CIPROFLOXACIN
Chemistry - A fluroquinolone antibiotic, ciprofloxacin HCl occurs as a faintly yellowish to yellow, crystalline powder. It is slightly soluble in water. Ciprofloxacin is related structurally to theveterinary-approved drug enrofloxacin (enrofloxacin has an additional ethyl group on the piperazinyl ring).
Both enrofloxacin and ciprofloxacin have similar spectrums of activity. These agents have goodactivity 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 fluroquinolones 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.
In humans, the volume of distribution in adults for ciprofloxacin is about 2-3.5 L/kg and it isapproximately 20-40% bound to serum proteins.
Ciprofloxacin is one of the metabolites of enrofloxacin. Approximately 15-50% of the drugs areeliminated unchanged into the urine, by both tubular secretion and glomerular filtration.
Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are less active than the parentcompounds. 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 prolongedhalf-lives and higher serum levels which may not require dosage adjustment.
The pharmacokinetics of ciprofloxacin have been studied in calves and pigs (Nouws et al. 1988).
Oral bioavailability is approximately 50% in calves and 40% (only one pig studied) in pigs and ithas an elimination half-life of about 2.5 hours in both species. Protein binding was significantlydifferent for each species, with calves having about 70% of the drug bound and pigs only about23% bound to plasma proteins.
Bubble-like changes in articular cartilage have been noted when the drug was given at 2-5 timesrecommend 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 ofage, so longer than 8 months may be necessary to avoid cartilage damage. Quinolones are alsocontraindicated 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.
Overdosage - Little specific information is available. See the enrofloxacin monograph for moreinformation.Drug/
Enrofloxacin/ciprofloxacin administered with theophylline may increase theophylline bloodlevels.
Probenecid blocks tubular secretion of enrofloxacin/ciprofloxacin and may increase its bloodlevel and half-life.
Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonasaeruginosa 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 fluroquinolones and theirconcomitant use is not recommended. Fluroquinolones may exacerbate the nephrotoxicity ofcyclosporine (used systemically).
Because the are relatively new additions to the therapeutic armamentarium, more interactions maybe forthcoming.
Drug/Laboratory Interactions - In some human patients, the fluroquinolones 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.
Storage, Stability, Compatibility
Unless otherwise directed by the manufacturer, ciprofloxacintablets should be stored in tight containers at temperatures less than 30°C. Protect from strong UVlight. The injection should be stored at 5°-25°C and protected from light and freezing.Pharmacology - CIPROFLOXACIN
Ciprofloxacin is a bactericidal agent. The bactericidal activity of ciprofloxacin isconcentration dependent, with susceptible bacteria cel death occurring within 20-30 minutes ofexposure. Ciprofloxacin 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 ofaction is not thoroughly understood, but it is believed to act by inhibiting bacterial DNA-gyrase (atype-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis.Both enrofloxacin and ciprofloxacin have similar spectrums of activity. These agents have goodactivity 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 fluroquinolones 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
Because of its similar spectrum of activity, ciprofloxacin could be used as analternative to enrofloxacin when a larger oral dosage form or intravenous product is desired. But thetwo compounds cannot be considered equivalent because of pharmacokinetic differences (seebelow).Pharmacokinetics - CIPROFLOXACIN
Both enrofloxacin and ciprofloxacin are well absorbed after oral administration in most species. But in dogs, enrofloxacin's bioavailability is about twice that ofciprofloxacin after oral dosing. In humans, the oral bioavailability of ciprofloxacin has been reported to be between 50-85%. Studies of the oral bioavailability in ponies have shown thatciprofloxacin is poorly absorbed (2-12%) while enrofloxacin in foals apparently is well absorbed.In humans, the volume of distribution in adults for ciprofloxacin is about 2-3.5 L/kg and it isapproximately 20-40% bound to serum proteins.
Ciprofloxacin is one of the metabolites of enrofloxacin. Approximately 15-50% of the drugs areeliminated unchanged into the urine, by both tubular secretion and glomerular filtration.
Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are less active than the parentcompounds. 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 prolongedhalf-lives and higher serum levels which may not require dosage adjustment.
The pharmacokinetics of ciprofloxacin have been studied in calves and pigs (Nouws et al. 1988).
Oral bioavailability is approximately 50% in calves and 40% (only one pig studied) in pigs and ithas an elimination half-life of about 2.5 hours in both species. Protein binding was significantlydifferent for each species, with calves having about 70% of the drug bound and pigs only about23% bound to plasma proteins.
Contraindications, Precautions, Reproductive Safety
Ciprofloxacin, like enrofloxacin shouldbe considered 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 timesrecommend 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 ofage, so longer than 8 months may be necessary to avoid cartilage damage. Quinolones are alsocontraindicated 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.
Adverse Effects, Warnings
With the exception of potential cartilage abnormalities in younganimals (see Contraindications above), the adverse effect profile of fluroquinolones 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 - Little specific information is available. See the enrofloxacin monograph for moreinformation.Drug/
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 bloodlevels.
Probenecid blocks tubular secretion of enrofloxacin/ciprofloxacin and may increase its bloodlevel and half-life.
Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonasaeruginosa 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 fluroquinolones and theirconcomitant use is not recommended. Fluroquinolones may exacerbate the nephrotoxicity ofcyclosporine (used systemically).
Because the are relatively new additions to the therapeutic armamentarium, more interactions maybe forthcoming.
Drug/Laboratory Interactions - In some human patients, the fluroquinolones 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.