Penicillin G is the “natural” or “native” penicillin;
all other penicillins are semisynthetic compounds. The basic structure
of penicillin consists of a 6-aminopenicillanic acid (6-APA) nucleus
and a variety of side chains. The 6-APA nucleus has a thiazolidine
ring connected to a β-lactam ring. The integrity
of the β-lactam ring is necessary for antibacterial
activity. Hence organisms that produce β-lactamases,
which break the ring configuration, render the drug inactive.
The penicillins are divided into three groups on the basis of
their antibacterial spectrum as detailed in the following discussion.
The prototype of this group is penicillin G. This antibiotic
is active against most Gram-positive bacteria with the exception
of penicillinase-producing S aureus. In recent
years, an increasing proportion of isolates of S pneumoniae have
developed relative or absolute resistance to penicillin. Penicillin
G is also active against most Neisseria species,
some Gram-negative anaerobes, and Treponema pallidum. Penicillin
G is not active against most Gram-negative aerobic organisms. Bacteria
sensitive to penicillin generally have a minimal inhibitory concentration
(MIC) less than 0.05 mg/L.
A 100,000-IU/kg dose of penicillin G (1 IU = 0.6 μg)
administered intravenously results in serum concentrations in excess
of 10 mg/L, 200-fold higher than the minimal inhibitory concentration
of most sensitive bacteria. This antibiotic also diffuses widely,
attaining therapeutic concentrations in most body tissues. For example,
up to 25% of serum concentrations are attained in the cerebrospinal
fluid during the treatment of bacterial meningitis. The t1/2 of
penicillin G is less than 1 hour, and it is eliminated primarily
by renal tubular secretion. This secretion can be inhibited by probenecid.
Because renal dysfunction will compromise the elimination of penicillin,
dosages may need to be reduced in patients with renal insufficiency.
This is necessary only in the most extreme circumstances, owing
to the low toxicity of penicillin.
Penicillin V, the phenoxymethyl analog of penicillin G, is much
more stable than is its parent compound and therefore better absorbed
from the gastrointestinal tract. A 250-mg dose of this preparation
results in concentrations roughly equivalent to those attained after
two doses of orally administered penicillin G. Procaine penicillin
is a commonly used intramuscular preparation that produces low (3
mg/L) concentrations of drug sustained over several days.
It is best suited to the single-dose outpatient treatment of very
sensitive organisms (eg, group A streptococci). Benzathine penicillin
is another preparation given intramuscularly. Serum concentrations
of less than 0.1 mg/L, sustained for as long as 3 to 4 weeks,
are attained with this formulation. It is used to prevent recurrent
group A streptococcal infections in patients with rheumatic fever.
The most frequent indications for the use of penicillin G and
its derivatives in children are for infections caused by most species
of streptococci and infections caused by sensitive Neisseria species.
However, in geographic areas where the incidence of penicillin-resistant Neisseria
gonorrhoeae exceeds 10%, empiric therapy with
penicillin is not recommended.
Examples of aminopenicillins include ampicillin and amoxicillin.
The activity of the aminopenicillins against Gram-positive bacteria
is similar to that of penicillin. Aminopenicillins are, however,
more active against enterococci, Listeria monocytogenes, and
non-β-lactamase-producing H influenzae. They
also are active against some Escherichia coli, Shigella,
Salmonella, and indole-negative Proteus species.
The minimal inhibitory concentrations necessary against Gram-negative
organisms are usually in the range of 1 to 5 mg/L.
The serum concentration of ampicillin after a 1-g intravenous
dose is approximately 40 mg/L; after a 500-mg dose taken
orally, it is approximately 4 mg/L. Concentrations of amoxicillin
are usually twice those of ampicillin after an equivalent oral dose.
The distribution, t1/2, and excretion
characteristics of the aminopenicillins are similar to those of
Ampicillin and its derivatives are among the most useful antibiotics
for treating children with infections caused by sensitive Gram-negative
aerobic bacteria, enterococci, L monocytogenes, and β-lactamase-negative H
influenzae. Amoxicillin is the drug of choice for the treatment
of acute otitis media.
Carboxypenicillins are represented by carbenicillin and ticarcillin;
ureidopenicillins are represented by piperacillin, azlocillin, and
mezlocillin. These antibiotics have a broader spectrum of Gram-negative
activity than do the aminopenicillins, and include activity against
most strains of P aeruginosa. The usual minimal
inhibitory concentrations of P aeruginosa range
from 12 to 25 mg/L, with piperacillin consistently being the
most active agent. Maximum serum concentrations of these antibiotics
are usually in excess of 150 mg/L, after a dose of 3 to
5 g. These antibiotics are used almost exclusively in the treatment
of urinary tract, lung, and bloodstream infections caused by ampicillin-resistant enteric
These penicillins include nafcillin, oxacillin, methicillin,
cloxacillin, dicloxacillin, and flucloxacillin. The principal bacteriologic
advantage of this group of antibiotics is their activity against β-lactamase-producing
staphylococci. Most isolates of methicillin-sensitive S
aureus have minimal inhibitory concentrations of 0.25 to
0.5 mg/L. These antibiotics are less active than penicillin
G against the other Gram-positive bacteria, and they are inactive
against Gram-negative enteric organisms. Maximum serum concentrations
after a 1-g intravenous dose of nafcillin, methicillin, or oxacillin range
from 20 to 40 mg/L; whereas after a 500-mg oral dose of
cloxacillin or oxacillin, they range from 4 to 8 mg/L.
Dicloxacillin and flucloxacillin have an enhanced absorption after
oral administration. Serum concentrations of these agents are twice
those of cloxacillin or oxacillin after an equivalent oral dose.
These penicillins are used almost exclusively for the treatment
of mild, moderate, and severe infections caused by methicillin-sensitive S
aureus, including cellulitis, osteomyelitis, pneumonia,
The adverse reactions of all penicillins are similar. In general,
these agents are well tolerated; however, suspension formulations
tend to have an unpleasant taste and aftertaste and, as a result,
may be poorly accepted. All penicillins have a wide toxic-to-therapeutic
ratio, although they can cause hypersensitivity reactions, neurotoxicity,
nephrotoxicity, and hematologic toxicity.
Hypersensitivity reactions are relatively common and include
rashes, serum sickness, anaphylaxis, nephritis, and drug fever.
Urticarial skin reactions and anaphylaxis, which occur within 20
to 30 minutes after a dose, are termed immediate reactions. These
are the most dangerous reactions and constitute absolute contraindications
to future treatment with a penicillin derivative. Fortunately, the
incidence of anaphylaxis is only 0.01% to 0.02% of
individual courses of therapy.7
Nonurticarial skin eruptions that occur several days after the
initiation of a course of penicillin are relatively common and do
not preclude future therapy with penicillins. Many such eruptions
represent the rash of a viral infection for which an antibiotic
has been inappropriately prescribed. Patients manifesting these
sorts of reactions should not be labeled “penicillin-allergic.”
Convulsions and other forms of central nervous system irritation
may occur when high doses of a penicillin have been administered, particularly
to patients with compromised renal function. Reactions are also
more likely when high cerebrospinal fluid concentrations of drug
are attained, such as in patients with meningeal inflammation.
Interstitial nephritis can occur during the course of therapy
with any penicillin, although it is most frequently associated with
the administration of methicillin. Hypokalemia is another renal
side effect of high-dose penicillin therapy that results from penicillins
acting as nonresorbable anions.
Coombs-positive hemolytic anemia may occur with any of the penicillins,
as may neutropenia. Neutropenia is most common among patients receiving
a β-lactamase-resistant penicillin and usually
resolves when the antibiotic is stopped. Decreased platelet aggregation,
which may precipitate bleeding, has been noted at high concentrations
of most penicillins. It is most marked with carbenicillin and ticarcillin.
In addition to the reactions noted above, which are common to
all of the penicillins, ampicillin or amoxicillin can cause a characteristic
nonurticarial maculopapular rash that does not appear to have an
allergic etiology. This rash usually appears 3 to 4 days after the onset
of therapy and is more frequent in patients with viral infections,
especially infectious mononucleosis.
The cephalosporins are currently divided into four generations,
with original agents being referred to as first-generation cephalosporins,
and the most recent agents as fourth-generation (see Table
246-6). In general, the spectrum of activity of the cephalosporins
increases with each generation because of decreasing susceptibility to
Table 246-6. Representative
Cephalosporins Classified by Generation ||Download (.pdf)
Table 246-6. Representative
Cephalosporins Classified by Generation
These cephalosporins are active against most staphylococci and
pneumococci and all streptococci, with the important exception of
enterococci. Minimal inhibitory concentrations against sensitive
Gram-positive organisms are usually less than 0.5 mg/L.
Their activity against aerobic Gram-negative bacteria and against
anaerobes is limited. Maximum serum concentrations after a 500-mg
dose of oral cephalexin are approximately 20 mg/L, whereas
they are 100 mg/L after 1-g intravenous doses of cefazolin.
These antibiotics distribute widely throughout the body but do not
penetrate well into the cerebrospinal fluid. Therefore, they must
not be used to treat meningitis. Their t1/2 ranges
from 30 minutes to 1.5 hours, and they are eliminated unchanged
in the urine. Doses may need adjustment in the presence of renal
insufficiency, although these agents have a wide toxic-to-therapeutic
The first-generation cephalosporins are rarely drugs of first
choice. They may, however, be useful in patients who are intolerant
to penicillins. Although cephalosporins and penicillins share the β-lactam
ring structure, the true incidence of cross-reactivity to cephalosporins in
skin-test-confirmed penicillin allergic patients is roughly 4%.
Cephalosporins should not be administered to patients with a history of
IgE-mediated hypersensitivity reactions to penicillins, as similar
reactions to cephalosporins may be observed. These antibiotics are
useful in the perioperative prophylaxis of surgical procedures that
carry a high risk of postoperative infections caused by staphylococcal
species, such as those involving the cardiovascular system and bones.
These cephalosporins have a broader bacteriologic spectrum than
do the first-generation agents. For example, cefuroxime and cefaclor not
only are more active against Gram-negative enteric bacteria but
are active against both β-lactamase-negative and
-positive strains of H influenzae, generally at
concentrations below 2 mg/L. The major bacteriologic advantage
of the cephamycins, cefoxitin and cefotetan, is their activity against
a broad range of anaerobic pathogens, most anaerobes being inhibited
by less than 16 mg/L. Maximum serum concentrations of cefuroxime
and cefoxitin after a 1-g intravenous dose are approximately 100
mg/L. Concentrations of cefaclor are approximately 10 mg/L
after a 200-mg oral dose. The half-lives of the second-generation
agents are similar to those of the first-generation agents. Excretion
of second-generation cephalosporins is primarily renal, and they
distribute widely. However, they do not attain sufficient concentrations
in the cerebrospinal fluid to warrant their use in the treatment
of bacterial meningitis.
Second-generation cephalosporins, like the first-generation agents,
are rarely drugs of first choice. Cefuroxime, because of its activity against
Gram-positive cocci and H influenzae, has been
actively promoted as a good agent for the treatment of a variety
of infections in children, including cellulitis, osteomyelitis,
septic arthritis, and pneumonia. However, it is not recommended
for the therapy of bacterial meningitis, because of several reports
of bacteriologic failures. The most common use of cefaclor is in
acute otitis media. However, other, less expensive, better tolerated,
and equally efficacious agents are available. Cefoxitin and cefotetan
are effective agents in the prevention and treatment of intra-abdominal
or pelvic infections.
Third-generation cephalosporins retain much of the Gram-positive
activity of the first two generations, although their antistaphylococcal activity
is reduced 5- to 10-fold. They are remarkably active against most
Gram-negative enteric isolates, with minimal inhibitory concentrations
usually less than 0.5 mg/L. Some third-generation cephalosporins
(eg, ceftazidime) also are active against most isolates of P aeruginosa. Maximum
serum concentrations of the third-generation agents range from 50
to 150 mg/L after a 1-g intravenous dose. In healthy subjects,
their half-lives range from 1 hour (cefotaxime) to between 6 and
8 hours (ceftriaxone). These antibiotics diffuse well into most
tissues, in contrast to members of the first two generations. Cefotaxime
and ceftriaxone, in particular, penetrate well into the cerebrospinal
fluid. Excretion of these agents is primarily renal.
The possible indications for third-generation cephalosporins
include empiric therapy of suspected bacterial meningitis, treatment
of hospital-acquired multiple-resistant Gram-negative aerobic infections,
and suspected infections in certain compromised hosts (eg, those
with fever and neutropenia). Ceftriaxone also is the drug of choice
in treating infections caused by N gonorrhoeae in
geographic areas with a high incidence of penicillin-resistant isolates.
Although these antibiotics show excellent activity against a
wide variety of enterobacteriaceae, their widespread use has led
to the development of antibiotic resistance. These plasmid-encoded
extended-spectrum β-lactamases (ESBLs) are considered
resistant to all cephalosporins and have rapidly spread over the past
decades, especially among strains of E coli and Klebsiella
pneumoniae. Although their prevalence has been low in US
pediatric populations, clinicians should continue to be judicious
in their use of third-generation cephalosporins. All microbiology
laboratories should screen for the presence of ESBL-producing enterobacteriacae.
This newest generation of cephalosporins combines the antistaphylococcal
activity of first-generation agents with the Gram-negative spectrum
(including Pseudomonas) of third-generation cephalosporins.
Currently cefepime is the only available fourth-generation cephalosporin.
Cefepime has excellent activity against multiple-resistant Gram-negative
bacteria including P aeruginosa, and bacteria that
produce the AmpC-inducible β-lactamase. Possible
indications for use include the therapy of infections suspected
or proved to be caused by multiple-resistant pathogens or in treating suspected
infections in immunocompromised hosts at risk of infections caused
by Pseudomonas species.
Serious adverse reactions to the cephalosporins are uncommon.
As with most antibiotics, the full spectrum of hypersensitivity
reactions may occur, including rashes, fever, eosinophilia, serum
sickness, and anaphylaxis. Allergic reactions are seen in approximately
5% of courses. Adverse reactions attributable to irritation
at the site of administration are common. These reactions include
local pain after intramuscular injection, phlebitis after intravenous administration,
and minor gastrointestinal complaints after oral administration.
Therapy with cephalosporins leads to the development of a positive
direct Coombs reaction during approximately 3% of courses.
This is, however, not commonly associated with hemolytic anemia.
Some of the cephalosporins are associated with dose-related nephrotoxicity,
whereas others are associated with an interstitial nephritis.
The third-generation drugs may cause transient elevations of
liver function test results and blood urea nitrogen concentrations. Ceftriaxone
has been associated with gallbladder sludging. These broad-spectrum
cephalosporins also have a profound inhibitory effect on the vitamin
K–synthesizing bacterial flora of the gastrointestinal
β-Lactamase inhibitors competively inhibit β-lactamase
enzymes, restoring the original spectrum of activity to enzyme-susceptible
Currently marketed inhibitors include clavulanic acid in fixed
combination with either amoxicillin or ticarcillin, and sulbactam
in fixed combination with ampicillin. Piperacillin is also available
in combination with the β-lactamase inhibitor tazobactam.
Although amoxicillin-clavulanate is effective in the therapy of such
infections as otitis media, sinusitis, lower respiratory tract infections,
and skin and soft-tissue infections, equally effective and less costly
alternatives for these infections are generally available. However,
some infections are polymicrobial and may involve anaerobes; for these the
addition of a β-lactamase inhibitor may be of value.
These infections include infected animal and human bites, odontogenic infections,
chronic sinusitis, and intra-abdominal infections.
The side effects of these agents reflect those of their parent
compounds. Gastrointestinal disturbances, especially diarrhea, are
common among those receiving orally administered β-lactamase
inhibitors. It appears that these symptoms can be partially ameliorated
by giving the drug with food and following each dose with 2 to 4
ounces of fluid.
The primary activity of this cell-wall-active antibiotic is against
Gram-positive bacteria. Most clinical isolates of S aureus and
coagulase-negative staphylococci are inhibited by less than 1.6 mg/L
of this antibiotic. However, recent reports of increasing minimal
inhibitory concentrations of strains of S aureus to
vancomycin have been associated with treatment failure. Vancomycin-resistant
enterococci (VRE) also are being reported at an increasing rate,
especially with hospital-acquired infections. Gram-positive bacilli, including Clostridium species,
are very sensitive to vancomycin, but Gram-negative bacteria are resistant.
Vancomycin is not absorbed from the gastrointestinal tract. Maximum
serum concentrations after a 10-mg/kg intravenous dose
are approximately 25 mg/L, sixfold higher than the minimal
inhibitory concentration of the usual bacteria being treated. It
diffuses quite widely throughout the body and, during meningeal
inflammation, attains concentrations in the cerebrospinal fluid
approximately 10% to 20% of serum concentrations.
However, penetration of vancomycin into epithelial lining fluid
of the lung is quite variable, with concentrations averaging 25% of
serum concentration. The t1/2 of vancomycin
is approximately 4 to 6 hours in patients with normal renal function.
The drug is excreted unmetabolized, almost exclusively in the urine.
Doses should be reduced in patients with decreased renal function.
Vancomycin historically has had a reputation for toxicity. Many
of its original adverse reactions, including ototoxicity and nephrotoxicity,
were probably due to impurities in the formulation. Now that a more
purified form is available, these adverse reactions are uncommon,
although nephrotoxicity may occur with concomitant administration
of an aminoglycoside. One of the more common side effects is the “red
man” syndrome, which is characterized by fever, chills,
erythema, and paresthesia. Although more likely to occur after a
rapid infusion of vancomycin, “red man” syndrome
also occurs after slow infusions and appears to be mediated by histamine.
Despite its introduction several decades ago, vancomycin recently
has gained widespread use. The reasons for its revival relate to the
emergence and increasing prevalence of several important pathogens.
These include methicillin-resistant S aureus and
coagulase-negative staphylococci, multiple-drug-resistant pneumococci,
and enterotoxin-producing Clostridium difficile.
Aztreonam is the first member of a unique class of antibiotics
referred to as monobactams. Although monobactams
are β-lactam antibiotics, their structure is so
different that cross-immunogenicity does not appear to be a problem;
they can be prescribed for patients with penicillin or cephalosporin
allergies. Aztreonam is resistant to a broad range of β-lactamases
produced by Gram-negative bacteria and therefore is active in vitro
against most Gram-negative organisms. Activity against Gram-positive
bacteria is limited. In comparison with the aminoglycosides,
aztreonam appears to be less nephrotoxic and ototoxic. Clinical
experience in children is limited.
Imipenem and meropenem are members of the carbapenem β-lactam
antibiotic family. Because imipenem is rapidly metabolized by renal
brush-border enzymes, it is administered with cilastatin, a substance
that inhibits imipenem metabolism by the kidney. Meropenem is administered alone,
as it is more stable in vivo to inactivation by human renal dehydropeptidase.
The carbapenems have activity against Gram-negative and Gram-positive
aerobes and anaerobes. These antibiotics diffuse widely throughout
the body and have excellent penetration into cerebrospinal fluid.
They appear to have toxicity profiles similar to that of other β-lactam
agents. Imipenem is epileptogenic in high doses, whereas meropenem appears
to have less neurotoxicity. Experience with these antibiotics in
children is limited, however carbapenems are useful in the treatment
of extended-spectrum β-lactamase-producing Gram-negative
bacteria that are resistant to all cephalosporins. In addition,
they can be used as monotherapy for polymicrobial infections, which
potentially include anaerobes such as intra-abdominal abscesses
and necrotizing fasciitis.
Rifampin is active against a wide range of Gram-positive and
Gram-negative bacteria. It also is active against the majority of Mycobacterium
tuberculosis strains, with minimal inhibitory concentrations
less than 0.5 mg/L. Rifampin is given orally and is well
absorbed from the gastrointestinal tract. Maximum serum concentrations
of 8 mg/L are usually attained after a 600-mg dose. Rifampin
penetrates well into most body tissues and fluids, including lungs,
liver, pleural and ascitic fluid, bone, tears, saliva, and cerebrospinal
fluid, even in the absence of inflammation. The t1/2 of rifampin
ranges from 2 to 5 hours. It is metabolized in the liver and excreted
principally in the bile and, to a lesser degree, in the urine.
Hypersensitivity reactions include dermatitis and a flulike syndrome,
occasionally with thrombocytopenia, hemolytic anemia, and acute
renal failure. Cholestatic hepatitis is another possible adverse
reaction. All patients receiving this antibiotic should be advised
that their bodily secretions, including urine, saliva, sweat, and
tears, will develop a reddish-orange discoloration. This is especially
important for patients who wear soft contact lenses, which may be
Important drug interactions with rifampin have been recognized.
For example, it enhances the metabolism of fluconazole, oral contraceptives,
warfarin, propranolol, and anticonvulsants, all of which are metabolized
in the liver. Doses of these concurrently administered agents may
need to be increased to maintain therapeutic concentrations.
The use of rifampin as a single agent is limited by the fact
that bacteria can rapidly develop resistance. It is, however, one
of the first-line agents to be used in combination in the treatment
of patients with most forms of tuberculosis. It also is the antibiotic
of choice for the prophylaxis of contacts of patients with serious
infections caused by H influenzae type b and N
meningitidis. Rifampin also has been used to eradicate
upper respiratory carriage of S aureus and group
The prototype of the quinolone antibiotics is nalidixic acid.
This naphthyridine derivative has been used almost exclusively as
a urinary antiseptic. It is as active as ampicillin against Gram-negative
enteric isolates, but has no useful activity against Gram-positive
bacteria or Pseudomonas species. Because nalidixic
acid is only partially absorbed from the gastrointestinal tract,
large doses are necessary to attain therapeutic urinary concentrations.
These high doses have caused side effects, including visual disturbances.
An additional problem has been the rapid development of bacterial
resistance during therapy. These factors have limited the use of
Research directed at modifying the chemical structure of nalidixic
acid resulted in the development of the ever-growing family of fluorinated
quinolone derivatives, including ciprofloxacin, ofloxacin, levofloxacin,
gatifloxacin, and moxifloxacin. The spectrum of activity of these
derivatives is continually increasing and now includes most Gram-positive bacteria,
including some strains of methicillin-resistant S aureus and
many Pseudomonas organisms. In addition, when compared
with nalidixic acid, most Gram-negative enterics have greatly reduced
minimal inhibitory concentrations to the new derivatives. Most quinolones
are absorbed well after oral administration, and thus represent the
first agents available for the oral treatment of systemic infections
caused by resistant Gram-negative enteric isolates and Pseudomonas species.
These agents are also of great value because their activity is unrelated
to that of other antibiotics and resistance is not plasmid-borne.
In adults, the quinolones may be preferred over alternate agents
for treatment of complicated urinary tract infections, suspected
bacterial gastroenteritis, osteomyelitis caused by Gram-negative
bacilli, and invasive external otitis.
In animal studies, the quinolones caused cartilaginous damage
in young animals. This limited their use in children to recalcitrant
infections for which alternatives were lacking. However, recent
data suggest that quinolones may be safe for administration to children, with
the frequency of cartilage or joint toxicity being similar to that
in adults. However, the American Academy of Pediatrics Committee on
Infectious Diseases recommends that the use of quinolones should
be limited in children because of high rates of resistance seen with
overuse and the theoretical risk of joint injury.8 There
are specific circumstances in which a quinolone may be the most
appropriate antibiotic such as in urinary tract infections due to Pseudomonas species
or other multidrug-resistant, Gram-negative bacteria or if other
antibiotics are contraindicated because of allergy or resistance
The antibacterial activity of metronidazole is limited to anaerobes,
with greatest activity against Gram-negative anaerobic bacilli such
as Bacteroides and Fusobacterium, most
of which have minimal inhibitory concentrations under 3.12 mg/L.
Activity against Gram-positive anaerobic cocci is less consistent,
with about 75% of such strains being inhibited by 12.5
Metronidazole can be administered intravenously, orally, or rectally.
Maximum serum concentrations after a 7.5-mg/kg dose administered intravenously
are 20 to 25 mg/L. Concentrations after an equivalent oral
dose are similar, and those after an equivalent rectal dose are
about half. The drug diffuses well into all tissues; therapeutic
concentrations can be attained in cerebrospinal fluid, bile, bone,
and abscesses. The t1/2 of metronidazole
is approximately 8 hours. It is metabolized to acid and hydroxy
metabolites. Between 60% and 80% of the drug is
eliminated by the kidneys, and 6% to 15% is eliminated
in the feces. Hepatic insufficiency prolongs the t1/2 of
unchanged metronidazole, and doses usually have to be adjusted.
Renal insufficiency usually does not necessitate dose adjustment.
Metronidazole therapy often is associated with a metallic taste
and nausea. More serious but less frequent adverse reactions include
a reversible peripheral neuropathy, seizures, encephalopathy, and
neutropenia. A disulfiramlike reaction can occur when metronidazole
is taken with alcohol. Several studies conducted in laboratory animals
have indicated that prolonged use of high-dose metronidazole can
be carcinogenic. However, there is no evidence that it is carcinogenic
Metronidazole has been shown to be effective in a wide variety
of infections caused by anaerobes. The most common indications for
this antibiotic are the treatment of pelvic and intra-abdominal
sepsis and brain abscesses. It also is an effective and less expensive
alternative to vancomycin in the treatment of pseudomembranous colitis
caused by C difficile. Also, despite inconsistent
in vitro activity of metronidazole against the principal etiologic agent
of “nonspecific vaginitis,” Gardnerella vaginalis, it
is the antibiotic of choice for treatment of this infection.
The aminoglycoside group of antibiotics contains a large number
of structurally related compounds. Streptomycin was the first of
these agents to be discovered. Subsequently developed agents include
neomycin, kanamycin, gentamicin, tobramycin, amikacin, and netilmicin.
Streptomycin is primarily used to treat tuberculosis. Gentamicin,
tobramycin, and amikacin are the most common aminoglycosides; they
are discussed as a group, with only their clinically important differences
These antibiotics are active primarily against Gram-negative
and limited numbers of Gram-positive aerobes. They are inactive
against the vast majority of anaerobes. All three of the aminoglycosides
are active against most strains of P aeruginosa, with
tobramycin consistently demonstrating the greatest activity. Gentamicin is
consistently the most active of these agents against strains of Serratia
marcescens. Otherwise, their relative antibacterial activities
are similar, with most sensitive strains being inhibited by less
than 3 to 4 mg/L.
An important aspect of aminoglycoside activity against Gram-negative
aerobes is the increasing resistance developed since their introduction.
Resistance is most often due to antibiotic inactivation by enzymes
produced by the bacteria. There are at least 12 such inactivating enzymes.
Gentamicin is susceptible to the largest number of these enzymes
(9 of 12), and amikacin is susceptible to the smallest number (1
of 12). When widespread resistance develops to one of the aminoglycosides
being used in a particular hospital, changing to an alternate agent usually
results in a return to increased sensitivity.
The pharmacokinetics of all the aminoglycosides are similar.
They are poorly absorbed from the gastrointestinal tract, but well
absorbed after intramuscular or intravenous administration. Maximum
serum concentrations of gentamicin and tobramycin are 5 to 8 mg/L
after unit doses of 1 to 2.5 mg/kg. Maximum serum concentrations
of amikacin range from 15 to 30 mg/L after a unit dose
of 7.5 mg/kg. The aminoglycosides are distributed in most
extracellular fluids, but do not attain therapeutic concentrations
in cerebrospinal fluid. The main site of deposition of these drugs
is the kidney, which accounts for approximately 40% of
the total antibiotic in the body. The cortex accumulates approximately 85% of
the load, and the resulting concentrations are more than 100-fold
greater than serum concentrations. Their half-lives range from 1.5
to 2.5 hours, and they are eliminated, primarily unchanged, by glomerular
filtration. The doses of the aminoglycosides must be carefully monitored
and adjusted in the presence of renal insufficiency. The total daily
dose is adjusted by either prolonging the dosing interval or reducing the
unit dose. Nomograms, based on the measured or approximated glomerular
filtration rate, are available to guide these adjustments.
Aminoglycosides demonstrate concentration-dependent killing,
that is, the bactericidal activity increases with increasing concentration
of drug. In addition, aminoglycosides exhibit a substantial postantibiotic
effect. Aminoglycosides will inhibit growth of bacteria even after
the serum level has fallen below the minimal inhibitory concentration
for that antibiotic. Because of these pharmacodynamic characteristics,
aminoglycosides may be effective when administered as a single daily
dose. Toxicity is not increased using this dosing strategy.9
The most important toxicities of the aminoglycosides are ototoxicity
and nephrotoxicity. These toxic effects are more common in adults than
in children, who generally tolerate this class of drugs well. Ototoxicity
may be primarily vestibular or cochlear. The agent most commonly associated
with vestibular toxicity is gentamicin, with an estimated incidence
in adult populations of 2%. This ranges from mild vertigo
to severe Ménière syndrome. Damage is usually
permanent, but symptoms may eventually be reduced by adaptation.
The agents most likely to cause cochlear toxicity are amikacin and
tobramycin. Although the frequency of hearing loss following treatment
with these drugs is low, it may occur without any warning and may
be irreversible. Risk factors that seem to predispose to ototoxicity
include cumulative dosage, advanced age, and maternal history of
preexisting renal compromise or hearing loss. Controlled trials
in adult patients have found little difference in the incidence
of ototoxicity following treatment with gentamicin, tobramycin,
Early manifestations of nephrotoxicity may include hypokalemia,
glycosuria, alkalosis, hypomagnesemia, hypocalcemia, and enzymuria. The
enzyme excreted as an early manifestation of aminoglycoside nephrotoxicity
is the lysosomal enzyme N-acetyl-β-d-glucosaminidase (NAG).
Renal damage is dose related and generally reversible.
Another less common but important side effect of the aminoglycosides
is a competitive type of neuromuscular blockade, seen most often
after intraperitoneal administration or after intravenous push.
Hypersensitivity reactions to systemically administered aminoglycosides
Because of their relatively narrow toxic-to-therapeutic ratio,
serum concentrations of the aminoglycosides should be monitored.
When using multiple daily dosing, peak concentrations of gentamicin
and tobramycin should not exceed 10 mg/L, and trough concentrations should
be below 2 mg/L. Amikacin peak and trough concentrations
should not exceed 30 mg/L and 10 mg/L, respectively.
When using single daily dosing, levels approximately 8 hours after
the start of dosing should be in the range of 2 to 5 mg/L
for gentamicin and tobramycin and 10 to 15 mg/L for amikacin.
The most important indications for using one of the aminoglycosides
are for treatment of proven or suspected Gram-negative infections
of the blood, bones, joints, respiratory tract, urinary tract, or
soft tissues. The aminoglycosides also are valuable in the empiric
therapy of febrile, neutropenic episodes in immunocompromised patients.
The tetracyclines are not frequently prescribed for children
because of their age-related toxicities. The tetracyclines are active
against a wide range of Gram-positive and Gram-negative bacteria, Mycoplasma, Rickettsia,
and Chlamydia. They also are active against Treponema
pallidum and moderately active against a wide range of
anaerobes. All tetracyclines are absorbed adequately, but incompletely,
from the gastrointestinal tract. They are chelated by various cations
and are absorbed more completely during fasting. These antibiotics
distribute widely and attain concentrations in the cerebrospinal fluid
of 10% to 50% of simultaneous serum concentrations.
Most of these agents are excreted primarily by renal glomerular
filtration, with lesser amounts being eliminated in the bile. Doxycycline
is an exception, with 90% appearing in the feces. The half-lives
of the tetracyclines range from 6 hours for tetracycline to approximately
20 hours for doxycycline.
The adverse effects of tetracyclines relate to tooth and bone
deposition. Permanent binding to dental calcium can produce a dose-related, brownish,
fluorescent discoloration of the teeth when the drugs are administered
during the period of dental calcification (from the fifth month
of gestation to approximately age 8). Bone deposition may result
in temporary cessation of bone growth. This effect is reversible
when the drug is discontinued.
Other adverse effects of tetracyclines that are not age related
include gastrointestinal disturbances, photosensitivity, hepatotoxicity, and neurotoxicity.
Hypersensitivity reactions to the tetracyclines are rare.
Photosensitivity reactions may be caused by any of the tetracyclines
but are most frequent with doxycycline. Unfortunately, doxycycline is
frequently prescribed as a prophylactic agent against diarrhea in
individuals traveling to tropical, sunny climates. Hepatotoxic reactions
are uncommon, but fatal liver necrosis has been described after
large intravenous doses in pregnant women. The pathogenesis of this
reaction is unknown.
Manifestations of neurotoxicity are observed frequently and almost
exclusively with minocycline. Dizziness, weakness, vertigo, and
ataxia appear within the first few days of therapy. Another neurologic
side effect of these agents is benign intracranial hypertension
that is self-limited and resolves when the therapy is discontinued.
Indications for tetracycline therapy in adults and children over
age 8 include infections caused by Mycoplasma pneumoniae, Q
fever, psittacosis, brucellosis, rickettsial species, ehrlichiosis,
and lymphogranuloma venereum. Tetracycline is also used to treat
gonorrhea and syphilis in the penicillin-allergic nonpregnant patient
and is frequently prescribed to patients with acne vulgaris. Doxycycline
is an effective chemoprophylactic agent against E coli–induced
diarrhea and against meningitis caused by N meningitidis or
Linezolid is the first member of the new oxazolidinone class
of antibiotics. Linezolid binds to the 50S ribosomal subunit and
prevents binding of the 30S subunit, mRNA, and initiation factors. It
has 100% bioavailability after oral administration and
has wide distribution throughout the body, including lung extracellular
lining fluid and cerebrospinal fluid. Maximum serum concentrations
of 11 to 16.7 μg/mL are achieved within
1 to 2 hours of an oral dose. Linezolid is cleared primarily by
nonrenal mechanisms, with only 30% of the drug eliminated
by the kidneys. The t1/2 is 1.5
to 5 hours; infants and young children clear the medication more
rapidly.10 Linezolid has been approved for the
treatment of complicated skin and skin-structure infections and
nosocomial pneumonia. It demonstrates activity against Gram-positive
bacteria such as staphylococcus, streptococcus, and enterococcus, including
methicillin-resistant S aureus and vancomycin-resistant
enterococcus (VRE).11 It also has been used as
second-line therapy for both tuberculous and nontuberculous mycobacterium species.
Linezolid generally is well-tolerated in children. Most adverse
effects occur only with prolonged (> 3 weeks) therapy. These include
reversible hepatoxicity and bone marrow suppression. Linezolid is
also a reversible monoamine oxidase inhibitor, so concurrent treatment
with selective-serotonin reuptake inhibitors is contraindicated as
this combination has been associated with serotonin-syndrome.
Chloramphenicol is active against aerobic bacteria except P
aeruginosa, most anaerobes, and the majority of Mycoplasma, Chlamydia,
and Rickettsia organisms. Most susceptible bacteria have
minimal inhibitory concentrations less than 5 mg/L.
Chloramphenicol is rapidly and completely absorbed from the gastrointestinal
tract. The intravenous formulation of chloramphenicol is a succinate
that must be hydrolyzed in vivo to biologically active free drug.
Maximum serum concentrations attained after an oral or intravenous
dose of 25 mg/kg range from 15 to 25 mg/L. There
is, however, considerable interpatient variability. Chloramphenicol
diffuses well into most body fluids and tissues. Even in the absence
of meningitis, concentrations in the cerebrospinal fluid often reach
70% to 80% of serum concentrations.
Chloramphenicol is metabolized in the liver. It is converted
to a biologically inactive, water-soluble monoglucuronide. Impaired
liver function can result in high serum concentrations. About 90% of
chloramphenicol is excreted in the urine, but only 5% to
10% of this is in the unchanged biologically active form;
dosage does not need to be adjusted in the presence of renal failure.
The serum t1/2 is approximately
The most feared adverse effect of chloramphenicol therapy is
aplastic anemia. This is not a dose-related phenomenon, and the
mechanism is unclear. The precise frequency of this complication
is not known but is estimated to be 1 in 40,000 treatment courses.
A second type of hematopoietic depression is dose related. Serum
concentrations in excess of 20 to 25 mg/L invariably result
in reduced iron utilization by the bone marrow. This eventually
leads to anemia and, less commonly, to thrombocytopenia and leukopenia.
This type of marrow toxicity is reversible when the antibiotic is
A toxic reaction to chloramphenicol in neonates is the “gray
baby syndrome.” This is a form of circulatory collapse
associated with excessive and sustained serum concentrations of unconjugated
drug. Neonates are susceptible because of their immature hepatic
Chloramphenicol serum concentrations should be monitored during
therapy, and dosing should be adjusted if peak concentrations exceed
25 to 30 mg/L.
Chloramphenicol is effective in treating typhoid fever, rickettsial
diseases, brain abscesses, and a variety of other infections in
which anaerobes are usually pathogenic. In the penicillin-allergic patient,
chloramphenicol is effective for infections caused by H
influenzae, S pneumoniae, and N meningitidis. Because
of the availability of equally effective, less-toxic agents, oral
formulations of chloramphenicol are no longer made or available
in the United States; an intravenous preparation is available.
Clindamycin is active against most Gram-positive bacteria, both
aerobic and anaerobic. It also is active against most Gram-negative
anaerobic rods, but it is inactive against most Gram-negative aerobes.
Sensitive organisms usually have minimal inhibitory concentrations
less than 0.5 mg/L.
Clindamycin is well absorbed from the gastrointestinal tract.
An oral dose of 300 mg results in maximum serum concentrations of
4 to 5 mg/L. It may be prescribed as a capsule or as a
suspension. Maximum serum concentrations after an intravenous dose
are two- to threefold higher than after an oral dose. Clindamycin
distributes widely, but penetrates into cerebrospinal fluid poorly.
The drug is metabolized primarily in the liver, with less than 25% of
a dose ultimately excreted in the urine. Thus, hepatic insufficiency has
a more profound effect on the disposition of this drug than does
renal insufficiency. The t1/2 of
clindamycin is 2 to 4 hours.
The most important group of adverse reactions to clindamycin
are gastrointestinal disturbances. Approximately 30% of
patients treated with this drug develop diarrhea. This diarrhea
is usually self-limited and subsides when therapy is discontinued.
It may be associated with nausea, vomiting, and abdominal cramps.
A more severe gastrointestinal side effect is pseudomembranous colitis,
which was first described in association with this antibiotic. It
is caused by gastrointestinal overgrowth of toxin-producing C
difficile. Almost every antibiotic has now been implicated
in the pathogenesis of pseudomembranous colitis, and clindamycin
is not the most frequent culprit. Furthermore, pseudomembranous
colitis is much less common in children than in adults.
Minor abnormalities of liver function tests are quite common
during clindamycin therapy, and cardiovascular collapse has been
observed after rapid intravenous administration.
The most important uses of clindamycin are in treating a variety
of anaerobic infections, including those caused by Bacteroides
fragilis. Some infections treated successfully with clindamycin, usually
combined with an aminoglycoside, include intra-abdominal and pelvic
infections, aspiration pneumonia, infected decubitus ulcers, and
periodontal disease. Recently, clindamycin has proved valuable in
treating community-associated methicillin-resistant S aureus infections,
as many of these isolates retain clindamycin susceptibility. Microbiology
labs must ensure that inducible clindamycin resistance is not present
by performing a D-test. Strains of methicillin-resistant S
aureus that are resistant to erythromycin are more likely
to demonstrate inducible resistance to clindamycin than strains
that are sensitive to erythromycin. The presence of inducible clindamycin
resistance has been associated with treatment failure.12 Clindamycin combined
with penicillin is often recommended for treatment of necrotizing
fasciitis due to group A streptococci.
The antibacterial activity of erythromycin is similar to that
of clindamycin. It is generally active against Gram-positive aerobes
and anaerobes. It is inactive against most Gram-negative enterics but
is active against certain nonenteric Gram-negative species, including Neisseria,
Haemophilus, Bordetella, Campylobacter, and Legionella. The
Gram-negative anaerobes are not reliably sensitive. Rickettsia,
Mycoplasma pneumoniae, Ureaplasma, and Chlamydia are
usually inhibited by attainable concentrations of erythromycin.
Most sensitive bacteria are inhibited by less than 1.0 mg/L
of this antibiotic.
Erythromycin base is adequately absorbed from the gastrointestinal
tract. The base is inactivated by gastric acidity, and therefore
absorption can be enhanced by enclosing the antibiotic in a capsule
or by administering it as a stearate or estolate derivative. Maximum
serum concentrations after a 500-mg dose of base or stearate are approximately
1 mg/L. Concentrations are two- to fourfold higher after
an equivalent dose of the estolate formulation. A 500-mg dose of
intravenous erythromycin results in maximum serum concentrations
of about 5 mg/L.
Erythromycin is distributed throughout body water. It attains
only low concentrations in the cerebrospinal fluid, even with inflamed
meninges. Only a small amount of erythromycin is excreted in its
original form; the remainder is metabolized. The t1/2 is
approximately 2 hours.
Oral erythromycin formulations often result in gastrointestinal
disturbances, including nausea, vomiting, diarrhea, and abdominal cramps. These
adverse effects are likely to occur at high doses. A much more serious
adverse reaction, fortunately rare among children, is cholestatic hepatitis.
It occurs most commonly with the estolate preparation and is probably
due to the propionyl ester linkage. Manifestations can include jaundice,
fever, pruritus, rash, increased liver size, and eosinophilia. Resolution
usually occurs when the antibiotic is discontinued. Erythromycin
use in neonates has been associated with the development of pyloric
Intravenous erythromycin is frequently associated with thrombophlebitis.
Ototoxicity, manifested as tinnitus and transient deafness, is a
rare adverse reaction.
Erythromycin is an effective alternative to penicillin for treating
streptococcal and pneumococcal infections, although many S
pneumoniae are becoming resistant. Erythromycin also is
indicated for treating respiratory Mycoplasma infections;
for eradicating Bordetella pertussis and Corynebacteria
diphtheria from the nasopharynx, Chlamydia infections,
Legionnaire’s disease, and gonorrhea or syphilis during pregnancy;
and for eradicating Campylobacter from the stools
of patients with Campylobacter gastroenteritis.
Erythromycin should not be used alone in treating otitis media.
Although it is active in vitro against the majority of bacteria
responsible for this infection, middle ear concentrations are not
consistently above the minimal inhibitory concentration for strains
of H influenzae. If used for this indication, it
should be given with a sulfonamide. An erythromycin-sulfonamide
fixed combination is marketed for this indication.
Azithromycin is an azalide antibiotic that is structurally related
to erythromycin. Its biochemical modifications result in superior
oral bioavailability, a greatly extended serum and tissue half-life
(both exceeding 48 hours), and excellent in vivo activity against
most of the organisms susceptible to erythromycin. In addition,
it has excellent activity against Chlamydia trachomatis, with
minimal inhibitory concentrations between 0.03 and 0.5 mg/L.
It is particularly well suited for treating genital infections caused
by Chlamydia. A single oral dose is as effective
as a 7-day course of erythromycin or doxycycline.
Clarithromycin is another macrolide antibiotic that is similar
to azithromycin. A special feature of clarithromycin is its activity
against selected mycobacteria. It is particularly useful in the
treatment of atypical mycobacteria infections, especially those
caused by Mycobacterium avium-intracellulare.
Sulfonamides were the first group of synthetic antibacterial
compounds. These antibiotics originally had a wide range of activity,
but this range is considerably compromised by acquired bacterial
resistance. Gram-positive bacteria that are usually sensitive to
sulfonamides include group A streptococci, Streptococcus
viridans, some S pneumoniae, and Nocardia species.
Staphylococci are variably sensitive, and Streptococcus faecalis is
resistant. The most sensitive Gram-negative bacteria are Neisseria species,
many enterobacteria, H influenzae, and B
pertussis. Chlamydia and nonbacterial pathogens such as Toxoplasma and Plasmodium
falciparum are also sensitive to the sulfonamides.
The sulfonamides are often classified on the basis of their half-lives,
which range from 2 to 6 hours with the short-acting sulfonamides,
such as sulfanilamide, sulfadiazine, and sulfisoxazole, to 150 to
200 hours with the ultralong-acting sulfonamide sulfadoxine. Most
of the sulfonamides are well absorbed from the gastrointestinal
tract. Serum concentrations vary somewhat among the different agents,
but after the usual recommended, orally administered doses, maximum
concentrations are typically in the range of 50 to 100 mg/L.
Concentrations are higher after intravenous administration. These
antibiotics are distributed widely and attain therapeutic concentrations
in cerebrospinal fluid. The sulfonamides are acetylated in the liver,
and some also undergo glucuronidation. Free and conjugated sulfonamides
are excreted by renal glomerular filtration and secretion. The longer-acting
sulfonamides undergo more complete tubular resorption than do the shorter-acting
agents. Minimal amounts of the sulfonamides are excreted in the
Sulfonamides may cause a variety of hypersensitivity reactions,
ranging from mild rashes to life-threatening Stevens-Johnson syndrome.
The latter reaction is more common with the longer-acting sulfonamides.
Hematologic toxicity also may occur with sulfonamide use. Reactions
include agranulocytosis, which is usually reversible on discontinuation
of the drug, and hemolytic anemia in patients with deficiency of G6PD.
Renal damage was common with the older sulfonamides, which were
poorly water soluble. Patients developed crystalluria, which led
to urinary obstruction and hematuria. Renal damage may be a manifestation
of a hypersensitivity reaction. Sulfonamides are contraindicated
in the neonate and during the latter part of pregnancy, as they
may displace bilirubin from protein-binding sites, possibly leading
to jaundice and kernicterus. Neonates seem to be more susceptible
to the potential renal toxicity of these agents.
Clinical uses of the sulfonamides include the treatment of acute,
uncomplicated urinary tract infections and infections caused by Chlamydia, Nocardia,
Toxoplasma, and chloroquine-resistant P falciparum. For
the latter two pathogens the sulfonamide is administered combined
with pyrimethamine. The sulfonamides are also used as prophylactic
agents; for example, in children with rheumatic fever who are allergic
to penicillin and in children with frequently recurring urinary
tract infections. When used to reduce the incidence of recurrent
urinary tract infections, the sulfonamide is usually administered
in combination with trimethoprim.
Trimethoprim has a bacterial spectrum similar to that of the
sulfonamides, although it generally has lower minimal inhibitory
concentrations against most isolates. Trimethoprim is active against
enterococci, whereas the sulfonamides are not.
Trimethoprim is well absorbed from the gastrointestinal tract.
Maximum serum concentrations of 2 mg/L are attained after
a 160-mg dose. Tissue concentrations of this antibiotic often exceed
serum concentrations except in the brain, skin, and fat. Trimethoprim
is metabolized primarily in the liver. Approximately 50% of
an administered dose is excreted unchanged in the urine, and the
remainder is excreted as metabolites. The t1/2 is
about 11 hours.
At high dosages, trimethoprim may cause nausea and vomiting.
Blood dyscrasias have occurred rarely. Because trimethoprim is an
antifolate, anemia secondary to folate deficiency may occur, especially
among patients with a preexisting folate deficiency.
Trimethoprim is commonly used with another antibiotic, usually
a sulfonamide. Infections treated with this combination include urinary
tract infections, sinusitis, otitis media, shigellosis, nocardiasis,
and Pneumocystis carinii pneumonitis. Systemic
infections caused by Gram-negative aerobes resistant to multiple antibiotics
have also been treated with this antibiotic combination. In addition,
the combination is effective prophylactically in patients with recurrent
urinary tract infections and in immunocompromised patients at risk
for pneumonia caused by P carinii.
Although nitrofurantoin was approved by the Food and Drug Administration
in 1953, its exact mechanism of action is still not known. It has
a hydantoin ring with a nitro-substituted furanyl side chain that
is metabolized by bacteria to activate its bactericidal activity.4 Nitrofurantoin
has broad activity against Gram-positive and Gram-negative enteric
Nitrofurantoin is well absorbed after oral administration and
rapidly cleared by the kidneys. Therefore, serum levels are not
maintained, but the antibiotic concentrates in the urine, making it
a useful antibiotic for urinary tract infections. Nitrofurantoin
has an extremely short half-life (~30 min) and a high volume of
distribution, which may be due to both rapid distribution into tissue
compartments and enzymatic degradation at those sites.
The primary side effect of nitrofurantoin therapy is nausea and
vomiting. These gastrointestinal adverse effects are the most common
reason for discontinuing therapy. Although there have been reports
of acute lung injury and pulmonary fibrosis in adults on long-term
nitrofurantoin therapy, similar toxicities have not been seen in
children. Hemolysis can occur in patients with glucose-6-phosphate
Because of the high concentrations of nitrofurantoin in urine
and its broad-spectrum of activity, it has primarily been used as
both therapy and prophylaxis in urinary tract infections (UTIs).
Some data suggest that nitrofurantoin may be more effective than
other antibiotics in preventing recurrent UTIs in children. However,
its gastrointestinal side effects may limit its utility.13