Nitrofurans are synthetic chemotherapeutic agents with a broad antimicrobial spectrum; they are active against both gram-positive and gram-negative bacteria, including Salmonella and Giardia spp, trichomonads, amebae, and some coccidial species. However, compared with other antimicrobial chemotherapeutic agents, their potency is not of particular note. The nitrofurans appear to inhibit a number of microbial enzyme systems, including those involved in carbohydrate metabolism, and they also block the initiation of translation. However, their basic mechanism of action has not yet been clarified.
Their primary action is bacteriostatic, but at high doses they are also bactericidal. They are much more active in acidic environments (a pH of 5.5 is optimal for nitrofurantoin activity). Resistant mutants are rare, and clinical resistance emerges slowly. Among themselves, nitrofurans show complete cross-resistance; however, there is no cross-resistance with any other antibacterial agents.
Because of very slight water solubility, the nitrofurans are administered either PO or topically. No nitrofuran is effective systemically. They are either not absorbed at all from the GI tract or are so rapidly eliminated that they reach inhibitory concentrations only in the urine. Toxic clinical signs develop with excessive doses of nitrofuran derivatives include CNS involvement (excitement, tremors, convulsions, and peripheral neuritis), GI disturbances, poor weight gain, and depression of spermatogenesis. Various hypersensitivity reactions can also occur. Some nitrofurans are carcinogenic, and their future use is in doubt.
Nitrofurans are among the drugs for which extralabel use is prohibited in production animals in the US due to their carcinogenic potential. Because there are no approved nitrofurans for use in production animals in the US, nitrofurans are therefore prohibited from use in production animals in the US. Of the nitrofurans, only furazolidone and nitrofurazone are approved for veterinary use in the US and are labeled for topical application in horses, cats, and dogs.
Nitrofurantoin
The mechanism of action of nitrofurantoin is unique. It is decreased by bacterial flavoproteins to reactive intermediates that inhibit bacterial ribosomes and other macromolecules. Protein synthesis, aerobic energy metabolism, DNA and RNA synthesis, and cell wall synthesis are inhibited. Nitrofurantoin is bactericidal in urine at therapeutic doses. Resistance is rare.
Nitrofurantoin is used in an extralabel fashion in dogs and cats to treat urinary tract infections due to susceptible bacteria, such as Escherichia coli, Staphylococcus aureus, Streptococcus pyogenes, and Aerobacter aerogenes. Proteus spp, Pseudomonas aeruginosa, and Streptococcus faecalis are usually resistant. After administration PO, nitrofurantoin is rapidly and completely absorbed (the macrocrystal form takes longer) and is swiftly eliminated via the kidneys, mainly by tubular secretion (~40% in the unchanged form). Serum concentrations are low, and little unbound drug is available for diffusion into the tissues. The plasma half-life is only ~20 minutes.
Nitrofurantoin is concentrated in acid urine. When the pH reaches ~5, the drug becomes supersaturated without precipitation, and its antibacterial action is maximal. Nitrofurantoin can be administered PO or parenterally. The dosage for dogs and cats is 4.4 mg/kg, PO, every 8 hours for 4–10 days. Adverse effects are not common at usual dosages, but nausea, vomiting, and diarrhea can develop; CNS disorders have occurred, and polyneuropathy is a serious effect seen in people. Animals with decreased renal function have a predisposition for polyneuritis. Various manifestations of hypersensitivity reactions can occur. Yellow discoloration of teeth occasionally has been reported in very young animals.
Nitrofurazone
Nitrofurazone is only slightly soluble in water but, in general, corresponds to nitrofurantoin in terms of its mechanism of action, antimicrobial spectrum, potency, and physicochemical characteristics. It is approved for veterinary use in dogs, cats, and horses in the US. Nitrofurazone is commonly used as a topical antimicrobial in wound management in approved species and as a topical agent in management of contagious equine metritis. However, pus, blood, and milk decrease the antibacterial activity.
Furazolidone
Furazolidone is a nitrofuran with a wide range of antimicrobial activity that includes Clostridium, Salmonella, Shigella, Staphylococcus and Streptococcus spp, and E coli. It is also active against Eimeria and Histomonas spp. It is labeled for use as a topical application for wound management in horses and dogs in the US. It was previously approved for oral use in swine, chickens, and turkeys but has been withdrawn from the market. Oral administration may result in neurotoxicity, with clinical signs including head tremors, ataxia, visual impairment, and convulsions.
