Enrofloxacin is a concentration-dependent fluoroquinolone with antimicrobial activity against mainly gram-negative and some gram-positive bacteria, and minimal activity against anaerobic bacteria.1 Enrofloxacin might also be effective against organisms in the genera Chlamydia, Mycoplasma (Haemobartonella), Mycobacterium, and Toxoplasma.1,2 The drug (enrofloxacin and its active metabolite ciprofloxacin) is primarily excreted through the kidneys and, depending on the species, can also be metabolized by the liver.1 In various taxa, enrofloxacin is an attractive antimicrobial treatment option because its MIC for susceptible bacteria is usually low and because it has low protein-binding activity, high bioavailability, an extended half-life, and good penetration to multiple body tissues.1
The black-tailed prairie dog (Cynomys ludovicianus) is a herbivorous, burrowing animal in the order Rodentia and the family Sciuridae.3 It is a keystone species in the grasslands of North America and is kept in zoological collections and also as privately owned pets.3–5 Because of a propensity to develop several biliary diseases, these animals are used in gallstone research.6 This species is also used as an animal model for diseases caused by Clostridium difficile, Yersinia pestis, and Francisella tularensis in humans.5 Given that prairie dogs are hindgut fermenters and at risk for digestive dysbiosis, they are suggested to be sensitive to narrow-spectrum antimicrobials that target gram-positive flora.7 Experimentally, prairie dogs given a single IM dose of 100 mg of cefoxitin have developed C difficile cecitis and diarrhea.8 To our knowledge, no antibacterial pharmacokinetic data have been reported for black-tailed prairie dogs to date.
The objective of the study reported here was to investigate the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin after administration to black-tailed prairie dogs as a single SC injection. Our study hypotheses were that a dose of 20 mg of enrofloxacin/kg SC would result in plasma concentrations within an anticipated therapeutic range and that enrofloxacin would not be further metabolized into ciprofloxacin.
Materials and Methods
Animals
Eight clinically healthy 6-month-old sexually intact male black-tailed prairie dogs with a mean ± SD body weight of 651 ± 85 g were included in the study. The animals were a new group kept in quarantine before placement in a zoological collection. The animals were group housed in a concrete-lined room bedded with hay and kept at a constant temperature range (21° to 23°C). Water and food were offered ad libitum, and the diet provided was a mix of vegetables and commercial rodent blocks.a The prairie dogs were acclimated to the new environment for 3 weeks before the beginning of the study. This study was approved by the Institutional Animal Care and Use Committee of Kansas State University (IACUC No. 3792.2) and the ethics committee of the participating zoo.
A week prior to study commencement, the prairie dogs underwent inhalation anesthesia for purposes of a general health examination that included a complete physical examination, accurate measurement of body weight, microchip implantation (for identification purposes), CBC, and plasma biochemical panel. On the basis of the assessment results, all prairie dogs were determined to be healthy prior to the start of the study. During the testing period, animals were individually housed in plastic crates.
Experimental design and sample collection
Individual prairie dogs were randomly assigned to one of the planned treatment route groups (IV or SC) by use of an online randomization tool. The assigned animals were allocated into 2 groups of 4 animals (IV treatment, n = 1; SC treatment, 3) to be tested separately in 2 consecutive 24-hour periods.
Each animal was anesthetized with 5% isoflurane delivered via chamber induction prior to blood sample collection at the 0-hour time point. A 24-gauge catheter was placed in the left cephalic vein. Following this first induction of anesthesia, a calculated dose of enrofloxacinb (20 mg/kg) was mixed with an equal volume of saline (0.9% NaCl) solution and then administered either SC or IV to 6 and 2 prairie dogs, respectively. The SC injections were administered in the lumbar area. The IV injections were administered through the catheter. Venous blood samples (0.5 mL each) were collected with a 25-gauge needle attached to a 1.0-mL heparin-flushed syringe. The blood samples were collected immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after enrofloxacin administration and placed into heparin-coated tubes. Each prairie dog remained anesthetized for the blood sample collections at the 0-, 0.5-, and 1-hour time points and were briefly (approx 10 minutes' duration) reanesthetized for blood sample collections at the 2-, 4-, 8-, 12-, and 24-hour time points. Blood samples were not collected from the same vein as that used when enrofloxacin was administered IV. Lactated Ringer solution (30 mL) was administered SC after the 12- and 24-hour blood sample collections. Following collection, each blood sample was immediately centrifuged (10 minutes at 3,000 × g); the separated plasma was placed in an individual microcentrifuge tube and stored in a −70°C freezer until analysis. Prairie dogs were monitored for general health status and adverse drug reactions for 1 week after the study was completed.
Plasma sample analysis
Concentrations of enrofloxacin and ciprofloxacin in each plasma sample were determined by ultra-performance liquid chromatographyc and triple quadrupole mass spectrometryd with electrospray ionization. The mobile phase consisted of 0.1% formic acid in deionized water and acetonitrile, and separation was achieved at 55°C with a 2.1 × 50-mm column (particle diameter, 1.7 μm).e The m/z for qualification and quantification were as follows (qualifying ions→quantifying ions): enrofloxacin, 360.19→71.99 and 245.10, respectively; ciprofloxacin, 332.12→231.06 and 245.12, respectively; and internal standard norfloxacin, 320.14→205.02 and 233.13, respectively. Plasma samples, plasma standards in prairie dog plasma, and plasma quality control samples in prairie dog plasma were processed by means of protein precipitation and pass-through sample plates.f Briefly, 50 μL of plasma was added to 100 μL of internal standard solution (norfloxacin [1 μg/mL] in acetonitrile with 1% formic acid) and vortexed. Positive pressure was applied to the pass-through plates, and the eluate was collected into the collection plate containing 100 μL of deionized water. Plasma standard curves for enrofloxacin were linear from 0.01 to 10 μg/mL. The mean ± SD accuracy for quality control samples (0.01 [n = 2], 0.05 [3], 1 [3], and 10 [3] μg/mL) was 94 ± 10%, and 10 of 11 quality control samples were within 15% of the actual concentration (1 of the 0.01-μg/mL quality control samples was 19.8%). Plasma standard curves for ciprofloxacin were linear from 0.05 to 10 μg/mL. The mean ± SD accuracy for quality control samples (0.05, 1, and 10 μg/mL [n = 3 at each concentration]) was 100 ± 7%, and 9 of 9 quality control samples were within 15% of the actual concentration.
Pharmacokinetic analysis
Noncompartmental pharmacokinetic analysis was performed with computer software.g The λz, T1/2, CMAX, TMAX, C0 (concentration at time 0 estimated by log-linear regression of the data for the first 2 time points after IV administration), AUCINF, AUCExtrap, volume of distribution (area method) for IV dosing or volume of distribution/fraction of the dose absorbed for SC dosing, and plasma Cl for IV dosing or Cl/F for SC dosing are reported. The TMAX and CMAX were determined directly from the data, and the AUCINF was determined by the linear-log trapezoidal method. To determine the total fluoroquinolone pharmacokinetics, the plasma concentrations of enrofloxacin and ciprofloxacin were summed at each time point for each individual animal, and then pharmacokinetics analyses were performed on those data. The AUCINF and CMAX for the total fluoroquinolone concentration (enrofloxacin and ciprofloxacin) were each divided by the targeted MIC of 0.5 μg/mL to estimate the AUCINF:MIC and CMAX:MIC values, respectively.
Results
Enrofloxacin was successfully administered to all 6 prairie dogs in the SC treatment group and the 2 prairie dogs in the IV treatment group. All of the prairie dogs remained healthy during a 1-week follow-up period after the study was completed, and none had any signs of an adverse drug reaction.
Prairie dogs converted enrofloxacin into its active metabolite ciprofloxacin. The pharmacokinetic variables that were calculated for enrofloxacin (Table 1), ciprofloxacin (Table 2), and total fluoroquinolones (enrofloxacin and ciprofloxacin [Table 3]) after SC and IV administration to black-tailed prairie dogs were summarized. The individual-animal concentration-over-time curves for enrofloxacin (Figure 1), ciprofloxacin (Figure 2), and total fluoroquinolones (Figure 3) were plotted. With an MIC of 5 μg/mL, the estimated AUCINF:MIC ratio ranged from 61 to 93 (mean, 80) and the estimated CMAX:MIC ratio ranged from 6.9 to 12.1 (mean, 9.8).
Plasma concentrations of enrofloxacin in black-tailed prairie dogs measured before (0 hours) and at intervals after SC (n = 6; white circles) or IV (2; black circles) administration of a single dose (20 mg/kg) of enrofloxacin. Each animal was anesthetized prior to blood sample collection at the 0-hour time point. Enrofloxacin (20 mg/kg) was mixed with an equal volume of saline (0.9% NaCl) solution and then administered either SC (in the lumbar area) or IV (through a catheter in the left cephalic vein). Venous blood samples (0.5 mL each) were collected into heparin-coated tubes immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after enrofloxacin administration. The animals remained anesthetized for the blood sample collections at the 0-, 0.5-, and 1-hour time points and were briefly (duration, approx 10 minutes) reanesthetized for blood sample collection at the 2-, 4-, 8-, 12-, and 24-hour time points. Lactated Ringer solution (30 mL) was administered SC after the 12- and 24-hour blood sample collections. Following collection, each blood sample was immediately centrifuged to obtain plasma. The concentration of enrofloxacin in each plasma sample was determined by ultraperformance liquid chromatography and triple quadrupole mass spectrometry with electrospray ionization.
Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.658
Plasma concentrations of ciprofloxacin in the black-tailed prairie dogs in Figure 1 measured before (0 hours) and at intervals after SC (n = 6; white squares) or IV (2; black squares) administration of a single dose (20 mg/kg) of enrofloxacin. The concentration of ciprofloxacin (an active metabolite of enrofloxacin) in each plasma sample was determined by ultraperformance liquid chromatography and triple quadrupole mass spectrometry with electrospray ionization. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.658
Plasma concentrations of total fluoroquinolones (sum of the plasma concentrations of enrofloxacin and ciprofloxacin) in the black-tailed prairie dogs in Figure 1 measured before (0 hours) and at intervals after SC (n = 6; white squares) or IV (2; black squares) administration of a single dose (20 mg/kg) of enrofloxacin. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.658
Pharmacokinetics of enrofloxacin in black-tailed prairie dogs after SC (n = 6) or IV (2) administration of a single dose (20 mg/kg) of enrofloxacin.
| SC | IV | ||||
|---|---|---|---|---|---|
| Parameter | Mean | Minimum | Maximum | Prairie dog A | Prairie dog B |
| λz (1/h) | 0.190 | 0.135 | 0.227 | 0.174 | 0.239 |
| T1/2 (h) | 3.65 | 3.05 | 5.14 | 2.90 | 3.99 |
| TMAX (h) | 1.41 | 0.50 | 2.00 | N/A | N/A |
| CMAX (g/mL) | 3.71 | 2.55 | 5.36 | N/A | N/A |
| C0 (μg/mL) | N/A | N/A | N/A | 6.40 | 9.81 |
| AUCINF (h•μg/mL) | 19.0 | 13.3 | 22.7 | 16.0 | 23.1 |
| AUCExtrap (%) | 0.8 | 0.4 | 1.9 | 0.3 | 0.8 |
| Vz* (L/kg) | 5.54 | 4.03 | 8.13 | 3.63 | 7.19 |
| Cl* (mL/min/kg) | 17.55 | 14.68 | 25.13 | 14.4 | 20.8 |
Each animal was anesthetized prior to blood sample collection at the 0-hour time point. Enrofloxacin (20 mg/kg) was mixed with an equal volume of saline (0.9% NaCl) solution and then administered either SC (in the lumbar area) or IV (through a catheter in the left cephalic vein). Venous blood samples (0.5 mL each) were collected into heparin-coated tubes immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after enrofloxacin administration. The animals remained anesthetized for the blood sample collections at the 0-, 0.5-, and 1-hour time points and were briefly (duration, approx 10 minutes) reanesthetized for blood sample collection at the 2-, 4-, 8-, 12-, and 24-hour time points. Lactated Ringer solution (30 mL) was administered SC after the 12- and 24-hour blood sample collections. Following collection, each blood sample was immediately centrifuged to obtain plasma. The concentration of enrofloxacin in each plasma sample was determined by ultraperformance liquid chromatography and triple quadrupole mass spectrometry with electrospray ionization. Noncompartmental pharmacokinetic analysis was performed with computer software. The TMAX and CMAX were determined directly from the data, and the AUCINF was determined by the linear-log trapezoidal method.
C0 = Concentration at 0 hours estimated by log-linear regression of the data for the first 2 time points after IV administration. Cl* = Plasma Cl for IV dosing or Cl/F for SC dosing. Vz* = Volume of distribution (area method) for IV dosing or volume of distribution/fraction of the dose absorbed for SC dosing.
Pharmacokinetics of ciprofloxacin in the black-tailed prairie dogs in Table 1 after SC (n = 6) or IV (2) administration of a single dose (20 mg/kg) of enrofloxacin.
| SC | IV | ||||
|---|---|---|---|---|---|
| Parameter | Mean | Minimum | Maximum | Prairie dog A | Prairie dog B |
| λz (1/h) | 0.123 | 0.101 | 0.137 | 0.111 | 0.123 |
| T1/2 (h) | 5.62 | 5.07 | 6.85 | 5.65 | 6.23 |
| TMAX (h) | 3.17 | 1 | 4 | 2 | 2 |
| CMAX (μg/mL) | 1.68 | 1.15 | 2.28 | 1.25 | 1.57 |
| C0 (μg/mL) | 18.9 | 15.9 | 22.5 | 12.6 | 18.9 |
| AUCINF (h•μg/mL) | 6.5 | 4.8 | 10.3 | 6.3 | 7.9 |
The concentration of ciprofloxacin (an active metabolite of enrofloxacin) in each plasma sample was determined by ultraperformance liquid chromatography and triple quadrupole mass spectrometry with electrospray ionization. Noncompartmental pharmacokinetic analysis was performed with computer software.
See Table 1 for remainder of key.
Pharmacokinetics of total fluoroquinolones (enrofloxacin and ciprofloxacin) in the black-tailed prairie dogs in Table 1 after SC (n = 6) or IV (2) administration of a single dose (20 mg/kg) of enrofloxacin.
| SC | IV | ||||
|---|---|---|---|---|---|
| Parameter | Mean | Minimum | Maximum | Prairie dog A | Prairie dog B |
| λz (1/h) | 0.150 | 0.133 | 0.172 | 0.128 | 0.159 |
| T1/2 (h) | 4.63 | 4.02 | 5.20 | 4.35 | 5.40 |
| TMAX (h) | 1.59 | 0.5 | 2 | 0.5 | 0.5 |
| CMAX (μg/mL) | 4.90 | 3.44 | 6.08 | 6.05 | 7.26 |
| C0 (μg/mL) | 40.0 | 30.7 | 46.1 | 34.7 | 35.2 |
| AUCINF (h•μg/mL) | 3.0 | 2.0 | 5.0 | 2.0 | 4.0 |
Discussion
In the present study, the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated following single-dose SC administration to 6 black-tailed prairie dogs. For purposes of intrastudy comparisons, 2 additional prairie dogs instead received IV administration of enrofloxacin once. The purpose of IV administration to 2 animals was to document plasma disposition when a known amount of drug was in the systemic circulation. Because IV administration is not clinically feasible in prairie dogs, the number of animals included in the IV treatment group was not equivalent to that in the SC treatment group to minimize animal usage for this study.
None of the animals used in the present study had any adverse responses. A dose range of 5 to 20 mg of enrofloxacin/kg is suggested for rodents9 and the higher dose of 20 mg/kg was chosen because it was anticipated that it would be necessary to result in adequate plasma concentrations.10 The pharmacokinetics of the enrofloxacin in the prairie dogs had similar characteristics to those typically described for fluoroquinolones in other mammalian species, including high parenteral absorption, large volume of distribution, and a T1/2 that ranged from 3 to 6 hours.11,12 To the authors' knowledge, this is the first report of enrofloxacin pharmacokinetics in black-tailed prairie dogs or any other member of the family Sciuridae.
Because of the fractious nature of this species, isoflurane-induced immobilization was required for blood sample collection13 from the prairie dogs of the present study. It is possible that this short-term period of anesthesia could have affected the pharmacokinetics (ie, absorption, distribution, metabolism, or elimination) of enrofloxacin. However, the short duration and sporadic nature of the episodes of anesthesia would have less of an effect because physiologic variables normalize when anesthesia is discontinued and the animal is allowed to recover (ie, reversal of dose- or concentration-dependent effects of isoflurane on physiologic variables). Additional pharmacological studies of enrofloxacin in prairie dogs could include the use of surgically implanted indwelling catheters with sampling ports to avoid sedation and anesthesia during blood sample collection, but such invasive procedures were beyond the scope of the present study.
Ciprofloxacin is an active metabolite of enrofloxacin; when generated, it therefore contributes to the resultant antimicrobial activity of enrofloxacin treatment.14 In the present study, plasma concentrations of ciprofloxacin were high following SC or IV enrofloxacin administration in prairie dogs, suggesting that the metabolic pathway for converting enrofloxacin to ciprofloxacin is well developed in this species. The biotransformation of enrofloxacin to ciprofloxacin varies among animal species.12,15,16 There are few reports for other rodent species, but 1 study17 of mice revealed low plasma concentrations of ciprofloxacin following SC administration of enrofloxacin (10 mg/kg). However, results of another study18 in mice indicated that the plasma concentration of ciprofloxacin following SC administration of enrofloxacin (5 mg/kg) was high, suggesting that the difference in the data from the 2 mice studies may have been attributable to differences in the testing methods.
With regard to infections in dogs and cats and in cattle, bacteria for which the enrofloxacin MIC is 0.5 and 0.25 μg/mL, respectively, are defined as susceptible to the drug by the Clinical Laboratory Standards Institute.19 However, direct extrapolation of these MIC data to other species may not be accurate because patient factors such as pharmacokinetics, dose, species of infective bacteria, resultant disease, metabolic factors, and location of infection within the body may differ and subsequently alter the MIC breakpoint.15 Several different ratios have been used to estimate fluoroquinolone efficacy, including an AUC:MIC ratio of > 100 to 125 and CMAX:MIC ratio of 8 to 10.20 The AUC:MIC ratio typically uses the 24-hour AUC (AUC0–24) for fluoroquinolone efficacy. We used the AUCINF for calculation of the AUC:MIC ratio because the AUCINF for a single dose is equivalent to the AUC0–24 when steady state has been achieved for once-daily administration.
Both the AUC:MIC and CMAX:MIC ratios have been shown to predict clinical cure in laboratory animal and human clinical studies.20 However, many of these studies were conducted in severely ill animals or patients and may overestimate the drug exposure needed to treat less severe infections. In the present study, an enrofloxacin MIC value of 0.5 μg/mL was used to calculate the mean total fluoroquinolones CMAX:MIC ratio. The mean total fluoroquinolones CMAX:MIC value was 9.8, which therefore achieved the targeted exposure in other species. Thus, results suggested that a daily single-dose protocol appears to achieve targeted surrogate markers of fluoroquinolone efficacy in prairie dogs, if the surrogate markers are similar to those in other rodent and animal species. The mean total fluoroquinolones AUC:MIC ratio in the present study was 80, which was less than the targeted AUC:MIC ratio of > 100. However, an AUC:MIC ratio of 30 to 55 can be curative depending on the clinical situation, and infections caused by gram-positive bacterial infections can be successfully treated when AUC:MIC ratios are in the range of 35 to 50.20,21 Although assessment of efficacy was not one of the aims of the present study, the information provided can be used to design future studies.
There are few reports of in vitro antimicrobial susceptibility studies in prairie dogs. Tularemia caused by F tularensis is reported to be common in free-ranging and wild-caught captive prairie dogs.22 Investigations of F tularensis isolated from wild-caught, commercially distributed prairie dogs revealed that the MIC of ciprofloxacin (and other fluoroquinolones) for F tularensis type B is low (≤ 0.064 μg/mL).22,23 Based on the present study's results, the mean total fluoroquinolones CMAX:MIC ratio is 76.56 and mean total fluoroquinolones AUC:MIC ratio is 625. These values are greater than the suggested breakpoints and indicated that fluoroquinolone treatment of F tularensis–infected prairie dogs is potentially curative. Bartonella strains and Y pestis have been detected in free-ranging prairie dogs, and both pathogens can be treated with fluoroquinolones.24–26 In vitro testing of the susceptibility of Bartonella spp to various antimicrobials revealed a ciprofloxacin MIC of < 0.5 μg/mL for 33% to 83% of the isolates, depending on the susceptibility test used.27 The calculated MIC suggests that the dose used in the present study might have also achieved the reported pharmacokinetics-pharmacodynamics for F tularensis and Bartonella bacteria in this species.
The pharmacokinetic data for enrofloxacin in the present study indicated that once-daily SC administration of 20 mg of enrofloxacin/kg would meet the surrogate markers of efficacy (ie, AUC:MIC and CMAX:MIC ratios) for treatment of susceptible bacteria (ie, bacteria for which the enrofloxacin MIC is ≤ 0.5 μg/mL) in black-tailed prairie dogs. Historically, the authors have used this dose of enrofloxacin in prairie dogs with no apparent adverse responses; however, assessment of other routes of enrofloxacin administration and long-term multidosing and efficacy studies are still indicated in this species.
Acknowledgments
The authors thank Certara for provision of an academic license for use of the Phoenix 64 software and Matt Warner, Christine Hackworth, Brandi Heckel, Sarah Ostrom, Valerie Head, Danielle Fuller, Kirk Nemechek, and Jessie Roberts for technical assistance.
ABBREVIATIONS
| AUC0–24 | Area under the concentration-versus-time curve from 0 to 24 hours |
| AUCExtrap | Percentage of the area under the concentration-versus-time curve extrapolated to infinity |
| AUCINF | Area under the concentration-versus-time curve extrapolated to infinity |
| Cl | Clearance |
| Cl/F | Clearance per fraction of the dose absorbed |
| CMAX | Observed maximum plasma concentration |
| λz | Plasma terminal rate constant |
| MIC | Minimum inhibitory concentration |
| T1/2 | Terminal half-life |
| TMAX | Time to reach maximum plasma concentration |
Footnotes
Mazuri Rodent Breeder 6F, Mazuri Exotic Pet Food, Richmond, Ind.
Baytril, 22.7 mg/mL, Bayer Co, Shawnee Mission, Kan.
Acquity UPLC, Waters Corp, Milford, Mass.
TQD, Waters Corp, Milford, Mass.
Waters CSH, Waters Corp, Milford, Mass
Ostro Pass-through Sample Preparation Plate, Waters Corp, Milford, Mass.
Phoenix 64, Winnonlin, version 7.0, Certara LP, Princeton, NJ.
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