44-Protein Synthesis Inhibitor

44
C H A P T E R
Tetracyclines,
Macrolides, Clindamycin,
Chloramphenicol,
Streptogramins, &
Oxazolidinones
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD
C ASE STUDY
A 22-year-old woman presents to her college medical clinic motion tenderness is present. A first-catch urine specimen is
complaining of a 2-week history of vaginal discharge. She obtained for chlamydia and gonorrhea nucleic acid amplifi-
denies any fever or abdominal pain but does report vaginal cation testing. A urine pregnancy test is also ordered as the
bleeding after sexual intercourse. When questioned about patient reports she “missed her last period.” Pending these
her sexual activity, she reports having vaginal intercourse, results, the decision is made to treat her presumptively for
at times unprotected, with two men in the last 6 months. A chlamydial cervicitis. What are two potential treatment
pelvic examination is performed and is positive for muco- options for her possible chlamydial infection? How does her
purulent discharge from the endocervical canal. No cervical potential pregnancy affect the treatment decision?
The drugs described in this chapter inhibit bacterial protein OH O OH O

OH
synthesis by binding to and interfering with ribosomes. Most are 11 1 O
10 12 C
bacteriostatic, but a few are bactericidal against certain organ- 9 2
NH2
isms. Tetracycline and macrolide resistance is common. Except 8
7
3
OH
6 5 4
for tigecycline and the streptogramins, these antibiotics may be R6 OH H R5 H N(CH3)2
R7
administered orally. Renal
Clearance
R7 R6 R5 (mL/min)
■ TETRACYCLINES
Chlortetracycline CI CH3 H 35
Oxytetracycline H CH3 OH 90
Tetracycline H CH3 H 65
Demeclocycline CI H H 35
All of the tetracyclines have the basic structure shown at right: Methacycline H CH2* OH 31
Doxycycline H CH3* OH 16
Minocycline N(CH3)2 H H 10
*There is no OH at position 6 on methacycline and doxycycline.
815
816 SECTION VIII Chemotherapeutic Drugs
Free tetracyclines are crystalline amphoteric substances of low Tetracyclines are active against many Gram-positive and Gram-
solubility. They are available as hydrochlorides, which are more negative bacteria, including certain anaerobes, rickettsiae, chla-
soluble. Such solutions are acidic and fairly stable. Tetracyclines mydiae, and mycoplasmas. For susceptible organisms, differences
chelate divalent metal ions, which can interfere with their absorp- in clinical efficacy may be attributable to features of absorption,
tion and activity. Tigecycline is a glycylcycline and a semisynthetic distribution, and excretion of individual drugs. Tetracycline-
derivative of minocycline. resistant strains may be susceptible to doxycycline, minocycline,
and tigecycline, all of which are poor substrates for the efflux
Mechanism of Action & Antimicrobial pump, if that is the mechanism of resistance.
Activity
Tetracyclines are broad-spectrum bacteriostatic antibiotics that Resistance
inhibit protein synthesis. Tetracyclines enter microorganisms in Three mechanisms of resistance to tetracycline analogs have
part by passive diffusion and in part by an energy-dependent been described: (1) impaired influx or increased efflux by
process of active transport. Susceptible organisms concentrate an active transport protein pump; (2) ribosome protection
the drug intracellularly. Once inside the cell, tetracyclines bind due to production of proteins that interfere with tetracycline
reversibly to the 30S subunit of the bacterial ribosome, block- binding to the ribosome; and (3) enzymatic inactivation. The
ing the binding of aminoacyl-tRNA to the acceptor site on the most important of these are production of an efflux pump
mRNA-ribosome complex (Figure 44–1). This prevents addition and ribosomal protection. Tet(AE) efflux pump-expressing
of amino acids to the growing peptide. Gram-negative species are resistant to the older tetracyclines,
50S
ribosome
Amino acid
1 C
6
2
M
3
4
2 t6
5 6 1
Charged
tRNA
t5 4
t6
3
mRNA
30S
T
t5 Uncharged tRNA
FIGURE 44–1 Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S
ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor
site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino
acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its
tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and
macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones 817
doxycycline, and minocycline. They are susceptible, how- Tetracyclines are classified as short-acting (tetracycline, as well
ever, to tigecycline, which is not a substrate of these pumps. as the agricultural agents chlortetracycline and oxytetracycline),
Similarly, a different pump [Tet(K)] of staphylococci confers intermediate-acting (demeclocycline), or long-acting (doxycy-
resistance to tetracycline, but not to doxycycline, minocycline, cline and minocycline) based on serum half-lives of 6–8 hours,
or tigecycline, none of which are pump substrates. The Tet(M) 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life
ribosomal protection protein expressed by Gram-positives of 36 hours. The almost complete absorption and slow excretion
produces resistance to tetracycline, doxycycline, and mino- of doxycycline and minocycline allow for once-daily dosing for
cycline, but not to tigecycline, which, because of its bulky certain indications, but, by convention, these two drugs are usu-
t-butylglycylamido substituent, has a steric hindrance effect on ally dosed twice daily.
Tet(M) binding to the ribosome. Tigecycline is a substrate of
the chromosomally encoded multidrug efflux pumps of Proteus
sp and Pseudomonas aeruginosa, accounting for their intrinsic Clinical Uses
resistance to all tetracyclines including tigecycline. A tetracycline is the drug of choice in the treatment of most
infections caused by rickettsiae and Borrelia sp, including Rocky
Mountain spotted fever and Lyme disease. Tetracyclines are used
Pharmacokinetics preferentially to treat Anaplasma phagocytophilum and Ehrlichia
Tetracyclines differ in their absorption after oral administration sp. Tetracyclines are also excellent drugs for the treatment of
and in their elimination. Absorption after oral administration is Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They
approximately 60–70% for tetracycline and demeclocycline (not are used in combination regimens to treat gastric and duodenal
typically used as an antibiotic; see below); and 95–100% for doxy- ulcer disease caused by Helicobacter pylori. They may be used in
cycline and minocycline. Tigecycline is poorly absorbed orally and various Gram-positive and Gram-negative bacterial infections,
must be administered intravenously. A portion of an orally admin- including vibrio infections, provided the organism is not resistant.
istered dose of tetracycline remains in the gut lumen, alters intes- In cholera, tetracyclines rapidly stop the shedding of vibrios, but
tinal flora, and is excreted in the feces. Absorption occurs mainly tetracycline resistance is an increasing problem. Tetracyclines
in the upper small intestine and is impaired by multivalent cations remain effective in most chlamydial infections, including sexually
2+ 2+ 2+ 3+
(Ca , Mg , Fe , Al ); by dairy products and antacids, which transmitted infections. Doxycycline is also an alternative agent
contain multivalent cations; and by alkaline pH. Tetracycline and recommended by the Centers for Disease Control and Preven-
demeclocycline should be administered on an empty stomach, tion for primary and secondary syphilis in patients with penicillin
while doxycycline and minocycline absorption is not impaired by allergy. A tetracycline—in combination with other antibiotics—is
food. Specially buffered doxycycline and minocycline solutions are indicated for plague, tularemia, and brucellosis. Tetracyclines are
formulated for intravenous administration. sometimes used in the treatment or prophylaxis of protozoal infec-
Tetracyclines are 40–80% bound by serum proteins. Oral tions, eg, those due to Plasmodium falciparum (see Chapter 52).
dosages of 500 mg every 6 hours of tetracycline hydrochlo- Other uses include treatment of acne, exacerbations of bronchitis,
ride produce peak blood levels of 4–6 mcg/mL. Peak levels of community-acquired pneumonia, leptospirosis, and some nontu-
2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or berculous mycobacterial infections (eg, Mycobacterium marinum).
minocycline. Steady-state peak serum concentrations of tigecy- Tetracyclines formerly were used for a variety of common
cline are 0.6 mcg/mL at the standard dosage. Tetracyclines are dis- infections, including bacterial gastroenteritis and urinary tract
tributed widely to tissues and body fluids except for cerebrospinal infections. However, many strains of bacteria causing these infec-
fluid, where concentrations are 10–25% of those in serum. Tet- tions are now resistant, and other agents have largely supplanted
racyclines cross the placenta and are also excreted in breast milk. tetracyclines.
As a result of chelation with calcium, tetracyclines bind to—and Minocycline, 100 mg orally twice daily for 5 days, can eradi-
damage—growing bones and teeth. Carbamazepine, phenytoin, cate the meningococcal carrier state, but because of side effects
barbiturates, and chronic alcohol ingestion may shorten the half- and resistance of many meningococcal strains, ciprofloxacin or
life of tetracycline and doxycycline by 50% due to induction of rifampin is preferred. Demeclocycline is rarely used as an antibac-
hepatic enzymes that metabolize the drugs. terial, but it has been used off-label in the treatment of inappropri-
Tetracyclines are excreted mainly in bile and urine. Concen- ate secretion of antidiuretic hormone because of its inhibition of
trations in bile exceed those in serum tenfold. Some of the drug antidiuretic hormone in the renal tubule (see Chapter 15).
excreted in bile is reabsorbed from the intestine (enterohepatic Tigecycline, the first glycylcycline to reach clinical practice, has
circulation) and may contribute to maintenance of serum levels. several unique features that warrant its consideration apart from the
Ten to fifty percent of various tetracyclines is excreted into the older tetracyclines. Its spectrum is very broad, and many tetracy-
urine, mainly by glomerular filtration. Ten to forty percent of the cline-resistant strains are susceptible to tigecycline because it is not
drug is excreted in feces. Doxycycline and tigecycline, in contrast affected by the common resistance determinants. Susceptible organ-
to other tetracyclines, are eliminated by nonrenal mechanisms isms include coagulase-negative staphylococci and Staphylococcus
and do not accumulate significantly in renal failure, requiring no aureus, including methicillin-resistant, vancomycin-intermediate,
dosage adjustment. and vancomycin-resistant strains; streptococci, penicillin-susceptible
and resistant; enterococci, including vancomycin-resistant strains; Adverse Reactions

Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains
Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines
of Acinetobacter sp; anaerobes, both Gram-positive and Gram-
are uncommon. Most adverse effects are due to direct toxicity of
negative; rickettsiae, Chlamydia sp, and Legionella pneumophila;
the drug or to alteration of microbial flora.
and rapidly growing mycobacteria. Proteus and Providencia sp and
P aeruginosa, however, are intrinsically resistant.
A. Gastrointestinal Adverse Effects
Tigecycline, formulated for intravenous administration only,
is given as a 100-mg loading dose, then 50 mg every 12 hours. Nausea, vomiting, and diarrhea are the most common reasons for
As with all tetracyclines, tissue and intracellular penetration is discontinuing tetracyclines. These effects are attributable to direct
excellent; consequently, the volume of distribution is quite large local irritation of the intestinal tract. Oral tetracyclines can rarely
and peak serum concentrations are low. Elimination is primarily cause esophageal ulceration, so patients should be instructed to
biliary, and no dosage adjustment is needed for patients with renal take them with 8 ounces of water and remain upright for at least
insufficiency. In addition to the tetracycline class effects, the chief 30 minutes after each dose.
adverse effect of tigecycline is nausea, which occurs in up to one Tetracyclines alter the normal gastrointestinal flora, with sup-
third of patients, and occasionally vomiting. Neither nausea nor pression of susceptible coliform organisms and overgrowth of
vomiting usually requires discontinuation of the drug. Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia,
Tigecycline is approved for treatment of skin and skin- and Candida. This can result in intestinal functional disturbances,
structure infection, intra-abdominal infections, and community- anal pruritus, vaginal or oral candidiasis, or Clostridium difficile–
acquired pneumonia. However, in a meta-analysis of clinical trials, associated colitis. However, the risk of C difficile colitis may be
tigecycline was associated with a small but significant increase in lower with tetracyclines than with other antibiotics.
the risk of death compared with other antibiotics used to treat
these infections. The increased risk was most apparent in hospital- B. Bony Structures and Teeth
acquired and ventilator-associated pneumonia but was also seen in Tetracyclines are readily bound to calcium deposited in newly
other infections. This has led the U.S. Food and Drug Adminis- formed bone or teeth in young children. When a tetracycline
tration (FDA) to issue a black box warning that tigecycline should is given during pregnancy, it can be deposited in the fetal teeth,
be reserved for situations where alternative treatments are not suit- leading to fluorescence, discoloration, and enamel dysplasia. It
able. Because active drug concentrations in the urine and serum can also be deposited in bone, where it may cause deformity or
are relatively low, tigecycline may not be effective for urinary tract growth inhibition. Because of these effects, tetracyclines are gener-
infections or primary bacteremia. Tigecycline has in vitro activ- ally avoided in pregnancy. If the drug is given for long periods to
ity against a wide variety of multidrug-resistant pathogens (eg, children younger than 8 years, similar changes can result.
methicillin-resistant S aureus, extended-spectrum β-lactamase-
producing Gram-negatives, and Acinetobacter sp); however, its C. Other Toxicities
clinical efficacy in infections with multidrug-resistant organisms, Tetracyclines can impair hepatic function, especially during
compared with other agents, is unproven. pregnancy, in patients with preexisting liver disease, and when
high doses are given intravenously. Hepatic necrosis has been
A. Oral Dosage reported with daily doses of 4 g or more intravenously. Renal
tubular acidosis and Fanconi syndrome have been attributed to
The oral dosage for rapidly excreted tetracyclines, equivalent to
the administration of outdated tetracycline preparations. Tetracy-
tetracycline hydrochloride, is 0.25–0.5 g four times daily for
clines given along with diuretics may cause nephrotoxicity. Tetra-
adults and 25–50 mg/kg/d for children (8 years of age and older).
cycline and minocycline may accumulate to toxic levels in patients
For severe systemic infections, the higher dosage is indicated, at
with impaired kidney function. Intravenous injection can lead
least for the first few days. The dosage for doxycycline is 100 mg
to venous thrombosis. Intramuscular injection produces painful
once or twice daily; the minocycline dose is 100 mg twice daily.
local irritation and should be avoided. Systemically administered
Doxycycline is the oral tetracycline of choice for most indications
tetracyclines commonly induce sensitivity to sunlight or ultravio-
because it is generally well tolerated, it can be given twice daily,
let light, particularly in fair-skinned persons. Dizziness, vertigo,
and its absorption is not significantly affected by food. All tetracy-
and tinnitus have been noted, particularly with high doses or
clines chelate with metals, and none should be orally administered
prolonged administration of minocycline. These symptoms may
with milk, antacids, or ferrous sulfate. To avoid deposition in
also occur with higher doses of doxycycline.
growing bones or teeth, tetracyclines should be avoided in preg-
nant women and children younger than 8 years.
■ MACROLIDES
B. Parenteral Dosage
Doxycycline and minocycline are available for intravenous injec- The macrolides are a group of closely related compounds charac-
tion at the same doses as the oral formulations. Intramuscular terized by a macrocyclic lactone ring (usually containing 14 or 16
injection is not recommended because of pain and inflammation atoms) to which deoxy sugars are attached. The prototype drug,
at the injection site. erythromycin, which consists of two sugar moieties attached to
a 14-atom lactone ring, was obtained in 1952 from Streptomyces Resistance to erythromycin is usually plasmid-encoded. Three
erythreus, now called Saccharopolyspora erythraea. Clarithromycin general mechanisms have been identified: (1) reduced perme-
and azithromycin are semisynthetic derivatives of erythromycin. ability of the cell membrane or active efflux; (2) production
(by Enterobacteriaceae) of esterases that hydrolyze macrolides;
Macrolide O and (3) modification of the ribosomal binding site (so-called
ring
R1 R1 ribosomal protection) by chromosomal mutation or by a mac-
rolide-inducible or constitutive methylase. Efflux and methylase
OH
production are the most important resistance mechanisms in
R2 O R1
R1 6 OH
Gram-positive organisms. Cross-resistance is complete between
R1 R1 erythromycin and the other macrolides. Constitutive methylase
O
O O C2H5 production also confers resistance to structurally unrelated but
N(R1)2 mechanistically similar compounds such as clindamycin and strep-
Desosamine
O O togramin B (so-called macrolide-lincosamide-streptogramin, or
OH MLS-type B, resistance), which share the same ribosomal binding
R1
O site. Because nonmacrolides are poor inducers of the methylase,
HO R1 strains expressing an inducible methylase will appear susceptible
OR1
Cladinose in vitro. However, constitutive mutants that are resistant can be
R1 selected out and emerge during therapy with clindamycin.
Erythromycin (R1 = CH3, R2 = H)
Clarithromycin (R1, R2 = CH3) Pharmacokinetics
Erythromycin base is destroyed by stomach acid and must be
administered with enteric coating. Food interferes with absorp-
ERYTHROMYCIN
tion. The stearate and ethylsuccinate formulations are fairly acid-
resistant and somewhat better absorbed. A 500-mg intravenous
Chemistry dose of erythromycin lactobionate produces serum concentrations
The general structure of erythromycin is shown with the mac- of 10 mcg/mL 1 hour after dosing. The serum half-life is approxi-
rolide ring and the sugars desosamine and cladinose. It is poorly mately 1.5 hours normally and 5 hours in patients with anuria.
soluble in water (0.1%) but dissolves readily in organic solvents. Adjustment for renal failure is not necessary. Erythromycin is
Solutions are fairly stable at 4°C but lose activity rapidly at 20°C not removed by dialysis. Large amounts of an administered dose
and at acid pH. Erythromycins are usually dispensed as various are excreted in the bile, and only 5% is excreted in the urine.
esters and salts. Absorbed drug is distributed widely except to the brain and cere-
brospinal fluid. Erythromycin is taken up by polymorphonuclear
Mechanism of Action & Antimicrobial leukocytes and macrophages. It traverses the placenta and reaches
Activity the fetus.
The antibacterial action of erythromycin and other macrolides
may be inhibitory or bactericidal, particularly at higher concentra- Clinical Uses
tions, for susceptible organisms. Activity is enhanced at alkaline Erythromycin is a traditional drug of choice in corynebacterial
pH. Inhibition of protein synthesis occurs via binding to the 50S infections (diphtheria, corynebacterial sepsis, erythrasma) and
ribosomal RNA. The binding site is near the peptidyltransferase in respiratory, neonatal, ocular, or genital chlamydial infections.
center, and peptide chain elongation (ie, transpeptidation) is While it was used in treatment of community-acquired pneu-
prevented by blocking of the polypeptide exit tunnel. As a result, monia because its spectrum of activity includes pneumococcus,
peptidyl-tRNA is dissociated from the ribosome. Erythromy- M pneumoniae, and L pneumophila, newer macrolides are better
cin also inhibits the formation of the 50S ribosomal subunit tolerated and more commonly selected. Macrolide resistance is
(Figure 44–1). increasing in pneumococci and M pneumoniae. Erythromycin had
Erythromycin is active against susceptible strains of Gram-pos- also been useful as a penicillin substitute in penicillin-allergic indi-
itive organisms, especially pneumococci, streptococci, staphylo- viduals with infections caused by staphylococci and streptococci.
cocci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Emergence of erythromycin resistance in staphylococci and in
Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila strains of group A streptococci has made macrolides less attractive
pneumoniae, H pylori, Listeria monocytogenes, and certain myco- as first-line agents for treatment of pharyngitis and skin and soft
bacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) tissue infections. Erythromycin has been studied as prophylaxis
also are susceptible. Gram-negative organisms such as Neisseria sp, against endocarditis during dental procedures in individuals with
Bordetella pertussis, Bartonella henselae, and Bartonella quintana as valvular heart disease, but clindamycin, which is better tolerated,
well as some Rickettsia species, Treponema pallidum, and Campylo- has largely replaced it.
bacter species are susceptible. Haemophilus influenzae is somewhat The oral dosage of erythromycin base or stearate is
less susceptible. 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage
of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral AZITHROMYCIN

erythromycin base (1 g) is sometimes combined with oral neo-
mycin or kanamycin for preoperative preparation of the colon. Azithromycin, a 15-atom lactone macrolide ring compound, is
The intravenous dosage of erythromycin lactobionate is 0.5–1.0 g derived from erythromycin by addition of a methylated nitrogen
every 6 hours for adults and 15–20 mg/kg/d divided every 6 hours into the lactone ring. Its spectrum of activity, mechanism of action,
for children. The higher dosage is recommended when treating and clinical uses are similar to those of clarithromycin. Azithromy-
pneumonia caused by L pneumophila. cin is active against M avium complex and T gondii. Azithromycin
is slightly less active than erythromycin and clarithromycin against
Adverse Reactions staphylococci and streptococci and slightly more active against
Anorexia, nausea, vomiting, and diarrhea are common. Gastro- H influenzae. Azithromycin is highly active against Chlamydia sp.
intestinal intolerance, which is due to a direct stimulation of gut Azithromycin differs from erythromycin and clarithromy-
motility, is the most common reason for selecting an alternative to cin mainly in pharmacokinetic properties. A 500-mg dose of
erythromycin. This side effect may actually be desirable in some azithromycin produces relatively low serum concentrations of
circumstances, leading to the off-label use of erythromycin to treat approximately 0.4 mcg/mL. However, azithromycin penetrates
patients with gastroparesis. into most tissues (except cerebrospinal fluid) and phagocytic
Erythromycins, particularly the older estolate formulation, can cells extremely well, with tissue concentrations exceeding serum
produce acute cholestatic hepatitis (fever, jaundice, impaired liver concentrations by 10- to 100-fold. The drug is slowly released
function), probably as a hypersensitivity reaction. Most patients from tissues (tissue half-life of 2–4 days) to produce an elimina-
recover from this, but hepatitis recurs if the drug is readministered. tion half-life approaching 3 days. These unique properties permit
Other allergic reactions include fever, eosinophilia, and rashes. once-daily dosing and shortening of the duration of treatment in
Erythromycin metabolites inhibit cytochrome P450 enzymes many cases. For example, a single 1-g dose of azithromycin is as
and, thus increase the serum concentrations of numerous drugs, effective as a 7-day course of doxycycline for chlamydial cervicitis
including theophylline, warfarin, cyclosporine, and methylpred- and urethritis. Azithromycin, as a 500-mg loading dose, followed
nisolone. Erythromycin increases serum concentrations of oral by a 250-mg single daily dose for the next 4 days, is commonly
digoxin by increasing its bioavailability. used alone or in combination with a beta-lactam antibiotic to treat
community-acquired pneumonia.
Azithromycin is rapidly absorbed and well tolerated orally. Alumi-
CLARITHROMYCIN num and magnesium antacids do not alter bioavailability but delay
absorption and reduce peak serum concentrations. Because it has a
Clarithromycin is derived from erythromycin by addition of a 15-member (not 14-member) lactone ring, azithromycin does not
methyl group and has improved acid stability and oral absorption inactivate cytochrome P450 enzymes and, therefore, is free of the
compared with erythromycin. Its mechanism of action is the same drug interactions that occur with erythromycin and clarithromycin.
as that of erythromycin. Clarithromycin and erythromycin are Macrolide antibiotics prolong the electrocardiographic QT
similar with respect to antibacterial activity except that clarithro- interval due to an effect on potassium ion channels. Prolongation
mycin is more active against Mycobacterium avium complex (see of the QT interval can lead to the torsades de pointes arrhythmia.
Chapter 47). Clarithromycin also has activity against Mycobacte- Recent studies have suggested that azithromycin may be associated
rium leprae, Toxoplasma gondii, and H influenzae. Erythromycin- with a small increased risk of cardiac death.
resistant streptococci and staphylococci are also resistant to
clarithromycin.
A 500-mg dose of clarithromycin produces serum concen- FIDAXOMICIN
trations of 2–3 mcg/mL. The longer half-life of clarithromycin
(6 hours) compared with erythromycin permits twice-daily Fidaxomicin, a minimally absorbed macrolide used to treat
dosing. The recommended dosage is 250–500 mg twice daily or Clostridium difficile infections, is discussed in Chapter 50.
1000 mg of the extended-release formulation once daily. Clar-
ithromycin penetrates most tissues well, with concentrations equal
to or exceeding serum concentrations. KETOLIDES
Clarithromycin is metabolized in the liver and is partially
eliminated in the urine. The major metabolite, 14-hydroxyclar- Ketolides are semisynthetic, 14-membered-ring macrolides, dif-
ithromycin, also has antibacterial activity and is eliminated in the fering from erythromycin by substitution of a 3-keto group for
urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg the neutral sugar l-cladinose. Telithromycin is approved for
once or twice daily) is recommended for patients with creatinine limited clinical use. It is active in vitro against Streptococcus pyo-
clearances less than 30 mL/min. Clarithromycin has drug interac- genes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis,
tions similar to those described for erythromycin. Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria
The advantages of clarithromycin compared with erythromy- gonorrhoeae, B fragilis, T gondii, and certain nontuberculous
cin are lower incidence of gastrointestinal intolerance and less mycobacteria. Many macrolide-resistant strains are susceptible to
frequent dosing. ketolides because the structural modification of these compounds
renders them poor substrates for efflux pump–mediated resis- with aminoacyl translocation reactions. The binding site for
tance, and they bind to ribosomes of some bacterial species with clindamycin on the 50S subunit of the bacterial ribosome is
higher affinity than macrolides. identical with that for erythromycin. Streptococci, staphy-
Oral bioavailability of telithromycin is 57%, and tissue and lococci, and pneumococci are inhibited by clindamycin at
intracellular penetration is generally good. Telithromycin is a concentration of 0.5–5 mcg/mL. Enterococci and Gram-
metabolized in the liver and eliminated by a combination of negative aerobic organisms are resistant. Bacteroides sp and
biliary and urinary routes of excretion. It is administered as a other anaerobes are often susceptible, though resistance may
once-daily dose of 800 mg, which results in peak serum concen- be increasing, particularly in Gram-negative anaerobes. Resis-
trations of approximately 2 mcg/mL. It is a reversible inhibitor of tance to clindamycin, which generally confers cross-resistance
the CYP3A4 enzyme system and may slightly prolong the QTc to macrolides, is due to (1) mutation of the ribosomal recep-
interval. In the USA, telithromycin is now indicated only for tor site; (2) modification of the receptor by a constitutively
treatment of community-acquired bacterial pneumonia. Other expressed methylase (see section on erythromycin resistance,
respiratory tract infections were removed as indications when it above); and (3) enzymatic inactivation of clindamycin. Gram-
was recognized that use of telithromycin can result in hepatitis negative aerobic species are intrinsically resistant because of
and liver failure. Telithromycin is also contraindicated in patients poor permeability of the outer membrane.
with myasthenia gravis because it may exacerbate this condition.
Due to its potential for serious toxicity, an FDA-approved patient
medication guide detailing these risks must be dispensed to any Pharmacokinetics
patient receiving the medication. Oral dosages of clindamycin, 0.15–0.3 g every 8 hours
Solithromycin is a novel fluoroketolide that is pending FDA (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL.
approval after two phase 3 clinical trials showed noninferior- When administered intravenously, 600 mg of clindamycin every
ity when compared with moxifloxacin in the treatment of 8 hours gives levels of 5–15 mcg/mL. The drug is about 90%
community-acquired pneumonia. Although not yet marketed, protein-bound. Clindamycin penetrates well into most tissues,
the dose used in clinical trials was a loading dose of 800 mg with brain and cerebrospinal fluid being important exceptions.
orally or intravenously, followed by 400 mg daily for a total of It penetrates well into abscesses and is actively taken up and con-
5 days. The intravenous formulation was associated with higher centrated by phagocytic cells. Clindamycin is metabolized by the
rates of infusion-related reactions compared with moxifloxacin. liver, and both active drug and active metabolites are excreted in
Similar to telithromycin, solithromycin maintains in vitro activ- bile and urine. The half-life is about 2.5 hours in normal indi-
ity against macrolide-resistant bacteria, including S pneumoniae, viduals, increasing to 6 hours in patients with anuria. No dosage
staphylococci, enterococci, Chlamydia trachomatis, and Neisseria adjustment is required for renal failure.
gonorrhoeae. Its chemical structure lacks the pyridine-imidazole
side chain group, which is thought to contribute to telithromy-
cin’s hepatotoxicity; severe toxicity has not been demonstrated in Clinical Use
Phase II or III clinical trials. Clindamycin is indicated for the treatment of skin and soft-
tissue infections caused by streptococci and staphylococci. It
may be active against community-acquired strains of methi-
■ CLINDAMYCIN cillin-resistant S aureus, though resistance has been increasing.
It is commonly used in conjunction with penicillin G to treat
Clindamycin is a chlorine-substituted derivative of lincomycin, toxic shock syndrome or necrotizing fasciitis caused by Group
an antibiotic that is elaborated by Streptomyces lincolnensis. A Streptococcus. In this setting, its use is typically limited to the
initial 48 to 72 hours of treatment with the goal of inhibiting
CH3
CH3 toxin production. Clindamycin is also indicated for treatment
N
CI CH
of infections caused by susceptible Bacteroides sp and other
C3H7 anaerobes. Clindamycin, sometimes in combination with an
C NH CH
aminoglycoside or cephalosporin, is used to treat penetrating
O
O HO wounds of the abdomen and the gut; infections originating in
OH the female genital tract, eg, septic abortion, pelvic abscesses, or
S CH3 pelvic inflammatory disease; and lung and periodontal abscesses.
OH Clindamycin is recommended for prophylaxis of endocarditis in
Clindamycin patients with specific valvular heart disease who are undergoing
certain dental procedures and have significant penicillin aller-
Mechanism of Action & Antibacterial gies. Clindamycin plus primaquine is an effective alternative
to trimethoprim-sulfamethoxazole for moderate to moderately
Activity severe Pneumocystis jiroveci pneumonia in AIDS patients. It is
Clindamycin, like erythromycin, inhibits protein synthesis also used in combination with pyrimethamine for AIDS-related
by interfering with the formation of initiation complexes and toxoplasmosis of the brain.
Adverse Effects ■ CHLORAMPHENICOL

Common adverse effects are diarrhea, nausea, and skin rashes.
Impaired liver function (with or without jaundice) and neutro- Crystalline chloramphenicol is a neutral, stable compound with
penia sometimes occur. Administration of clindamycin is a risk the following structure:
factor for diarrhea and colitis due to C difficile. OH CH2OH O
NO2 C C N C CHCI2
■ STREPTOGRAMINS H H H
Chloramphenicol
MECHANISM OF ACTION &

It is soluble in alcohol but poorly soluble in water. Chloram-
ANTIBACTERIAL ACTIVITY phenicol succinate, which is used for parenteral administration,
is highly water-soluble. It is hydrolyzed in vivo with liberation of
Quinupristin-dalfopristin is a combination of two
free chloramphenicol.
streptogramins—quinupristin, a streptogramin B, and dalfopris-
tin, a streptogramin A—in a 30:70 ratio. The streptogramins share
the same ribosomal binding site as the macrolides and clindamy- Mechanism of Action & Antimicrobial
cin and thus inhibit protein synthesis in an identical manner. Activity
Quinupristin-dalfopristin is rapidly bactericidal for most suscep-
Chloramphenicol is an inhibitor of microbial protein synthesis and
tible organisms except Enterococcus faecium, which is killed slowly.
is bacteriostatic against most susceptible organisms. It binds revers-
Quinupristin-dalfopristin is active against Gram-positive cocci,
ibly to the 50S subunit of the bacterial ribosome (Figure 44–1)
including multidrug-resistant strains of streptococci, penicillin-
and inhibits peptide bond formation (step 2). Chloramphenicol
resistant strains of S pneumoniae, methicillin-susceptible and resis-
is a broad-spectrum antibiotic that is active against both aerobic
tant strains of staphylococci, and E faecium (but not Enterococcus
and anaerobic Gram-positive and Gram-negative organisms. It is
faecalis). Resistance is due to modification of the quinupristin
active also against rickettsiae but not chlamydiae. Most Gram-
binding site (MLS-B type resistance), enzymatic inactivation of
positive bacteria are inhibited at concentrations of 1–10 mcg/mL,
dalfopristin, or efflux.
and many Gram-negative bacteria are inhibited by concentrations
of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some
Pharmacokinetics strains of Bacteroides are highly susceptible; for these organisms,
Quinupristin-dalfopristin is administered intravenously at a chloramphenicol may be bactericidal.
dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentra- Low-level resistance to chloramphenicol may emerge from
tions following an infusion of 7.5 mg/kg over 60 minutes are large populations of chloramphenicol-susceptible cells by selection
3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin. of mutants that are less permeable to the drug. Clinically signifi-
Quinupristin and dalfopristin are rapidly metabolized, with cant resistance is due to production of chloramphenicol acetyl-
half-lives of 0.85 and 0.7 hours, respectively. Elimination is prin- transferase, a plasmid-encoded enzyme that inactivates the drug.
cipally by the fecal route. Dose adjustment is not necessary for
renal failure, peritoneal dialysis, or hemodialysis. Patients with Pharmacokinetics
hepatic insufficiency may not tolerate the drug at usual doses,
however, because of increased area under the concentration The usual dosage of chloramphenicol is 50–100 mg/kg/d divided
curve of both parent drugs and metabolites. This may neces- every 6 hours. It is no longer available in the USA as an oral for-
sitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg mulation. The parenteral formulation is a prodrug, chlorampheni-
every 8 hours. Quinupristin and dalfopristin significantly inhibit col succinate, which is hydrolyzed to yield free chloramphenicol,
CYP3A4, which metabolizes warfarin, diazepam, quetiapine, giving blood levels somewhat lower than those achieved with
simvastatin, and cyclosporine, among many others. Dosage orally administered drug. Chloramphenicol is widely distributed
reduction of cyclosporine may be necessary. to virtually all tissues and body fluids, including the central ner-
vous system and cerebrospinal fluid, such that the concentration
of chloramphenicol in brain tissue may be equal to that in serum.
Clinical Uses & Adverse Effects The drug penetrates cell membranes readily.
Quinupristin-dalfopristin is approved for treatment of infec- Most of the drug is inactivated either by conjugation with gluc-
tions caused by staphylococci or by vancomycin-resistant strains uronic acid (principally in the liver) or by reduction to inactive
of E faecium, but not E faecalis, which is intrinsically resistant, aryl amines. Active chloramphenicol, about 10% of the total dose
probably because of an efflux-type resistance mechanism. The administered, and its inactive degradation products are eliminated
principal toxicities are infusion-related events, such as pain at the in the urine. A small amount of active drug is excreted into bile
infusion site, and an arthralgia-myalgia syndrome. Quinupristin- and feces. There are no specific dosage adjustments recommended
dalfopristin is used to a limited extent in the USA due to the in renal or hepatic insufficiency; however, the drug will accumu-
availability of better-tolerated alternatives. late and should be used with extra caution in these situations.
Newborns less than a week old and premature infants also clear Linezolid inhibits protein synthesis by preventing formation of the
chloramphenicol less well, and the dosage should be reduced to ribosome complex that initiates protein synthesis. Its unique binding
25 mg/kg/d. site, located on 23S ribosomal RNA of the 50S subunit, results in no
cross-resistance with other drug classes. Resistance is caused by muta-
Clinical Uses tion of the linezolid binding site on 23S ribosomal RNA.
Because of potential toxicity, bacterial resistance, and the availabil-
ity of many other effective alternatives, chloramphenicol is rarely Pharmacokinetics
used in the United States. It may be considered for treatment of Linezolid is 100% bioavailable after oral administration and has a
serious rickettsial infections such as typhus and Rocky Mountain half-life of 4–6 hours. It is metabolized by oxidative metabolism,
spotted fever. It is an alternative to a β-lactam antibiotic for treat- yielding two inactive metabolites. It is neither an inducer nor an
ment of bacterial meningitis occurring in patients who have major inhibitor of cytochrome P450 enzymes. Peak serum concentra-
hypersensitivity reactions to penicillin. tions average 18 mcg/mL following a 600-mg oral dose; cerebro-
spinal fluid (CSF) concentrations reach approximately 60–70% of
Adverse Reactions the serum level. The recommended dosage for most indications is
Adults occasionally develop gastrointestinal disturbances, includ- 600 mg twice daily, either orally or intravenously.
ing nausea, vomiting, and diarrhea. These symptoms are rare
in children. Oral or vaginal candidiasis may occur as a result of Clinical Uses
alteration of normal microbial flora. Linezolid is approved for vancomycin-resistant E faecium infec-
Chloramphenicol commonly causes a dose-related revers- tions, health care–associated pneumonia, community-acquired
ible suppression of red cell production at dosages exceeding pneumonia, and both complicated and uncomplicated skin and
50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence soft tissue infections caused by susceptible Gram-positive bacte-
(1 in 24,000 to 40,000 courses of therapy) of chloramphenicol ria. Off-label uses of linezolid include treatment of multidrug-
administration by any route, is an idiosyncratic reaction unrelated resistant tuberculosis and Nocardia infections.
to dose, although it occurs more frequently with prolonged use.
Aplastic anemia tends to be irreversible and can be fatal, although
it may respond to bone marrow transplantation or immunosup- Adverse Effects
pressive therapy. Due to the severity of this reaction, a boxed The principal toxicity of linezolid is hematologic; the effects are
warning has been added to its U.S. labeling. reversible and generally mild. Thrombocytopenia is the most
Newborn infants lack an effective glucuronic acid conjugation common manifestation (seen in approximately 3% of treatment
mechanism for the degradation and detoxification of chloram- courses), particularly when the drug is administered for longer
phenicol. Consequently, when infants are given dosages above than 2 weeks. Anemia and neutropenia may also occur, most
50 mg/kg/d, the drug may accumulate, resulting in the gray baby commonly in patients with a predisposition to or underlying bone
syndrome, with vomiting, flaccidity, hypothermia, gray color, marrow suppression. Cases of optic and peripheral neuropathy
shock, and vascular collapse. To avoid this toxic effect, chloram- and lactic acidosis have been reported with prolonged courses of
phenicol should be used with caution in infants and the dosage linezolid. These side effects are thought to be related to linezolid-
limited to 50 mg/kg/d (or less during the first week of life) in full- induced inhibition of mitochondrial protein synthesis. There are
term infants and 25 mg/kg/d in premature infants. case reports of serotonin syndrome (see Chapter 16) occurring
Chloramphenicol inhibits hepatic microsomal enzymes that when linezolid is co-administered with serotonergic drugs, most
metabolize several drugs. Half-lives of these drugs are prolonged, frequently selective serotonin reuptake inhibitor antidepressants.
and the serum concentrations of phenytoin, tolbutamide, chlor- The FDA has issued a warning regarding the use of the drug with
propamide, and warfarin are increased. serotonergic agents.
Tedizolid is the active moiety of the prodrug tedizolid phos-
phate, a next-generation oxazolidinone, with high potency against
■ OXAZOLIDINONES Gram-positive bacteria, including methicillin-resistant S aureus.
It is FDA-approved at a dose of 200 mg orally or intravenously
MECHANISM OF ACTION & once daily for 6 days for the treatment of skin and soft tissue
ANTIMICROBIAL ACTIVITY infection. Potential advantages over linezolid include increased
potency against staphylococci and a longer half-life of 12 hours,
Linezolid is a member of the oxazolidinone class of synthetic allowing once-daily dosing. It may be associated with a decreased
antimicrobials. It is active against Gram-positive organisms risk of marrow suppression; however, it has not been studied over
including staphylococci, streptococci, enterococci, Gram-positive a prolonged duration of therapy. It is thought to have a lower risk
anaerobic cocci, and Gram-positive rods such as corynebacteria, of serotonergic toxicity, but concomitant use with serotonin reup-
Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic take inhibitors has not been formally evaluated. Tedizolid is more
agent but is bactericidal against streptococci. It is also active highly protein-bound (70–90%) than linezolid (31%); there are
against Mycobacterium tuberculosis. no data on CSF penetration of tedizolid.
SUMMARY Tetracyclines, Macrolides, Clindamycin, Chloramphenicol,

Streptogramins, & Oxazolidinones
Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions
TETRACYCLINES
Prevents bacterial protein Bacteriostatic activity Infections caused by
synthesis by binding to the against susceptible mycoplasma, chlamydiae,
30S ribosomal subunit bacteria rickettsiae, some spirochetes Toxicity: Gastrointestinal upset,
H pylori hepatotoxicity, photosensitivity, deposition in
bone and teeth
Doxycycline: Oral and IV; longer half-life (18 h) so dosed twice daily; nonrenal elimination; absorption is minimally affected by divalent cations; used to treat community-
acquired pneumonia and exacerbations of bronchitis
bacteria; nausea and vomiting are the primary toxicities
MACROLIDES
Prevents bacterial protein Bacteriostatic activity Community-acquired
synthesis by binding to the against susceptible
50S ribosomal subunit bacteria Toxicity: Gastrointestinal upset, hepatotoxicity,
chlamydial infections QTc prolongation
M avium M leprae
Telithromycin: Oral; unaffected by efflux-mediated resistance so is active versus many erythromycin-resistant strains of pneumococci; rare cases of fulminant hepatic
failure
LINCOSAMIDE
Prevents bacterial protein Bacteriostatic activity Skin and soft tissue infections
synthesis by binding to the against susceptible Toxicity:
50S ribosomal subunit bacteria Gastrointestinal upset, C difficile colitis
STREPTOGRAMINS
Prevents bacterial protein Rapid bactericidal Infections caused by
dalfopristin synthesis by binding to the activity against most staphylococci or vancomycin- Toxicity: Severe
50S ribosomal subunit susceptible bacteria resistant strains of E faecium infusion-related myalgias and arthralgias
CHLORAMPHENICOL
Prevents bacterial protein Bacteriostatic activity Use is rare in the developed
synthesis by binding to the against susceptible world because of serious
50S ribosomal subunit bacteria toxicities Toxicity: Dose-related anemia, idiosyncratic
aplastic anemia, gray baby syndrome
OXAZOLIDINONES
Prevents bacterial protein Bacteriostatic activity Infections caused by
synthesis by binding to the against susceptible methicillin-resistant Toxicity: Duration-dependent bone
23S ribosomal RNA of 50S bacteria staphylococci and vancomycin- marrow suppression, neuropathy, and optic
subunit resistant enterococci
co-administered with other serotonergic drugs
(eg, selective serotonin reuptake inhibitors)
Tedizolid: Oral and IV; longer half-life (12 h) so dosed once daily; increased potency versus staphylococci; approved for use in skin and soft tissue infections.
P R E P A R A T I O N S Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications,

molecular biology, and epidemiology of bacterial resistance. Microbiol Mol
A V A I L A B L E Biol Rev 2001;65:232.
De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthe-
sis. Clin Infect Dis 2006;42:1111.
GENERIC NAME AVAILABLE AS
Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treat-
Chloramphenicol Generic, Chloromycetin ment. 2011;66(Suppl 4):S7.
TETRACYCLINES File Jr. TM et al: SOLITAIRE-IV: A randomized, double-blind, multicenter study
Demeclocycline Generic, Declomycin comparing the efficacy and safety of intravenous-to-oral solithromycin to
intravenous-to-oral moxifloxacin for treatment of community-acquired
Doxycycline Generic, Vibramycin, others bacterial pneumonia. Clin Infect Dis 2016;63:1007.
Minocycline Generic, Minocin, others Hancock RE: Mechanisms of action of newer antibiotics for gram-positive
Tetracycline Generic, others pathogens. Lancet Infect Dis 2005;5:209.
Tigecycline Tygacil Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature
of the resistance elements and their clinical implications. Clin Infect Dis
MACROLIDES
2002;34:482.
Generic, Zithromax Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
Clarithromycin Generic, Biaxin losis. N Engl J Med 2012;367:1508.
Generic, others Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob
KETOLIDES Chemother 2005;56:611.
Moran GJ et al: Methicillin-resistant S aureus infections among patients in the
Telithromycin Ketek
emergency department. N Engl J Med 2006;355:666.
LINCOMYCIN Moran GJ et al: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial
Clindamycin Generic, Cleocin skin and skin-structure infections (ESTABLISH-2): A randomized, double-
STREPTOGRAMINS blind, phase 3, non-inferiority trial. Lancet 2014;14:696.
Quinupristin and dalfopristin Synercid Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial
skin and skin structure infections. JAMA 2013;309:559.
OXAZOLIDINONE
Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious
Generic, Zyvox diseases: A meta-analysis. Lancet Infect Dis 2011;11:834.
Sivextro Van Bambeke F: Renaissance of antibiotics against difficult infections: Focus on
oritavancin and new ketolides and quinolones. Ann Med 2014;46:512.
Wayne RA et al: Azithromycin and risk of cardiovascular death. N Engl J Med
2012;366:1881.
Woytowish MR, Rowe AS: Clinical relevance of linezolid-associated serotonin
toxicity. Ann Pharmacother 2013;47:388.
REFERENCES Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithro-
Barrera CM et al: Efficacy and safety of oral solithromycin versus oral moxifloxa- mycin. Infect Dis Clin North Am 2004;18:621.
cin for treatment of community-acquired bacterial pneumonia: A global,
double-blind, multicenter, randomized, active-controlled, non-inferiority
trial (SOLITAIRE-ORAL). Lancet 2016;16:421.
C ASE STUDY ANSWER
A tetracycline or a macrolide is effective in the treatment of patient is pregnant, then tetracyclines would be contraindi-
chlamydial cervicitis. Doxycycline at a dose of 100 mg PO cated and she should receive azithromycin, which is safe in
bid for 7 days is the preferred tetracycline, while azithro- pregnancy.
mycin as a single 1 g dose is the preferred macrolide. If the
44
C H A P T E R
Tetracyclines,
Macrolides, Clindamycin,
Chloramphenicol,
Streptogramins, &
Oxazolidinones
The antimicrobial drugs reviewed in this chapter selectively and in the chemical composition and functional specificities of
inhibit bacterial protein synthesis. The mechanisms of protein component nucleic acids and proteins. Such differences form
synthesis in microorganisms are not identical to those of mam- the basis for the selective toxicity of these drugs against micro-
malian cells. Bacteria have 70S ribosomes, whereas mammalian organisms without causing major effects on protein synthesis in
cells have 80S ribosomes. Differences exist in ribosomal subunits mammalian cells.
Bacterial protein synthesis inhibitors
Broad spectrum Moderate spectrum Narrow spectrum
Chloramphenicol Macrolides Ketolide Lincosamides
Tetracyclines Streptogramins
Oxazolidinones
INHIBITORS OF MICROBIAL to be discovered. Because they had a broad spectrum of antibac-

PROTEIN SYNTHESIS terial activity and were thought to have low toxicities, they were
overused. Many once highly susceptible bacterial species have
Drugs that inhibit protein synthesis vary considerably in terms become resistant, and most of these drugs are now used for more
of chemical structures and their spectrum of antimicrobial activity. selected targets. Erythromycin, an older macrolide antibiotic, has
Chloramphenicol, tetracyclines, and the aminoglycosides (see a narrower spectrum of action but continues to be active against
Chapter 45) were the first inhibitors of bacterial protein synthesis several important pathogens. Azithromycin and clarithromycin,
377
Trevor_Ch44_p377-p384.indd 377 7/13/18 6:48 PM

378 PART VIII Chemotherapeutic Drugs
semisynthetic macrolides, have some distinctive properties com- which share a common binding site on the 50S ribosome, also
pared with erythromycin, as does clindamycin. Newer inhibitors block transpeptidation. Tetracyclines bind to the 30S ribosomal
of microbial protein synthesis, which include streptogramins, subunit preventing binding of amino acid-charged tRNA to the
linezolid, telithromycin, and tigecycline (a tetracycline analog), acceptor site of the ribosome-mRNA complex.
have activity against certain bacteria that have developed resistance Streptogramins are bactericidal for most susceptible organ-
to older antibiotics. isms. They bind to the 50S ribosomal subunit, constricting the
exit channel on the ribosome through which nascent polypeptides
MECHANISMS OF ACTION are extruded. In addition, tRNA synthetase activity is inhibited,
leading to a decrease in free tRNA within the cell. Linezolid is
Most of the antibiotics reviewed in this chapter are bacterio- mainly bacteriostatic. The drug binds to a unique site on the
static inhibitors of protein synthesis acting at the ribosomal level 50S ribosome, inhibiting initiation by blocking formation of the
(Figure 44–1). With the exception of tetracyclines, the binding tRNA-ribosome-mRNA ternary complex.
sites for these antibiotics are on the 50S ribosomal subunit. Selective toxicity of these protein synthesis inhibitors against micro-
Chloramphenicol inhibits transpeptidation (catalyzed by peptidyl organisms may be explained by target differences. Chloramphenicol
transferase) by blocking the binding of the aminoacyl moiety does not bind to the 80S ribosomal RNA of mammalian cells,
of the charged transfer RNA (tRNA) molecule to the acceptor although it can inhibit the functions of mitochondrial ribosomes,
site on the ribosome-messenger (mRNA) complex. Thus, the which contain 70S ribosomal RNA. Tetracyclines have little effect
peptide at the donor site cannot be transferred to its amino on mammalian protein synthesis because an active efflux mecha-
acid acceptor. Macrolides, telithromycin, and clindamycin, nism prevents their intracellular accumulation.
50S
ribosome
Amino acid
1 C
6
2
M
3
4
2 t6
5 6 1
Charged
tRNA
t5 4
t6
3
mRNA
30S
T
t5 Uncharged tRNA
FIGURE 44–1 Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The
70S ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the
acceptor site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain
to amino acid 6 (transpeptidation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with
its tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic-binding sites are shown schematically as triangles. Chloramphenicol
(C) and macrolides (M) bind to the 50S subunit and block transpeptidation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1). (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 44–1.)

TETRACYCLINES activity of tigecycline includes Gram-positive cocci resistant

to methicillin (MRSA strains) and vancomycin (VRE strains),
A. Classification beta-lactamase–producing Gram-negative bacteria, anaerobes,
Drugs in this class are broad-spectrum bacteriostatic antibiotics chlamydiae, and mycobacteria. The drug is formulated only for
that have only minor differences in their activities against specific intravenous use.
organisms.
E. Toxicity
B. Pharmacokinetics 1. Gastrointestinal disturbances—Effects on the gastrointes-
Oral absorption is variable, especially for the older drugs, and tinal system range from mild nausea and diarrhea to severe, pos-
may be impaired by foods and multivalent cations (calcium, iron, sibly life-threatening enterocolitis. Disturbances in the normal
aluminum). Tetracyclines have a wide tissue distribution and cross flora may lead to candidiasis (oral and vaginal) and, more rarely,
the placental barrier. All the tetracyclines undergo enterohepatic to bacterial superinfections with S aureus or Clostridium difficile.
cycling. Doxycycline is excreted mainly in feces; the other drugs
are eliminated primarily in the urine. The half-lives of doxycycline and 2. Bony structures and teeth—Fetal exposure to tetracyclines
minocycline are longer than those of other tetracyclines. Tigecycline, may lead to tooth enamel dysplasia and irregularities in bone
formulated only for IV use, is eliminated in the bile and has a growth. Although usually contraindicated in pregnancy, there
half-life of 30–36 h. may be situations in which the benefit of tetracyclines outweighs
the risk. Treatment of younger children may cause enamel dysplasia
C. Antibacterial Activity and crown deformation when permanent teeth appear.
Tetracyclines are broad-spectrum antibiotics with activity against
Gram-positive and Gram-negative bacteria, species of Rickettsia, 3. Hepatic toxicity—High doses of tetracyclines, especially in
Chlamydia, Mycoplasma, and some protozoa. pregnant patients and those with preexisting hepatic disease, may
However, resistance to most tetracyclines is widespread. Resis- impair liver function and lead to hepatic necrosis.
tance mechanisms include the development of mechanisms (efflux
pumps) for active extrusion of tetracyclines and the formation 4. Renal toxicity—One form of renal tubular acidosis, Fanconi’s
of ribosomal protection proteins that interfere with tetracycline syndrome, has been attributed to the use of outdated tetracyclines.
binding. These mechanisms do not confer resistance to tigecycline Though not directly nephrotoxic, tetracyclines may exacerbate
in most organisms, with the exception of the multidrug efflux preexisting renal dysfunction.
pumps of Proteus and Pseudomonas species.
5. Photosensitivity—Tetracyclines, especially demeclocycline,
D. Clinical Uses may cause enhanced skin sensitivity to ultraviolet light.
1. Primary uses—Tetracyclines are recommended in the
treatment of infections caused by Mycoplasma pneumoniae 6. Vestibular toxicity—Dose-dependent reversible dizziness
(in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. and vertigo have been reported with doxycycline and minocycline.
Doxycycline is currently an alternative to macrolides in the
initial treatment of community-acquired pneumonia.
MACROLIDES
2. Secondary uses—Tetracyclines are alternative drugs in the
treatment of syphilis. They are also used in the treatment of respi- A. Classification and Pharmacokinetics
ratory infections caused by susceptible organisms, for prophylaxis The macrolide antibiotics (erythromycin, azithromycin, and
against infection in chronic bronchitis, in the treatment of lepto- clarithromycin) are large cyclic lactone ring structures with
spirosis, and in the treatment of acne. attached sugars. The drugs have good oral bioavailability, but
azithromycin absorption is impeded by food. Macrolides distribute
3. Selective uses—Specific tetracyclines are used in the treat- to most body tissues, but azithromycin is unique in that the levels
ment of gastrointestinal ulcers caused by Helicobacter pylori achieved in tissues and in phagocytes are considerably higher than
(tetracycline), in Lyme disease (doxycycline), and in the menin- those in the plasma. The elimination of erythromycin (via biliary
gococcal carrier state (minocycline). Doxycycline is also used excretion) and clarithromycin (via hepatic metabolism and urinary
for the prevention of malaria and in the treatment of amebiasis excretion of intact drug) is fairly rapid (half-lives of 2 and 6 h,
(Chapter 52). Demeclocycline inhibits the renal actions of antidi- respectively). Azithromycin is eliminated slowly (half-life 2–4 d),
uretic hormone (ADH) and is used in the management of patients mainly in the urine as unchanged drug.
with ADH-secreting tumors (Chapter 15).
B. Antibacterial Activity
4. Tigecycline—Unique features of this glycylcycline derivative Erythromycin has activity against many species of Campylo-
of minocycline include a broad spectrum of action that includes bacter, Chlamydia, Mycoplasma, Legionella, Gram-positive cocci,
organisms resistant to standard tetracyclines. The antimicrobial and some Gram-negative organisms. The spectra of activity of

azithromycin and clarithromycin are similar but include greater TELITHROMYCIN

activity against species of Chlamydia, Mycobacterium avium com-
plex, and Toxoplasma. Telithromycin is a ketolide structurally related to macrolides.
Azithromycin is also effective in gonorrhea, as an alterna- The drug has the same mechanism of action as erythromycin
tive to ceftriaxone and in syphilis, as an alternative to penicillin and a similar spectrum of antimicrobial activity. However, some
G. Resistance to the macrolides in Gram-positive organisms macrolide-resistant strains are susceptible to telithromycin because
involves efflux pump mechanisms and the production of a meth- it binds more tightly to ribosomes and is a poor substrate for
ylase that adds a methyl group to the ribosomal binding site. bacterial efflux pumps that mediate resistance. The drug can be
Cross-resistance between individual macrolides is complete. In used in community-acquired pneumonia including infections
the case of methylase-producing microbial strains, there is partial caused by multidrug-resistant organisms. Telithromycin is given
cross-resistance with other drugs that bind to the same ribosomal orally once daily and is eliminated in the bile and the urine. The
site as macrolides, including clindamycin and streptogramins. adverse effects of telithromycin include hepatic dysfunction and
Resistance in Enterobacteriaceae is the result of formation of drug- prolongation of the QTc interval. The drug is an inhibitor of the
metabolizing esterases. CYP3A4 drug-metabolizing system.
C. Clinical Uses
Erythromycin is effective in the treatment of infections caused by
CLINDAMYCIN
M pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamydia A. Classification and Pharmacokinetics
trachomatis, Chlamydophila pneumoniae, Legionella pneumophila,
Clindamycin inhibits bacterial protein synthesis via a mechanism
Ureaplasma urealyticum, and Bordetella pertussis. The drug is also
similar to that of the macrolides, although it is not chemically
active against Gram-positive cocci (but not penicillin-resistant
related. Mechanisms of resistance include methylation of the
Streptococcus pneumoniae [PRSP] strains) and beta-lactamase–
binding site on the 50S ribosomal subunit and enzymatic inactiva-
producing staphylococci (but not methicillin-resistant S aureus
tion. Gram-negative aerobes are intrinsically resistant because of
[MRSA] strains).
poor penetration of clindamycin through the outer membrane.
Azithromycin has a similar spectrum of activity but is more
Cross-resistance between clindamycin and macrolides is common.
active against H influenzae, Moraxella catarrhalis, and Neisseria.
Good tissue penetration occurs after oral absorption. Clindamycin
Because of its long half-life, a single dose of azithromycin is
undergoes hepatic metabolism, and both intact drug and metabo-
effective in the treatment of urogenital infections caused by
lites are eliminated by biliary and renal excretion.
C trachomatis, and a 4-d course of treatment has been effective in
community-acquired pneumonia.
B. Clinical Use and Toxicity
Clarithromycin has almost the same spectrum of antimicrobial
activity and clinical uses as erythromycin. The drug is also used The main use of clindamycin is in the treatment of severe infec-
for prophylaxis against and treatment of M avium complex and tions caused by certain anaerobes such as Bacteroides. Clindamycin
as a component of drug regimens for ulcers caused by H pylori. has been used as a backup drug against Gram-positive cocci (it is
Fidaxomicin is a narrow-spectrum macrolide antibiotic that active against community-acquired strains of methicillin-resistant
inhibits protein synthesis and is selectively active against Gram- S aureus) and is recommended for prophylaxis of endocarditis in
positive aerobes and anaerobes. Given orally, systemic absorption valvular disease patients who are allergic to penicillin. The drug is
is minimal. Fidaxomicin has proved to be as effective as vanco- also active against Pneumocystis jirovecii and is used in combina-
mycin for the treatment of C difficile colitis, possibly with a lower tion with pyrimethamine for AIDS-related toxoplasmosis. The
relapse rate. toxicity of clindamycin includes gastrointestinal irritation, skin
rashes, neutropenia, hepatic dysfunction, and possible superinfec-
tions such as C difficile pseudomembranous colitis.
D. Toxicity
Adverse effects, especially with erythromycin, include gastroin-
testinal irritation (common) via stimulation of motolin receptors, STREPTOGRAMINS
skin rashes, and eosinophilia. A hypersensitivity-based acute cho-
lestatic hepatitis may occur with erythromycin estolate. Hepatitis Quinupristin-dalfopristin, a combination of 2 streptogramins,
is rare in children, but there is an increased risk with erythromycin is bactericidal (see prior discussion of mechanism of action) and
estolate in the pregnant patient. Erythromycin inhibits several has a duration of antibacterial activity longer than the half-lives
forms of hepatic cytochrome P450 and can increase the plasma of the 2 compounds (postantibiotic effects). Antibacterial activity
levels of many drugs, including anticoagulants, carbamazepine, includes penicillin-resistant pneumococci, methicillin-resistant
cisapride, digoxin, and theophylline. Similar drug interactions (MRSA) and vancomycin-resistant staphylococci (VRSA), and
have also occurred with clarithromycin. The lactone ring structure resistant E faecium; E faecalis is intrinsically resistant via an efflux
of azithromycin is slightly different from that of other macrolides, transport system. Administered intravenously, the combination
and drug interactions are uncommon because azithromycin does product may cause pain and an arthralgia-myalgia syndrome.
not inhibit hepatic cytochrome P450. Streptogramins are potent inhibitors of CYP3A4 and increase

plasma levels of many drugs, including astemizole, cisapride, OXAZOLIDINONES

cyclosporine, diazepam, nonnucleoside reverse transcriptase
inhibitors, and warfarin. The first of a novel class of antibiotics (oxazolidinones),
linezolid is active against drug-resistant Gram-positive cocci,
including strains resistant to penicillins (eg, MRSA, PRSP)
CHLORAMPHENICOL and vancomycin (eg, VRE). The drug is also active against
L monocytogenes and corynebacteria. Linezolid binds to a unique
A. Classification and Pharmacokinetics site located on the 23S ribosomal RNA of the 50S ribosomal
Chloramphenicol has a simple and distinctive structure, and no subunit, and there is currently no cross-resistance with other
other antimicrobials have been discovered in this chemical class. It is protein synthesis inhibitors. Resistance (rare to date) involves
effective orally as well as parenterally and is widely distributed, read- a decreased affinity of linezolid for its binding site. Linezolid is
ily crossing the placental and blood-brain barriers. Chloramphenicol available in both oral and parenteral formulations and should be
undergoes enterohepatic cycling, and a small fraction of the dose reserved for treatment of infections caused by multidrug-resistant
is excreted in the urine unchanged. Most of the drug is inactivated Gram-positive bacteria. The drug is metabolized by the liver
by a hepatic glucuronosyltransferase. and has an elimination half-life of 4–6 h. Thrombocytopenia
and neutropenia occur, most commonly in immunosuppressed
B. Antimicrobial Activity patients. Linezolid has been implicated in the serotonin syn-
Chloramphenicol has a wide spectrum of antimicrobial activity drome when used in patients taking selective serotonin reuptake
and is usually bacteriostatic. Some strains of Haemophilus influenzae, inhibitors (SSRIs).
Neisseria meningitidis, and Bacteroides are highly susceptible, and Tedizolid is a prodrug of tedizolid phosphate, a next-generation
for these organisms chloramphenicol may be bactericidal. It is not oxazolidinone, with high potency against Gram-positive bacteria,
active against Chlamydia species. Resistance to chloramphenicol, including methicillin-resistant S aureus.
which is plasmid-mediated, occurs through the formation of acet-
yltransferases that inactivate the drug.
QUESTIONS
C. Clinical Uses
1. A 4-year-old child is brought to the hospital after ingesting
Because of its toxicity, chloramphenicol has very few uses as a pills that a parent had used for bacterial dysentery when trav-
systemic drug. It is a backup drug for severe infections caused eling outside the United States. The child has been vomiting
by Salmonella species and for the treatment of pneumococcal for more than 24 h and has had diarrhea with green stools.
and meningococcal meningitis in beta-lactam-sensitive persons. She is now lethargic with an ashen color. Other signs and
Chloramphenicol is sometimes used for rickettsial diseases and symptoms include hypothermia, hypotension, and abdominal
distention. The drug most likely to be the cause of this
for infections caused by anaerobes such as Bacteroides fragilis. The
problem is
drug is commonly used as a topical antimicrobial agent. (A) Ampicillin
(B) Azithromycin
D. Toxicity (C) Chloramphenicol
1. Gastrointestinal disturbances—These conditions may (D) Doxycycline
occur from direct irritation and from superinfections, especially (E) Erythromycin
candidiasis. 2. Tetracyclines are the drugs of choice for Rocky Mountain
spotted fever and Lyme disease. The mechanism of antibacte-
2. Bone marrow—Inhibition of red cell maturation leads to a rial action of tetracycline involves
decrease in circulating erythrocytes. This action is dose-dependent (A) Antagonism of bacterial translocase activity
(B) Binding to a component of the 50S ribosomal subunit
and reversible. Aplastic anemia is a rare idiosyncratic reaction
(C) Inhibition of DNA-dependent RNA polymerase
(approximately 1 case in 25,000–40,000 patients treated). It is (D) Interference with binding of aminoacyl-tRNA to bacterial
usually irreversible and may be fatal. ribosomes
(E) Selective inhibition of ribosomal peptidyl transferases
3. Gray baby syndrome—This syndrome occurs in infants
3. Clarithromycin and erythromycin have very similar spectra
and is characterized by decreased red blood cells, cyanosis, and of antimicrobial activity. The major advantage of clarithro-
cardiovascular collapse. Neonates, especially premature neonates, mycin is that it
are deficient in hepatic glucuronosyltransferase and are sensitive (A) Does not inhibit hepatic drug-metabolizing enzymes
to doses of chloramphenicol that would be tolerated in older (B) Eradicates mycoplasmal infections in a single dose
infants. (C) Has greater activity against H pylori
(D) Is active against methicillin-resistant strains of
staphylococci
4. Drug interactions—Chloramphenicol inhibits hepatic drug- (E) Is active against strains of streptococci that are resistant
metabolizing enzymes, thus increasing the elimination half-lives to erythromycin
of drugs including phenytoin, tolbutamide, and warfarin.

4. The primary mechanism of resistance of Gram-positive 8. If this patient were to be treated with erythromycin, she
organisms to macrolide antibiotics including erythromycin is should
(A) Changes in the 30S ribosomal subunit (A) Avoid exposure to sunlight
(B) Decreased drug permeability of the cytoplasmic (B) Avoid taking supplementary iron tablets
membrane (C) Decrease her intake of caffeinated beverages
(C) Formation of drug-inactivating acetyltransferases (D) Have her plasma urea nitrogen or creatinine checked
(D) Formation of esterases that hydrolyze the lactone ring before treatment
(E) Methylation of binding sites on the 50S ribosomal subunit (E) Temporarily stop taking loratadine
5. A 26-year-old woman was treated for a suspected chlamydial 9. A 5-d course of treatment for community-acquired pneumonia
infection at a neighborhood clinic. She was given a pre- would be effective in this patient with little risk of drug inter-
scription for oral doxycycline to be taken for 14 d. Three actions if the drug prescribed were
weeks later, she returned to the clinic with a mucopurulent (A) Azithromycin
cervicitis. On questioning she admitted not having the (B) Clindamycin
prescription filled. The best course of action at this point (C) Doxycycline
would be to (D) Erythromycin
(A) Delay drug treatment until the infecting organism is (E) Vancomycin
identified
(B) Rewrite the original prescription for oral doxycycline 10. Concerning quinupristin-dalfopristin, which statement is
(C) Treat her in the clinic with a single oral dose of accurate?
azithromycin (A) Active in treatment of infections caused by E faecalis
(D) Treat her in the clinic with an intravenous dose of (B) An effective drug in treatment of multidrug-resistant
amoxicillin streptococcal infections
(E) Write a prescription for oral erythromycin for 10 d (C) Bacteriostatic
(D) Hepatotoxicity has led to FDA drug alerts
6. A 55-year-old patient with a prosthetic heart valve is to (E) Increase the activity of hepatic drug-metabolizing
undergo a periodontal procedure involving scaling and root enzymes
planing. Several years ago, the patient had a severe allergic
reaction to procaine penicillin G. Regarding prophylaxis
against bacterial endocarditis, which one of the following ANSWERS
drugs taken orally is most appropriate?
(A) Amoxicillin 10 min before the procedure 1. Chloramphenicol is commonly used outside the United
(B) Clindamycin 1 h before the procedure States for treatment of bacillary dysentery. The drug causes
(C) Erythromycin 1 h before the procedure and 4 h after the a dose-dependent (reversible) suppression of erythropoiesis.
procedure Although the gray baby syndrome was initially described in
(D) Vancomycin 15 min before the procedure neonates, a similar syndrome has occurred with overdosage
(E) No prophylaxis is needed because this patient is in the of chloramphenicol in older children and adults, especially
negligible risk category those with hepatic dysfunction. The answer is C.
Questions 7–9. A 24-year-old woman comes to a clinic with 2. Tetracyclines inhibit bacterial protein synthesis by interfering
complaints of dry cough, headache, fever, and malaise, which with the binding of aminoacyl-tRNA molecules to bacterial
have lasted 3 or 4 d. She appears to have some respiratory dif- ribosomes. Peptidyl transferase is inhibited by chloramphenicol.
ficulty, and chest examination reveals rales but no other obvious The answer is D.
signs of pulmonary involvement. However, extensive patchy 3. Clarithromycin can be administered less frequently than
infiltrates are seen on chest x-ray film. Gram stain of expecto- erythromycin, but it is not effective in single doses against
susceptible organisms. Organisms resistant to erythromycin,
rated sputum fails to reveal any bacterial pathogens. The patient including pneumococci and methicillin-resistant staphylococci,
mentions that a colleague at work had similar symptoms to those are also resistant to other macrolides. Drug interactions have
she is experiencing. The patient has no history of serious medical occurred with clarithromycin through its ability to inhibit
problems. She takes loratadine for allergies and supplementary cytochrome P450. Clarithromycin is more active than eryth-
iron tablets, and she drinks at least 6 cups of caffeinated coffee romycin against M avium complex, T gondii, and H pylori.
per day. The physician makes an initial diagnosis of community- The answer is C.
acquired pneumonia. 4. Methylase production and methylation of the receptor site
are established mechanisms of resistance of Gram-positive
7. Regarding the treatment of this patient, which of the follow- organisms to macrolide antibiotics. Such enzymes may
ing drugs is most suitable? be inducible by macrolides or constitutive; in the lat-
(A) Ampicillin ter case, cross-resistance occurs between macrolides and
(B) Clindamycin clindamycin. Increased expression of efflux pumps is also a
(C) Doxycycline mechanism of macrolide resistance. Esterase formation is a
(D) Linezolid mechanism of macrolide resistance seen in coliforms. The
(E) Vancomycin answer is E.

5. Cervicitis or urethritis is often caused by C trachomatis. Such doxycycline, or a quinolone active against respiratory patho-
infections may develop slowly because of the long incubation gens (Chapter 46). Ampicillin, clindamycin, and vancomycin
period of chlamydial infection. Treatment with oral doxycycline have low activity against atypical pathogens in CAP. The
for 14 d (as originally prescribed) would have eradicated answer is C.
C trachomatis and most other organisms commonly associ- 8. The inhibition of liver cytochrome P450 by erythromycin
ated with nongonococcal cervicitis or urethritis. Given the has led to serious drug interactions. Although erythromycin
limited compliance of this patient, the best course of action does not inhibit loratadine metabolism, it does inhibit the
would be the administration (in the clinic) of a single oral CYP1A2 form of cytochrome P450, which metabolizes
dose of azithromycin. The answer is C. methylxanthines. Consequently, cardiac and/or CNS toxic-
6. This patient is in the high-risk category for bacterial endo- ity may occur with excessive ingestion of caffeine. Unlike
carditis and should receive prophylactic antibiotics before the tetracyclines, the oral absorption of erythromycin is not
many dental procedures. The American Heart Association affected by cations and the drug does not cause photosen-
recommends that clindamycin be used in patients allergic to sitivity. Because erythromycin undergoes biliary excretion,
penicillins. Oral erythromycin is not recommended because there is little reason to assess renal function before treatment.
it is no more effective than clindamycin and causes more The answer is C.
gastrointestinal adverse effects. Intravenous vancomycin (not 9. Azithromycin has a half-life of more than 70 h, which allows
oral), sometimes with gentamicin, is recommended for pro- for once-daily dosing and a 5-d course of treatment for
phylaxis in high-risk penicillin-allergic patients undergoing community-acquired pneumonia. Unlike other macrolides,
genitourinary and lower gastrointestinal surgical procedures. azithromycin does not inhibit cytochrome P450 enzymes
Complete cross-allergenicity must be assumed between indi- involved in drug metabolism. The answer is A.
vidual penicillins. The answer is B.
10. Quinupristin-dalfopristin is bactericidal against many drug-
7. It is often difficult to establish a definite cause of community- resistant Gram-positive cocci, including multidrug-resistant
acquired pneumonia (CAP). More than 80% of cases are caused streptococci, MRSA, and vancomycin-resistant enterococci.
by typical pathogens such as S pneumoniae, H influenzae, The streptogramins have activity against E faecium (not
or M catarrhalis, and 15% are due to the nonzoonotic atypi- E faecalis). The drugs are potent inhibitors of CYP3A4 and
cal pathogens such as Legionella species, Mycoplasma species, interfere with the metabolism of many other drugs. The
or C pneumoniae. Currently, monotherapy coverage of both streptogramins are not hepatotoxic. The answer is B.
typical and atypical pathogens in CAP is preferred to double-
drug therapy. Preferred initial therapy includes a macrolide,
CHECKLIST
When you complete this chapter, you should be able to:

❑ Explain how these agents inhibit bacterial protein synthesis.
❑ Identify the primary mechanisms of resistance to each of these drug classes.
❑ Name the most important agents in each drug class, and list 3 clinical uses of each.
❑ Recall distinctive pharmacokinetic features of the major drugs.
❑ List the characteristic toxic effects of the major drugs in each class.

DRUG SUMMARY TABLE: Tetracyclines, Macrolides, & Other Protein Synthesis Inhibitors
Pharmacokinetics
Subclass Mechanism of Action Activity & Clinical Uses & Interactions Toxicities
Tetracyclines
Tetracycline Bind to 30S ribosomal Infections due to chlamydiae, GI upsets, deposition in
Doxycycline mycoplasma, rickettsiae, developing bones and
Minocycline tigecycline has broadest spirochetes, and H pylori mainly gastrointestinal teeth, photosensitivity,
Tigecycline spectrum (grm(+)ve, treatment of acne (low dose) (GI) elimination and long superinfection
grm(–)ve, & anaerobes) half-life
and resistance is less com-
mon (too large for efflux
pump)
Macrolides
Erythromycin Bind to 50S ribosomal Community-acquired GI upsets, hepatic
Azithromycin pneumonia, pertussis, dysfunction
Clarithromycin corynebacteria, and clearance, azithromycin
Telithromycin telithromycin (too large chlamydial infections long half-life (>40 h)
for efflux pump) (not azithromycin)
Lincosamide
Clindamycin Bind to 50S ribosomal Skin, soft tissue, and anaero- GI upsets C difficile
bic infections clearance colitis
Streptogramins
Binds to 50S ribosomal Staphylococcal infections, Infusion-related
vancomycin-resistant arthralgia and myalgia
E faecium
Chloramphenicol Binds to 50S ribosomal Wide spectrum, but mainly - Dose-related anemia
backup ance, short half-life
Oxazolidinones
Linezolid Binds to 23S RNA of 50S Dose-related anemia,
and VRE strains neuropathy, optic
Tedizolid MRSA (skin & soft tissue
infections) once daily dosing) syndrome with SSRIs
MRSA, methicillin-resistant staphylococci; PRSP, penicillin-resistant Streptococcus pneumoniae; SSRIs, selective serotonin reuptake inhibitors; VRE, vancomycin-resistant enterococci.

44-Protein Synthesis Inhibitor

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44-Protein Synthesis Inhibitor

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44

The drugs described in this chapter inhibit bacterial protein OH O OH O

and resistant; enterococci, including vancomycin-resistant strains; Adverse Reactions

of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral AZITHROMYCIN

Adverse Effects ■ CHLORAMPHENICOL

MECHANISM OF ACTION &

SUMMARY Tetracyclines, Macrolides, Clindamycin, Chloramphenicol,

bacteria; nausea and vomiting are the primary toxicities

P R E P A R A T I O N S Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications,

C ASE STUDY ANSWER

Bacterial protein synthesis inhibitors

Broad spectrum Moderate spectrum Narrow spectrum

Chloramphenicol Macrolides Ketolide Lincosamides

INHIBITORS OF MICROBIAL to be discovered. Because they had a broad spectrum of antibac-

Trevor_Ch44_p377-p384.indd 377 7/13/18 6:48 PM

Trevor_Ch44_p377-p384.indd 378 7/13/18 6:48 PM

TETRACYCLINES activity of tigecycline includes Gram-positive cocci resistant

Trevor_Ch44_p377-p384.indd 379 7/13/18 6:48 PM

azithromycin and clarithromycin are similar but include greater TELITHROMYCIN

Trevor_Ch44_p377-p384.indd 380 7/13/18 6:48 PM

plasma levels of many drugs, including astemizole, cisapride, OXAZOLIDINONES

Trevor_Ch44_p377-p384.indd 381 7/13/18 6:48 PM

Trevor_Ch44_p377-p384.indd 382 7/13/18 6:48 PM

When you complete this chapter, you should be able to:

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Trevor_Ch44_p377-p384.indd 384 7/13/18 6:48 PM

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