WRML. Dobson papers- resistance, monepantel and refugia

To: WormMail list (recipients undisclosed).

WRML.20110722. Dobson papers- resistance, monepantel and refugia

[1] RJ Dobson, BC Hosking, RB Besier, S Love, JWA Larsen,  PF Rolfe and JN Bailey (May 2011). Minimising the development of anthelmintic resistance, and optimising the use of the novel anthelmintic monepantel, for the sustainable control of nematode parasites in Australian sheep grazing systems. Aust Vet J 2011;89:160–166.

The aim was to compare the risk of different treatment scenarios on selecting for anthelmintic resistance on Australian sheep farms.

Nematode populations and the progression of drug resistance for a variety of treatment options and management practices in sheep-rearing areas of Western Australia (WA), Victoria (VIC) and New South Wales (NSW) were simulated. The simulation was done using a computer model that predicted populations of Trichostrongylus colubriformis, Haemonchus contortus or Teladorsagia (Ostertagia) circumcincta, and the frequency of anthelmintic resistance genes.

A scoring system was used to measure the success of each option in delaying resistance to each anthelmintic and in controlling nematode populations.

In summary the best option at all sites was combining the new anthelmintic (monepantel) with a triple mixture of benzimidazole, levamisole and abamectin (BZ+LEV+ABM).

The next best option according to the model was:

        in NSW, rotation at each treatment between monepantel, moxidectin and BZ+LEV+ABM;

        in VIC, rotation at each treatment between monepantel and BZ+LEV+ABM;

        and in WA, rotation at each treatment between monepantel (used in winter) and BZ+LEV+ABM or moxidectin (used in summer–autumn).

In WA, rapid selection for resistance occurred because of summer–autumn treatments. But, if a small percentage (1-4%) of adult sheep were left untreated then this selection could be greatly reduced.

Although relatively high resistance to benzimidazole and levamisole was deliberately assumed, BZ+LEV+ABM was still effective in controlling worms and delaying resistance.

The authors concluded that,  because of cost, it may not be feasible or profitable for producers to always use the combination of all drugs. However, the second- and third-best options still considerably slowed the development of anthelmintic resistance.

(Source: paper abstract).

[2] RJ Dobson, EH Barnes, KL Tyrrell, BC Hosking, JWA Larsen, RB Besier, S Love, PF Rolfe and JN Bailey (June 2011). A multi-species model to assess the effect of refugia on worm control and anthelmintic resistance in sheep grazing systems.Aust Vet J 2011;89:200–208.

The authors aimed to to develop a computer simulation model that uses daily meteorological data and farm management practices to predict populations of Trichostrongylus colubriformis, Haemonchus contortus and Teladorsagia (Ostertagia) circumcincta and the evolution of anthelmintic resistance within a sheep flock. Model predictions were compared with field observations from a breeding flock in Armidale, NSW.

The model  was used to see if increased refugia (leaving 1–10% of adult sheep untreated in diverse sheep-grazing systems) would delay development of anthelmintic resistance without compromising nematode control.

It was found  that predicted populations of Tr. colubriformis and T. circumcincta were less than those observed in the field. This was attributed to nutritional stress experienced by the sheep during drought and not accounted for by the model.

Observed variation in faecal egg counts explained by the model (R2) for these species was 40–50%. The H. contortus populations and R2 were both low.

Leaving some sheep untreated worked best in situations where animals were already grazing or were moved onto pastures with low populations of infective larvae. In those cases, anthelmintic resistance was delayed and nematode control was maintained when 1–4% of adult stock remained untreated.

The authors concluded that, in general, the model predicted that leaving more than 4% of adults untreated did not sufficiently delay the development of anthelmintic resistance to justify the increased production risk from such a strategy.

The choice of a drug rotation strategy had an equal or larger effect on nematode control, and selection for resistance, than leaving 1–10% of adults untreated.

(Source: paper abstract).

Read the whole of both papers for yourself.  

To interpret the summary findings (above and below), you need to know what assumptions were made (eg levels of resistance)  i.e. read the paper.

Some comments/notes from (re-) reading these papers follow. (No, I can’t remember all the details for any length of time. Dr Dobson might).

From paper 1:

* (Citing Barger), when considering a worm control program, farmers will consider effectiveness, cost and ease of application, with sustainability being a lower priority. Although routine worm egg count (WEC) monitoring is advocated, only a minority do it.

* Using a combination of effective, unrelated drenches is a simple, sustainable way of delaying resistance. But this is not always possible for obvious reasons.

* Using monepantel in combination with or rotated with existing drugs was studied, with the resistance (R)-allele frequency deliberately being set higher than might be expected for a new drug (say 1 in 1 million). Resistance was also assumed to be co-dominant so that resistance would develop faster.

*  Initial R frequencies for monepantel were set to 0.001 to 0.003% for the three nematode species.  ML resistance was assumed to be common (R frequency 30%; which meant MOX efficacy was still 85%+)) and BZ+LEV resistance very common (R frequency 40%).  All simulations ran for 20 years.

*  Four options simulated: monepantel+ABM+BZ+LEV; monepantel/MOX rotation; monepantel/ABM+BZ+LEV rotation; monepantel/ABM+BZ+LEV/MOX rotation.  These options + Leaving 1-10% of adults untreated was also simulated, because refugia is a key issue, especially in WA.

* Broad recommendations from the model generally consistent across the three states:  provide a source of refugia, use combinations, rotate monepantel with combination products.

From paper 2:

* Teladorsagia circumcincta (Tc) and Haemonchus contortus (Hc) can cause abomasal pH to rise,  reducing establishment of incoming Hc larvae. Removing Tc and Hc infections increases establishment of Hc larvae.   (The model accounted for this) (Paper 2).

* In paper 2, simulations were done using the multi-species model for Merino flocks at two winter rainfall areas ( Kojonup (WA (severe hot dry summers)), and Hamilton (Vic), and two summer rainfall areas ( Glen Innes and Armidale (NSW), comparing medium and high risks for haemonchosis).

* Some assumptions: BZ+LEV modelled as a single gene; initial R-allele frequency 40%. Initial R-allele frequency for ML set at 3% (emerging resistance) (the current reality may be different) and assumed to be incomplete recessive.  Monepantel resistance was assumed to be co-dominant and initial R-allele frequencies were set for the three nematode species at 0.001% to 0.003% so that resistance would emerge within 10 years if monepantel was used exclusively. The initial R-allele frequency for Hc had to be increased 10-fold to 0.01% because resistance would not develop within the 20-year simulation period due to high refugia.

* Four control options (ie  ‘Untreated’, or exclusive use of monepantel or MOX or ABM+BZ+LEV) and four drug management control options (combinations and rotations) were simulated for each site.

* Leaving 1, 4, 7 or 10 % of adults untreated (animals selected at random) was also simulated. It was assumed that leaving animals < 1 year old would be regarded as an unacceptable risk.

* Death rates, nematode burdens and effectiveness at delaying resistance were scored.

* According to this paper (for all sites simulated), worm control can be maintained when all young sheep and  96% or more of adult sheep are treated with a highly effective (>95% effective)  product or combination of drugs. As drug resistance increases/drug efficacy declines, the % of animals required to be left untreated becomes to high and would compromise worm control.

e&oe   🙂

Regards
SL

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WRML.Australian Sheep Veterinarian?s Conference 16-18 September 2011 Barossa Valley South Australia

To: WormMail mailing list (recip. undisclosed. Subscribers ~ 400) + other lists (apologies if you get this more than once (list overlap).

WRML. Australian Sheep Veterinarian’s Conference 16-18 September 2011  Barossa Valley South Australia

Information regarding this conference is attached. (Obviously this conference is not limited to veterinarians! or professional advisors  🙂

More information:

        * Technical: to either Colin Trengove (Colin@apal.com.au; 0418 808045), or Brown Besier: brown.besier@agric.wa.gov.au; 08 9892 8470);

        * Registration: ASV Executive Officer, Anne Cover (anne@acv.com.au)

 

Attached is a draft of the program and  a conference registration form. This has a hotel accom booking sheet with it.

Regards

SL

ASV 2011 Conference – Registration form.pdf Download this file

draft program Barossa Valley ASV 24 6 11-from RBB 20110721.pdf Download this file

WRML.Dobson R.van Wyk J. Midgley D.On-going Discussion _ drench combinations or not?

Dobson R.van Wyk J. Midgley D. 20110721 WormMail Discussion _ drench combinations or not.doc Download this file

TO: WormMail list (recip. undisclosed; ~ 400 subscribers)

WRML.201107211230.Dobson R.van Wyk J. Midgley D. On-going Discussion _ drench combinations or not

Comments enabled at WordPress

If you wish to discuss this further, I have – for a trial period – enabled comments at WordPress.

https://wormmailinthecloud.wordpress.com

See: https://wormmailinthecloud.wordpress.com/comments-policy/

WormMail. Discussion – drench combinations or not

Rob Dobson, Jan van Wyk and David Midgley interact on the matter of drench combinations.

Earlier parts of the thread:

27 June 2011. Comments from Dave Midgley, South Africa:

https://wormmailinthecloud.wordpress.com/2011/06/27/wrml-saffers-startect-combos-quarantine-drenches-etc/

12 July. Response from Jan van Wyk, South Africa:

https://wormmailinthecloud.wordpress.com/2011/07/12/saffers-and-startect-a-contrary-view-jvw-comments-on-dave-midgley-inverview/

The thread continues, with a response from Rob Dobson, Western Australia (Murdoch University; previously, CSIRO Australia):

Rob Dobson (RD):

I would like to clarify some issues in favour of combination anthelmintic treatments in relation to the points raised by Jan.
 
 In summary, the fewer worms that survive in the host after treatment then the more likely resistance to a new drug will be delayed; this is why combinations are advocated. The worms that can survive one drug in the combination are removed by the other drug(s), i.e. the drugs in the combination afford some protection to each other.  This strategy is reliant on there being some larvae on pasture that will reinfect the treated sheep (larvae in refugia), an issue raised by Jan, and addressed below.  

Jan Van Wyk (JvW):

I have no qualm (if that’s the right word !) with the above, Rob; as the amateur I am in this field but with the same (though unsubstantiated at the time) reasoning, I already designed programs (unpublished) involving use of closantel with BZs much like in WormKill soon after closantel had arrived on our market  (registered first in South Africa).

[Closantel (at 7.5mg/kg) came on to the market in Australia in 1982 (brand name: Seponver® (Smith-Kline). The first version of WormKill (KM Dash and others) was launched in the New England region of northern New South Wales in July 1984.-SL]  

However, at least for Haemonchus the question of comparison between speed of selection rests very much on all else being equal. In other words, especially given the prevalence and extent of multiple resistance, what is the situation if animals are moved to "clean" grazing at the time of being de-wormed.  A combo of two or more very highly effective "unrelated" new drugs (a luxury we practically don’t have due to impracticality of a combo of the two new candidates) may leave too low numbers of worms to be viable on clean pasture. However, as I see it, in those cases where the worms do succeed in infecting hosts in any but extremely low numbers (as in our present situation of very prevalent multiple resistance), selection with a combo could be expected to have much more serious consequences than when a single one were to be used.
 
RD:

FIRST.  Jan makes the point that generally farmers do not check for resistance or adopt a quarantine treatment strategy, I would agree.  In this situation Jan advocates using one product till it fails, and then move to another product, the farmer will thus be aware when resistance emerges.  This strategy will fail because the lack of quarantine treatments will have allowed other drug resistant strains to be imported and is a strategy designed for worst-practice farming.  Jan also makes the point that combinations will mask the development of resistance, but that is because they will remain effective for longer.  The issue is how much longer will drugs remain effective when used in combinations than if the drugs were used sequentially till they fail?  The conclusion from modelling is that resistance will be substantially delayed by using combinations when compared with rotation or sequence strategies (see:  Parasitol Today 1995; 11:56-63;   Int J Parasitol 1990;20:913-921)

JvW:

In the above two sentences, could the same not be expected to be true with combos especially under our conditions of relatively poor survival of worms and general practice of drenching and moving, Rob?  If so, it becomes a matter of how common this strategic approach is applied in practice.

RD:

SECOND. Jan also raises the issue that strategies involving anthelmintic treatment and a move to "clean" or "very safe" pasture are “not considered either in the published mathematical model articles or in the combo debate”.  The following is a direct quote from a review paper (Aust Vet J 2001; 79:756-760).
“A potential risk to combination therapy is when treated sheep graze clean pastures, because in this situation the worm population is mostly within the host population and consequently few worms if any evade selection. In such circumstances consideration may be given to leaving a few sheep untreated, to ensure the survival of sufficient non-resistant worms to dilute resistant survivors of anthelmintic treatment.  …  If a highly effective mixture cannot be found there is little point to this strategy.”

Also on this point two recent modelling papers have explored this issue and concluded that generally: leaving up to 4% of adult sheep untreated will minimize the risk of drug resistance associated with treating sheep on clean pastures without compromising worm control; combinations best delay selection for anthelmintic resistance (Aust Vet J., 2011 89:200–208.; Aust Vet J., 2011 89:160–166).

JvW:

Obviously I did not make my meaning clear – I meant testing the effect of a drench and move with actual model(s) as an indication of the risk of the strategy if combos do let any worms through, as is a very high likelihood today, at least in South Africa.
 
Another issue that does not receive attention in debates on the use of  combos or single drugs  –  also in our present discussion  –  is the level of resistance to be expected when worms do manage to get past the combination of very highly effective drugs in a given combo, i.e. the difference between hetero- and homozygous worms that survive the treatment.
 

JvW:

Sorry, I had not seen these papers (Aust Vet J., 2011) when I wrote my contribution now.  However, my impression is that, excepting perhaps in cases such as parts of Brazil and the southern states of the USA where rock bottom has literally been reached for relatively high proportions of farmers with serious resistance to everything they have available, we are at least as far away from convincing farmers to leave sheep un-drenched, as to getting them to apply quarantine drenching or to test for resistance.

David Midgely (response to WormMail of 12th July):

After reading through Jan’s comments thoroughly (WormMail 20110712), I seem to find more things that we do agree on than disagree, except for:

1.       The use of combinations

2.       The use of long acting preparations, and

3.       “find something like FAMACHA that works, irrespective of farm economics and then to set about making it practical in relation to said farming economics”

 I believe that the statement made in 3 above is the “wrong way around” – if you want to get farmers against you, you do this! How are you then going to get them on your side later?!  

It also seems that when we do disagree, it is a “total” disagreement!

 Instead of getting involved in a lengthy discussion with Jan, I think we should maybe just “agree to disagree”!

———————

The thread has now come to an end.

Regards

SL

WRML: WormFaxNSW June 2011

TO: WormMail list (recip. undisclosed). WRML.20110719.WormFaxNSW June 2011

WormFaxNSW June 2011 is now on-line:

http://www.dpi.nsw.gov.au/aboutus/resources/periodicals/newsletters/wormfax

Summary data comes each month from Veterinary Health Research, Armidale, and from Primary Industries State Veterinary Laboratory at EMAI, Menangle, NSW.
The assistance of these labs is gratefully acknowledged.

As yet, information is not available from other labs.

Of course worms especially Haemonchus are no longer an issue as it is winter. 🙂     Right??

Consider some ‘highlights’ from the June WormFax (some WormTests with higher EPGs):

Northern New England (Glen Innes, NSW and district) (New England LHPA)

        Weaners. Average (ie arithmetic mean) strongyle worm egg count (WEC): 2952 eggs per gram faeces (epg); range: 0 – 15040 epg.  Larval culture: 91% Haemonchus.

Armidale (New England LHPA)

        Rams.   Av. WEC: 3240.   Range: 240-1120. 75% Haemonchus.

        Weaners. Av. WEC: 2880 Range: 360-9520.  97% Haemonchus.

Central North LHPA (main towns: Tamworth, Mudgee, Coonabarabran)

        Ewe hoggets (ie 2 tooth).  Average WEC: 13084.   Range: 3480-31600.  67% Haemonchus  33% Trichostrongylus sp

Central West LHPA (Main towns: Dubbo, Nyngan, Coonamble).

        Ewes. Av. WEC: 3612. Range: 520-8280.  100% Haemonchus

Tablelands LHPA (main towns: Bathurst, Orange, Goulburn, Yass)

        Ewes.   Av. WEC: 3268 Range: 160-6640.   No larval culture.

        Weaners. Av. WEC: 1987.  Range: 960-3320.   95% Haemonchus.

Lachlan LHPA  (towns incl. Young, Forbes, Condobolin).

        Lambs. (age unknown):   Av. WEC: 11264   Range: 40-33320 (an extraordinary range and a very high egg count). 98% Haemonchus

Narrandera (Riverina LHPA)

        Ewes. Av. WEC: 2088.  Range: 240-5040.  20% Haemonchus.  75% Trichostrongylus sp

Cooma  ( South East LHPA)

        Weaners. Av. WEC: 1192 (3230-3880).  42% Haemonchus

Information on LHPAs:  www.lhpa.org.au

See media release on winter vs Haemonchus:  

http://www.dpi.nsw.gov.au/aboutus/news/recent-news/agriculture-news-releases/frosts-dont-finish-barbers-pole-worms

Map of LHPAs (and NSW ‘Sheep WormZones’) is pasted below

(Note: since the NSW state election, ‘Industry and Investment’ is now ‘Trade and Investment’ (short name), which includes ‘Primary Industries’). ‘Having trouble keeping up?   Me too).

Unknownname

Regards

SL

WRML: [1] possible Haemonchus vaccine(s) (sheep) [2]worms in horses

Worm-control-in-horses.pdf Download this file

TO: WormMail list (recip. undisclosed).  WRML.20110718.

Swiss Haemonchus vaccine

One of my South African’ spies’ (after whom FAMACHA was named), alerted me to this after returning from travels in Europe.

"This information from Dr Irene Schiller, CMO of Malcisbo:

‘Thanks for your interest in our company. Malcisbo is a spin-off from the  Swiss Federal Institute of Technology Zurich (ETH Zurich) and was incorporated in May 2010. We develop novel carbohydrate-based vaccines. Based on a novel platform technology, we develop vaccines against parasitic and bacterial diseases.
One of our development projects is a Haemonchus vaccine. The concept of our vaccine is absolutely new. You will find some information on our homepage www.malcisbo.com.
Our vaccine is still in a research stage’"

Moredun Haemonchus vaccine

Of course there is the Haemonchus vaccine from the Moredun Research Institute, developed by Dr David Smith and colleagues.. Trials of this vaccine are currently underway in Australia.

http://www.moredun.org.uk/research/research-%40-moredun/parasitic-worms/nematode-vaccines

Worms in horses

‘Just had a query or two re worms in horses.

 I am not an expert on horse parasites. (In fact, given the usual definitions, of’ expert’, I don’t like to be called an expert on anything.  As to ‘specialist’, a specialist is someone who knows more and more about less and less, ’till they know everything about nothing).

The last time I drenched a horse was when I worked in private practice (1970s) and we used to stomach tube them (piperazine, thibenzole and neguvon). Would you believe I never got a nose bleed?   (one of my few claims to fame…:-)

However, NSW DPI has quite a  useful Primefact on horse worms (by Dr Sarah Robertson nee Robinson):
  http://www.dpi.nsw.gov.au/__data/assets/pdf_file/0005/333374/Worm-control-in-horses.pdf  

Regards

SL

WRML. poll-how many have done a drench resistance test. SheepConnectNSW Event at Yass. WormBoss redevelopment.

Sheep Connect Yass Flyer [yass]-20110713.pdf Download this file

To WormMail mailing list (recip. undisclosed)  

WRML.20110713.poll-how many have done a drench resistance test. SheepConnectNSW Event at Yass. WormBoss redevelopment.

Next: Haemonchus vaccines.

Here are the answers to the question Arthur Le Feuvre put in a recent WormMail.

https://wormmailinthecloud.wordpress.com/2011/06/27/wrml-question-from-arthur-cars-saffers-and-startect-redux-drenchgroup-info-on-label-redux-flesh-eaters-solstices/

Arthur thanks all those who responded.

Straw poll – how many producers have done a Drench Resistance Test? – Arthur Le Feuvre

In Australia from drench company reps, vets, researchers ( 6 respondents)

Overall Aus: 10% – 20%

Tasmania (1 consultant)

 50% of clients (working hard to get them!!), overall in Tasmania perhaps 15%.

North West NSW

 1% to 4%

New Zealand

In a large veterinary consultancy 10% of 1000 clients have DRTs

USA

Estimate <1%.  Properly performed FECs are rare.

Some comments included in the responses:

* Amazingly enough I have done resistance testing on farms and shared results only to find out later the farmers were using the same ineffective drugs as before — they often just don’t get it.

* Very strong message for last 25 years re this + lots education

* 10% of client base of 1000 know their status ie bugger all!!!

* =hard ongoing work

* About 50% of my clients and I’m screaming at them to get one done.  Did a straw poll of farmers at the interschool footy yesterday.  Private schools = bigger farms and (generally) better educated owners (maybe).  2/13 had one from the last 2 yrs

* This (our estimates) would be based on a post drench FEC. So most people just shot first and don’t ask questions later.

* I would agree with your assessment that it is only 10-20% of producers in my area that have ever done any drench resistance testing … and with the drought many of them would not have any recent data (eg. last 3 years)… so picture could be changed by now!

* Very few – less than 1%, if any for that matter

        Firstly we don’t really have a lab that does “proper FECRT”

        And then who would ask for it to be done? If I was the seller, why would I like to “warn” potential buyers about possible problems on my farm? On the other hand, most buyers are not very “concerned” about resistance at this stage, because of the fact that it plays such a small role if compared to stock theft, predation and diseases like which have been causing major losses!

        The few farmers that know this were most probably tested by pharmaceutical companies and would not make the info known into the “public domain” if it would have a “negative impact” on their business… (e.g. a stud farmer selling rams could lose clients if this was known!)

        Having worked in private practice particularly sheep practice before this job and now dealing with adverse events related to inefficacies to drenches, which I admit might give me a slightly jaundiced view.

Notes (SL):

FEC = faecal (worm) egg count.   FECRT = faecal (worm) egg count reduction test, aka ‘DrenchTest’, ‘DRT’ (drench resistance test).

In Australia we also talk about  ‘DrenchChecks’ (e.g. ‘DrenchCheck Day10’), which is simply a worm egg count (WEC or FEC) 7-14 days after a mob of sheep is drenched, hopefully matched by a WEC done 0-7 days before the mob was drenched.


 
Sign on Arthur’s desk “ Those of you who think you know everything are very annoying to those of us who do!”

SheepConnectNSW Update at Yass 15 August

http://www.sheepconnectnsw.com.au/event.html?eventId=324

Be in the know. Register for SheepConnectNSW:  http://www.sheepconnectnsw.com.au/register.html

wormboss.com.au

While you are at it,  register for WormBoss News.

To subscribe to the monthly WormBoss email newsletter, please contact webmaster@wool.com and quote "WormBoss" in the subject line.

Note: the original URL – wormboss.com.au – still works. You will just be redirected to the AWI website where WormBoss currently lives.

WormBoss is undergoing redevelopment (website + content), plus ‘WormBoss regional worm management programs’ are being developed, plus WormBoss will be going to a new home (a nicer website, and the URL wormboss.com.au will work fine, with no redirection).

Regards,

SL