ENROFLOXACIN
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 drugciprofloxacin (enrofloxacin has an additional ethyl group on the piperazinyl ring).
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 thecurrently commercially available quinolones, ciprofloxacin and enrofloxacin have the lowest MICvalues for the majority of these pathogens treated. Other organisms that are generally susceptibleinclude Brucella sp, Chlamydia trachomatis, Staphylococci (including penicillinase-producing andmethicillin-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 anaerobesand are ineffective in treating anaerobic infections.
Resistance does occur by mutation, particularly with Pseudomonas aeruginosa, Klebsiellapneumonia, Acinetobacter and enterococci, but plasmid-mediated resistance is not thought to occur.
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 pleuralfluid. Low concentrations are found in the CSF, and levels may only reach 6-10% of those found inthe serum.
Enrofloxacin/ciprofloxacin is eliminated via both renal and non-renal mechanisms. Approximately15-50% of the drugs are eliminated unchanged into the urine, by both tubular secretion andglomerular filtration. Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are lessactive than the parent compounds. Approximately 30-40% of circulating enrofloxacin ismetabolized to ciprofloxacin. These metabolites are eliminated both in the urine and feces. Becauseof the dual (renal and hepatic) means of elimination, patients with severely impaired renal functionmay have slightly prolonged half-lives and higher serum levels which may not require dosageadjustment. The elimination half-lives in dogs are approximately 4-5 hours and in cats, 6 hours.
Because ciprofloxacin has occasionally been reported to cause crystalluria, animals should not beallowed 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 patientswith seizure disorders. Patients with severe renal or hepatic impairment may require dosageadjustments 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 malebreeding performance. Safety in breeding, pregnant, or lactating cats has not been established.
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 reportedwhen used with clindamycin against strains of Peptostreptococcus, Lactobacillus and Bacteroidsfragilis. Nitrofurantoin may antagonize the antimicrobial activity of the fluoroquinolones andtheir concomitant use is not recommended. Fluoroquinolones may exacerbate the nephrotoxicity ofcyclosporine (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.
It is slightly soluble in water. Enrofloxacin is related structurally to the human-approved drugciprofloxacin (enrofloxacin has an additional ethyl group on the piperazinyl ring).
Storage, Stability, Compatibility
Unless otherwise directed by the manufacturer, enrofloxacintablets should be stored in tight containers at temperatures less than 30°C. Protect from strong UVlight.Pharmacology - ENROFLOXACIN
Enrofloxacin is a bactericidal agent. The bactericidal activity of enrofloxacin is concentration dependent, with susceptible bacteria cel 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 thecurrently commercially available quinolones, ciprofloxacin and enrofloxacin have the lowest MICvalues for the majority of these pathogens treated. Other organisms that are generally susceptibleinclude Brucella sp, Chlamydia trachomatis, Staphylococci (including penicillinase-producing andmethicillin-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 anaerobesand are ineffective in treating anaerobic infections.
Resistance does occur by mutation, particularly with Pseudomonas aeruginosa, Klebsiellapneumonia, 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 - ENROFLOXACIN
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 pleuralfluid. Low concentrations are found in the CSF, and levels may only reach 6-10% of those found inthe serum.
Enrofloxacin/ciprofloxacin is eliminated via both renal and non-renal mechanisms. Approximately15-50% of the drugs are eliminated unchanged into the urine, by both tubular secretion andglomerular filtration. Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are lessactive than the parent compounds. Approximately 30-40% of circulating enrofloxacin ismetabolized to ciprofloxacin. These metabolites are eliminated both in the urine and feces. Becauseof the dual (renal and hepatic) means of elimination, patients with severely impaired renal functionmay have slightly prolonged half-lives and higher serum levels which may not require dosageadjustment. 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 beallowed 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 patientswith seizure disorders. Patients with severe renal or hepatic impairment may require dosageadjustments 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 malebreeding performance. Safety in breeding, pregnant, or lactating cats has not been established.
Adverse Effects, Warnings
With the exception of potential cartilage abnormalities in younganimals (see Contraindications above), the adverse effect profile of these drugs appears to beminimal. GI distress (vomiting, anorexia) is the most common, yet infrequently reported adverseeffect. Although not reported thus far in animals, hypersensitivity reactions, crystalluria and CNSeffects (dizziness, stimulation) could potentially occur.Overdosage, Acute Toxicity
It is unlikely an acute overdose of either compound would result insymptoms more serious than either anorexia and vomiting. Dogs receiving 10 times the labeleddosage rate of enrofloxacin for at least 14 days developed only vomiting and anorexia. Death didoccur 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 reportedwhen used with clindamycin against strains of Peptostreptococcus, Lactobacillus and Bacteroidsfragilis. Nitrofurantoin may antagonize the antimicrobial activity of the fluoroquinolones andtheir concomitant use is not recommended. Fluoroquinolones may exacerbate the nephrotoxicity ofcyclosporine (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.