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Quinolones, including Fluoroquinolones

By Dawn Merton Boothe, DVM, PhD, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

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, whereas 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. Examples of the quinolone carboxylic acids and species in which they are approved are presented in Quinolones and Species Approvals in the USA. Nalidixic acid, considered a first-generation drug, is the earliest of the quinolones. In general, subsequent generations are based on spectrum, but this often reflects similar changes in chemical structure. Subsequent drugs contain a fluorine group and, as such, are referred to as fluoroquinolones. Most veterinary drugs and many human drugs, including ciprofloxacin, are considered second generation. Pradofloxacin is an example of a later-generation drug approved for use in cats (USA) or dogs and cats (European Union).

Quinolones and Species Approvals in the USA

Quinolone

Species

Ciprofloxacin

Dogs, cats

Danofloxacin

Dogs, cattle

Difloxacin

Dogs

Enrofloxacin

Dogs, cats, cattle, swine

Marbofloxacin

Dogs, cats

Norfloxacin

Dogs, cats

Orbifloxacin

Dogs, cats

Pradofloxacin

Cats

Sarafloxicin

Voluntarily withdrawn

General Properties

Within the diversity of their various ring structures, the quinolones have a number of common functional groups 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, whereas 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. Although the impact on therapeutic efficacy is not clear, they appear to act as weak bases in that they are much less effective in acidic than in nonacidic urine pH. 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

Mode of Action:

The quinolones inhibit bacterial enzyme topoisomerases, including topoisomerase II (otherwise known as DNA gyrase) and topoisomerase IV. Bacterial DNA supercoils and then uncoils during replication. Supercoiling requires transient nicks that are subsequently sealed after DNA polymerase passes. Topoisomerase II allows for single strand nicks in the DNA that support coiling and uncoiling. Topoisomerase IV supports disentanglement of DNA as chromosomes separate. Inhibition of topoisomerases reduces supercoiling, resulting in disruption of the spatial arrangement of DNA, and reduces DNA repair. 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 fluoroquinolones. 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 postantibiotic effect in a number of bacteria, principally gram-negative (eg, E coli, Klebsiella pneumoniae, P aeruginosa). The effect generally lasts 4–8 hr after exposure.

Efficacy of the fluorinated quinolones depends on concentrations in plasma that exceed the MIC of the infecting organism by 10- to 12- fold. As such, the drugs are concentration dependent. However, efficacy also is correlated to the magnitude of the area under the inhibitory curve (AUC:MIC); as such, efficacy also takes into account elimination half-life.

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 mcg/mL), whereas the MIC for a significant number of other isolates is very high (>64 mcg/mL). In general, MIC for most susceptible microbes, including E coli, Klebsiella, Proteus, P aeruginosa, and Staphylococcus have increased since the approval of the quinolones in the early 1990s.

Bacterial Resistance:

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 times the breakpoint MIC) generally reflects a second-step mutation that leads to changes in the amino acid sequence of subsequent topoisomerase targets. However, even with this second step of resistance, MIC are often below the resistant breakpoint range on which susceptibility testing is based. With the second increase in MIC, mutations in efflux pump regulators also emerge, causing marked increase in expression. As a result, high-level, multidrug resistance emerges.

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.

Note that if resistance does emerge to one fluoroquinolone, it is likely to impact all fluoroquinolones. However, resistance may be slower to emerge to newer drugs, including gemifloxacin, trovafloxacin, gatifloxacin, or pradofloxacin, because of larger side chains that facilitate binding to either DNA gyrase or topoisomerase IV.

Antimicrobial Spectra:

The fluoroquinolones are active against a wide range of gram-negative organisms and several gram-positive aerobes. This includes E coli, Salmonella, Klebsiella, Enterobacter, Proteus, and generally Pseudomonas aeruginosa. The fluoroquinolones are active against intracellular pathogens, including, 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 enterococci (previously group D Streptococcus spp (Enterococcus faecalis and Enterococcus faecium). Nocardia and atypical mycobacteria may also be susceptible.

The newer third- and fourth-generation fluorinated quinolones, such as pradofloxacin, are often 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 can markedly differ. Because of the physicochemical nature of the group, this is to be expected. A general overview follows, but some diversity should be anticipated.

Absorption:

Quinolones are commonly administered PO, although forms of enrofloxacin and ciprofloxacin are available for IV, IM, and SC (enrofloxacin) administration. Absorption into the blood after IM or SC delivery is rapid; after administration PO, blood concentrations usually peak 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, which may impact efficacy. The bioavailability of ciprofloxacin after administration PO in dogs is variable and can be as little as 40%; it is 0–20% in cats and horses. Marbofloxacin oral bioavailability is almost 100%.

Distribution:

With few exceptions, the quinolones penetrate all tissues well and quickly. Particularly high concentrations are found in organs of elimination (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 30% for enrofloxacin in dogs and >90% for nalidixic acid. Fluorinated quinolones as a group accumulate in phagocytic WBCs.

Biotransformation:

Some quinolones are eliminated unchanged (eg, ofloxacin), some are partially metabolized (eg, ciprofloxacin, enrofloxacin), and a few are completely degraded. Metabolites are sometimes active; enrofloxacin is de-ethylated to form ciprofloxacin. Characteristically, phase I reactions result in a number of primary metabolites (up to six have been described for some quinolones) that retain some antibacterial action. Conjugation with glucuronic acid then ensues, followed by excretion. In contrast, only ~10% of marbofloxacin is metabolized.

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.

Pharmacokinetic Values:

The clearance and volume of distributions of the drugs vary among species, resulting in differences in plasma half-lives. Plasma concentrations attained are usually directly proportional to the dose administered but also vary with volume of distribution and oral bioavailability. Package inserts should be consulted for Cmax for those drugs approved for use in the target species.

Pharmacokinetics of Selected Fluoroquinolones

Drug

Species

Elimination Half-life (hr)

Volume of Distribution (L/kg)

Clearance (mL/min/kg)

Enrofloxacin

Cats

7

4.3

Dogs

4.4

3.7

11

Mares

4–7

2

0.5–4

Marbofloxacin

Dogs

12

2

1.5

Orbifloxacin

Cats

4.5

1.3

Dogs

5.4

1.2

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. Because of their lipid solubility and ability to accumulate in phagocytic WBCs, quinolones should be considered for use in infections located in tough to penetrate tissues. Therapeutic failure is likely to result with multidrug-resistant organisms; this coupled with their emerging adverse events should cause these drugs to be considered second tier for dogs and cats.

A selection of general dosages for some quinolones is listed in Dosages of Quinolones. The dose rate and frequency should be adjusted as needed for the individual animal and the MIC of the infecting organisms. Plasma drug concentrations should approximate 10 times the MIC of the infecting microbe. Higher doses are encouraged unless mitigating circumstances preclude the increase; in such instances, unless the MIC is very low, alternative antimicrobials might be considered. In dogs and cats, use ideally is based on culture and susceptibility testing when possible. Extra-label use of fluoroquinolones is prohibited in food animals.

Dosages of Quinolones

Quinolonea

Species

Dosage, Route, and Frequency

Nalidixic acid

Cats, dogs

3 mg/kg, PO, qid

Enrofloxacin

Dogs

5–20 mg/kg, PO, once to twice daily

2.5 mg/kg, SC, once, then PO

Beef cattle (not veal or dairy)

7.5–12.5 mg/kg, SC, once

2.5–5 mg/kg/day, SC

Pigs

2.5–5 mg/kg/day, PO or IM

Preruminant calves

2.5–5 mg/kg/day, PO or SC

Marbofloxacin

Cats, dogs

2.75–5.5 mg/kg/day, PO

Difloxacin

Dogs

5–10 mg/kg/day, PO

Orbifloxacin

Cats, dogs

2.5–7.5 mg/kg/day, PO

Pradofloxacin

Cats

7.5 mg/kg/day, PO

a Extra-label use of fluorinated quinolones in food-producing animals is prohibited in the USA.

Special Clinical Concerns

Adverse Effects and Toxicity:

Although adverse 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; because these drugs are concentration dependent, enrofloxacin probably should not be used in cats. The presence of renal disease may increase this risk. Pradofloxacin may be the least retinotoxic, followed by marbofloxacin and orbifloxacin, but each of these appears to be safe in cats at doses that would be necessary to achieve targeted Cmax:MIC ratios for susceptible organisms. 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 people, 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.

In 2008, the FDA added a "black-box" warning for seven fluoroquinolones that increased the risk of tendinitis and a tendon rupture.

An emerging toxicity associated with fluoroquinolones is mitotoxicity, ie, damage to mitochondrial topoisomerase or other mitochondrial structures. Mitochondrial effects may not emerge until some time after fluoroquinolone therapy is instituted. Although the entirety of the clinical impact of this toxicity is not known, nor its relevance to veterinary medicine, adverse events ranging from neurologic to musculoskeletal to cardiovascular may ultimately be attributed to this effect.

Interactions:

The fluorinated quinolones may be involved in a number of drug interactions. Antacids or other drugs containing multivalent cations and sucralfate appear to interfere with the GI absorption of the quinolones. Nitrofurantoin impairs the efficacy of quinolones if used concurrently for urinary tract infections. Quinolones inhibit the biotransformation of methylxanthines, with theophylline being the most clinically relevant, but also including caffeine and theobromine. This is a class effect, with the risk varying among the fluoroquinolones in people. A similar ranking of risk is not available for veterinary medicine. In people, cyclosporine concentrations may also be increased by concurrent administration with fluoroquinolones, leading to prolonged and potentially toxic plasma concentrations.

Effects on Laboratory Tests:

AST, ALT, alkaline phosphatase, and BUN may be increased. Urine glucose may be altered, and urinalysis may reveal needle-shaped crystals.

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