CASE NOTES


ADVERSE REACTIONS TO TETRAVET FLEXI-DOSE OXYTETRACYCLINE PVP INJECTION

Tony Morton, District Veterinarian, Hume LHPA

Posted Flock & Herd June 2011

INTRODUCTION

Antibiotics have been recommended for the treatment of Dermatophilus /Mycotic Dermatitis/Lumpy Wool since the work of Roberts and Graham showed that high doses of penicillin/streptomycin were effective in 1966(1).

With the withdrawal of penicillin/streptomycin from the market there has been a move to the use of long-acting tetracyclines. Farquarson (2) recommends long acting tetracyclines at the rate of 20mg/kg eight weeks prior to shearing.

Long acting tetracyclines are widely and commonly used for the treatment of Lumpy Wool and frequently injected into the hind leg as they were for countless 10's of thousands of sheep for footrot treatments without adverse effect.

This paper describes adverse reactions on three properties in the Hume LHPA following the use of Tetravet Flexi-Dose Oxytetracycline PVP Injection® as a single IM injection at the rate of 1mL/10kg body weight (10mg/kg body weight). This is half the rate recommended by Farquarson.

Tetravet Flexi-Dose Oxytetracycline PVP Injection® is composed of oxytetracycline hydrochloride 100mg/mL and it is claimed 'the virtual absence of irritation also produces minimal residue and inflammation at the injection site' (3).

HISTORY

Case 1 - 8 September 2010 (Tony Morton, DV Hume - Wagga)

A self replacing merino flock on Hazeldean bloodlines where the father and two sons have used antibiotics (e.g. Engemycin®, Tetravet Flexi-Dose Oxytetracycline PVP Injection®) injected IM into the hind limb of lumpy wool affected weaners and hoggets in August six weeks pre shearing. This has been a long established practice and apparently almost trouble free until 2010.

There was a lesser problem with tetravet and lameness in the hoggets in June 2010 which was not reported or investigated prior to the case now reported.

The lambs (weaners) were 20- 30kg and were injected between 27-29 August 2010 into the upper hind leg using a 20g x 1" needle (99% of the lambs) or 18G x 0.5" needle (a few after problems noted, but problems still experienced using the shorter needle) with 3ml of Tetravet Flexi-Dose Oxytetracycline PVP Injection®. Within 20-30 minutes some lambs were noted stamping the foot on the injected limb and becoming lame. About 10 -20 minutes later the toe started to knuckle under.

Approximately 280 lambs were injected, 200 into the back leg and 80 into the neck cranial to the shoulder. An estimated 70 ex 200 became lame with knuckling (see photo below). None of the 80 injected in the neck were noted to have a severe reaction however some discomfort was noted in 2 or 3.

An estimated 10 ex 110 treated (IM hind limb) hoggets also became lame and had to be destroyed as the knuckling led to skin damage and infection of the foot.

2 ex 25 treated (IM hind limb 18g x 1.5" needle) ewes had a similar lameness.

A used empty bottle was available batch: 0910298-02 exp 210-2012

Picture 1: Knuckling from the fetlock of the injected hindlimb (Case 1)

Case 2 - 4 February 2011 (Tony Morton, DV Hume - Wagga)

A self replacing merino flock on Pastoral bloodlines where the owner has routinely been treating 40 -50 lumpy wool affected weaners with intramuscular antibiotics into the hind limb for at least the last 10 years. Last year about 100 weaners were treated with penicillin based product with no ill effects.

This year as was the normal practice the mobs were yarded, put up the race and those with lumpy wool treated while in the race. Tetravet Flexi-Dose Oxytetracycline PVP Injection® was administering IM into the back leg with 3-4mL for the weaners and 5mL for the 3 year old ewes. A total of approximately 625mL was used. At say 4 mL average dose this would mean approximately 156 sheep were treated. All the sheep were treated after this with Vetrazin® spray and the ewe weaners were also drenched.

The owner had done the treatments of the ewe weaners 4 weeks before my visit, the 3 year old ewes 3.5 weeks before the visit and the wether weaners 3 weeks before my visit. No problems were noted by the owner in the yards or when returning the sheep to either the paddock or when he checked the ewes one week post treatment. He then went on holidays while his elderly father kept an eye on the sheep and returned to a sorry sight.

In both the wether weaners and ewe weaners (not the 3 year old ewes) there were sheep with severe single hind limb knuckling, extensive swelling and infection in the affected lower limb and even the sight of protruding bone.

A paddock inspection revealed 17 affected ewe weaners but the feed in one of their three paddocks was waist high so it was possible that dead sheep were not identified. In the wether weaner paddock there were 3 dead sheep with the typical foot lesions, 8 alive with the typical foot lesions plus three back at the shearing shed the owner had caught the previous day in case forecast heavy rain made paddock inspection and necropsy impractical.

Two of the three bottles used were available (one empty, one part used, batch 1010277-01, exp 10-2013).

Picture 2: Severe knuckling and necrosis of the lower limb of the leg injected (Case 2)
Picture 3: Severe necrosis of the lower portion of the injected hindlimb (Case 2)

Case 3 - 8 February 2011 (Brigit Pitman, DV Hume - Albury)

I visited the property at Mangoplah to assess three 1st cross wethers that had become suddenly lame in either the right or left hind leg. They presented with non weight bearing paresis to paralysis in the affected leg, with swollen foot and necrotic skin over the dorsal fetlock joint. The mixed sex lambs had been yarded on 23 January 2011 for drenching and jetting with an estimated ten individuals treated for dermatitis by injection with Tetravet Flexi-Dose Oxytetracycline PVP Injection® (Batch No. 09 1029802 Exp.10 2012) injection in a hind leg while they were in the Robertson sheep handler. This unusual hind leg lameness had been appearing over the past week in the ewe and wether portion, in six lambs to date, of which three had been presented for examination. When the lameness first started the lambs were reported to have no swelling in the lame foot.

On 14 February 2011 the owner reported he had destroyed seven mixed sex lambs and another one was developing similar symptoms. Unlike the previous two cases these were 1st cross lambs (not merinos) and this was the first time the owner had treated for lumpy wool. As a footrot contractor he has injected huge numbers of sheep with antibiotics in his sheep handler.

The bottle was first used a couple of days earlier for a small number of rams and ewes (e.g. abscess) and a couple of days after the lamb treatments for a small number of sheep (e.g. lumpy wool) in a different site with one adverse reaction noted in a merino ewe (i.e. knuckling and the leg swinging out). The owner said this is definitely the treated ewe as she was the only one in the mob with significant lumpy wool.

POST MORTEM AND PATHOLOGY FINDINGS

Case 1

There were no significant post mortem findings other than damage to tissues of the lower limb from the knuckling at the injection site and damage associated with the site of placement of the antibiotic. There was a greenish discoloration of the muscular tissues adjacent to the sciatic nerve (Picture 4).

J Glastonbury at CSU reported:

Histopathology:

The findings in both affected limbs were similar and will be described as one.

'Affected' skeletal muscle:

Deep in the muscle mass, there was a large cystic space containing copious fibrin and walled off by a prominent layer of relatively mature white fibrous tissue, which was infiltrated by moderate numbers of mononuclear leucocytes along the inner border. Within the border region, there were areas of 'mummified' skeletal muscle and fascicules of peripheral nerve; in both types of tissue, the fibres were of normal diameter and were pale eosinophilic, no nuclei were present, there was no immediate cellular response and there were no cross striations in the skeletal muscle.

Peripheral nerve:

Fascicules of peripheral nerve neighbouring the above cystic space showed similar findings. There were numerous segmentally swollen myelin sheaths or 'digestion chambers', many of which contained myelin macrophages or gitter cells, showing evidence of necrosis. Only small numbers of swollen axons were found.

Diagnosis:

Severe, chronic, focal/locally extensive degenerative myopathy.

Severe, chronic, degenerative peripheral neuropathy.

Picture 4: Greenish discolouration of the muscular tissues adjacent to the sciatic nerve (Case 1)

Case 2

Two of the affected wethers at the shearing shed were euthanased for post mortem. Both had lumpy wool, moderate grass seed infestation (but still had adequate body fat reserves) and putrid swollen infected knuckled single lower limbs with bones showing through the lesions.

The first wether post mortemed had hepatisation ventrally in the left apical and cardiac lobes and ostertagia were noted in the abomasum. The popliteal lymph node was enlarged. A small area of muscle around the sciatic nerve was greyish/green.

The second wether also contained ostertagia, there were miliary lesions along the top of the abomasal folds, and the kidney cortex was pale. The popliteal lymph node was enlarged. The muscle adjacent to the sciatic nerve when transacted had a core of pale necrotic looking muscle surrounded by a fibrous capsule (Picture 5).

Picture 5: Pale, abnormal muscle tissue with fibrous capsule to the sciatic nerve (Case 2)

Pi-Jie Yang at CSU reported:

Histopathology:

SHEEP 1 MUSCLE

Sections of the muscle contain skeletal muscle, adipose tissue and nerves. There is widespread coagulative necrosis of the adipose tissue and some nerves with areas of liquefactive necrosis, oedema and fibrin accumulation. Saponification of adipocytes with surrounding macrophages and lymphocytes are scattered around the edges of the necrotic adipose tissue. Minimal inflammation is associated with the areas of coagulative necrosis. Viable nerves are surrounded by marked oedema, and there is marked neural degeneration, as characterised by swelling of the myelin sheaths, presence of digestion chambers and gitter cells. Nerves, muscles and pockets of adipose tissue are interspersed by marked fibroplasia. Scattered muscle fascicles within viable musculature are degenerate, as characterised by swelling, sarcoplasmic hypereosinophilia and hyalinisation. Fascicles at the edge of the muscle and fibrous tissue are shrunken and hypereosinophilic.

SHEEP 1 ABOMASUM

The section of abomasum is characterised by moderate superficial oedema in the mucosal layer, with scattered dilated gastric glands lined by squamous attenuated epithelium. Some of these dilated glands contain few round necrotic epithelial cells and one dilated gland contains nematode larvae. There is minimal inflammation associated with changes in the abomasum.

SHEEP 2 MUSCLE

The section of muscle from sheep 2 is characterised by marked interstitial fibroplasia with a central core of coagulative necrosis involving nerves and adipose tissue. Few viable nerves are observed, with mild to moderate myelin degeneration as characterised by presence of gitter cells. At the margin of the necrotic zone there is a marked accumulation of degenerate neutrophils, fibrin, and oedema, which are surrounded by numerous macrophages. Saponification of the adipose tissue is again scattered in the viable adipose tissue, accompanied by an accumulation of macrophages, lymphocytes, and rare multinucleate giant cell.

SHEEP 2 ABOMASUM

The section of abomasum is characterised by marked moderate gastric hyperplasia with loss of parietal cells, and numerous nematode larvae in the lumen and embedded within dilated and attenuated glands. Scattered throughout the lamina propria are small to medium sized pockets of lymphocytes and histiocytes.

SHEEP 2 KIDNEY

No significant pathological changes are detected in the kidney.

Case 3

Autopsy of one lamb revealed necrosis of the skin in an area 10x10cm over the plantar aspect of the affected fetlock/pastern, and septic arthritis with subdural abscessation at the dorsal end of the necrotic skin. The femoral muscles were atrophied. The popliteal lymph nodes were enlarged 2-4 fold. There was no obvious femoral muscle damage.

On removal of the leg a necrotic-small, triangular in cross section, dark brown muscle close to the femoral neck was transected and a section taken in formalin.

Specimens were collected in buffered formalin but not submitted as the syndrome has been adequately described with the previous cases.

DISCUSSION

Case 1

The CSU laboratory report concluded:

The degree of peripheral neuropathy would certainly explain the clinical signs. The type of degeneration, Wallerian degeneration, found in the fascicules neighbouring the cystic spaces is consistent with severe pressure being applied to the nerve; in this case the injected substance. Whether the 'Tetravet' was directly neurotoxic is problematical.

The 'mummified' skeletal muscle within the borders of the walled off cyst were unusual and possibly are the consequence of sudden and complete anoxia.

Case 2

The CSU laboratory report concluded:

1) Necrotising myositis and fasciitis, severe, chronic, focally extensive with marked degenerative neuropathy, marked fibroplasia, localised granulomatous steatitis.

2) Verminous gastritis, mild (sheep 1) to moderately severe (sheep 2), sub-acute to chronic.

Changes in the muscle and nerves of both sheep are suggestive of severe vascular compromise. Widespread coagulative necrosis with minimal inflammation in sheep 1 suggests there has been relative quick arrest of blood supply to the area, resulting in hypoxia but minimal influx of leucocytes. In the adjacent, more viable muscles there is necrosis of selected individual muscle fascicles, which may be due to compromised vascular supply to each individual fascicle. In sheep 2 there is more inflammation associated with the necrosis, which may be a result of partially compromised vascular supply, or secondary bacterial infection from the injection.

It is difficult to ascertain whether the drug itself was toxic to the muscle and nerves, but one would expect more liquefactive necrosis if there had been direct chemical insult. It may be that there is extensive liquefactive necrosis in the tissue upstream to the submitted sample, resulting in compromised vascular supply to the tissues downstream. Small areas of liquefactive necrosis are visible at the edge of some muscle sections.

Case 3

Specimens were not submitted when Bomac declined to cover the costs of histopathology.

Clearly the history, gross post mortem and histopathology all lead to the conclusion that the product was responsible for damage to muscle and nerve either directly or indirectly.

Discussions with the veterinary practice that supplied all three of the producers revealed one previous case in August 2010 seen incidental to a farm visit. The farmer uses Tetravet Flexi-Dose Oxytetracycline PVP Injection® for conditions such as foot abscess. One white Suffolk ram treated IM in the back leg had a unilateral hind limb paralysis with knuckling. It was euthanased. The practitioner assumed the farmer must have hit a nerve and took no further action. The farmer had used substantial quantities of Tetravet Flexi-Dose Oxytetracycline PVP Injection® for abscess in ewes with no ill effects noted. The 61 year old farmer has treated many sheep over the years and cannot recall a similar case.

The practitioner said they sell 'bucket loads', have received no adverse reports re cattle but from time to time have had problems with the product 'going off' prior to its expiry resulting in them returning it to their supplier. The only adverse reports they have received are the three investigations described in this paper plus the August case they saw.

OUTCOMES

In the first case all of the affected sheep (70 weaners, 10 hoggets and 2 ewes) either died or were destroyed and the owner purchased additional sheep. A valuation determined that the total loss at the time was $9,075. This was calculated on the basis of $125 for the ewe weaners, $100 for the wether weaners, $100 for the 10 hoggets and $100 for the 2 ewes.

The owner in the second case phoned on 10 February 2011 and reported that 'fifteen ewe weaners had been killed or died (total so far) and another eight to ten ewe weaners will need destroying. Eleven wether weaners have died or been killed (total so far) and another up to five wether weaners will require destruction. All the above figures are based on paddock inspection; neither mob has been driven to yards for close inspection or count.' The owner's agent suggests the wether weaners would be valued at $120 -125 and the ewe weaners $150 - $160. The owner said at Wagga today he saw merino ewe weaners poorer than any of his made $126. Total cost is therefore approximated at $5,835.

The owner in the third case had at 14 February 2011 destroyed seven lambs with an estimated value of $150 per head. Total cost approximately $1,050. During discussions on 16 February 2011 he said a further lamb was almost certain to require destruction as was the merino ewe treated a couple of days after the lambs.

Following our second case on 4 February 2011 (and Bomac's 9th case), I was advised that a number of batches were being recalled. On checking my second case I advised Bomac that it was different batch to those they were recalling and on 11 February 2011, I was notified of a voluntary product recall of Tetravet Flexi-Dose Oxytetracycline PVP Injection® 100mL and 250mL all batch numbers and expiries.

Case 1 still had further sheep that required treatment after my initial investigation on 8 September 2010. I spoke to Pfizer and was told that Terramycin LA is registered for subcutaneous use in the USA. I provided written advice and this was what was used thereafter. This meant the sheep treated received the correct recommended dose of long acting tetracycline but SC not IM. The owner was delighted with the results six weeks post treatment as were his sons who are also shearers! They reported even large patches of lumpy wool separated from the skin allowing them to be 'shorn off without hacking the skin off'.


ADDITIONAL REPORT AFTER PREPARATION OF THIS PAPER

A further case was reported on 18 February 2011. A producer reported that he still had on hand some Tetravet Flexi-Dose Oxytetracycline PVP injection®, batch number 0910298-02. He advised that on the 18th and 23rd November 2010 he treated about 220 merino August 2010 drop unweaned lambs. The largest weighed approximately 30kg. The producer recalled a 4mL maximum dose (as per diary entry) with less given to smaller lambs. On the 18th November, some of the lambs went down in the race obviously in pain and struggled to get up. The producer had previously been made aware of proper technique for injecting into the hind limb to avoid the sciatic nerve so he tried to inject from the side rather than the back and also used a shorter needle (1"). He also tried injecting into the neck but the small size of some of the weaners made this difficult due to insufficient muscle mass. On 23rd November with the modified technique no major problems were noted, but even when injecting into the neck or the lateral leg a substantial number were showing pain.

Three or four were recalled as being destroyed in early December 2010, and it was recorded in the owners diary that on 22 December 2010 fourteen were destroyed because of persistent unilateral hind limb knuckling causing damage and infection to the lower limb. A further two were destroyed in January 2011 because of knuckling.

One mildly affected lamb remains on the property.

Following our conversation on 18 February 2011, the producer treated one more weaner in the hindleg with the same bottle of Tetravet Flexi-Dose and it caused substantial pain. He then injected about 30 more weaners with Engemycin 100® with negligible pain reactions. It is significant that the batch 0910298-02 used by this producer is the same as used in Case 1 where immediate pain was also reported.

The producer has obtained a valuation for the lambs at the time the problem occurred from Aaron Seaman of Elders Wagga Wagga. The lambs were valued at approximately $70 each, giving a total cost of $1,400.

Comments by Michael Findlay, Bomac for DV Conference 2011 on ongoing company investigations.

Some time ago Bomac was made aware of reports of adverse experiences in sheep which were injected in the back leg with our PVP oxytetracycline product. This product has been registered and sold in sheep for some years prior to these reports.

Bomac then embarked on a process to try and find out why this was occurring. We tested the product extensively and found no answers as to what would cause these types of reactions. Not all sheep treated were affected and in the batches of the product in question, in excess of 300,000 doses were sold.

To rectify this issue, Bomac put in place a voluntary recall of the product which is ongoing. Bomac is also working with the APVMA on what future steps will be taken to try and prevent these types of adverse experience in the future.

Bomac has now begun working with the producers who have had sheep affected. It is envisaged that a satisfactory outcome for the producers involved will be reached.  

REFERENCES

  1. Hungerford's Diseases of Livestock Ninth Ed
  2. The T G Hungerford Vade Medecum Series A, No 14 Sheep Dr Bruce Farquarson
  3. MIMS 2009 IVS Annual

 


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