58
Chapter
MECHANISM OF ACTION
ANTIMICROBIAL ACTIVITY
Aminoglycosides
Conan MacDougall
RESISTANCE TO THE AMINOGLYCOSIDES
ADME
DOSING AND MONITORING
THERAPEUTIC USES OF AMINOGLYCOSIDES
■■ Urinary Tract Infections
■■ Pneumonia
■■ Meningitis
■■ Peritonitis
■■ Bacterial Endocarditis
■■ Sepsis
■■ Tularemia
■■ Plague
■■ Mycobacterial Infections
ORIGINS
Aminoglycosides are natural products or semisynthetic derivatives of
compounds produced by a variety of soil actinomycetes. Strepto-
mycin was first isolated from a strain of Streptomyces griseus. Gen-
tamicin and netilmicin are derived from species of the actinomycete
Micromonospora. The difference in spelling (-micin) compared with
the other aminoglycoside antibiotics (-mycin) reflects this difference
in origin. Tobramycin is one of several components of an aminogly-
coside complex known as “nebramycin” that is produced by Streptomyces
tenebrarius. It is most similar in antimicrobial activity and toxicity
to gentamicin. In contrast to the other aminoglycosides, amikacin, a
derivative of kanamycin, and netilmicin, a derivative of sisomicin, are
semisynthetic products.
Aminoglycosides are natural products or semisynthetic derivatives of
compounds produced by a variety of soil actinomycetes. Amikacin, a
derivative of kanamycin, and netilmicin, a derivative of sisomicin, are
semisynthetic products.
Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin,
kanamycin, streptomycin, paromomycin, and neomycin) are used primarily
to treat infections caused by aerobic gram-negative bacteria. Streptomy-
cin and amikacin are important agents for the treatment of mycobacte-
rial infections, and paromomycin is used orally for intestinal amebiasis.
Aminoglycosides are bactericidal inhibitors of protein synthesis. Mutations
affecting proteins in the bacterial ribosome can confer marked resistance
to their action. Most commonly, resistance is due to aminoglycoside-
metabolizing enzymes or impaired transport of drug into the cell; these mech-
anisms may confer resistance to all aminoglycosides or only select agents.
Resistance genes are frequently acquired via plasmids or transposons.
Brunton_Ch58_p1039-p1048.indd 1039
■■ Cystic Fibrosis
■■ Topical Applications
ADVERSE EFFECTS OF AMINOGLYCOSIDES
■■ Ototoxicity
■■ Nephrotoxicity
■■ Neuromuscular Blockade
■■ Other Adverse Effects
PHARMACOLOGICAL PROPERTIES OF INDIVIDUAL
AMINOGLYCOSIDES
■■ Gentamicin
■■ Tobramycin
■■ Amikacin
■■ Netilmicin
■■ Streptomycin
■■ Neomycin
■■ Paromomycin
■■ Kanamycin
Aminoglycosides contain amino sugars linked to an aminocyclitol
ring by glycosidic bonds (Figure 58–1). They are polycations, and their
polarity is responsible in part for pharmacokinetic properties shared by
all members of the group. For example, none is absorbed adequately after
oral administration, inadequate concentrations are found in CSF, and all
are excreted relatively rapidly by the normal kidney. All members of the
group share the same spectrum of toxicity, most notably nephrotoxicity
and ototoxicity, which can involve the auditory and vestibular functions
of the eighth cranial nerve.
Mechanism of Action
The aminoglycoside antibiotics are rapidly bactericidal. Bacterial killing
is concentration dependent: the higher the concentration, the greater the
rate of bacterial killing. The ratio of the peak concentration to the organ-
ism’s MIC is thus a key predictor of aminoglycoside efficacy. The inhibi-
tory activity of aminoglycosides persists after the serum concentration has
fallen below the MIC, a phenomenon known as the postantibiotic effect.
These properties probably account for the efficacy of high-dose, extended-
interval dosing regimens.
Aminoglycosides diffuse through aqueous channels formed by porin
proteins in the outer membrane of gram-negative bacteria to enter the
periplasmic space. Transport of aminoglycosides across the cytoplasmic
(inner) membrane depends on a transmembrane electrical gradient cou-
pled to electron transport to drive permeation of these antibiotics. This
energy-dependent phase is rate limiting and can be blocked or inhibited
by divalent cations (e.g., Ca2+ and Mg2+), hyperosmolarity, a reduction in
pH, and anaerobic conditions. Thus, the antimicrobial activity of amino-
glycosides is reduced markedly in the anaerobic environment of an abscess
and in hyperosmolar acidic urine.
Once inside the cell, aminoglycosides bind to polysomes and interfere
with protein synthesis by causing misreading and premature termination
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 1040
Abbreviations AC ACI ACII ACIII

AC: acetylase H
AD: adenylase HC NH2 NH2
CHAPTER 58 AMINOGLYCOSIDES

ADME: absorption, distribution, metabolism, excretion NH2

O
CNS: central nervous system
CSF: cerebrospinal fluid O
OH
GI: gastrointestinal HO
IM: intramuscular NH2
IV: intravenous CH2OH
O
MIC: minimum inhibitory concentration AC
O
mRNA: messenger RNA
PO: by mouth NH2
HO
UTI: urinary tract infection
OH AD

of mRNA translation (Figure 58–2). The primary intracellular site of
action of the aminoglycosides is the 30S ribosomal subunit. At least three
of these ribosomal proteins, and perhaps the 16S ribosomal RNA as well,
contribute to the streptomycin-binding site. Aminoglycosides interfere with
the initiation of protein synthesis, leading to the accumulation of abnormal
initiation complexes; the drugs also can cause misreading of the mRNA
template and incorporation of incorrect amino acids into the growing
polypeptide chains (Davis, 1988). The resulting aberrant proteins may be
inserted into the cell membrane, leading to altered permeability and
further stimulation of aminoglycoside transport (Busse et al., 1992).
Antimicrobial Activity
The antibacterial activity of gentamicin, tobramycin, and amikacin
is directed primarily against aerobic gram-negative bacilli (Mingeot-
Leclercq et al., 1999). Kanamycin, like streptomycin, has a more limited
spectrum. The aerobic gram-negative bacilli vary in their susceptibility to
the aminoglycosides (see Table 58–1). Gram-negative aerobic cocci such
as Neisseria, Moraxella, and Haemophilus have varying susceptibilities. An
increasing number of gram-negative bacilli encountered in healthcare set-
tings (especially Klebsiella and Pseudomonas) display extensive resistance
to multiple classes of antibacterials; in these isolates, aminoglycosides may
be the only class of commonly used agents with in vitro activity.
Aminoglycosides have little activity against anaerobic microorganisms
or facultative bacteria under anaerobic conditions. Their action against
most gram-positive bacteria is limited, and they should not be used as
Tobramycin
AC Acetylase AD Adenylase
Figure 58–1 Aminoglycoside structure and sites of activity of plasmid-mediated
enzymes capable of inactivating aminoglycosides. Tobramycin is shown as a
representative; structural characteristics protect some aminoglycosides from
the actions of some of these enzymes, explaining differences in spectrum of
activity.
single agents to treat infections caused by gram-positive bacteria. How-
ever, in combination with a cell wall–active agent, such as a penicillin
or vancomycin, an aminoglycoside can produce a synergistic bacteri-
cidal effect in vitro. This effect has been most commonly employed for
treatment of infections due to staphylococci, enterococci, viridans group
streptococci, and Listeria. Clinically, the superiority of aminoglycoside
combination regimens over cell-wall agents alone is not proven except in
relatively few infections (discussed further in the chapter).
Resistance to the Aminoglycosides
Bacteria may be resistant to aminoglycosides through
• inactivation of the drug by microbial enzymes;
• failure of the antibiotic to penetrate intracellularly; and
• low affinity of the drug for the bacterial ribosome.

Blocks initiation
5′ 3′ of protein synthesis
Growing polypeptide

Blocks further
5′ 3′ translation and elicits
5′ 3′ premature termination

X
Incorporation of
aminoglycoside 5′ 3′ incorrect amino acid

Figure 58–2 Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by red circles) binds to the 30S ribosomal subunit and interferes
with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. As 30S-50S complexes downstream complete
translation of mRNA and detach; the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blocking further translation of the mes-
sage. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B, premature termination of translation with detachment of the
ribosomal complex and incompletely synthesized protein or C, incorporation of incorrect amino acids (indicated by the red X), resulting in the production of
abnormal or nonfunctional proteins.

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TABLE 58–1 ■ SUSCEPTIBILITY TO AMINOGLYCOSIDES AND TYPICAL MINIMAL CONCENTRATIONS THAT WILL INHIBIT
90% (MIC90) OF CLINICAL ISOLATES FOR SEVERAL SPECIES
SPECIES GENTAMICIN
Enterobacter spp. 97.0% (1)
Escherichia coli 88.2% (8)
Klebsiella pneumoniae 89.2% (8)
Pseudomonas aeruginosa 88.0% (16)
Serratia spp. 97.0% (1)
Acinetobacter baumanii 37.0% (>128)
Staphylococcus aureus 95.0% (0.5)
Source: Data from Sader HS, et al. Arbekacin activity against contemporary clinical bacteria isolated from patients hospitalized with pneumonia. Antimicrob Agents Chemother,
2015, 59:3263–3270.
Clinically, drug inactivation is the most common mechanism for
acquired microbial resistance. The genes encoding aminoglycoside-
modifying enzymes are acquired primarily by conjugation and transfer of
resistance plasmids (see Chapter 52). These enzymes phosphorylate, ade-
nylate, or acetylate specific hydroxyl or amino groups (see Figure 58–1).
The ability of these enzymes to attack these groups in differing amino-
glycosides explains some of the variability in antimicrobial activity
across the class. Amikacin is a suitable substrate for only a few of these
inactivating enzymes; thus, strains that are resistant to multiple other
aminoglycosides tend to be susceptible to amikacin, particularly amongst
gram-negative bacilli. A significant percentage of clinical isolates of
Enterococcus faecalis and Enterococcus faecium are highly resistant to all
aminoglycosides (Eliopoulos et al., 1984). Resistance to gentamicin indi-
cates cross-resistance to tobramycin, amikacin, kanamycin, and netilmi-
cin because the inactivating enzyme is bifunctional and can modify all
these aminoglycosides. Owing to differences in the chemical structures
between streptomycin and other aminoglycosides, the most common
enzyme seen in enterococci does not modify streptomycin, which is inac-
tivated by another enzyme. Consequently, gentamicin-resistant strains of
enterococci may be susceptible to streptomycin. Intrinsic resistance to
aminoglycosides may be caused by failure of the drug to penetrate the
cytoplasmic (inner) membrane. Transport of aminoglycosides across the
cytoplasmic membrane is an active process that depends on oxidative
metabolism. Strictly anaerobic bacteria thus are resistant to these drugs
because they lack the necessary transport system.
Missense mutations in Escherichia coli that substitute a single amino
acid in a crucial ribosomal protein may prevent binding of streptomycin.
Although highly resistant to streptomycin, these strains are not wide-
spread in nature. Similarly, 5% of strains of Pseudomonas aeruginosa
exhibit such ribosomal resistance to streptomycin. Because ribosomal
resistance usually is specific for streptomycin, enterococci with ribosomal
mutations typically remain sensitive to a combination of penicillin and
gentamicin in vitro.
ADME
Absorption
The aminoglycosides are polar cations and therefore are poorly absorbed
from the GI tract. Less than 1% of a dose is absorbed after either oral or
rectal administration. Nonetheless, long-term oral or rectal administra-
tion of aminoglycosides may result in accumulation to toxic concentra-
tions in patients with renal impairment. Absorption of gentamicin from
the GI tract may be increased by GI disease (e.g., ulcers or inflammatory
bowel disease). Instillation of these drugs into body cavities with serosal
Brunton_Ch58_p1039-p1048.indd 1041
1041
% SUSCEPTIBLE (MIC90 μg/mL)
SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES
TOBRAMYCIN AMIKACIN
96.0% (1) 100.0% (2)
86.3% (8) 99.0% (4)
82.4% (32) 88.2% (32)
90.0% (4) 98.0% (16)
94.0% (4) 99.0% (4)
51.0% (>128) 58.0% (>128)
76.0% (>128) 96.0% (8)
surfaces also may result in rapid absorption and unexpected toxicity
(i.e., neuromuscular blockade). Intoxication may occur when aminogly-
cosides are applied topically for long periods to large wounds, burns, or
cutaneous ulcers, particularly if there is renal insufficiency.
All the aminoglycosides are absorbed rapidly from intramuscular sites
of injection. Peak concentrations in plasma occur after 30–90 min. These
concentrations range from 4 to 12 μg/mL following a 1.5- to 2-mg/kg dose
of gentamicin, tobramycin, or netilmicin and from 20 to 35 μg/mL follow-
ing a 7.5-mg/kg dose of amikacin or kanamycin. There is increasing use
of aminoglycosides administered via inhalation, primarily for the man-
agement of patients with cystic fibrosis who have chronic P. aeruginosa
pulmonary infections (Geller et al., 2002). Amikacin and tobramycin solu-
tions for injection have been used, as well as a commercial formulation of
tobramycin designed for inhalation.
Distribution
Because of their polar nature, the aminoglycosides do not penetrate well
into most cells, the CNS, or the eye. Except for streptomycin, there is negli-
gible binding of aminoglycosides to plasma albumin. The apparent volume
of distribution of these drugs is 25% of lean body weight and approximates
the volume of extracellular fluid. The aminoglycosides distribute poorly
into adipose tissue, which must be considered when using weight-based
dosing regimens in obese patients.
Concentrations of aminoglycosides in secretions and tissues are low
(Panidis et al., 2005). High concentrations are found only in the renal
cortex and the endolymph and perilymph of the inner ear; the high
concentration in these sites likely contributes to the nephrotoxicity and
ototoxicity caused by these drugs. As a result of active hepatic secretion,
concentrations in bile approach 30% of those found in plasma, but this
represents a very minor excretory route for the aminoglycosides. Inflam-
mation increases the penetration of aminoglycosides into peritoneal and
pericardial cavities. Concentrations of aminoglycosides achieved in CSF
with parenteral administration usually are subtherapeutic (Kearney and
Aweeka, 1999). Treatment of meningitis with intravenous administration
is generally suboptimal. Intrathecal or intraventricular administration of
aminoglycosides has been used to achieve therapeutic levels in the CNS
but the availability of extended-spectrum cephalosporins has generally
made this unnecessary.
Administration of aminoglycosides to women late in pregnancy may
result in accumulation of drug in fetal plasma and amniotic fluid. Strepto-
mycin and tobramycin can cause hearing loss in children born to women
who receive the drug during pregnancy. Insufficient data are available
regarding the other aminoglycosides; therefore, these agents should be
used with caution during pregnancy and only for strong clinical indications
in the absence of suitable alternatives.
08/09/17 5:58 PM
 1042 Metabolism and Excretion
The aminoglycosides undergo minimal metabolism and are excreted
almost entirely by glomerular filtration, achieving urine concentrations
of 50–200 μg/mL. The half-lives of the aminoglycosides in plasma are
2–3 h in patients with normal renal function. Because the elimination
CHAPTER 58 AMINOGLYCOSIDES
of aminoglycosides depends almost entirely on the kidney, a linear rela-
tionship exists between the concentration of creatinine in plasma and
the t1/2 of all aminoglycosides in patients with moderately compromised
renal function. In anephric patients, the t1/2 varies from 20 to 40 times that
determined in normal individuals. Because the incidence of nephrotoxicity
and ototoxicity is likely related to the overall exposure to aminoglycosides, it
is critical to reduce the maintenance dose and dosing interval of these drugs
in patients with impaired renal function.
Although excretion of aminoglycosides is similar in adults and chil-
dren older than 6 months, half-lives of aminoglycosides may be prolonged
significantly in the newborn: 8–11 h in the first week of life in newborns
weighing less than 2 kg and about 5 h in those weighing more than 2 kg.
Thus, it is critically important to monitor plasma concentrations of amino-
glycosides during treatment of neonates. Aminoglycoside clearances are
increased and half-lives are reduced in patients with cystic fibrosis (Mann
et al., 1985). Larger doses of aminoglycosides may likewise be required in
burn patients because of more rapid drug clearance, possibly because of
drug loss through burn tissue. Aminoglycosides can be removed from the
body by either hemodialysis or peritoneal dialysis.
Aminoglycosides can be inactivated by various penicillins in vitro and
thus should not be admixed in solution (Blair et al., 1982). Some reports
indicate that this inactivation may occur in vivo in patients with end-stage
renal failure, making monitoring of aminoglycoside plasma concentrations
even more necessary in such patients. Amikacin appears to be the amino-
glycoside least affected by this interaction; penicillins with more nonrenal
elimination (such as piperacillin) may be less prone to cause this interaction.
Dosing and Monitoring
High-dose, extended-interval administration of aminoglycosides is the
preferred means of administering aminoglycosides for most indications
and patient populations. Administering higher doses at extended intervals
(i.e., once daily) is likely to be at least equally efficacious and potentially
less toxic than administration of divided doses. This dosing strategy takes
advantage of the concentration-dependent activity of aminoglycosides to
achieve maximal initial bacterial killing, and because of the postantibiotic
effect of aminoglycosides, good therapeutic response can be attained even
when concentrations fall below inhibitory concentrations for a substan-
tial fraction of the dosing interval. High-dose, extended-interval dosing
schemes for aminoglycosides may also reduce the characteristic oto- and
nephrotoxicity of these drugs. This diminished toxicity is probably due
to a threshold effect from accumulation of drug in the inner ear or in the
kidney. High-dose, extended-interval regimens, despite the higher peak
concentration, provide a longer period when concentrations fall below the
threshold for toxicity than does a multiple-dose regimen (compare the two
dosage regimens shown in Figure 58–3).
Populations in which use of the high-dose/extended-interval dosing
strategy is more controversial include pregnancy, neonates, and pediat-
rics and as combination therapy for endocarditis (Contopoulos-Ioannidis
et al., 2004; Knoderer et al., 2003; Nestaas et al., 2005; Ward and Theiler,
2008). In these infections, multiple daily doses (with a lower total daily
dose) may be preferred because data documenting equivalent safety and
efficacy of extended-interval dosing are limited. Extended-interval dosing
is also usually avoided in patients with significant renal dysfunction (i.e.,
creatinine clearance < 25 mL/min).
Concentrations of aminoglycosides achieved in plasma after a given
dose vary widely amongst patients, and therapeutic drug monitoring is
standard practice (Bartal et al., 2003). For twice- or thrice-daily dosing
regimens, both peak and trough plasma concentrations are determined.
The peak concentration documents that the dose produces therapeutic
concentrations, while the trough concentration is used to avoid toxicity.
Brunton_Ch58_p1039-p1048.indd 1042
35
30
25
CP (µg/mL)
20
15
10
5
Toxicity
threshold 0
0 8 16 24
Time (hours)
Figure 58–3 Comparison of single-dose and divided-dose regimens for gen-
tamicin. In a hypothetical patient, a dose of gentamicin (5.1 mg/kg) is admin-
istered intravenously as a single bolus (red line) or in three portions, a third
of the dose every 8 h (purple line), such that the total drug administered is
the same in the two cases. The threshold for toxicity (green dashed line) is the
plasma concentration of 2 μg/mL, the maximum recommended for prolonged
exposure. The single-dose regimen produces a higher plasma concentration
than the regimen given every 8 h; this higher peak provides efficacy that
otherwise might be compromised due to prolonged subthreshold concentra-
tions later in the dosing interval or that is provided by the lower peak levels
achieved with the regimen every 8 h. The once-daily regimen also provides a
13-h period during which plasma concentrations are below the threshold for
toxicity. The every-8-h regimen, by contrast, provides only three short (~1 h)
periods in 24 h during which plasma concentrations are below the threshold
for toxicity. The single high-dose, extended interval is generally preferred for
aminoglycosides, with a few exceptions (during pregnancy, in neonates, etc.),
as noted in the text.
Steady-state trough concentrations should be less than 1–2 μg/mL for
gentamicin, netilmicin, and tobramycin and less than 10 μg/mL for ami-
kacin and streptomycin. Peak level goals vary by indication and infection
severity, but range from 4 to 8 μg/mL with gentamicin, netilmicin, and
tobramycin and 20–35 μg/mL for amikacin. Monitoring of aminogly-
coside plasma concentrations also is important when using an extend-
ed-interval dosing regimen. For routine monitoring of extended-interval
dosing, a single random concentration obtained 6 to 14 h after the start
of the infusion can be obtained and plotted against a standard nomo-
gram to determine if dosage adjustment is required (Barclay et al., 1999).
However, the most accurate method for monitoring plasma levels for dose
adjustment is to measure the concentration in two plasma samples drawn
several hours apart (e.g., at 2 and 12 h after a dose). The clearance then
can be calculated and the dose adjusted to achieve the desired target range.
Therapeutic Uses of Aminoglycosides
Gentamicin, tobramycin, amikacin, and netilmicin can be used inter-
changeably for the treatment of most of the infections mentioned in this
section. For most indications, gentamicin is preferred because of long
experience with its use and its lower cost. Many different types of infec-
tions can be treated successfully with these aminoglycosides; however,
owing to their toxicities, prolonged use should be restricted to the therapy
of life-threatening infections and those for which a less-toxic agent is
contraindicated or less effective.
Aminoglycosides frequently are used in combination with a cell wall–
active agent (β-lactam or glycopeptide) for the therapy of serious proven or
suspected bacterial infections. The three rationales for this approach are
• to expand the empiric spectrum of activity of the antimicrobial regimen
• to provide synergistic bacterial killing
• to prevent the emergence of resistance to the individual agents
08/09/17 5:58 PM
 Combination therapy is used in infections such as healthcare-
associated pneumonia or sepsis, where multidrug-resistant gram-negative
organisms such as P. aeruginosa, Enterobacter, Klebsiella, and Serratia may
be causative and the consequences of failing to provide initially active
therapy are dire. The use of aminoglycosides to achieve synergistic bacte-
rial killing and improve clinical response is most well established for the
treatment of endocarditis due to gram-positive organisms, most impor-
tantly Enterococcus (Le and Bayer, 2003). Clinical data do not support
the use of combination therapy for synergistic killing of gram-negative
organisms, with the possible exceptions of serious P. aeruginosa infections.
Aminoglycosides (primarily streptomycin and amikacin) are occasionally
used in multidrug regimens for treatment of mycobacterial infections, in
part because of the need to suppress the emergence of resistant subpopu-
lations during therapy; data do not strongly support this practice for other
bacteria (Bliziotis et al., 2005).
Urinary Tract Infections
Although the spectrum of activity and concentration in the urinary tract
of aminoglycosides make them well-suited for treatment of urinary tract
infections, less-toxic alternatives are preferred for uncomplicated infec-
tions. However, as strains of E. coli have acquired resistance to β-lactams,
trimethoprim-sulfamethoxazole, and fluoroquinolones, use of aminogly-
cosides for urinary tract infections may increase. A single intramuscular
dose of gentamicin (5 mg/kg) has been effective in uncomplicated infec-
tions of the lower urinary tract. A 10- to 14-day course of gentamicin or
tobramycin is an alternative for treatment of pyelonephritis if other agents
cannot be used.
Pneumonia
The organisms that cause community-acquired pneumonia are susceptible to
broad-spectrum β-lactam antibiotics, macrolides, or a fluoroquinolone, and
usually it is not necessary to add an aminoglycoside. Aminoglycosides are
ineffective for the treatment of pneumonia due to anaerobes or Streptococcus
pneumoniae, which are common causes of community-acquired pneumo-
nia. In hospital-acquired pneumonia where aerobic multidrug-resistant
gram-negative bacilli are frequently causative pathogens, an aminoglycoside
in combination with a β-lactam antibiotic is recommended as standard
empiric therapy to increase the likelihood that at least one agent is active
against the infecting pathogen (American Thoracic Society, 2005). Once it
is established that the β-lactam is active against the causative agent, there is
generally no benefit from continuing the aminoglycoside.
Meningitis
Availability of third-generation cephalosporins, especially cefotaxime and
ceftriaxone, has reduced the need for treatment with aminoglycosides in
most cases of meningitis, except for infections caused by gram-negative
organisms resistant to β-lactam antibiotics (e.g., species of Pseudomonas
and Acinetobacter). If an aminoglycoside is necessary, direct instillation
into the CNS is more likely to achieve therapeutic levels than intravenous
administration. In adults, this can be achieved with 5 mg of a preservative-
free formulation of gentamicin (or equivalent dose of another aminogly-
coside) administered intrathecally or intraventricularly once daily.
Peritonitis
Patients who develop peritonitis as a result of peritoneal dialysis may be
treated with aminoglycoside diluted into the dialysis fluid to a concentra-
tion of 4–8 mg/L for gentamicin, netilmicin, or tobramycin or 6–12 mg/L
for amikacin. Intravenous or intramuscular administration of drug is
unnecessary because serum and peritoneal fluid will equilibrate rapidly.
Bacterial Endocarditis
“Synergistic” or low-dose gentamicin (3 mg/kg/d) in combination with a
penicillin or vancomycin has been recommended in certain circumstances
for treatment of bacterial endocarditis due to certain gram-positive organ-
isms. Penicillin and gentamicin in combination are effective as a short-
course (i.e., 2-week) regimen for uncomplicated native-valve streptococcal
Brunton_Ch58_p1039-p1048.indd 1043
endocarditis. For this indication, the administration of gentamicin may 1043
be given as a consolidated once-daily dose. In cases of enterococcal
endocarditis, concomitant administration of penicillin (or ampicillin)
and gentamicin (given as divided doses) for 4–6 weeks is recommended
as standard therapy. However, safer alternatives such as ampicillin/
SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES
ceftriaxone combinations or use of the aminoglycoside for only the first
2–3 weeks, are gaining favor to limit the risk of toxicity due to prolonged
aminoglycoside administration (Olaison and Schadewitz, 2002). A 2-week
regimen of gentamicin in combination with nafcillin is effective for the
treatment of selected cases of staphylococcal tricuspid native-valve endo-
carditis. For patients with native mitral or aortic valve staphylococcal
endocarditis, the risks of aminoglycoside administration likely outweigh
the benefits (Cosgrove et al., 2009).
Sepsis
Inclusion of an aminoglycoside in an empirical regimen is commonly
recommended for the febrile patient with neutropenia and for sepsis
when P. aeruginosa is a potential pathogen. However, studies using potent
broad-spectrum β-lactams (e.g., carbapenems and antipseudomonal
cephalosporins) have demonstrated no benefit from adding an amino-
glycoside to the regimen unless there is concern that an infection may
be caused by a multiple-drug-resistant organism (Paul et al., 2003). Thus,
local susceptibility patterns should be considered when weighing the risks
and benefits of adjunctive aminoglycoside administration for empiric
therapy in patients with sepsis.
Tularemia
Streptomycin (or gentamicin) is the drug of choice for the treatment of
tularemia. Most cases respond to the administration of 1–2 g (15–25 mg/kg)
streptomycin per day (in divided doses) for 10–14 days.
Plague
A 10-day treatment course of streptomycin or gentamicin is recommended
for severe forms of plague (Boulanger et al., 2004).
Mycobacterial Infections
Streptomycin is a second-line agent for the treatment of active tubercu-
losis, and streptomycin always should be used in combination with at
least one or two other drugs to which the causative strain is susceptible.
Amikacin is another alternative agent for infections due to drug-resistant
Mycobacterium tuberculosis or to other nontuberculous mycobacteria
(e.g., M. avium, M. abscessus, M. chelonae).
Cystic Fibrosis
Recurrent infections due to multidrug-resistant gram-negative bacilli,
especially Pseudomonas species, are a hallmark of cystic fibrosis. Amino-
glycosides are frequently used as therapy during acute exacerbations of
cystic fibrosis, for which higher-than-standard doses (e.g., 10 mg/kg of
tobramycin) are frequently employed due to the unusual pharmacok-
inetics observed in patients with cystic fibrosis. These agents may also
be administered via inhalation between exacerbations to improve lung
function and reduce exacerbation frequency.
Topical Applications
Aminoglycosides, especially neomycin and paromomycin, may be
employed as topical agents in skin and mucous membrane infections.
Oral administration of aminoglycosides may be employed as “bowel prep”
prior to surgical procedures or as “selective digestive decontamination” to
reduce the risk of ventilator-associated pneumonia.
Adverse Effects of Aminoglycosides
All aminoglycosides have the potential to produce reversible and irre-
versible vestibular, cochlear, and renal toxicity and neuromuscular
blockade.
08/09/17 5:58 PM
 1044 Ototoxicity
Vestibular and auditory dysfunction can follow the administration of
any of the aminoglycosides (Guthrie, 2008). Aminoglycoside-induced
ototoxicity may result in irreversible, bilateral, high-frequency hearing
loss or vestibular hypofunction. Degeneration of hair cells and neurons
CHAPTER 58 AMINOGLYCOSIDES
in the cochlea correlates with the loss of hearing. Accumulation within the
perilymph and endolymph occurs predominantly when aminoglycoside
concentrations in plasma are high. Diffusion back into the bloodstream
is slow; the half-lives of the aminoglycosides are five to six times longer
in the otic fluids than in plasma. Drugs such as ethacrynic acid and furo-
semide potentiate the ototoxic effects of the aminoglycosides in animals,
but data from humans implicating furosemide are less convincing (Smith
and Lietman, 1983).
Streptomycin and gentamicin produce predominantly vestibular effects,
whereas amikacin, kanamycin, and neomycin primarily affect auditory
function; tobramycin affects both equally. The incidence of ototoxicity is
difficult to determine. Audiometric data suggest that the incidence could
be as high as 25% (Brummett and Morrison, 1990). The incidence of ves-
tibular toxicity is particularly high in patients receiving streptomycin;
nearly 20% of individuals who received 500 mg twice daily for 4 weeks for
enterococcal endocarditis developed clinically detectable irreversible ves-
tibular damage. Because the initial symptoms may be reversible, patients
receiving high doses or prolonged courses of aminoglycosides should be
monitored carefully for ototoxicity; however, deafness may occur several
weeks after therapy is discontinued.
A high-pitched tinnitus often is the first symptom of cochlear toxicity.
If the drug is not discontinued, auditory impairment may develop after a
few days. The tinnitus may persist for several days to 2 weeks after ther-
apy is stopped. Because perception of sound in the high-frequency range
(outside the conversational range) is lost first, the affected individual is not
always aware of the difficulty, and it will not be detected except by careful
audiometric examination. If the hearing loss progresses, the lower sound
ranges are affected.
Amongst patients experiencing vestibular toxicity, moderately intense
headache lasting 1–2 days may precede the onset of labyrinthine dysfunction.
This is followed immediately by an acute stage in which nausea, vomiting,
and difficulty with equilibrium develop and persist for 1–2 weeks. Prominent
symptoms include vertigo in the upright position, inability to perceive
termination of movement (“mental past-pointing”), and difficulty in
sitting or standing without visual cues. The acute stage ends suddenly
and is followed by chronic labyrinthitis, in which the patient has difficulty
when attempting to walk or make sudden movements; ataxia is the most
prominent feature. The chronic phase persists for about 2 months. Recovery
from this phase may require 12–18 months, and most patients have some
permanent residual damage. Early discontinuation of the drug may permit
recovery before irreversible damage of the hair cells.
Nephrotoxicity
Approximately 8%–26% of patients who receive an aminoglycoside for
several days develop mild renal impairment that is almost always revers-
ible. The toxicity results from accumulation and retention of aminogly-
coside in the proximal tubular cells. The initial manifestation of damage at
this site is excretion of enzymes of the renal tubular brush border followed
by mild proteinuria and the appearance of hyaline and granular casts.
The glomerular filtration rate is reduced after several additional days. The
nonoliguric phase of renal insufficiency is thought to be due to the effects
of aminoglycosides on the distal portion of the nephron with a reduced
sensitivity of the collecting duct epithelium to vasopressin. Although
severe acute tubular necrosis may occur rarely, the most common sig-
nificant finding is a mild rise in plasma creatinine. The impairment in
renal function is almost always reversible because the proximal tubular
cells have the capacity to regenerate (Lietman and Smith, 1983). Toxicity
correlates with the total amount of drug administered and with longer
courses of therapy (de Jager and van Altena, 2002). High-dose, extend-
ed-interval dosing approaches lead to less nephrotoxicity at the same
level of total drug exposure (as measured by the area under the curve)
Brunton_Ch58_p1039-p1048.indd 1044
than divided-dose approaches (see Figure 58–3). Neomycin, which con-
centrates to the greatest degree, is highly nephrotoxic in human beings
and should not be administered systemically. Streptomycin does not con-
centrate in the renal cortex and is the least nephrotoxic. Drugs such as
amphotericin B, vancomycin, angiotensin-converting enzyme inhibitors,
cisplatin, and cyclosporine may potentiate aminoglycoside-induced neph-
rotoxicity (Wood et al., 1986).
Neuromuscular Blockade
Acute neuromuscular blockade and apnea have been attributed to the
aminoglycosides; patients with myasthenia gravis are particularly sus-
ceptible. The order of decreasing potency for blockade is neomycin,
kanamycin, amikacin, gentamicin, and tobramycin. In humans, neuro-
muscular blockade generally has occurred after intrapleural or intrap-
eritoneal instillation of large doses of an aminoglycoside; however, the
reaction can follow intravenous, intramuscular, and even oral admin-
istration of these agents. Most episodes have occurred in association
with anesthesia or the administration of other neuromuscular blocking
agents. Neuromuscular blockade may be reversed by intravenous admin-
istration of a Ca2+ salt.
Aminoglycosides may inhibit prejunctional release of acetylcholine
while also reducing postsynaptic sensitivity to the transmitter, but Ca2+
can overcome this effect, and the intravenous administration of a calcium
salt is the preferred treatment of this toxicity (Sarkar et al., 1992). Inhib-
itors of acetylcholinesterase (e.g., edrophonium and neostigmine) also
have been used with varying degrees of success.
Other Adverse Effects
In general, the aminoglycosides have little allergenic potential. Rare
hypersensitivity reactions—including skin rashes, eosinophilia, fever,
blood dyscrasias, angioedema, exfoliative dermatitis, stomatitis, and ana-
phylactic shock—have been reported as cross-hypersensitivity amongst
drugs in this class. Aminoglycosides appear to be less commonly associ-
ated with superinfection due to Clostridium difficile than other classes of
antibacterials.
Pharmacological Properties of Individual
Aminoglycosides
Gentamicin
Gentamicin is an important agent for the treatment of many serious
gram-negative bacillary infections. It is the aminoglycoside of first choice
because of its lower cost and reliable activity against all but the most
resistant gram-negative aerobes. Gentamicin preparations are available
for parenteral, ophthalmic, and topical administration. The typical rec-
ommended intramuscular or intravenous dose of gentamicin sulfate when
used for the treatment of known or suspected gram-negative organisms
as a single agent or in combination therapy for adults with normal renal
function is 5–7 mg/kg daily given over 30–60 min. For patients with
renal dysfunction, the interval may be extended. For patients who are
not candidates for extended-interval dosing, a loading dose of 2 mg/kg
and then 3–5 mg/kg per day, given as divided doses every 8–12 h, are
recommended. Dosages at the upper end of this range may be required to
achieve therapeutic levels for trauma or burn patients, those with septic
shock, patients with cystic fibrosis, and others in whom drug clearance is
more rapid or volume of distribution is larger than normal.
Several dosage schedules have been suggested for newborns and infants:
3 mg/kg once daily for preterm newborns less than 35 weeks of gesta-
tion; 4 mg/kg once daily for newborns more than 35 weeks of gestation;
5 mg/kg daily in two divided doses for neonates with severe infections;
and 2–2.5 mg/kg every 8 h for children up to 2 years of age. Peak plasma
concentrations range from 4 to 10 mg/mL (dosing: 1.7 mg/kg every 8 h)
and 16–24 mg/mL (extended-interval dosing: 5 mg/kg once daily).
It should be emphasized that the recommended doses of gentamicin
do not always yield desired concentrations. Periodic determinations of
08/09/17 5:58 PM
 the plasma concentration of aminoglycosides are recommended strongly.
Gentamicin is absorbed slowly when it is applied topically in an ointment
and somewhat more rapidly when it is applied as a cream. When the anti-
biotic is applied to large areas of denuded body surface, as may be the case
in burn patients, plasma concentrations can reach 4 μg/mL, and 2%–5%
of the drug may appear in the urine.
Tobramycin
The antimicrobial activity, pharmacokinetic properties, and toxicity pro-
file of tobramycin are similar to those of gentamicin. Tobramycin may be
given intramuscularly, intravenously, or by inhalation. Tobramycin also is
available in ophthalmic ointments and solutions. The superior activity of
tobramycin against P. aeruginosa makes it the preferred aminoglycoside
for treatment of serious infections known or suspected to be caused by this
organism, typically in combination with an antipseudomonal β-lactam
antibiotic. In contrast to gentamicin, tobramycin shows poor activity in
combination with penicillin against many strains of enterococci. Most
strains of E. faecium are highly resistant. Tobramycin is ineffective against
mycobacteria. Dosages and serum concentrations are identical to those
for gentamicin.
Amikacin
The spectrum of antimicrobial activity of amikacin is the broad-
est of the group. Because of its resistance to many of the aminogly-
coside-inactivating enzymes, amikacin has a special role for the initial
treatment of serious nosocomial gram-negative bacillary infections in
hospitals where resistance to gentamicin and tobramycin has become a
significant problem. Amikacin is active against most strains of Serratia,
Proteus, and P. aeruginosa as well as most strains of Klebsiella, Enterobac-
ter, and E. coli that are resistant to gentamicin and tobramycin. Most resis-
tance to amikacin is found amongst strains of Acinetobacter, Providencia,
and Flavobacterium and strains of Pseudomonas other than P. aeruginosa;
these all are unusual pathogens. Amikacin is less active than gentamicin
against enterococci and should not be used for this organism. Amikacin
is not active against the majority of gram-positive anaerobic bacteria. It
is active against M. tuberculosis, including streptomycin-resistant strains
and atypical mycobacteria.
The recommended dose of amikacin is 15 mg/kg/d as a single daily
dose or divided into two or three equal portions, which must be reduced
for patients with renal failure. The drug is absorbed rapidly after intra-
muscular injection, and peak concentrations in plasma approximate
20 μg/mL after injection of 7.5 mg/kg. The concentration 12 h after a
7.5-mg/kg dose is 5–10 μg/mL. A 15-mg/kg once-daily dose produces
peak concentrations of 50–60 μg/mL and a trough of less than 1 μg/mL.
For treatment of mycobacterial infections, thrice-weekly dosing sched-
ules are used, with doses up to 25 mg/kg (Peloquin et al., 2004). As with
the other aminoglycosides, amikacin causes ototoxicity, hearing loss, and
nephrotoxicity.
Netilmicin
Netilmicin (not marketed in the U.S.) is similar to gentamicin and
tobramycin in its pharmacokinetic properties and dosage (Panwalker
et al., 1978). Its antibacterial activity is broad against aerobic
gram-negative bacilli. Like amikacin, it is not metabolized by most of
the aminoglycoside-inactivating enzymes; thus, it may be active against
certain bacteria that are resistant to gentamicin (with the exception of
resistant enterococci). Netilmicin is useful for the treatment of serious
infections owing to susceptible Enterobacteriaceae and other aerobic
gram-negative bacilli. The recommended dose of netilmicin for com-
plicated urinary tract infections in adults is 1.5–2 mg/kg every 12 h.
For other serious systemic infections, a total daily dose of 4–7 mg/kg is
administered as a single dose or two to three divided doses. Children
should receive 3–7 mg/kg/d in two to three divided doses; neonates
receive 3.5–5 mg/kg/d as a single daily dose. The t1/2 for elimination
is usually 2–2.5 h in adults and increases with renal insufficiency.
Netilmicin may produce ototoxicity and nephrotoxicity.
Brunton_Ch58_p1039-p1048.indd 1045
Streptomycin 1045
Streptomycin is used for the treatment of certain unusual infections, gen-
erally in combination with other antimicrobial agents. It generally is less
active than other members of the class against aerobic gram-negative rods.
SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES
The combination of penicillin G (bacteriostatic against enterococci) and
streptomycin is effective as bactericidal therapy for enterococcal endo-
carditis, although gentamicin is generally preferred for its lesser toxicity.
Streptomycin should be used instead of gentamicin when the strain is
resistant to the latter and has demonstrable susceptibility to streptomycin,
which may occur because the enzymes that inactivate these two amino-
glycosides are different.
Streptomycin may be administered by deep intramuscular injec-
tion or intravenously. Intramuscular injection may be painful, with a
hot tender mass developing at the site of injection. The dose range of
streptomycin for most indications is 15–25 mg/kg daily or in divided
doses twice daily. During initial therapy for tuberculosis, it is frequently
administered as a 1000-mg single daily dose, resulting in peak serum
concentrations of about 50–60 and 15–30 μg/mL, and trough concentra-
tions of less than 1 and 5–10 μg/mL, respectively. The dosing frequency
may be reduced to two or three times a week after the initial phase of
tuberculosis treatment.
Streptomycin has been replaced by gentamicin for most indica-
tions because the toxicity of gentamicin is primarily renal and revers-
ible, whereas that of streptomycin is vestibular and irreversible. The
administration of streptomycin may produce dysfunction of the optic
nerve, including scotomas, presenting as enlargement of the blind spot.
Amongst the less-common toxic reactions to streptomycin is peripheral
neuritis.
Neomycin
Neomycin is a broad-spectrum antibiotic. Susceptible microorgan-
isms usually are inhibited by concentrations of 10 μg/mL or less.
Gram-negative species that are highly sensitive are E. coli, Enterobacter
aerogenes, Klebsiella pneumoniae, and Proteus vulgaris. Gram-positive
microorganisms that are inhibited include S. aureus and E. faecalis.
Mycobacterium tuberculosis also is sensitive to neomycin. Strains of
P. aeruginosa are resistant to neomycin. Neomycin sulfate is available
for topical and oral administration. Neomycin currently is available
in many brands of creams, ointments, and other products alone and
in combination with polymyxin, bacitracin, other antibiotics, and a
variety of corticosteroids.
Neomycin is used widely for topical application in a variety of infec-
tions of the skin and mucous membranes. The oral administration of
neomycin (usually in combination with erythromycin base) has been
employed primarily for “preparation” of the bowel for surgery. Orally
administered neomycin is poorly absorbed from the GI tract—about
97% of an oral dose of neomycin is not absorbed and is eliminated
unchanged in the feces. The portion that is absorbed is excreted by the
kidney; a total daily intake of 10 g for 3 days yields a blood concentration
below that associated with systemic toxicity if renal function is normal.
Neomycin and polymyxin B have been used for irrigation of the bladder
to prevent bacteriuria and bacteremia associated with indwelling cathe-
ters. For this purpose, 1 mL of a preparation containing 40 mg neomycin
and 200,000 units polymyxin B per milliliter is diluted in 1 L of 0.9%
sodium chloride solution and is used for continuous irrigation of the
urinary bladder through appropriate catheter systems. The bladder is
irrigated at the rate of 1 L every 24 h.
Hypersensitivity reactions, primarily skin rashes, occur in 6%–8% of
patients when neomycin is applied topically. The most important toxic
effects of neomycin are ototoxicity and nephrotoxicity; as a consequence,
the drug is no longer available for parenteral administration. Neuromus-
cular blockade with respiratory paralysis also has occurred after irriga-
tion of wounds or serosal cavities. Individuals treated with 4–6 g/d of the
drug by mouth sometimes develop a sprue-like syndrome with diarrhea,
steatorrhea, and azotorrhea. Overgrowth of yeasts in the intestine also
may occur.
08/09/17 5:58 PM
 1046 Paromomycin of intestinal cryptosporidiosis and giardiasis, which can be particularly
challenging to treat in immunocompromised patients. Orally admin-
Paromomycin (also known as aminosidine) is an aminoglycoside that
istered paromomycin is associated with dose-related gastrointestinal
is structurally related to neomycin. It has antibacterial activity simi-
toxicity, including nausea, abdominal pain, and diarrhea. A topical
lar to other aminoglycosides but has particularly notable antiparasitic
formulation is also used internationally for treatment of cutaneous leish-
activity. Parasites that are usually susceptible to paromomycin include
CHAPTER 58 AMINOGLYCOSIDES

maniasis (Ben Salah et al., 2013).

Leishmania spp., Entamoeba histolytica, Giardia lamblia, and Cryptospo-
ridium parvum. Internationally, the parenteral form is used as a treatment
of infections due to Leishmania spp. (visceral leishmaniasis), although
this formulation is not available in the U.S. (Sundar et al., 2007). Like
other aminoglycosides, it has poor systemic absorption when adminis-
tered orally; this characteristic is exploited to achieve high luminal con-
centrations in the treatment of intestinal parasitic diseases. It is available
as oral capsules and indicated for treatment of intestinal amebiasis at a
dose of 25–35 mg/kg/d in three divided doses. It is also used for treatment
Kanamycin
Kanamycin is amongst the most toxic aminoglycosides, and there are few
indications for its use. Its primary remaining indication is for treatment of
extensively drug-resistant tuberculosis; even in this condition, less-toxic
alternatives are generally preferred.
Acknowledgment: Henry F. Chambers contributed to this chapter in recent
editions of this book. We have retained some of his text in the current edition.

Drug Facts for Your Personal Formulary: Aminoglycosides

Drug Therapeutic Uses Clinical Pharmacology and Tips
Aminoglycosides—Inhibitors of Bacterial Protein Synthesis
General: Bactericidal, no GI absorption (<1%), oral administration used only for bowel decontamination or intestinal parasites, poor
CSF penetration, renal elimination, nephrotoxicity, ototoxicity (cochlear and vestibular), neuromuscular blockade
Gentamicin (IV) • UTI • Good activity vs. Enterobacteriaceae, Pseudomonas
• Peritonitis • Some activity vs. Neisseria, Haemophilus,
• Endocarditis in combination with a cell-wall Moraxella
active agent • Synergistic activity when combined with a cell-wall
• Plague agent against many organisms
• Tularemia • Vestibular > cochlear toxicity
• Toxicity primarily renal and reversible
Tobramycin (IV, inhalation) • UTI • Similar to gentamicin, with better activity against
• Lung infections, including cystic fibrosis Pseudomonas aeruginosa
exacerbations • Cochlear ≈ vestibular toxicity
• Nosocomial sepsis of unknown origin
Amikacin (IV) • UTI • Similar to tobramycin, with activity against
• Lung infections, including cystic fibrosis some gram-negative bacilli resistant to other
exacerbations aminoglycosides
• Nosocomial sepsis of unknown origin • Activity against a variety of mycobacteria
• Mycobacterial infections • Cochlear > vestibular toxicity
Streptomycin (IV) • Endocarditis in combination with a cell-wall • Similar to gentamicin, with activity against some
active agent gentamicin-resistant enterococci
• Tuberculosis • Activity against Mycobacterium tuberculosis
• Plague • Vestibular > cochlear toxicity
• Tularemia • Vestibular toxicity is irreversible
Neomycin (PO, topical; urologic irrigation) • Minor skin infections • Similar activity to gentamicin but only used topically,
• Bowel preparation prior to intra-abdominal surgery not systemically
• Bladder irrigation • Can cause skin rash
Paromomycin (PO, IM, topical) • Cryptosporidia infection • Diarrhea, nausea, vomiting
• Intestinal amebiasis • IM use for visceral leishmaniasis
• Leishmaniasis • Topical use for cutaneous leishmaniasis

Blair DC, et al. Inactivation of amikacin and gentamicin by carbenicillin

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