Most antibiotics in this subclass are bacteriostatic. Figure
27–4 illustrates the specific binding sites on the 70S
bacterial ribosomal complex for chloramphenicol, tetracyclines,
and the macrolides. With the exception of tetracyclines and aminoglycosides,
the binding sites for these antibiotics are on the 50S ribosomal
subunit. Chloramphenicol, clindamycin, and the macrolides prevent
a step called transpeptidation, in which the next new amino acid
is added to the nascent peptide chain. Tetracyclines bind to the
30S ribosomal subunit at a site that blocks the binding of amino
acid–carrying tRNA (charged tRNA) to the acceptor site
of the ribosome-mRNA complex.
Steps in bacterial protein synthesis and targets of chloramphenicol,
the macrolides, and tetracyclines. Individual amino acids are shown
as numbered circles. The 70S bacterial ribosomal mRNA complex is
shown with its 50S and 30S subunits. In step 1, the charged tRNA
carrying amino acid 8 binds to the acceptor site A on the 70S ribosome.
Transpeptidation occurs when the peptidyl tRNA at the donor site
(with amino acids 1 through 7) binds the growing amino acid chain
to amino acid 8 (step 2). The uncharged tRNA left at the donor site
is released (step 3), and the new 8–amino acid chain with
its tRNA shifts to the peptidyl site (transpeptidation, step 4). The
antibiotic binding sites are shown schematically as triangles. Chloramphenicol
(C) and the macrolides (M) bind to the 50S subunit and block transpeptidation
(step 2). Tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
The streptogramins are bactericidal for most susceptible organisms.
They bind to the 50S ribosomal subunit, and prevent extrusion of
the nascent polypeptide chain. In addition, streptogramins inhibit
the activity of enzymes that synthesize tRNA, leading to a decrease
in free tRNA within the cell. Linezolid also binds to the 50S subunit.
It blocks formation of the tRNA-ribosome-mRNA complex. The action
of the aminoglycosides is described below.
Chloramphenicol has a simple and distinctive structure, and no
other antimicrobials have been discovered in this chemical class.
It is effective orally as well as parenterally and is distributed throughout
all tissues. It readily crosses the placental and blood-brain barriers.
The drug undergoes enterohepatic cycling, and is mostly inactivated
by the liver. Chloramphenicol has a wide spectrum of antimicrobial activity
and is usually bacteriostatic. It is not active against Chlamydia. Although chloramphenicol
does not bind to ribosomal RNA of mammalian cells, it can inhibit the
functions of mammalian mitochondrial ribosomes, which are more similar
to bacterial ribosomes. Clinically significant resistance to chloramphenicol
occurs through the formation of plasmid-encoded enzymes that inactivate
Because of its toxicity and bacterial resistance, chloramphenicol
has very few uses as a systemic drug. It is a back-up drug for severe
infections caused by Salmonella species
and for the treatment of penicillin-resistant pneumococcal or meningococcal
meningitis, or in patients who have major hypersensitivity reactions
to penicillin. Chloramphenicol is commonly used as a topical agent
for eye infections because of its broad spectrum and ability to
penetrate ocular tissue.
Patients taking chloramphenicol occasionally develop nausea,
vomiting, and diarrhea. Oral or vaginal candidiasis may occur as
a result of alteration of normal microbial flora. Chloramphenicol commonly
causes dose-related reversible suppression of red blood cell production.
Idiosyncratic aplastic anemia, which involves suppression of production
of all blood cells, can also occur, but is rare and unrelated to
dose. Unfortunately, it occurs more frequently with prolonged use
and is usually irreversible.
If newborn infants are given high dosages, chloramphenicol may
accumulate because infants lack effective mechanisms for metabolism
of the drug. The resulting gray baby syndrome includes
vomiting, flaccidity, hypothermia, gray color, cyanosis, and cardiovascular
Because chloramphenicol inhibits hepatic enzymes that metabolize
several drugs, it has significant interactions when taken with other
drugs. Half-lives are prolonged, and serum concentrations of phenytoin,
tolbutamide, chlorpropamide, and warfarin are increased. Like other
bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol
can antagonize bactericidal drugs such as penicillins or aminoglycosides.
Tetracyclines (tetracycline, doxycycline,
minocycline, demeclocycline) are broad-spectrum bacteriostatic
antibiotics that inhibit protein synthesis in gram-positive and gram-negative
bacteria, Rickettsia (the cause of
Rocky Mountain spotted fever and some other difficult to treat infections), Chlamydia, Mycoplasma,Borrelia (the cause of Lyme disease),
and some protozoa. Drugs in this class have only minor differences in
their activities against specific organisms. Susceptible organisms
accumulate tetracyclines intracellularly via energy-dependent transport
systems in their cell membranes. Tetracyclines have little effect
on mammalian protein synthesis because an active efflux mechanism
prevents their intracellular accumulation.
Oral absorption is variable, especially for the older drugs,
and may be impaired by foods and multivalent cations (calcium, iron,
aluminum). Tetracyclines have a wide tissue distribution and cross the
placental barrier. All of the tetracyclines undergo enterohepatic
cycling. Doxycycline is excreted mainly in feces; the other tetracyclines
are eliminated primarily in the urine. The half-lives of doxycycline
and minocycline are longer than those of other tetracyclines.
Plasmid-mediated resistance to tetracyclines is widespread. Resistance
mechanisms include decreased activity of the uptake systems and,
most importantly, the development of mechanisms such as efflux pumps
for active extrusion of tetracyclines. Plasmids that include genes
involved in producing efflux pumps for tetracyclines commonly include
resistance genes for multiple antibiotics.
A tetracycline is the drug of choice in infections caused by Mycoplasma pneumoniae (in adults), Chlamydia, Rickettsia, and Vibrio (e.g., cholera). Specific tetracyclines are used
in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline),
in Lyme disease (doxycycline), and in the meningococcal carrier
state (minocycline). Doxycycline is also used for the prevention
of malaria and in the treatment of amebiasis. Demeclocycline inhibits
the renal actions of antidiuretic hormone (ADH) and is used in the
management of patients with ADH-secreting tumors.
Tetracyclines are alternative drugs in the treatment of syphilis.
They are also used in the treatment of respiratory infections caused
by susceptible organisms, for prophylaxis against infection in chronic
bronchitis, in the treatment of leptospirosis, and in the treatment of
Hypersensitivity reactions (i.e., fever, rashes) to tetracyclines
are uncommon. Most of the adverse reactions are due to direct toxicity
of the tetracycline agent or due to alterations in microbial flora.
Effects on the gastrointestinal system range from mild nausea
and diarrhea to severe, possibly life-threatening colitis. Disturbances
in the normal flora are due to suppression of tetracycline-susceptible
organisms and overgrowth of resistant organisms, especially pseudomonas,
staphylococci, and candida. This can result in intestinal disturbances,
anal pruritus, vaginal or oral candidiasis, or enterocolitis.
Tetracyclines bind to calcium deposited in newly formed bone
or teeth in young children. Thus, fetal exposure to tetracyclines
may lead to tooth enamel dysplasia and discoloration and irregularities
in bone growth. Although usually contraindicated in pregnancy, there
may be situations in which the benefit of administering tetracyclines
outweighs the risk. If taken for long periods of time in children
under 8 years of age, tetracyclines may cause similar changes in
teeth and bone.
High doses of tetracyclines, especially in pregnant patients
and those with preexisting hepatic disease, may impair liver function
and lead to hepatic necrosis. Likewise, in patients with kidney
disease, tetracyclines may exacerbate renal dysfunction.
Systemic tetracyclines (especially demeclocycline) may enhance
skin sensitivity to ultraviolet light, particularly in fair-skinned
Dose-dependent reversible dizziness and vertigo have been reported
with doxycycline and minocycline.
The macrolide antibiotics are large cyclic lactone ring structures
with attached sugars. The macrolides include the prototypic drugs erythromycin, azithromycin, and clarithromycin. The
macrolides have good oral bioavailability, but azithromycin absorption
is impeded by food. Macrolides distribute to most body tissues,
but azithromycin is unique in that the levels achieved in tissues
and in phagocytes are considerably higher than those in the plasma.
The elimination of erythromycin (via biliary excretion) and clarithromycin
(via hepatic metabolism and urinary excretion of intact drug) is
fairly rapid (half-life 2 to 5 hours). Azithromycin is eliminated
slowly (half-life 2 to 4 days), mainly in urine as unchanged drug.
Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma,
Legionella, gram-positive cocci (including β-lactamase–producing
staphylococci), and some gram-negative organisms. The antibacterial action
may be bacteriostatic or bactericidal; the latter effect occurring
more commonly at higher concentrations for susceptible organisms.
Erythromycin does not have activity against penicillin-resistant Streptococcus pneumoniae or methicillin-resistant S aureus (MRSA).
The spectra of activity of azithromycin and clarithromycin are
similar to erythromycin, but include greater activity against Chlamydia,Mycobacterium
avium complex, and Toxoplasma species. Because of its long half-life, a
4-day course of treatment with azithromycin has been effective in community-acquired
pneumonia. Clarithromycin is approved for prophylaxis against and
treatment of M avium complex and
as a component of drug regimens for ulcers caused by Helicobacter pylori.
Resistance to macrolide antibiotics in gram-positive organisms
involves efflux pump mechanisms and the production of an enzyme
(methylase) that alters the drugs’ ribosomal binding site.
Cross-resistance among individual macrolides is complete; that is,
if an organism is resistant to one macrolide agent, it will be resistant
to all other macrolides. In the case of methylase-producing bacterial
strains, there is partial cross-resistance with other drugs that
bind to the same ribosomal site as macrolides, including clindamycin
and streptogramins. Resistance in Enterobacteriaceae is due to formation of drug-metabolizing
Gastrointestinal irritation (anorexia, nausea, vomiting) is often
associated with oral administration. Stimulation of gut motility
is the most common reason for discontinuing erythromycin and choosing
another antibiotic. This action is sometimes exploited therapeutically
in patients with inadequate gastrointestinal motility. A hypersensitivity-based
acute cholestatic hepatitis (fever, jaundice, impaired liver function)
may occur with erythromycin estolate. This condition usually resolves.
Hepatitis is rare in children, but there is an increased risk with
erythromycin estolate in pregnant patients. Because erythromycin
inhibits several forms of hepatic cytochrome P450, it increases
the plasma levels of anticoagulants, carbamazepine, cisapride, digoxin,
and theophylline. Similar drug interactions have also occurred with
clarithromycin. Drug interactions are uncommon with azithromycin
because this agent does not inhibit hepatic cytochrome P450.
Telithromycin is a ketolide structurally related to macrolides.
It has the same mechanism of action as erythromycin and a similar
moderate spectrum of antimicrobial activity. However, some macrolide-resistant
microbial strains are susceptible to telithromycin because it binds
more tightly to ribosomes and is a poor substrate for bacterial
efflux pumps that mediate resistance. Clinical uses include community-acquired
bacterial pneumonia and other upper respiratory tract infections.
Telithromycin is given orally once daily and is eliminated in the
bile and the urine.
Clindamycin inhibits bacterial protein synthesis via a mechanism
similar to that of the macrolides, although it is not chemically
related. Mechanisms of resistance include alteration of the drug’s ribosomal
binding site and enzymatic inactivation of the drug. Cross-resistance
between clindamycin and the macrolides is common. Good tissue penetration
occurs after oral absorption. Clindamycin is eliminated partly by
metabolism and partly by biliary and renal excretion.
The main use of clindamycin is in the treatment of severe infections
caused by certain anaerobes such as Bacteroides (most
common bacteria in the colon) that often participate in mixed infections. Clindamycin (sometimes in combination
with an aminoglycoside or cephalosporin) is used to treat penetrating
wounds of the abdomen and the gut, infections originating in the
female genital tract (e.g., septic abortion and pelvic abscesses),
or aspiration pneumonia. Clindamycin has been used as a back-up
drug against gram-positive cocci, and is currently recommended for
prophylaxis of endocarditis in patients with cardiac valve disease
who are allergic to penicillin. Clindamycin plus primaquine is an
effective alternative to trimethoprim-sulfamethoxazole for moderate to
moderately severe Pneumocystis jiroveci pneumonia
in AIDS patients. It is also used in combination with pyrimethamine
for AIDS-related toxoplasmosis of the brain.
Adverse effects of clindamycin include gastrointestinal irritation,
skin rashes, neutropenia, and hepatic dysfunction. Severe diarrhea
and enterocolitis have followed clindamycin administration. Antibiotic-associated
colitis due to superinfection with C difficile is
a potentially fatal complication and must be recognized promptly
Quinupristin-dalfopristin is a combination of two streptogramins.
The combination has rapid bactericidal activity that lasts longer
than the half-lives of the individual compounds. Antibacterial activity
includes penicillin-resistant pneumococci, methicillin-resistant
and vancomycin-resistant staphylococci (MRSA and VRSA, respectively),
and resistant Enterococcus faecium. Administered
intravenously, the combination product may cause pain at the infusion
site and an arthralgia-myalgia syndrome. Streptogramins are potent
inhibitors of CYP3A4 and increase plasma levels of many drugs, including
cisapride, cyclosporine, diazepam, nonnucleoside reverse transcriptase inhibitors,
Linezolid is the first of a new class of antibiotics called oxazolidinones.
Linezolid is mainly bacteriostatic, and is active against gram-positive
cocci, including strains resistant to β-lactams
and vancomycin (e.g., vancomycin-resistant E
faecium). Linezolid binds to a unique site on one of the ribosomal
subunits, and there is currently no cross-resistance with other
protein synthesis inhibitors. Although rare to date, resistance
can occur with a decreased affinity of linezolid for its binding
site. Linezolid is available in both oral and parenteral formulations.
The primary adverse effect is hematologic; thrombocytopenia and neutropenia
occur, most commonly in immunosuppressed patients.
Aminoglycosides exert bactericidal activity and are useful mainly
against aerobic gram-negative microorganisms. One of the primary
advantages of aminoglycosides is that they can often be used in
a once-daily dosing protocol, which can save time and lends itself
to outpatient therapy with these agents. In addition, once-daily
dosing can be more effective and less toxic than traditional dosing
regimens. Aminoglycosides have greater efficacy when administered
as a single large dose because their bactericidal effectiveness
is concentration dependent. That is, as the plasma level is increased
above the MIC, aminoglycosides kill an increasing proportion of
bacteria and do so more rapidly. Aminoglycosides can also exert
a postantibiotic effect, so that that their killing action continues
when plasma levels have declined below measurable levels. The single
large daily dose of an aminoglycoside generally results in fewer
adverse effects because toxicity depends both on a critical plasma
concentration and on the time that such a level is exceeded. With
single large doses, the time above such a threshold is shorter than
with administration of multiple smaller doses.
The aminoglycosides include gentamicin,
amikacin, neomycin, tobramycin, and
others. They are structurally related amino sugars attached by glycosidic
linkages. All of the aminoglycosides are polar compounds, so they
are not absorbed after oral administration. Therefore, they must
be given intramuscularly or intravenously for systemic effect. They
have limited tissue penetration and do not readily cross the blood-brain
barrier. The major mode of excretion is via the kidney, and plasma
levels of these drugs are greatly affected by changes in renal function. With
normal renal function, the elimination half-life of aminoglycosides
is 2 to 3 hours. Patients receiving aminoglycosides for more than
1 day must have plasma levels of the drug monitored for safe and
effective dosage selection and adjustment. Even with once-daily
dosing, plasma levels may be monitored, especially in patients with
decreased kidney function.
To kill susceptible bacteria, aminoglycosides must penetrate
the bacterial cell envelope. This process is partly dependent
on oxygen-dependent active transport; therefore, these agents have minimal
activity against strict anaerobes. To assist entry of aminoglycosides
into bacterial cells, aminoglycosides may be co-administered with
a cell wall synthesis inhibitor such as a β-lactam
agent. Once inside the bacterial cell, aminoglycosides bind to the
30S ribosomal subunit and interfere with protein synthesis in at
least three ways: (1) they block formation of the initiation complex;
(2) they cause misreading of mRNA; and (3) they inhibit translocation
Putative mechanisms of
action of the aminoglycosides. Normal protein synthesis is shown
in the top panel. At least three different aminoglycoside effects
have been described (bottom panel):
block of formation of the initiation complex; miscoding of amino
acids in the emerging peptide chain due to misreading of the mRNA;
and block of translocation on mRNA. Block of movement of the ribosome
may occur after the formation of a single initiation complex, resulting
in an mRNA chain with only a single ribosome on it, a so-called
Aminoglycosides are mostly used against gram-negative enteric
(i.e., intestinal) bacteria. The main differences among the individual
aminoglycosides lie in their activities against specific organisms,
particularly gram-negative rods. Gentamicin, tobramycin, and amikacin
are important drugs for the treatment of serious infections caused
by aerobic gram-negative bacteria, including E
coli and Enterobacter, Klebsiella (especially
important in respiratory infections and urinary tract infections), Proteus, Providencia, Pseudomonas, and Serratia (important in septicemia
and pulmonary infections) species. These aminoglycosides also have activity
against other species (e.g., H influenzae,
although they are not drugs of choice for infections caused by these
organisms. When used alone, aminoglycosides are not reliably effective
for treating infections caused by gram-positive cocci. Antibacterial
synergy may occur when aminoglycosides are used in combination with
cell wall synthesis inhibitors. For example, aminoglycosides may
be combined with penicillins to treat pseudomonal, listerial (important in
some cases of meningitis), and enterococcal infections.
Streptomycin is an aminoglycoside
that is often used in the treatment of tuberculosis, plague, and
tularemia (rabbit fever). Because of the risk of irreversible
ototoxicity, streptomycin should not be used when other drugs will
serve. Owing to its toxic potential, neomycin is
only used topically or locally (e.g., in the gastrointestinal tract
to eliminate bowel flora). Netilmicin is
usually reserved for treatment of serious infections caused by organisms
resistant to the other aminoglycosides.
All aminoglycosides are ototoxic and nephrotoxic. Auditory or
vestibular damage (or both) may occur and may be irreversible. Auditory
impairment, which may manifest as tinnitus and high-frequency hearing
loss initially, is more likely with amikacin and kanamycin. Vestibular
dysfunction, which may manifest as vertigo, ataxia, and loss of
balance, is more likely with gentamicin and tobramycin. These toxic
risks are proportionate to plasma levels of the drug. Precautions taken
to reduce these risks include once-daily dosing (versus traditional
dosing regimens), monitoring plasma levels of aminoglycosides with
appropriate dose modification, and avoiding the additive ototoxicity
of loop diuretics during dosing. Because ototoxicity has been reported
after fetal exposure, aminoglycosides are contraindicated in pregnancy
unless their potential benefits are judged to outweigh risk.
Renal toxicity usually takes the form of acute tubular necrosis,
which is often reversible. It is more common in elderly patients
and in those concurrently receiving amphotericin B, cephalosporins,
or vancomycin. Gentamicin and tobramycin are the most nephrotoxic
Allergic skin reactions may occur in patients, and contact dermatitis
may occur in personnel handling these drugs. Neomycin is the most
Although rare, respiratory paralysis may occur at high doses.
It is usually reversible by prompt treatment with calcium and neostigmine,
but ventilatory support may be required.