrhoeae in men less than 35 years of
`age. Effective regimens include a single injection of cef-
`
`f0
`
`triaxone (250 mg) plus doxycycline, 100 mg orally t
`daily for 10 days. Sexual partners of patients with any
`the above conditions should also be treated.
`Nonpregnant, penicillin-allergic patients who
`primary, secondary, or latent syphilis can be treated With
` a tetracycline regimen such as doxycycline 100 rug ora11
`
`twice daily for 2 weeks (Centers for Disease Control
`Prevention, 1998). Tetracyclines should not be used
`treatment of neurosyphilis.
`Brucellosis. Tetracyclines are e
`Bacillary Infections.
`fective for acute and chronic infections caused by Bruce ii0
`melitensis, Brucella suis, and Brucella abortus.
`nation therapy with doxycycline, 200 rug per day, plus
`rifampin (see Chapter 48), 600 to 900 mg daily for 6
`weeks, is recommended by the World Health Organiz a-
`tion for the treatment of acute brucellosis (World Health
`Organization, 1986). Relapses usually respond to a Sec-
`ond course of therapy. The combination of doxycyclj 0
`given with streptomycin (1 g daily, intramuscularly) also
`is effective and may be more efficacious than doxy
`cycline-rifampin in patients with spondylitis (Ariza et al.
`1992).
`Tularemia. Although streptomycin (see Chapter 48)
`is preferable, treatment with the tetracyclines also pro-
`duces prompt results in tularemia. Both the ulceroglan-
`dular and typhoidal types of the disease respond well.
`Fever, toxemia, and clinical signs and symptoms all are
`improved.
`Cholera. Doxycycline (300 mg as a single dose) is
`effective in reducing stool volume and eradicating Vibrio
`cholerae from the stool within 48 hours. Antimicrobial
`agents, however, are not substitutes for fluid and elec-
`trolyte replacement in this disease. In addition, some strains
`of V cholerae are resistant to tetracyclines (Khan et al.
`1996).
`Other Bacillary Infections. Therapy with the tetra-
`cyclines is often ineffective in infections caused by Shigella,
`Salmonella, or other Enterobacteriaceae because of a high
`prevalence of drug-resistant strains in many areas. Doxy
`cycline has been used successfully to reduce the incidence
`of travelers’ diarrhea, but a high prevalence of resistance
`in enteric bacteria limits the usefulness of the drug for this
`indication.
`Coccal Infections. Because of the emergence of resis-
`tance, the tetracyclines are no longer indicated for infec-
`tions caused by staphylococci, streptococci, or meningO
`cocci. Approximately 85% of strains of S. pneumoniae are
`susceptible to tetracyclines. Doxycycline remains an effec -
`tive agent for empirical therapy of community-acquired
`pneumonia (Ailani et al., 1999; Bartlett et al., 1998).
`Tetracyclines are no longer
`Urinary Tract Infections.
`recommended for routine treatment of urinary tract
`
`8
`
`

`

`infections,because many enteric organisms, including
`oli, that cause these infections are resistant.
`Other Infections. Actinomycosis, although most respon-
`sive to penicillin G, may be successfully treated with a
`tetracycline. Minocycline has been suggested as an alter-
`native for the treatment of nocardiosis, but a sulfonamide
`should be used concurrently. Yaws and relapsing fever
`respond favorably to the tetracyclines. Tet