AMINOGLYCOSIDES

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Nacional Autonoma de Mexico UNAM
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Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14e
Chapter 59: Miscellaneous Antibacterials: Aminoglycosides, Polymyxins, Urinary
Antiseptics, Bacteriophages
AMINOGLYCOSIDES
ORIGINS
Aminoglycosides are natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes. Streptomycin was
first isolated from a strain of Streptomyces griseus. Gentamicin 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 aminoglycoside 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 and
plazomicin (derivatives of sisomicin) are semisynthetic products.
Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin, plazomicin, kanamycin, streptomycin, paromomycin, and neomycin) are used
primarily to treat infections caused by aerobic gramnegative bacteria. Streptomycin and amikacin are important agents for the treatment of
mycobacterial infections, and paromomycin is used orally for intestinal amebiasis. Aminoglycosides are bactericidal inhibitors of protein synthesis.
Most commonly, resistance is due to aminoglycosidemodifying enzymes or impaired accumulation of drug at the target site; these mechanisms may
confer resistance to all aminoglycosides or only select agents. Resistance genes are frequently acquired via plasmids or transposons.
Aminoglycosides contain amino sugars linked to an aminocyclitol ring by glycosidic bonds (Figure 59–1). 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, although the relative propensities for toxicity vary somewhat among the agents.
Figure 59–1
Aminoglycoside structure and sites of activity of plasmidmediated 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. AC, acetylase; AD, adenylase.
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Figure 59–1
Universidad Nacional Autonoma de Mexico UNAM
Aminoglycoside structure and sites of activity of plasmidmediated enzymes capable of inactivating aminoglycosides. Tobramycin is shown as a
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representative; structural characteristics protect some aminoglycosides from the actions of some of these enzymes, explaining differences in spectrum
of activity. AC, acetylase; AD, adenylase.
Mechanism of Action
The aminoglycoside antibiotics are rapidly bactericidal against susceptible gramnegative organisms. Bacterial killing is concentration dependent: The
higher the concentration, the greater is the rate of bacterial killing. The ratio of the peak concentration to the organism’s MIC is thus a driver of
aminoglycoside efficacy, although total drug exposure (AUC:MIC) is also an important predictor of antibacterial effect (Bland et al., 2018). The
inhibitory activity of aminoglycosides persists after the serum concentration has fallen below the MIC, a phenomenon known as the postantibiotic
effect. These properties help to explain the efficacy of highdose, extendedinterval dosing regimens.
Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of gramnegative bacteria to enter the
periplasmic space. Transport of aminoglycosides across the cytoplasmic (inner) membrane depends on a transmembrane electrical gradient coupled
to electron transport to drive permeation of these antibiotics. This energydependent 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 aminoglycosides 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 of
mRNA translation (Figure 59–2). 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 streptomycinbinding 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).
Figure 59–2
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 30S50S ribosomal complex at the start codon (AUG) of mRNA. As 30S50S complexes downstream complete
translation of mRNA and detach; the abnormal initiation complexes, socalled streptomycin monosomes, accumulate, blocking further translation of
the message. 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.
translation of mRNA and detach; the abnormal initiation complexes, socalled streptomycin monosomes, accumulate, blocking further translation of
the message. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B, premature termination of translation with
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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.
Antimicrobial Activity
The antibacterial activity of gentamicin, tobramycin, amikacin, and plazomicin is directed primarily against aerobic gramnegative bacilli (Mingeot
Leclercq et al., 1999). Kanamycin, like streptomycin, has a more limited spectrum. The aerobic gramnegative bacilli vary in their susceptibility to the
aminoglycosides (Table 59–1), although most Enterobacterales are susceptible. The superior activity of tobramycin against Pseudomonas aeruginosa
makes it the preferred aminoglycoside for treatment of serious infections known or suspected to be caused by this organism. Among other
nonfermenting gramnegative rods such as Acinetobacter, Stenotrophomonas, and Burkholderia, aminoglycosides are uncommonly to rarely active.
Gramnegative aerobic cocci such as Neisseria, Moraxella, and Haemophilus have varying susceptibilities. An increasing number of gramnegative
bacilli encountered in healthcare settings (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. Amikacin and plazomicin are typically the most
active aminoglycosides against multidrugresistant gramnegative bacilli.
TABLE 59–1
SUSCEPTIBILITIES AND TYPICAL MINIMAL CONCENTRATIONS THAT WILL INHIBIT 90% (MIC9 0) OF CLINICAL ISOLATES FOR GRAMNEGATIVE
ORGANISMS
% SUSCEPTIBLE (MIC9 0 μg/mL)
SPECIES GENTAMICIN TOBRAMYCIN AMIKACIN POLYMYXIN B NITROFURANTOIN FOSFOMYCIN
Escherichia coli 88.2% (8) 86.3% (8) 99.0% (4) N/A (<=0.5) 90.3% (32) 99.6% (4)
Klebsiella spp 89.2% (8) 82.4% (32) 88.2% (32) N/A (<=0.5) 9.0% (128) N/A (32)
Enterobacter spp. 97.0% (1) 96.0% (1) 100.0% (2) N/T 11.4% (128) N/A (32)
Pseudomonas aeruginosa 88.0% (16) 90.0% (4) 98.0% (16) N/A (1) N/T N/A (128)
Serratia spp. 97.0% (1) 94.0% (4) 99.0% (4) N/T N/T N/T
Acinetobacter baumanii 37.0% (>128) 51.0% (>128) 58.0% (>128) N/A (<=0.5) N/T N/T
N/A: not applicable; N/T: not tested. 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; Gales AC, et al. Contemporary activity of colistin and polymyxin B against a worldwide
collection of Gramnegative pathogens: results from the SENTRY Antimicrobial Surveillance Program (20062009). J Antimicrob Chemother, 2011, 66:20702074;
Keepers TR, et al. Fosfomycin and comparator activity against select Enterobacteriaceae, Pseudomonas, and Enterococcus urinary tract infection isolates from the
United States in 2012. Infect Dis Ther, 2017, 6:233243.
Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions. Their action against most
grampositive bacteria is limited, and they should not be used as single agents to treat infections caused by grampositive bacteria. However, in
AMINOGLYCOSIDES, Conan MacDougall; Robert T. Schooley Page
combination with a cell wall–active agent, such as a penicillin or vancomycin, an aminoglycoside may produce a synergistic bactericidal effect 3 / 10
in vitro.
This effect has been most commonly employed for treatment of infections due to staphylococci, enterococci, viridans group streptococci, and Listeria.
Gentamicin (or in some cases streptomycin) is the drug of choice for use in combination therapies against grampositive organisms, since other agents
with pneumonia. Antimicrob Agents Chemother, 2015, 59:3263–3270; Gales AC, et al. Contemporary activity of colistin and polymyxin B against a worldwide
collection of Gramnegative pathogens: results from the SENTRY Antimicrobial Surveillance Program (20062009). J Antimicrob Chemother, 2011, 66:20702074;
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Keepers TR, et al. Fosfomycin and comparator activity against select Enterobacteriaceae, Pseudomonas, and Enterococcus urinary tract infection isolates from the
United States in 2012. Infect Dis Ther, 2017, 6:233243.
Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions. Their action against most
grampositive bacteria is limited, and they should not be used as single agents to treat infections caused by grampositive bacteria. However, in
combination with a cell wall–active agent, such as a penicillin or vancomycin, an aminoglycoside may produce a synergistic bactericidal effect in vitro.
This effect has been most commonly employed for treatment of infections due to staphylococci, enterococci, viridans group streptococci, and Listeria.
Gentamicin (or in some cases streptomycin) is the drug of choice for use in combination therapies against grampositive organisms, since other agents
such as tobramycin and amikacin are minimally active. Clinically, the superiority of aminoglycoside combination regimens over cell wall agents alone is
not proven except in relatively few infections (discussed later in the chapter).
Paromomycin (also known as aminosidine) is an aminoglycoside that is structurally related to neomycin. It has antibacterial activity similar to other
aminoglycosides but has particularly notable antiparasitic activity. Parasites that are usually susceptible to paromomycin include Leishmania spp.,
Entamoeba histolytica, Giardia lamblia, and Cryptosporidium parvum.
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.
Clinically, drug inactivation is the most common mechanism for acquired microbial resistance. The genes encoding aminoglycosidemodifying
enzymes are acquired primarily by conjugation and transfer of resistance plasmids. These enzymes phosphorylate, adenylate, or acetylate specific
hydroxyl or amino groups (see Figure 59–1). The ability of these enzymes to attack these groups in differing aminoglycosides 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 among gramnegative bacilli. Plazomicin likewise has
structural modifications that make it a poor substrate for most aminoglycosidemodifying enzymes, expanding its activity against resistant gram
negatives, including among carbapenemresistant isolates. 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 in these organisms indicates crossresistance to
tobramycin, amikacin, kanamycin, and netilmicin 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 inactivated by another enzyme. Consequently, gentamicinresistant 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.
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, longterm oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations 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 surfaces also may result in rapid absorption and unexpected toxicity (i.e., neuromuscular
blockade). Intoxication may occur when aminoglycosides 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 to 90 min. These
concentrations range from 4 to 12 μg/mL following a 1.5 to 2mg/kg dose of gentamicin, tobramycin, or netilmicin; from 20 to 35 μg/mL following a
7.5mg/kg dose of amikacin or kanamycin; and from 100 to 150 μg/mL following a 15mg/kg dose of plazomicin. There is increasing use of
aminoglycosides administered via inhalation, primarily for the management of patients with cystic fibrosis who have chronic P. aeruginosa or
mycobacterial pulmonary infections (Geller et al., 2002). Amikacin and tobramycin solutions for injection have been used, and commercially available
preparations of these agents designed specifically for inhalation are now available. Neomycin is not used for parenteral administration; it is currently
available in many brands of creams, ointments, and other products alone and in combination with polymyxin, bacitracin, other antibiotics, a variety of
corticosteroids, and lidocaine. Paromomycin is available for parenteral use outside of the United States but is primarily used for its intraluminal
activity as a poorly absorbed antiparasitic agent.
All the aminoglycosides are absorbed rapidly from intramuscular sites of injection. Peak concentrations in plasma occur after 30 to 90 min. These
concentrations range from 4 to 12 μg/mL following a 1.5 to 2mg/kg dose of gentamicin, tobramycin , or netilmicin; from 20 to 35 μg/mL following a
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7.5mg/kg dose of amikacin or kanamycin; and from 100 to 150 μg/mL following a 15mg/kg dose of plazomicin. There is increasing use of
aminoglycosides administered via inhalation, primarily for the management of patients with cystic fibrosis who have chronic P. aeruginosa or
mycobacterial pulmonary infections (Geller et al., 2002). Amikacin and tobramycin solutions for injection have been used, and commercially available
preparations of these agents designed specifically for inhalation are now available. Neomycin is not used for parenteral administration; it is currently
available in many brands of creams, ointments, and other products alone and in combination with polymyxin, bacitracin, other antibiotics, a variety of
corticosteroids, and lidocaine. Paromomycin is available for parenteral use outside of the United States but is primarily used for its intraluminal
activity as a poorly absorbed antiparasitic agent.
Distribution
Because of their polar nature, the aminoglycosides do not penetrate well into many tissues. Except for streptomycin, there is negligible 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 weightbased 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. Inflammation 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), and owing
to their doserelated toxicity, dose increases to provide greater concentrations are not feasible. 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 extendedspectrum 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. Streptomycin
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.
Metabolism and Excretion
The aminoglycosides undergo minimal metabolism and are excreted almost entirely by glomerular filtration, achieving urine concentrations of 50 to
200 μg/mL. The halflives of the aminoglycosides in plasma are 2 to 3 h in patients with normal renal function. Because the elimination of
aminoglycosides depends almost entirely on the kidney, a linear relationship 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/or extend the dosing interval of these drugs in patients with impaired renal function.
Although excretion of aminoglycosides is similar in adults and children older than 6 months, halflives of aminoglycosides may be prolonged
significantly in the newborn: 8 to 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 aminoglycosides during treatment of neonates. Aminoglycoside clearances are increased
and halflives are reduced in patients with cystic fibrosis (Young et al., 2013). 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 endstage renal failure, making monitoring of aminoglycoside plasma concentrations even
more necessary in such patients. Amikacin appears to be the aminoglycoside least affected by this interaction; penicillins with more nonrenal
elimination (e.g., piperacillin) may be less prone to cause this interaction.
Dosing and Monitoring
Highdose, extendedinterval 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 concentrationdependent 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 substantial fraction of the dosing interval. Highdose, extendedinterval dosing
schemes for aminoglycosides may also reduce the characteristic oto and nephrotoxicity of these drugs. This diminished toxicity is probably due to a
elimination (e.g., piperacillin) may be less prone to cause this interaction.
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Dosing and Monitoring
Highdose, extendedinterval 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 concentrationdependent 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 substantial fraction of the dosing interval. Highdose, extendedinterval 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. Highdose, extendedinterval regimens, despite the higher peak
concentration, provide a longer period when concentrations fall below the threshold for toxicity than does a multipledose regimen (compare the two
dosage regimens shown in Figure 59–3). Typical doses for highdose, extendedinterval strategies are 5 to 7 mg/kg for gentamicin and tobramycin, 15
to 25 mg/kg for amikacin, and 15 mg/kg for plazomicin; among patients with normal renal function, these doses are administered every 24 h.
Figure 59–3
Comparison of singledose and divideddose regimens for gentamicin. In a hypothetical patient, a dose of gentamicin (5.1 mg/kg) is administered
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 singledose 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 concentrations later in the dosing interval or that is provided by the
lower peak levels achieved with the regimen every 8 h. The oncedaily regimen also provides a 13h period during which plasma concentrations are
below the threshold for toxicity. The every8h 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 highdose, extended interval is generally preferred for aminoglycosides, with a few
exceptions (during pregnancy, in neonates, etc.), as noted in the text.
Populations in which use of the highdose/extendedinterval dosing strategy is more controversial include pregnant patients, neonates, and pediatric
patients and as combination therapy for endocarditis (ContopoulosIoannidis et al., 2004; Nestaas et al., 2005; Ward and Theiler, 2008). In these
infections, multiple daily doses (with a lower total daily dose) are preferred by some clinicians since data documenting equivalent safety and efficacy of
extendedinterval dosing are more limited than in other adult populations. Extendedinterval dosing is sometimes avoided in patients with significant
renal dysfunction (i.e., creatinine clearance <25 mL/min), since every36h or every48h dosing schedules are often required. Typical doses for
divideddosing strategies are 1.7 to 2 mg/kg every 8 h for gentamicin and tobramycin. The dose range of streptomycin for most indications is 15 to 25
mg/kg daily or in divided doses twice daily. For longterm therapy of mycobacterial infections, threetimesweekly dosing of amikacin or streptomycin
may be employed.
Concentrations of aminoglycosides achieved in plasma after a given dose vary widely among patients, and therapeutic drug monitoring is standard
practice, especially among seriously ill patients (AbdulAziz et al., 2020). Traditionally, the peak concentration has been used to document that the
dose produces therapeutic concentrations, while the trough concentration is used to avoid toxicity. For highdose, extendedinterval dosing regimens,
fully characterizing the pharmacokinetics can be done through drawing peak and “midpoint” (6–18 h after the end of infusion) concentrations and
calculating the predicted AUC (Bland et al., 2018). Alternatively, use of “random” concentrations obtained 6 to 18 h after infusion with comparison to a
AMINOGLYCOSIDES, Conan MacDougall; Robert T. Schooley
published nomogram is a lessintensive monitoring approach. For plazomicin, the manufacturer recommends obtaining trough concentrations, with
Page 6 / 10
dosage adjustment as necessary to maintain a trough below 3 μg/mL. For twicedaily and threetimesdaily dosing strategies, steadystate trough
concentrations should be less than 1 to 2 μg/mL for gentamicin, netilmicin, and tobramycin and less than 10 μg/mL for amikacin and streptomycin.
may be employed.
Concentrations of aminoglycosides achieved in plasma after a given dose vary widely among patients, and therapeutic drug monitoring is standard
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practice, especially among seriously ill patients (AbdulAziz et al., 2020). Traditionally, the peak concentration has been used to document that the
dose produces therapeutic concentrations, while the trough concentration is used to avoid toxicity. For highdose, extendedinterval dosing regimens,
fully characterizing the pharmacokinetics can be done through drawing peak and “midpoint” (6–18 h after the end of infusion) concentrations and
calculating the predicted AUC (Bland et al., 2018). Alternatively, use of “random” concentrations obtained 6 to 18 h after infusion with comparison to a
published nomogram is a lessintensive monitoring approach. For plazomicin, the manufacturer recommends obtaining trough concentrations, with
dosage adjustment as necessary to maintain a trough below 3 μg/mL. For twicedaily and threetimesdaily dosing strategies, steadystate trough
concentrations should be less than 1 to 2 μg/mL for gentamicin, netilmicin, and tobramycin and less than 10 μg/mL for amikacin and streptomycin.
Peak level goals vary by indication and infection severity but range from 4 to 8 μg/mL for gentamicin, netilmicin, and tobramycin and from 20 to 35
μg/mL for amikacin under twicedaily and threetimesdaily strategies. When gentamicin is used at lower doses for synergistic effects with cell wall–
acting agents to treat grampositive infections, peak levels of 3 to 4 μg/mL and less than 1 μg/mL are recommended.
Therapeutic Uses
Several different types of infections can be treated successfully with aminoglycosides; however, owing to their toxicities, prolonged use should be
restricted to the therapy of lifethreatening infections and those for which a lesstoxic agent is contraindicated or less effective. When multiple
aminoglycosides are appropriate for an indication, gentamicin is typically preferred because of long experience with its use and its lower cost.
Aminoglycosides may be used in combination with a cell wall–active agent (βlactam or glycopeptide) for the therapy of serious proven or suspected
bacterial infections. The three rationales for this approach are as follows:
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
Empiric combination therapy is used in infections such as healthcareassociated pneumonia or sepsis, where multidrugresistant gramnegative
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 bacterial killing and improve clinical response is most well established for the
treatment of endocarditis due to grampositive organisms, most importantly Enterococcus (Le and Bayer, 2003). Clinical data do not support the
routine use of combination therapy for synergistic killing or suppression of emergent resistance of gramnegative organisms, with the possible
exceptions of serious P. aeruginosa infections (Bliziotis et al., 2005). Aminoglycosides (primarily streptomycin and amikacin) may be a component of
combination regimens for treatment of mycobacterial infections, usually due to the presence of multidrug resistance (see Chapter 65).
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, lesstoxic alternatives are preferred for uncomplicated infections. However, as strains of Escherichia coli have acquired resistance to β
lactams, trimethoprimsulfamethoxazole, and fluoroquinolones, use of aminoglycosides for urinary tract infections may increase. A single
intramuscular dose of gentamicin (5 mg/kg) has been effective in uncomplicated infections of the lower urinary tract. A 10 to 14day course of
gentamicin or tobramycin is an alternative for treatment of pyelonephritis if other agents cannot be used. Plazomicin is FDAapproved for treatment of
complicated urinary tract infections including pyelonephritis when patients have limited or no treatment options, at a dose of 15 mg/kg daily.
Pneumonia
Aminoglycosides are ineffective for the treatment of pneumonia due to Streptococcus pneumoniae, which is a common cause of communityacquired
pneumonia. In hospitalacquired pneumonia where aerobic multidrugresistant gramnegative bacilli are frequently causative pathogens, an
aminoglycoside in combination with a βlactam antibiotic is recommended as standard empiric therapy to increase the likelihood that at least one
agent is active against the infecting pathogen (Kalil et al., 2016). Once it is established that the βlactam is active against the causative agent, there is
generally no benefit from continuing the aminoglycoside.
Meningitis
Availability of thirdgeneration cephalosporins, especially cefotaxime and ceftriaxone, has reduced the need for treatment with aminoglycosides in
most cases of meningitis, except for infections caused by gramnegative organisms resistant to βlactam antibiotics (e.g., species of Pseudomonas and
Acinetobacter) and for Listeria meningitis (where a combination of ampicillin and gentamicin is recommended). 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
preservativefree formulation of gentamicin (or equivalent dose of another aminoglycoside) administered intrathecally or intraventricularly once daily.
Bacterial Endocarditis
generally no benefit from continuing the aminoglycoside.
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Meningitis
Availability of thirdgeneration cephalosporins, especially cefotaxime and ceftriaxone, has reduced the need for treatment with aminoglycosides in
most cases of meningitis, except for infections caused by gramnegative organisms resistant to βlactam antibiotics (e.g., species of Pseudomonas and
Acinetobacter) and for Listeria meningitis (where a combination of ampicillin and gentamicin is recommended). 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
preservativefree formulation of gentamicin (or equivalent dose of another aminoglycoside) administered intrathecally or intraventricularly once daily.
Bacterial Endocarditis
“Synergistic” or lowdose gentamicin (3 mg/kg per day) in combination with a penicillin or vancomycin has been recommended in certain
circumstances for treatment of bacterial endocarditis due to certain grampositive organisms. Penicillin and gentamicin in combination are effective as
a shortcourse (i.e., 2week) regimen for uncomplicated nativevalve streptococcal endocarditis. For this indication, gentamicin may be given as a
consolidated oncedaily dose. In cases of enterococcal endocarditis, concomitant administration of penicillin (or ampicillin) and gentamicin (given as
divided doses) for 4 to 6 weeks is recommended as standard therapy. However, safer alternatives, such as ampicillin/ceftriaxone combinations or use
of the aminoglycoside for only the first 2 to 3 weeks, are gaining favor to limit the risk of toxicity due to prolonged aminoglycoside administration
(Baddour et al., 2015). A 2week regimen of gentamicin in combination with nafcillin is effective for the treatment of selected cases of staphylococcal
tricuspid nativevalve endocarditis. For patients with native mitral or aortic valve staphylococcal endocarditis, the risks of aminoglycoside
administration likely outweigh the benefits (Cosgrove et al., 2009).
Tularemia
Streptomycin (or gentamicin) is the drug of choice for the treatment of tularemia. Most cases respond to the administration of 1 to 2 g (15–25 mg/kg)
streptomycin per day (in divided doses) for 10 to 14 days.
Plague
A 10day treatment course of streptomycin or gentamicin is recommended for severe forms of plague.
Mycobacterial Infections
Amikacin and streptomycin are secondline agents for the treatment of active tuberculosis as part of a combination regimen, usually employed if the
patient’s organism is resistant to standard therapy. Amikacin is also used as a component of combination regimens for nontuberculous mycobacteria
(e.g., M. avium, M. abscessus, M. chelonae). See Chapter 65 for more about the use of these agents in treating tuberculosis and M. avium complex.
Parasitic Infections
Paromomycin’s antiparasitic activity is leveraged to treat intestinal protozoal infections due to E. histolytica, G. lamblia, and C. parvum. It is available as
oral capsules and indicated for treatment of intestinal amebiasis at a dose of 25 to 35 mg/kg per day in three divided doses. The drug also has activity
against Leishmania spp., and is used parenterally for visceral leishmaniasis and topically for cutaneous leishmaniasis, although these formulations are
not available in the United States (Ben Salah et al., 2013).
Cystic Fibrosis
Recurrent infections due to multidrugresistant gramnegative bacilli, especially Pseudomonas species, are a hallmark of cystic fibrosis.
Aminoglycosides are frequently used as therapy during acute exacerbations of cystic fibrosis, for which higherthanstandard doses (e.g., 10 mg/kg of
tobramycin) are frequently employed due to the unusual pharmacokinetics 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
Neomycin is used widely for topical application in a variety of infections 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 catheters. For this purpose, 1 mL of a preparation containing 40 mg
AMINOGLYCOSIDES, Conan MacDougall; Robert T. Schooley neomycin and 200,000 units polymyxin B
Page 8 / 10
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.
Neomycin is used widely for topical application in a variety of infections 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
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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 catheters. 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.
Neomycin is frequently employed as a topical agent for treatment of skin and mucous membrane infections, including as a component of overthe
counter therapies. Oral administration of aminoglycosides may be employed as “bowel prep” prior to surgical procedures or as “selective digestive
decontamination” to reduce the risk of ventilatorassociated pneumonia.
Adverse Effects
All aminoglycosides have the potential to produce reversible and irreversible vestibular, cochlear, and renal toxicity and neuromuscular blockade.
Ototoxicity
Vestibular and auditory dysfunction can follow the administration of any of the aminoglycosides (Guthrie, 2008). Aminoglycosideinduced ototoxicity
may result in irreversible, bilateral, highfrequency hearing loss or vestibular hypofunction. Degeneration of hair cells and neurons 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 halflives of the aminoglycosides are five to six times longer in the otic fluids than in
plasma. Drugs such as ethacrynic acid and furosemide 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 vestibular 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 vestibular 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 highpitched 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 therapy is stopped. Because perception of sound in the highfrequency 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.
Among patients experiencing vestibular toxicity, moderately intense headache lasting 1 to 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 to 2 weeks.
Prominent symptoms include vertigo in the upright position, inability to perceive termination of movement (“mental pastpointing”), 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 to 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% to 26% of patients who receive an aminoglycoside for several days develop mild renal impairment that is almost always reversible.
The toxicity results from accumulation and retention of aminoglycoside 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 significant 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). Highdose, extendedinterval dosing approaches
lead to less nephrotoxicity at the same level of total drug exposure (as measured by the area under the curve) than divideddose approaches (see
Figure 59–3). Neomycin, which concentrates to the greatest degree, is highly nephrotoxic in human beings and should not be administeredPage 9 / 10
AMINOGLYCOSIDES, Conan MacDougall; Robert T. Schooley
systemically. Streptomycin does not concentrate in the renal cortex and is the least nephrotoxic. Drugs such as amphotericin B, vancomycin,
angiotensinconverting enzyme inhibitors, cisplatin, and cyclosporine may potentiate aminoglycosideinduced nephrotoxicity.
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
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tubular necrosis may occur rarely, the most common significant 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). Highdose, extendedinterval dosing approaches
lead to less nephrotoxicity at the same level of total drug exposure (as measured by the area under the curve) than divideddose approaches (see
Figure 59–3). Neomycin, which concentrates to the greatest degree, is highly nephrotoxic in human beings and should not be administered
systemically. Streptomycin does not concentrate in the renal cortex and is the least nephrotoxic. Drugs such as amphotericin B, vancomycin,
angiotensinconverting enzyme inhibitors, cisplatin, and cyclosporine may potentiate aminoglycosideinduced nephrotoxicity.
Neuromuscular Blockade
Acute neuromuscular blockade and apnea have been attributed to the aminoglycosides; patients with myasthenia gravis are particularly susceptible. In
humans, neuromuscular blockade generally has occurred after intrapleural or intraperitoneal instillation of large doses of an aminoglycoside;
however, the reaction can follow intravenous, intramuscular, and even oral administration 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
administration of a Ca2+ salt.
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 anaphylactic shock—have been reported as crosshypersensitivity among drugs in this
class. Aminoglycosides appear to be less commonly associated with superinfection due to Clostridium difficile than other classes of antibacterials.
Individuals treated with 4 to 6 g/day of neomycin by mouth sometimes develop a spruelike syndrome with diarrhea, steatorrhea, and azotorrhea;
overgrowth of yeasts in the intestine also may occur. Orally administered paromomycin is associated with doserelated gastrointestinal toxicity,
including nausea, abdominal pain, and diarrhea.

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SPECIES GENTAMICIN TOBRAMYCIN AMIKACIN POLYMYXIN B NITROFURANTOIN FOSFOMYCIN

Escherichia coli 88.2% (8) 86.3% (8) 99.0% (4) N/A (<=0.5) 90.3% (32) 99.6% (4)

Klebsiella spp 89.2% (8) 82.4% (32) 88.2% (32) N/A (<=0.5) 9.0% (128) N/A (32)

Enterobacter spp. 97.0% (1) 96.0% (1) 100.0% (2) N/T 11.4% (128) N/A (32)

Pseudomonas aeruginosa 88.0% (16) 90.0% (4) 98.0% (16) N/A (1) N/T N/A (128)

Serratia spp. 97.0% (1) 94.0% (4) 99.0% (4) N/T N/T N/T

Acinetobacter baumanii 37.0% (>128) 51.0% (>128) 58.0% (>128) N/A (<=0.5) N/T N/T

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