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Nalidixic Acid - The Parent Drug of the Fluoroquinolones

The parent drug of the quinolone family was Nalidixic acid, this was found to be very narrow spectrum. It worked well only against gram negative enterobacteriaceae and resistance quickly developed. This limited it's use now for just urinary tract infections and for treatment of Aeromonas salmonicida in fish. Due to the restricted spectrum of the quinolones fluoroquinolones were developed to increase the range. The most commonly used in practice are Enrofloxacin, Marbofloxacin, Danofloxacin, Difloxacin, Ibafloxacin and Orbifloxacin.

Mechanism of Action

Fluoroquinolones work by inhibiting bacterial DNA gyrase or the topoisomerase enzyme and thus inhibit bacterial DNA replication and transcription. The gyrase enzyme is usually the target in gram-negative bacteria, whilst the topoisomerase enzyme is the target in most gram-positive bacteria. This kills the bacteria and so the drug is a bactericidal and concentration dependent.

These drugs also have the ability to cross animal's cell membranes through porins. This means that this group of drugs is capable of acting upon intracellular pathogens.

Spectrum of Activity

  • Active against gram-negative species including aerobic species such as Pseudomonas aeruginosa.
  • Active against gram-positives (doesn't work that well against Streptococcal species and enterococci.)
  • Works well against Mycoplasmas and Rickettsia.
  • Poor activity against obligate anaerobes.
  • Their activity is very pH dependent with their activity increasing above pH 7.4 and decreasing below pH 7.0.

It should be noted that they are active at very low concentrations, they don't kill protective enterococci and anaerobes, and they will inhibit aminoglycoside and beta-lactam resistant bacteria.

Pharmacokinetic Considerations

  • They are highly lipophilic and have a low degree of ionisation.
  • They are well absorbed from the gastrointestinal tract.
  • They aren't very well protein bound and so distribute well into extracellular and all intracellular fluids, including the CSF and prostatic fluid. They on do have a tendency to accumulate in the prostate, kidney and lung.
  • As mentioned earlier they are capable of crossing cell membranes and will reach high concentrations intracellularly.
  • They are excreted in both the bile and urine, 70% in the bile. Urine concentrations do reach high levels and remain high up to a day after a single dose.
  • Some metabolites are active (such as ciprofloxacin of enrofloxacin). The formation of these active metabolites are highly species dependent as it depends upon the liver enzymes present in each species. For example the horse doesn't metabolise enrofloxacin very well.

Side Effects and Contraindications

They are on the whole safe drugs with few side effects; those of significance are mentioned below:

  • High doses of enrofloxacin in cats can cause retinal blindness.
  • In young growing dogs there can be erosion of the articular cartilages. This may be the case in other young growing animals, we however do know that it is safe to use danofloxacin with calves.
  • In man small CNS problems have been reported, as yet these haven't been confirmed in animals. They include nausea, vomiting, headaches and a predisposition of seizures if a patient is an epileptic. There is an increased risk of these problems if NSAIDs are given concurrently.

Fluoroquinolones Learning Resources
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