AN ANALYSIS OF THE TREATMENT OF SARCOPTIC MANGE IN WOMBATS USING MACROCYCLIC LACTONES, WITH SUGGESTIONS FOR FUTURE RESEARCH

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1 Unusual Pet and Avian Veterinarians Annual Conference 2016 p AN ANALYSIS OF THE TREATMENT OF SARCOPTIC MANGE IN WOMBATS USING MACROCYCLIC LACTONES, WITH SUGGESTIONS FOR FUTURE RESEARCH (Anne Martin Scholarship Winner) Madeleine Rowe BSc Faculty of Veterinary and Agricultural Sciences The University of Melbourne INTRODUCTION Sarcoptic mange is a major infectious disease affecting the bare- nosed wombat (Vombatus ursinus) (Skerrat et al., 1998) and a growing threat to the southern hairy- nosed wombat (Lasiorhinus latifrons; SHNW) (Ruykys et al.,2013) In high density populations, the disease can spread rapidly, resulting in epizootics and local extirpations due to reduced reproduction and increased mortalities.(hartley and English, 2005; Martin et al., 1998; Skerrat et al., 1998). The disease is caused by the Sarcoptes scabiei var. wombati mite (S. wombati) and infection manifests as a debilitating dermatological condition that causes death secondary to dehydration, starvation and bacterial infection (Triggs, 1988). The welfare implications have incited both scientists and community groups (an example of the latter being Mange Management Inc.) to investigate treatment and control options. The available treatment regimens utilising macrocyclic lactones described in the literature and currently used in the field are evaluated within this report and directions for future research are discussed. TREATMENTS Method one: Multiple injections of macrocyclic lactones Study one - A study involving captive bare- nosed wombats (Skerratt, 2003) 7 3 x 300µg/kg subcutaneous ivermectin every 10 days. Injectable long- acting procaine penicillin (15mg/kg) and benzathiane penicillin (11mg/kg) delivered with the first ivermectin injection. Outcome: Three subcutaneous injections of ivermectin eliminated clinical signs of sarcoptic mange in all wombats (N=7), however, a second course of treatment was required for complete elimination of infection in the worst affected wombats (N=3). Discussion: This study demonstrated the efficacy of ivermectin injections as a treatment for sarcoptic mange, but it is not without limitations. The effectiveness of the ivermectin injections was determined by visual observation of the resolution of the clinical signs of mange, which does not determine whether the treatments eliminated infestation or simply reduced the parasite burden to sub- clinical levels. A recrudescence of mild sarcoptic mange occurred in three wombats two months after the first course of treatment, although it is speculated that this may have been due to re- infection from mites persisting in the environment. The entire treatment protocol was repeated for these three wombats, and they were considered free of infection when they failed to show signs of mange four months after treatment ceased. These wombats also had the heaviest level of infection prior to treatment, which suggests that wombats with a heavier level of infection either shed more mites into the environment or require a 1

2 more intensive treatment regimen than wombats with mild infections to eliminate S. wombati. Further research is recommended before drawing conclusions, as this was a small- scale study (N=7). Study two - A study involving free- living bare- nosed wombats (Skerratt et al., 2004) 8 (1) 400µg/kg subcutaneous ivermectin 100 days following experimental infection of wild wombats with S. wombati (N=5). (2) 800µg/kg subcutaneous ivermectin and topical amitraz wash 128 days post- infection in wombats with unresolved infestations (N=2). (3) 2 x 800µg/kg subcutaneous ivermectin every 10 days in a single wombat (N=1) whose mange failed to resolve after (2). Outcome: A single injection of ivermectin (400µg/kg) eliminated infection in mildly affected wombats (N=2), while moderately infected wombats (N=3) required up to four more injections of ivermectin (800µg/kg) used in combination with topical amitraz for complete elimination of infection, as determined by negative skin scrapings. Discussion: This study indicated that wombats with mild mange infections may be cured while living in the wild, in spite of the potential for environmental re- exposure, and suggests that wombats do not necessarily spread mange to unaffected wombats when mildly infected. One hundred days following the initial infection of wild wombats with mites, 34 wombats that had shared burrows with the infected wombats were trapped and evaluated for signs of mange. These wombats lacked clinical signs of mange and returned negative skin scrapings. Inherent immunity to S. wombati infection in the wombat colony selected for this study is a possible explanation of these findings. Past exposure of the study group to S. wombati was unknown, although the authors remark that there may have been some acquired immunity in the population prior to this study. Unlike dogs and humans, it is unknown whether wombats are capable of developing resistance to reinfection with Sarcoptes and their antibody response to S. wombati has not been examined. 9 Method two: a single injection of a macrocyclic lactone Study three - A pharmacokinetics trial involving healthy SHNW s (Death et al., 2011) 10 1 x 200µg/kg subcutaneous moxidectin. Outcome: The average peak plasma moxidectin concentration (98.6ng/ml) was higher than that seen in livestock species and the average plasma elimination half- life (5.03 days) was shorter. Due to its short half- life, Death et al. hypothesised that a single subcutaneous injection of 200µg/kg macrocyclic lactone would not reliably clear a mange infection, due to re- infection from mites in the environment and eggs hatching on the animal. Discussion: The small scale of the study (N=4 wombats), coupled with the marked variation between the pharmacokinetic parameters measured between the wombats (for instance, half- lives varied from days) makes it difficult to draw conclusions about the pharmacokinetic parameters of moxidectin in wombats. Rather, the study demonstrates the great variation in the pharmacokinetics of moxidectin between SHNW s, highlighting the need for further research with a greater sample size. If these findings were replicated in a larger study, Death et al. indicated that the dosing protocol recommended by Bryant and Reiss ( mg/kg weekly of a macrocyclic lactone, until two weeks after negative skin scrapings are obtained) 11 would be the most likely regimen to maintain reasonably consistent plasma levels and reliably eliminate sarcoptic mange infections in circumstances where it is possible to repeatedly treat wombats. Study four A study involving free- living and captive wombats (Ruyskys et al., 2013) 2 1 x 200µg/kg subcutaneous ivermectin. Outcome: The treatment eliminated severe mange in captive SHNW s and mild but not severe mange in free- living wombats. Discussion: In spite of the hypothesis by Death et al. (above), a single 200µg/kg subcutaneous injection of ivermectin eliminated mild mange from free- living SHNW s and severe mange from captive wombats without immediate reinfection from the 2

3 environment. However, this outcome may be due to differences in the pharmacokinetics of ivermectin versus moxidectin in wombats. Elimination of S. wombati infection in free- living wombats was confirmed by negative skin scrapings and the absence of alopecia, parakeratosis and erythema 70 days post- treatment. These findings suggest that re- infection from the environment is not necessarily an immediate threat following treatment. Further studies that monitor a larger number of wombats for a recrudescence of clinical mange beyond 70 days post- treatment would be useful for drawing stronger conclusions, as this study was limited by a small sample size (N=5 animals). Method three: Topical moxidectin Treatment 5 - Mange Management Inc. in- field treatment regimen for bare- nosed wombats 12 (1) 12 x 500µg/kg topical moxidectin (Cydectin pour- on) every 7 days. (2) 4 x 500µg/kg topical moxidectin every 14 days, following (1). Method of delivery: Burrow flaps (an ice- cream lid with a milk lid inserted, placed over entrances to wombat burrows - see Figure 1.). Figure 1. Image of a burrow flap used to deliver mange treatments. 12 Volume delivered: Mange Management Inc. considers the average adult wombat affected by mange to be 25kg, equating to a dose of 2.5mL. However, a 4mL dose is placed in the burrow flap to account for spillage. Outcome: Unknown. No controlled clinical trials or pharmacokinetic studies into topical moxidectin have been published thus far. Discussion: Though this is a clever and innovative low cost approach to the problem of administering treatment to wombats without the need for capture, the evidence for its effectiveness is limited. The topical dosage rate (500µg/kg) has been directly extrapolated from the dose rate indicated by Cydectin pour- on for cattle and red deer 13, but there is currently no experimental evidence into its use in wombats. In 2015, mass- treatment trials were undertaken in Queensland (personal communication, Dr Julie Old), in Bents Basin in New South Wales (personal communication, Dr Tanya Leary) and in Narawnaptu National Park in Tasmania (personal communication, Dr Scott Carver) however, the results of these trials are yet to be published. Rather, wide- spread use of the treatment protocol is supported by anecdotal information obtained from wildlife carers, visual sightings and photos taken by camera traps outside of wombat burrows. Whilst burrow camera traps appear to demonstrate a decrease in the severity of infection with treatments, 14 photographs are unable to assess whether the treatments are completely eliminating mite infections or simply reducing mite burdens to sub- clinical levels. As such, wombats with a low level of infection could be re- developing clinical mange following the termination of treatments, as occurred in Skerratt s initial study. 7 Further analysis of the treatment protocol reveals that using a uniform volume (4mL) may be under- dosing for larger wombats, increasing the risk of resistance developing. 15 The current volume of drug delivered by the burrow- flaps is determined for wombats with an average weight of 25kg, however, the adult bare- nosed wombat can weigh anywhere between 22-50kg. 16 When using a pour- on, where the specific weight of the individual animal cannot be measured, animals should be dosed according to the weight of the heaviest animal in a group to reduce the speed of onset of resistance. 17,18 According to these principles, wombats should be dosed to a weight of 50kg, thus delivering 5mL of moxidectin per burrow- flap, plus an additional volume to accommodate for spillage and evaporation. While excessive dosing increases the risk of toxicity in compromised animals, 7,10 moxidectin has a high safety margin in many 3

4 species 19,20 and in the pharmacokinetics study by Death et al. there were no ill- effects documented in SHNW s following subcutaneous injection of moxidectin (200µg/kg). 10 For future use of topical moxidectin, investigating an effective dose rate for wombats may yield better results than using the suggested dose rates for cattle and red deer. Pharmacokinetic tests have demonstrated that the plasma elimination half- life of subcutaneously injected moxidectin in the SHNW (ranging from 2-9 days) is shorter and the average peak plasma concentration (98.6ng/ml) 7 is higher than values cited for cattle receiving the same treatment (14.5 days and 39.4ng/ml, respectively). 21 This may be due, in part, to the drug s lipophilic nature and the differences in body fat reserves between wombats and livestock. The levels of body fat encountered in livestock are likely to be higher than that of the wombat afflicted with mange and moxidectin will preferentially sequester in adipose tissue and be slowly released, influencing its persistence. 22 Treatment protocols extrapolated from livestock need to take these considerations into mind, and wombats with chronic mange and weight loss may require more frequent dosing. To further improve outcomes, the dermatological changes that occur in wombats with progressed mange should also be considered when determining a dosage rate for wombats. The skin over the rump of the wombat is thicker than the skin of the cow (10mm 23 vs. 6.2mm 24, respectively) and is thickened further by crusts when infected with sarcoptic mange. 7 The combination of thicker skin and lack of access to healthy dermis may decrease the extent of transdermal absorption of topical moxidectin, 25,26 thus decreasing the drug s bioavailability and efficacy in wombats with crusted mange. SUGGESTIONS FOR FURTHER RESEARCH 1. Undertake clinical and field trials to investigate the efficacy of the 12 dose topical moxidectin treatment protocol. Justification: To ensure wombats are not being delivered sub- therapeutic levels of moxidectin, thus selecting for resistance and introducing chemical residues to the environment. Also, to allow the creation of a dosage treatment baseline for further research into other topical moxidectin treatment protocols, with the view of decreasing the total number of treatments required to control infection. 2. Undertake long- term studies to determine whether wombats treated to the point of sub- clinical infection re- develop clinical signs of mange following the termination of treatments and determine under what circumstances wombats with complete elimination of infection become re- infected from their environment. Justification: To determine the value of treating free- living wombats with mange, and as such, to determine whether the focus of research should shift towards preventative mechanisms, such as developing a vaccine or identifying and propagating genetics that confer wombats greater resistance to S. wombati infections. 3. Determine the pharmacokinetic parameters and plasma drug deposition profile of topical moxidectin in wombats. Justification: To determine the minimum dose necessary for parasiticidal activity in wombats and the protocol required to maintain plasma concentrations at this level for an adequate duration. CONCLUSION Subcutaneous macrocyclic lactone injections have demonstrated efficacy at eliminating mild- severe sarcoptic mange infections in captive wombats 2,7 and mild mange in free- ranging wombats. 8 However, there is currently no proven effective treatment that eliminates moderate- severe mange in free- ranging wombats that avoids recapture. There is a clear indication to perform rigorously designed long- term clinical trials and further pharmacological studies into the pharmacodynamics of moxidectin in wombats. These trials should use objective outcomes to examine the effectiveness of topical moxidectin at eliminating sarcoptic mange from wombats and preventing its recurrence. References 1. Skerratt LF, Martin RW, Handasyde KA. Sarcoptic mange in wombats. Aus Vet J. 1998;77: Ruykys L, Breed B, Schultz D et al. Effects and treatment of sarcoptic mange in southern 4

5 hairy- nosed wombats (Lasiorhinus Latifrons). J Wildl Dis. 2013;49: Hartley M, English A. Sarcoptes scabiei var. wombati infection in the common wombat (Vombatus ursinus). Eur J Wildl Res. 2005;51: Martin RW, Handasyde KL, Skerratt LF. Current Distribution of sarcoptic mange in wombats. Aus Vet J. 1998;77: Skerratt LF, Martin RW, Handasyde KA. Sarcoptic mange in wombats. Aus Vet J. 1998;77: Triggs B. The Wombat; Common Wombats in Australia. New South Wales University Press, Kensington, Skerratt LF. Clinical response of captive common wombats (Vombatus ursinus) infected with sarcoptes scabiei var. wombati. J Wildl Dis. 2003;39: Skerratt LF, Skerratt HL, Martin R et al. The effects of sarcoptic mange on the behaviour of wild common wombats (Vombatus ursinus). Aust J Zool. 2004;52: Emery D. Host- parasite relationships, pathophysiologic & immunity. In: Beveridge I, Emery D. Australasian Animal Parasites: Inside and Out. The Australian Society for Parasitology Inc, 2015: Death CE, Taggart DA, Williams DB et al. Pharmacokinetics of moxidectin in the southern hairy- nosed wombat (Lasiorhinus Latifrons). J Wildl Diseases. 2011;47: Vogelnest L, Woods R. Medicine of Australian Mammals. CSIRO Publishing, Collingwood, Treatment Methods. methods/. Retrieved 12 May Cydectin pour- on for cattle and red deer: Quick reference guide. producers/beef/products/drenches- broad- spectrum/cydectin- pour- on.html. Retrieved 10 May Success stories. stories/. Retrieved 10 June FDA s public meeting on antiparasitic drug use and resistance in ruminants and equines an overview. ary/resourcesforyou/ucm pdf - pg 16. Retrieved 27 July Jackson S. Australian Mammals: Biology and Captive Management. CSIRO publishing, Collingwood, Levot G. Off- shears backline treatment. Off_shears_backline_treatments.pdf. Retrieved 28 July Love S. Wormkill the basics. data/assets/pdf _file/0007/365956/wormkill- the- basics.pdf. Retrieved 28 July Virbac (Australia) Pty Limited. Cydectin Pour- On for Cattle and Red Deer. public/files/pdf/sds/livestock/cydectinpouron- SDS.pdf May Food and Drug Administration. ProHeart 6 (moxidectin). Fort Dodge Animal Health. mittees/committeesmeetingmaterials/veterina rymedicineadvisorycommittee/ucm pd f. January Retrieved April Lanusse C, Lifschitz A, Virkel G et al. Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle. J Vet Pharmacol Ther. 1997;20: Craven J, Bjorn H, Hennessy DR et al. The effects of body composition on the pharmacokinetics of subcutaneously injected ivermectin and moxidectin in pigs. J Vet Pharmacol Ther. 2002;25: Woodford R. The secret life of wombats. Text Publishing, Melbourne, Dowling DF. The thickness of cattle skin. Aust J Agric Res. 1955;5: Grasso P, Lansdown ABG. Methods of measuring, and factors affecting, percutaneous absorption. J Soc Cosmet Chem. 1972;23: Nair A, Jacob, Al- Dhubiab B et al. Basic considerations in the dermatokinetics of topical formulations. Braz J Pharm Sci. 2013;49: