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Serum concentrations and
pharmacokinetics enrofloxacin after
intravenous and intragastric administration to mares
Gregory R. Haines, Murray P. Brown, Ronald R. Gronwall, Kelly A. Merritt
Abstractpharmacokinetics of enrofloxacin were studied in 6 mares after intravenous and intragastric (IG)
single rate of 7.5 mg/kg body weight. In experiment 1, an injectable formulation of enrofloxacinmg/mL) given At 5 min after injection, mean serum concentration was 9.04pg/mL and decreased to 0.09 pg/mL
by half-life was 5.33 ± 1.05 h and the area under the serum concentration vs time curve (AUC)was 21.03 ±
mg h/L. experiment 2, the same injectable formulation was givenIG. The mean peak serum concentrationwas 0.94 ±
pg/mL administration and declined to 0.29 ± 0.12 pg/mL by 24 h. Absorption of this enrofloxacin preparationhighly variable, and for this reason, pharmacokinetic values for each mare could not be determined.
experiment 3, poultry formulation (32.3 mg/mL) was givenIG. The mean peak serum concentration was 1.85 ± 1.47 iig/mLminand declined to 0.19 ± 0.06 pg/mL by 24 h. Elimination half-life was 10.62 ± 5.33 h and AUC was
± mg h/L. Bioavailability was calculated at 78.29 ± 16.55%7. Minimum inhibitory concentrations of enrofloxacin were
equine bacterial culture specimens submitted to the microbiology laboratory over an 11-month period. The min-inhibitory concentration of enrofloxacin required to inhibit 90% of isolates (MIC9,)) was 0.25 pg/mL for Stapllylococculsalireits, Esc/liricliia co/i, Sal/nionella spp., Kiebsiella spp., and Pastel rel/a spp. The poultry formulation was well tolerated and could
potentially treatment of susceptible bacterial infections in adult horses. The injectable enrofloxacin solution should
not be used orally.
ReusumL cs conccnti rationesscrtIcs ct/la pl iari tacociuetiqiie d c I'e rofloxaci e fure it etiid iesee cc/ic Z 6 Jl cinptsaprn s admiiin istration i d'lne doseii iiliqupar v)oic jut raieielisc (IV) ol in tragastrique (IG) dc 7,5 ig/kg dii produ it. Dons la premieree xppricnc, iine preiparation iJnlectabledroeu iirofloxacinec (100 mg/niL)tirelit par v7oic IV Ciniq minuilstesapr'sl 'iuilcction lam0io y/e desc
onceentsoeWratioin st iques tait de
9,04,gug miL ct dimiiiniiapoulr attcii dr c 0,09 .gl/mLaprns 24 Ii. La demi-zv i d elnuniation itait d c5, 33 ± 1,05e tla surtface sons la colurbedic /a concen ration i seif/slie eni fo ction l dii tcenips (SSC)
e tait de 21,03 ± 5,19 miig/.iL Dan7s /a 2Iexp iriiecc /a m niciiie iparatiou i
Iebilccta ble fiit ad iinistir( ai IGLo no1La mpic dii pic dcil a concern tration sfriqule f lit attei te 4 Ii apr"s /'admii sist ration tiidim idicamnc t
ctetait d 0,94 0,97 tg/ lle diminiiiiia par /asuiitepourtattcinedre 0,29 p.g/inL apris 24 /i. L'absorptio dcde cette prpr ipa ration d'cirofloxaci ic
aprn s adniii ist rationparnie oi I G e tait trifs variab/ee,e tpo urcette raiso,,l /es do eInes de /a pl iarnmiacoci itiquec pour-c/iaqii cl unicut ui cp ir ct
iftrc detcrniiuees. Dons /a330 exp eifiience iun e preiparatio ii pouri,uo/ai//e (32,3 iig/niL) ffutadninlitd istri par,noic IC. La mtio ye iie diil pic Lie conC-ceintrationi s'rrietni iitait Lie 1,85 ±, g/mL4 5mlis1 npresiii aprs /'admiiniist rationi ct diminjiia Ji0sqii9 0,19 ± 0,06 aprns 24 Ii. La dcmin 7ic d /imi-nnationi etait Lie 10 6255 33/ i ct la SSC d 16,30 ± 4,69mng/iL L. La biodispotnibiiti flit jz7a/ia 78,29 ± 16,55%S . Les coni entrations miniiii-;iia/esi /i1ibitrics LiL'Cil rofoxaciuie rcqluises pouiri/iibcer 90 %dles iso/ats (CMIk) iftalcit de 0,25 pg/iiL pour Staphylococcus aureus,
Escherichia coli, Salmonella spp., Klebsiella spp. et Pasteurella spp. La priparatioii poutr zo/ai//eflt bici to/ifrrife et pourrait s'azifrer
iiti/c pourl /c traiteniicut diinfectiouis d ue s des bactiries se zsib/es c/ic: des c/ic aiix adii/tcs. La fformncin jectab/e ien rof/oxacbic iic
d eulrait pas ftre ad nilin istreC par- rlOiC01'ora/C. (Tr7aiiiit twarioctcScirge M e) swrc
good tissue penetration following once
administration (2,3). The drug has been shown haveinci-Enrofloxacin, a fluoroquinolone antibiotic, at therapeutic con- dence of development of bacterial resistance (1,2). Enrofloxacin
centrations, is rapidly bactericidal against a broad spectrum of has been shown to be effective against most gram-negative and some
equine pathogens (1,2). Pharmacokinetic studies have revealed gram-positive aerobic bacteria, but has limited activity against
Department of Large Ainial Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida 32610-0136
Address correspondence and reprint requests to Dr. M.P. Brown; telephone: 352-392-4700 ext. 4000; fax: 352-392-8289; e-mail:
Received January 5, 200(0. Accepted March 27, 2000.
1 71
Streptococcus spp. and anaerobes (2,4). These factors have made it aneffective antibiotic for use in equine musculoskeletal infections.Isolates from 233 horses with musculoskeletal infection revealed thatgram-negative aerobic bacteria were the most common bacterialgroup identified in these types of infections (5). Gram-negativebacteria are common isolates in equine pleuropneumonia (6), peri-tonitis (7), endometritis (8), and cholelithiasis (9). Recently, thepharmacokinetics of enrofloxacin were investigated in healthyadult horses and dosage regimens were recommended for thesmall animal formulations (3).
Articular cartilage damage has occurred following the treat-ment of young foals with enrofloxacin (10). Systemic fluoro-quinolone administration at greater than 5 times the manufac-turer's recommended dosage produced cartilage lesions in juvenilerats, dogs, guinea pigs, rabbits, and non-human primates (11-16).Other reported side effects include gastrointestinal tract distur-bances and stimulatory central nervous signs (17). Enrofloxacinis not approved for use in horses. In spite of this, extra-label use ofenrofloxacin is common in equine practice, particularly for thetreatment of infections caused by bacteria resistant to more con-ventional antimicrobial drugs.An oral enrofloxacin product (32.3 mg/mL solution) has been
approved for use in poultry and is less expensive per mg than the68 mg enrofloxacin tablets approved for use in dogs and cats.Because of economic considerations and the frequent need for anorally administered product, the poultry product has been used inclinical practice for the treatment of bacterial infections in horses.An enrofloxacin solution (100 mg/mL) is currently available
and has approval for subcutaneous use in cattle in the UnitedStates. This product has been used in the treatment of bacterial infec-tions in horses. No signs of toxicity were observed in horses givenenrofloxacin at 5.0 mg/kg, IV, q24h for 3 wk (18). To our knowledge,no one has investigated the pharmacokinetic properties of either theinjectable cattle product or oral poultry product in horses.The purposes of this study were to determine the serum con-
centrations and pharmacokinetics of enrofloxacin after a single IVdose of the 100 mg/mL injectable solution in adult horses and to com-pare these values with those found after a single intragastric (IG) doseof the same formulation. We also compared these results with thosefound when a 32.3 mg/mL oral solution of enrofloxacin was givenas a single IG dose. An additional objective was to determine the min-imum inhibitory concentrations (MIC) of enrofloxacin for pathogenicbacteria isolated from equine patients in our hospital. The phar-macokinetic data and MIC data were then used to make dosagerecommendations for treatment of clinical patients.
AnimalsSix healthy adult mares of various breeds, weighing between 465
and 608 kg, were used for experiments 1 and 3. One of the 6 mareswas unavailable for experiment 2. They were given no other med-ications before or during experiments, and at least 10 d wereallowed between experiments. A physical examination and completeblood count were performed for each mare prior to each experiment.
A physical examination was also conducted after each experiment.Horses were considered healthy on the basis of these findings. Adlibitum water and bermuda grass hay constituted their diet. Thehorses were kept on pasture between experiments and in individ-ual stalls during experiments. The project was approved by theUniversity of Florida Institutional Animal Care and Use Committee.Experiment 1 - IV administration of 100 mg/mL injectable solution.An isotonic solution of enrofloxacin (100 mg/mL; Baytril 100,Bayer Corp., Toronto, Ontario) was administered as a single IV bolus(7.5 mg/kg) through a teflon catheter (Abbocath-T, AbbottLaboratories, St-Laurent, Quebec) into the left jugular vein of eachmare. Blood samples were obtained by venipuncture of the rightjugular vein just prior to injection (time 0) and at 5, 10, 15, 20, 30, and45 min. Blood samples were also obtained at 1, 1.5, 2, 3, 4, 6, 8, 12, 18,and 24 h after dose administration. Time 0 was set when half the dosehad been administered.
Experiment 2 - IG administration of 100 mg/mL injectable solution.The 100 mg/mL solution of enrofloxacin was administered as a sin-gle dose (7.5 mg/kg) via nasogastric tube, without fasting. Bloodsamples were obtained in the same manner and times as describedfor experiment 1.
Experiment 3 - IG administration of 32.3 mg/mL oral solution. Eachmare was given a dose (7.5 mg/kg) of the 32.3 mg/mL oral solution(Baytril 3.23% Concentrate Antibacterial Solution, Bayer Corp.)via nasogastric tube without fasting. Blood samples were obtainedin a similar manner and times as described in experiment 1.
Preparation of samplesBlood samples were allowed to clot and then were centrifuged at
2800 X g for 5 min, and the supernatant was decanted. Serum wasstored in polypropylene tubes at -70°C until assayed.
Enrofloxacin assayConcentrations of enrofloxacin were determined using an agar gel
diffusion microbiological assay with a Bacillus subtilis strain (Bacto,Difco Laboratories Inc., USA) as the assay organism (19). Knownstandards of enrofloxacin were prepared in normal equine serum onthe date of each experiment and assayed simultaneously with thesamples. The lowest limit of detection of the assay was 0.07 jLg ofenrofloxacin/mL.
Minimum inhibitory concentration ofenrofloxacin for equine pathogensMinimum inhibitory concentrations (MIC) of enrofloxacin were
determined for all equine bacterial culture specimens submitted tothe microbiology laboratory of the University of Florida VeterinaryMedical Teaching Hospital from June 16, 1998 to May 18, 1999,using a microtitration strip (JustOne antimicrobial strip,Microbiologics, USA). Enrofloxacin concentrations tested rangedfrom 0.12 to 8.0 pg/mL. The assay was validated once monthly bydetermining MIC values for known standard organismsStaphylococcus auireuis (ATCC29213, Microbiologics) and Escherichiacoli (ATCC25922, Microbiologics). Minimum inhibitory concen-trations required to inhibit growth of 50% of isolates (MIC50) and 90%of isolates (MIC90) were both determined to give some indication ofdistribution of MIC range for each organism.
172 -t _i , e -- e
0 6 12 18 24
0 6 12 18 24
0 6 12
Time (h)
computer algorithm that minimized the sum of the squareddeviations (20):
IV: Ct = Cl.e XA1t + C2.e X2t andIG: Ct = C1.e XA1t + C2.eA2 t- (C1 +2) e A3 t
where Ct is the serum drug concentration at time t; e is the base ofNaperian logarithms; Cl, C2, A1, X2, and X3 are the model values thatare fit to the data; and X2 is the elimination rate constant Kel'Elimination half-life (t112) was calculated as the natural logarithm of2 divided by K2. Pharmacokinetic parameters were calculated basedon non-compartmental kinetics (21). The area under the serumconcentration vs time curve (AUC) was calculated from the modelcurve using the following equations:
AUCIV = C1/X1 + C2/X2AUCIG = C1/X1 + C2/X2 - (C1 + C2)/X3The area under the moment curve (AUMC) was calculated as:
AUMCIV = C1/K12 + C2/X2AUMCIG = C1 /K12 + C2/K22 - (C1 + C2)/X3Mean residence time (MRT) was calculated from the following:
MRT = AUMC/AUC
Volume of distribution based on area under the curve (Vdarea) wascalculated as follows:
Vdarea = dose/AUC/KelVolume of distribution at steady state (Vd5s) was determined
from:
Vdss = dose/AUMC/AUC2Clearance was calculated from dose divided by AUC and bioavail-
ability (F) was determined from AUCIG divided by AUCIV.Steady-state maximum and minimum serum enrofloxacin con-
centrations were estimated by use of Curry's method, in whichmaximum and minimum serum concentrations after a single doseare used to predict steady-state values after multiple doses; thismethod assumes dose-independent kinetics (22).
Statistical analysisSerum enrofloxacin concentrations after IV administration (exper-
iment 1) were compared with those after IG administration (exper-iments 2 and 3) by using student's paired t-test. The Spearmanpaired nonparametric test was used to test for significant differencesin serum concentrations between experiment 2 and experiment 3.
18 24
Figure 1. Serum enrofloxacin concentrations (mean ± SD) in mares givensingle doses of enrofloxacin at 7.5 mg/kg: A) IV dose (100 mg/mL);B) IG dose (100 mg/mL); C) IG dose (32.3 mg/mL). The lines representmathematical model fit to mean concentrations.
Pharmacokinetic analysisThe following equations were fit to the enrofloxacin concentration
vs time data for each experiment for each horse; a weighted non-
linear fit of the mathematical model to the data was done using a
No adverse affects, including gastrointestinal, neurologic, or
articular problems, were observed after enrofloxacin administrationin any of the mares. After IV administration (experiment 1), meanserum concentration was 9.04 ± 2.34 Rg/mL at 5 min (Figure 1A).Serum concentrations decreased to a mean value of 0.09 ± 0.08
j±g/mL at 24 h. Mean elimination half-life was 5.33 ± 1.05 h (Table I).
After IG administration of the 100 mg/mL solution (experiment2), the mean peak serum concentration was 0.94 ± 0.97 ,ug/mL at 4 h.
The Canadian Journal of Veterinary Research 173
20
10
1
0.1
3
-zE
cm
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0
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00c0
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1
0.1
3
1
0.1
TABLE 1. Pharmacokinetic parameters (mean ± SD) ofenrofloxacin in 6 mares after IV or 10 administration at adose of 7.5 mg/kg BW
TABLE 11. Predicted steady-state maximum and minimumserum concentrations In mares given enrofloxacin (7.5 mg/kg)IG at 12- and 24-hour dose intervals
Parameters(units)AUC (mg-h/L)kel (/h)t1/2 (h)MRT (h)Vdarea (L/kg)Vdss (L/kg)Clearance (L/h-kg)Bioavailability (%)
IV(expt. 1)
21.03 ± 5.190.13 ± 0.035.33 ± 1.056.55 ± 0.932.93 ± 1.122.46 ± 0.730.37 ± 0.09
IG(expt. 3)
16.30 ± 4.690.07 ± 0.02
10.62 ± 5.3314.48 ± 7.747.71 ± 4.627.28 ± 4.630.49 ± 0.1378.29 ± 16.55
AUC - area under the serum concentration vs time curve; kel - elim-ination rate constant; t1/2 -elimination half-life; MRT - mean res-idence time; Vdarea -the apparent volume of distribution based onarea under the curve; Vdss -the apparent volume of distribution atsteady state
Mean serum concentration decreased to 0.29 ± 0.12 jLg/mL at 24 h.Maximum and minimum enrofloxacin serum concentrations atsteady state were estimated at 1.36 ,ug/mL and 0.42 ,ug/mL, respec-tively (Table II). Absorption of this enrofloxacin preparation afterintragastric administration was highly variable, as seen from the highstandard deviation values from Figure 1B. For this reason, phar-macokinetic values for each mare could not be determined.
After IG administration of the 32.3 mg/mL oral solution (exper-iment 3), the mean peak serum concentration was 1.85 ± 1.47 ,ug/mLat 45 min. Mean serum concentration decreased to 0.19 ± 0.06 j,g/mLat 24 h. Maximum and minimum enrofloxacin serum concentrationsat steady state were estimated at 2.06 ,ug/mL and 0.21 ,ug/mL,respectively (Table II). Mean elimination half-life was 10.62 ± 5.33 h(Table I).Serum enrofloxacin concentrations after IV administration were
significantly different from those observed after IG administra-tion of both preparations (P < 0.0001). Serum concentrations after IGadministration of the 32.3 mg/mL solution were significantlyhigher than those after IG administration of the injectable formu-lation (P < 0.0001).Minimum inhibitory concentrations were determined for a total
of 121 isolates. Culture specimens were obtained from sourcessuch as synovial fluid, pleural fluid, transtracheal washes, abscesses,and wounds. The minimum inhibitory concentration of enrofloxacinrequired to inhibit 90% of isolates (MIC90) ranged from 0.25 ,ug/mLto 2 ,ug/mL, depending on the organism (Table III).
A dose of 7.5 mg/kg was chosen for the present study based onthe oral dose recommendation of Giguere et al (3), using the smallanimal formulation. The same dose was used for each experimentto facilitate determination of bioavailability.
This study used a microbiological assay to determine enrofloxacinserum concentrations. The bioassay does not differentiate betweenenrofloxacin and its active metabolites. In several animal species,
Enrofloxacin Dose Cmax(ss) Cmin(ss)formulation interval (h) (pg/mL) (pg/mL)100 mg/mL 24 1.36 0.42(cattle formulation) 12 2.54 1.5932.3 mg/mL 24 2.06 0.21(poultry formulation) 12 2.43 0.59Cmax(ss) - maximum serum concentration at steady state; Cmin(ss)minimum serum concentration at steady state
including equine species, enrofloxacin is partially de-ethylated tociprofloxacin in concentrations sufficient to be therapeuticallyeffective (23,24). By measuring the total antimicrobial activity, themicrobiological assay overestimates actual enrofloxacin concen-trations (25). However, in a study comparing IV and intramuscular(IM) administration of enrofloxacin to horses, serum concentrationsof the drug were determined by microbiological assay and by highperformance liquid chromatography. It was concluded that most ofthe antimicrobial activity originated from the parent drug andthat the half-life of the antibacterial activity paralleled the half-livesof enrofloxacin and its metabolite, ciprofloxacin (26). In a clinical sit-uation, this total activity is adequate to determine a dosage.
In the present study, mean serum enrofloxacin concentrations inhorses given a single IV dose of 7.5 mg/kg were similar to those pre-viously reported at a lower dosage of 5.0 mg/kg (26,27). In a studyby Zehl (27), enrofloxacin was given IV to 5 horses at 5.0 mg/kg in3 consecutive doses at 24-hour intervals. In that study, mean serumconcentrations were 9.44 pg/mL at 10 min after the first dose.However, 10 min after the second and third doses, the mean serumconcentrations were 5.87 pg/mL and 6.25 pg/mL, respectively. Itwas suggested that this reduction in subsequent serum concen-trations may be a result of enzyme induction. Serum concentrationsobserved after 1 h were similar after all 3 doses. Giguere et al (3) useda small animal injectable formulation of enrofloxacin (22.7 mg/mL)given at 2.5 mg/kg and 5.0 mg/kg. Ten minutes after injection of5.0 mg/kg, the mean serum concentration was 12.47 pg/mL.
Elimination half-life (t1/2) after IV administration was 5.33 ±1.05 h, which compared closely to previous reports of 5.5 ± 0.6 h (28),6.49 ± 0.70 h (27), and 6.09 h (3). These values were obtained after anIV dose of 5.0 mg/kg, compared with the 7.5 mg/kg used in ourstudy. The AUC in the present study (21.03 ± 5.19 mg-h/L) was sim-ilar to values previously reported at the 5.0 mg/kg dose (19.5 to23.24 mg-h/L) (26,27). In contrast, at the same 5.0 mg/kg dose,Giguere et al (3) reported an AUC of 58.3 ± 8.40 mg h/L.
After IG administration of enrofloxacin (32.3 mg/mL), t1/2 was10.62 ± 5.33 h, compared to a previously published value of 7.75 hfor the tablet form of the drug (23). The AUC (16.30 ± 4.69 mg h/L)was similar to previous reports when given at 5.0 mg/kg (12.04 to18.94 mg-h/L) (23,27). This is in contrast to another study, whichreported an AUC of 35.62 ± 9.65 mg-h/L at the 5.0 mg/kg dose (3).
Significant differences were seen in serum concentrations after IGadministration of the injectable solution (100 mg/mL; experiment2) compared with the oral solution (32.3 mg/kg; experiment 3). The
174 The Canadian Journal of Veterinary Research
TABLE Ill. Minimum inhibitory concentrations of enrofloxacin (pg/mL) required to inhibitgrowth in 50% (MIC50) and 90% (MIC90) of 121 equine isolates from bacterial submissionsat the University of Florida Veterinary Medical Teaching Hospital
Gram-negative organismsAcinetobacter baumanniiActinobacillus equuliAeromonas hydrophiliaBurkholderia cepaciaCitrobacter diversusEnterobacter cloacoeEnterobacter sakazakiiEscherichia coliFlavobacterium spp.Klebsiella pneumoniaePasteurella pneumotropicaPasteurella spp.Proteus vulgarisProvidencia spp.Pseudomonas aeruginosaPseudomonas spp.Psychrobacter phenylpyruvicaSalmonella spp.
n MIC501 NA1 NA1 NA2 NA2 NA2 .0.251 NA
22 ' 0.251 NA9 NA4 NA3 NA1 NA2 NA3 . 0.52 NA2 NA6 NA
Gram-positive organisms
Corynebacterium pseudotuberculosis 1Enterococcus spp. 6Rhodococcus equi 4Staphylococcus aureus 13Staphylococcus spp. 1Streptococcus equisimilis 5Streptococcus Group D 5Streptococcus zooepidemicus 21n = Number of isolates; NA = Not applicable
NA' 0.5' 1.0' 0.25NA
' 1.0' 1.0' 1.0
main difference in the vehicles of these 2 products is that the latterproduct contains 60% propylene glycol. It is possible that propyleneglycol may have enhanced absorption, but this effect was not
investigated in this study. Based on the variability of absorption andsignificant difference in serum concentrations achieved after IGadministration of the injectable solution (experiment 2), we wouldnot recommend once daily IG or oral administration of this product.If this product were given twice daily by the IG or oral route (TableII), the cost may be prohibitive in many circumstances and toxicity,including gastrointestinal disturbances, may be of greater concern.
In the study by Zehl (27), enrofloxacin solution (250 mg/mL) was
administered IG at 5.0 mg/kg in 3 consecutive doses at 24-hour inter-vals. When given to fed horses, the mean peak serum concentrationwas 1.88 pg/mL 1 h after the first dose, with similar peaks after thesecond and third doses. In another study (23), crushed enrofloxacintablets (5.0 mg/kg; 68 mg/tablet) were given in a single dose,orally, in syrup. Mean peak serum concentration was 1.85 pg/mLat approximately 1 h after administration. These results are similar
to our findings at a higher dose, with a mean peak serum concen-
tration of 1.85 ± 1.47 pg/mL at 45 min after administration. This is
in contrast to the study by Giguere et al (3), in which crushedenrofloxacin tablets were given at 5.0 mg/kg by nasogastric tube and
after 24 h, an additional 5 doses were given at 12-hour intervals. Themean peak serum concentration 1 h after the first dose was
5.44 pg/mL and 5.97 pg/mL at 1.25 h after the sixth dose.Although serum enrofloxacin concentrations were lower in our
IG studies than those reported by others, we calculated the bioavail-ability of the oral poultry solution (32.3 mg/mL) to be higher thanthat reported for an enrofloxacin solution containing 250 mg/mL(27). Zehl (27) reported a bioavailability of 51.81% in fed horses and65.36% in fasted horses. Bioavailability of enrofloxacin tablets(68 mg/tablet) was reported at 57.39% when dosed at 2.5 mg/kg and62.53% when dosed at 5.0 mg/kg (3). Serum concentrations in our
study were also lower after IV administration than those in otherreports (3,27). Because bioavailability is calculated from
AUCIG/AUC,v, a lower value for AUCjv would result in a higherestimate of bioavailability.Many of the MIC values determined in the present study were
similar to those previously reported (28,29). However, our MIC val-ues for several gram-negative isolates were 2- to 10-fold higherthan those reported in other studies (28,29). Culture and suscepti-bility data may slightly underestimate the efficacy of enrofloxacinbecause of its metabolization to ciprofloxacin, a more potentantimicrobial (30). Efficacy of fluoroquinolones against pathogenic
The Canadian Journal of Veterinary Research 175
MiC90NANANANANA< 1.0NA
< 0.25NANANANANANA< 0.5NANANA
NA< 2.0< 2.0< 0.25NA< 1.0< 1.0< 1.0
Range0.250.250.250.50.25
0.25-1.00.25
0.12-2.00.250.250.250.250.250.25
0.25-0.50.50.250.25
0.250.5-2.00.5-2.00.25-1.00.25
0.25-1.00.25-1.00.5-2.0
bacteria has been evaluated in neutropenic rats and in ill humanpatients (31-34). Based on these studies, it has been suggested thatCmax/MIC > 10 and AUC/MIC > 125 are critical breakpoints indetermining maximum efficacy (32,33). When these criteria areapplied to pathogens with an MIC value of 0.25 pg/mL, after IVadministration of the injectable solution, AUCIv/MIC = 84. This sug-gests that our IV dose of 7.5 mg/kg, if given every 24 h, may be inad-equate for therapy of infections caused by pathogens with an MICof 0.25 pg/mL. This is in contrast to the findings of Giguere et al (3),in which a single daily IV dose of 5.5 mg/kg was predicted toachieve AUC/MIC ' 125 for pathogens with an MIC value of0.5 pg/mL. It should be emphasized that the above criteria werebased on determination of maximum efficacy in other species.
This also suggests that our IG dose of 7.5 mg/kg for the32.3 mg/mL oral solution, if given every 24 h, may be inadequate forinfections caused by pathogens with an MIC of 0.25 pg/mL, becauseAUCIG/MIC = 65. At steady state (Table II), Cmax/MIC = 9.72 for theIG dose of 7.5 mg/kg given every 12 h. This is near the desired ratioof Cmax /MIC ' 10 and may be adequate for the successful treatmentof pathogens with a MIC value of 0.25 pg/mL.Our study suggests, using the above-mentioned methods of
evaluating maximum fluoroquinolone efficacy (32,33), a once ortwice daily 7.5 mg/kg, IG, dosing of a 3.23% concentrate enrofloxacinsolution in non-fasted adult horses may be inadequate for treatinginfections caused by bacteria that have an MIC value ' 0.25 pg/mL.Our data also suggest that the 100 mg/mL injectable solution ofenrofloxacin administered IV at a once daily dosage of 7.5 mg/kgmay not be effective in treating similar bacterial infections. However,to our knowledge, the Cmax/MIC > 10 and AUC/MIC > 125 criteriafor maximum therapeutic effect have not been validated forenrofloxacin in the horse and should be further investigated.The poultry formulation (32.3 mg/mL) demonstrated good oral
bioavailability. It was well tolerated and could be potentially use-ful in the treatment of susceptible bacterial infections in the adulthorse. Additional studies are required to confirm the efficacy andsafety of this formulation in a clinical setting. Conversely, we wereunable to validate the oral or IG use of the injectable formulation ofenrofloxacin (100 mg/mL).
The authors thank Lance Baltzley, Tonya Clauss, GeorgeannEllis, and Matthew Levesque for technical assistance.
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