Orbifloxacin

Overview

Orbifloxacin (Orbax®) is a fluoroquinolone antimicrobial used in dogs and cats for the treatment of susceptible bacterial infections. It is a broad-spectrum agent with activity against mycoplasmas, many Gram-negative organisms and some Gram-positive organisms including Staphylococcus.

Following oral administration, orbifloxacin penetrates most tissues and body fluids, reaching particularly high concentrations in the prostate, kidneys, liver, lungs, lymph nodes, and several other tissues. Its tissue distribution supports its use for susceptible skin, soft-tissue, and urogenital infections, including prostatic infections. As with other fluoroquinolones, its use should be reserved for cases where culture and susceptibility testing indicate that first- or second-line antimicrobials are unlikely to be effective.

Mechanism of Action (MOA): Orbifloxacin exerts concentration-dependent antibacterial activity through inhibition of bacterial DNA gyrase and topoisomerase IV. This interferes with bacterial DNA replication and results in bacterial cell death. Because its activity is concentration dependent, pulse-dosing strategies may be effective in some situations.

Indications

Orbifloxacin is used in dogs and cats for the treatment of susceptible bacterial infections, particularly when culture and susceptibility testing support its use.

• Bacterial cystitis: Treatment of susceptible urinary tract infections (cystitis) in dogs, including infections caused by Staphylococcus pseudintermedius, Proteus mirabilis and Escherichia coli.
• Skin infections: Management of susceptible bacterial skin infections in dogs and cats.
• Soft tissue infections: Treatment of susceptible soft tissue infections – specifically wounds and abscesses – in dogs and cats.
• Urogenital infections: In dogs, infections involving the urogenital tract; orbifloxacin is regarded as a good first-line choice for pyelonephritis and for infections that involve the prostate.
• Ear disease: Otitis externa in dogs, as part of a combination otic suspension with mometasone furoate and posaconazole, where yeast and bacteria are both involved.
• Hair follicle infection: Bacterial folliculitis, where fluoroquinolones are a second-tier choice selected on culture and susceptibility testing.
• Anal sac disease: Anal sac infection and sacculitis in dogs and cats, as one of the appropriate oral antibiotic choices.
• Spinal infection: Discospondylitis in dogs and cats that has not responded to first-line therapy.

Dosage (Reference)

Dog

Orbifloxacin is administered orally for susceptible bacterial infections in dogs. An otic formulation is also available, licensed for otitis externa in dogs only.

Cat

Orbifloxacin is administered orally for susceptible skin and soft tissue infections in cats.

Warnings & Precautions

Orbifloxacin should be used carefully in selected patients, particularly young growing animals and patients with neurologic or reproductive concerns.

• Young growing dogs: Contraindicated in immature dogs during the rapid growth phase—between 2 and 8 months of age in small- and medium-sized breeds and up to 18 months of age in large and giant breeds—because quinolones may cause cartilage erosion and arthropathy in growing animals
• Pregnancy and lactation: Safety in pregnant or lactating dogs and cats has not been established; use only when the expected maternal benefit outweighs the potential risks to the offspring.
• Breeding animals: The safety of orbifloxacin in dogs and cats used for breeding has not been established.
• Otic formulation: Do not use the otic preparation in animals younger than 4 months of age.
• Epilepsy and seizure disorders: Use with caution in animals with known or suspected CNS disorders, including seizure disorders, because quinolones have rarely been associated with CNS stimulation that may lead to seizures.
• High-dose therapy: Do not exceed 7.5 mg/kg per day in cats. In dogs, higher doses within the licensed 2.5 to 7.5 mg/kg range may be preferable, because activity is concentration dependent.
• Cats: Fluoroquinolones have been associated with retinal blindness in cats. Although this appears less likely with orbifloxacin, the labeled ceiling of 7.5 mg/kg per day in cats must not be exceeded.
• Hypersensitivity: Contraindicated in dogs and cats known to be hypersensitive to orbifloxacin or to other quinolones.
• Hepatic impairment: Use with caution in animals with hepatic insufficiency or impairment.
• Otic product — long-term use: Avoid prolonged or repeated use of the combination otic suspension; long-term topical otic corticosteroid use has been associated with adrenocortical suppression and iatrogenic hyperadrenocorticism in dogs.

Drug Interactions

Several medications may alter the absorption, metabolism or safety profile of orbifloxacin, which has itself been shown to inhibit CYP1A activity in dogs. Separate oral products containing cations by at least 2 hours, avoid the combinations that are contraindicated, and monitor where concurrent use is permitted.

• Antacids and absorbents containing magnesium or aluminum: Antacids, absorbents and dairy products containing magnesium, aluminum or calcium may bind orbifloxacin in the gastrointestinal tract and prevent its absorption; separate administration by at least 2 hours.
• Sucralfate: May decrease oral absorption of orbifloxacin; separate administration by at least 2 hours.
• Zinc salts: Oral zinc and iron salts may reduce gastrointestinal absorption of orbifloxacin; separate administration by at least 2 hours.
• Theophylline: Fluoroquinolones may increase plasma theophylline concentrations; reduce the theophylline dose when the two are used together.
• Cimetidine: May reduce the clearance of orbifloxacin; use cautiously when administered together.
• Ciclosporin: Fluoroquinolones may reduce the metabolism and worsen the nephrotoxicity of systemically administered ciclosporin; the manufacturer states that concurrent use with orbifloxacin is contraindicated.
• Tacrolimus: In humans, some fluoroquinolones may decrease tacrolimus metabolism and increase nephrotoxicity; until veterinary information is available, concurrent use in animals is best avoided.
• Oral anticoagulants: Orbifloxacin may increase the effects of orally administered anticoagulants.
• Nitrofurantoin: May antagonize the antimicrobial activity of fluoroquinolones; concurrent use is not recommended.
• Phenytoin: Orbifloxacin may alter phenytoin levels.
• Glyburide: Severe hypoglycemia is possible when given with glyburide.
• NSAID co-administration: Flunixin alters enrofloxacin exposure in dogs, but whether orbifloxacin or other NSAIDs interact in the same way is unknown.
• Combination therapy: Synergy with aminoglycosides, third-generation cephalosporins and extended-spectrum penicillins may occur but is not predictable; in vitro synergy against some anaerobes has been reported with clindamycin.

Side Effects & Overdose

Side Effects

Orbifloxacin is generally well tolerated – no drug-related adverse reactions were reported in the licensing field study at 2.5 mg/kg per day – but adverse effects associated with fluoroquinolones should be considered, particularly in young animals and patients with neurologic disorders.

• Cartilage abnormalities: Fluoroquinolones have been associated with cartilage damage in growing animals; dogs are most sensitive between 4 and 28 weeks of age, and large, rapidly growing dogs are the most susceptible.
• CNS effects: Use cautiously in epileptic patients, as fluoroquinolones may potentiate central nervous system adverse effects; high concentrations can cause CNS toxicity, and the risk is greater in animals with kidney disease.
• Retinal toxicity in cats: Fluoroquinolones have been associated with retinal blindness in cats. Blindness, mydriasis, abnormal retinal appearance and ataxia have all been reported in cats after approval, and in some cases the blindness has been temporary.
• Gastrointestinal and neurological signs: Anorexia, vomiting, hypersalivation, diarrhea, depression, lethargy and convulsions have been reported.
• Necrotizing fasciitis: Induction of Streptococcus canis necrotizing fasciitis, which can occur with enrofloxacin, does not appear to be a problem with orbifloxacin.
• Hearing loss (otic product): Stop the combination otic suspension immediately if hearing loss is noticed; in the field study one of 143 treated dogs developed hearing loss, which resolved a week after treatment was stopped.

Overdose

Dogs and cats given up to five times the label dose (37.5 mg/kg) for 30 days showed no significant adverse effects. Patients receiving excessive doses should be monitored carefully and treated according to their clinical signs. At 75 mg/kg dogs developed anorexia, vomiting, diarrhea, mild weight loss and glucosuria; cats at 45 and 75 mg/kg per day developed emesis, salivation, lacrimation, soft feces, reduced food intake and retinal degeneration.

• Management: Provide supportive and symptomatic care as needed, and consult a 24-hour veterinary poison control service for case-specific advice.
• Monitoring: Closely monitor patients following accidental overdose or administration of higher-than-recommended doses.

Key Notes

Practical clinical points that may help optimize the use of orbifloxacin in dogs and cats:

• Culture-guided therapy: Use should be guided by culture and susceptibility testing and reserved for cases where first- or second-line antimicrobials are unlikely to be effective. Orbifloxacin is an EMA category B (Restrict) antimicrobial, and the World Health Organization classifies it as critically important for human medicine.
• Beta-lactamase-producing bacteria: Fluoroquinolones remain active against many beta-lactamase-producing bacterial isolates.
• Intracellular penetration: Orbifloxacin penetrates into most tissues and body fluids, reaching particularly high levels in the prostate, kidney, liver, bile, lung, lymph node, small intestine, cartilage, muscle, salivary gland and testis.
• Anaerobic infections: Orbifloxacin is not effective for the treatment of infections caused by obligate anaerobic bacteria.
• Concentration-dependent activity: Antibacterial efficacy is concentration dependent, which is why the drug is given once daily at a high dose; clinical efficacy is associated with a peak concentration about 10 times the bacterial MIC. Orbifloxacin also has a significant postantibiotic effect against both Gram-negative and Gram-positive bacteria.
• Pharmacokinetics: Oral absorption is near complete in both species, with a serum half-life of about 5.5 hours in dogs and 4.5 to 7.5 hours in cats. Protein binding is low (8% in dogs, 15% in cats). About half the dose is excreted unchanged by the kidney, and urine concentrations stay well above the MIC of susceptible organisms for at least 24 hours after dosing.
• Formulation-specific dosing in cats: In cats the tablet and the oral suspension are not bioequivalent: on a mg/kg basis the suspension gives lower and more variable plasma levels than the tablet. The suspension dose is 7.5 mg/kg once daily; the tablet dose is 2.5–7.5 mg/kg once daily.
• What a susceptible report means: The CLSI susceptibility breakpoint for orbifloxacin in dogs and cats is 1 mcg/mL; isolates reported as intermediate may respond to doses at the higher end of the range.
• Administration and dispensing: Give on an empty stomach where possible; if the animal vomits or seems unwell, give with a small amount of food or a treat – but not with dairy products, antacids or anything containing calcium, iron or aluminum, which reduce absorption. In cats, food does not change the peak concentration or half-life of the suspension, although it delays the peak and raises total exposure. Shake the suspension before use, rinse the dosing syringe after each dose, and give the full prescribed course even if the animal seems well.
• Storage: Store tablets at 2–30°C protected from moisture, and the oral suspension at 2–25°C; the suspension does not need refrigeration, should be stored upright and shaken before use, and is used within 30 days of first opening. Store the otic suspension at 2–30°C and shake it well before use.
• Compounding: A crushed 22.7 mg tablet mixed with molasses, corn syrup, tuna water, fish sauce or simple syrup stayed stable for up to 7 days unrefrigerated and protected from light, but mixing with oral supplements containing calcium or magnesium caused significant inactivation within 4 days.
• Enterococci: Enterococcus faecalis is named on the canine urinary license, but most enterococci are reported to be resistant to fluoroquinolones – treat an enterococcal isolate on susceptibility testing rather than on the labeled indication.
• Resistance: Some Pseudomonas strains are resistant, and acquired resistance is encountered most often in Enterobacteriaceae such as Escherichia coli and in staphylococci – confirm activity on culture and susceptibility testing rather than assuming it.
• Choosing over an aminoglycoside: In peritonitis protocols, orbifloxacin may substitute for an aminoglycoside, especially when renal function is impaired.
• When to re-evaluate: Start treatment on clinical grounds if necessary, then continue with the therapy the susceptibility result supports; if there is no improvement within five days, re-evaluate the diagnosis and consider a different course of therapy.