Preserving new anthelmintics: a simple method for estimating faecal egg count reduction test (FECRT) confidence limits when efficacy and/or nematode aggregation is high

Dobson, R. J., Hosking, B. C., Jacobson, C. L., Cotter, J. L., Besier, R. B., Stein, P. A. and Reid, S. A. (2012) Preserving new anthelmintics: a simple method for estimating faecal egg count reduction test (FECRT) confidence limits when efficacy and/or nematode aggregation is high. Veterinary Parasitology, 186 1-2: 79-92. doi:10.1016/j.vetpar.2011.11.049


Author Dobson, R. J.
Hosking, B. C.
Jacobson, C. L.
Cotter, J. L.
Besier, R. B.
Stein, P. A.
Reid, S. A.
Title Preserving new anthelmintics: a simple method for estimating faecal egg count reduction test (FECRT) confidence limits when efficacy and/or nematode aggregation is high
Journal name Veterinary Parasitology   Check publisher's open access policy
ISSN 0304-4017
1873-2550
Publication date 2012-05-01
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.vetpar.2011.11.049
Open Access Status Not yet assessed
Volume 186
Issue 1-2
Start page 79
End page 92
Total pages 14
Place of publication Amsterdam, The Netherlands
Publisher Elsevier
Language eng
Subject 2405 Parasitology
3400 Veterinary
Abstract As it has been 30 years since a new anthelmintic class was released, it is appropriate to review management practices aimed at slowing the development of anthelmintic resistance to all drug classes. Recommendations to delay anthelmintic resistance, provide refugia and the use of a simulation model were reviewed to find optimum treatment strategies that maintain nematode control. Simulated Australian conditions indicated that a common successful low-risk treatment program was a rapid rotation between a " triple-combination" product (benzimidazole. +. levamisole. +. abamectin) and a new high-efficacy drug (monepantel). Where . Haemonchus contortus was a threat, moxidectin was required at critical times because of its persistent activity against this parasite. Leaving up to 4% of adult sheep untreated provided sufficient " refugia" for non-selected worms to reduce the risk of selecting for anthelmintic resistance without compromising nematode control.For a new anthelmintic, efficacy estimated by faecal egg count reduction (FECR) is likely to be at or close to 100%, however using current methods the 95% confidence limits (CL) for 100% are incorrectly determined as 100%. The fewer eggs counted pre-treatment, the more likely an estimate of 100% will occur, particularly if the true efficacy is >90%. A novel way to determine the lower-CL (LCL) for 100% efficacy is to reframe FECR as a binomial proportion, i.e. define: . n and . x as the total number of eggs counted (rather than eggs per gram of faeces) for all pre-treatment and post-treatment animals, respectively; . p the proportion of resistant eggs is . p=. x/. n and percent efficacy is 100. ×. (1. -. p) (assuming equal treatment group sizes and detection levels, pre- and post-treatment). The LCL is approximated from the cumulative inverse beta distribution by: 95%LCL. =. 100. ×. (1. -. (BETAINV(0.975, . x+. 1, . n-. x+. 1))). This method is simpler than the current method, independent of the number of animals tested, and demonstrates that for 100% efficacy at least 37 eggs (not eggs per gram) need to be counted pre-treatment before the LCL can exceed 90%. When nematode aggregation is high, this method can be usefully applied to efficacy estimates lower than 100%, and in this case the 95% upper-CL (UCL) can be estimated by:. 95%UCL. =. 100. ×. (1. (. (BETAINV(0.025, . x+. 1, . n-. x+. 1))), with the LCL approximated as described above. A simulation study to estimate the precision and accuracy of this method found that the more conservative 99%CL was optimum; in this case 0.975 and 0.025 are replaced by 0.995 and 0.005 to estimate the LCL and UCL, respectively.
Formatted abstract
As it has been 30 years since a new anthelmintic class was released, it is appropriate to review management practices aimed at slowing the development of anthelmintic resistance to all drug classes. Recommendations to delay anthelmintic resistance, provide refugia and the use of a simulation model were reviewed to find optimum treatment strategies that maintain nematode control. Simulated Australian conditions indicated that a common successful low-risk treatment program was a rapid rotation between a “triple-combination” product (benzimidazole + levamisole + abamectin) and a new high-efficacy drug (monepantel).  Where Haemonchus contortus was a threat, moxidectin was required at critical times because of its persistent activity against this parasite. Leaving up to 4% of adult sheep untreated provided sufficient “refugia” for non-selected worms to reduce the risk of selecting for anthelmintic resistance without compromising nematode control.  For a new anthelmintic, efficacy estimated by faecal egg count reduction (FECR) is likely to be at or close to 100%, however using current methods the 95% confidence limits (CL) for 100% are incorrectly determined as 100%. The fewer eggs counted pre-treatment, the more likely an estimate of 100% will occur, particularly if the true efficacy is >90%. A novel way to determine the lower-CL (LCL) for 100% efficacy is to reframe FECR as a binomial proportion, i.e. define: n and x as the total number of eggs counted (rather than eggs per gram of faeces) for all pre-treatment and post-treatment animals, respectively; p the proportion of resistant
eggs is p = x/n and percent efficacy is 100 × (1− p) (assuming equal treatment group sizes and detection levels, pre- and post-treatment). The LCL is approximated from the cumulative inverse beta distribution by: 95%LCL = 100 × (1 − (BETAINV(0.975, x + 1, n − x + 1))).  This method is simpler than the current method, independent of the number of animals tested, and demonstrates that for 100% efficacy at least 37 eggs (not eggs per gram) need to be counted pre-treatment before the LCL can exceed 90%. When nematode aggregation is high, this method can be usefully applied to efficacy estimates lower than 100%, and in this case the 95% upper-CL (UCL) can be estimated by:  95%UCL = 100 × (1 ( (BETAINV(0.025, x + 1, n − x + 1))), with the LCL approximated as described above. A simulation study to estimate the precision and accuracy of this method found that the more conservative 99%CL was optimum; in this case 0.975 and 0.025 are replaced by 0.995 and 0.005 to estimate the LCL and UCL, respectively.

Keyword Monepantel
Drug resistance
Refugia
Faecal egg count reduction test
Anthelmintic efficacy
Confidence limits
Precision accuracy
New-Zealand
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Public Health Publications
 
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Created: Thu, 17 Jan 2013, 01:15:30 EST by Geraldine Fitzgerald on behalf of School of Public Health