Aminoglycoside Antibiotics

Aminoglycoside Antibiotics

Mark G. Papich and Jim E. Riviere

Aminoglycoside antibiotics have been used in veterinary and human medicine for many years and have retained their importance for treating serious and routine infections. They are particularly valuable for treating infections caused by gram-negative bacilli, including bacteria that may be resistant to other agents. Their therapeutic importance derives from the rapid bactericidal effects, pharmacokinetics derived from a large variety of animal species, and relatively low rate of resistance. These advantages must be weighed against their potentially toxicity, requirement for administration by injection for systemic use, and high potential to produce chemical residues in food-producing animals.

Pharmacology of Aminoglycosides

General Properties

Aminoglycosides include the familiar drugs gentamicin, amikacin, kanamycin, and tobramycin. They also include less familiar drugs such as neomycin, dihydrostreptomycin, and paromomycin. Spectinomycin has been included with aminoglycosides in some textbooks, but we have instead included it with the miscellaneous antibiotics in Chapter 36. Aminoglycosides are a class of antimicrobial compounds produced from strains of Streptomyces spp. or Micromonospora spp. fungi. Those produced from Streptomyces are spelled with “mycin” and those produced from Micromonospora are spelled with “micin”. Chemically, they are aminocyclitols: hydroxyl and amino or guanidine substituted cyclohexane with amino sugars joined by glycosidic linkages to one or more of the hydroxyl groups. These molecules have excellent solubility in water but poor lipid solubility, and are thermodynamically stable over a wide range of pH values and temperatures (Lancini and Parenti, 1982; Leitner and Price, 1982; Nagabhusban et al., 1982; Pechere and Dugal, 1979). They are large molecules with molecular weights ranging from 450 to 585. The aminoglycosides are basic polycations with pKa values that range from 7.2 to 8.8 (Ziv and Sulman, 1974; Katzung, 1984; Prescott and Baggot, 1988).

The chemical structure of gentamicin is shown in Figure 35.1. A search for gentamicin reveals several products that have been identified (e.g., gentamicin C1, C2, C1A, A2, and A3). The commercially available form contains a complex of gentamicin C1, C2, and C1A as sulfate salts in a mixture. The proportion of each compound in a gentamicin complex can vary among commercial products. The other commonly used aminoglycosides are shown in Figure 35.2 Amikacin is a semisynthetic form synthesized from kanamycin to increase antimicrobial activity. The various mechanisms of nephrotoxicity (binding to proximal tubule brush-border vesicles and phospholipids, inhibition of mitochondrial function, etc.) may be associated with the number of free amino groups on the aminoglycoside molecule. In general, the most ionized aminoglycosides (i.e., neomycin, with six groups) are more toxic and show greater binding affinity than the least ionized aminoglycosides of the class (i.e., streptomycin, with three groups) (Bendirdjian et al., 1982; Cronin, 1979; Feldman et al., 1981; Humes et al., 1982; Just and Habermann, 1977; Kunin, 1970; Lipsky and Lietman, 1982; Luft and Evan, 1980a, 1980b; Weinberg et al., 1980). Other structural characteristics may account for differences in toxicity within groups of drugs with similar total ionization potentials (i.e., netilmicin, tobramycin, amikacin, and gentamicin, all with five ionizable groups).

Image described by caption and surrounding text

Figure 35.1 Structures of gentamicin.

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Figure 35.2 Structure of kanamycin, streptomycin, tobramycin, neomycin, and amikacin.

Mechanism of Action

Aminoglycosides exert their antibacterial action by irreversibly binding to one or more receptor proteins on the 30S subunit of the bacterial ribosome and thereby interfering with several mechanisms in the mRNA translation process. These include disrupting an initiation complex between the mRNA and the 30S subunit, blocking further translation and thereby causing premature chain termination, or causing incorporation of an incorrect amino acid in the protein product. Although most antimicrobials that interfere with ribosomal protein synthesis are bacteriostatic, aminoglycosides are bactericidal. Because of irreversible binding, significant postantibiotic effects can be observed.

The mechanism of bacterial penetration by the aminoglycoside through the cell membrane is biphasic. Aminoglycosides diffuse through the outer membrane of gram-negative bacteria through aqueous channels formed by the porin proteins. Once in the periplasmic space, an oxygen-requiring process transports the drug into the cell, where it interacts with the ribosome. Anaerobic bacteria are therefore resistant to the antibacterial effects of aminoglycosides. The oxygen-dependent transport is linked to an electron transport system, which causes the bacterial cytoplasm to be negatively charged with respect to the periplasm and external environment.

An additional mechanism is independent of ribosomal binding. These agents are positively charged by virtue of their amino groups (Figures 35.1 and 35.2). These agents disrupt the cell surface biofilm, particularly on gram-negative bacteria, to produce disruption, loss of cell wall integrity, and a rapid bactericidal effect. Magnesium and calcium are important to cross-bridge adjacent lipopolysaccharide molecules. Aminoglycosides competitively displace Ca++ and Mg++ and destabilize the bacteria outer membrane. Therefore, rapid death of the bacteria can be caused by a cell surface effect rather than inhibition of the ribosome. This helps explain the concentration-dependent effect and rapid bactericidal action that is a feature of aminoglycosides. This property is not as prominent for gram-positive bacteria unless administered with a cell-wall disrupting agent such as vancomycin or a β-lactam antibiotic.

The positively charged aminoglycosides also affect the accumulation in bacteria. Because of the positive charge, they are attracted electrostatically into the bacterial cytoplasm. Some divalent cations (such as Ca++ and Mg++) are competitive inhibitors of this transport system. This proton-motive force also functions in the lysosomes and mitochondria in which aminoglycosides accumulate and may also be a factor in the intralysosomal accumulation of the aminoglycosides.

A characteristic of aminoglycoside activity is that bacterial killing is concentration-dependent, and a postantibiotic effect (PAE) is evident. The PAE is a persistent suppression of bacterial growth following the removal of an antimicrobial agent. Bactericidal action persists after serum concentrations fall below minimum inhibitory concentrations (MICs). This has ramifications for the design of clinical dosage regimens.

Spectrum of Activity

Aminoglycosides are effective against most gram-negative bacteria, including gram-negative bacteria of the Enterobacteriaceae and Pseudomonas aeruginosa. They are effective against staphylococci, although resistance can occur if used as monotherapy. Their action against streptococci and enterococci is limited unless they are combined with a β-lactam antibiotic. They have poor activity against Pasteurella multocida. Anaerobic bacteria are inherently resistant because drug transport into bacteria is oxygen dependent. Breakpoints for susceptibility testing have been established by the Clinical Laboratory Standards Institute (CLSI, 2015) and are shown in Table 35.1 .

Table 35.1 Once-daily dosages for selected aminoglycosides

Species Dose (in most cases the dose can be administered IV, IM, or SC)
Dog 9–14 mg/kg q 24 h
Cat 5–8 mg/kg q 24 h
Horse Adult: 4–6.8 mg/kg q 24 h
            Foal (<2 weeks): 12–14 mg/kg q 24 h
Cattle Adult: 5–6 mg/kg q24h
            Calf (<2 weeks): 12–15 mg/kg q 24 h
Sheep Same as cattle
Dog 15–30 mg/kg q 24 h
Cat 10–15 mg/kg q 24 h
Horse Adult: 10 mg/kg q 24 h, IV, IM
            Foal (<weeks): 20–25 mg/kg q 24 h, IV

Comparison among drugs

Compared to other drugs in this group, amikacin usually has greater activity against gram-negative bacteria because it resists degradation by bacterial enzymes. This difference is observed with E. coli and particularly Pseudomonas aeruginosa. It is common for isolates obtained from dogs, cats, and horses to be resistant to gentamicin, yet still susceptible to amikacin. Gentamicin is approximately equal to tobramycin in activity, but tobramycin can be more active against some strains of E. coli and Pseudomonas aeruginosa. Kanamycin is least active compared to the others in this class, except for streptomycin.

Effect of tissue environment and other drugs on activity

pH effect:

The action of aminoglycosides is pH dependent. The activity is less at low pH because high cation concentrations inhibit activity. The optimum pH for antibacterial activity is between 6 and 8. For example, gentamicin is 30 to 100-fold less active in an acidic (pH of 5.5 to 6.0) environment than at a pH of 7.4. Consequently, in some tissues and fluids (e.g., urine and abscesses) drug activity may be less because of lower pH.

Cellular debris:

Aminoglycosides are bound to, and inactivated by, cellular debris and nucleic acid material that is released by decaying white blood cells. Therefore, the activity in an abscess is poor. (One ml of purulent material can inactivate 700 μg of gentamicin.)

Oxygen tension:

Low oxygen tension, such as that found in anaerobic tissue or decaying tissue, decreases the activity of aminoglycosides.


Because the uptake into bacteria is dependent on the drug’s positive charge, divalent cations (e.g., Ca++, Mg++) can interfere with uptake of aminoglycosides into bacteria. Monovalent cations also may have some nonspecific inhibitory effect. The effects of cations on activity are discussed in Section Aminoglycoside Toxicity.

Other drugs:

Aminoglycosides are inactivated if combined in vitro (for example in a vial or syringe) with other drugs, especially penicillins. This inactivation does not occur in vivo because concentrations in serum are not high enough to interact when two drugs are administered concurrently at the usual recommended doses. Aminoglycosides are synergistic with β-lactams against some bacteria in vitro, but this may not translate to improved clinical efficacy when the drugs are used simultaneously.

Resistance mechanisms

Anaerobic bacteria are intrinsically resistant because oxygen is necessary for aminoglycosides to enter bacteria. Resistance can occur by way of multiple effects. Some bacteria have an altered cell surface receptor, which is necessary to transport the drug into the bacteria. Bacteria can have a mutation in the target (ribosome) that resists binding, but this is uncommon.

A significant mechanism of resistance is degradation by bacterial enzymes. Several enzymes can be produced by bacteria that inactivate aminoglycosides. These enzymes can phosphorylate, adenylate, or acetylate groups on the molecule to render the drug inactive. The inactive drug can compete with the active drug for transport. Most drugs in this class are susceptible to many of the enzymes, but amikacin is susceptible to only one of the acetylase enzymes, which may account for amikacin’s increased activity against some resistant bacterial strains in comparison to other aminoglycosides.

Pharmacokinetic–Pharmacodynamic Properties

The aminoglycosides are concentration-dependent bactericidal agents; therefore the higher the drug concentration, the greater the bactericidal effect. An optimal bactericidal effect occurs with peak drug concentration of 8–10 times the MIC, with little added benefit for concentrations above 10 times MIC. This target can be accomplished by administering a single dose once daily. This regimen is at least as effective, and perhaps less nephrotoxic, than lower doses administered more frequently (Freeman et al., 1997; Maglio et al., 2002; Drusano et al., 2007). Currently accepted dose regimens in small animals and horses employ this strategy. An additional benefit may be decreased resistance. According to Freeman et al. (1997), “Peak/MIC ratio of at least 10/1 may prevent the emergence of aminoglycoside-resistant pathogens”. The single daily dose is usually calculated from the drug’s volume of distribution. The peak may be achieved from IV, IM, or SC dosing. Total plasma concentration can be used because these drugs are essentially unbound (protein binding less than 10%).

Clinical Uses

The drugs used most often to any extent in veterinary medicine are amikacin, gentamicin, kanamycin, and neomycin (neomycin is used topically only). Netilmicin, sisomicin, and dibekacin are newer compounds but there are no reports of their use in veterinary medicine. Many streptomycin products have either been removed from the human market or are used only for certain infections (e.g., tuberculosis in people). Penicillin–dihydrostreptomycin combinations have been discontinued in the USA for use in animals.

Aminoglycosides are still considered to be important drugs of choice for treating serious aerobic gram-negative infections in veterinary medicine, although newer and less toxic antimicrobials (i.e., third-generation cephalosporins and fluoroquinolones) have replaced the use of aminoglycosides for some bacterial infections.

Neomycin is too toxic to be used systemically but is still used topically or oral for treating diarrhea. Kanamycin, was first introduced in the late 1950s, but many organisms are now resistant to this aminoglycoside and its use has subsequently declined. Gentamicin, introduced in the 1960s, has a broader spectrum and is associated with less resistance than kanamycin. Amikacin, a semisynthetic derivative of kanamycin, was introduced clinically in the 1970s, has the broadest spectrum of activity of all the aminoglycoside antibiotics used clinically to date, and is the preferred antibiotic in severe gram-negative infections that are resistant to gentamicin or tobramycin.

Table 35.2  lists the dosage regimens for some of the aminoglycosides. It is important to note that these doses can be modified proportionately to correct for age, clinical or subclinical disease processes, renal insufficiency, or any of the other factors that may predispose the patient to aminoglycoside toxicosis (see Section Aminoglycoside Toxicity). Alterations in the dose can be best determined by monitoring serum creatinine concentrations or optimally by monitoring aminoglycoside serum concentrations at predetermined time points after dosing.

Table 35.2 Susceptibility testing guidelines for aminoglycosides. Source: Data from CLSI. (2015). Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated From Animals; Third Informational Supplement. CLSI document VET01-S3. Wayne, PA: Clinical and Laboratory Standards Institute.

                        MIC interpretive category (μg/ml)            
Drug Species S I R Comments
Gentamicin Dogs ≤ 2 4 ≥ 8 Once-daily dose of 10 mg/kg
            Horses ≤ 2 4 ≥ 8 Once-daily dose of 6.6 mg/kg
            Dogs ≤ 4 8 ≥ 16 Once-daily dose of 15 mg/kg
Amikacin Horses adult ≤ 4 8 ≥ 16 Once-daily dose of 10 mg/kg
            Foals ≤ 2 4 ≥ 8 For foals less than 11 days of age, 20 mg/kg, q 24 h, IV
Spectinomycin Bovine ≤ 32 64 ≥ 128 Respiratory pathogens

S, susceptible; I, intermediate; R, resistant.

Single Daily Dose Administration

Because of the PK-PD properties, discussed in Section Pharmacokinetic–Pharmacodynamic Properties, single daily dosing of aminoglycosides may be as efficacious as administering the same dose divided over 24 hours. The concept of single daily dosing of aminoglycosides has been utilized and generally accepted within the human medical community (Bass et al., 1998; Christensen et al., 1997; Freeman et al., 1997; Karachalios et al., 1998; Rodvold et al., 1997). The efficacy of single dose administration is attributed to the rapid bactericidal action and the PAE, discussed in Section Mechanism of Action. Once-daily aminoglycoside dosage regimens that produce high peak and low trough concentrations also have less propensity to induce renal toxicity than multiple-dose regimens, which produce lower peak but higher trough concentrations. The clinical doses listed in Table 35.2  are derived from studies in these species that show that once-daily administration can achieve the targeted PK-PD value (Albarellos et al., 2004; Godber et al., 1995; Tudor et al., 1999; Martin et al., 1998; Magdesian et al., 1998; Bauquier et al., 2015; Tudor et al., 1999).

Local Administration

Intraarticular administration of aminoglycosides achieves higher concentrations in joint fluid compared to systemic therapy. This mode of administration may not be practical in all cases and is used most often in horses compared to other animals. In studies performed in experimental horses with septic arthritis, intraarticular administration of gentamicin (150 mg/joint) produced a much higher concentration in synovial fluid than IV administration. Twenty-four hours later, horses that received intraarticular gentamicin also had fewer bacteria in the synovial fluid. Amikacin and other drugs also have been administered via this route.

Aminoglycosides can be implanted directly using antibiotic-impregnated polymethylmethacrylate (AIPMMA) in the infection site. This material is a type of bone cement that hardens at the site once mixed and prepared. Antibiotics impregnated in this matrix results in high local concentrations that are released for a long period of time – sometimes for as long as 80 days. This technique avoids high systemic levels of drugs, reduces drug costs, and the need for frequent systemic administration. Aminoglycosides (tobramycin, amikacin, and gentamicin) are often used for this technique (Streppa et al., 2001).

Regional perfusion of antibiotics involves intravenous or interosseous administration of antibiotic in the limb of an animal while a tourniquet is applied proximal to the site of drug administration. This technique was reviewed by Rubio-Martinez and Cruz (2006). It has been performed in horses, cattle, and large zoo animals (e.g., elephants). It produces high concentrations of antibiotic in the distal limb (joint fluid and bone) of an animal (Murphey et al., 1999). High bactericidal concentrations are achieved during the interval when the tourniquet is applied. Then, concentrations quickly dissipate after tourniquet release. The high concentrations enter adjacent tissue via perfusion and can penetrate ischemic tissue and exudate via gradient diffusion. This technique reduces the total amount of drug used and maintains high concentrations in bone and joint fluid distal to the tourniquet. The advantage of regional limb perfusion has been that it confines the drug to the lower limb, preventing systemic exposure, and avoids the need for high systemic doses (Anderson et al., 1995). Drugs used in this technique have usually been amikacin, gentamicin, or tobramycin. For example, gentamicin has been used to treat infections in horses using regional limb perfusion, particularly for lower limb and joint infections (Whitehair et al., 1992a, 1992b).

Susceptibility Testing

Clinical breakpoints have been established by the Clinical and Laboratory Standards Institute (CLSI) through an analysis of pharmacokinetics, PK-PD criteria, and MIC distributions. These breakpoints are listed in Table 35.1 .

Regulatory Status

Although they are not banned by the US FDA, much of the use in food-producing animals is considered extralabel, except for a few oral products used to treat diarrhea. Under the animal medical drug use clarification act (AMDUCA) of 1994, extralabel use is not allowed if there are other approved animal products effective for the condition being treated. More information is available in Chapters 52 and 61 of this book. These drugs have very long withdrawal times for slaughter. As long as 18 months for withdrawal prior to slaughter in cattle is suggested by the food animal residue avoidance data bank (FARAD). The American Association of Bovine Practitioners (AABP) and Academy of Veterinary Consultants (AVC) have recommended that, until further scientific information becomes available, aminoglycosides should not be used in cattle.

Pharmacokinetics of Aminoglycosides


A comprehensive review of aminoglycoside pharmacokinetics has been reported by Brown and Riviere (1991) and is found in earlier editions of this book. The pharmacokinetics of the aminoglycosides is similar across species lines, but the variability within each animal population is large, indicating a significant amount of heterogeneity in aminoglycoside disposition in both diseased and normal animals (Sojka and Brown, 1986; Frazier et al., 1988). Although there is variability in aminoglycoside pharmacokinetic parameters, the therapeutic range for all of the aminoglycosides is relatively narrow, and the potential for toxicosis is greater than for most other classes of antimicrobials. Altered physiological or pathological states such as pregnancy (Lelievre-Pegorier et al., 1985), obesity (Sketris et al., 1981), subnormal body weight (Tointon et al., 1987), kidney disease (Frazier and Riviere, 1987; Martin et al., 1998; Martin-Jimenez and Riviere, 2001), dehydration (LeCompte et al., 1981; Brown et al., 1985a), immaturity (Sojka and Brown, 1986), sepsis (Mann et al., 1987), dietary protein (Grauer et al., 1994; Behrend et al., 1994), endotoxemia (Wilson et al., 1984; Jernigan et al., 1988c), and intraindividual variability (Mann et al., 1987), among many others, may alter the distribution, clearance, and half-life of aminoglycosides by as much as 1000-fold between individuals in a single study (Zaske et al., 1982).


Aminoglycosides are not appreciably absorbed from the gastrointestinal tract because of their highly polar and cationic nature. However, if there is significant disruption of the intestinal mucosa from enteritis (Gemer et al., 1983; Miranda et al., 1984; Gookin et al., 1999), some absorption may occur. For example, neomycin administered orally to calves with enteritis could increase the risk of residues at slaughter. The aminoglycosides are not inactivated in the intestine and are eliminated in the feces unchanged after oral administration to normal animals. This lack of significant absorption through the gastrointestinal tract requires that all aminoglycosides be given by parenteral routes if therapeutic plasma concentrations are desired. Aminoglycoside absorption is practically complete after IM or SC injection. The peak serum concentrations after extravascular injection occur 14–120 minutes after the dose (Blaser et al., 1983; Ristuccia, 1984). Absorption is extremely rapid and complete if aminoglycosides are instilled into body cavities that contain serosal surfaces; administration by this route closely mimics parenteral administration (Jawetz, 1984; Sande and Mandell, 1985). Absorption from topical administration in open wounds also is possible and may increase the risk of nephrotoxicosis if high doses are used (Mealey and Boothe, 1994).


The aminoglycoside antibiotics are highly hydrophilic and distribute rapidly in extracellular body fluids. Because of their polycationic nature, the penetration of aminoglycosides across membranous barriers by simple diffusion is limited; therefore, low concentrations of aminoglycosides are found in cerebrospinal fluid or in respiratory secretions (Riviere and Coppoc, 1981b; Strausbaugh and Brinker, 1983). Aerosol or intratracheal administration of aminoglycosides produces negligible serum concentrations in animals and this has been used for in-hospital treatment of bronchitis. Through this route, substantial bronchial and pulmonary concentrations can be achieved (Riviere et al., 1981b; Wilson et al., 1981). Delivery with devices that nebulize these agents for delivery to the airways has been employed in hospitalized patients with gentamicin, amikacin, and tobramycin.

Plasma protein binding is negligible for all drugs in this group. These drugs easily pass from the capillaries through fenestrations in capillaries to achieve concentrations in interstitial fluids that are equivalent to plasma drug concentrations. The volume of distribution is approximately equal to the volume of extracellular fluid (typically in the range of 20–25% for most adult animals).

Physiological changes can alter the distribution. Decreases in body water (dehydration) can decrease the volume of distribution and increase plasma drug concentrations. Increases in body water caused by pregnancy, third-compartment fluid accumulation (e.g., ascites), and young age (neonate) will increase the volume of distribution and lower plasma drug concentrations. In studies performed in calves, foals, and puppies, the high body water – particularly extracellular water – produces a high volume of distribution for aminoglycosides. Because the plasma concentration is proportional to the volume of distribution: the larger the volume of distribution, the higher the dose that is needed to attain a targeted peak plasma concentration (Cmax). For example, the volume of distribution for gentamicin or amikacin in foals is more than double the value for adult horses. Subsequently the dose needed to maintain the same blood concentration should be increased, at least by twofold.

Metabolism and Excretion

Several studies in animals (Black et al., 1963; Chiu et al., 1976; Chung et al., 1980; Gyselynck et al., 1971; Schentag and Jusko, 1977; Silverman and Mahon, 1979) have clearly demonstrated that aminoglycosides are eliminated nonmetabolized from the body in all animal primarily by renal glomerular filtration. Some degree of proximal tubular reabsorption occurs and results in an intracellular sequestration or storage in the tubule cells without a significant transepithelial flux from the intraluminal to peritubular space. Net aminoglycoside secretion along more distal nephron segments may also occur. Proximal tubule luminal absorption of aminoglycoside appears quantitatively to be the primary mechanism of intracellular uptake; however, selective peritubular or basolateral reabsorption, evident in isolated tissue slice studies, does occur and may be of toxicological significance in specific situations. Reabsorption requires metabolic energy and occurs along the midconvoluted and straight portions of the proximal tubule (Barza et al., 1980; Bennett et al., 1982; Hsu et al., 1977; Kaloyanides and Pastoriza-Munoz, 1980; Kluwe and Hook, 1978a, 1978b; Kuhar et al., 1979; Pastoriza-Munoz et al., 1979; Senckjian et al., 1981; Silverblatt, 1982; Silverblatt and Kuehn, 1979; Silverman and Mahon, 1979; Tulkens and Trouet, 1978; Vandewalle et al., 1981; Williams et al., 1981a, 1981b; Zaske, 1980). Renal cortical uptake of the aminoglycosides is dose-dependent up to a threshold concentration; then, cortical accumulation increases at a progressively slower rate as the dose is increased. Cumulative uptake of aminoglycosides in tissues indicates that the kidney is the major site of drug sequestration.

A typical plasma vs time profile for IV administration of an aminoglycoside antibiotic to animals shows three phases. The α (distribution) phase occurs within the first hour after IV dosing, the β phase (elimination) occurs between 1 and 24 hours after IV dosing (and probably the most useful in determining dose adjustments in clinical situations), and the γ phase occurs 24 hours after dosing and is the most important part of the elimination curve of aminoglycosides when considering drug residues in food-producing animals. Values for the beta- and gamma-phases are shown in Table 35.4 for gentamicin. The primary difference in pharmacokinetics among species is related to the glomerular filtration rate (GFR). The GFR is lower for larger animals because of allometric scaling; therefore, larger animals tend to have slower clearance and the half-lives are longer (Riviere, 1985; Riviere et al., 1997). Reptiles have lower GFR and lower renal clearance of aminoglycosides. This produces longer half-lives in reptile species.

The prolonged terminal elimination phase of aminoglycosides has major implication for veterinary therapeutics in food-producing animals. As discussed in Section Metabolism and Excretion, aminoglycosides accumulate in the renal cortex for prolonged periods of time, resulting in violative tissue residues even after short periods of administration. In some cases, aminoglycosides such as gentamicin may be detected for a year after parenteral administration! A withdrawal time of 18 months for cattle treated with gentamicin has been recommended by FARAD (see Chapter 61), but it is best to simply avoid use in these species altogether. Piglets may be treated up to 3 days of age with oral products, but even in this case the withdrawal time is 40 days.

Pharmacokinetics in Nonmammals

Veterinarians involved in nonmammal practice should be aware of variations in elimination in some animals. In birds the elimination half-life is usually 2–3 hours and dosing intervals are similar to what has been used in mammals. For amphibians and reptiles, however, elimination rates are much slower. Half-lives range from 38 to 72 hours in alligators and dose intervals of 72 to 96 hours have been used. In snakes half-lives can be as long as 80–121 hours. In turtles and tortoises, the half-life of aminoglycosides has been in the range of 20–70 hours, with dose intervals usually every 48 hours to every 96 hours. Kidney injury may be greater because of the slower elimination in reptiles. Therefore, use these drugs cautiously in animals with slow clearance.

Aminoglycoside Toxicity

Aminoglycoside toxicity in domestic and laboratory animals was reviewed extensively by Riviere (1985). The possible risk factors that may predispose a patient to aminoglycoside toxicity are shown in Table 35.3 .

Table 35.3 Risk factors that predispose to aminoglycoside toxicosis

Volume contraction (shock)
Sodium or potassium depletion
Renal transplantation
Prior renal insufficiency
Prior aminoglycoside exposure
Cumulative dose of aminoglycoside
Peak and trough serum concentrations
Hepatic disease
Total dose of drug administered
Duration of treatment
Concurrent administration of loop diuretics
Methoxyflurane anesthesia
Cephalosporin antibiotics
Nephrotoxic drugs

Aminoglycosides can induce ototoxicity and nephrotoxicity because both organs have higher-than-normal concentrations of phospholipid (in particular, phosphatidylinositol) (Sastrasinh et al., 1982a, 1982b) in their cellular matrixes. Cationic aminoglycosides are chemically attracted to anionic membrane phospholipids. The tissues into which gentamicin preferentially accumulates (renal cortex and cochlear tissue) have disproportionately high amounts of phosphatidylinositol in their membranes compared with other tissues of the body (Hauser and Eichberg, 1973). Basolateral membranes of the renal proximal tubular epithelium also have a higher capacity for binding aminoglycosides than brush-border membranes because of their higher phosphatidylinositol content (Josepovitz et al., 1985).

Ototoxicity studies in a variety of species have shown injury from aminoglycosides that may affect both auditory and vestibular function due to destruction of the sensory hair cells in the cochlea and vestibular labyrinth. The mechanism of ototoxicity was described in a review (Lanvers-Kaminsky et al., 2017). Initially the outer hair cells of the cochlea are affected, which impars hearing at high frequencies. With continued exposure the inner hair cells are injured, which causes additional hearing imparirment and deafness. Injury may be caused by oxidative stress and inhibition of mitochondrial protein synthesis. Aminoglycosides enter the inner ear by active transport mechanisms. Once in the ear, they are cleared slowly with half-lives of 10–13 days after a single dose, but up to 30 days after multiple doses. Ototoxicity may be irreversible in some cases (Johnson and Hardin, 1992). Of pertinence to veterinary medicine, dogs tend to present with auditory toxicity, and cats tend to present with vestibular toxicity, although both usually occur after nephrotoxicity has ensued.

The interaction between the cationic aminoglycosides and the kidney anionic phospholipids appears to be electrostatic and proportional to the cationic charge of the drug. This interaction is saturable and is competitively inhibited by divalent cations (magnesium and calcium), spermine, poly-L-lysine, and other aminoglycosides. For example, diets high in calcium, or calcium supplementation may decrease the risk of aminoglycoside nephrotoxicity (Schumacher et al., 1991; Brashier et al., 1998). After binding, the aminoglycoside is internalized into the cell by pinocytosis (Bennett et al., 1982; Elliott et al., 1982; Feldman et al., 1981; Humes et al., 1982; Lipsky et al., 1980; Lipsky and Lietman, 1982; Pastoriza-Munoz et al., 1979; Schacht, 1978), where concentrations of the aminoglycoside can reach as high as 50 times the concentrations achieved in serum or plasma. The uptake of aminoglycosides into lysosomes is competitive and is dependent in part upon the charge density of the aminoglycoside molecule, which is a function of the number of amino groups. For example, neomycin (valence + 4.37 at pH 7.40) accumulates in the renal cortex more than gentamicin (valence + 3.46 at pH 7.40) due to a higher cationic charge.

There are several mechanisms that may explain the mechanism by which aminoglycosides initially damage the proximal renal tubule cells (Swann et al., 1990; Schumacher et al., 1991; Beauchamp et al., 1992). Lysosomal dysfunction is a component of the early phase of renal injury (Carbon et al., 1978; Feldman et al., 1982; Hull et al., 1981; Kaloyanides and Pastoriza-Munoz, 1980; Laurent et al., 1982; Lipsky and Lietman, 1982; Mazze, 1981; Meisner, 1981; Morin et al., 1980, 1981; Tulkens and Trouet, 1978). This view is consistent with the idea that lysosomes are the primary locus of aminoglycoside sequestration in proximal tubule cells. Lysosomes are also the first organelle to demonstrate morphological changes (myeloid body or cytosegresome formation) after exposure to the drugs (Riviere et al., 1981a). Decreased lysosomal function may also result in a decreased ability to degrade endogenous intracellular proteins and exogenous low-molecular-weight proteins reabsorbed from the tubular filtrate, events that would perturb nephron function (Cojocel et al., 1983; Cojocel and Hook, 1983). The increase in lysosomal permeability could result in proximal tubule cell dysfunction, although this event is probably a late change in aminoglycoside-induced toxic nephropathy occurring after cell necrosis has been initiated by another factor (Humes et al., 1982). The appearance of lysosomal enzymes (for example, urinary γ-glutamyl transferase, GGT) in the urine of aminoglycoside-induced toxic nephropathy patients is secondary to proximal tubule cell necrosis, apical plasma membrane damage, or lysosome exocytosis.

Mitochondria are a second possible target of aminoglycosides because, both in vitro and in vivo, aminoglycosides decrease mitochondrial respiration, thereby impairing the tubule cell’s bioenergetic profile (Appel and Neu, 1977; Cuppage et al., 1977; Kaloyanides and Pastoriza-Munoz, 1980; Kluwe and Hook, 1978a; Sastrasinh et al., 1982b; Simmons et al., 1980; Weinberg et al., 1980, 1990; Weinberg and Humes, 1980). This could selectively produce tubule dysfunction, which would initially be detectable biochemically but not morphologically. The mechanism of this toxicity may be secondary to a direct aminoglycoside interaction with mitochondrial membrane phospholipids, to a competitive interaction with the divalent cations magnesium or calcium, or to an alteration in the intracellular milieu that would indirectly affect mitochondrial function. The magnitude of aminoglycoside effects on mitochondrial respiration is associated with the net positive charge of the specific drug.

The third possible site of initial intracellular aminoglycoside is an interaction with the proximal tubule cell plasma membrane’s phospholipids and enzymes (Feldman et al., 1981; Humes et al., 1982; Knauss et al., 1983; Lullmann and Vollmer, 1982; Sastrasinh et al., 1982a, 1982b; Schacht, 1979; Silverman and Mahon, 1979; Williams et al., 1981a, 1981b). Binding of aminoglycosides to membrane polyphosphoinositides could perturb the regulation of membrane permeability, thereby promoting cellular dysfunction. The enzyme interactions at the basolateral membrane could result in significant cellular dysfunction by altering intracellular electrolyte balance or osmolality.

An additional site of aminoglycoside interaction with the nephron is at the level of the glomerulus, where gentamicin has been demonstrated to reduce the glomerular ultrafiltration coefficient and to reduce the number and size of glomerular endothelial fenestrae (Avasthi et al., 1981; Huang et al., 1979; Luft and Evan, 1980a, 1980b; Luft et al., 1978). These effects may be mediated by a charge interaction between the cationic aminoglycosides and the anionic endothelial cell surfaces or could be a feedback response to a primary tubular injury (known as tubuloglomerular feedback).

The relative contributions of the lysosomal, mitochondrial, and membrane tubular mechanisms and glomerular injury to clinical aminoglycoside-induced toxic nephropathy is not known. It is possible that cellular dysfunction is a result of a combination of the above processes.


Aminoglycoside-induced kidney injury in dogs follows a progression that consists of an initial subclinical (subazotemic) phase marked by a urinary concentrating defect followed by a clinical (azotemic) phase. It also serves as the basis for simple noninvasive clinical monitoring (for example, monitoring urine specific gravity and proteinuria) for toxicosis since urinary changes preceded the more irreversible systemic changes. If identified early, aminoglycoside-induced kidney injury can recover.

Urine GGT (γ-glutamyl transferase):creatinine and NAG (N-acetyl-β-D-glucosaminidase):creatinine ratios and 24-hour urinary excretions of NAG and GGT have been used as markers of aminoglycoside-induced kidney injury. Elevated GGT:creatinine ratio precedes clinically significant elevations in serum creatinine, urine specific gravity, and urine protein:creatinine ratios.

Risk factors in dogs (Brown et al., 1985a) were identified that contributed to nephrotoxicosis in 10 dogs. Risk factors included dehydration, fever, old age, and preexisting renal disease. In addition, low protein and electrolyte abnormalities were documented in these dogs. Other risk factors are shown in Table 35.3.

Ototoxicity in dogs, manifested as either vestibulotoxic and/or ototoxic effects, can occur after systemic aminoglycoside therapy, but toxicity after topical use of aminoglycosides is apparently rare (Strain et al., 1995). Although it is sometimes recommended among dermatologists to avoid topical gentamicin in animals with a ruptured tympanum (ear drum) this apparently is not a risk. In a study designed to detect ototoxicity in dogs treated with topically administered gentamicin using brain stem auditory evoked potential (BAEP), dogs underwent a unilateral myringotomy, followed by instillation of 7 drops of the 3 mg/ml buffered aqueous solution of gentamicin instilled into one ear twice a day for 3 weeks. There was no evidence in any treated dogs of drug-induced detectable changes in cochlear or vestibular function.


Cats have a relatively more concentrated urine and retain the ability to produce concentrated urine even when the GFR is significantly reduced (Ross and Finco, 1981), making urine monitoring less successful than in dogs. Consistent with the studies cited in dogs, studies in cats have shown that high doses, prolonged administration, or both, can produce kidney injury, with histological changes and increases in serum urea nitrogen and creatinine (Welles et al., 1973; Waitz et al., 1971).

Nephrotoxicosis associated with the topical use of gentamicin has been reported in cats (Mealey and Boothe, 1994). A cat was administered 10 ml of an undiluted gentamicin injectable solution (50 mg/ml) to lavage an open wound twice. The cat eventually progressed to an azotemic state and was euthanized. Histologically, the kidneys showed severe acute proximal tubular necrosis compatible with aminoglycoside toxicosis. Elevated serum levels of gentamicin were noted as late as 96 hours after administration. Although a number of factors may have contributed to the death of this cat, the topical administration of such large quantities of gentamicin was most likely the major determinant.


As in other animals, aminoglycoside-induced kidney and otic injury has been documented in horses (Nostrandt et al., 1991). Clinically, aminoglycoside-induced toxic nephropathy is more common in young animals, with toxicity rarely reported in adults (Riviere et al., 1982; Tobin, 1979). As in other animals the injury is marked by elevations in serum creatinine and serum urea nitrogen (Tobin, 1979; Riviere, 1982). The shift in dosing regimens from multiple times per day, to once per day has apparently decreased the risk of aminoglycoside-induced kidney injury in recent years and is now the accepted protocol used clinically (Tudor et al., 1999; Geor and Papich, 2003; Godber et al., 1995).

Examples of Drugs


Gentamicin is available in solutions of 5, 50, and 100 mg/ml (Garasol, Gentocin, and generic), as well as oral solution for pigs (4.35 or 5 mg/ml) and powder for oral solution (66.7 or 333.3 mg per gram of powder) Gentamicin has been the most commonly administered drug in this class used in veterinary medicine. The common clinical approach is to rely on gentamicin for IV, IM, or SC administration when routine use of an aminoglycoside is indicated. In some instances (for example, to broaden the spectrum) it may be administered with a β-lactam antibiotic (e.g., penicillin, ampicillin, or a cephalosporin). Examples of gentamicin dosages are listed in Table 35.2. Representative pharmacokinetic data for gentamicin in animals are shown in Table 35.4 .

Table 35.4 Single-dose intravenous serum or plasma pharmacokinetics of gentamicin in various species. Source: Adapted from Brown and Riviere, 1991.

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Aminoglycoside Antibiotics

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                        Volume of             Half-life Half-life            
            Dose Distribution Clearance (β) (γ)            
Species (mg/kg) (l/kg) (ml/min/kg) (hour) (hour) Reference
Dogs (juvenile) 10 0.354 (0.036) 4.08 (0.62) 1.01 (0.12) N/A Riviere and Coppoc, 1981a
Dogs 10 0.38 (0.029) 4.20 (0.70) 1.05 (0.13) N/A Riviere et al., 1981a; Riviere et al., 1981b
Dogs 10 0.30 (0.06) 3.44 (0.38) 1.01 (0.08) N/A Rivierie et al., 1981a; Riviere et al., 1981b
Dogs 10 0.335 (0.094) 2.94 (0.67) 1.36 (0.09) N/A Baggot, 1977
Dogs 4.4 0.227 (0.076) 2.27 (0.41) 1.09a N/A Brown et al., 1991
Dogs 4 0.255 3.33 1.06 N/A Batra et al., 1983
Dogs 3 NR 2.29 (0.48) 0.91 (0.25) N/A Wilson et al., 1989
Cats 4.4 0.190 1.61 1.36 N/A Short et al., 1986
Cats 5 ND 1.38 (0.35) 1.25 (0.30) 86a Jernigan et al., 1988e
Cows 5 0.19 (0.04) 1.32 (0.17) 1.83 (0.18) N/A Haddad et al., 1986
Cattle (1 day old) 4.4 0.393 (0.040) 1.92 (0.43) 2.49 (0.73) N/A Clarke et al., 1985
Cattle (5 days old) 4.4 0.413 (0.050) 2.44 (0.34) 1.99 (0.33) N/A Clarke et al., 1985
Cattle (10 days old) 4.4 0.341 (0.021) 2.02 (0.27) 1.97 (0.21) N/A Clarke et al., 1985