Journal of the American Association for Laboratory Animal Science Vol 47, No 3 Copyright 2008 May 2008 by the American Association for Laboratory Animal Science Pages 20–24

Use of and in the Treatment of Mouse Fur Mites

Deborah M Mook,1,2,* and Kimberly A Benjamin3

A breeding colony consisting of 250 different strains of mice was treated with the topical acaricide selamectin for the mouse fur mite Myocoptes musculinus, with no apparent ill effect, suggesting that this drug is safe for use in mice. To further evaluate their efficacy in treating Myocoptes spp., we compared selamectin with another acaricide, moxidectin, in a controlled manner. Infested mice were treated with selamectin or moxidectin at the time of cage change, and a subset of mice was retreated 10 d later. Mice underwent routine cellophane tape examination of the pelage for 1 y. Although no adult mites were found in any group at 1 mo after treatment, egg casings were found in the selamectin treatment group as late as 6 mo after treatment, prompting concern about its effectiveness. Moxidectin used in combination with cage changing was effective in eradicating mites, with mice negative for traces of mites on cellophane tape examination of the pelage from months 2 through 12 after treatment.

Fur mites are a common pathogen of laboratory mice. In 1 of the moxidectin is unclear. Because the mice were housed in study, more than 33% of research institutions were reported to microisolation caging and were not exposed to any other mice, have had fur mites in at least 1 of their colonies.16 Myocoptes a new infestation was unlikely. Treatment failure might indi- musculinus is the most common fur mite of mice, although cate failure of the drug itself or its administration schedule to coinfestations with Myobia musculi are possible. M. musculinus adequately eradicate mites; treatment failure might also result is a surface-dwelling mite, feeding on epidermal tissue. Its from human error leading to inadequate treatment. Moxidectin lifecycle ranges from 8 to 14 d, with eggs hatching in 5 d, and has been shown to be effective in treating mites in other species neonates becoming infested within 4 to 5 d of birth. Transmis- but may require more than a single dose.6 sion is by close contact, and transmission via eggs or nymphs in Another new drug, selamectin, is an like iver- bedding is the foundation of many sentinel programs. The mite mectin, but has been modified to improve safety.1 Selamectin M. musculi has a 23-d lifecycle, with eggs hatching in 7 to 8 d. is effective in the treatment of companion animals with both Adults appear by day 15 and lay eggs within 24 h. These mites surface-feeding (Otodectes cynotis, yasurgi) and bur- also dwell on the skin surface and are transmitted in the same rowing (Sarcoptes scabei) mites.6,8,29 Some studies in companion way as M. musculinus. The potential adverse effects of fur mites animals have achieved complete resolution of mites after a include dermatitis, allergic-type responses, abnormal behavior single topical application,2 and others report the use of an and immune dysfunction.17,18,25 additional application 1 mo later.4,21 Controlled studies with Until recently, was the drug of choice for treating selamectin administered to laboratory , , and rabbits fur mites in mice.5 However, this drug is labor-intensive to use resulted in ectoparasite eradication with the use of a single because several treatments are required. Furthermore, ivermec- dose.1,21 The use of selamectin has been described in CD1 mice, tin can cause neurotoxicity and confound behavioral research in which have been used as an animal model to determine the ef- some strains of mice, so it must be used with caution.5,7 Recently ficacy of flea-control compounds.27 Safety testing, also in CD1 the availability of medications for both companion mice, showed no clinical signs at 3 times the recommended dose and production animals has dramatically increased. These drugs PGNHLH POMZNJMEBOEUSBOTJFOUDMJOJDBMTJHOTBUUJNFT may be underused by research institutions attempting to control the recommended dose, and mild clinical signs at 30 times the parasite outbreaks. In 2004 our group used 1 relatively new recommended dose.1 Like ivermectin, selamectin can be toxic in drug, moxidectin, to treat fur mites discovered in 1 room of our P-glycoprotein knockout mice, which are about 100 times more facilities.26 Moxidectin belongs to the drug class, sensitive to the potential toxicity of than are wild- similar to avermectins, but is longer-acting in the prevention type mice.1,20 The degree of residual action of selamectin in mice of heartworm in dogs19 and is ovicidal in the treatment of ticks is unknown, but residual action occurs in other species.9,10,28 In in cattle.13 In our facility, a single dose of moxidectin appeared cats, for example, selamectin is effective against reinfestation of to eradicate the fur mites in 2 strains of knockout mice, with fleas for as long as 14 d after treatment and is partially effective negative pelage tape tests at 2, 4, and 8 wk.26 Unfortunately, for 30 d after treatment.9 Both avermectins and act in other mice treated with this regimen, fur mites were redis- by potentiating the effect of H-aminobutyric acid and interfering covered approximately 1 y later. Whether the reappearance of with glutamate-gated ion channels of parasites.11,20 fur mites constituted a new infestation or a treatment failure At our institution, 3 sentinel mice exposed to soiled bedding in the breeding colony showed Myocoptes musculinus fur mites on pelage tape examination; 1 sentinel had monitored mice Received: 30 Aug 2007. Revision requested: 25 Sep 2007. Accepted: 30 Nov 2007. previously infested with fur mites and treated with moxidectin. 1Division of Animal Resources, 2Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; 3Georgia Institute of Technology, Atlanta, GA Pelage tape tests of the mice previously treated with moxidectin *Corresponding author. Email: [email protected] showed that they were again infested with fur mites. In addition,

20 Acaricidal selamectin and moxidectin

another infested mouse strain had passed through the inhouse and managed by entirely different personnel, eliminating the quarantine program without detection of mite infestation. Al- possibility of reinfestation from the breeding colony though the mice underwent multiple pelage tape examinations, Mice. The breeding colony at our facility consisted of 4 no mites were detected during the 6-wk quarantine period. In rooms, containing 15 ventilated racks, 4 static racks, and more an effort to eradicate fur mites from our breeding colony, all than 250 different strains of mice. Mouse strains included both mice within the colony (approximately 8400 mice) were treated. transgenics and knockouts but not P-glycoprotein knockout Selamectin was chosen because it had been shown to be safe mice. The total number of mice treated was estimated at 8400. in mice,1,20 was ovicidal,22 and has been effective as a single Mice originated from approved commercial vendors and other treatment1,21 and because we had lost confidence in moxidec- biomedical research institutions. Some mice in the colony had tin. In addition, to further evaluate the therapeutic efficacy of undergone quarantine at our facility, and more recent arrivals selamectin and moxidectin, we compared these 2 drugs in the had undergone quarantine at the contract institution. Outbred treatment of infested CF1 mice. mice of the CF1 strain were used as sentinels; outbred female CF1 mice were used for the therapeutic evaluation of moxidectin Materials and Methods and selamectin. Humane care and use of animals. Animals were housed in an The pathogen status of mice in our colonies was monitored AAALAC-accredited facility and in compliance with the Guide by means of a sentinel program. Two dedicated sentinel mice on for the Care and Use of Laboratory Animals.23 All procedures in- each side of a ventilated rack were exposed to soiled bedding volving animal use were approved by the Institutional Animal by being placed directly into a soiled cage that had just been Care and Use Committee at Emory University. vacated by its occupant(s). Sentinels were placed into new soiled Housing and husbandry. Until June 2005, incoming mice cages in a rotating fashion 3 d per week. Quarterly, sentinels that had not been purchased from approved vendors were were evaluated for ecto- and endoparasites by using cellophane quarantined at our facility. On arrival, mice were placed in tape tests of the pelage, fecal floatation, and anal tape methods. polycarbonate shoebox cages with isolator tops and corncob Mice were anesthetized with isoflurane, and blood was collected bedding. The room was kept on a 12:12-h light:dark cycle, and from the retroorbital sinus or facial vein. Serum was diluted 1:4 mice were fed -containing rodent chow (150 ppm, with normal saline, frozen, and sent to a commercial rodent Rodent Diet 5T40, Purina Mills Test Diet, Richmond, VA) and diagnostic laboratory (Charles River Laboratories) for serologic autoclaved tap water ad libitum. Each cage was assessed 6 times evaluation for Sendai virus, pneumonia virus of mice, mouse in 8 wk for ecto- and endoparasites by using cellophane tape hepatitis virus, mouse minute virus, Theiler’s murine encepha- tests of the pelage, fecal floats, and anal tape methods. At the lomyelitis virus, reovirus 3, Ectromelia, Mycoplasma pulmonis, 6th week after arrival, mice were anesthetized with isoflurane, rotavirus, mouse adenovirus, lymphocytic choriomeningitis and blood was collected from the retroorbital sinus. Serum was virus, K virus, polyoma virus, and mouse parvovirus. Ectromelia diluted 1:4 with normal saline, frozen, and sent to a commer- serology was performed every 6 mo. The panel was expanded cial rodent diagnostic laboratory (Charles River Laboratories, once yearly to include lymphocytic choriomeningitis virus, Wilmington, MA) for serologic evaluation for Sendai virus, K virus, polyoma virus, and mouse adenovirus. Starting in pneumonia virus of mice, mouse hepatitis virus, mouse minute September 2007, sentinel mice were euthanized quarterly and virus, Theiler’s murine encephalomyelitis virus, reovirus 3, replaced with new sentinels. Ectromelia, Mycoplasma pulmonis, rotavirus, mouse adenovirus, Breeding colony treatment and testing. Consistent with rec- lymphocytic choriomeningitis virus, K virus, polyoma virus, ommended practice, breeding colony mice were treated only and mouse parvovirus. Mice seronegative for the listed patho- after a representative sample of mutant mice had been treated 32 gens and negative on parasitology panels were released into to evaluate selamectin for safety (data not shown). Mice were the mouse maintenance and breeding colonies. USFBUFEUPQJDBMMZXJUINHLHTFMBNFDUJO 3FWPMVUJPO 1à[FS Beginning in June 2005, 2 changes were made to these quar- Animal Health, Exton, PA) at the time of cage changing. Adults antine practices. First, the quarantine program was contracted were treated with 5 μl selamectin between the scapulae by us- to an outside source, which placed each shipment of mice in ing an automatic pipettor (Pipetman, Gilson, Middleton, WI), its own isolation cage and followed the procedures described and unweaned pups were treated with 3 μl. Hairless neonates earlier. In addition, all incoming mice were treated once topi- were not treated, but the dams and sires with which they were DBMMZCFUXFFOUIFTIPVMEFSCMBEFTXJUINPYJEFDUJO NH caged were. Mice were placed into clean cages immediately after kg; Cydectin pour-on containing 0.5% moxidectin as active treatment and were observed daily for signs of illness or injury, ingredient in coconut oil, Fort Dodge Animal Health, Fort including neurologic complications. Efficacy of treatment was Dodge, IA). evaluated by using the routine sentinel surveillance program. After successful completion of quarantine at the contract loca- Acaricide treatment and evaluation. Thirty 6- to 7-wk-old tion, mice were transferred back to our facility. Those comprising female CF1 mice were exposed by means of direct contact to the inhouse breeding colony, mice were housed in polycarbonate sentinel mice infested with Myocoptes mites and tested weekly shoebox cages with isolator tops and corncob bedding. The room by using cellophane tapes of the pelage weekly until the female was kept on a 14:10-h light:dark cycle, and mice were fed rodent CF1 mice were confirmed to be infested with mites. Because chow (Rodent Diet 5021, Purina Mills Test Diet, Richmond, VA) Myocoptes mites have a predilection for colonizing the ventral 15 and autoclaved tap water ad libitum. Mice on the acaricide abdominal and inguinal areas, tape tests were collected from study were kept inhouse in similar cages in a cubicle suite on a the axillary and inguinal areas as well as the more traditional 32 different floor from the breeding colony. The study room was area of the dorsal fur between the shoulders and neck. Infested kept on a 12:12-h light:dark cycle, and mice were fed rodent mice were allocated randomly into 5 groups of 6 mice each: chow (Rodent Diet 5001, Purina Mills Test Diet) and autoclaved 2 groups each receiving 1 dose of selamectin or moxidectin tap water ad libitum. The study mice were treated in sequence (groups Moxidectin 1 and Selamectin 1), 2 groups each receiving after the breeding colony was treated, and rooms were entered 2 doses of moxidectin or selamectin 10 d apart (groups Moxid- ectin 2 and Selamectin 2), and 1 group receiving no treatment.

21 Vol 47, No 3 Journal of the American Association for Laboratory Animal Science May 2008

Drugs were applied to the dorsum of the mice, between the all groups. Tape tests of the untreated control group continued scapulae, by using an automatic pipettor in a volume of 5 μl to reveal adults, eggs, and casings through the 6th month, at GPSTFMBNFDUJO NHLH BOE•MGPSNPYJEFDUJO$BHFTXFSF which point the mice were euthanized. Necropsy with skin changed at the time of treatment. Because the pharmacokinetics histopathology at 12 mo did not reveal any evidence of mites of moxidectin and selamectin in mice are unknown, the 10-d in any treatment group. timeframe was chosen so as to interrupt the lifecycle of mites should the first treatment not prove to be ovicidal. Pelage tape Discussion tests were done on days 0, 2, 4, 7, 14, and, to determine long- Treatment of ectoparasites can be a costly and labor-intensive term efficacy, on months 1, 2, 3, 6, 9, and 12. The presence of undertaking. The topic is of obvious interest to laboratory ani- adult mites (live or dead), eggs, or empty egg casings were mal clinicians, and a recent review of the literature using the recorded. No distinction was made between live or dead adult keywords mouse, acariasis, and treatment revealed 48 citations mites, because finding even an adult carcass is considered a discussing various permutations of ectoparasite infestations positive result in our facility. Mice were observed daily for in mice. Studies used various medications, combinations of signs of illness or injury, including neurologic complications. medications and husbandry practices in attempt to eradicate The group receiving no treatment showed signs of alopecia ectoparasites, including Myocoptes spp., Myobia spp., Radfordia and mild pruritis by 6 mo, was euthanized, and therefore no spp., and Orthnythonyssus bacoti. One of the more recent articles tape tests were done for this group in months 9 and 12. In ad- advocated a particularly cumbersome multimodal drug ap- dition, 2 mice in the Moxidectin 1 group developed unrelated proach, using selamectin and nestlets, changed weekly, soaked illness that necessitated euthanasia at 6 mo, so these additional in amitraz and ,3 presumably an expensive method of fur 2 animals also did not receive tape tests at 9 and 12 mo. Thus mite treatment. Another recent article eradicated fur mites by us- a total of 312 pelage tape tests were evaluated over the course ing cross-fostering in combination with ivermectin.14 Although of 1 y. Subsequent to the 12-mo pelage tape test, mice were this strategy was effective, cross-fostering is labor-intensive and euthanized and submitted for pathologic examination. They therefore costly. The goal of the work done here was to evaluate underwent gross necropsy, with histopathology of the skin and the efficacy of 2 relatively simple, and therefore presumably of any gross abnormalities. relatively cost-effective, treatment schemes in combination Cost analysis. Costs were determined by calculating the cost with the routine cage change and to test whether administering of drug used per mouse. This figure was added to the cost of each drug twice instead of once improved efficacy. In addition, an average of 1 automatic pipettor tip per cage, the use of the the comparison of the 2 drugs and timing of treatment at cage automatic pipettor itself (assuming 25,000 uses over its lifetime), changing was driven by a treatment failure in a prior use of a and labor at an average of 1 mouse per minute, which includes single treatment with moxidectin without a cage change. setup and cleanup. In our experience, treating 1 group of rooms (the breeding colony, with a census of approximately 8400 mice) with a single Results dose of selamectin for fur mites cost approximately US$5000, Breeding colony treatment. Veterinary staff and animal care the majority of which was associated with labor (approximately staff worked together during cage changeout to accomplish the 100 man-hours). Our calculations show the drug cost of sela- single selamectin treatment of the breeding colony. Organiza- mectin to be US$0.0459 per mouse (US$385.56 for 8400 mice) tion and administration of the treatment took 1 mo, with an and moxidectin to be US$0.0007 per mouse (US$5.88 for 8400 estimated total of 100 man-hours of labor. No clinical signs or mice). The difference in drug cost initially may seem large, but fatalities were attributed to the treatment in any of the more it pales in comparison with the overall $5000 price tag, which than 250 strains treated. The total cost for the treatment was reflects the intensive labor involved in topically treating each estimated at US$5000, including drug and labor. At the time individual mouse. Although this expense and amount of labor of this publication (2 y after treatment), the standard sentinel may appear burdensome, it is likely to be considerably less program has tested 443 sentinels, all of which have been nega- costly than other recently reported effective methods, including tive for evidence of mites on cellophane tape examination of the cross-fostering and multimodal drug approaches described the pelage, showing that the breeding colony remains free of above. fur mites. Over the long term and on the surface, both drugs appeared to Therapeutic evaluation of moxidectin and selamectin. be effective in eradicating mites, with no adults found in either Transmission of infestation from sentinel to study mice took treatment group after 1 mo. Treating twice with selamectin may approximately 2 mo of contact exposure. Pelage tape test results have been of some benefit at 1 mo, potentially resulting in more are presented in Table 1. Adult mites, eggs, or egg casings were rapid depletion of the mite population, but later months showed found on the pelage of all mice in all treatment groups through no difference between treating once and twice. Although no day 14 after acaricide treatment. By 1 mo, adults were no longer adult mites were found after the first month, the egg casings found in either selamectin group, although eggs or casings found at 2 and 6 mo in the selamectin group are a source of were found in both the Selamectin 1 group (6 of 6 mice) and concern, because the hairs to which the casings adhered could Selamectin 2 group (2 of 6 mice). In the moxidectin treatment have been shed by that time or the casings could have been groups at 1 mo, adult mites were found on 2 mice, 1 that had removed by grooming. Although much is known about mouse been treated once and 1 that had been treated twice. Eggs and hair cyclicity, the duration of telogen in the adult mouse var- egg casings also were found in both the Moxidectin 1 group (4 ies by strain,31 and when the hair shaft would have been shed of 6 mice) and Moxidectin 2 group (3 of 6 mice). From months is unknown, although in CD1 mice, an outbred strain similar 2 through 12, adult mites and eggs were no longer found in to CF1, the majority of hair is shed by 8 wk.24 Likewise, while any treatment group. Egg casings were found in 3 mice, all of grooming is an intensive part of the normal behavioral repertoire which had been treated with selamectin: at 2 mo in a mouse of mice, it cannot be said how long it would take for a mouse to treated twice, and at 6 mo in 2 mice treated once. Pelage tapes groom one particular hair. Therefore whether the remaining egg on months 9 and 12 were negative for all evidence of mites in casings were evidence of continuing, albeit attenuated, infesta-

22 Acaricidal selamectin and moxidectin

Table 1. Positive signs of mites in mice treated with moxidectin and selamectin Day 2 Day 4 Day 7 Day 14 Day 28 Month 2 Month 3 Month 6 Month 12 Treatment A E C A E C A E C A E C A E C A E C A E C A E C A E C None 2 6 1 1 6 4 3 4 4 4 5 5 4 5 6 4 4 0 6 2 1 4 6 5 – – – Moxidectin 1 1 6 6 2 6 6 1 6 4 1 5 4 1 1 4 0 0 0 0 0 0 0 0 0 0 0 0 Moxidectin 2 5 5 2 1 6 5 4 1 1 5 2 1 1 3 3 0 0 0 0 0 0 0 0 0 0 0 0 Selamectin 1 3 6 3 2 4 6 0 2 6 3 3 4 0 3 4 0 0 1 0 0 0 0 0 0 0 0 0 Selamectin 2 1 5 3 0 6 4 2 3 6 1 6 6 0 1 1 0 0 0 0 0 0 0 0 2 0 0 0 A, adults; E, eggs; C, egg casings At the 9-mo point, all animals were negative for adults, eggs, and egg casings. tion or a remnant of the original one which was now resolved The previous single treatment was not associated with a cage is unclear. Our suspicion is that an attenuated infestation may change, and perhaps, if there was little residual action from the have still been present. moxidectin, mice could have been reinfested from eggs or larvae Along with limitations in knowledge about hair cycles and remaining in the bedding. Moxidectin is highly lipid-soluble grooming are the inherent limitations of the pelage tape test. (100 times more so than ivermectin), and when administered This test appears to be robust when an infestation is accompa- orally or by injection, redistributes to fat, where it acts as a nied by a heavy burden, as we found in untreated mice and as reservoir to be released into the blood for redistribution to the has been shown previously.33 However, there is a risk of false site of parasite burden.20 Similar residual activity after topical negatives in situations where the mite burden is low, either treatment in mice remains to be determined and is an important because the mice are early in the stage of infestation or because piece missing from the fur mite treatment puzzle. mature mice have stable and controlled burdens.14 In the case of The possibility also remains, as it always does, that human Myocoptes mites, the sensitivity of the test likely was increased error was the source of the previous treatment failure and that a by sampling the axillary and inguinal areas as well as behind cage of mice was either not treated or was treated insufficiently. the neck,15 but false negatives are still possible, particularly in The initial moxidectin treatments were done by using a Hamil- cases of light mite burdens. Mathematical calculations suggest ton syringe, which, although highly accurate, is tedious to use. that the evaluation of 312 samples would be sufficient to detect A single person treating hundreds of mice this way might well at least 1 positive sample with a 95% level of confidence if 1% miss a mouse. In addition, because mice were not placed into of the samples were positive for parasites.30 However, these a fresh cage, a mouse might have been assumed to have been calculations do not consider assay sensitivity, and previous treated when it was not. Use of the automatic pipettor made work has estimated that the sensitivity of the pelage tape test the process less tedious and more rapid, and the addition of the for detecting Myocoptes is approximately 84%;14 therefore it cage change to the regimen allowed treated mice to be placed in remains an assay with some limitations. Because direct com- a fresh cage, ameliorating the chance of personnel losing track parisons were not done, whether the sensitivity of the test was of which mice had been treated. Moxidectin in combination increased by sampling from the axillary and inguinal regions with a cage change proved effective, and we currently use it in addition to the more traditional site of between the shoulder as part of our routine program for mice entering the breeder blades is difficult to say. colony and in quarantine. In light of the possible limited sensitivity of the pelage tape test, the findings of egg casings several months after treatment Acknowledgments with selamectin make selamectin a drug of dubious value for The authors with to thank Ellen Adams, Hansen Acheampong, Casey the treatment of fur mites in mice. This conclusion apparently Brinsfield, Minida Dowdy, Kirk Hubbard, Karen Lieber, Kasie Moore, contradicts another recent study indicating success in clearing Kendall Smith, Samantha Smith, Dr Karen Strait, and Gideon Usifoh mite infestation with selamectin.12 However, the cited study for their technical assistance with mite treatments; Lynne Morelock-Roy evaluated mice only twice after they were treated, tested only for her assistance with financial calculations; and the helpful comments until 3 wk after treatment, and did not consider eggs or egg cas- of Drs Doug Taylor and Mike Huerkamp. ings in their assessment. The length of time of our study (1 y after treatment), evaluation of multiple tests, and consideration of any References evidence of mite presence adds to the robustness of our findings. 1. Bishop BF, Bruce CI, Evans NA, Goudie AC, Gration KA, Gibson Even though subsequent sentinel results indicate that the breed- SP, Pacey MS, Perry DA, Walshe ND, Witty MJ. 2000. Selamectin: ing colony has remained free of mites, the finding of the egg a novel broad-spectrum endectocide for dogs and cats. Vet Parasitol 91:163–176. casings several months after treatment in the selamectin group 2. Blot C, Kodjo A, Reynaud MC, Bourdoiseau G. 2003. Efficacy has led us to rule out selamectin as a treatment, and we have of selamectin administered topically in the treatment of feline discontinued its use. Moxidectin, a less-expensive alternative, otoacariosis. Vet Parasitol 112:241–247. fared better therapeutically in our study, with nothing found on 3. Bornstein DA, Scola J, Rath A, Warren HB. 2006. Multimodal the pelage of mice from months 2 to 12. With that said, however, approach to treatment for control of fur mites. J Am Assoc Lab this study was inspired initially by perceptions of previous Anim Sci 45:29–32. treatment failure involving moxidectin. A notable difference 4. Chailleux N, Paradis M. 2002. Efficacy of selamectin in the between this study and our previous experience was the cage treatment of naturally acquired cheyletiellosis in cats. Can Vet J 43:767–770. change at the time of treatment. This intervention would have 5. Conole J, Wilkinson MJ, McKellar QA. 2003. Some observations removed any eggs or nymphs from the environment, markedly on the pharmacological properties of ivermectin during treat- ameliorating the chance for reinfestation from the environment ment of a mite infestation in mice. Contemp Top Lab Anim Sci should moxidectin prove to have minimal residual activity. 42:42–45.

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