IV. Using anthelmintics effectivelyProducts, usage, resistance, refugia, alternatives, future

What is an anthelmintic?An agent that kills or causes the expulsion of parasitic worms.Also called dewormer, wormer, drench, or parasiticide.

There are three anthelmintic classes.Based on similar chemistries, modes of action, and cross-resistance.

1. Benzimidazoles (BZ)

2. Macrocylic lactones (ML)1) Avermectins2) Milbemycins

3. Nicotinic antagonists1) Imidazothiazoles (IMID)2) Tetrahydropyrimidines (TETR)

1 - Benzimidazoles (BZ) First class of modern anthelmintics (1961)

1. FenbendazoleSafe-guard®Panacur®

2. AlbendazoleValbazen®

3. OxfendazoleSynanthic®

4. Thiabendazole TBZ

Benzimidazoles kill worms by interfering with energy metabolism on a cellular level by binding to beta tubulin.

1 - Benzimidazoles (white drenches)

• Broad spectrum1. Adult and 4th stage larvae of roundworms2. Adult liver flukes

(Valbazen® only)3. Heads and segments of tapeworms

(Valbazen® or 2x labeled dose of Safe-Guard®)

4. Effective against hypobiotic larvae5. One of the drugs of choice for meningeal

worm (Safe-Guard®)

• Wide margin of safety– Do not use Valbazen® during

first 30 days of pregnancy or removal of ram(s).

• Widespread resistance reported.

2- Macrocylic lactones (ML) Newest family of anthelmintics - circa 1980’s

1) Avermectinsa) Ivermectin

Ivomec®Primectin®

b) EprinomectrinEprinex®

c) DoramectinDectomax®

2) Milbemycinsa) Moxidectin

Cydectin®Quest® Macrocylic lactones interfere with GABA-mediated

neurotransmission, causing paralysis and death of the parasite.

2 - Macrocylic lactones (ML)• Potent

• Persistent activity (+/-)

• Broad spectrum1. Adult and 4th stage larvae of

roundworms2. Some external parasites

(Ivermectin: larval stages of nasal bots)

3. Effective against hypobiotic larvae4. One of the drugs of choice for

meningeal worm (ivermectin).

• Potential negative effect on dung insects.

• Widespread resistance reported, especially avermectins.

3- Nicotinic agonists

1) Imidazothiazoles (IMID)a) Levamisole

Prohibit®Tramisol®Levasol®

2) Tetrahydropyrimidines (TETR)a) Morantel

Rumatel®b) Pyrantel

Strongid®

Act as agonists at nicotinic acetylcholine

receptors of nematodes, causing

paralysis of the worms.

3 - Nicotinic agonists

1. Levamisole– Clear (yellow) dewormer– Broad spectrum

• Adult and 4th stage roundworm larvae

• Hypobiotic larvae (?)

– Narrower margin of safety (esp. injectable)

– Resistance varies from high to low.– Resistance is sex-linked.

2. Rumatel– Oral feed additive– Effective against adult worms only– Not much is known about resistance levels.

FDA-approved anthelmintics

SHEEP1. Ivomec® sheep drench

Ivermectin2. Cydectin® sheep drench

Moxidectin3. Prohibit® drench

Levamisole4. Valbazen® liquid

Albendazole

GOATS1. Safe-Guard® suspension

Fenbendazole2. Valbazen® liquid

Albendazole[liver flukes only]

3. Rumatel® premixMorantel

Different anthelmintics may be approved and available in different countries.

Withdrawal periods for FDA-approved anthelmintics

AnthelminticSheep Goats

Meat Milk Meat Milk

Valbazen® suspension 7 days Not est. 7 days Not est.

Prohibit® drench 3 days Not est. NA NA

Cydectin® drench 7 days Not est. NA NA

Ivomec® drench 11 days Not est. NA NA

Rumatel® premix NA NA 30 days Not est.

Safe-Guard® suspension NA NA 6 days Not est.

Source: Animal Drugs @ FDA and product labels

Withdrawal periods for extra-label anthelmintics in goats

Anthelmintic Meat Milk

Valbazen® suspension 9 days 7 days

Safe-Guard® @ 2x label dose 16 days 4 days

Ivomec® sheep drench 14 days NA

Prohibit® drench(1 packet/262 ml water) 4 days NA

Cydectin® pour-on (orally) 23 days NA

Cydectin® sheep drench 14 days NA

Cydectin® injectable 120 days NA

Source: Food Animal Residue Avoidance Database (FARAD) and/or http://www.luresext.edu/goats/training/GoatDewormerChart.pdf

Anthelmintic resistanceAbility of the worms to survive anthelmintic treatment

• Official definition: 95% or less reduction in fecal egg count (FECRT).

a) Widespread in parasites of sheep, goats, and horses. Has been reported in all anthelmintics.

b) Developing in cattle parasites.

c) Has been detected in pig parasites.

• Is likely (inevitable) to develop wherever anthelmintics are frequently used.– There will always be some worms that survive

an anthelmintic treatment.

Tx

Anthelmintic resistanceResearch conducted by Delaware State University (2009)

Anthelmintic % farms

Fenbendazole 97

Ivermectin 56

Moxidectin 50

Levamisole 2819 goat and 13 sheep farms in MD, DE, PA, VA, and WV were tested for anthelmintic resistance using the larval development assay at the University of Georgia.

• Varies by geographic region and individual farm.• A result of past anthelmintic use.• Anthelmintic resistance is PERMANENT.

Anthelmintic Sheep Goat

Fenbendazole 5/5 5/5

Ivermectin 3/4 5/5

Moxidectin 2/4 1/5

Levamisole 1/4 0/54 sheep and 5 goat farms in the Mid-Atlantic region were tested for anthelmintic resistance using the FECRT and larval development assay.

Causes of anthelmintic resistance

❶ Frequent deworming

• Treating all animals at the same time.

• Putting treated animals onto a clean pasture.

Causes of anthelmintic resistance❷ Under-dosing

– Not weighing animals– Inability to accurately

estimate weights– Not calibrating equipment for

heaviest animals in group.

• Using anthelmintics with residual activity– Persistent-activity anthelmintics– Injectables– Pour-ons

Refugia (Worms in “refuge”)

• Worms that have not been exposed to anthelmintic treatment.

• Worms that are still susceptible to anthelmintic treatment.

• There will always be some worms that are resistant to a particular anthelmintic. Image source: Meat & Wool New Zealand

How to increase refugiaand slow (delay) anthelmintic resistance

• Selective deworming– Do not treat everyone

every time.– Leave some animals

untreated.

• Pasture management– Do not put treated

animals onto a clean pasture.

– Put untreated animals onto pasture previously grazed by treated animals.

Anthelmintic combinations

• Combining anthelmintics from two (or more) different broad spectrum groups– Synergistic effect– Broaden spectrum of

activity– Delay development of

resistant worms

+

+Temporary “fix”

Preliminary dataEfficacy of anthelmintic combinations in goats

Treatment FECR %Albendazole 76Levamisole 39

Moxidectin 74

Albandazole + levamisole 85

Albendazole + moxidectin 98

Levamsiole + moxidectin 98Albendazole + levamisole + moxidectin 99

Copper oxide wire particles (2 g) 28

Control 14

Initial FECs ranged from 250 to 13,500 and averaged 2,550 epg. 8.6 animals/Tx

Treatment FECR %

Moxidectin 100

Levamisole 14

Albendazole 21

Levamisole + albendazole 94

Levamisole + albendazole + moxidectin 100

4 animals/Tx

Research conducted at Langston University (OK)

Proper anthelmintic use

• Give proper dose based on accurate weight.– Goats require higher doses of

anthelmintics, usually 1.5 to 2x the sheep or cattle dose.

• Administer all anthelmintics orally to sheep and goats.

• Use drench (liquid) formulations of anthelmintics.

• Fasting may improve efficacy of some anthelmintic treatments.

Proper oral drenching technique• Use proper equipment

– Smaller nozzle for lambs and kids

• Maintain equipment properly• Calibrate equipment for proper

dosage• Hold head horizontal for

drenching• Insert nozzle in side of mouth• Put nozzle over back

of tongue• Don’t rush• Ensure swallowing

before release.• Be gentle.• Avoid injury

Putting the drench in the mouth will activate the esophageal groove and cause the drench to by-pass

the rumen into the lower gut . . . and not work!

CoccidiostatsA chemical agent added to animal feed that serves to retard the life cycle or reduce the population of pathogenic coccidia to the point that disease is minimized and the host develops immunity .

Coccidiostats

1. Ionophoresa) Lasalocid

Bovatec®

b) Rumensin®Monensin

2. Quinolonea) Decoquinate

Deccox®

3. Amprolium (Rx)Corid®

Affect mitochondrial function

Coccidiostats

• Do not kill coccidia.

• Slow down shedding of coccidia into the environment.

• Need to be fed ahead of risk period, at least 21 days before.

• Adequate consumption is a limitation to their effectiveness.

• Should not feed year-round – risk of resistance developing

• Permissible under USDA natural standards (if declared).

Coccidiostats FDA-approved for use in sheep and goats

Trade name Ingredient Dosage Approved species and class

Bovatec® Lasalocid 15-70 mg/d20-30 g/ton of feed Sheep in confinement

Deccox® Decoquinate 22.7 mg/100 lbs. BW13.6 g/ ton of feed

Young, non-lactating sheep and goats

Rumensin® Monensin 20 g/ton of feed Goats in confinement

Corid® Amprolium Consult with veterinarian Extra-label

Source: Animal Drugs @ FDA

Rumensin® can be toxic to equines and dogs.

There is no withdrawal period for slaughter.

Treating coccidiosis (Tx)

• Coccidiostats will not treat coccidiosis.

• Treatment needs to be administered to individual animals.

• None of the drugs that are used to treat coccidiosis are FDA-approved for sheep and/or goats.

• Use must meet requirements for extra label drug use.

Two treatment choices1. Amprolium (Corid®)2. Sulfa drugs

http://old.cvm.msu.edu/extension/Rook/ROOKpdf/coccidia.PDF

1 - Corid® (amprolium)

• Labeled as an aid in the prevention and treatment of coccidiosis in beef and dairy cattle.

21 day prevention 5 day treatment

• Mimics thiamine (vitamin B1), causing a thiamine deficiency in coccidia → starvation from malnutrition.

– Polioencephalomalacia (polio) is a possible side effect of treatment.

http://old.cvm.msu.edu/extension/Rook/ROOKpdf/coccidia.PDF

2 - SulfonamidesSsulfadimethoxine (Di-methox®, Albon®), Sulfamethazine (Sulmet®)

• Used to treat many infections.

• Common treatment for coccidiosis.

• Cause folic acid deficiency

• More effective than Corid® (?)

http://old.cvm.msu.edu/extension/Rook/ROOKpdf/coccidia.PDF

What’s “new” in parasite control?

New anthelmintics

ZOLVIX® • Monepantel• New class of anthelmintic: amino-

Acetonitrile derivatives (ADDs)

• Paralyzes worms by attacking a previously undiscovered receptor (Hco-MPTL-1) only present in nematodes

• Available in New Zealand, Australia, Europe, UK, and South America.

STARTECT®• Derquantel + abamectin• New class of anthelmintic:

Spiroindole (SI)• Acts as a channel blocker to

cause flaccid paralysis in worms.• Acts on different binding sites

than other anthelmintic classes.• Only available in New Zealand

Copper for internal parasite controlRisk: copper toxicity in sheep

1. Dietary Mineral mix Feed supplement

2. DrenchCopper sulfate

3. BolusCopper oxide wire particles (COWP) CuSO4

Copper oxide wire particles (COWP) http://www.attra.org/attra-pub/PDF/copper_wire.pdf

• Copper boluses are available for use for copper deficiency in cattle.

• Boluses can be repackaged into doses suitable for lambs and kids.

• Minimum dose is 0.5 g; as much as 2-4 g may be necessary.

• Effective against barber pole worm only.

• Mechanism of action is not known.

• Form of copper is poorly absorbed.

http://www.attra.org/attra-pub/PDF/copper_wire.pdf

Natural “anthelmintics”Significant research effort underway

• Garlic juice• Pumpkin seed• Mustard seed• Oregano oil• Papaya • Diatomaceous earth (DE)• Bioactive plants (herbal)

– Artemisia spp. – Sericea lespedeza– Birdsfoot trefoil– Chicory– Pine bark

Sesquiterpene lactonesCondensed tannins

Nematode-trapping fungusDuddingtonia flagrans

• Spores are fed to livestock as part of their diet.

• Spores pass through digestive tract of livestock and are deposited in the feces.

• Spores germinate alongside worm eggs.

• Spores trap and feed on newly emerging larvae.

No commercial product (yet)Image source: Louisiana State University

Natural “anthelmintics”• Natural “anthelmintics”

are not likely to replace the therapeutic use of anthelmintics.

• However, they may reduce the need for anthelmintic treatments disrupting the parasite’s life cycle.

• They may become an important aspect of holistic or integrated parasite management systems.

What about a vaccine?• So far, limited success in developing

vaccines for internal parasites.

• Paravac Consortium received record €9 million EU grant to fund development of vaccines against parasitic worms.

• Promising vaccine for Haemonchus developed by Moredun Institute (Scotland) and currently being tested in Australia.

• Would the vaccine be available to U.S. producers?

Thank you for your attention.

Any questions?

SUSAN SCHOENIANsschoen@umd.edu

www.sheepandgoat.com

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• Recordings of the 2011 Worm Webinar series are available at http://www.sheepandgoat.com/ recordings.html.

• PowerPoint presentations from the 2011 Worm webinar series may be viewed or downloaded from http://www.slideshare.net/schoenian.

• Additional questions may be sent to Susan @ sschoen@umd.edu.

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