Fluoroquinolone use in cats

© Gottlieb, S et al. (2008) Susceptibility of canine and feline Escherichia coli and canine Staphylococcus intermedius isolates to fluoroquinolones. AVJ 86(4): 147-152

Fluoroquinolones are an important class of antimicrobials used to treat bacterial infections in humans and companion animals. Presently, Australian veterinarians can prescribe four veterinary fluoroquinolones: enrofloxacin (Baytril^®), orbifloxacin (Orbax^®), difloxacin (Dicural^®) and marbofloxacin (Zenequin^®) (see drugs for dosages).

Ciprofloxacin, a fluoroquinolone registered for use in humans and available in generic formulations, is also administered to dogs and cats due to its greater activity against some isolates of Pseudomonas aeruginosa compared with other fluoroquinolones. Newer or fourth generation fluoroquinolones such as moxifloxacin are also available to treat respiratory tract infections in humans because of their additional activity against anaerobic bacteria and improved efficacy against Gram positive organisms. Pradofloxacin, which has a similar spectrum of activity and chemical composition to moxifloxacin is presently undergoing registration for veterinary use.

Exposure of bacteria to fluoroquinolones and other antimicrobial agents in unfavourable sites with impaired body defences is likely to select for bacteria with high-level resistance which is conferred by genes located in mobile genetic elements (integrons, transposons and plasmids) capable of encoding mechanisms that resist the actions of antimicrobials.

Baytril use and blindness

The toxicology and safety of Baytril has been extensively studied in various laboratory animals, as well as in the target species dog and cat, where it has been proven to be safe and well tolerated. No adverse effects on blood composition or kidney function were observed, nor was it teratogenic or mutagenic.

In eukaryotes, Baytril like other modern quinolones, has a broad margin of safety because compared to prokaryotes, their enzyme analogue to DNA gyrase is 100-1000 times less susceptible to "topoisomerase inhibitors".

For quinolones in general, side effects on different organ systems (CNS, gastrointestinal tract or locomotory system) have been reported. Enrofloxacin has undergone considerable toxicological and safety testing in laboratory species such as mice, rats and guinea pigs, as well as in the target species dog and cat (2).

Common to all quinolones is that they may produce cartilage lesions in weight-bearing joints of growing dogs. Safety studies have shown that puppies between 1 and 4 weeks of age tolerated treatment with Baytril for up to 10 days at maximum doses of 25 mg/kg b.w. without showing adverse effects. In young dogs above 6 weeks of age, however, cartilage was affected depending on the dose and duration of Baytril administration. By contrast, young cats dosed with Baytril at maximum doses of 25 mg/kg b.w. for up to 30 days did not develop cartilage lesions. Thus, as a matter of precaution, all growing dogs were excluded from treatment. However, no evidence exists that Baytril treatment of pregnant or nursing dogs would have a negative influence on the cartilage development of the offspring.

Detailed information:

- Central Nervous System
For Baytril, no noteworthy effects on the CNS of mice and rats have been observed; there is also no indication of central nervous system effects in dogs and cats. The recommendation not to treat dogs with CNS disorders, e.g., epilepsy, is a matter of precaution, which applies to all fluoroquinolones (2).

In human patients undergoing quinolone therapy, however, CNS effects of mild symptoms such as dizziness, headache and insomnia have been reported. It was suggested that these drugs competitively inhibit receptor binding of gamma-aminobutyric acid (GABA), an inhibitory transmitter of the CNS (3). Structural similarity of substituents of some quinolones at the C7-position with the binding region of the GABA molecule may be the reason for this phenomenon (4).

- Gastrointestinal Tract
As with all antiinfectives, gastrointestinal disturbances such as nausea, vomiting or diarrhea may occasionally occur. In experimental studies on dogs, vomiting was induced only in doses far exceeding the therapeutic recommendations (> 1000 mg/kg b.w. PO) (2). As Baytril has only minimal effects on anaerobic organisms, which represent a considerable part of the normal bowel flora, the incidence of intestinal side effects may be less frequent compared to antiinfectives of other families (3).

- Cartilage Lesions
Quinolones have been demonstrated to cause cartilage erosion in the joints of growing dogs. Histologically, vesicles in the articular cartilage are formed, which can progressively rupture and produce cartilaginous erosion. This observation is due to an early phase burst in oxidative metabolism and to disturbances in the electrolyte (Mg ++) household of immature chondrocytes. Experimental and clinical findings suggest that bearing of weight by joints may be important in the pathogenesis of these lesions (4).

To clarify whether Baytril can safely be used at therapeutic doses in growing dogs, a number of studies in animals of different breeds and ages have been conducted (2).

It appears that very young dogs between 1 and 4 weeks of age tolerate treatment with Baytril from 5 to 25 mg/kg b.w. for up to 10 days without developing cartilage lesions.

In animals older than 6 weeks, lesions occurred to a certain extent, depending on dosage and duration of treatment. As it is not possible to exactly determine the age up until which the drug is to be considered safe in puppies, all dogs under 12 months (18 months in giant breeds) were excluded from treatment as a matter of precaution (2). There is, however, no evidence that treatment of pregnant or nursing dogs would have any negative influence on the joint cartilage development of the offspring (2).

In contrast to dogs, cartilage lesions could not be demonstrated in growing cats from two to 10 months of age when treated with Baytril doses of up to 25 mg/kg b.w. for up to 30 days. It can be concluded that cartilage tolerance towards enrofloxacin is higher in cats than in dogs (2).

Other Safety Issues
Studies on safety pharmacology using standard test designs were conducted in laboratory animals. Oral enrofloxacin doses of up to 100 mg/kg b.w., 20 times the recommended dosage, showed no significant adverse effects on blood composition, blood coagulation or diuresis. In the bronchoactivity test, no evidence of any effect on the smooth muscles of the respiratory system was found.

It could also be shown that Baytril does not elicit any antiallergic or pseudoallergic reactions. In the rabbit local irritation test and guinea pig skin sensitization test, enrofloxacin as the active substance was not a skin irritant and only slightly irritating to the eye (2). A Baytril 0.5% eyedrop formulation, however, did not produce any irritation after application to the rabbit eye.

- Acute Toxicity
The LD50 values were determined in different species. All acute effects appear at doses far exceeding the therapeutic range (5). Dogs vomit after oral application of doses above 1000 mg/kg b.w., which is 200 times the recommended dosage, such that an LD50 could not be determined (2).

- Subchronic toxicity
In subchronic feeding studies with enrofloxacin as the active substance, carried out over 13 weeks, the no-effect level (NOEL), which is the dose that can be administered with food over prolonged periods without adverse effects, was determined (2).

For rats, mice and adult dogs, general NOELs of 165, 550, and 52 mg/kg b.w., respectively, were found. This means that at the recommended doses adult dogs can be treated safely and for longer time without unwanted effects (2).

- Embryotoxicity and Teratogenicity
Trials in rats daily treated with enrofloxacin (0, 50, 210, and 875 mg/kg b.w.) from the 6th to the 15th day of gestation produced no evidence of teratogenic effects from enrofloxacin, including the highest dosage group. Maternal toxic effects after 210 and 875 mg/kg, however, resulted in slightly reduced fetal weights and delayed ossification. In the highest dosage group, which received 175 times the dosage recommended for dogs and cats, smaller litter sizes were observed. A dosage of 50 mg enrofloxacin per kg body weight was tolerated without any adverse effect to mothers and offspring (5).

- Mutagenicity
The point mutagenic effect of enrofloxacin was studied in the Salmonella Microsome Test (Ames-Test) and in ovarian cells of the Chinese hamster (CHO-HGPRT forward mutation assay). The Unscheduled DNA Synthesis Test was performed to check for damage to the DNA. These test systems produced no evidence of any mutagenic effect (5).


- Retinal Toxicity in Cats

It is well known that old quinolones, such as nalidixic acid, may affect the eye as a potential target organ (6). In this connection alteration of the lens or melanin-containing eye tissues (retina, iris, ciliary body) have been reported from human medicine.

As a matter of precaution Baytril therefore has been evaluated in ophthalmoscopic and histopathological studies on laboratory animals, dogs, and cats. Those toxicological studies with repeated administration of high doses did not reveal any evidence of   unwanted effects on the eyes of the animals examined.

Sporadic reports of blindness in cats previously treated with Baytril, however, have been received mainly from the US in the last few years. In an additional safety study on cats Baytril was given over 3 weeks at different doses (5, 20, 50 mg/kg body weight) once daily. No adverse effects were observed in cats that received 5 mg Baytril per kg body weight. The administration of doses of 20 mg/kg body weight or greater caused salivation, vomition and depression and additionally resulted in mild to severe fundic lesions on ophthalmologic examination, changes in   electroretinograms (including blindness) and diffuse light microscopic alterations.

It has therefore been recommended to treat cats with Baytril at daily doses not exceeding 5 mg/kg b.w., which is the officially registered dose in most countries of the world.

In contrast to cats there is no evidence that visual alterations can also occur in other species, e.g. dogs.

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