A study on parenteral antibiotic treatment in sheep footrot was conducted on 10 farms in southern Germany to obtain information on the efficacy of gamithromycin under practical use conditions compared with a positive control. On each farm, 20 (10 on one farm) lame sheep were clinically evaluated and divided into two groups. On day 1, sheep were treated once according to group with either long-acting oxytetracycline (OTC) at 20 mg/kg bodyweight or gamithromycin at 6 mg/kg; clinical responses were assessed 21 days later. When compared with day 1, both treatments reduced clinical lameness, as reflected in the reduction in the number of footrot-affected feet (OTC: 79.3 per cent; gamithromycin: 93.7 per cent) and in the severity of the lesions. The difference between the two treatments was significant (P<0.01) with an OR of 6.1 in favour of gamithromycin. Of the 33 sheep that were still lame on day 21, nine mildly affected animals were not re-treated and the remaining 24 sheep were re-treated with gamithromycin. On day 42, all but two (on the same farm) of the 33 sheep were cured, giving an overall response rate in this study to one or two parenteral antibiotic treatments of 99 per cent.
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Footrot in sheep is a common cause of lameness that is self-evidently painful and hence has an impact on welfare and productivity (Ley and others 1995, Nieuwhof and others 2008, Winter 2008). Treatment and control have centred on one or more of the following: foot trimming, foot bathing, pasture and premises management, vaccination, topical and parenteral antibiotics, and culling and breeding for genetic resistance (Strobel 2009, Winter 2009). The efficacy of parenteral antibiotics in the treatment of footrot in sheep was first reported in Australia (Egerton, 1966) and this was followed by a more detailed study (Egerton and others 1968). Efficacy can, however, be affected by prevailing environmental conditions and sheep generally show better responses to parenteral antibiotics when kept in dry conditions compared with when they are on wet pastures with rainy conditions following treatment (Egerton and others 1968). There is now strong evidence that parenteral antibiotics can provide superior treatment of footrot compared with therapeutic hoof trimming (Green and others 2007, Green and George 2008, Winter 2009, Kaler and others 2010, Wassink and others 2010).
The main causal agent of footrot in sheep is the anaerobic bacterium Dichelobacter nodosus, although Fusobacterium necrophorum is also frequently isolated from clinical cases and is the cause of the related disease, interdigital dermatitis (scald) (Green and George 2008, Winter 2008, Kennan and others 2011). Sheep isolates of these organisms show in vitro sensitivity to the β-lactam antibiotics (eg, penicillins and cephalosporins) with minimum inhibitory concentration (MIC90) values of less than 8 μg/ml (Jimenez and others 2004). The corresponding MIC90 values for tetracycline and oxytetracycline (OTC) were 16 and 32 μg/kg, respectively. The macrolides erythromycin, spiramycin and tylosin had MIC90 values of 1 μg/ml or less for D nodosus and 128 or less for F necrophorum. The MIC90 values in isolates from goats were generally lower than those from sheep, being 8 μg/ml or less for the majority of antibiotics tested (Lacombe-Antoneli and others 2007).
OTC has proven efficacy in the treatment of footrot (Rendell and Callinan 1997, Piriz and others 2001, Kaler and others 2010,2012, Wassink and others 2010) and in some countries is licensed for this disease in sheep.
Gamithromycin is a macrolide antibiotic in the azalide subclass; it is currently licensed in Europe, North America and other regions for use in cattle in the treatment and control of bovine respiratory disease (BRD) (Baggott and others 2011). The pharmacokinetics (pK) following subcutaneous injection in cattle show a pattern of very rapid diffusion from the site of injection into the bloodstream and thence into the tissues (Huang and others 2010). Concentrations of gamithromycin in the lung tissues exceed the MIC90 of the major bovine bacterial respiratory pathogens within 30 minutes of administration and remain so over the subsequent 10 and 15 days (Giguere and others 2011). This pK profile is consistent with therapeutic responses that show a rapid response when gamithromycin is given to clinical BRD cases (Sifferman and others 2011) and persistent activity of at least 10 days when previously treated cattle were challenged with Mannheimia haemolytica (Forbes and others 2011).
Although not currently licensed for use in sheep, gamithromycin has been used in the field in the control of footrot (Stamphoj 2011), and this and other observations prompted the present study. Bacteriological diagnosis of hoof infections and antibiotic resistance testing are not routinely conducted in Germany (Strobel and others 2012), therefore veterinarians in practice rely on clinical, rather than bacteriological, responses as measures of antibiotic efficacy. The objective of this trial was to assess the clinical efficacy of gamithromycin in the treatment of footrot in sheep, using OTC injection as a positive control.
Materials and methods
Recruitment of farms and enrolment of animals
In order to recruit sufficient lame sheep into the study, 10 Merinolandschaf flocks with a history of endemic footrot over a minimum of the previous 3 years were selected from clients of Schafpraxis in the Swabian region of southern Germany (Strobel 2011). These flocks were all managed in a transhumance system with summer grazing in upland areas and winter housing in lowland farms (Luick 2004). The study took place over the winter when the sheep were housed. Other than trial procedures, normal farm management practices were continued for the duration of the study. This work was conducted in accordance with local ethical regulations for veterinary practice, which included the use of a positive control group rather than an untreated group.
Allocation and treatment
Twenty sheep per flock with typical footrot lesions, including under-running horn and clinical lameness, were selected and individually identified. Animals were blocked in pairs and each animal assigned to one or other treatment in order of presentation and inspection.
Footparing was restricted to the removal of overgrown horn, and only if necessary for confirming the diagnosis of footrot and for scoring the lesions.
The two treatments were:
Group 1: single treatment with OTC at 20 mg/kg administered by intramuscular injection (Duphacycline LA, Pfizer)
Group 2: single treatment with gamithromycin at 6 mg/kg administered by subcutaneous injection (Zactran, Merial).
For each animal, the estimated or actual liveweights were recorded. In line with normal farm practice, the dosage for all the sheep (ewes) was standardised to a liveweight of 90 kg, hence 10 ml OTC/animal and 4 ml gamithromycin/animal were used throughout.
The farm history of antibiotic (OTC injection and topical spray) use for lameness over the year prior to the start of the study was used as a means of estimating the impact of the disease on each farm.
On day 1, when sheep were recruited into the study and allocated to treatment, and subsequently on days 21 and 42, lame sheep were identified and given a lameness score based on severity. Each lame sheep was placed in a rotating crush so that the animals could be positioned in ventral recumbency to facilitate examination of the feet and administration of the antibiotics. The number of feet affected and the severity of the footrot lesions were documented by digital photography and scored on a 0–5 scale according to severity.
In addition, the presence or absence of sternal decubital necrosis was recorded as an indicator of sheep that lay for abnormally long periods because of chronic lameness. Other diagnoses, such as white line disease, hoof/horn deformations and abscesses, were recorded separately.
At the first examination, wooden swabs were used to sample visible lesions for subsequent bacteriological identification using PCR methodology (Frosth and others 2012).
Scoring of footrot lesions
For each foot, a 6-score system, adapted and extended from a 5-score system, was used (Egerton and Roberts 1971):
0=normal, dry interdigital skin, hair; 1=hoof temperature high, inflammation of interdigital skin, interdigital, hair loss; 2=necrotising interdigital dermatitis, characteristic smell; 3=under-running of the medial wall and soft horn of the heel; 4=under-running of the sole, extending to the outer edge; 5=necrotising inflammation extending to the tip, separation of the hoof.
Day 1: First visit—lame sheep identified; all feet examined and scored for footrot lesions; non-traumatic paring (overgrown horn removed); decubitus recorded; treatment with OTC or gamithromycin
Day 2: Farmer assessment of adverse reactions
Day 21: Second visit—all sheep inspected and feet scored; non-traumatic paring (loose horn removed); second antibiotic treatment if necessary.
Day 42: Third visit—sheep lame on day 21 inspected and feet scored.
Data collection and handling
All raw data were collected on the farm as hard copies and then transferred to an Excel data sheet at the clinic. Digital photos were down-loaded and labelled by date, sheep ear number and foot.
For each sheep, the following were determined: the sum of the lesion scores on all four feet, the mean lesion score for all four feet, the number of feet affected (score >1) and the mean lesion score for all affected feet. For each treatment group on each farm, these parameters were summed and divided by the number of animals to give means for each group. For clarity, only the number of affected feet and the mean sums of lesion scores per affected foot are shown in Table 2, although the clinical responses and the results of the statistical analyses were similar, irrespective of which parameter was included in the model.
A binomial logistic regression model was used to assess the effect of the medication on the probability of successful treatment on the foot level, adjusted for the following covariates: initial score, foot position, farm and decubitus. Random effects were considered to account for the clustering of feet within a sheep. Treatment success was defined as a score of zero at day 21. An OR of 1 denotes equal probabilities of success, while an OR greater than 1 represents a group that had a higher probability of treatment success than the respective reference group. The initial score was grouped into four categories, with a score of 1 or 2 as the reference category. Only affected feet were considered, since re-infection was negligible.
All computations were done with R 2.13.0.
Descriptive statistics of the 10 farms are provided in Table 1. The flock size was between 100 and 870 head and the estimated prevalence of lameness ranged from 10 to 30 per cent. Among the sheep enrolled in the study, the mean footrot scores of affected feet ranged between 3.01 in the least affected and 4.33 in the worst affected. The number of doses of OTC given per year over the 3 years prior to this study is provided as a surrogate measure of the previous impact of footrot in the participating farms.
Inspection of treated sheep the day after antibiotic administration revealed no signs of any systemic adverse reactions. The therapeutic responses at day 21 are shown in Table 2 and an example of the response to gamithromycin is illustrated in Fig 1. On all farms there was a reduction in the mean lesion scores of affected feet, albeit small in some cases, on day 21 compared with those on day 1. According to the logistic regression model based on 302 affected feet (Table 3), the probability of successful treatment was significantly (OR=6.10, 95% CI (1.84 to 20.21), P<0.01) higher in the gamithromycin group compared with the OTC group. Re-infection was observed in only three cases (two feet of one sheep treated with OTC and one foot of a sheep treated with gamithromycin). There were no significant effects of initial clinical scores and position of foot on the therapeutic outcome. Animals with decubitus responded better than those without, although numbers of affected sheep were small. The cure rates on day 21, expressed as the percentage reduction in the number of affected feet, were 79.3 per cent in the OTC group and 93.7 per cent in the gamithromycin group. Differences in treatment responses amongst the farms were observed (Table 2), for example, on farm 9. Here, the cure rates on day 21, expressed as the per cent reduction in the number of affected feet, were 46 per cent in the OTC group and 100 per cent in the gamithromycin group, possibly indicating a lower susceptibility of D nodosus to OTC on this farm. On farm 6, the treatment responses to both antibiotics on day 21 were incomplete and several sheep required re-treatment.
On day 21, across all farms 33 sheep had a footrot lesion score of 1 or more. Nine of these sheep with a score of 1 were not re-treated and these were normal by day 42; three of these sheep were sampled on day 21 and were PCR negative for D nodosus. The 24 remaining sheep with clinical scores greater than 1 on day 21 were treated with gamithromycin. From these 24 animals, 10 were sampled for D nodosus on day 21; nine of these were positive. On day 42 at the third inspection, 22 of these animals were cured, but two were still lame on farm 6 and D nodosus was isolated from one of the sheep.
The clinical responses to treatment with parenteral antibiotics in this study were consistent with other reports in the literature on sheep footrot in which OTC and a macrolide antibiotic were used (Rendell and Callinan 1997, Piriz and others 2001, Kaler and others 2010,2012, Wassink and others 2010). In contrast to another study (Kaler and others 2012), there was no association between the clinical score before treatment and the response to parenteral antibiotics, even in sheep with severe under-run horn or decubitus.
The higher clinical cure rates seen in the gamithromycin group in comparison with the OTC group may be a reflection of previous antibiotic use on the trial farms. In all farms, OTC in topical and parenteral form had been used in the treatment of footrot over at least the preceding 3 years. The apparent treatment failure of OTC on farm 9 was associated with high usage over previous years and may indicate a lower sensitivity to tetracycline antibiotics in D nodosus, although no relevant MIC data were generated in this field study.
The responses to treatment on farm 6 were atypical insofar as the use of neither antibiotic resulted in a good clinical response. This may have been because the isolate(s) of D nodosus on this farm was relatively insensitive to the antibiotics or some aspect of the pharmacokinetics or administration procedures were suboptimal. Although several animals recovered following treatment with gamithromycin on day 21, two remained lame on day 42 and D nodosus was isolated from one animal.
Differences in the D nodosus MICs and tissue affinity between the two antibiotics may exist. Previous studies have shown that generally the macrolide antibiotics had lower MICs (<1 μg/ml) than OTC (32 μg/ml) (Jimenez and others 2004). In addition, the MIC90 of gamithromycin was 0.0234 mg/l against several bovine and ovine isolates of Treponema species, bacteria associated with digital dermatitis (Evans and others 2012).
A preliminary study (unpublished data) has shown that following subcutaneous injection of gamithromycin in sheep at 6 mg/kg bodyweight, the concentration in healthy metacarpal skin was greater than 200 ng/g up to 10 days after administration. In addition, there was a marked accumulation of gamithromycin in the skin, resulting in skin/plasma concentration ratios of 20–130 over the 10-day measurement period.
This study demonstrated that a single administration of either long-acting OTC or gamithromycin resulted in good clinical cure rates in sheep with footrot. Gamithromycin had a significantly higher cure rate at day 21 compared with OTC and this could be therapeutically relevant on some individual farms. From limited sampling it also appeared the gamithromycin treatment resulted in a bacteriological cure, indicating that antibiotics could contribute to elimination of D nodosus in some flocks (Stamphoj 2011). Group treatment with gamithromycin has already been shown to be effective in treating an outbreak of lameness thought to be caused by Bacteroides melaninogenicus in sheep (Sargison and Scott 2011).
The cooperation of all the farmers who participated in this study is gratefully acknowledged. The laboratory is acknowledged for carrying out the PCR tests.
- Accepted November 24, 2013.
Provenance: not commissioned; externally peer reviewed
Funding Funding for this study was provided by Merial SAS, 29 Avenue Tony Garnier, Lyon 69007, France.
Competing interests A. B. F. was a full time employee of Merial when the study was conducted.
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