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Paper Treatment of naturally occurring bovine respiratory disease in juvenile calves with a single administration of a florfenicol plus flunixin meglumine formulation J. Thiry, J. V. González-Martín, L. Elvira, E. Pagot, F. Voisin, G. Lequeux, A. Weingarten, V. de Haas The efficacy and safety of a florfenicol plus flunixin meglumine formulation in the treatment of respiratory disease was evaluated in calves less than six weeks of age, compared with a positive control group treated with a well-established florfenicol formulation. A total of 210 calves, selected from nine sites in Belgium, France and Spain, showing severe signs of respiratory disease, were randomly assigned to treatment with either florfenicol plus flunixin meglumine (Resflor; MSD Animal Health) or florfenicol (Nuflor; MSD Animal Health), both administered subcutaneously once. Animals were clinically observed daily for 10 days following treatment initiation. The predominant respiratory pathogens were Pasteurella multocida, Mycoplasma bovis, Mannheimia haemolytica and Histophilus somni. All isolates were subject to in vitro sensitivity testing and found susceptible to florfenicol. In both groups, rectal temperature dropped and clinical index (depression and respiratory signs) significantly improved after treatment. Specifically, for the change in rectal temperature from pretreatment to six hours post-treatment, the florfenicol-flunixin formulation was found significantly superior to florfenicol. Moreover, the florfenicol-flunixin formulation alleviated the clinical signs of disease more rapidly, and was demonstrated to be non-inferior to florfenicol on days 4 and 10. The use of the product combining florfenicol and flunixin in calves is safe and efficacious in the treatment of outbreaks of bovine respiratory disease.

Introduction

Bovine respiratory disease (BRD) is a worldwide disease that has considerable economic significance in cattle. It is a major impediment to production as a result of morbidity, mortality and poor growth rates (Taylor and others 2010, Nicholas 2011). Taking into account death, reduced feed efficiency and treatment cost, BRD leads to substantial economic losses that were estimated in 2003 to exceed 576 million annually in Europe (Nicholas and Ayling 2003). Respiratory disease in cattle often presents a multifactorial ­complex because it results from the interactions between the micro-­ Veterinary Record (2014) J. Thiry, MSc, MVSc, PhD, V. de Haas, DVM, MSD Animal Health Innovation, Beaucouzé 49071, France J. V. González-Martín2, DVM, PhD, Dipl. ECBHM, L. Elvira, DVM, Trialvet S.L., Cabanillas de la Sierra 2872, Spain E. Pagot, DVM, F. Voisin, DVM, Centre Technique des Productions Animales, Ploufragan 22440, France

doi: 10.1136/vr.102017 G. Lequeux, DVM, MSc, Institut Santé et Agro-Environnement, Fougères 35306, France A. Weingarten, DVM, Merck Animal Health, Summit 07901, USA E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed Accepted February 12, 2014

organisms of the respiratory tract, environmental stress factors and the animal’s susceptibility, depending on its immune status and ‘hardiness’ (Makoschey and others 2008, Taylor and others 2010). The disease can be initiated by a primary viral infection which may impair the animal’s innate immune response and trigger subsequent bacterial infection (Makoschey and others 2008). However, bacteria can also act as primary pathogens. The most important infectious bacterial agents involved in BRD are Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis. They play an essential role in the development of pulmonary lesions. Although the infectious agents may not always be the primary inducers of the syndrome, they decrease the defence capabilities at the pulmonary level, contributing to the amplification of the bacterial population and toxin secretion (Lekeux and Coghe 2004). Thus, the early use of efficacious antimicrobials is important to stop progression of infection and the spread of the disease in the herd. Among the various antimicrobials available, florfenicol (Nuflor, MSD Animal Health) is a broad-spectrum antibiotic, and its injectable formulation is designed to provide prolonged levels of the antibiotic following either a single subcutaneous injection or two intramuscular injections administered 48 hours apart (Varma and others 1986, Adams and others 1987, de Haas and others 1994, Lobell and others 1994, Varma 1994, Varma and others 1998, de Haas and others 2002, Catry and others 2008, Gonzalez-Martin and others 2011, Thiry and others 2011). The pathogenesis of BRD involves the development of ­inflammatory processes that are supposed to play a beneficial role April 26, 2014 | Veterinary Record

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Paper in controlling the invasion of infectious agents. However, when it is too intense, some mediators (eg, cytokines) released particularly after toxin secretion contribute to pathological changes leading to the development of pulmonary consolidation and lesions. The degree of this inflammatory process can determine whether the disease results in chronic pathological changes including death or animal recovery (Lekeux 2006). In this situation, an antimicrobial alone is not sufficient and must be accompanied by an anti-inflammatory agent to control the pathologic inflammatory process. Among the various anti-inflammatory agents available, the NSAID flunixin meglumine (marketed as Finadyne and Banamine; MSD Animal Health) has been demonstrated to be effective in rapidly reducing pyrexia associated with BRD, to reduce pulmonary consolidation and the need for retreatment with antibiotics (Landoni and others 1995, Hellwig and others 2000, Radeloff and Hellmann 2001, Lockwood and others 2003, Halloy and others 2006). As florfenicol (Nuflor) and flunixin meglumine (Finadyne or Banamine) were frequently administered concurrently, a new therapeutic agent combining both products was developed and marketed as Resflor (MSD Animal Health) (Simmons and others 2002). Since its first registration in the mid-2000, the product combining florfenicol and flunixin has been shown in several studies to have similar efficacy than florfenicol in the treatment of the BRD and flunixin in the reduction of pyrexia, while having the advantage of eliminating the need for separate injections (Weingarten and others 2006, Cavirani and others 2009, Gonzalez-Martin and others 2009). However, its use in animals less than six weeks of age was contraindicated, while florfenicol was approved for use in the same indication with no contraindication in juvenile calves. The objective of the present study was, therefore, to confirm the efficacy and the safety of the florfenicol-flunixin formulation for the treatment of naturally occurring BRD in juvenile calves less than six weeks of age in comparison to an approved positive control, florfenicol, that represented a negative control in regards to flunixin meglumine.

Materials and methods

This field study was conducted in accordance with the Veterinary International Conference on Harmonisation (VICH) guideline on good clinical practices (EMEA/CVMP 2000).

Experimental unit and sample size justification

The experimental unit was the calf. The sample size justification was based on a test of non-inferiority of florfenicol-flunixin against florfenicol. Assuming a 79.4 per cent success rate with florfenicol and 83.5 per cent for florfenicol-flunixin (based on historical data), the minimum sample size to claim non-inferiority (no higher rates) of florfenicol-flunixin, within a ±15 per cent margin with 80 per cent power and α of 5 per cent, was n=52 (nQuery Advisor V.4.0). This number was rounded to 100 calves per treatment group for field safety inferential evaluation.

Animals, husbandry and pre-enrolment observation period

Nine different sites were selected in Belgium, France and Spain, in farms which were typical veal operations of various sizes. Calves, originating from local or auction markets, were monitored until a BRD outbreak occurred. Pure breeds including beef, blonde d’Aquitaine, Charolais, dairy, Holstein, red pied Lowland, Montbeliard, Normande and cross breeds were enrolled in the study. Calves were preruminating and were maintained according to the customary practices of the farm. They were housed in standard pens (individual or grouped) with natural light and natural ventilation. All animals were uniquely identified by their national identification number and were fed with a commercial non-medicated cattle ration. Water was restricted. No vaccination, antibiotics nor anti-inflammatory drugs or other medications were administered to calves after arrival at the site.

Enrolment

At the time of the outbreak, all calves were clinically examined for depression (normal=0; mild=1; moderate=2 and severe=3) and the c­ haracterisation of the respiratory signs, such as polypnoea Veterinary Record | April 26, 2014

(≥40 breaths/minute), dyspnoea (abnormal respiration), cough and mucopurulent nasal discharge (each sign counted for one point to establish respiratory character score). The rectal temperature was also measured. All animals with a depression score ≥2, a respiratory score ≥2 and a rectal temperature ≥40.3°C were enrolled in the study (day 0).

Randomisation and drug administration

After clinical examination and qualification at day 0, calves were weighed to ensure accurate treatment dosage. Then, calves were assigned to treatment groups, following a chronological order regardless of gender, using a computer-generated randomisation code, which was given to the dispenser under separate cover to preserve masking of the clinicians. Randomisation was accomplished in advance according to a randomised complete block design based on batch and order of enrolment. Enrolled calves remained in their original pen at arrival. Once randomly allocated, each calf was treated either with the test product, 300 mg/ml florfenicol plus 16.5 mg/ml flunixin formulation (Resflor; 40 mg/kg florfenicol and 2.2 mg/kg flunixin; 2 ml/15 kg; MSD Animal Health), or the control product, 300 mg/ml florfenicol formulation (Nuflor; 40 mg/kg; 2 ml/15 kg; MSD Animal Health). Both products were administered once subcutaneously in the neck on day 0. To avoid observation bias, treatments were dispensed and administered by dispensers not involved in the clinical assessment.

Clinical assessment and treatment success

Following treatment on day 0, individual animals were processed through the chute, for rectal temperature (°C) measurements at 6 hours±1 hour (target: six hours) following dosing. From day 0 at 6 hours±1 hour until day 3, individual animals were processed through the chute daily, for clinical assessment including depression, respiratory characters and rectal temperature measurements. During this period that was considered the recovery period, animals were not considered for failure evaluation. From day 4 to day 10, daily observation continued except for rectal temperature which was only measured when the animal exhibited either a depression score ≥1 or a respiratory score ≥2. The skin was observed and palpated for potential local lesion and site reaction. The injection site reactions (number, size and consistency) were evaluated twice on day 0 (prior to treatment, and 6 hours±1 hour post-treatment), and once daily from day 1 to day 10. The pain on injection was evaluated once on day 0. Any adverse effects were also recorded. From day 4 to day 10, animals with a depression score ≥1 or a respiratory score ≥2 that had a rectal temperature ≥40.0°C were classified as treatment failures and removed from the study. If these criteria were not met, the animals remained on study and were classified as treatment successes (depression score=0 or a respiratory score ≤1 with a rectal temperature

Treatment of naturally occurring bovine respiratory disease in juvenile calves with a single administration of a florfenicol plus flunixin meglumine formulation.

The efficacy and safety of a florfenicol plus flunixin meglumine formulation in the treatment of respiratory disease was evaluated in calves less than...
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