Comparative pharmacokinetics of marbofloxacin in healthy and Mannheimia haemolytica infected calves

Research in Veterinary Science 82 (2007) 398–404 www.elsevier.com/locate/rvsc

Comparative pharmacokinetics of marbofloxacin in healthy and Mannheimia haemolytica infected calves M. Ismail a

a,*

, Y.A. El-Kattan

b

Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt b Animal Health Research Institute, Egypt Accepted 2 October 2006

Abstract The pharmacokinetics of marbofloxacin were investigated in healthy (n = 8) and Mannheimia haemolytica naturally infected (n = 8) Simmental ruminant calves following intravenous (i.v.) and intramuscular (i.m.) administration of 2 mg kg1 body weight. The concentration of marbofloxacin in plasma was measured using high performance liquid chromatography with ultraviolet detection. Following i.v. administration of the drug, the elimination half-life (t1/2b) and mean residence time (MRT) were significantly longer in diseased calves (8.2 h; 11.13 h) than in healthy ones (4.6 h; 6.1 h), respectively. The value of total body clearance (CLB) was larger in healthy calves (3 ml min1 kg1) than in diseased ones (1.3 ml min1 kg1). After single intramuscular (i.m.) administration of the drug, the elimination half-life, mean residence time (MRT) and maximum plasma concentration (Cmax) were higher in diseased calves (8.0, 12 h, 2.32 lg ml1) than in healthy ones (4.7, 7.4 h, 1.4 lg ml1), respectively. The plasma concentrations and AUC following administration of the drug by both routes were significantly higher in diseased calves than in healthy ones. Protein binding of Marbofloxacin was not significantly different in healthy and diseased calves. The mean value for MIC of marbofloxacin for M. haemolytica was 0.1 ± 0.06 lg ml1. The Cmax/ MIC and AUC24/MIC ratios were significantly higher in diseased calves (13.0–64.4 and 125–618 h) than in healthy calves (8–38.33 and 66.34–328 h). The obtained results for surrogate markers of antimicrobial activity (Cmax/MIC, AUC/MIC and T P MIC) indicate the excellent pharmacodynamic characteristics of the drug in diseased calves with M. haemolytica, which can be expected to optimize the clinical efficacy and minimize the development of resistance.  2006 Elsevier Ltd. All rights reserved. Keywords: Bioavailability; Calves; Fluoroquinolones; HPLC; Mannheimia haemolytica; Minimum inhibitory concentration; Marbofloxacin; Pharmacodynamics; Pharmacokinetics; Protein binding

1. Introduction

Abbreviations: t1/2a, distribution half-life; t1/2b, elimination half-life (i.v.); Vc, apparent volume of the central compartment; Vdss, volume of distribution at steady state; ClB, total body clearance; AUC0–24, area under curve from zero time to 24 h post-administration; AUC0–1, area under curve from zero time to infinity; MRT, mean residence time; AUMC0–1, area under the moment curve from zero time to infinity; Kab, firstorder absorption rate constant; t1/2(ab), absorption half-life; Kel, first-order elimination rate constant; t1/2(el), elimination half-life (i.m.); MAT, mean absorption time; Cmax, maximum plasma concentration; Tmax, time to peak plasma concentration; F, systemic bioavailability; MIC, minimum inhibitory concentration; AUIC, AUC/MIC. * Corresponding author. Fax: +20 25720877. E-mail address: [email protected] (M. Ismail). 0034-5288/$ - see front matter  2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.rvsc.2006.10.001

Marbofloxacin is a new third generation fluoroquinolone developed exclusively for veterinary use (Schneider et al., 1996). It has broad spectrum bactericidal activity against Gram negative bacteria, including Mannheimia haemolytica and Haemophillus species, Gram positive bacteria and Mycoplasma species (Drugeon et al., 1997; Meunier et al., 2004). Marbofloxacin is used for the treatment of bovine respiratory disease (Thomas et al., 2001) and calf neonatal diarrhea (Grandemange et al., 2002). Bovine pneumonia caused by M. haemolytica is one of the most important causes of death in feedlot cattle. The pharmacokinetics of several drugs is profoundly

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altered in animals experimentally infected with M. haemolytica (Ames et al., 1983; Ole-Mapenay et al., 1997; Burrows, 1985). The disposition kinetic of marbofloxacin has been extensively examined in a variety of animal species as sows (Petracca et al., 1993), calves (Thomas et al., 1994a; Aliabadi and Lees, 2002), dogs (Schneider et al., 1996; Heinen, 2002), cows, ewes (Shem-Tov et al., 1997), birds of prey (Waxman et al., 2000), goats (Waxman et al., 2001), horses (Bousquet-Melou et al., 2002), cats (Albarellos et al., 2005) and ostriches (De Lucas et al., 2005). Additionally, disposition kinetics of the drug have been studied in pneumonic calves using the protocol of experimental infection with M. haemolytica (Thomas et al., 1994b). The experimental induction of pasteurellosis results in rapid onset of the disease in a severe form that could be refractory to treatment within a few hours (Dassanayake and White, 1994). Thus, the efficacy of the drug tested in such experiment may not be fully assessed as compared to its use in a field situation in which calves with a wider spectrum of disease severity would likely be encountered. Therefore, the aim of the present study was to investigate the pharmacokinetic profile of marbofloxacin in healthy calves and those naturally infected with M. haemolytica following a single intravenous and intramuscular injection of the drug. Moreover, the minimum inhibitory concentrations of marbofloxacin against M. haemolytica were determined and the pharmacokinetic–pharmacodynamic integration was also estimated using the surrogate markers of antimicrobial activity (Cmax/MIC, AUC/MIC and T P MIC). 2. Materials and methods

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greater than 40 C, dyspnoea, nasal discharge, abnormal lung sounds and tachypnoea (higher than 30 respirations min1). Nasal swabs were collected aseptically and then streaked into blood agar, chocolate or Macconkey agar media. Growing colonies were identified by using standard techniques based on cultural characteristics and biochemical reactions (MAFF, 1984). Blood samples were taken and subjected to serological examination for antibody to bovine virus diarrhea (BVD), infectious bovine rhinotracheitis (IBR), parainfluenza 3 virus (PI3) and respiratory syncytial virus using enzyme linked immunosorbent assay (ELISA) technique and antibody to M. haemolytica, Pasteurella multocida, Mycoplasma bovis and Haemophilus somnus using indirect haemagglutination technique. Animals allocated to a healthy group (n = 8) were obtained from a healthy flock, they were determined to be clinically normal by physical, serological and bacteriological examinations using the same standard techniques. 2.3. Experimental design The protocol of this study was reviewed and approved by the animal care and use committee in the Faculty of Veterinary Medicine, Cairo University. Four calves in each group (diseased and healthy) were given a 2 mg kg1 body weight dose of 10% aqueous solution of marbofloxacin intravenously into the right jugular vein. The other four calves in each group were given the same dose of the drug deeply into the gluteal muscle. Blood samples were collected from the left Jugular vein into heparinized syringes before and 5, 10, 15, 30 min and 1, 2, 4, 6, 8, 10, 12, 24 and 48 h after marbofloxacin injection. Plasma was separated by centrifugation at 2000g for 10 min and stored at 20 C until assayed.

2.1. Drug 2.4. Marbofloxacin assay Marbofloxacin was used as 10% injectable aqueous solution obtained from Veterinary Pharmaceutical Laboratories, France (Marbocyl, Vetoquinol, Lure, France). Marbofloxacin standard was provided by Vetoquinol (Lure, France) and ofloxacin was purchased from Sigma Chemical Company (St. Louis, MO, USA). 2.2. Animals Sixteen cross breed Simmental ruminant calves, 10 months old (mean weight, 170 ± 12 kg) were used in this study. Calves were fed hay, alfalfa and drug free concentrates and water was provided ad libitum. Diseased calves (n = 8) were selected from a naturally infected flock with M. haemolytica. Animals were allocated into the diseased group when they met specific diagnostic criteria including clinical signs, positive bacteriological examination for M. haemolytica, sero positive result for antibody of M. haemolytica and seronegative result for antibody of other common causative agents for pneumonia. Clinical signs of acute pneumonia include a rectal temperature equal to or

2.4.1. Instrumentation Drug concentration in plasma was determined by using reverse phase high performance liquid chromatography (HPLC) according to the method previously described by Waxman et al. (2001). The HPLC system consisted of a Model 616 solvent delivery pump (Waters, Milford, MA, USA), a Waters Model 600 S controller, a Model 717 plus autosampler equipped with a temperature-controlled rack (Waters), a variable wavelength UV detector (Shimadzu, UV12). 2.4.2. Chromatographic conditions The mobile phase consisted of buffer, pH, 2.7-methanol– acetonitrile–acetic acid–triethylamine (74:20:4:1:1 v/v/v/v/ v). The buffer pH 2.7 consisted of 0.4% aqueous solution of tetrabutylammonium hydrogensulphate (p/v) and diammonium hydrogenphosphate (p/v). Separation was achieved with a reverse phase C18 column (Discovery, Supelco, 5 lm, 4.6 · 150 mm). The UV detection wavelength was 295 nm and the flow rate was 1 ml/min.

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2.4.3. Calibration curve For preparation of the calibration curves, antibiotic naı¨ve calves plasma obtained from healthy and diseased animals were spiked with 0.04, 0.08, 0.25, 0.5, 1.0, 2.0 and 4.0 lg ml1 marbofloxacin and ofloxacin was used as an internal standard. The standard curves of marbofloxacin in plasma from healthy and diseased calves were linear between 0.04 and 4 lg ml1. The correlation coefficients (r2) of standard curves were >0.97 for plasma of healthy and diseased calves with lower quantitation limit (LOQ) of 0.04 lg ml1. 2.4.4. Sample extraction The plasma samples or calibration standards to be assayed (300 ll) were placed in a centrifuge tube and spiked with 75 ll of internal standard (ofloxacin 5 lg ml1 in 0.05 M phosphate buffer) and vortexed. Trichloromethane (4.5 ml) was added, the samples were vortexed, the aqueous layer was removed by aspiration, and the organic layer was evaporated to dryness. The residue was reconstituted using HPLC mobile phase (150 ll) and transferred to an autosampler vial for injection. 2.4.5. Validation of the assay method The precision and accuracy of the method were evaluated by repetitive analysis of the plasma samples (n = 12) spiked with 0.04, 0.08, 0.1, 0.5 and 4 lg ml1 marbofloxacin. The recovery was calculated by comparison of plasma and aqueous samples (n = 6). The values of intra-assay and interassay precision were <4.4% for plasma of healthy and diseased calves. The intraassay and interassay accuracies were >94% for plasma of healthy and diseased calves. Recovery of marbofloxacin from plasma of healthy and diseased animals was found to be 94%. 2.5. Estimation of protein binding The extent of plasma protein binding was determined in vitro according to the method previously described by Singhvi et al. (1977). Plasma samples from healthy and diseased calves were spiked with 0.05, 0.1, 0.5, 1, 5 and 10 lg/ml marbofloxacin and 1 ml was added to a commercial ultrafiltration device (Centrifree 4104, Amicon Corp., Danvers, MA). The ultrafiltration device was centrifuged at a fixed (28) angle (Sorvall, RC-5B Refrigerated super speed centrifuge, GSA rotor, DuPont Instruments, Newtown, Conecticut) at 1200g for 30 min at 37 C. This resulted in an ultrafiltrate volume of at least 200 ll. The ultrafiltrate was frozen until assayed for marbofloxacin. The percentage of protein bound fraction (B) was calculated according to the following equation: B = (initial plasma (concentration)  ultrafiltrate (concentration))/initial plasma (concentration) · 100. The coefficients of variation for this method were <4.7%. 2.6. Minimum inhibitory concentration The minimum inhibitory concentrations (MIC) of marbofloxacin for M. haemolytica were determined by broth

microdilution technique (NCCLS, 1993). Ten replicates of twofold dilutions of marbofloxacin (0.02, 0.04, 0.08, 0.16, 0.32, 0.64, 1.28 and 2.56 lg ml1) were used. Fifty microlitres of each concentration was added to each well. One well in each row contained only Muller–Hinton broth (MH) to serve as an inoculation and growth control. Clinical isolates (24-h old cultures) were subcultured to MH broth to a density of approximately 108 colony forming units (CFU) ml1, compared with a density of 0.5 McFarland standard. This suspension was further diluted to 105 CFU ml1 in MH broth. Fifty microlitres of the suspension was delivered to each well. The MIC was the lowest concentration of marbofloxacin for which no visible growth was observed after 18 h of incubation at 37 C. The coefficients of variation for this method were <3.6%. 2.7. Pharmacokinetic analysis Following intravenous administration, the plasma concentration time data of the drug in healthy and diseased calves were fitted to a two compartment open model system (Baggot, 1978) according to the following biexponential equation: Ct = A eat + B ebt, where Ct is the plasma concentration of marbofloxacin, t is time after intravenous administration, A and a are the intercept and slope, respectively, of the distribution phase and B and b are the intercept and slope of the elimination phase. Pharmacokinetic variables were obtained by use of a computer program (R Strip, Micromath, Salt Lake, UT, USA). The distribution and elimination half-lives (t1/2a and t1/2b), the volume of distribution at steady state (Vdss), the volume of the central compartment (Vc) and the total body clearance (ClB) were computed according to standard equations (Gibaldi and Perrier, 1982). Following intramuscular (i.m.) administration, plasma concentration data in healthy and diseased calves were analyzed by compartmental and non-compartmental methods based on the statistical moment theory (Gibaldi and Perrier, 1982). In compartmental analysis, best fitting of the data was accomplished using one compartment open model and first order absorption rate constant according to the following equation: C t ¼ E eK el t  C eK ab t , where Ct is the plasma concentration of marbofloxacin, t is time after i.m. administration, Kel is the elimination rate constant, Kab is the first-order absorption rate constant and E and C are the mathematical intercepts. The terminal elimination half-life (t1/2(el)) and absorption half-life (t1/2(ab)) were calculated as ln 2/Kel or ln 2/Kab, respectively. The area under the plasma concentration time curve (AUC0–1) and the area under the first moment curve (AUMC0–1) were calculated by the trapezoidal rule for all measured data with extrapolation to infinity using C24/b or C24/Kel, where C24 is the plasma concentration at 24 h. The mean residence time (MRT) was calculated as MRT = AUMC0–1/AUC0–1. The mean absorption time (MAT) was calculated as MAT = MRT(i.m.)  MRT (i.v.).

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The peak plasma concentration (Cmax) and time to maximum concentration (Tmax) were taken from the plot of each calf’s concentration time curves. Bioavailability (F; fraction of drug systemically available) was calculated as follows: F = AUC i.m/AUCi.v · dosei.v./dosei.m. · 100. 2.8. Pharmacokinetic–pharmacodynamic integration The Cmax/MIC and AUC0–24/MIC (AUIC) ratios were calculated by using MIC of M. haemolytica isolated from diseased calves. These ratios represent the inhibitory activity or surrogate markers of efficacy of marbofloxacin against M. haemolytica (McKellar et al., 2004). 2.9. Statistical analysis

3. Results Following intravenous administration of marbofloxacin (2 mg kg1) in healthy and diseased calves, the plasma concentration versus time data comply the two compartment open model and exhibit a biphasic decline. Table 1 shows the pharmacokinetic parameters of marbofloxacin following i.v. administration in healthy and diseased calves. As compared with normal calves, the values of t1/2b, AUC and MRT were significantly higher, whereas b and ClB were significantly lower following i.v. administration of marbofloxacin in diseased calves. Following a single i.m. administration of marbofloxacin (2 mg kg1), maximum plasma concentrations (Cmax) of 1.4 and 2.32 lg ml1 (Table 2) were attained at (Tmax) 1.0 and 0.8 h post-dosing in healthy and diseased calves, respectively. Marbofloxacin was detected in plasma of Table 1 Pharmacokinetic variables of marbofloxacin in healthy and Mannheimia haemolytica infected calves following intravenous administration of 2 mg kg1 body weight (mean ± SD, n = 4) Parameters

t1/2a b t1/2b Vc Vdss ClB AUC0–24 AUC0–1 AUMC0–1 MRT a

P < 0.001.

Units

h h1 h l kg1 l kg1 ml min1 kg1 lg h ml1 lg h ml1 lg h2 ml1 h

Table 2 Pharmacokinetic parameters of marbofloxacin in healthy and M. haemolytica infected calves following single intramuscular administration of 2 mg kg1 body weight (mean ± SD, n = 4) Parameters

Unit

t1/2(ab) Kel t1/2el Cmax Tmax AUC0–24 AUC0–1 AUMC0–1 MRT F

h h1 h lg ml1 h lg h ml1 lg h ml1 lg h2 ml1 h %

a

All the data are presented as mean ± SD. The data were evaluated by a one-way analysis of variance (ANOVA) using the SPSS 6.1.3 software package (SAS, Cary, NC, USA) and the difference between the means were assessed using the test of least significant difference (LSD). Statistical significance was at P < 0.05.

Mean ± SD Healthy

Diseased

0.13 ± 0.02 0.152 ± 0.02 4.6 ± 0.6 0.42 ± 0.06 1.1 ± 0.14 3.0 ± 0.36 11.7 ± 1.34 12 ± 1.58 73 ± 9.6 6.1 ± 0.8

0.2 ± 0.02 0.1 ± 0.01a 8.2 ± 1.1a 0.4 ± 0.04 1.0 ± 0.12 1.30 ± 0.16a 22.2 ± 3.0a 25.54 ± 3.2a 284.4 ± 37.8a 11.13 ± 1.48a

401

Mean ± SD Healthy

Diseased

0.51 ± 0.034 0.14 ± 0.01 4.7 ± 0.31 1.4 ± 0.1 1.0 ± 0.4 12.0 ± 0.8 12.31 ± 1.0 91.2 ± 6.1 7.4 ± 0.5 103 ± 7

0.44 ± 0.04 0.1 ± 0.01a 8.0 ± 1.1a 2.32 ± 0.3a 0.8 ± 0.64 22.24 ± 3.0a 26.1 ± 3.5a 312.3 ± 41.6a 12 ± 1.6a 102.3 ± 6.4

P < 0.001.

healthy and diseased calves for 24 h post-administration. The plasma concentrations of the drug were exceeding the MIC of M. haemolytica for 12 and 24 h postadministration in healthy and diseased calves, respectively. The elimination half-life and MRT were significantly longer (P < 0.001) in diseased calves than in healthy ones. No significant difference was reported in systemic bioavailability of marbofloxacin following i.m. administration in healthy and diseased calves. Marbofloxacin was bound to the extent of 29 ± 2.2% and 27 ± 2.6% to plasma protein of healthy and diseased calves, respectively. Binding of the drug to plasma protein in healthy and diseased calves was not concentration dependent. The MICs of marbofloxacin for M. haemolytica isolates (n = 4) were within the range of 0.04–0.178 lg ml1 with a mean value of 0.1 ± 0.06 lg ml1. The Cmax/MIC ratios were within the ranges of 8–38.33 and 13.0–64.4 and AUC/MIC ratios were within the ranges of 66.34–328 and 125–618 h in healthy and diseased calves, respectively. 4. Discussion In the present study, pharmacokinetics of marbofloxacin were characterized in normal calves and calves naturally infected with M. haemolytica. The use of naturally infected calves for studying the pharmacokinetics/pharmacodynamics integration of marbofloxacin enables the assessment of the relevant parameters in diseased condition resembling those encountered clinically in the field. Nevertheless, the results of the present study are different from those previously reported in animals with experimental pasteurellosis, the design of the present study could not explain the reason for such difference. However, our findings could be supported by the successful use of fluoroquinolones in clinical field trials (Highland et al., 1994; Vancustem et al., 1990) comparable to their use in experimentally induced pasteurellosis (Olchowy et al., 2000). Following i.v. administration of marbofloxacin (2 mg kg1 b.w.), plasma concentration versus time data were best

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fitted to a two compartment open model. The Vdss of marbofloxacin did not alter in pneumonic calves. On the contrary, a significant increase in Vdss of oxytetracycline and doxycycline has been reported in pneumonic calves (Ames et al., 1983) and pneumonic goats (Ole-Mapenay et al., 1997). Baggot (1980) stated that the disease increases the volume of distribution of drugs due to changes in the pH of infected tissues and the degree of ionization of drugs. These changes are not likely to profoundly affect the distribution characters of marbofloxacin as a result of its amphoteric nature and double pKa (Brown, 1996). The elimination half-life (t1/2b) and mean residence time (MRT) of marbofloxacin were longer in pneumonic calves than in healthy ones. Taken into consideration that protein binding of marbofloxacin was not significantly different in healthy and diseased calves, this delay in the elimination of the drug may be the result of renal and/or hepatic abnormalities caused by fever and endotoxin production accompanied with M. haemolytica infection (Hodgson et al., 2003). Endotoxin (lipopolysaccharide) reduces the content and the activity of cytochrome p-450, which metabolize the drugs (van-Miert, 1990; Hasegawa et al., 1999). Endotoxin produces direct tubular cell injury as well as some functional changes in the kidney, including a decrease in the renal blood flow and glomerular filtration rate, and changes the intrarenal hemodynamics (Jernigan et al., 1988). In addition, endotoxin causes metabolic acidosis and reduces urinary pH in febrile animals (Baggot, 1980; Salam Abdullah and Baggot, 1984; Spurlock et al., 1985; van-Miert, 1990). It is probable that the decrease in glomerular filtration rate and metabolic acidosis induced by endotoxin plays an important role in the reduction of body clearance of marbofloxacin and consequently increases its elimination half-life (Waxman et al., 2003). The decrease in body clearance has been previously observed for danofloxacin and marbofloxacin in pneumonic calves (Apley and Upson, 1993; Thomas et al., 1994b). Moreover, our findings are consistent with those reported for other fluoroquinolones in febrile goats (Jha et al., 1996; Rao et al., 2000), but it was inconsistent with that reported in M. haemolytica infected calves treated with erythromycin (Burrows, 1985). The systemic bioavailabilities were 103% in healthy calves and 102.34% in diseased calves. This finding indicates excellent absorption of the drug from the site of injection. Our result is consistent with those previously reported in cow (Shem-Tov et al., 1997) and calves (Thomas et al., 1994a). From previous study with the fluoroquinolones, ciprofloxacin, it has been proposed that treatment should be optimized by providing a breakpoint for AUIC of at least 125 h (Forrest et al., 1993) and a breakpoint for Cmax/MIC ratio of 10 or greater (Sullivan et al., 1993). In vitro sensitivity test in the present study revealed that M. haemolytica was very sensitive to marbofloxacin with MIC equal to 0.10 lg ml1 consistent with previous results (0.08 lg ml1)

reported by Meunier et al. (2004). Marbofloxacin pharmacokinetic/pharmacodynamic (PK/PD) integration revealed for serum a significantly higher value for Cmax/MIC and AUC/MIC (AUIC) ratios in diseased calves than those in healthy calves. The concentrations of the drug were exceeding the MIC for M. haemolytica (T P MIC) for 12 and 24 h post-i.m. dosing in healthy and diseased calves, respectively. These pharmacokinetic–pharmacodynamic interrelationships predict that marbofloxacin treatment at a dosage of 2 mg kg1 should be very effective against other strains of the same species with the same or lower MIC. Comparable to our results, marbofloxacin PK/PD integration following i.m. administration in healthy calves in a study done by Aliabadi and Lees (2002) revealed for serum a Cmax/MIC ratio of 37.6, an AUIC of 252.7 h, and T P MIC was 22.7 h. In making these comparisons, it should be noted that there are significant differences between the in vitro MIC (0.04 lg/ml) for M. haemolytica reported in the previous study by Aliabadi and Lees (2002) comparable to the value (0.1 lg/ml) reported in the present study. In another study by Aliabadi and Lees (2003), the value of in vitro MIC reported for danofloxacin against M. haemolytica was 0.04 lg/ml and the results of integration of pharmacokinetic and pharmacodynamic data following i.m. administration of danofloxacin (1.25 mg/kg) in healthy calves indicated that mean Cmax/MIC ratio, AUIC and T P MIC were 5.3, 35.4 and 10.2 h, respectively. These values fall short below the effective values estimated by others (McKellar et al., 2004) and indicated the importance of using the approach of pharmacokinetic– pharmacodynamic integration for predicting the clinical efficacy of fluoroquinolones against infection by M. haemolytica. It must be recognized that the breakpoints for surrogates of clinical response described elsewhere were determined with models for human and small animals either naturally compromised by neutropenia or with experimentally induced neutropenia. Appropriate values for success are likely to be quite different for immunocompetent calves. In conclusion, the dose of marbofloxacin used in the present study produced therapeutically useful marbofloxacin concentration in plasma (P0.1 lg ml1) for 24 h in M. haemolytica infected calves. In addition, M. haemolytica infection produced significant changes in the plasma levels and some pharmacokinetic variables of marbofloxacin as well as surrogate markers of efficacy (Cmax/MIC ratio and AUIC) and when taken together, these changes can be expected to optimize efficacy and minimize the development of resistance. Finally, there is a need to generate information for clinical efficacy of the drug versus data for pharmacokinetic–pharmacodynamic intergration calculated in diseased animals. Acknowledgements The authors appreciate the great effort of the members of Microbiology Department, (Animal Health Research

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