THE MERCK VETERINARY MANUAL
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Quinolones

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Quinolone carboxylic acid derivatives are synthetic antimicrobial agents. Nalidixic acid and its congener oxolinic acid have been used for treatment of urinary tract infections for years, while flumequine has been used successfully in several countries to control intestinal infections in livestock. Many broad-spectrum antimicrobial agents have been produced by modification of the various 4-quinolone ring structures.

Classes

Known generically as quinolones or 4-quinolones, these drugs are derived from several closely related ring structures that have certain common features. The major classes are presented in see Classes of QuinolonesTableswith several clinically useful examples of each.

Table 11

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General Properties

Within the diversity of their various ring structures, the quinolones have a number of common functional groups that are essential for their antimicrobial activity. For example, the quinolone nucleus contains a carboxylic acid group at position 3 and an exocyclic oxygen at position 4 (hence the term 4-quinolones), which are believed to be the active DNA gyrase binding sites. Various modifications have produced compounds with differing physical, chemical, pharmacokinetic, and antimicrobial properties. For example, the side chain attached to the nitrogen at position 1 affects potency. Replacement of the ethyl group at this position with a bulkier group (eg, the cyclopropyl group of ciprofloxacin and similar drugs) enhances gram-negative and positive spectra. Addition of a fluorine atom at position 6 profoundly enhances the gram-positive spectrum, whereas the addition of a (heterocyclic nitrogen containing) piperazyl ring at position 7 enhances bacterial penetration and potency, including toward Pseudomonas aeruginosa. Substitutions on the piperazyl (eg, ofloxacin and its L isomer, levofloxacin; sparfloxacin) enhance gram-positive penetration, while substitutions at position 8 enhance anaerobic activity (eg, sparfloxacin, pradofloxacin, moxifloxacin). If the substitution is with a methoxy group (rather than a halogen), the risk of phototoxicity is reduced.

The quinolones are amphoteric and, with a few exceptions, generally exhibit poor water solubility at pH 6–8. In concentrated acidic urine, some quinolones form needle-shaped crystals, although this apparently has not been reported with clinical use. Liquid formulations of various quinolones for PO or parenteral administration usually contain freely soluble salts in stable aqueous solutions. Solid formulations (eg, tablets, capsules, or boluses) contain the active ingredient either in its betaine form or, occasionally, as the hydrochloride salt.

Antimicrobial Activity

The quinolones inhibit bacterial enzyme topoisomerases, including topoisomerase II and topoisomerase IV, otherwise known as DNA-gyrase. Topoisomerases support supercoiling and subsequent uncoiling of DNA so that the DNA can twist into the chromosomal domains that conform to the RNA core. Supercoiling requires transient nicks that are subsequently sealed after DNA polymerase passes. Inhibition of topoisomerases reduces supercoiling, resulting in disruption of the spatial arrangement of DNA. Mammalian topoisomerase enzymes fundamentally differ from bacterial gyrase and are not susceptible to quinolone inhibition. The quinolones are usually bactericidal; susceptible organisms lose viability within 20 min of exposure to optimal concentrations of the newer fluoro-quinolones. Typically, clearing of cytoplasm at the periphery of the affected bacterium is followed by lysis, rendering bacteria recognizable only as “ghosts.”

Quinolones are associated with a post-antibiotic effect in a number of bacteria, principally gram-negative (eg, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa). The effect generally lasts 4–8 hr after exposure.

Ideal bactericidal concentrations of the quinolones are often 0.1–10 μg/mL; efficacy tends to diminish at higher concentrations. This unusual biphasic effect is thought to be due to suppression of RNA synthesis at higher quinolone concentrations. Efficacy of the fluorinated quinolones depends on concentrations in plasma that exceed the MIC of the infecting organism by 10- to 12- fold.

The fluoroquinolones can have significant antibacterial activity at extraordinarily low concentrations, although efficacy toward some organisms (eg, E coli) is bimodal: some isolates are very susceptible (MIC <0.01–0.5 μg/mL) whereas the MIC for a significant number of other isolates is very high (>64 μg/mL). In general, MIC for P aeruginosa and Staphylococcus have increased since the approval of the quinolones in the early 1990s.

Chromosomal mutational resistance to the original fluoroquinolones was considered to be low in frequency and plasmid-mediated resistance nonexistent. However, resistance is increasingly being recognized, indicating that therapy based on culture and susceptibility is prudent. In general, cross-resistance should be anticipated among the more closely related members of this class.

Gram-negative bacteria more commonly target DNA gyrase; emerging resistance is more often associated with changes in the GyrA compared to the GyrB subunit. In contrast, the primary target of gram-positive organisms tends to be topoisomerase IV, with resistance mechanisms targeting it followed by changes in DNA gyrase. Use of the drug selects for resistance. High level resistance (3–4 × the breakpoint MIC) generally reflects a second-step mutation that leads to changes in the amino acid sequence of subsequent topoisomerase targets. Newer drugs, including gemifloxacin, trovafloxacin, gatifloxacin, or pradofloxacin, may target both DNA gyrase and topoisomerase IV and thus may lead to less resistance.

Another mechanism of resistance is the combined effect of increased efflux pumps and decreased porins that act in concert to reduce intracellular concentrations. Virulence of refractory mutants may not diminish.

The fluoroquinolones are active against a wide range of gram-negative and a number of gram-positive aerobes. They are highly effective against all intestinal bacterial pathogens, as well as several intracellular pathogens, eg, Brucella spp. Quinolones also have significant activity against Mycoplasma and Chlamydia spp. Obligate anaerobes tend to be resistant to most quinolones, as are most enterococcal group D Streptococcus spp (S faecalis and S faecium).

The older quinolones (eg, nalidixic acid and oxolinic acid) and the nonfluorinated quinolones (eg, cinoxacin) tend to have only a moderately extended gram-negative spectrum. The newest third- and fourth-generation fluorinated quinolones may be characterized by an effective anaerobic spectrum.

A synergistic effect has been demonstrated in vitro between quinolones and β-lactams, aminoglycosides, clindamycin, and metronidazole.

Pharmacokinetic Features

Among the few quinolones that have been studied to any degree in domestic animals, pharmacokinetic differences are significant. Because of the physicochemical nature of the group, this is to be expected. A general overview follows, but some diversity should be anticipated.

Quinolones are commonly administered PO, although forms of enrofloxacin and ciprofloxacin are available for IV, IM, and SC administration. Absorption into the blood after IM or SC delivery is rapid; after administration PO, peak blood concentrations are usually attained within 1–3 hr. Bioavailability is often >80% for most quinolones, except for ciprofloxacin and in ruminants with functional forestomachs, in which bioavailability may be as low as 0–20%. The presence of food may delay absorption in monogastric animals. The bioavailability of ciprofloxacin after administration PO in dogs is variable and can be as little as 40%; it is 0–20% in cats.

The quinolones, with few exceptions (eg, cinoxacin), penetrate all tissues well and quickly. Particularly high concentrations are found in the kidneys, liver, and bile, but concentrations found in prostatic fluid, bone, endometrium, and CSF are also quite notable. Most quinolones also cross the placental barrier. The apparent volume of distribution of most quinolones is large. The degree of plasma-protein binding is extremely variable, from ∼10% for norfloxacin to >90% for nalidixic acid. Fluorinated quinolones as a group accumulate in phagocytic WBC.

Some quinolones are eliminated unchanged (eg, ofloxacin), some are partially metabolized (eg, cinoxacin, ciprofloxacin, enrofloxacin), and a few are completely degraded (eg, acrosoxacin, pefloxacin). Metabolites are sometimes active; enrofloxacin is de-ethylated to form ciprofloxacin. Characteristically, phase I reactions result in a number of primary metabolites (up to 6 have been described for some quinolones) that retain some antibacterial action. Conjugation with glucuronic acid then ensues, followed by excretion.

Renal excretion is the major route of elimination for most quinolones. Both glomerular filtration and tubular secretion are involved. Urine concentrations are often high for 24 hr after administration, and crystals may form in concentrated acidic urine. The clinical significance of this finding is unclear. In renal failure, clearance is impaired, and reductions in dose rates are essential. Biliary excretion of parent drug, as well as conjugates, is an important route of elimination in some cases (eg, ciprofloxacin, marbofloxacin, difloxacin, pefloxacin, nalidixic acid). Quinolones appear in the milk of lactating animals, often at high concentrations that persist for some time.

The plasma half-lives are quite variable among species and the different quinolone classes: 3–6 hr are common, but prolonged plasma half-lives are seen (eg, 10 hr for pefloxacin in humans). Plasma concentrations attained are usually directly proportional to the dose administered. Although somewhat lower, the plasma drug concentration after administration PO is not greatly different from that after SC injection. The elimination patterns are also quite similar for PO and parenteral routes.

Therapeutic Indications and Dose Rates

Quinolones are indicated for the treatment of local and systemic infections caused by susceptible microorganisms, particularly against deep-seated infections and intracellular pathogens. Therapeutic success has been obtained in respiratory, intestinal, urinary, and skin infections, as well as in bacterial prostatitis, meningoencephalitis, osteomyelitis, and arthritis.

A selection of general dosages for some quinolones is listed in see Dosages of QuinolonesTables. The dose rate and frequency should be adjusted as needed for the individual animal.

Table 12

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Special Clinical Concerns

Although side effects with the older quinolones (nalidixic and oxolinic acids) were relatively common, the newer ones seem to be well tolerated. However, several adverse effects can limit use in selected species. Retinal degeneration may occur acutely in cats, with the risk greatest for enrofloxacin and least for marbofloxacin. The mechanism is not known. Quinolones tend to be neurotoxic, and convulsions can occur at high doses. Vomiting and diarrhea rarely develop with fluoroquinolones. Dermal reactions and photosensitization have been described in humans, but the occurrence seems low. Hemolytic anemia has also been seen. Administering large doses of quinolones for any length of time during pregnancy has resulted in embryonic loss and maternal toxicity. Because high prolonged dosages in growing dogs have produced cartilaginous erosions leading to permanent lameness, excessive use of quinolones should be avoided in immature animals. Quinolone administration in horses has not yet been extensively studied, but there is some indication that damage to the cartilage in weightbearing joints may be seen.

The likelihood of interactions has not yet been clearly established. Antacids probably interfere with the GI absorption of the quinolones. It also seems that nitrofurantoin impairs the efficacy of quinolones if used concurrently for urinary tract infections. Quinolones do inhibit the biotransformation of theophylline, leading to prolonged and potentially toxic plasma concentrations.

AST, ALT, alkaline phosphatase, and BUN may be increased. Urinalysis may reveal needle-shaped crystals.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

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