The fluoroquinolone antibacterial agents are among the most important antimicrobials used in veterinary medicine. They are used in practically all species and have a broad spectrum of activity that includes most of the important veterinary bacterial pathogens. Since their first introduction in the late 1980s (discussed in previous editions of this book), the use of fluoroquinolones has expanded tremendously.

The fluoroquinolones are synthetic antibacterial agents introduced in veterinary medicine first as enrofloxacin. Since then, there has been a great deal of research on this class of drugs to better understand their mechanism of action, antimicrobial spectrum, pharmacokinetics in a wide variety of animal species, and clinical uses. In addition, pharmaceutical companies have developed new agents in this class to increase the number of drug choices available to veterinarians. The advantages of the fluoroquinolones are that they are rapidly bactericidal against a wide variety of clinically important bacterial organisms, are potent, are well tolerated by animals, and have been administered via a variety of routes (orally via tablets and drinking water, subcutaneously, intravenously, intramuscularly, and topically).

Fluoroquinolones approved for use in veterinary medicine for small animals are shown in Table 37.1. Fluoroquinolones that are approved for humans and are of potential interest for veterinary medicine include ciprofloxacin. The newest generation of fluoroquinolones, with increased activity against gram-positive cocci and anaerobic bacteria, includes levofloxacin, moxifloxacin, gatifloxacin, and the veterinary drug pradofloxacin.

Chemical Features

The currently available fluoroquinolones have the same quinolone structure (Figure 37.1). The addition of the fluorine group at position 6 gives these the characteristics of a fluoroquinolone, and various other chemical substitutions and side groups account for the different physical characteristics of each drug. Enrofloxacin has one fluorine substitution, difloxacin has two fluorine substitutions, and orbifloxacin has a three-fluorine substitution, but the presence of more than one fluorine does not increase antibacterial effects (Asuquo and Piddock, 1993). When lipid solubility is expressed as the octanol: water partition coefficient, enrofloxacin has among the highest lipophilicity. By comparison, ciprofloxacin has a partition coefficient that is approximately 100-fold less than that of enrofloxacin; the corresponding partition coefficients of orbifloxacin and marbofloxacin are slightly higher than that of ciprofloxacin (Asuquo and Piddock, 1993; Takács-Novák et al., 1992). But there are no studies available to show that these chemical differences among the drugs can account for differences in clinical response. However, chemical differences may account for some variation in absorption and distribution. For example, ciprofloxacin oral absorption is approximately one-half that of enrofloxacin in dogs; ciprofloxacin absorption in horses is less than 10%, compared to 60% for enrofloxacin. The less lipid-soluble fluoroquinolones (marbofloxacin, orbifloxacin) have a lower volume of distribution (Vd) than the ones with higher lipid solubility (enrofloxacin) (Table 37.2 ). One explanation for this observation is that the more lipid-soluble drugs have higher intracellular concentrations, but higher tissue binding also could explain the differences in volume of distribution.

The most important structural difference in recent years is the addition of a substitution at position 8. These are usually referred to as third-generation fluoroquinolones to distinguish them from the second-generation drugs such as ciprofloxacin and enrofloxacin. For some human drugs, the addition is a methoxy (moxifloxacin), and for one of the veterinary drugs, it is a cyano group at position 8 that confers increased spectrum of activity.

Quinolones are amphoteric molecules that can be protonated at the carboxyl and the tertiary amine portion of the molecule (Martinez et al., 2006). The pK_a varies among the drugs slightly, but generally the pK_a for the carboxyl group is 6.0–6.4 (5.5–6.3 in some references) and the pK_a for the nitrogen of the piperazine group is 7.5–8 (Nikaido and Thanassi, 1993) (as high as 7.6–9.3 in some references). For two common drugs, enrofloxacin and ciprofloxacin, the pK_a for the carboxyl group is 6.0 and 6.1, respectively, and 8.8 and 8.7 for the amine, respectively (Martinez et al., 2006). The isoelectric point is midway between the pK_a for each ionizable group. Therefore, at physiological pH fluoroquinolones exist as zwitterions, in which both of the respective anionic and cationic groups are charged. It is at the isoelectric point (near the physiological pH) that fluoroquinolones are the most lipophilic and capable of diffusing across lipid membranes (Takács-Novák et al., 1992; Martinez et al., 2006).

Structure–Activity Relationships

Figure 37.1 shows the basic quinolone structure. The carboxyl group at position 3 and the ketone at position 4 are necessary for the antibacterial activity. The fluorine at position 6 differentiates the quinolones from the fluoroquinolones and accounts for the improved gram-negative and gram-positive activity over the nonfluorinated quinolones, increased potency, and increased entry into bacteria. At position 1, addition of a cyclopropyl (as for enrofloxacin and ciprofloxacin in Figure 37.2), an ethyl or a fluorophenyl improve the spectrum of activity against gram-positive and gram-negative bacteria. Addition of a piperazine at position 7, as demonstrated for ciprofloxacin, marbofloxacin, and enrofloxacin (Figure 37.2), improves the spectrum of activity to include pseudomonads, among other gram-negative bacteria. The change from a nitrogen (nalidixic acid) to a carbon at position 8 decreased some of the adverse central nervous system effects and increased activity against staphylococci.

The third-generation fluoroquinolones have a bicyclic substitution at position 7, instead of a piperazine. This increased the activity to include a wider range of bacteria. In addition, a substitution at the 8 position on the ring enhances the bactericidal effects and improves the spectrum of activity to include more gram-positive and anaerobic bacteria. For example, the 8-methoxy substitution produces the drug moxifloxacin, a human quinolone with improved activity against gram-positive bacteria (Behra-Miellet et al., 2002; Aktaç et al., 2002; Pestova et al., 2000). Pradofloxacin, a veterinary quinolone with similar activity has a cyano substitution at position 8, which improves the activity against gram-positive and anaerobic activity compared to enrofloxacin and ciprofloxacin (Silley et al., 2007). This drug is discussed in more detail in Section Pradofloxacin Use in Dogs and Cats. A comparison of the activities of the veterinary fluoroquinolones against gram-positive and gram-negative bacteria can be illustrated in Figure 37.3 (using data from Wetzstein, 2005).

Mechanism of Action

Quinolones are bactericidal by inhibiting bacterial DNA replication and transcription. Two-stranded DNA is tightly coiled in the cell and must be separated for transcription and translation. To facilitate coiling, winding, and unwinding, the enzyme DNA gyrase allows the strands to be cut and reconnected. This allows coiling because negative supercoils can be introduced. DNA gyrase, a topoisomerase, consists of A and B subunits. The most common target site for quinolones is the A subunit of DNA gyrase coded by the gene gyrA. Mammals are resistant to the killing effects of quinolone antimicrobials because topoisomerase II in mammalian cells is not inhibited until the drug concentration reaches 100–1000 µg/ml. Bacteria are inhibited by concentrations of 0.1–10 µg/ml or less. Concentrations achieved in animals and people are much lower as seen by the Clinical Laboratory Standards Institute (CLSI, 2015) breakpoints (Table 37.2 ). Another target is the topoisomerase IV enzyme composed of subunits parC and parE. This site of action is less important for gram-negative bacteria but is a target of fluoroquinolones in some gram-positive bacteria such as streptococci and staphylococci (Ferrero et al., 1995). Among the newer generation fluoroquinolones – for example the veterinary drug pradofloxacin, and the human drugs moxifloxacin and gatifloxacin – the primary target for gram-positive bacteria may be the DNA-gyrase rather than topoisomerase IV, or these drugs also may be dual inhibitors against both targets (Intorre et al., 2007). Therefore, older fluoroquinolones have high activity against DNA-gyrase in gram-negative bacteria, but less against the topoisomerase IV of gram-positive bacteria. But the broader activity of newer fluoroquinolones can be attributed to higher affinity for both the DNA-gyrase in gram-negative and gram-positive bacteria, as well as activity for the topoisomerase IV of gram-positive bacteria (Drlica and Zhao, 1997; Blondeau et al., 2004).

Antibacterial Spectrum

Fluoroquinolones in general exhibit good activity against most gram-negative bacteria, especially those of the Enterobacteriaceae. Representative minimum inhibitory concentration (MIC) values are shown in Table 37.3. Escherichia coli, Klebsiella spp., Proteus spp., Salmonella spp., and Enterobacter spp. are usually susceptible. Pseudomonas aeruginosa is variably susceptible and, when it is susceptible, usually has a higher MIC than other susceptible organisms. Against P. aeruginosa, ciprofloxacin is the most active (Rubin et al., 2008). Other bacteria susceptible to fluoroquinolones include intracellular organisms (Rickettsia spp., Chlamydia, and Mycobacterium spp.) and Mycoplasma spp.

Gram-positive bacteria are variably susceptible. Staphylococcus aureus, Staphylococcus pseudintermedius, and other Staphylococcus species usually are susceptible. However, the MIC values for staphylococci typically are higher than for gram-negative bacteria, and staphylococcal resistance to fluoroquinolones can be common.

In general, ciprofloxacin is more active than enrofloxacin against gram-negative bacilli, and enrofloxacin is more active against Staphylococcus species (Grobbel et al., 2007; Blondeau et al., 2012). Marbofloxacin activity usually falls between enrofloxacin and ciprofloxacin. The newer fluoroquinolones, such as moxifloxacin, gatifloxacin, and the veterinary drug pradofloxacin, have increased activity against gram-positive cocci and anaerobic bacteria (Behra-Miellet et al., 2002; Aktaç et al., 2002; Pestova et al., 2000; Silley, 2007) (Figure 37.3).

Factors that may affect activity are cations at the site of infection and low pH. Cations such as Al⁺³, Mg⁺³, Fe⁺², and Ca⁺² can bind a carboxyl group on the drug and significantly decrease activity. Low pH at the site of action also can affect the MIC (Ross and Riley, 1994), especially for drugs that have a piperazine at position 7 (Figures 37.1 and 37.2). For example, in urine, the MIC for fluoroquinolones may increase due to the presence of cations in the urine and low pH (Fernandes, 1988). This activity in urine may increase the MIC from fourfold to 64-fold. Fluoroquinolone activity in an abscess is not diminished despite the observation that in pus there is cellular material that can bind drugs, a low pH, and slow-growing bacteria (Bryant and Mazza, 1989). The presence of a foreign body, albumin, globulin, pus, anaerobic conditions, and dead bacteria did not affect the activity of fluoroquinolones (Rubinstein et al., 2000). The activity of fluoroquinolones in this milieu may explain its efficacy for treating infections associated with abscessation.

Resistance

Pharmacokinetics

Extensive pharmacokinetic data is provided in Table 37.4. These are presented as examples because there are far more pharmacokinetic studies available in the literature than can be presented in this table. A literature search of pharmacokinetic studies in animals will reveal many available studies in the entire array of species treated by veterinarians – ranging from large animal species of elephants and whales, to mice and small invertebrate species.

Mammals are relatively consistent in elimination half-life and volume of distribution. Reptiles with lower renal clearance generally demonstrate longer half-lives – as long as 55 and 36 hours for enrofloxacin in alligators and monitor lizards, respectively (Papich, 1999). There may be an allometric relationship in pharmacokinetic parameters among mammals ranging in size from mice to cattle (Bregante et al., 1999; Cox et al., 2004). The allometric relationship was improved considerably when the pharmacokinetic parameters were corrected for the percentage of protein-unbound enrofloxacin in the plasma (Table 37.5 ).

Because most of these drugs are administered either once daily or as a one-time administration, the elimination half-lives shown in Table 37.4  may have little effect on clinical outcome. For example, it does not appear that differences in half-life can account for different clinical results for skin infection treatment in dogs because enrofloxacin, which has the shortest half-life, and marbofloxacin, which has a long half-life, have both been reported to be effective when administered once daily (Paradis et al., 1990; Carlotti et al., 1995; Carlotti, 1996; Gruet et al., 1997; Koch and Peters, 1996; Ihrke, 1996, 1998; Cester et al., 1996). In cattle and pigs, enrofloxacin is approved for either a one-time dose of 7.5–12.5 mg/kg, or 2.5–5 mg/kg once daily for three to five treatments. With either regimen, the outcome is the same. Likewise, danofloxacin is approved for use in cattle at a dose of 6 mg/kg administered twice, or a single dose of 8 mg/kg, with similar outcomes.

Although the volume of distribution varies among animals (and among studies), these differences have not translated into differences in clinical efficacy. Marbofloxacin and orbifloxacin, which have a volume of distribution in the range of 1–2– l/kg, achieve effective skin concentrations and appear as clinically effective as drugs such as enrofloxacin with a volume of distribution of 2.5–5 l/kg. Heinen (2002) demonstrated that even though approved doses may vary among enrofloxacin, marbofloxacin, and orbifloxacin in dogs, they are all capable of achieving pharmacokinetic–pharmacodynamic (PK-PD) targets (these targets are discussed in Section Pharmacokinetics / Pharmacodynamics). The data published (Bidgood and Papich, 2005, Walker et al., 1990, 1992; Messenger et al., 2012; Davis et al., 2007) or available from manufacturer technical information show that the fluoroquinolones, regardless of their volume of distribution and lipophilicity, achieve effective concentrations in tissues. Some exceptions are tissues not easily penetrated such as the central nervous system and eye.

Oral Absorption

Whether fluoroquinolones are administered with or without food has little effect on oral absorption. Feeding may delay the time to peak concentration (T_max), but this has little effect on clinical outcome because the extent of absorption, determined by the total AUC (area under the curve of the plasma concentration versus time curve) is not affected significantly. Administration with food has prolonged the terminal half-life when enrofloxacin was administered orally to reptiles (Papich, 1999), sheep, pigs (Gyrd-Hansen and Nielsen, 1994), and chickens (Anadón et al., 1995). This may be caused by a “flip-flop” pharmacokinetic effect introduced in Chapter 3 and discussed below in this section.

In clinical situations involving animals difficult to dose, fluoroquinolones may be added to a patient’s food in order to provide a more convenient dosing form. For example, enrofloxacin tablets were placed in whole fish, which were fed to dolphins to produce good absorption (Linnehan et al., 1999), and enrofloxacin was injected into mice and fed to monitor lizards, also producing good absorption (Hungerford et al., 1997). Chewable tablets of enrofloxacin (Taste-Tabs) do not affect oral absorption (manufacturer’s data).

In dogs, cats, and pigs, oral absorption of fluoroquinolones approaches 100% (Table 37.4 ), but in large animals, the extent of absorption has been less. Oral absorption of fluoroquinolones is variable in horses. Ciprofloxacin showed an oral absorption of only 6.8% in ponies (Dowling et al., 1995) and only 10% (mean) in adults (Yamarik et al., 2010). But enrofloxacin absorption is 63% (Giguère et al., 1996) in adult horses and 42% in foals (Bermingham et al., 2000). The value reported for adult horses is probably artificially high because the study used a bioassay that overestimates the concentration of enrofloxacin in plasma. With the exception of ciprofloxacin, other studies listed in Table 37.4

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