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Dawn Merton Boothe

, DVM, PhD, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

Last full review/revision Nov 2015 | Content last modified Nov 2015
Topic Resources

Aminoglycosides are mostly bactericidal drugs that share chemical, antimicrobial, pharmacologic, and toxic characteristics.


Narrow-spectrum Aminoglycosides:

Included in this group are streptomycin and dihydrostreptomycin, which are mainly active against aerobic, gram-negative bacteria.

Expanded-spectrum Aminoglycosides:

Neomycin, framycetin (neomycin B), paromomycin (aminosidine), and kanamycin have broader spectra than streptomycin that includes many gram-negative aerobic bacteria, as well as synergistic activity toward selected gram-positive organisms. Gentamicin, tobramycin, amikacin (synthesized from kanamycin), sisomicin, and netilmicin are aminoglycosides with extended spectra that include Pseudomonas aeruginosa.

Miscellaneous Aminoglycoside Antibiotics:

The chemical structure of apramycin differs somewhat from that of the typical aminoglycosides but is similar enough to be included in this class. The structure of spectinomycin is unusual, but it is fairly comparable to other aminocyclitols with regard to its mechanism of action and antibacterial spectrum.

General Properties

Chemically, the aminoglycoside antibiotics are characterized by an aminocyclitol group, with aminosugars attached to the aminocyclitol ring in glycosidic linkage. Because of minor differences in the position of substitutions on the molecules, there may be several forms of a single aminoglycoside. For example, gentamicin is a complex of gentamicins C1 and C2, and neomycin is a mixture of neomycins B and C and fradiomycin. The amino groups contribute to the basic nature of this class of antibiotics, and the hydroxyl groups on the sugar moieties contribute to high aqueous solubility and poor lipid solubility. If these hydroxyl groups are removed (eg, tobramycin), antibiotic activity is markedly increased. Differences in the substitutions on the basic ring structures within the various aminoglycosides account for the relatively minor differences in antimicrobial spectra, patterns of resistance, and toxicities. Aminoglycosides are typically quite stable. When the water solubility of an aminoglycoside is marginal, it is usually the sulfate salt that is used for PO or parenteral administration. The pKas of these drugs are generally between 8 and 10, and as a result, they tend to be ionized at physiologic pH, which may limit drug movement, particularly in acidic environments.

Antimicrobial Activity

Mode of Action:

Aminoglycosides are more effective against rapidly multiplying organisms, and they affect and ultimately destroy bacteria by several mechanisms. They need only a short contact with bacteria to kill them and, as such, are concentration dependent in their actions. Their main site of action is the membrane-associated bacterial ribosome through which they interfere with protein synthesis. To reach the ribosome, they must first cross the lipopolysaccharide (LPS) covering (gram-negative organisms), the bacterial cell wall, and finally the cell membrane. Because of the polarity of these compounds, a specialized active transport process is required.

The first concentration-dependent step requires binding of the cationic aminoglycoside to anionic components in the cell membrane. The subsequent steps are energy dependent and involve the transport of the polar, highly charged cationic aminoglycoside across the cytoplasmic membrane, followed by interaction with the ribosomes. The driving force for this transfer is probably the membrane potential. These processes are much more efficient if the energy used is aerobically generated. The efficacy of the aminoglycosides is markedly curtailed in an anaerobic environment. Aminoglycosides are associated with a postantibiotic effect in a number of bacteria, principally gram-negative (eg, E coli, Klebsiella pneumoniae, P aeruginosa). The effect generally lasts 2–8 hr after exposure and allows for dosing intervals longer than the half-lives of the drugs.

Several features of these mechanisms are of clinical significance: 1) The antibacterial activity of the aminoglycosides depends on an effective concentration of antibiotic outside the cell. 2) Anaerobic bacteria and induced mutants are generally resistant, because they lack appropriate transport systems. 3) With low oxygen tension, as in hypoxic tissues, transfer into bacteria is diminished. 4) Divalent cations (eg, calcium and magnesium) located in the LPS, cell wall, or membrane can interfere with transport into bacteria because they can combine with the specific anionic sites and exclude the cationic aminoglycosides. 5) Passive movement of aminoglycosides across bacterial cell membranes is facilitated by an alkaline pH; a low pH may increase membrane resistance more than 100-fold. 6) Changes in osmolality also can alter the uptake of aminoglycosides. 7) Some aminoglycosides are transported more efficiently than others and thus tend to have greater antibacterial activity. 8) Synergism is common when aminoglycosides and β-lactam antibiotics (penicillins and cephalosporins) are used in combination. The cell-wall injury induced by the β-lactam compounds allows increased uptake of the aminoglycoside by the bacteria because of easier accessibility to the bacterial cell membrane.

The intracellular site of action of the aminoglycosides is the ribosome, which is irreversibly bound by aminoglycosides, particularly at the 30 S but also the 50 S subunits (which comprise the 70 S subunit). Variability occurs between aminoglycosides with respect to their affinity and degree of binding. The number of steps in protein synthesis that are affected also varies. Spectinomycin cannot induce misreading of the mRNA and often is not bactericidal, in contrast to the other bactericidal members. However, at low concentrations, all aminoglycosides may be only bacteriostatic.

A cell-membrane effect also occurs with aminoglycosides. The functional integrity of the bacterial cell membrane is lost during the late phase of the transport process, and high concentrations of aminoglycosides may cause nonspecific membrane toxicity, even to the point of bacterial cell lysis.

Efficacy of aminoglycosides is enhanced if peak plasma or tissue drug concentrations exceed MIC by 10–12 times. Once-daily dosing has been used to enhance both efficacy and safety.

Bacterial Resistance:

Several mechanisms of resistance to the aminoglycoside antibiotics have been described. These may be plasmid or chromosomally mediated.

Impaired transport across the cell membrane is an inherent mechanism of nonplasmid-mediated resistance that occurs in anaerobic bacteria (eg, Bacteroides fragilis and Clostridium perfringens), because the transport process is active and oxygen-dependent. Facultative anaerobes (eg, enterobacteria and Staphylococcus aureus) are more resistant to the aminoglycosides when in an anaerobic environment. Impaired transport can be induced by exposure to sublethal concentrations of these antibiotics. Examples include streptomycin resistance among strains of P aeruginosa, low-level aminoglycoside resistance among enterococci, and gentamicin resistance in Streptococcus faecalis.

Impaired ribosomal binding may not be a clinically important form of single-step resistance, because generally the drugs bind to multiple sites on the ribosomes. Exceptions include E coli strains in which a single-step mutation prevents the binding of streptomycin to the ribosome. The same mechanism has been described in P aeruginosa.

Enzymatic modification of aminoglycosides may be either plasmid-encoded or chromosomally mediated. Enzymes occur in both gram-negative and gram-positive bacteria. More than 50 enzymes have been identified, with three major types, each including several subclasses: acetylating enzymes (acetyltransferases), adenylating enzymes (nucleotidyltransferases), and phosphorylating enzymes (phosphotransferases). The susceptibility of each aminoglycoside to specific enzymatic attack varies among each subclass. Although cross-resistance is common, there are differences in susceptibility patterns. Chemical modification stabilizes the drug, which decreases susceptibility to enzymatic destruction. For example, chemically modified kanamycin yields amikacin, which is more resistant to enzymatic hydrolysis.

Other mechanisms of resistance include 1) increased concentration of divalent cations (especially Ca2+ and Mg2+), which act to repel ionized drug from the microbe, and 2) increased production by P aeruginosa mutants of the outer cell membrane protein, H1, resulting in resistance to gentamicin. Note that efficacy will be reduced in the presence of decreased pH (eg, acidic urine or abscesses), which increases resistance to relatively high concentrations of aminoglycosides.

Antibacterial Spectra:

Streptomycin and dihydrostreptomycin (no longer available in the USA) are characterized by narrow spectra, and efficacy is limited by bacterial resistance. Gram-negative bacilli are still susceptible, including strains of Actinomyces bovis, Pasteurella spp, E coli, Salmonella spp, Campylobacter fetus, Leptospira spp, and Brucella spp. Mycobacterium tuberculosis is also sensitive to streptomycin.

The spectra of neomycin, framycetin, and kanamycin are broader, with clinical use targeting gram-negative organisms, including E coli and Salmonella, Klebsiella, Enterobacter, Proteus, and Acinetobacter spp. Aminoglycosides with spectra that include Pseudomonas aeruginosa (gentamicin, tobramycin, amikacin, sisomicin, and netilmicin) are also often highly effective against a wide variety of aerobic bacteria. Because of their efficacy against P aeruginosa, aminoglycosides might be considered higher-tier drugs. Selected staphylococci are susceptible, but treatment should be based on synergistic effects, ie, combination with other antimicrobials (eg, β-lactams). With such combination therapy, generally low doses of aminoglycosides are used. Because oxygen is necessary for active transport of drug into the microbe, caution is recommended when treating facultative anaerobes in a low-oxygen environment. Obligate anaerobic bacteria and fungi are not appreciably affected; streptococci are usually only moderately sensitive or quite resistant.

Pharmacokinetic Features

The pharmacokinetic features of the aminoglycosides are similar in most species.


Aminoglycosides are poorly absorbed (usually <10%) from the healthy GI tract. However, permeability may be increased in the neonate and in the presence of enteritis and other pathologic changes, allowing absorption to be significantly greater. In the presence of renal failure, toxic (trough) concentrations may accumulate. Aminoglycosides can be administered slowly by bolus IV injection or SC or IM routes. Absorption from IM injection sites is rapid and nearly complete (>90% availability), except in severely hypotensive animals. Blood concentrations usually peak within 30–90 min after IM administration. Absorption after SC injection may be protracted. Absorption after IP administration can be rapid and substantial. Short dosing intervals, including continuous infusions, are contraindicated for all aminoglycosides. Once-daily therapy is indicated for safety considerations. Serum concentrations of aminoglycosides may reach bactericidal levels after repeated intrauterine infusion, particularly in endometritis.


Aminoglycosides are polar at physiologic pH, limiting distribution to extracellular fluids, with minimal penetration into most tissues. Exceptions include the renal cortex of the kidneys and the endolymph of the inner ear, sites at which aminoglycosides increasingly accumulate as ionization increases. The extracellular fluid compartment normally approximates 25% of body weight, but this volume can change substantially, which leads to indirectly proportional changes in the concentration of an aminoglycoside. For example, extracellular fluid space contracts with dehydration and during gram-negative sepsis, causing concentrations to increase, whereas the distribution volume of aminoglycosides increases with congestive heart failure or ascites, causing concentrations to decrease. Concentrations tend to be lower in neonates, which have a large extracellular fluid compartment relative to body weight. Aminoglycosides are not appreciably bound to plasma proteins (usually <20%). Therapeutic concentrations (~10 times the MIC of the infecting microbe) can be achieved in the synovial, pleural, and even peritoneal fluids, especially if inflammation is present. However, effective concentrations are not reached in CSF, ocular fluids, milk, intestinal fluids, or prostatic secretions. Fetal tissue and amniotic fluid concentrations are very low in most species.

Biotransformation, Excretion, and Pharmacokinetic Values:

The aminoglycosides are excreted unchanged in the urine by glomerular filtration, with 80%–90% of administered drug recoverable from the urine within 24 hr of IM administration. A variable fraction of filtered aminoglycoside is absorbed onto the brush border of the proximal tubule and loop of Henle cells. Binding is facilitated by ionization. After binding, the drug is transported into the cell, sequestered in lysosomes. Rupture of lysozymes results in release into the cytosol. Excessive accumulation (mainly in the renal cortex) leads to a characteristic tubular cell necrosis. Glomerular filtration rates differ between species and are often less in neonates, which may explain the greater sensitivity to aminoglycosides in newborn foals and puppies.

Elimination varies with glomerular filtration changes associated with cardiovascular and renal function, age, fever, and several other factors. Half-life also will vary directly and proportionately with the volume of the extracellular fluid compartment. The aminoglycosides have relatively short plasma half-lives (~1 hr in carnivores and 2–3 hr in herbivores). The elimination kinetics often follow a three-compartment model, indicating a “deep” compartment that reflects binding of drug in the renal tubular cell. Approximately 90% of the injected drug, including that within therapeutic concentrations, is excreted unchanged through the kidneys during the β phase of elimination. The remaining deep or γ phase is excreted over a protracted period, probably due to the gradual release of the antibiotic from renal intracellular binding sites (terminal elimination half-life often 20–200 hr). Concentrations in plasma during this phase are generally below what would be considered therapeutic. The limited selection of pharmacokinetic values for two typical aminoglycosides (see Table: Elimination, Distribution, and Clearance of Aminoglycosides Elimination, Distribution, and Clearance of Aminoglycosides Aminoglycosides are mostly bactericidal drugs that share chemical, antimicrobial, pharmacologic, and toxic characteristics. Included in this group are streptomycin and dihydrostreptomycin, which... read more ) serves as a basis for any required dosage modifications that may be necessary because of age or renal insufficiency. The best way to alter a dosage regimen of aminoglycosides is to monitor plasma concentrations to assure that 10 times the MIC is achieved at peak concentrations, and concentrations less than target (generally <2 mcg/mL) are achieved before the next dose ("trough" concentrations).


Therapeutic Indications and Dose Rates

Despite their potential to cause nephrotoxicity, the aminoglycosides are commonly used to control local and systemic infections caused by susceptible aerobic bacteria (generally gram-negative). Several aminoglycosides are used topically in the ears and eyes and via intrauterine infusion to treat endometritis. Aminoglycosides occasionally may be infused into the udder to treat mastitis. In general, because of their concentration dependency and potential for nephrotoxicity, aminoglycosides are administered once daily (same total daily dose; "high" dose), thus minimizing the risk of nephrotoxicity. If used at lower doses for synergistic activity against gram-positive organisms, such as staphylococci, lower doses (30%–50% of the higher dose) might be given at more frequent intervals.


If monitoring, two time points (a peak and a second sample 4 hr later) is ideal such that an extrapolated peak concentration can be determined, along with an elimination half-life. The peak should be collected after distribution into tissues is complete, or ~1 hr. The "trough" in this scenario should be collected 2–3 half-lives later (eg, 4–6 hr after dosing) such that concentrations will still be detectable. If a single sample is collected to determine safety, a trough concentration (just before the next dose) is indicated. Trough concentrations generally should be <2 mcg/mL. For efficacy, a 1.5–2 hr peak concentration might be collected; peak concentrations should be 10–12 times the MIC of the infecting organism. For renal function, both a peak and detectable trough (taken well before the next dose, because concentrations may not otherwise be detectable) are indicated so that a half-life, and, if IV administration is used, clearance might be calculated. As a precaution, the following general guidelines may be followed in cases of renal failure in which plasma creatinine values are increased (see Table: Dosage Modifications of Aminoglycosides in Renal Failure Dosage Modifications of Aminoglycosides in Renal Failure Aminoglycosides are mostly bactericidal drugs that share chemical, antimicrobial, pharmacologic, and toxic characteristics. Included in this group are streptomycin and dihydrostreptomycin, which... read more ).


The treatment interval should be increased in neonates (especially puppies and foals), in renal failure, and in obese animals. Doses may be increased in neonates or pediatric animals, in which the volume of distribution is greater than in adults, and in animals with edema, hydrothorax, or ascites, provided their renal function is unimpaired.

Special Clinical Concerns

Adverse Effects and Toxicity:

Ototoxicity, neuromuscular blockade, and nephrotoxicity are reported most frequently; these effects may vary with the aminoglycoside and dose or interval used, but all members of the group are potentially toxic. Nephrotoxicity is of major concern and may result in renal failure due to acute tubular necrosis with secondary interstitial damage. Aminoglycosides accumulate in proximal tubular epithelial cells, where they are sequestered in lysosomes and interact with ribosomes, mitochondria, and other intracellular constituents to cause cell injury. The greater the ionization (eg, the more the amine groups and the lower the pH), the greater the active uptake. Kidneys must have a drug-free period to eliminate accumulated drugs. As such, persistence of aminoglycosides in plasma and thus urine is likely to predispose the tubular cells to toxicity, and the risk may by reduced by allowing plasma drug concentrations to drop below recommended concentrations (generally 1–2 mcg/mL) before the next dose. Nonoliguric renal failure is the usual observation; it is generally reversible if damage is not sufficiently extensive to harm the basement membrane, although recovery may be prolonged.

Renal function should be monitored during therapy; however, no indicator of renal disease is sufficiently sensitive to prevent continued damage once nephrotoxicity is detected. Polyuria, decreased urine osmolality, enzymuria, proteinuria, cylindruria, and increased fractional sodium excretion are indicative of aminoglycoside nephrotoxicity. Later, BUN and creatinine concentrations may be increased. Early changes or evidence of nephrotoxicity can be detected in 3–5 days, with more overt signs in 7–10 days. Several factors predispose to aminoglycoside nephrotoxicosis, including age (with young [especially the newborn foal] and old animals being sensitive), compromised renal function, total dose, duration of treatment, dehydration and hypovolemia, aciduria, acidosis, hypomagnesemia, severe sepsis or endotoxemia, concurrent administration of furosemide, and exposure to other potential nephrotoxins (eg, methoxyflurane, amphotericin B, cisplatinum, and perhaps some cephalosporins). In renal insufficiency, generally the interval between doses is prolonged (rather than reducing the dose) to minimize toxicity, while avoiding a negative impact on efficacy. Dosing in the morning may decrease toxicity in diurnal animals. The risk of toxicity is less in alkaline urine. Nephroactive drugs, including those that alter renal vascular response (eg, autoregulation) should be avoided or used cautiously (eg, NSAIDs, diuretics). Treatment with N-acetylcysteine should be considered (see ototoxicity, below).

Aminoglycosides can cause ototoxicity, which may manifest as either auditory or vestibular dysfunction. Binding or damage to mitochondria plays a prominent role in ototoxicity. Vestibular injury leads to nystagmus, incoordination, and loss of the righting reflex. The lesion is often irreversible, although physiologic adaptation can occur. Ototoxicity is not unusual in people, but relevance to veterinary patients is not clear. Cats are particularly sensitive to the toxic vestibular effects, although occurrence at therapeutic concentrations after systemic administration is unlikely. However, aminoglycosides should not be administered topically into the ear unless the tympanic membrane is intact. Hearing impairment reflects permanent damage and loss of the hair cells in the organ of Corti. Loss of high-frequency hearing is followed by deafness, which may not be complete if sufficiently low doses or durations were used. Aminoglycosides should be avoided in working dogs that depend on hearing (eg, guide dogs). Factors increasing the risk of vestibular and cochlear damage are the same as for nephrotoxicity but also include preexisting acoustic or vestibular impairment and concurrent treatment with potentially ototoxic drugs. The ototoxic potential is greatest for gentamicin, sisomicin, and neomycin, and least for netilmicin. In people, treatment with N-acetylcysteine has deceased the risk of aminoglycoside ototoxicity.

All aminoglycosides, when administered in doses that result in high plasma concentrations, have been associated with muscle weakness and respiratory arrest attributable to neuromuscular blockade. The effect is more pronounced when aminoglycosides are used with other drugs that cause neuromuscular blockade and with gas anesthetics. Neomycin, kanamycin, amikacin, gentamicin, and tobramycin are listed in order of most to least potent for these neuromuscular effects. The effect is due to the chelation of calcium and competitive inhibition of the prejunctional release of acetylcholine in most instances (there are some differences among aminoglycosides). The blockade is antagonized by calcium gluconate and somewhat less consistently by neostigmine.

CNS disturbances rarely include convulsions or collapse after rapid IV administration. Other adverse effects include superinfection when used topically or PO, a malabsorption syndrome due to attenuation of intestinal villous function when used PO in neonates, occasional hypersensitivity reactions, contact dermatitis, cardiovascular depression, and inhibition of some WBC functions (eg, neutrophil migration and chemotaxis and even bactericidal activity at high concentrations).


Enhanced nephrotoxicity may become evident with concurrent administration of aminoglycosides and other potentially nephroactive (such as diuretics) or nephrotoxic (such as NSAIDs) agents. Neuromuscular blockade is more likely when aminoglycosides are administered at the same time as skeletal muscle relaxants and gas anesthetics. Aminoglycoside ototoxicity is enhanced by the loop-acting diuretics, especially furosemide. Cardiovascular depression may be aggravated by aminoglycosides when administered to animals under halothane anesthesia. High concentrations of carbenicillin, ticarcillin, and piperacillin inactivate aminoglycosides because of direct interactions both in vitro and in vivo in the presence of renal failure. Synergistic interactions that enhance antibacterial efficacy have been documented when aminoglycosides are administered with other antimicrobials, particularly β-lactams.

Effects on Laboratory Tests:

BUN, serum creatinine, serum transaminases, and alkaline phosphatase values may be increased. Proteinuria is a significant laboratory finding.

Drug Withdrawal and Milk Discard Times:

Note that withdrawal times do not exist for drugs not approved for used in food animals. Regulatory requirements for withdrawal times for food animals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health implications. The times listed serve only as general guidelines (see Table: Drug Withdrawal and Milk Discard Times of Aminoglycosides Drug Withdrawal and Milk Discard Times of Aminoglycosides Aminoglycosides are mostly bactericidal drugs that share chemical, antimicrobial, pharmacologic, and toxic characteristics. Included in this group are streptomycin and dihydrostreptomycin, which... read more ).


Miscellaneous Aminocyclitol Antibiotics

Apramycin (administered orally) is used to control enteric gram-negative infections, particularly E coli and salmonellae in calves and piglets. It also is active against Proteus, Klebsiella, Brachyspira, and Mycoplasma spp. There is little cross-resistance within the aminoglycosides, and plasmid-mediated resistance is yet to be confirmed. Apramycin is poorly absorbed after administration PO (<10%). It is rapidly absorbed from parenteral injection sites. Plasma concentrations peak within 1–2 hr of IM administration. Apramycin distributes only into the extracellular fluid and is excreted unchanged in the urine (95% within 4 days). The elimination half-life in calves is ~4–5 hr. Apramycin is toxic in cats but considered safe in most other species (3–6 times the recommended oral dose rarely produces toxicity). The oral dose rate is 20–40 mg/kg/day, for 5 days. The parenteral dose rate is 20 mg/kg, bid. The withdrawal time in pigs and calves (in Europe) is 28 days after oral use.

The structure of spectinomycin differs from that of the aminoglycosides, but it also binds to bacterial ribosomes and interferes with protein synthesis. However, the effect is bacteriostatic rather than bactericidal. Spectinomycin can be inactivated by an enzyme coded for by an R factor, but mutant resistance due to diminished ribosomal binding is perhaps more common. It is active against several strains of streptococci, a wide range of gram-negative bacteria, and Mycoplasma spp; most Chlamydia spp are resistant. It is poorly absorbed from the GI tract but is rapidly absorbed after IM administration, with blood concentrations peaking within 1 hr. Like aminoglycosides, spectinomycin penetrates tissues rather poorly and distributes principally into extracellular fluid. Metabolic transformation of spectinomycin is limited, and 80% can be recovered unchanged in the urine over 24–48 hr; ~75% is eliminated by glomerular filtration in ~4 hr. At usual doses, no major toxic reactions have been reported. It is administered both PO at 20 mg/kg, bid, and IM at 5–10 mg/kg, bid. Withdrawal time for pigs is usually ~3 wk.

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