Elephant specific information, if available, is in blue.

Chemistry – A fluoroquinolone antibiotic, enrofloxacin occurs as a pale yellow, crystalline powder. It is slightly soluble in water. Enrofloxacin is related structurally to the human-approved drug ciprofloxacin (enrofloxacin has an additional ethyl group on the piperazinyl ring).

 

Storage/Stability/Compatibility – Unless otherwise directed by the manufacturer, enrofloxacin tablets should be stored in tight containers at temperatures less than 30°C. Protect from strong UV light.

 

Pharmacology – Enrofloxacin is a bactericidal agent. The bactericidal activity of enrofloxacin is concentration dependent, with susceptible bacteria cell death occuring within 20-30 minutes of exposure. Enrofloxacin has demonstrated a significant post-antibiotic effect for both gram – and + bacteria and is active in both stationary and growth phases of bacterial replication.

 

Its mechanism of action is not thoroughly understood, but it is believed to act by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis.

 

Both enrofloxacin and ciprofloxacin have similar spectrums of activity. These agents have good activity against many gram negative bacilli and cocci, including most species and strains of Pseudomonas aeruginosa, Klebsiella sp., E. coli, Enterobacter, Campylobacter, Shigella, Salmonella, Aeromonas, Haemophilus, Proteus, Yersinia, Serratia, and Vibrio species. Of the currently commercially available quinolones, ciprofloxacin and enrofloxacin have the lowest MIC values for the majority of these pathogens treated. Other organisms that are generally susceptible include Brucella sp, Chlamydia trachomatis, Staphylococci (including penicillinase-producing and methicillin-resistant strains), Mycoplasma, and Mycobacterium sp. (not the etiologic agent for Johne’s Disease).

 

The fluoroquinolones have variable activity against most Streptococci and are not usually recommended to be used for these infections. These drugs have weak activity against most anaerobes and are ineffective in treating anaerobic infections.

 

Resistance does occur by mutation, particularly with Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter and enterococci, but plasmid-mediated resistance is not thought to occur.

 

Uses/Indications – Enrofloxacin is approved for use in dogs and cats (oral only) for the management of of diseases assicaited with bacteria susceptible to enrofloxacin. It is also been approved for use in cattle (not dairy cattle or veal calves) and for chickens and turkeys.

 

Pharmacokinetics – Both enrofloxacin and ciprofloxacin are well absorbed after oral administration in most species. But in dogs, enrofloxacin’s bioavailability (approximately 80%) is about twice that of ciprofloxacin after oral dosing. 50% of Cmax is reportedly attained within 15 minutes of dosing and peak levels (Cmax) occur within one hour of dos­ing. The presence of food in the stomach may delay the rate, but not the extent of absorp­tion.

 

Enrofloxacin/ciprofloxacin are distributed throughout the body. Volume of distribution in dogs is at least 2.8 L/kg. Only about 27% is bound to canine plasma proteins. Highest concentrations are found in the bile, kidney, liver, lungs, and reproductive system (including prostatic fluid and tissue). Therapeutic levels are also attained in bone, synovial fluid, skin, muscle, aqueous humor and pleural fluid. Low concentrations are found in the CSF, and levels may only reach 6-10% of those found in the serum.

 

Enrofloxacin/ciprofloxacin is eliminated via both renal and non-renal mechanisms. Approximately 15-50% of the drugs are eliminated unchanged into the urine, by both tubular secretion and glomerular filtration.

 

Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are less active than the parent compounds. Approximately 30-40% of circulating enrofloxacin is metabolized to ciprofloxacin. These metabolites are eliminated both in the urine and feces. Because of the dual (renal and hepatic) means of elimination, patients with severely impaired renal function may have slightly prolonged half-lives and higher serum levels which may not require dosage adjustment. The elimination half-lives in dogs are approximately 4-5 hours and in cats, 6 hours.

 

Contraindications/Precautions/Reproductive Safety – Enrofloxacin is contraindicated in small and medium breed dogs from 2 months to 8 months of age. Bubble-like changes in articular cartilage have been noted when the drug was given at 2-5 times recommend doses for 30 days, although clinical symptoms have only been seen at the 5X dose. Large and giant breed dogs may be in the rapid-growth phase for periods longer than 8 months of age, so longer than 8 months may be necessary to avoid cartilage damage. Quinolones are also contraindicated in patients hypersensitive to them.

 

Because ciprofloxacin has occasionally been reported to cause crystalluria, animals should not be allowed to become dehydrated during therapy with either ciprofloxacin or enrofloxacin. In humans, ciprofloxacin has been associated with CNS stimulation and should be used with caution in patients with seizure disorders. Patients with severe renal or hepatic impairment may require dosage adjustments to prevent drug accumulation.

 

The safety of enrofloxacin in pregnant dogs has been investigated. Breeding, pregnant and lactating dogs receiving up to 15 mg/kg day demonstrated no treatement related effects. However, because of the risks of cartilage abnormalities in young animals, the fluoroquinolones are not generally recommended to be used during pregnancy unless the benefits of therapy clearly outweigh the risks. Limited studies in male dogs at various dosages have indicated no effects on male breeding performance. Safety in breeding, pregnant, or lactating cats has not been established.

 

Adverse Effects/Warnings – With the exception of potential cartilage abnormalities in young animals (see Contraindications above), the adverse effect profile of these drugs appears to be minimal. GI distress (vomiting, anorexia) is the most common, yet infrequently reported adverse effect. Although not reported thus far in animals, hypersensitivity reactions, crystalluria and CNS effects (dizziness, stimulation) could potentially occur.

 

Overdosage/Acute Toxicity – It is unlikely an acute overdose of either compound would result in symptoms more serious than either anorexia and vomiting. Dogs receiving 10 times the labeled dosage rate of enrofloxacin for at least 14 days developed only vomiting and anorexia. Death did occur in some dogs when fed 25 times the labeled rate for 11 days, however.

 

Drug Interactions – Antacids containing cations (Mg++, Al+++, Ca++) may bind to enrofloxacin/ciprofloxacin and prevent its absorption. Sucralfate may inhibit absorption of enrofloxacin/ciprofloxacin, separate doses of these drugs by at least 2 hours.  Enrofloxacin/ciprofloxacin administered with theophylline may increase theophylline blood levels. Probenecid blocks tubular secretion of enrofloxacin/ciprofloxacin and may increase its blood level and half-life. Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonas aeruginosa or other Enterobacteriaceae) with these compounds and amino­glycosides, 3rd generation cephalosporins agents, and extended-spectrum penicillins. Although enrofloxacin/ciprofloxacin has minimal activity against anaerobes, in vitro synergy has been reported when used with clindamycin against strains of Peptostreptococcus, Lactobacillus and Bacteroids fragilis. Nitrofurantoin may antagonize the antimicrobial activity of the fluoroquinolones and their concomitant use is not recommended. Fluoroquinolones may exacerbate the nephrotoxicity of cyclosporine (used systemically). Because the fluoroquinolones are relatively new additions to the therapeutic armamentarium, more interactions may be forthcoming.

 

Drug/Laboratory Interactions – In some human patients, the fluoroquinolones have caused increases in liver enzymes, BUN, and creatinine and decreases in hematocrit. The clinical relevance of these mild changes is not known at this time.

 

Doses –

Horses:

Note: Usage of enrofloxacin in horses is controversial. While there has been much discussion regarding the potential for cartilage abnormalities or other arthropathies in horses, objective data are lacking. At the present time however, it probably should only be used in adult horses when other antibiotics are inappropriate with the client in­formed of, and agrees to accept the risks for any potential adverse effects.

a) 2.5 mg/kg q12h (Whittem 1993)

 

Elephants:

a) 1.07 – 1.25 mg/kg orally BID.  No adverse effects noted after 2 weeks (Schmidt, 1986).

b) 1.5 – 2.8 mg/kg orally once daily. Blood levels evaluated on one elephant found that once daily dosing maintained blood levels (Houck, 1986).

c) 2.5 mg/kg PO (Sanchez, 2005).

 

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. 538

b) Houck, R: Senior Veterinarian, Ringling Brothers and Barnum and Bailey Circus, 8607 Westwood Center Drive, Vienna, Virginia, 22182, 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.538

c) Sanchez, C.R. Murray, S.Z., Isaza, R., Papich, M.G. 2005. Pharmacokinetics of a single dose of enrofloxacin administered orally to captive Asian elephants (Elephas maximus). Am J Vet Res. 66 (11):1948-53.

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin after oral administration to captive elephants. ANIMALS: 6 clinically normal adult Asian elephants (Elephas maximus). PROCEDURE: Each elephant received a single dose of enrofloxacin (2.5 mg/kg, PO). Three elephants received their complete diet (pellets and grain) within 2 hours after enrofloxacin administration, whereas the other 3 elephants received only hay within 6 hours after enrofloxacin
administration. Serum concentrations of enrofloxacin and ciprofloxacin were measured by use of high-performance liquid chromatography. RESULTS: Harmonic mean half-life after oral administration was 18.4 hours for all elephants. Mean +/- SD peak serum concentration of enrofloxacin was 1.31 +/- 0.40 microg/mL at 5.0 +/- 4.2 hours after administration. Mean area under the curve was 20.72 +/- 4.25 (microg x h)/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of enrofloxacin to Asian elephants has a prolonged elimination half-life, compared with the elimination half-life for adult horses. In addition, potentially therapeutic concentrations in elephants were obtained when enrofloxacin was
administered orally at a dosage of 2.5 mg/kg. Analysis of these results suggests that enrofloxacin administered with feed in the manner described in this study could be a potentially useful antimicrobial for use in treatment of captive Asian elephants with infections attributable to organisms, such as Bordetella spp, Escherichia coli, Mycoplasma spp, Pasteurella spp, Haemophilus spp, Salmonella spp, and Staphylococcus spp.

d) Miller, J. and McClean, M. Pharmacokinetics of enrofloxacin in African elephants (Loxodonta africana) after a single rectal dose. Proc American Associaton of Zoo Veterinarians and Assoc of Reptile and Amphibian Veterinarians. 224-225. 2008. 11-10-2008.

Abstract: Captive African elephants (Loxodonta Africana) are susceptible to many types of gram negative bacterial infections such as Escherichia coli, Mycoplasma spp., Salmonella spp., Klebsiella spp., Pseudomonas spp., and Proteus spp. Enrofloxacin (Baytril®, Bayer Health Care, Animal Health Division, P.O. Box 390, Shawnee Mission, KS 66201) is a potentially effective antibiotic for treatment of these bacterial infections in elephants. Very limited data exists on the pharmacokinetics of enrofloxacin in elephants2 and most of the dosage regimes for gastrointestinal absorption are based on horse dosages since they share a similar  gastrointestinal tract. Three African elephants from Wildlife Safari in Winston, Oregon, two females both 37-yr-old and one male 26-yr-old, were used to determine whether therapeutic levels of enrofloxacin could be achieved thru rectal administration of liquid injectable enrofloxacin (Baytril 100®, 100 mg/ml, Bayer Health Care, Animal Health Division, P.O. Box 390, Shawnee Mission, KS 66201) at a dosage of 2.5 mg/kg. A pretreatment baseline blood sample was collected. Following administration, blood samples were collected at 45 min, 1.5hr, 2.5hr, 5hr, 9hr, 23hr, 36hr to determine plasma enrofloxacin levels. Plasma enrofloxacin levels were measured at North Carolina State University, College of Veterinary Medicine using high performance liquid chromatography (HPLC) analysis. Plasma ciprofloxacin levels were measured concurrently. Results indicate plasma concentrations of enrofloxacin did not reach adequate bacteriocidal levels for any of the the following common bacterial isolates in captive elephants: Mycoplasma spp., Escherichia coli, Salmonella spp., Klebsiella spp., Pseudomonas spp., and Proteus spp. The study determined that a rectally administered dosage of 2.5 mg/kg of liquid injectable enrofloxacin was insufficient to obtain therapeutic levels in African elephants. The low plasma levels of enrofloxacin in all three elephants may be a result of poor absorption in the distal large intestine. A future study will determine if oral administration will provide a more efficient mode of drug delivery and absorption in African elephants. It is also possible that the current dosage of 2.5 mg/kg is too low to achieve adequate therapeutic levels.

ACKNOWLEDGMENTS I would like to thank the elephant and veterinary staff at Wildlife Safari for their participation in conducting this study. Thanks to Doctors: Modesto McClean, Jason Bennett, Andi Chariffe, Tessa Lohe, Benji Alacantar. Also thanks to Dinah Wilson, Carol Matthews, Anthony Karels, Mary Iida, Shawn Finnell, Patches Stroud, Katie Alayan.

LITERATURE CITED
1. Haines, G.R., et. al. 2000. Serum concentrations and pharmacokinetics of enrofloxacin after intravenous and intragastric administration to mares. Can. J.Vet. Res. 64(3):171-177.
2. Sanchez, C.R., et. al. 2005. Pharmacokinetics of a single dose of enrofloxacin administered orally to captive Asian elephants (Elephas maximus). Am. J. Vet. Res. 66:1948-1953.

Monitoring Parameters -1) Clinical efficacy; 2) Adverse effects

Client Information – Do not crush tablets as drug is very bitter tasting.

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

Veterinary-Approved Products: (Note: See additional dosage forms in the dosage section for cattle and birds)

Enrofloxacin Oral Tablets 22.7 mg, 68 mg; Baytril®  (Miles); (Rx)  Approved for use in dogs and cats.

 

Enrofloxacin Injection 22.7 mg/ml in 20 ml vials; Baytril®  (Miles); (Rx)  Approved for use in dogs. A non-approved method for diluting the IM injectable product for IV administration has been described: Dilute 1 part of Baytril® injection with 2 parts of sterile water for injection and administer IV over 20 minutes or so.

Human-Approved Products: None. Note: Use of enrofloxacin by humans cannot be recommmended due to a high degree of CNS effects.