Anthelmintic Resistance

Question 1

DEfinition of prophylaxis

Answer 1

prevent high levels of parasite infection by reducing transmission, therefore reducing the incidence of disease/production losses

Question 2

What is the strategy for control?

Answer 2

not used routinely but at a time of year where most likely to be effective with intervention

Question 3

List the strategies for control

Answer 3

1. interval dosing (1960s)
    used commonly with benthemedazoles
    basically treat every 3 weeks – realised this isn’t ideal
2. strategic dosing
    treat when parasite number highest to disrupt seasonal cycle of transmission
    using at certain year when risk period for highest transmission levels
    N.B no diagnosis of infection involved
3. targeted dosing – became way forward to provide adequate control and reduce risk of disease
    treat on the basis of diagnostic indicators
    using in targeted way, provides drug ability to work over longer period of time as reduce exposure of parasite to drug therefore resistance

Question 4

What do you need to consider when using anthelmintics?

Answer 4

THINK about Spectrum of activity - Parasite species, stage and pharmacokinetics of different formulations.
Egg reappearance period (ERP)
Dosage and frequency of treatment
RESISTANCE

Question 5

Why do you need to consider spectrum of activity when using anthelmintics?

Answer 5

1. Not all anthelmintics will work against all parasite species
2. Within species not all drugs will kill all stages of the parasite that might be inside the animal
3. ERP - time interval between the last effective anthelmintic treatment and the resumption of significant strongyle egg shedding
4. Dosage and freq of treatment - don’t use unless really have to
5. Resistance - particularly for those GI nematodes causing PGE

Question 6

Anthelmintic resistance

Answer 6

A heritable trait whereby a parasites usually killed by a specific drug at a specific dose are no longer killed by it

Question 7

What must occur for anthelmintic resistance to occur?

Answer 7

• For drug resistance to develop it must be a heritable trait!
• Much be some genetic change, conferred to subsequent generations

Question 8

How does resistance vary between the 3 main anthelmintic groups?

Answer 8

1. 1 BZ - Benzemedazoles - extensive resistance, so least effective drug now
2. LEV Imidazothiazoles, tetrahydropyrimidines - resistance evident
3. 3 MLs
   Macrocyclic lactones - resistance is emerging.Currenty the most effective drug in killing GI nematodes

Question 9

Which parasites are resistant to drugs in sheep and goats

Answer 9

1. Haemonchus contortus
2. Nematodirus battus
3. Teladorsagia circumcincta
4. Trichostrongylus spp
5. Trematodes (flat worms e.g. livre fluke) Fasciola hepatica

Question 10

Which parasites are resistant and clinically relevant to PGE

Answer 10

Trichostrongylus spp and Teladorsagia circumcincta

Question 11

For Teladorsagia circumcincta adn Trichostrongylus spp what type of drug are you likely to use and why in sheep adn goats?

Answer 11

1. Macrocyclic lactones as least resistance vs 1 BZ and 2 LEV, hwoever still wouln’t know if these parasites would be killed as they have shown resistance

Question 12

Which parasites are resistant to drugs in Cattle

Answer 12

Nematodes:

1. Cooperia oncophora
2. Ostertagia ostertagi

Trematodes:
3. liver fluke, same that infects sheep
Fasciola hepatica

Question 13

Which parasites are resistant to drugs in horses

Answer 13

1. Cyathostomin spp

2. Parascaris equorum

Question 14

Why does anthelmintic resistance occur?

Answer 14

1. Nematode populations are very large and genetically diverse
   -Naturally resistant parasites exist at low frequency
   -Role of random mutation?
2. Selection pressures (i.e drug treatment) enriches for resistant parasites until they dominate. Frequent use of drugs = high selection pressure
3. • Proportion of parasite population “in refuge” (untreated) = refugia
   o Provides a pool of sensitive genes to dilute out resistant genes surviving treatment

Question 15

How does anthelmintic resistance occur

Answer 15

 Change the target site
 Altered metabolism of the drug to prevent it reaching the target site
 Increased efflux of drug to prevent it reaching the target site

Question 16

How can we slow anthelmintic resistance

Answer 16

 Bzs know definitely  BZs affect polymerization. When P resistant mean drug can no longer bind and prevent polymerization occurring
 2LEV and 3ML  Change in conformation in transporter molecules so drug can no longer get inside cell

Question 17

Macrocyclic lactones mode of action

Answer 17

• Work in diff way so if parasites resistant to previous 2, this should kill!
• Act on nervous system of parasite
o Musculature and pharyngeal pumping
o Paralysis so affects on body AND feeding
• Potentiators causing hyperpolarisation
o Targets are thought to be multiple but include invertebrate glutamate-gated chloride channels (GluCls)

Question 18

What is refugia?

Answer 18

 The proportion of the population that is not selected by drug treatment
 “In Refuge” from drug
 Provides a pool of sensitive genes
 To dilute resistant genes in that population
 Considered an important component of drug resistance selection in nematodes such as GIN of sheep – little empirical data available

Question 19

When to suspect resistance?

Answer 19

1. Therapeutic failute of drug - treat animal but clinical signs persist
   OR failure to achieve target weights
2. Prophylactic - FEC and/ or clinical signs remain following anthelmintic treatment

Question 20

Diagnosis of resistance

Answer 20

1. Faecal egg count reduction test
2. Analysis - effective anthelmintic is there is a greater than 95% reduction.
   Resistance is less than 90% reduction
   Ambiguous is 90-95%

Question 21

How to do FECRT

Answer 21

1. FEC and give treatment
2. Repeat FEC 10-14 days after treatment
3. large group of animal - more than 10

Question 22

Why do you repeat FEC 10-14 days after treatment when carrying out a faecal egg count reduction test?

Answer 22

If leave 3 weeks can become reinfected so got to be early enough so any eggs there are due to drug not working NOT due to reinfection (which it would be after 3 weeks)

Question 23

Other reasons drugs fail?

Answer 23

 An inadequate dose of drug was administered for the weight of the animal
 Activity of the drug is reduced (e.g drug stored inappropriately or is out of date)
 Parasite species/stage present were not susceptible to drug
 Errors in methods used for FEC or interpretation of results

Question 24

What could be errors in methods used for FEC or interpretation of results

Answer 24

 Underestimated weight
 Drug was spilled/spit-out
 Intentional underdosage (trying to save money)
 Errors of calculation
 Suspensions not thoroughly mixed before use
 Extrapolation of dose from other hosts not valid
 Beyond its expiry date
 Stored improperly
 Wrong drug for target species
 Wrong stage of life cycle present
 FEC were checked too soon or too late after treatment to detect an effect of the drug
 reinfection has occurred
 eggs present at time of treatment still being passed
 An improper or non-quantitative egg counting technique was used

Question 25

Non drug based approaches

Answer 25

• Grazing management – pasture as clean as possible
-Evaluation of farm specific strategies
-Dependent to farm – can’t really make blanket recommendations
•Host genetic resistance
- Breeding animals that are resistant to infection
-Identification of quantitative trait loci affecting resistance to gastrointestinal parasites
-E.g. within a group of lambs will be some that are really susceptible to high egg shedding and parasite levels and some with low.