Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio <sup>&reg;</sup> Plus) for the prevention of heartworm disease ( <i>Dirofilaria immitis</i>) in client-owned dogs in the USA

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Abstract

Background

Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio ^® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months.

Methods

In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75–1.53 mg/kg milbemycin oxime and 20–41.5 mg/kg lotilaner ( n = 159) or the CP (Sentinel ^® Flavor Tabs ^®; milbemycin oxime/lufenuron) at the label-recommended dose rate ( n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott’s) testing to assess the establishment of any patent adult heartworm infections.

Results

All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs.

Conclusions

This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis.

Graphic Abstract

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Most cited references 24

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Heartworm biology, treatment, and control.

Dwight D Bowman, Clarke E Atkins (2009)

This article is a review of the systematics, taxonomy, biology, prevention, control, and treatment of the canine heartworm, Dirofilaria immitus. This filarioid parasite remains one of the most important and dangerous diseases of the dog throughout the United States. The geographic range of the parasite is expanding, and in many parts of the country it has emerged as a threat to canine welfare only in the last 50 or so years. The article also discusses the pathophysiological mechanisms behind the disease induced, the means for diagnosing the disease, and the means of assessing the success of therapy. The treatment of potential complications of heartworm infection, such as post-adulticide thromboembolism, eosinophilic granulomatous pneumonitis, and caval syndrome, is also discussed.

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Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance.

Catherine Bourguinat, Alice C Y Lee, Regina Lizundia … (2015)

Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom(®) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms.

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Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs

Cassan N Pulaski, John B. Malone, Catherine Bourguinat … (2014)

Background Strains of Dirofilaria immitis suspected of lack of efficacy (LOE) to macrocyclic lactone (ML) preventive drugs have been increasingly reported in dogs by practicing veterinarians since 2005 in the Lower Mississippi Delta region. If proven, and not controlled in the early stages, the emergence of ML drug resistance threatens to become a widespread problem in the US that may limit the effectiveness of current preventive drug treatment methods. Methods To validate practice reports, a statewide survey of Louisiana veterinarians was done to define the extent of the problem and identify focal ‘hotspots’ of reported ML LOEs using Geographic Information Systems (GIS) methods. The present study then utilized microfilariae (Mf) from two canine field cases from different state locations that fit criteria for a high index of suspicion of LOE against heartworms by ML drugs. Blood containing Mf from the canine field cases was used to infect and produce L3 in Aedes aegypti for experimental infection of two groups of dogs, each of which contained two laboratory dogs, one treated with prophylactic ivermectin (12 μg/kg) monthly for 6 months at twice the label dose (6 μg/kg), and one untreated control. Results Both treated and untreated dogs from Group I and Group II developed patent D. immitis infections by 218 DPI and 189 DPI, respectively, as evidenced by a positive occult heartworm antigen test and microfilaremia by the Knott’s test. Mf counts gradually increased post-patency in test and control dogs. Infective larvae raised from microfilariae from the treated Group I dog were used to successfully establish a second generation isolate, confirming heritability of resistance in the face of a monthly ivermectin challenge dose of 24 μg/kg, given monthly for 3 months. Conclusions These experimental infection studies provide in vivo evidence of the existence of ML drug resistance in dogs infected by D. immitis L3 from suspect field LOE cases in the Lower Mississippi Delta. Results encourage further work on mechanisms underlying the emergence of ML resistance in D. immitis and development of evidence-based resistance management strategies for heartworm preventives in order to extend the useful life of current drugs.

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Author and article information

Contributors

Daniel E. Snyder:

ORCID: http://orcid.org/0000-0002-4091-6297

Daniel.Snyder@network.elancoah.com

Journal

Journal ID (nlm-ta): Parasit Vectors

Journal ID (iso-abbrev): Parasit Vectors

Title: Parasites & Vectors

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-3305

Publication date (Electronic): 28 May 2021

Publication date PMC-release: 28 May 2021

Publication date Collection: 2021

Volume: 14

Electronic Location Identifier: 284

Affiliations

[1 ]GRID grid.414719.e, ISNI 0000 0004 0638 9782, Elanco Animal Health Research and Development, ; 2500 Innovation Way, Greenfield, IN 46140 USA

[2 ]Elanco Animal Health, Form 2, Bartley Way, Bartley Wood Business Park, Hook, RG27 9XA Hants UK

[3 ]Daniel E. Snyder, DVM PhD. Consulting, LLC, Indianapolis, IN 46229 USA

Author information

Daniel E. Snyder http://orcid.org/0000-0002-4091-6297

Article

Publisher ID: 4767

DOI: 10.1186/s13071-021-04767-6

PMC ID: 8161898

PubMed ID: 34044864

SO-VID: d55bb6f2-1511-4835-a439-67adc490b535

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 February 2021

Date accepted : 3 May 2021

Custom metadata

ScienceOpen disciplines: Parasitology

Keywords: dirofilaria immitis,heartworm,prevention,macrocyclic lactone,milbemycin oxime,lotilaner,field study,dog

Data availability:

ScienceOpen disciplines: Parasitology

Keywords: dirofilaria immitis, heartworm, prevention, macrocyclic lactone, milbemycin oxime, lotilaner, field study, dog