632
|
wileyonlinelibrary.com/journal/jvp © 2019 John Wiley & Sons Ltd J vet Pharmacol Therap. 2019;42:632–639.1 | INTRODUCTION
Calves born at a gestational age of 230–260 days are defined as premature, wherein several basic organs, including lungs, liver, car‐ diovascular system, kidneys, and the gastrointestinal tract, do not mature completely (Sangild, 2006; Yildiz & Ok, 2017). This situa‐ tion may lead to major changes in body composition and metabolic
capacity, both of which can affect the pharmacokinetics (PKs) and the pharmacodynamics (PDs) of drugs used in premature calves. Antimicrobial drugs are used for animals of all ages. The most critical decisions regarding the use of these drugs are probably mostly made in case of premature animals because of immaturity. Several studies have determined the PKs of drugs in premature infants in human medicine (Anderson, Allegaert, Van Den Anker, Cossey, & Holford,
Received: 30 January 2019
|
Revised: 25 April 2019|
Accepted: 21 May 2019 DOI: 10.1111/jvp.12789P H A R M A C O K I N E T I C R E P O R T
Pharmacokinetics and bioavailability of cefquinome and
ceftriaxone in premature calves
Orhan Corum
1| Ramazan Yildiz
2| Merve Ider
3| Feray Altan
4| Mahmut Ok
3|
Kamil Uney
51Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey
2Department of Internal Medicine, Faculty
of Veterinary Medicine, University of Mehmet Akif Ersoy, Burdur, Turkey
3Department of Internal Medicine, Faculty
of Veterinary Medicine, University of Selcuk, Konya, Turkey
4Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Dicle, Diyarbakir, Turkey
5Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey
Correspondence
Orhan Corum, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, 37200, Kastamonu, Turkey.
Email: orhancorum46@hotmail.com
Abstract
The aim of this study was to evaluate the pharmacokinetics and bioavailability of cefquinome (CFQ) and ceftriaxone (CTX) following intravenous (IV) and intramus‐ cular (IM) administrations in premature calves. Using a parallel design, 24 premature calves were randomly divided into the two antibiotic groups. Each of the six ani‐ mals in the first group received CFQ (2 mg/kg) through IV or IM administration. The second group received CTX (20 mg/kg) via the same administration route. Plasma concentrations of the drugs were analyzed by high‐performance liquid chromatog‐ raphy and noncompartmental methods. Mean pharmacokinetic parameters of CFQ and CTX following IV administration were as follows: elimination half‐life (t1/2λz) 1.85 and 3.31 hr, area under the plasma concentration–time curve (AUC0–∞) 15.74 and 174 hr * μg/ml, volume of distribution at steady‐state 0.37 and 0.45 L/kg, and total body clearance 0.13 and 0.12 L hr−1 kg−1, respectively. Mean pharmacokinetic pa‐ rameters of CFQ and CTX after IM injection were as follows: peak concentration 4.56 and 25.04 μg/ml, time to reach peak concentration 1 and 1.5 hr, t1/2λz 4.74 and 3.62 hr, and AUC0–∞ 22.75 and 147 hr * μg/ml, respectively. The bioavailability of CFQ and CTX after IM injection was 141% and 79%, respectively. IM administra‐ tion of CFQ (2 mg/kg) and CTX (20 mg/kg) can be recommended at 12‐hr interval for treating infections caused by susceptible bacteria, with minimum inhibitory con‐ centration values of ≤0.5 and ≤4 μg/ml, respectively, in premature calves. However, further research is indicated to assess the pharmacokinetic parameters following multiple doses of the drug in premature calves.
K E Y W O R D S
2007; Lo et al., 2010). However, whether there is any difference in the PK attitude of antimicrobial drugs used in premature animals still remains unclear.
In premature calves, bactericidal antimicrobial drugs are indi‐ cated for the treatment of septicemia and pneumonia because of the inadequate development of the immune system and the high mortality rate (Refsdal, 2000; Yildiz & Ok, 2017). Third‐ and fourth‐ generation cephalosporins are the first choice antimicrobial drugs for the treatment of these diseases (Shpigel et al., 1997). Ceftriaxone (CTX) is a third‐generation cephalosporin recommended to treat infections caused by susceptible pathogens in farm animals, dogs, and cats at doses of 15–50 mg/kg (Anonymous, 2018a). It has a broad‐spectrum bactericidal activity against a wide range of gram‐ positive (Staphylococcus spp.) and gram‐negative bacteria (Klebsiella spp., Escherichia coli, Enterobacter, Proteus, Pasteurella spp.) (Perry & Schentag, 2001). Cefquinome (CFQ), a fourth‐generation ceph‐ alosporin, is effective against clinically important bacteria such as Streptococcus spp., Staphylococcus spp., Enterobacteriaceae,
Pasteurellaceae, and gram‐positive anaerobes (Amiridis, Fthenakis,
Dafopoulos, Papanikolaou, & Mavrogianni, 2003; Kasravi et al., 2011; Limbert et al., 1991; Orden, Ruiz‐Santa‐Quiteria, García, Cid, & De La Fuente, 1999). CFQ has been recommended for the treat‐ ment of septicemia caused by E. coli in neonatal calves at 2 mg/kg dose, given once daily (CVMP, 1995; Thomas et al., 2004).
Several studies on the PKs of CFQ and CTX have been per‐ formed in calves (Dinakaran, Dumka, Ranjan, Balaje, & Sidhu, 2013; Soback & Ziv, 1988); however, no studies have yet determined the PKs of CFQ and CTX in premature calves. To our knowledge, we de‐ scribe the first PK analysis of CFQ and CTX in premature calves. The aims of the present study were (a) to determine the PKs of CTX and CFQ after a single intravenous (IV) and intramuscular (IM) adminis‐ tration in premature calves and (b) to integrate the PK parameters obtained from this study and the minimum inhibitory concentration (MIC) values reported in previous studies. This information would allow for a recommendation of alternative dosage regimens for CTX and CFQ to treat infections caused by susceptible pathogens in pre‐ mature calves.
2 | MATERIAL AND METHODS
2.1 | Chemicals and reagents
The CFQ and CTX (≥98.0%) standards were supplied from Provet and Sigma‐Aldrich, respectively. Trifluoroacetic acid (TFA), acetoni‐ trile (ACN) and methanol (MeOH) were supplied from Merck. All rea‐ gents were of analytical grade.
2.2 | Animals
Premature calves were admitted to the clinic within 12–24 hr after birth. The gestational ages were between 245 and 260 days. Prematurity was determined based on insemination records, an‐ amnesis, and general clinical signs such as short soft claw, silky hair
coat, incomplete eruption of the incisor teeth, low body weight, weak or no suckling reflex, and inability to stand (Guzelbektes, Coskun, Ok, Aydogdu, & Sen, 2012; Yildiz & Ok, 2017). The calves were housed in an intensive care room for premature calves, which consist of an infrared heater, a sternal position bed, and a moni‐ toring device. Standard care, including oxygen therapy and sup‐ portive and clinical treatment, was provided to each calf in all the groups (Yildiz & Ok, 2017). Briefly, all premature calves received oxygen therapy (5–6 L/min) via a mask. Fluticasone (15 μg/kg q. 12‐hr intervals for 48 hr [Flixotide®, GlaxoSmithKline]) was admin‐
istered using a nebulizer. A single dose of selenium‐vitamin E (1 ml, IM, [Yeldif®, Ceva‐Dif]) was administrated to each premature
calve. Phosphorus (3 ml/day, SC, [Fosfotonik®, Topkim]), calcium
(0.2 ml kg−1 day−1, SC, [Kalsimin®, Vilsan]), vitamin ADE (1 ml/day,
IM, [Ademin®, Ceva‐Dif]), and vitamin C (3 ml/day, SC, [Cevit®,
Biovita]) were administered for 72 hr. Isotonic sodium chloride (Ulugay), sodium bicarbonate (Bikarvil, Vilsan)] and 5% dextrose (Dekstrosol, Vilsan) were slowly infused into the premature calves, which were found to have a base excess < −3 mmol/L in blood gas analyses. The premature calves received 10% of body weight of fresh or frozen colostrum in a day. Calves with a weak suckle reflex received colostrum through a stomach tube. Premature calves, whose vital signs returned to the normal (such as abdominal respi‐ ration and arterial blood gas findings) at 72 hr of treatment, were implicated in groups. There were 12 male and 12 female Holstein calves with a mean body weight of 25.04 kg (range 15–35 kg) on admission.
2.3 | Study design and dosage forms
Following the treatment for correcting of vital functions (such as O2 application), 24 premature calves were divided into two equal groups with 12 animals each. The study was completed in 6 months with 3 months for each group. The first group was called the “CFQ group” and consisted of 6 male and 6 female premature calves. The first group received CFQ (Cobactan injection®, 25 mg/ml; Intervet)
via IV (n = 6, 253 ± 5.40 days, 3 male and 3 female) and IM (n = 6, 252 ± 4.59 days, 3 male and 3 female) at 2 mg/kg dose. The second group was the “CTX group,” which consisted of 6 male and 6 female premature calves. In the second group, CTX (Unacefin®, 1 g Yavuz
Drug Comp.) was administered via IV (n = 6, 250 ± 3.98 days, 3 male and 3 female) and IM (n = 6, 249 ± 2.97 days, 3 male and 3 female) at 20 mg/kg dose. Premature calves in each group were randomized and assigned to the administration route based on gender or sequen‐ tial. The IM injections were administered to the lower third region of the neck. The IV injections were administered via an IV catheter placed to left Vena jugularis immediately prior to treatment.
Blood samples were collected immediately prior to treatment and approximately at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hr after drug administration. Samples (1 ml) were collected into heparinized test tubes by catheter (22 G, 0.9 × 25 mm, Bicakcilar Medical Devices Industry and Trade Co.) placed to the jugular vein contralateral to that used for drug administration. The blood tubes were centrifuged
at 4,000 g for 10 min, and plasma samples stored at −70°C until analysis.
2.4 | Analytical procedure
The high‐pressure liquid chromatography (HPLC) system was con‐ trolled using a Shimadzu‐LC system (Shimadzu) equipped with a CBM‐20A controller, equipped with a low‐pressure gradient flow control valve (LPGE unit) pump (LC‐20AT) with a degasser (DGU‐20A), autosampler (SIL‐20A), and column oven (CTO‐10A). The reverse‐ phase chromatography was performed using the Gemini C18 column (250 mm by 4.6 mm; internal diameter [i.d.], 5 μm; Phenomenex). The detection of CFQ and CTX were performed using an SPD‐20A UV–VIS detector, which set at 268 and 274 nm, respectively. The column and autosampler were set at 40°C and at room temperature, respectively. For CFQ, the optimized method used a binary‐gradient mobile phase with a flow rate of 0.9 ml/min consisted of ACN and HPLC grade water containing 0.1% TFA. For CTX, the mobile phase containing ACN and 0.1% TFA (15:85, v/v) was sent to 1 ml of HPLC per minute by means of a pump containing a low‐pressure gradient system. The injection volume was 30 μl. The LC solution software program (Shimadzu) running on an HP PC was used for instrument control and data analysis.
The analytical procedures were performed using a HPLC method for CFQ (Uney, Altan, & Elmas, 2011) and CTX (Maradiya, Goriya, Bhavsar, Patel, & Thaker, 2010) reported by previously with minor modifications. The plasma samples (200 μl) were added to 1.5‐ml microcentrifuge tubes. Then, 400 μl of MeOH was added and mixed for 30 s, and the samples were centrifuged at 10,000 g for 10 min. Following centrifugation, 200 μl of clear supernatant was pipetted into an autosampler vial.
The method was validated using blank premature calve plasma. CFQ and CTX were linear in the range of 0.02–10 and 0.1–100 μg/ml, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) for CFQ were 0.01 and 0.02 μg/ml, respectively. For CTX, LOD, and LOQ were 0.02 and 0.1 μg/ml, respectively. The percent‐ age recoveries of CFQ and CTX from plasma samples were >92%
and >94%, respectively. The inter‐assay and intra‐assay coefficients of variation and the bias of the assay of CFQ were ≤4.7%, ≤3.7%, and ±5.2%, respectively, for quality control samples prepared in concentrations of 0.1, 1, and 10 μg/ml. The inter‐assay and intra‐ assay coefficients of variation and the bias of the assay of CTX were ≤6.4%, ≤4.7% and ±4.6%, respectively, for quality control samples prepared in concentrations of 0.4, 4, and 40 μg/ml, respectively.
2.5 | Pharmacokinetic analysis
Pharmacokinetic analyses were performed with computer software WinNonlin 6.3 software (Phoenix 64, Pharsight, Certara). The PK parameters including the area under the concentration–time curve (AUC), total plasma clearance (ClT), apparent volume of distribu‐ tion (Vdarea), volume of distribution at steady‐state (Vdss), elimina‐ tion rate constant (λz), terminal elimination half‐life (t1/2λz), and mean
residence time (MRT) calculated by noncompartmental method. The peak concentration (Cmax) and time to reach Cmax (Tmax) were deter‐ mined directly from plasma concentration–time curve of each ani‐ mal. The t1/2λz was calculated by ln 2/λz. AUC was estimated by the
log‐trapezoidal rule. Bioavailability (F) after IM administrations was calculated by following formula:
Mean absorption time (MAT) was calculated by the following equation:
2.6 | Pharmacokinetic‐pharmacodynamic analysis
The percentage of time (%T > MIC) that drug plasma concentrations exceed the MIC was calculated as:
where D; the recommended dose (mg/kg), Vdarea; the apparent volume
of the distribution (L/kg), MIC; the minimum inhibitory concentration (mg/L), In; natural logarithm, t1/2λz; elimination half‐life (hr) and DI; dos‐ ing interval (hr) (Turnidge, 1998).
2.7 | Statistical analyses
Statistical analyses were carried out the commercially available software (SPSS, 19.0 software, IBM). MRT, MAT, and t1/2λz were presented as a harmonic mean ± SD. Tmax was presented as median. Other PK parameters were expressed as mean ± SD. A p value of <0.05 was accepted as statistically significant. Statistical signifi‐ cance was determined by Mann–Whitney U test (nonparametric data, such as Tmax, MRT, and t1/2λz) or independent t test (parametric data, such as ʎz and AUC0–∞).
F = (AUCIM∕AUCIV) × 100. MAT = MRTIM− MRTIV. %T > MIC = In ( D Vdarea× MIC ) × (t 1∕2𝜆z In(2) ) ×( 100 DI )
F I G U R E 1 Semi‐logarithmic plasma concentration–time curves
of cefquinome following intravenous (IV) and intramuscular (IM) administrations at a dose of 2 mg/kg in premature calves (n = 6, mean ± SD)
3 | RESULTS
3.1 | Pharmacokinetics
The plasma concentration–time curves following the IV and IM ad‐ ministrations of CFQ at 2 mg/kg and CTX at 20 mg/kg are shown in Figures 1 and 2, respectively. The PK parameters obtained following IV and IM administrations of CFQ (2 mg/kg) and CTX (20 mg/kg) are presented in Table 1.
Significant differences (p < 0.05) were observed in t1/2λz, AUC0–∞, and MRT between the IV and IM administration routes of CFQ. The F value for CFQ after IM administration (141.22%) was higher than 100%. The Vdss and ClT of CFQ following IV administration were
0.37 ± 0.10 L/kg and 0.13 ± 0.03 L hr−1 kg−1, respectively. The MAT
value of CFQ was 2.58 hr.
No significant differences were observed in the PK parameters between the IV and IM administrations of CTX. The Vdss of CTX was
0.45 ± 0.11 L/kg, and the ClT of CTX was 0.12 ± 0.03 L hr−1 kg−1 fol‐
lowing IV administration. The F value and the MAT for CTX after IM administration were 78.48% and 1.52 hr, respectively.
3.2 | Pharmacokinetics‐pharmacodynamics
The %T MIC values calculated using the PK data obtained in this study and the MIC90 values reported for CFQ and CTX are presented
in Table 2. The 2 mg/kg dose of CFQ following IV and IM administra‐ tions at the 12‐hr interval provided T > MIC of >80% for susceptible bacteria, with MIC90 values of ≤0.125 and 0.5 μg/ml, respectively. The 20 mg/kg dose of CTX following IV and IM administrations maintained a T > MIC value of >80% for the bacteria, with the MIC90 being ≤4 μg/ml at the 12 hr interval.
4 | DISCUSSION
Premature birth interrupts prenatal organ maturation including the lungs, liver, cardiovascular system, kidneys, and the gastrointesti‐ nal tract (Sangild, 2006). Immaturity may impair the ability to cope
with the disease in calves and predispose them to serious health problems (Aydogdu, Yildiz, Guzelbektes, Coskun, & Sen, 2016; Bittrich et al., 2004). Moreover, because of abnormal absorption associated with an immature intestine and the absence or weak‐ ness of the sucking reflex related to prematurity, premature calves could not take enough colostrum and immunoglobulin, which leads to a greater risk of developing infectious diarrhea, pneumonia, and sepsis than that in mature calves (Bleul, 2009; Weaver, Tyler, VanMetre, Hostetler, & Barrington, 2000; Yildiz & Ok, 2017). Respiratory distress syndrome, diarrhea, and septicemia, which are caused especially by E. coli and Pasteurella spp., are the major reason for neonatal complications (Bleul, 2009; Fecteau, Smith, & George, 2009; Guerin‐Faublee, Carret, & Houffschmitt, 2003). Therefore, there is a need to use antimicrobial drugs for treating premature calves suffering from serious health problems due to bacterial agents. Nevertheless, there is no clear information regarding the safe and effective dosage regimens for the treatment of sick pre‐ mature calves.
Drug PKs in premature animals differs from that of other age groups because of higher volume of extracellular fluid, immature functions, and postnatal maturation of kidneys and liver (Silver, 1990). In addition, drug PKs in neonatal calves due to immature organ func‐ tions can exhibit differences from that of other age groups (Brown, Chester, & Robb, 1996; Burrows, Barto, & Martin, 1987; Mzyk et al., 2017; Nouws, Vree, Degen, & Mevius, 1991). However, the imma‐ ture elimination rate in neonatal calves (≤6 weeks) cannot reliably predict the PK behavior of a drug. Studies comparing the antibiotic PKs in neonatal and older calves have shown that antibiotic elimi‐ nation in neonatal calves is not always different from that in older calves (Brown et al., 1996; Burrows et al., 1987). Although the PKs of neomycin and gentamicin was not influenced significantly by age (Burrows et al., 1987), the elimination of oxytetracycline (Burrows et al., 1987), sulfamethoxazole (Nouws et al., 1991), and ceftiofur sodium (Brown et al., 1996) from the body was found to increase with increasing age. These data suggest that drug PKs is also not predictable in premature calves.
In this study, the Vdss of CFQ after IV administration in premature calves was 0.37 L/kg, which was slightly higher than that reported in calves aged 6–8 months (0.26 L/kg, Dinakaran et al., 2013). The
t1/2λz and ClT of CFQ in premature calves were 1.85 ± 0.44 hr and 0.13 ± 0.03 L hr−1 kg−1, respectively, indicating rapid elimination
compared to that in calves aged 6–8 months (t1/2λz; 3.56 ± 0.05 hr, ClT; 0.06 L hr−1 kg−1, Dinakaran et al., 2013). However, the elimina‐
tion process of CFQ was observed to be delayed in neonatal sheep (Tohamy, 2011). The binding rate of CFQ to plasma proteins was found to be approximately 11% in buffalo calves (Venkatachalam & Dumka, 2015). Another study reported that the excretion extent of CFQ correlated with glomerular filtration rate in dogs; however, data in calves are not available (Taverne, van Geijlswijk, Heederik, Wagenaar, & Mouton, 2016). The rapid elimination of the drug in premature calves could be due to increased cardiac output, which would lead to an increase in glomerular filtration rate (Stritzke, Thomas, Amin, Fusch, & Lodha, 2017). These cardiovascular changes
F I G U R E 2 Semi‐logarithmic plasma concentration–time curves
of ceftriaxone following intravenous (IV) and intramuscular (IM) administrations at a dose of 20 mg/kg in premature calves (n = 6, mean ± SD)
may be caused due to hypoxia associated with premature birth (Aydogdu et al., 2016).
In this study, IM administration (4.74 ± 0.69 hr) resulted in a prolonged t1/2λz of CFQ compared to that with IV administration (1.85 ± 0.44 hr). Similar results were found in pigs (IV; 2.32 hr, IM; 4.92 hr, Yang et al., 2009), piglets (IV; 1.85 hr, IM; 4.36 hr, Li et al., 2008), and sheep (IV; 0.78 hr, IM; 1.88 hr, Uney et al., 2011). In this study, the F value of CFQ was 141.22% after IM injection. It is known that a drug exhibits flip‐flop kinetics when MAT is longer than MRTIV (Toutain & Bousquet‐Mélou, 2004). However, the MAT (2.58 ± 0.60 hr) of CFQ in premature calves was similar to MRTIV (2.60 ± 0.07 hr). The use of the parallel design for IV and IM administration may have lead to a bioavailability of >100% (Toutain & Bousquet‐Mélou, 2004; Yáñez, Remsberg, Sayre,
Forrest, & Neal, 2012). In addition, the hydration status, diuresis, hypertension, or hypotension in premature calves and the random variability related to the experimental design can contribute to the high bioavailability.
The t1/2λz and ClT of CTX following IV administration in this study were 3.31 hr and 0.12 L hr−1 kg−1, respectively, which indi‐
cated slow elimination compared to that in calves aged 6–10 months that showed a mean t1/2λz of 1.27–1.58 hr and a mean ClT of 0.19– 0.26 L hr−1 kg−1 (Gohil, Patel, Bhavsar, & Thaker, 2009; Maradiya
et al., 2010) and a t1/2λz of 1.4 hr and a ClT of 0.20 L hr−1 kg−1 in neo‐
natal animals (Soback & Ziv, 1988). The immature elimination organs in premature animals may contribute to the slow elimination of drugs (Mangoni & Jackson, 2004). In the present study, the Vdss of CTX was 0.45 L/kg. In calves aged 6–18 months, studies have indicated that the Vdss of CTX at 10 mg/kg dose ranges from 0.2 to 0.69 L/kg (Gohil et al., 2009; Johal & Srivastava, 1999; Maradiya et al., 2010). The volume of distribution is affected by age‐related changes such as the hemodynamic parameters and the binding ratio to plasma proteins (Mangoni & Jackson, 2004). The binding ratio of CTX to the plasma protein is 20%–38% in calves (Soback & Ziv, 1988). Moreover, the mean binding activity of CTX to plasma proteins in calves has been determined to be 53.5%–11.9% over a concentration range of 5–75 μg/ml, with concentration dependency (Johal & Srivastava, 1999). In this study, the binding ratio of CTX to plasma protein was not evaluated. The different Vdss of CTX in calves could be clarified by variations in the binding activity to plasma protein and fat‐water composition in relation with age.
In the present study, the PK parameters of CTX between the IV and IM administrations revealed no significant differences. However, a longer t1/2λz following IM administration (1.95–5.02 hr) than after IV administration (1.27–1.58 hr) has been obtained in calves (Gohil
Parameters Cefquinome Ceftriaxone IV IM IV IM ʎz (1/hr) 0.40 ± 0.11 0.15 ± 0.02* 0.21 ± 0.02 0.20 ± 0.03 t1/2ʎz (hr) (HM) 1.85 ± 0.44 4.74 ± 0.69* 3.31 ± 0.37 3.62 ± 0.68 AUC0–∞ (hr * μg/ml) 15.74 ± 3.57 22.75 ± 6.18* 174.34 ± 40.75 147.33 ± 52.86 MRT (hr) (HM) 2.61 ± 0.07 5.19 ± 0.58* 3.65 ± 0.89 5.16 ± 1.29 MAT (hr) (HM) – 2.58 ± 0.60 – 1.52 ± 1.53 ClT (L hr−1 kg−1) 0.13 ± 0.03 – 0.12 ± 0.03 – Vdarea (L/kg) 0.36 ± 0.10 0.66 ± 0.28 0.59 ± 0.22 0.77 ± 0.27 Vdss (L/kg) 0.37 ± 0.10 – 0.45 ± 0.11 – Cmax (μg/ml) – 4.56 ± 0.75 – 25.04 ± 10.11 Tmax (hr) (M) – 1.00 – 1.50 F (%) – 141.22 – 78.48
Abbreviations: ʎz, elimination rate constant; AUC, area under the concentration versus time curve;
ClT, total clearance; Cmax, peak concentration; F, absolute bioavailability; HM, harmonic means; M, median; MAT, mean absorption time; MRT, mean residence time; Tmax, time to reach the peak
concentration; Vdarea, apperant volume of distribution; Vdss, volume of distribution at steady‐state;
t1/2ʎz, elimination half‐life.
*Significantly different from IM administration for the same drug (p < 0.05).
TA B L E 1 Pharmacokinetics parameters
of cefquinome (2 mg/kg) and ceftriaxone (20 mg/kg) following intravenous (IV) and intramuscular (IM) administrations in premature calves (n = 6, mean ± SD)
TA B L E 2 %T > MIC of cefquinome (2 mg/kg) and ceftriaxone
(20 mg/kg) for 12 hr dosing interval in premature calves
MIC90 (μg/ml) Cefquinome Ceftriaxone IV IM IV IM 0.03 139 263 280 294 0.125 98 182 224 232 0.25 78 142 196 193 0.5 58 103 169 172 1 38 63 141 142 2 18 24 114 112 4 – – 86 81 16 – – 31 21
Abbreviations: IM, intramuscular; IV, intravenous; MIC, minimum inhibi‐ tory concentration.
et al., 2009; Maradiya et al., 2010; Soback & Ziv, 1988). The mean bioavailability following IM administration in calves was 78.48%, which was similar to a previous reported in neonatal calves (78% and 83% at 10 and 20 mg/kg doses, respectively, Soback & Ziv, 1988) but higher than that in calves aged 6–9 months (47%, Maradiya et al., 2010).
Cefquinome and CTX exhibited time‐dependent killing charac‐ teristics, and the PK/PD parameter for their optimal bactericidal ac‐ tivity was calculated as %T > MIC. Premature calves are susceptible to infections, in part due to relative immunological incompetence and in part due to invasive techniques commonly used in the hos‐ pital environment. It has been reported that the T > MIC must be maintained at >80% of the dosing interval for achieving the bacteri‐ cidal effect of cephalosporin in critically ill patients and patients with compromised immune responses (Toutain, Del Castillo, & Bousquet‐ Mélou, 2002). In this study, the T > MIC for CFQ and CTX was based on >80% due to the insufficiency of the immune system in prema‐ ture calves.
The MIC90 of CFQ and CTX for E. coli and P. multocida isolated from neonatal calves was 0.03–1 μg/ml (Katsuda, Hoshinoo, Ueno, Kohmoto, & Mikami, 2013; Orden et al., 1999; Soback & Ziv, 1988; Thomas et al., 2004). The susceptibility breakpoints of 2 and 16 μg/ ml were recommended for CFQ and CTX, respectively (Anonymous, 2018b; AVID, 1999). In this study, the %T > MIC was calculated using the MIC90 values of 0.03–1 μg/ml reported for the above‐mentioned susceptible pathogens and the susceptibility breakpoint of 2 μg/ml (CFQ) and 16 μg/ml (CTX). IV and IM administration of 2 mg/kg dose of CFQ at the 12 hr interval provided a T > MIC of >80% for sus‐ ceptible bacteria, with the MIC90 values being ≤0.125 and 0.5 μg/ml, respectively. The T > MIC value of >80% was achieved with IV and IM administrations of CTX at 12 hr interval, with an MIC90 of ≤4 μg/ml for bacteria. However, the aggressive PD parameter for the maximal bac‐ tericidal activity was found to be % T > 4 × MIC for beta‐lactam anti‐ biotics in critically ill patients and patients with compromised immune responses. This value has been shown to be maintained at 100% of the dosing interval (Sime, Roberts, Peake, Lipman, & Roberts, 2012). In this study, a T > 4 × MIC of ≤100% was maintained at 12 hr intervals for bacteria, with the MIC values being ≤0.125 μg/ml following IM administration of CFQ only and for bacteria, with the MIC value being ≤0.5 μg/ml following IV and IM administration of CTX.
In conclusion, IM administration of CFQ and CTX in premature calves demonstrated long t1/2ʎz and good bioavailability. IM adminis‐ tration of CFQ (2 mg/kg) and CTX (20 mg/kg) can be recommended at 12 hr intervals for the treatment of infections caused by suscep‐ tible bacteria, with the MIC values of ≤0.5 and ≤4 μg/ml, respec‐ tively, in premature calves. However, further research exploring the PKs following multiple doses of the drug in premature calves would shed more light on this aspect. Additional studies such as the spec‐ ification of the MIC90 value of each pathogenic species in prema‐ ture calves and the determination of the PK profile of the drug in diseased premature calves showing clinical findings associated with the pathogenic species may also be necessary to confirm the drug dosage regimen.
ACKNOWLEDGMENTS
This research did not receive any specific grant from funding agen‐ cies in the public, commercial, or not‐for‐profit sectors. This study was presented in an abstract form as poster presentation in the 3rd International Convention of Pharmaceuticals and Pharmacies, Istanbul, Turkey, April 26–29, 2017.
CONFLIC T OF INTEREST
The authors declare no conflicts of interest.
AUTHORS’ CONTRIBUTION
OC, KU, and FA contributed to conception, design, analysis, and ac‐ quisition, drafted the manuscript, critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. RY, MI, and MO contributed to design, analysis, and acquisition and agreed to be accountable for all aspects of work ensuring integrity and accuracy.
ORCID
Orhan Corum https://orcid.org/0000‐0003‐3168‐2510
Feray Altan https://orcid.org/0000‐0002‐9017‐763X
Kamil Uney https://orcid.org/0000‐0002‐8674‐4873
REFERENCES
Amiridis, G. S., Fthenakis, G. C., Dafopoulos, J., Papanikolaou, T., & Mavrogianni, V. S. (2003). Use of cefquinome for preven‐ tion and treatment of bovine endometritis. Journal of Veterinary
Pharmacology and Therapeutics, 26, 387–390. https ://doi.
org/10.1046/j.1365‐2885.2003.00490.x
Anderson, B. J., Allegaert, K., Van Den Anker, J. N., Cossey, V., & Holford, N. H. G. (2007). Vancomycin pharmacokinet‐ ics in preterm neonates and the prediction of adult clearance.
British Journal of Clinical Pharmacology, 63, 75–84. https ://doi.
org/10.1111/j.1365‐2125.2006.02725.x
Anonymous (2018a). https ://www.squar ephar ma.com.bd/downl oads/ Ceftr on‐Vet%20Inj ection.pdf. Accessed 09 Sep 2018.
Anonymous (2018b). https ://aac.asm.org/conte nt/aac/suppl/ 2017/11/13/AAC.01537‐17.DCSup pleme ntal/zac01 21767 04s1.pdf. Accessed 15 Sep 2018.
AVID (Arbeitskreis fur veterinarmedizinische Infecktionsdiagnostik) (1999). Appendix, 40, 5.
Aydogdu, U., Yildiz, R., Guzelbektes, H., Coskun, A., & Sen, I. (2016). Cardiac biomarkers in premature calves with respiratory distress syndrome. Acta Veterinaria Hungarica, 64, 38–46. https ://doi. org/10.1556/004.2016.004
Bittrich, S., Philipona, C., Hammon, H. M., Romé, V., Guilloteau, P., & Blum, J. W. (2004). Preterm as compared with full‐term neonatal calves are characterized by morphological and functional immaturity of the small intestine. Journal of Dairy Science, 87, 1786–1795. https ://doi.org/10.3168/jds.S0022‐0302(04)73334‐2
Bleul, U. (2009). Respiratory distress syndrome in calves. Veterinary
Clinics of North America ‐ Food Animal Practice, 25, 179–193. https ://
Brown, S. A., Chester, S. T., & Robb, E. J. (1996). Effects of age on the pharmacokinetics of single dose ceftiofur sodium admin‐ istered intramuscularly or intravenously to cattle. Journal of
Veterinary Pharmacology and Therapeutics, 19, 32–38. https ://doi.
org/10.1111/j.1365‐2885.1996.tb000 05.x
Burrows, G. E., Barto, P. B., & Martin, B. (1987). Comparative pharma‐ cokinetics of gentamicin, neomycin and oxytetracycline in newborn calves. Journal of Veterinary Pharmacology and Therapeutics, 10, 54– 63. https ://doi.org/10.1111/j.1365‐2885.1987.tb000 77.x
CVMP (1995). Cefquinome. Summary report. EMEA/MRL/005/95. European Agency for the Evaluation of Medicinal Products, London, UK.
Dinakaran, V., Dumka, V. K., Ranjan, B., Balaje, R., & Sidhu, P. K. (2013). Pharmacokinetics following intravenous administration and phar‐ macodynamics of cefquinome in buffalo calves. Tropical Animal
Health and Production, 45, 1509–1512. https ://doi.org/10.1007/
s11250‐013‐0390‐7
Fecteau, G., Smith, B. P., & George, L. W. (2009). Septicemia and men‐ ingitis in the newborn calf. Veterinary Clinics of North America
‐ Food Animal Practice, 25, 195–208. https ://doi.org/10.1016/j.
cvfa.2008.10.004
Gohil, P. V., Patel, U. D., Bhavsar, S. K., & Thaker, A. M. (2009). Pharmacokinetics of ceftriaxone in buffalo calves (Bubalus buba‐
lis) following intravenous and intramuscular administration. Iranian Journal of Veterinary Research, 10, 33–37.
Guerin‐Faublee, V., Carret, G., & Houffschmitt, P. (2003). In vitro activ‐ ity of 10 antimicrobial agents against bacteria isolated from cows with clinical mastitis. Veterinary Record, 152, 466–471. https ://doi. org/10.1136/vr.152.15.466
Guzelbektes, H., Coskun, A., Ok, M., Aydogdu, U., & Sen, I. (2012). Prevalence of gastroesophageal reflux disease in premature calves.
Journal of Veterinary Internal Medicine, 26, 1051–1055. https ://doi.
org/10.1111/j.1939‐1676.2012.00934.x
Johal, B., & Srivastava, A. K. (1999). Disposition kinetics and dos‐ age regimen of ceftriaxone in crossbred calves (short commu‐ nication). Acta Veterinaria Hungarica, 47, 243–248. https ://doi. org/10.1556/004.47.1999.2.9
Kasravi, R., Bolourchi, M., Farzaneh, N., Seifi, H. A., Barin, A., Hovareshti, P., & Gharagozlou, F. (2011). Efficacy of conventional and ex‐ tended intra‐mammary treatment of persistent sub‐clinical mas‐ titis with cefquinome in lactating dairy cows. Tropical Animal
Health and Production, 43, 1203–1210. https ://doi.org/10.1007/
s11250‐011‐9826‐0
Katsuda, K., Hoshinoo, K., Ueno, Y., Kohmoto, M., & Mikami, O. (2013). Virulence genes and antimicrobial susceptibility in Pasteurella multo‐ cida isolates from calves. Veterinary Microbiology, 167, 737–741. https ://doi.org/10.1016/j.vetmic.2013.09.029
Li, X. B., Wu, W. X., Su, D., Wang, Z. J., Jiang, H. Y., & Shen, J. Z. (2008). Pharmacokinetics and bioavailability of cefquinome in healthy piglets. Journal of Veterinary Pharmacology and Therapeutics,
31, 523–527. https ://doi.org/10.1111/j.1365‐2885.2008.
00989.x
Limbert, M., Isert, D., Klesel, N., Markus, A., Seeger, K., Seibert, G., & Schrinner, E. (1991). Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR IIIV), a new broad‐spectrum cephalosporin. Antimicrobial Agents Chemotherapy, 35, 14–19. https ://doi.org/10.1128/AAC.35.1.14
Lo, Y. L., Van Hasselt, J. G. C., Heng, S. C., Lim, C. T., Lee, T. C., & Charles, B. G. (2010). Population pharmacokinetics of vancomycin in prema‐ ture malaysian neonates: Identification of predictors for dosing de‐ termination. Antimicrobial Agents and Chemotherapy, 54, 2626–2632. https ://doi.org/10.1128/AAC.01370‐09
Mangoni, A. A., & Jackson, S. H. D. (2004). Age‐related changes in phar‐ macokinetics and pharmacodynamics: Basic principles and practical applications. British Journal of Clinical Pharmacology, 57, 6–14.
Maradiya, J. J., Goriya, H. V., Bhavsar, S. K., Patel, U. D., & Thaker, A. M. (2010). Pharmacokinetics of ceftriaxone in calves. Veterınarski Arhiv,
80, 1–9.
Mzyk, D. A., Gehring, R., Tell, L. A., Vickroy, T. W., Riviere, J. E., Ragan, G., … Smith, G. W. (2017). Considerations for extralabel drug use in calves. Journal of the American Veterinary Medical Association, 250, 1275–1282. https ://doi.org/10.2460/javma.250.11.1275
Nouws, J. F., Vree, T. B., Degen, M., & Mevius, D. (1991). Pharmacokinetics of sulphamethoxazole in calves and cows. Veterinary Quarterly, 13, 10–15. https ://doi.org/10.1080/01652 176.1991.9694279
Orden, J. A., Ruiz‐Santa‐Quiteria, J. A., García, S., Cid, D., & De La Fuente, R. (1999). In vitro activities of cephalosporins and quinolones against Escherichia coli strains isolated from diarrheic dairy calves.
Antimicrobial Agents and Chemotherapy, 43, 510–513. https ://doi.
org/10.1128/AAC.43.3.510
Perry, T. R., & Schentag, J. J. (2001). Clinical use of ceftriaxone: A phar‐ macokinetic‐pharmacodynamic perspective on the impact of mini‐ mum inhibitory concentration and serum protein binding. Clinical
Pharmacokinetics, 40, 685–694. https ://doi.org/10.2165/00003 088‐
20014 0090‐00004
Refsdal, A. O. (2000). To treat or not to treat: A proper use of hormones and antibiotics. Animal Reproduction Science, 60–61, 109–119. https ://doi.org/10.1016/S0378‐4320(00)00094‐4
Sangild, P. T. (2006). Gut responses to enteral nutrition in preterm infants and animals. Experimental Biology and Medicine, 231, 1695–1711. https ://doi.org/10.1177/15353 70206 23101106
Shpigel, N. Y., Levin, D., Winkler, M., Saran, A., Ziv, G., & Böttner, A. (1997). Efficacy of cefquinome for treatment of cows with mastitis experimentally induced using Escherichia coli. Journal of Dairy Science,
80, 318–323. https ://doi.org/10.3168/jds.S0022‐0302(97)75941‐1
Silver, M. (1990). Prenatal maturation, the timing of birth and how it may be regulated in domestic animals. Experimental Physiology, 75, 285– 307. https ://doi.org/10.1113/expph ysiol.1990.sp003405
Sime, F. B., Roberts, M. S., Peake, S. L., Lipman, J., & Roberts, J. A. (2012). Does beta‐lactam pharmacokinetic variability in critically III patients justify therapeutic drug monitoring? A systematic review. Annals of
Intensive Care, 2, 35. https ://doi.org/10.1186/2110‐5820‐2‐35
Soback, S., & Ziv, G. (1988). Pharmacokinetics and bioavailability of cef‐ triaxone administered intravenously and intramuscularly to calves.
American Journal of Veterinary Research, 49, 535–538.
Stritzke, A., Thomas, S., Amin, H., Fusch, C., & Lodha, A. (2017). Renal consequences of preterm birth. Molecular and Cellular Pediatrics, 4, 2. https ://doi.org/10.1186/s40348‐016‐0068‐0
Taverne, F. J., van Geijlswijk, I. M., Heederik, D. J., Wagenaar, J. A., & Mouton, J. W. (2016). Modelling concentrations of antimicrobial drugs: Comparative pharmacokinetics of cephalosporin antimi‐ crobials and accuracy of allometric scaling in food‐producing and companion animals. BMC Veterinary Research, 12, 185. https ://doi. org/10.1186/s12917‐016‐0817‐2
Thomas, E., Roy, O., Skowronski, V., Zschiesche, E., Martin, G., & Böttner, A. (2004). Comparative field efficacy study between cefquinome and gentamicin in neonatal calves with clinical signs of septicaemia.
Revue de Medecine Veterinaire, 155, 6–10.
Tohamy, M. A. (2011). Age‐related intramuscular pharmacokinetics of cefquinome in sheep. Small Ruminant Research, 99, 72–76. https :// doi.org/10.1016/j.small rumres.2011.03.004
Toutain, P. L., & Bousquet‐Mélou, A. (2004). Bioavailability and its as‐ sessment. Journal of Veterinary Pharmacology and Therapeutics, 27, 455–466. https ://doi.org/10.1111/j.1365‐2885.2004.00604.x Toutain, P. L., Del Castillo, J. R. E., & Bousquet‐Mélou, A. (2002). The
pharmacokinetic‐pharmacodynamic approach to a rational dosage regimen for antibiotics. Research in Veterinary Science, 73, 105–114. https ://doi.org/10.1016/S0034‐5288(02)00039‐5
Turnidge, J. D. (1998). The pharmacodynamics of beta‐lactams. Clinical
Uney, K., Altan, F., & Elmas, M. (2011). Development and validation of a high‐performance liquid chromatography method for determination of cefquinome concentrations in sheep plasma and its application to pharmacokinetic studies. Antimicrobial Agents and Chemotherapy, 55, 854–859. https ://doi.org/10.1128/AAC.01126‐10
Venkatachalam, D., & Dumka, V. K. (2015). Pharmacokinetic profile of cefquinome after oral subchronic flubendiamide exposure and in vitro plasma protein binding in buffalo calves. Environmental
Toxicology and Pharmacology, 39, 321–326. https ://doi.org/10.1016/j.
etap.2014.12.004
Weaver, D. M., Tyler, J. W., VanMetre, D. C., Hostetler, D. E., & Barrington, G. M. (2000). Passive transfer of colostral immunoglobulins in calves.
Journal of Veterinary Internal Medicine, 14, 569–577. https ://doi.
org/10.1111/j.1939‐1676.2000.tb022 78.x
Yáñez, J. A., Remsberg, C. M., Sayre, C. L., Forrest, M. L., & Neal, M. D. (2012). Flip‐flop pharmacokinetics‐delivering a reversal of dis‐ position: Challenges and opportunities during drug development.
Therapeutics Delivery, 2, 643–672.
Yang, D., Chen, Z., Ding, H., Shen, X., Xu, S., & Gu, X. (2009). Pharmacokinetics and bioavailability of cefquinome in pigs. Chinese
Journal of Veterinary Science, 29, 1182–1185.
Yildiz, R., & Ok, M. (2017). Clinical efficacy of combinations of nebulised fluticasone, salbutamol and furosemide on lung function in prema‐ ture calves with respiratory distress syndrome. Veterinární Medicína,
62, 541–552. https ://doi.org/10.17221/ VETMED
How to cite this article: Corum O, Yildiz R, Ider M, Altan F, Ok
M, Uney K. Pharmacokinetics and bioavailability of cefquinome and ceftriaxone in premature calves. J vet Pharmacol Therap. 2019;42:632–639. https ://doi.org/10.1111/jvp.12789
