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 pK_a values that range from 7.2 to 8.8 (Ziv and Sulman, 1974; Katzung, 1984; Prescott and Baggot, 1988).

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.

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.

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 (C_max). 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.

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.

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-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).