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Gentamicin Sulfate

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - An aminoglycoside obtained from cultures of Micromonaspora purpurea, gentamicin sulfate occurs as a white to buff powder that is soluble in water and insoluble in alcohol. The commercial product is actually a combination of gentamicin sulfate C1, C2 and C3, but all these compounds apparently have similar antimicrobial activities. Commercially available injections have a pH from 3 - 5.5.

 

Storage/Stability/Compatibility - Gentamicin sulfate for injection and the oral solution should be stored at room temperature (15-30°C); freezing or temperatures above 40°C should be avoided. The soluble powder should be stored from 2-30°C. Do not store or offer medicated drinking water in rusty containers or the drug may be destroyed.

 

While the manufacturer does not recommend that gentamicin be mixed with other drugs, it is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: bleomycin sulfate, cefoxitin sodium, cimetidine HCl, clindamycin phosphate, methicillin sodium, metronidazole (with and without sodium bicarbonate), penicillin G sodium and verapamil HCl.

 

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with gentamicin: amphotericin B, ampicillin sodium, carbenicillin disodium, cefamandole naftate, cephalothin sodium, cephapirin sodium, dopamine HCl, furosemide, and heparin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

 

In vitro inactivation of aminoglycoside antibiotics by beta-lactam antibiotics is well documented. Gentamicin is very susceptible to this effect and it is usually recommended to avoid mixing these compounds together. Refer to the Drug Interaction section in the amikacin sulfate monograph for more information.

 

Pharmacology - Gentamicin has a mechanism of action and spectrum of activity (primarily gram negative aerobes) similar to the other aminoglycosides. This information is outlined in more detail in the amikacin monograph. Gentamicin resistance by certain bacteria, principally Klebsiella, E. coli and Pseudomonas aeruginosa is a continuing concern for many areas. However, most strains of gentamicin-resistant bacteria of these species remain susceptible to amikacin.

 

Uses/Indications - The inherent toxicity of the aminoglycosides limit their systemic (parenteral) use to the treatment of serious gram negative infections when there is either a documented lack of susceptibility to other less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram negative infection before culture and susceptibility results are reported.

 

Various gentamicin products are approved for parenteral use in dogs, cats, chickens, turkeys and swine. Although routinely used parenterally in horses, gentamicin is only approved for intrauterine infusion in that species. Oral products are approved for gastrointestinal infections in swine and turkeys. For more information refer to the Dosage section below.

 

Pharmacokinetics - Gentamicin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not skin or urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from 1/2 to 1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bioavailability from extravascular injec­tion (IM or SQ) is greater than 90%.

 

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids and high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier or penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues, such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta. Fetal concentrations range from 15-50% of those found in maternal serum.

 

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The elimination half-lives for gentamicin have been reported to be 1.82- 3.25 hours in horses, 2.2-2.7 hours in calves, 2.4 hours in sheep, 1.8 hours in cows, 1.9 hours in swine, 1 hour in rabbits, and 0.5-1.5 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibi­otics.

 

Contraindications/Precautions/Reproductive Safety - Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

 

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye”, herding, dogs for the hearing impaired, etc.).

 

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

 

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

 

Aminoglycosides are generally considered contraindicated in rabbits as they adversely affect the GI flora balance in these animals.

 

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxi­city or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks.

 

Adverse Effects/Warnings - The aminoglycosides are infamous for their nephrotoxic and ototoxic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by increases in BUN, creatinine, nonprotein nitrogen in the serum and decreases in urine specific gravity and creatinine clearance.  Proteinuria and cells or casts may also be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

 

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can be manifested by either auditory and/or vestibular symptoms and may be irreversible. Vestibular symptoms are more frequent with streptomycin, gentamicin, or tobramycin. Auditory symptoms are more frequent with amikacin, neomycin, or kanamycin, but either forms can occur with any of the drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

 

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI symptoms, hematologic and hepatic effects have been reported.

 

Overdosage/Acute Toxicity - Should an inadvertant overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug, but is not a viable option for most veterinary patients. Peritoneal dialy­sis also will reduce serum levels, but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis.

 

Drug Interactions - Aminoglycosides should be used with caution with other nephrotoxic, ototoxic, and neurotoxic drugs. These include amphotericin B, other aminoglycosides, acyclovir, bacitracin (parenteral use), cisplatin, methoxyflurane, polymyxin B, or vancomycin. The concurrent use of aminoglycosides with cephalosporins is controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with aminoglycosides, but this interaction has only been well documented with cephaloridine (no longer marketed) and cephalothin. Concurrent use with loop (furosemide, ethacrynic acid) or osmotic diuretics (mannitol, urea) may increase the nephrotoxic or ototoxic potential of the aminoglycosides. Concomitant use with general anesthetics or neuromuscular blocking agents could potentiate neuromuscular blockade. Synergism against Pseudomonas aeruginosa and enterococci may occur with beta-lactam antibiotics and the aminoglycosides. This effect is apparently not predictable and its clinical usefulness is in question.

 

Drug/Laboratory Interactions - Gentamicin serum concentrations may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored prior analysis. It is recommended that if assay is delayed, samples be frozen and if possible, drawn at times when the beta-lactam antibiotic is at a trough.

 

Doses -Note: There is significant interpatient variability with regards to aminoglycoside pharmacokinetic parameters. To insure therapeutic levels and to minimize the risks for toxicity development, it is recommended to consider monitoring serum levels for this drug.

 

For small animals, one pair of authors (Aronson and Aucoin 1989) make the following recommendations with regard to minimizing risks of toxicity yet maximizing efficacy:

1)   Dose according to animal size. The larger the animal, the smaller the dose (on a mg/kg basis).

2)   The more risk factors (age, fever, sepsis, renal disease, dehydration) the smaller the dose.

3)   In old patients or those suspected of renal disease, increase dosing interval from q8h to q16-24h.

4)   Determine serum creatinine prior to therapy and adjust by changes in level even if it remains in “normal range”.

5)   Monitor urine for changes in sediment (e.g., casts) or concentrating ability. (Not very useful in patients with UTI.)

6)   Therapeutic drug monitoring is recommended when possible.

 

Horses:

For susceptible infections:

a)   1 - 3 mg/kg IM qid (Robinson 1987)

b)   For gram negative respiratory infections: 2.2 mg/kg IM or IV 4 times a day in mature horses and 3 times a day in foals. (Beech 1987a)

c)   In foals: 2 - 3 mg/kg IV q12h; use lower dose in premature foals or those less than 7 days of age. Monitor serum levels if possible. (Caprile and Short 1987)

d)   For prophylaxis (with penicillin G) for surgical colic: 2.2. mg/kg tid IV. (Stover 1987)

e)   2.2 mg/kg IV q6h; animals must be well hydrated. (Sweeney et al. 1988)

f)    2 - 4 mg/kg IM q8-12h (Baggot and Prescott 1987)

g)   4.4 mg/kg IV q12h (Duran 1992)

h)   There is increased interest in giving gentamicin once daily at an initial dosage of 6.6 mg/kg preferably as an IV infusion over one hour. Therapeutic drug moni­toring would be beneficial. Watch for futher references documenting the safety and efficacy of this dosing method. (Plumb)

 

Elephants:

a) 4.4 mg/kg IV (or IM) once daily.  The IV injection can be diluted with 10% saline.  Based on trough levels measured at 24 hours, this dose will maintain blood levels at 1.7 – 1.8 µg /ml (recommended trough levels for humans are < 2 µg /ml). (Schmidt, 1986).

 

Elephant References:

a) Schmidt, M.J: Senior Research Veterinarian, Washington Park Zoo, Portland, Oregon, personal communication, 1986. In: Olsen,J.H., 1999. Antibiotic therapy in elephants. In: Fowler,M.E. and Miller R.E. (Editors), Zoo and Wild Animal Medicine: Current Therapy 4. W.B. Saunders, Philadelphia, PA,USA p. 537

Monitoring Parameters (parenteral use)-

1)   Efficacy (cultures, clinical signs and symptoms associated with infection).

2)   Renal toxicity; baseline urinalysis, serum creatinine/BUN. Casts in the urine are often the initial sign of impending nephrotoxicity. Frequency of monitoring during therapy is controversial. It can be said that daily urinalyses early in the course of treatment is not too often nor are daily creatinines once casts are seen or increases noted in serum creatinine levels.

3)   Gross monitoring of vestibular or auditory toxicity is recommended.

4)   Serum levels, if possible; see the reference by Aronson and Aucoin for more in­formation.

 

Client Information - With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done. Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times -

 

Veterinary-Approved Products:

Gentamicin Sulfate Injection 50 mg/ml & 100 mg/ml (horses only) in 50 ml & 100 ml vials ; Gentocin®  (Schering);Ultragex ® 100 (Anthony); Generic (Rx)  Approved for use in dogs, cats, and horses (not for food).

 

Gentamicin Sulfate Injection 5 mg/ml in 250 ml vials; Garacin®  Piglet Injection (Schering); (OTC)  Approved for use in swine. Slaughter withdrawal = 40 days.

 

Gentamicin Sulfate Oral Solution 50 mg/ml in 80 ml bottles; Garacin® Oral Solution (Schering); (OTC)  Approved for use in swine. Slaughter withdrawal = 3 days.

 

Gentamicin Sulfate Oral Solution 4.35 mg/ml in 115 ml pump bottles (1 pump delivers approximately 5 mg); Garacin® Pig Pump Oral Solution (Schering); (OTC)  Approved for use in swine. Slaughter withdrawal = 14 days.

 

Gentamicin Sulfate Soluble Powder 2 g gentamicin/30 grams of powder in 360 gram jar or 2 g gentamicin in 120 gram packets; Garacin® Soluble Powder (Schering); (OTC)  Approved for use in swine. Slaughter withdrawal = 10 days.

 

Veterinary-approved injections for chickens and turkeys plus a water additive for egg dipping are available. Ophthalmic, otic and topical preparations are also available with veterinary labeling.

 

Human-Approved Products (partial listing):

 

Gentamicin Sulfate Injection 40 mg/ml & 10 mg/ml as sulfate and 2 mg/ml as sulfate  in 2 & 20 ml vials and 1.5 & 2 ml cartridge-needle units/disp. syringes and 2 ml amps; Garamycin ® (Schering); Jenamicin® (Hauck); Pediatric Gentamicin Sulfate® (Elkins-Sinn; Garamycin Pediatric® (Schering); Garamycin Intrathecal® (Schering); generic, (Rx)

 

Topical, otic and ophthalmic labeled products are also available.

 

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