Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
EFSA J. 2021 Oct; 19(10): e06854.
Published online 2021 Oct 26. doi: 10.2903/j.efsa.2021.6854
PMCID: PMC8546521
PMID: 34729083

Maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed.
Part 3: Amprolium

EFSA Panel on Biological Hazards (BIOHAZ),corresponding author Konstantinos Koutsoumanis, Ana Allende, Avelino Alvarez‐Ordóñez, Declan Bolton, Sara Bover‐Cid, Marianne Chemaly, Robert Davies, Alessandra De Cesare, Lieve Herman, Friederike Hilbert, Roland Lindqvist, Maarten Nauta, Giuseppe Ru, Marion Simmons, Panagiotis Skandamis, Elisabetta Suffredini, Dan I Andersson, Vasileios Bampidis, Johan Bengtsson‐Palme, Damien Bouchard, Aude Ferran, Maryline Kouba, Secundino López Puente, Marta López‐Alonso, Søren Saxmose Nielsen, Alena Pechová, Mariana Petkova, Sebastien Girault, Alessandro Broglia, Beatriz Guerra, Matteo Lorenzo Innocenti, Ernesto Liébana, Gloria López‐Gálvez, Paola Manini, Pietro Stella, and Luisa Peixe
Author information Copyright and License information PMC Disclaimer

Abstract

The specific concentrations of amprolium in non‐target feed for food‐producing animals, below which there would not be an effect on the emergence of, and/or selection for, resistance in bacteria relevant for human and animal health, as well as the specific antimicrobial concentrations in feed which have an effect in terms of growth promotion/increased yield were assessed by EFSA in collaboration with EMA. Details of the methodology used for this assessment, associated data gaps and uncertainties, are presented in a separate document. To address antimicrobial resistance, the Feed Antimicrobial Resistance Selection Concentration (FARSC) model developed specifically for the assessment was applied. However, due to the lack of data on the parameters required to calculate the FARSC for amprolium, it was not possible to conclude the assessment. To address growth promotion, data from scientific publications obtained from an extensive literature review were used. Levels of amprolium in feed that showed to have an effect on growth promotion/increased yield were reported. The lack of antibacterial activity at clinically relevant concentrations for amprolium suggests that further studies relating to bacterial resistance are not a priority.

Keywords: amprolium, antimicrobial resistance, subinhibitory concentration, Feed Antimicrobial Resistance Selection Concentration (FARSC), growth promotion, yield increase, food‐producing animals

1. Introduction

The European Commission requested EFSA to assess, in collaboration with the European Medicines Agency (EMA), (i) the specific concentrations of antimicrobials resulting from cross‐contamination in non‐target feed for food‐producing animals, below which there would not be an effect on the emergence of, and/or selection for, resistance in microbial agents relevant for human and animal health (term of reference 1, ToR1), and (ii) the levels of the antimicrobials which have a growth promotion/increase yield effect (ToR2). The assessment was requested to be conducted for 24 antimicrobial active substances specified in the mandate.1

For the different substances (grouped by class if applicable)1, separate scientific opinions included within the ‘Maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed’ series (Scientific Opinions Part 2–Part 13, EFSA BIOHAZ Panel 2021b‐l – see also the Virtual Issue; for practical reasons, they will be referred as ‘scientific opinion Part X’ throughout the current document) were drafted. They present the results of the assessments performed to answer the following questions: Assessment Question 1 (AQ1), which are the specific antimicrobial concentrations in non‐target feed below which there would not be emergence of, and/or selection for, resistance in the large intestines and/or the rumen, and AQ2, which are the specific antimicrobial concentrations in feed of food‐producing animals that have an effect in terms of growth promotion/increased yield. The assessments were performed following the methodology described in Section 2 of the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (EFSA BIOHAZ Panel, 2021a, see also the Virtual Issue). The present document reports the results of the assessment for amprolium.

1.1. Background and Terms of Reference as provided by the requestor

The background and ToRs provided by the European Commission for the present document are reported in Section 1.1 of the Scientific Opinion “Part 1: Methodology, general data gaps and uncertainties” (see also the Virtual Issue).

1.2. Interpretation of the Terms of Reference

The interpretation of the ToRs to be followed for the assessment is in Section 1.2 of the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue).

1.3. Additional information

1.3.1. Short description of the class/substance

Amprolium hydrochloride (1‐[(4‐amino‐2‐propyl‐5‐pyrimidinyl)methyl]‐2‐methylpyridinium chloride monohydrochloride) is a small synthetic molecule consisting of a quaternised derivative of pyrimidine (C14H19ClN4) that belongs to the class of organic compounds known as methylpyridines, containing a pyridine ring substituted at two positions by a methyl group. This thiamine (vitamin B1) analogue interferes with thiamine metabolism, blocking thiamine uptake, thus preventing synthesis of carbohydrates in coccidia (Bauchop and King, 1968).

Amprolium has coccidiostatic activity at low doses but is coccidiocidal at higher levels, although significant antibacterial activity is not considered to occur. It can be used for prevention and treatment of coccidiosis in a range of animals, especially poultry, as it blocks the thiamine transporter mechanism in meronts of Eimeria spp. interfering with intracellular metabolism. This inhibits the development of coccidial merozoites and second‐generation meronts. Amprolium also has some activity against the sexual stages of Eimeria and potentially also inhibits the development of sporozoites (Duszynski et al., 2018; Noack et al., 2019).

1.3.2. Main use2

Amprolium hydrochloride is marketed solely for veterinary use, either as a single compound or combined with ethopabate; a p‐aminobenzoic acid analogue that inhibits folic acid biosynthesis. It can also be administered in combination with sulfonamides or pyrimethamine (Duszynski et al., 2018). It is mainly used in poultry, cattle and sheep. Amprolium has been used for many years in some countries to control coccidiosis in sheep and cattle. It is mainly used orally for the treatment of animals showing clinical illness but may also be used for prevention by inclusion in feed (Baker et al., 1972; Norcross et al., 1974; Talmon et al., 1989).

Amprolium is also used for the treatment and prevention of coccidiosis in chickens, including laying hens and turkeys (Osman et al., 2020). For treatment, it can be administered via the birds’ drinking water or in the feed. Amprolium is authorised as a feed additive for poultry according to Council Directive 70/524/EEC3; for poultry at concentrations in the range of 62.5–125 mg/kg of compound feed; use is prohibited from laying age onwards and for at least 3 days before slaughter (EMEA/CVMP, 2001; EFSA FEEDAP Panel, 2018, 2021). Amprolium is included in Table 1 of Commission Regulation (EU) No 37/20104 as not requiring a maximum residue limit (MRL) for meat and offal, or eggs. It is also sometimes used by the ethanol industry to manage yeast cultures and has been found in yeast residues used as feed ingredients (Hoff et al., 2021).

1.3.3. Main pharmacokinetic data

When administered orally to chickens, one study reported a very low bioavailability (around 2–3% of amprolium) (Hamamoto et al., 2000) whereas another study reported a bioavailability of 66% (El‐Sayed et al., 1995). This discrepancy prevents the use of any of these values for calculations.

In one study, 8 h after dosing of chickens with amprolium, the residue concentrations were 46 and 74 mg/kg in the caecum in birds treated with 10 or 20 mg/kg body weight (bw), respectively (EMEA/CVMP, 2001). No information on the nature of the residues (parent drug or metabolites) is provided.

In rats, faecal excretion is the major route of elimination of radioactivity after oral administration of 14C‐labelled amprolium, with mean values of around 82% (EMEA/CVMP, 2001). Parent amprolium was detected in faecal samples at levels from 45% to 64% (EMEA/CVMP, 2001).

1.3.4. Main resistance mechanisms

Resistance develops rapidly in Eimeria spp. following the introduction of anticoccidials in the field. The molecular mechanisms involved in resistance are unclear, although mating experiments suggest that resistance may be transferable between coccidial gametes, which may supplement the main mechanism of clonal expansion of resistant strains (Jeffers, 1974; Chapman, 1997; Abbas et al., 2011a). E. acervulina and E. maxima are more likely to be intrinsically resistant than E. tenella (EFSA FEEDAP Panel, 2018, 2021).

Since, unlike the ionophore anticoccidials, amprolium is not considered to have antimicrobial activity other than its anticoccidial properties, selection of resistant bacteria or promotion of antimicrobial resistance (AMR) gene transfer would not be expected to be a relevant hazard (EMEA/CVMP, 2001; VKM, 2015; EFSA FEEDAP Panel, 2018, 2021). However, one old in vitro study did show that it was possible to inhibit the growth and to induce resistant mutants of Lactobacillus fermenti by sequential exposure to very high (175–1,400 μg/mL) concentrations of amprolium (Kishi et al., 1970).

2. Data and methodologies

The data sources and methodology used for this opinion are described in a dedicated document, the Scientific Opinion the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue).

3. Assessment

3.1. Introduction

As indicated in the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue), exposure to low concentrations of antimicrobials (including sub‐minimum inhibitory concentrations, Sub‐MIC) may have different effects on bacterial antimicrobial resistance evolution, properties of bacteria and in animal growth promotion. Some examples including emergence of, and selection for, antimicrobial resistance, mutagenesis, virulence and/or horizontal gene transfer (HGT), etc., for the antimicrobials under assessment are shown below.

3.1.1. Resistance development/spread due to sub‐MIC concentrations of amprolium: examples

3.1.1.1. Effects of Sub‐MIC concentrations on selection for resistance and mutagenesis

No MICs are available for amprolium. No studies describing bacterial resistance development using sub‐MIC concentrations are available.

3.1.1.2. Effects of Sub‐MIC concentrations on horizontal gene transfer and virulence

No MICs are available for amprolium. No studies describing effects on bacterial HGT and virulence of sub‐MIC concentrations are available.

3.2. ToR1. Estimation of the antimicrobial levels in non‐target feed that would not result in the selection of resistance: Feed Antimicrobial Resistance Selection Concentration (FARSC)

As explained in the Methodology Section (2.2.1.3) of the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue), the estimation of the FARSC value for amprolium for different animal species, if suitable data were available, would follow a two‐step approach as described below:

The first step would be the calculation of the predicted minimal selective concentration (PMSC). However, no minimal selective concentration (MSC) data required to do the calculations is available.

Due to the lack of PMSC, no FARSC could be calculated. If PMSC was available, the FARSC corresponding to the maximal concentrations in feed would be calculated for each species from the equations below (for details, see Section 2.2.1.3.2 of the Scientific Opinion Part 1; see also the Virtual Issue) by including specific values for amprolium.

FARSCintestine(mg/kg feed)=PMSC×daily faeces(1−I)×(1−F+F×GE)×daily feed intake

FARSCrumen(mg/kg feed)=PMSC×volume of rumen(1−I)×daily feed intake

With daily faeces being the daily fresh faecal output in kg, I the inactive fraction, F the fraction available, GE the fraction of the antimicrobial that is secreted back into the intestinal tract for elimination, after initially being absorbed into the bloodstream, and daily feed intake being the daily dry‐matter feed intake expressed in kg.

The reported oral bioavailability of amprolium in chickens is uncertain and there is no value for other species. There are also no data on the fate of amprolium after absorption and especially on the metabolism before gut elimination in the food‐producing animal species.

In consequence, no pharmacokinetic (PK) parameter value, that could be used to calculate FARSC for amprolium, was proposed.

3.2.1. Associated data gaps and uncertainties

With regard to the uncertainties and data gaps described in the Scientific Opinion Part 1 (Sections 3.1 and 3.3; see also the Virtual Issue), we identified the following for amprolium:

  1. MSC data: no data for MSCs are available.
  2. MIC data: no MIC data for bacteria are available.
  3. Bioavailability: data were only available for chickens but seem uncertain.
  4. Fraction eliminated in gut: an elimination of amprolium as inactive metabolites was described in rats. However, there are no quantitative data for other animal species to consider this process.
  5. Inactive fraction: no data on the possible binding of amprolium in digestive tract are available.
  6. Ruminants: no data are available for amprolium administered to ruminants by the oral route.

3.2.2. Concluding remarks

Due to the lack of data on the parameters required to calculate the FARSC, it is not possible to conclude the ToR1 assessment until further experimental data are available.

3.3. ToR2. Specific antimicrobial concentrations in feed which have an effect in terms of growth promotion/increased yield

3.3.1. Amprolium

3.3.1.1. Literature search results

The literature search, conducted according to the methodology described in Section 2.2.2.1 of the Scientific Opinion Part 1 (see also the Virtual Issue), resulted in 199 papers mentioning amprolium and any of the food‐producing animal species considered5 and any of the performance parameters identified as relevant for the assessment of the possible growth‐promoting effects of amprolium.6 After removing the reports not matching the eligibility criteria, 55 publications were identified.

3.3.1.2. Evaluation of the studies

The 55 publications identified in the literature search were appraised for suitability for the assessment of the effects of amprolium on growth or yield of food‐producing animals; this appraisal was performed by checking each study against a series of predefined exclusion criteria (see Section 2.2.2.2.1 of the Scientific Opinion Part 1; see also the Virtual Issue).7 A total of 52 publications were not considered suitable for the assessment because of several shortcomings identified in the design of the study or in the reporting of the results. The list of excluded publications and their shortcomings are presented in Appendix A (Table A.1).

Table A.1

Publications not relevant for the assessment of the effects of amprolium on growth promotion/increased yield and excluding criteria

Author (year)SpeciesExcluding criteria
Combination of substances administered to the animalsAntimicrobial used different from the one under assessmentAdministration via route different from oralUse of the antimicrobial with a therapeutic scopeAnimals subjected to challenges with pathogensAnimals in the study sick or not in good healthZootechnical parameters not reportedInsufficient reporting/statisticsOther (indicate)
Abbas et al. (2011b)PoultryXX
Abbas et al. (2011c)PoultryXX
Abou‐Elkhair et al. (2014)PoultryXX
Adamu and Boonkaewwan (2014)PoultryXX
Ahad et al. (2016)PoultryXX
Ahad et al. (2016)PoultryXX
Ahad et al. (2017)PoultryXX
Ahad et al. (2018)PoultryXX
Ali et al. (2019)PoultryXX
Allam et al. (2008)PoultryXX
Amer et al. (2010)PoultryXX
Cabel and Waldroup (1991)PoultryXXX
Cabel et al. (1991)PoultryXX
Chand et al. (2016)PoultryXX
Chapman (1989)PoultryXXXX
Chauhan et al. (2017)PoultryXX
Dakpogan et al. (2019)PoultryXX
Damron (1994)PoultryX
El‐Ghany et al. (2007)PoultryXX
El‐Ghoneimy and El‐Shahawy (2017)RabbitXX
El‐Morsy et al. (2016)PoultryXX
Fitz‐Coy and Edgar (1992)PoultryXXX
Fitzgerald (1972)RabbitXXX
Furusawa (2001)PoultryXX1
Galyen et al. (2020)RuminantsXXX
Gerhold et al. (2011)PoultryXXX
Golomazou et al. (2006)FishXXX
Hamed and Eladl (2011)PoultryXX
Holderread et al. (1983)PoultryXX2 , 3
Malik et al. (2014)PoultryXX
Malik et al. (2016)PoultryXX
McDougald (1979)PoultryXX
McDougald and McQuistion (1978)PoultryXX
McDougald and Seibert (1998)PoultryXX
Meskerem and Boonkaewwan (2013)PoultryXX
Munir et al. (2018)PoultryXX
Nabian et al. (2018)PoultryXXX
Norton (1967)PoultryXXX
Oe and Arakawa (1975)PoultryXXX
Ogbe et al. (2008)PoultryXXX3
Ogbe et al. (2009)PoultryXXX3
Ogbuookiri (2013)PoultryXXXXX4
Ohe and Arakawa (1976)PoultryXXX
Ojimelukwe et al. (2018)PoultryXX
Patton et al. (1984)PoultryX
Pop et al. (2019)PoultryXX
Riddell and Classen (1992)PoultryXX5
Ruff et al. (1991)PoultryXX
Selvarani et al. (2014)PoultryXXX
Spencer and Waldroup (1985)PoultryX4
Waibel et al. (1991)PoultryXX4
Zaman et al. (2012)PoultryXX
1Designed to study the transfer of antibiotics to eggs.
2The study investigated the adverse effects of anticoccidial drugs administered to ducklings.
3Small number of animals per group, no replicates.
4Unclear number of birds/replicates per treatment.
5No untreated control group.

The publications considered suitable for the assessment are described and assessed in Section 3.3.1.3.

3.3.1.3. Assessment of the effects of amprolium on growth performance and yield

Three publications were considered suitable for the assessment of the effects of amprolium on growth and yield performance in food‐producing animals. The effects of the administration of the antimicrobial on the endpoints described in Section 2.2.2.2.2 of the Scientific Opinion Part 1 (see also the Virtual Issue) were evaluated. The selected publications and the effects on the relevant endpoints are described below. The summary of the studies includes the description of the source of amprolium used – either as the base or as any specific form/commercial preparation – and the concentration(s) applied as reported in each study; where a specific compound has been used, the calculation of the concentration applied to the base substance is provided.

3.3.1.3.1. Study in ruminants

In the study of Silzell et al. (2001), a total of 96 mix‐breed cattle for fattening were distributed in four dietary treatments (24 animals/treatment), each including four pens with six animals. Two controls and two treatment groups, which involved the dietary administration of amprolium (unspecified chemical form; Amprolium 1.25% Cattle Pellets; Nutra Blend Corp) at a concentration of 5 mg/kg initial body weight (BW) (equivalent to 250 mg/kg dry matter (DM), using the default value 20 g DM intake/kg BW,8 initial BW 211 kg), with or without supplementation with thiamine at 140 mg/kg DM. The study lasted 35 days, but amprolium was only administered for the first 21 days. Steers were observed daily for signs of morbidity. BW was measured weekly and faecal samples were evaluated for coccidia oocyst counts. At the end of the trial steers treated with amprolium showed lower oocyst counts compared to controls but no effect on growth performance parameters was found regardless of the thiamine supplementation. Dietary amprolium supplementation at 250 mg/kg DM did not have growth‐promoting effects in cattle for fattening.

3.3.1.3.2. Studies in poultry

In the study of Chauhan et al. (2015), a total of 168 1‐day‐old commercial chickens for fattening (unspecified breed/genotype) were distributed in seven experimental groups (24 birds/treatment), each including 12 birds with two replicates. The diets were either not supplemented or supplemented with different treatments (four groups were infected with Eimeria spp.). For the assessment only two were the relevant treatments: a control and a treatment consisting of amprolium (unspecified form) supplemented at 125 mg/kg feed without experimental Eimeria infection. The study lasted 30 days. Feed intake (FI) and weight gain were measured every 5 days; feed efficiency and performance index (weight gain × feed efficiency ratio) were calculated. At the end of the trial, the chickens treated with amprolium showed a decrease in cumulative FI (1,922 vs 1,998 g), cumulative weight gain (1,259 vs 1,314 g) and performance index (825 vs 865) compared to the control group. Dietary amprolium supplementation at 125 mg/kg feed had a negative effect on performance of chickens for fattening.

3.3.1.3.3. Study in fish

In the study of Manning et al. (2013), a total of 320 juvenile Channel catfish (Ictalurus punctatus) were distributed in four dietary treatments (80 fish/treatment) each including four replicate tanks at 20 fish each. The diets were either not supplemented or supplemented with amprolium (unspecified form) at the concentrations of 50, 100 and 200 mg per kg initial total weight of fish, corresponding to 2,000, 4,000 and 8,000 mg/kg feed, respectively; fish were given weighed diets calculated as 2.5% of total initial weight. The study lasted 10 days. Endpoints included total FI, weight gain and feed to gain ratio (F:G). Total FI and weight gain showed no differences among experimental groups. Dietary amprolium supplementation at 2,000, 4,000 and 8,000 mg/kg feed did not have a growth‐promoting effect in Channel catfish.

3.3.1.4. Discussion

From the studies examined, the test item has been described as ‘amprolium’ (unspecified form; four studies). Therefore, an uncertainty on the exact product used/concentration applied has been identified.

A detailed analysis of the uncertainties for amprolium is included in Appendix B (Table B.1) of this document, and the Section 3.3 of the Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue).

Table B.1

Potential sources of uncertainty identified in the levels of amprolium in feed which have growth promotion/increase yield effect and assessment of the impact that these uncertainties could have on the conclusion 

Source of the uncertaintyNature or cause of uncertaintyImpact of the uncertainty on the conclusion on the level(s) which have growth promotion/increase yield effect
Form(s) of antimicrobial usedThe specific form of the antimicrobial used in the study (as the ‘(free) base’ substance, its salts or specific products/formulations containing the base substance) has not been clearly described in several publications. In summarising the results, the concentrations have been reported as for ‘base’ substance when the form of the antimicrobial is not specified (conservative assumption)Underestimation of the concentration which may have shown growth‐promoting effect
Evidence synthesis and integrationAs described in Section 2.2.3 of the Scientific Opinion Part 1 (see also the Virtual Issue), the low number of studies retrieved prevented evidence synthesis.Underestimation/Overestimation

3.3.1.4.1. Ruminants

Only one study reporting the effect of oral administration of amprolium is available for cattle for fattening (Silzell et al., 2001), from which the concentration of 250 mg/kg DM did not show a growth‐promoting effect.

3.3.1.4.2. Poultry

Only one study reporting the effect of oral administration is available for chicken for fattening (Chauhan et al., 2015). Dietary amprolium supplementation at 125 mg/kg feed had a negative effect on the performance of chickens for fattening.

3.3.1.4.3. Fish

Only one study reporting the effect of oral administration of amprolium is available for Channel catfish (Manning et al., 2013). Dietary amprolium supplementation at 50, 100 and 200 mg/kg bw (2,000, 4,000 and 8,000 mg/kg feed) did not have a growth‐promoting effect on Channel Catfish.

3.3.1.5. Concluding remarks

No data are available in the scientific literature showing effect of amprolium on growth promotion/increased yield when added to feed of any food‐producing animal species or categories. It is judged 33–66% certain (‘about as likely as not’) that amprolium has negative effects on performance of chickens for fattening at the concentration of 125 mg/kg complete feed (one study).

4. Conclusions

ToR1: to assess the specific concentrations of antimicrobials resulting from cross‐contamination in non‐target feed for food‐producing animals, below which there would not be an effect on the emergence of, and/or selection for, resistance in microbial agents relevant for human and animal health.

AQ1. Which are the specific concentrations of amprolium in non‐target feed below which there would not be emergence of, and/or selection for, resistance in the large intestines/rumen?

  • Due to the lack of data on the parameters required to calculate the Feed Antimicrobial Resistance Selection Concentration (FARSC) corresponding to the concentrations of amprolium in non‐target feed below which there would not be expected to be an effect on the emergence of, and/or selection for, resistance in microbial agents relevant for human and animal health, it is not possible to conclude until further experimental data are available.

ToR2: to assess which levels of the antimicrobials have a growth promotion/increase yield effect.

AQ2. Which are the specific concentrations of amprolium in feed of food‐producing animals that have an effect in terms of growth promotion/increased yield?

  • No data are available in the scientific literature showing effects of amprolium on growth promotion/increased yield when added to feed of any food‐producing animal species or categories.
  • It is judged 33–66% certain (‘about as likely as not’) that amprolium has negative effects on performance of chickens for fattening at the concentration of 125 mg/kg complete feed (one study).

The results from these assessments for the different animal species are summarised in Annex F (Tables F.1 and F.2) of EFSA BIOHAZ Panel, 2021a ‐ Scientific Opinion ‘Part 1: Methodology, general data gaps and uncertainties’ (see also the Virtual Issue).

5. Recommendation

To carry out studies to generate the data that are required to fill the gaps which have prevented calculation of the FARSC for amprolium. However, due to the absence of antibacterial activity on the concentrations used for the prevention and treatment of coccidiosis, those studies are not a priority.

Abbreviations

ATP
adenosine triphosphate
AQ
assessment question
BW
body weight
bw
body weight used in toxicity studies
DM
dry matter
EUCAST
European Committee on Antimicrobial Susceptibility testing
F
fraction of the antimicrobial that is absorbed from the digestive tract to the blood
FARSC
Feed Antimicrobial Resistance Selection Concentration
F:G
feed to gain ratio
FI
feed intake
GE
fraction of the antimicrobial that is secreted back into the intestinal tract for elimination, after initially being absorbed into the bloodstream
I
fraction of the antimicrobial present in the digestive tracts that would be inactive on the microbiota
LPS
lipopolysaccharide
MIC
minimum inhibitory concentration
MIClowest
minimum inhibitory concentration of the most susceptible species/strain included in the EUCAST database for a certain antimicrobial used to calculate the PMSC (see below)
MICres
minimum inhibitory concentration of the resistant strain
MICsusc
minimum inhibitory concentration of the susceptible strain
MICtest
minimum inhibitory concentration of the susceptible isolate used in the competition experiments to calculate the MSC
MRL
maximum residues limit
MSC
minimal selective concentration
PK
pharmacokinetic
PMSC
predicted MSC
rRNA
ribosomal ribonucleic acid
ToRs
Terms of Reference

Appendix A – List of excluded publications and their shortcomings

1.

The publications excluded from the assessment of the effects of amprolium on growth promotion/increased yield following the criteria defined in Section 2.2.2.2.1 of the Scientific Opinion Part 1 (see also the Virtual Issue) are summarised in Table A.1.

Appendix B – Table of uncertainties

1.

Uncertainties associated with the growth promotion assessment

Notes

Suggested citation: EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards) , Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021. Scientific Opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 3: Amprolium . EFSA Journal 2021;19(10):6854, 20 pp. 10.2903/j.efsa.2021.6854 [CrossRef]

Requestor: European Commission

Question number: EFSA‐Q‐2021‐00503

Panel members: Ana Allende, Avelino Alvarez‐Ordóñez, Declan Bolton, Sara Bover‐Cid, Marianne Chemaly, Robert Davies, Alessandra De Cesare, Lieve Herman, Friederike Hilbert, Konstantinos Koutsoumanis, Roland Lindqvist, Maarten Nauta, Luisa Peixe, Giuseppe Ru, Marion Simmons, Panagiotis Skandamis and Elisabetta Suffredini.

Declarations of interest: The declarations of interest of all scientific experts active in EFSA's work are available at https://ess.efsa.europa.eu/doi/doiweb/doisearch.

Acknowledgements: The BIOHAZ Panel, leading Panel in charge of the adoption of the scientific opinion and assessment of Term of Reference 1 (ToR1, antimicrobial resistance) wishes to thank the following for the support provided to this scientific output: EFSA Panel on Animal Health and Welfare (AHAW Panel), who supported ToR1 assessments development and endorsement of those sections under their remit (animal production, main use of antimicrobials); EFSA Panel for Additives and Products or Substances used in Animal Feed (FEEDAP), in charge of the assessment and endorsement of ToR2, and providing advice and data needed for ToR1 assessments; European Medicines Agency (EMA), who was represented by an external expert and EMA secretariat as members of the Working Group (WG); Valeria Bortolaia, who was member of the WG until 17 April 2020; EFSA staff members: Angelica Amaduzzi, Gina Cioacata, Pilar García‐Vello, Michaela Hempen, Rita Navarrete, Daniel Plaza and Anita Radovnikovic; EMA staff members: Barbara Freischem, Zoltan Kunsagi, Nicholas Jarrett, Jordi Torren, and Julia Fábrega (currently EFSA staff). The BIOHAZ Panel wishes also to acknowledge the EMA Committee for Medicinal Products for Veterinary Use (CVMP) and their experts.

Adopted: 15 September 2021

Notes

1Aminoglycosides: apramycin, paromomycin, neomycin, spectinomycin; Amprolium; Beta‐lactams: amoxicillin, penicillin V; Amphenicols: florfenicol, thiamphenicol; Lincosamides: lincomycin; Macrolides: tilmicosin, tylosin, tylvalosin; Pleuromutilins: tiamulin, valnemulin; Sulfonamides; Polymyxins: colistin; Quinolones: flumequine, oxolinic acid; Tetracyclines: tetracycline, chlortetracycline, oxytetracycline, doxycycline; Diaminopyrimidines: trimethoprim.

2Antimicrobials are currently used in food‐producing animal production for treatment, prevention and/or metaphylaxis of a large number of infections, and also for growth promotion in non‐EU countries. In the EU, in future, use of antimicrobials for prophylaxis or for metaphylaxis is to be restricted as addressed by Regulation (EU) 2019/6 and Regulation (EU) 2019/4.

3Council Directive 70/524/EEC of 23 November 1970 concerning additives in feeding‐stuffs. OJ L 270, 14.12.1970, p. 1–17.

4Commission Regulation (EU) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin. OJ L 15, 20.1.2010, p. 1–72.

5Ruminants: growing and dairy (cattle, sheep, goats, buffaloes); pigs: weaned, growing and reproductive; equines; rabbits; poultry: chickens and turkeys for fattening, laying hens, turkeys for breeding, minor avian species (ducks, guinea fowl, geese, quails, pheasants, ostrich); fish: salmon, trout, other farmed fish (seabass, seabream, carp, other); crustaceans; other animal species.

6(i) Intake‐related parameters: feed intake, feed/gain ratio, feed efficiency, feed intake/milk yield, feed intake/egg mass; (ii) Weight‐related parameters: body weight, body weight gain; (iii) Carcass‐related parameters: carcass weight, carcass yield, carcass chemical composition, relative weight of the (different sections of) intestine; (iv) Milk or egg production/quality: milk yield, fat/protein yield, egg production/laying rate, egg weight, egg mass; (v) Digestibility/utilisation of nutrients: utilisation of some nutrients (e.g. DM, Ca, P), digestibility; (vi) Health‐related parameters: reduction of morbidity and/or mortality; (vii) Herd/flock‐related parameters; (viii) Other endpoints: e.g. intestinal morphological characteristics (villi height/width), changes in microbiota.

7The following exclusion criteria were applied: ‘Combination of substances administered to the animals’, ‘Antimicrobial used different from the one under assessment’, ‘Administration via route different from oral’, ‘Use of the antimicrobial with a therapeutic scope’, ‘Animals subjected to challenges with pathogens’, ‘Animals in the study sick or not in good health, Zootechnical parameters not reported’, ‘Insufficient reporting/statistics’, ‘Other (indicate)’.

8Default values for daily feed intake scaled to body weight from the EFSA FEEDAP Guidance on the assessment of the safety of feed additives for the target species. Available online: https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2017.5021

References

  • Abbas R, Iqbal Z, Blake D, Khan MN and Kashif M, 2011a. Anticoccidial drug resistance in fowl coccidia: the state of play revisited. World's Poultry Science Journal, 67, 337–350. 10.1017/S004393391100033X [CrossRef] [Google Scholar]
  • Abbas RZ, Manzoor Z, Munawar SH, Iqbal Z, Khan MN, Saleemi MK, Zia MA and Yousaf A, 2011b. Anticoccidial activity of hydrochloric acid (HCl) against Eimeria tenella in broiler chickens. Pesquisa Veterinária Brasileira, 31, 425–429. 10.1590/S0100-736X2011000500010 [CrossRef] [Google Scholar]
  • Abbas RZ, Munawar SH, Manzoor Z, Iqbal Z, Khan MN, Saleemi MK, Zia MA and Yousaf A, 2011c. Anticoccidial effects of acetic acid on performance and pathogenic parameters in broiler chickens challenged with Eimeria tenella . Pesquisa Veterinária Brasileira, 31, 99–103. 10.1590/S0100-736X2011000200001 [CrossRef] [Google Scholar]
  • Abou‐Elkhair R, Gaafar KM, Elbahy NM, Helal MA, Mahboub HDH and Sameh G, 2014. Bioactive effect of dietary supplementation with essential oils blend of Oregano, thyme and garlic oils on performance of broilers infected with Eimeria species. Global Veterinaria, 13, 977–985. 10.5829/idosi.gv.2014.13.06.9137 [CrossRef] [Google Scholar]
  • Adamu M and Boonkaewwan C, 2014. Effect of Lepidium sativum L. (garden cress) seed and its extract on experimental Eimeria tenella infection in broiler chickens. Kasetsart Journal, Natural Science, 48, 28–37 [Google Scholar]
  • Ahad S, Tanveer S and Malik TA, 2016. Anticoccidial activity of aqueous extract of a wild mushroom (Ganoderma applanatum) during experimentally induced coccidial infection in broiler chicken. Journal of Parasitic Diseases, 40, 408–414. 10.1007/s12639-014-0518-3 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Ahad S, Tanveer S, Nawchoo IA and Malik TA, 2017. Anticoccidial activity of Artemisia vestita (Anthemideae, Asteraceae) ‐ a traditional herb growing in the Western Himalayas, Kashmir, India. Microbial Pathogenesis, 104, 289–295. 10.1016/j.micpath.2017.01.053 [PubMed] [CrossRef] [Google Scholar]
  • Ahad S, Tanveer S, Malik TA and Nawchoo IA, 2018. Anticoccidial activity of fruit peel of Punica granatum L. Microbial Pathogenesis, 116, 78–83. 10.1016/j.micpath.2018.01.015 [PubMed] [CrossRef] [Google Scholar]
  • Ali M, Chand N, Khan RU, Naz S and Gul S, 2019. Anticoccidial effect of garlic (Allium sativum) and ginger (Zingiber officinale) against experimentally induced coccidiosis in broiler chickens. Journal of Applied Animal Research, 47, 79–84. 10.1080/09712119.2019.1573731 [CrossRef] [Google Scholar]
  • Allam HH, Bayoumie HAA, Malhat SMH and Mohamed IAA, 2008. Effect of toltrazuril and amprolium plus in broiler chickens infected with coccidiosis. Assiut Veterinary Medical Journal, 54, 253–266. [Google Scholar]
  • Amer MM, Awaad MHH, Abo‐Elezz NMN, El‐Khateeb RM, Sherein‐Said A, Ghetas MM and Kutkat MA, 2010. Experimental study on the efficacy of some commonly used anticoccidial drugs in controlling of coccidiosis with mixed field isolates in broiler chickens. World Applied Sciences Journal, 9, 359–366. [Google Scholar]
  • Baker NF, Walters GT and Fisk RA, 1972. Amprolium for control of coccidiosis in feedlot lambs. American Journal of Veterinary Research, 33, 83–86. [PubMed] [Google Scholar]
  • Bauchop T and King L, 1968. Amprolium and thiamine pyrophosphotransferase. Applied Microbiology, 16, 961–962. [PMC free article] [PubMed] [Google Scholar]
  • Cabel MC and Waldroup PW, 1991. Effects of different coccidiostats on performance of large white turkeys. Poultry Science, 70, 241–249. 10.3382/ps.0700241 [PubMed] [CrossRef] [Google Scholar]
  • Cabel MC, Norton RA, Yazwinski TA and Waldroup PW, 1991. Efficacy of different anticoccidials against experimental coccidiosis in large white turkeys. Poultry Science, 70, 289–292. 10.3382/ps.0700289 [PubMed] [CrossRef] [Google Scholar]
  • Chand N, Faheem H, Khan RU, Qureshi MS, Alhidary IA and Abudabos AM, 2016. Anticoccidial effect of mananoligosacharide against experimentally induced coccidiosis in broiler. Environmental Science and Pollution Research, 23, 14414–14421. 10.1007/s11356-016-6600-x [PubMed] [CrossRef] [Google Scholar]
  • Chapman HD, 1989. Chemotherapy of caecal coccidiosis: efficacy of toltrazuril, sulphaquinoxaline/pyrimethamine and amprolium/ethopabate, given in drinking water, against field isolates of Eimeria tenella . Research in Veterinary Science, 46, 419–420. 10.1016/S0034-5288(18)31193-7 [PubMed] [CrossRef] [Google Scholar]
  • Chapman HD, 1997. Biochemical, genetic and applied aspects of drug resistance in Eimeria parasites of the fowl. Avian Pathology, 26, 221–244. 10.1080/03079459708419208 [PubMed] [CrossRef] [Google Scholar]
  • Chauhan S, Singh VS, Vatsya S, Palod J, Thakur V, Tiwari S and Kandpal N, 2015. Effect of Calotropis procera (Madar) and amprolium supplementation on growth performance of broilers during mixed Eimeria species infection. Haryana Veterinarian, 54, 198–201. [Google Scholar]
  • Chauhan S, Singh VS and Thakur V, 2017. Effect of Calotropis procera (madar) and amprolium supplementation on parasitological parameters of broilers during mixed Eimeria species infection. Veterinary World, 10, 864–868. 10.14202/vetworld.2017.864-868 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Dakpogan HB, Gandaho CS, Houndonougbo PV, Dossa LH, Houndonougbo MF and Chrysostome C, 2019. Anticoccidial activity of Khaya senegalensis, Senna siamea and Chamaecrista rotundifolia in chicken (Gallus gallus). International Journal of Biological and Chemical Sciences, 13, 2121–2128. 10.4314/ijbcs.v13i4.19 [CrossRef] [Google Scholar]
  • Damron BL, 1994. The relationship of maximum or intermediate coccidiostat levels to broiler chick water intake. Poultry Science, 73, 33–36. 10.3382/ps.0730033 [PubMed] [CrossRef] [Google Scholar]
  • Duszynski DW, Kvic\ˇerová J and Seville RS, 2018. Chapter 18 ‐ Treatment and drug therapies of coccidiosis in carnivora. In: Duszynski DW, Kvic\ˇerová J and Seville RS (eds.). The Biology and Identification of the Coccidia (Apicomplexa) of Carnivores of the World, Academic Press, pp. 445–463. [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021a. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 1: Methodology, general data gaps and uncertainties. EFSA Journal 2021;19(10):6852, 57 pp. 10.2903/j.efsa.2021.6852 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021b. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 2: Aminoglycosides/aminocyclitols: apramycin, paromomycin, neomycin and spectinomycin. EFSA Journal 2021;19(10):6853, 40 pp. 10.2903/j.efsa.2021.6853 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021c. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 4: β‐lactams: amoxicillin and penicillin V. EFSA Journal 2021;19(10):6855, 26 pp. 10.2903/j.efsa.2021.6855 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021d. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 5: Lincosamides: lincomycin. EFSA Journal 2021;19(10):6856, 21 pp. 10.2903/j.efsa.2021.6856 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021e. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 6: Macrolides: tilmicosin, tylosin and tylvalosin. EFSA Journal 2021;19(10):6858, 52 pp. 10.2903/j.efsa.2021.6858 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021f. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 7: Amphenicols: florfenicol and thiamphenicol. EFSA Journal 2021;19(10):6859, 27 pp. 10.2903/j.efsa.2021.6859 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021g. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 8: Pleuromutilins: tiamulin and valnemulin. EFSA Journal 2021;19(10):6860, 27 pp. 10.2903/j.efsa.2021.6860 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021h. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 9: Polymyxins: colistin. EFSA Journal 2021;19(10):6861, 33 pp. 10.2903/j.efsa.2021.6861 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021i. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 10: Quinolones: flumequine and oxolinic acid. EFSA Journal 2021;19(10):6862, 18 pp. 10.2903/j.efsa.2021.6862 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021j. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 11: Sulfonamides. EFSA Journal 2021;19(10):6863, 26 pp. 10.2903/j.efsa.2021.6863 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021k. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 12: Tetracyclines: tetracycline, chlortetracycline, oxytetracycline, and doxycycline. EFSA Journal 2021;19(10):6864, 115 pp. 10.2903/j.efsa.2021.6864 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), Koutsoumanis K, Allende A, Alvarez‐Ordóñez A, Bolton D, Bover‐Cid S, Chemaly M, Davies R, De Cesare A, Herman L, Hilbert F, Lindqvist R, Nauta M, Ru G, Simmons M, Skandamis P, Suffredini E, Andersson DI, Bampidis V, Bengtsson‐Palme J, Bouchard D, Ferran A, Kouba M, López Puente S, López‐Alonso M, Nielsen SS, Pechová A, Petkova M, Girault S, Broglia A, Guerra B, Innocenti ML, Liébana E, López‐Gálvez G, Manini P, Stella P and Peixe L, 2021l. Scientific opinion on the maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 13: Diaminopyrimidines: trimethoprim. EFSA Journal 2021;19(10):6865, 19 pp. 10.2903/j.efsa.2021.6865 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA FEEDAP Panel (EFSA Panel on Additives Products or Substances used in Animal Feed), Rychen G, Aquilina G, Azimonti G, Bampidis V, Bastos MdL, Bories G, Chesson A, Cocconcelli PS, Flachowsky G, Kolar B, Kouba M, López‐Alonso M, López Puente S, Mantovani A, Mayo B, Ramos F, Saarela M, Villa RE, Wallace RJ, Wester P, Brantom P, Halle I, van Beelen P, Holczknecht O, Vettori MV and Gropp J, 2018. Safety and efficacy of COXAM® (amprolium hydrochloride) for chickens for fattening and chickens reared for laying. EFSA Journal 2018;16(7):5338, 28 pp. 10.2903/j.efsa.2018.5338 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed), Bampidis V, Azimonti G, Bastos MdL, Christensen H, Dusemund B, Fas\ˇmon Durjava M, Kouba M, López‐Alonso M, López Puente S, Marcon F, Mayo B, Pechová A, Petkova M, Ramos F, Sanz Y, Villa RE, Woutersen R, Gropp J, Rychen G, Holczknecht O and Vettori MV, 2021. Efficacy of the feed additive consisting of amprolium hydrochloride (COXAM®) for use in chickens for fattening and chickens reared for laying (Huvepharma N.V.). EFSA Journal 2021;19(3):6457, 6 pp. 10.2903/j.efsa.2021.6457 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • El‐Ghany WAA, Madian K, Amer AM, El‐Gaied SSA and Amer MM, 2007. Comparative study on the efficacy of a probiotic and different anticoccidial drugs against Eimeria tenella infection in broiler chickens. Veterinary Medical Journal Giza, 55, 245–274. [Google Scholar]
  • El‐Ghoneimy A and El‐Shahawy I, 2017. Evaluation of amprolium and toltrazuril efficacy in controlling natural intestinal rabbit coccidiosis. Iranian Journal of Veterinary Research, 18, 164–169. 10.22099/IJVR.2017.4217 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • El‐Morsy MA, El‐Azm KIA and Awad SS, 2016. Efficacy of some anticoccidial drugs on experimentally induced cecal coccidiosis (E. tsunodai) in Japanese quails. Egyptian Journal of Veterinary Sciences, 47, 165–177. [Google Scholar]
  • El‐Sayed MG, Abd el‐Aziz MI and el‐Kholy MH, 1995. Kinetic behaviour of sulphaquinoxaline and amprolium in chickens. Deutsche Tierärztliche Wochenschrift, 102, 481–485. [PubMed] [Google Scholar]
  • EMEA/CVMP (European Agency for the Evaluation of Medicinal Products/Committee for Veterinary Medicinal Products), 2001. Amprolium. Summary report (2). EMEA/MRL/767/00-FINAL. Available online: https://www.ema.europa.eu/en/documents/mrl-report/amprolium-summary-report-2-committee-veterinary-medicinal-products_en.pdf
  • Fitz‐Coy SH and Edgar SA, 1992. Pathogenicity and control of Eimeria mitis infections in broiler chickens. Avian Diseases, 36, 44–48. 10.2307/1591713 [PubMed] [CrossRef] [Google Scholar]
  • Fitzgerald PR, 1972. Efficacy of monensin or amprolium in the prevention of hepatic coccidiosis in rabbits. The Journal of Protozoology, 19, 332–334. 10.1111/j.1550-7408.1972.tb03469.x [PubMed] [CrossRef] [Google Scholar]
  • Furusawa N, 2001. Transference of dietary veterinary drugs into eggs. Veterinary Research Communications, 25, 651–662. 10.1023/A:1012743230180 [PubMed] [CrossRef] [Google Scholar]
  • Galyen WL, Beck PA, Hess TW, Hubbell DS, Gadberry MS, Kegley EB, Cravey M and Powell JG, 2020. Effects of bambermycin with amprolium or monensin on beef cattle growth performance, coccidia infection, and bovine respiratory disease morbidity during receiving. Applied Animal Science, 36, 423–429. 10.15232/aas.2019-01971 [CrossRef] [Google Scholar]
  • Gerhold RW, Fuller AL, Lollis L, Parr C and McDougald LR, 2011. The efficacy of anticoccidial products against Eimeria spp. in northern bobwhites. Avian Diseases, 55, 59–64. 10.1637/9572-101310-Reg.1 [PubMed] [CrossRef] [Google Scholar]
  • Golomazou E, Athanassopoulou F, Karagouni E, Vagianou S, Tsantilas H and Karamanis D, 2006. Efficacy and toxicity of orally administrated anti‐coccidial drug treatment on Enteromyxum leei infections in sharpsnout seabream (Diplodus puntazzo C.). Israeli Journal of Aquaculture ‐ Bamidgeh, 58, 157–169 [Google Scholar]
  • Hamamoto K, Koike R and Machida Y, 2000. Bioavailability of amprolium in fasting and nonfasting chickens after intravenous and oral administration. Journal of Veterinary Pharmacology and Therapeutics, 23, 9–14. 10.1046/j.1365-2885.2000.00239.x [PubMed] [CrossRef] [Google Scholar]
  • Hamed HR and Eladl AH, 2011. Efficacy of commonly used anticoccidial drugs in broiler chickens. In: Proceedings of the 4th Scientific Conference of Animal Wealth Research in the Middle East and North Africa, Foreign Agricultural Relations (FAR), Egypt, 3‐5 October 2011, Massive Conferences and Trade Fairs, Cairo, 499 pp.
  • Hoff RB, Molognoni L, Deolindo CTP, de Oliveira T, Mattos JLS, Oliveira LVA and Daguer H, 2021. Residues of antibiotics in yeasts from ethanol production: a possible contamination route for feedingstuffs. Journal of Environmental Science and Health. Part B: Pesticides, Food Contaminants, and Agricultural Wastes, 56, 307–312. 10.1080/03601234.2021.1880223 [PubMed] [CrossRef] [Google Scholar]
  • Holderread D, Nakaue HS and Arscott GH, 1983. Anticoccidial drugs and duckling performance to four weeks of age. Poultry Science, 62, 1125–1127. 10.3382/ps.0621125 [PubMed] [CrossRef] [Google Scholar]
  • Jeffers TK, 1974. Genetic transfer of anticoccidial drug resistance in Eimeria tenella . Journal of Parasitology, 60, 900–904. [PubMed] [Google Scholar]
  • Kishi H, Okumoto C and Hiraoka E, 1970. Isolation and properties of mutants of Lactobacillus fermenti resistant to Amprolium. Journal of Vitaminology (Kyoto), 17, 59–63. 10.5925/jnsv1954.17.59 [PubMed] [CrossRef] [Google Scholar]
  • Malik TA, Kamili AN, Chishti MZ, Tanveer S, Ahad S and Johri RK, 2014. In vivo anticoccidial activity of berberine [18, 5,6‐dihydro‐9,10‐ dimethoxybenzo(g)‐1,3‐benzodioxolo(5,6‐a) quinolizinium] ‐ an isoquinoline alkaloid present in the root bark of Berberis lycium . Phytomedicine, 21, 663–669. 10.1016/j.phymed.2013.11.005 [PubMed] [CrossRef] [Google Scholar]
  • Malik TA, Kamili AN, Chishti MZ, Tanveer S, Ahad S and Johri RK, 2016. Synergistic approach for treatment of chicken coccidiosis using berberine ‐ a plant natural product. Microbial Pathogenesis, 93, 56–62. 10.1016/j.micpath.2016.01.012 [PubMed] [CrossRef] [Google Scholar]
  • Manning BB, Griffin MJ, Khoo LH, Wise DJ and Greenway T, 2013. Palatability of diets for channel catfish that contain Amprolium or Salinomycin using feed conversion ratio as the criterion. North American Journal of Aquaculture, 75, 99–101. 10.1080/15222055.2012.736448 [CrossRef] [Google Scholar]
  • McDougald LR, 1979. Efficacy and compatibility of amprolium and carbarsone against coccidiosis and blackhead in turkeys. Poultry Science, 58, 76–80. 10.3382/ps.0580076 [PubMed] [CrossRef] [Google Scholar]
  • McDougald LR and McQuistion TE, 1978. Innate and acquired immunity vs. anticoccidial medication in managing coccidiosis in turkeys. Avian Diseases, 22, 765–770. 10.2307/1589654 [PubMed] [CrossRef] [Google Scholar]
  • McDougald LR and Seibert BP, 1998. Residual activity of anticoccidial drugs in chickens after withdrawal of medicated feeds. Veterinary Parasitology, 74, 91–99. 10.1016/S0304-4017(97)00172-6 [PubMed] [CrossRef] [Google Scholar]
  • Meskerem A and Boonkaewwan C, 2013. Protective effects of moringa stenopetala leaf supplemented diets on Eimeria tenella infected broiler chickens in Debre Zeit, central, Ethiopia. Kasetsart Journal, Natural Science, 47, 398–406. [Google Scholar]
  • Munir HA, Akbar H, Lateef M, Rashid I, Akhtar R, Nazir J and Farooqi SH, 2018. Anticoccidial activity of different forms of Aloe vera . Indian Journal of Animal Research, 52, 470–473. 10.18805/ijar.B-534 [CrossRef] [Google Scholar]
  • Nabian S, Arabkhazaeli F, Seifouri P and Farahani A, 2018. Morphometric analysis of the intestine in experimental coccidiosis in broilers treated with anticoccidial drugs. Iranian Journal of Parasitology, 13, 493–499. [PMC free article] [PubMed] [Google Scholar]
  • Noack S, Chapman HD and Selzer PM, 2019. Anticoccidial drugs of the livestock industry. Parasitology Research, 118, 2009–2026. 10.1007/s00436-019-06343-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Norcross MA, Siegmund OH and Fraser CM, 1974. Amprolium for coccidiosis in cattle: a review of efficacy and safety. Veterinary Medicine, Small Animal Clinician: VM, SAC, 69, 459 passim. [PubMed] [Google Scholar]
  • Norton CC, 1967. Eimeria colchici sp. nov. (Protozoa: Eimeriidae), the cause of cecal coccidiosis in English covert pheasants. The Journal of Protozoology, 14, 772–781. 10.1111/j.1550-7408.1967.tb02077.x [CrossRef] [Google Scholar]
  • Oe O and Arakawa A, 1975. Effect of feed additive antibiotics on chickens infected with Eimeria tenella . Poultry Science, 54, 1008–1018. [PubMed] [Google Scholar]
  • Ogbe AO, Mgbojikwe LO, Abdu PA and Atawodi SE, 2008. Organ and carcass weight variation and histopathological changes in Eimeria tenella infected broiler chickens treated with aqueous extract of a wild mushroom (Ganoderma lucidum). Electronic Journal of Environmental, Agricultural and Food Chemistry, 7, 2906–2913. [Google Scholar]
  • Ogbe AO, Atawodi SE, Abdu PA, Sannusi A and Itodo AE, 2009. Changes in weight gain, faecal oocyst count and packed cell volume of Eimeria tenella‐infected broilers treated with a wild mushroom (Ganoderma lucidum) aqueous extract. Journal of the South African Veterinary Association, 80, 97–102. 10.4102/jsava.v80i2.179 [PubMed] [CrossRef] [Google Scholar]
  • Ogbuookiri UDE, 2013. Sustainability of veterinary drugs against field isolates of E. maxima . International Journal of Veterinary Science, 2, 65–67. [Google Scholar]
  • Ohe O and Arakawa A, 1976. Effect of dietary antibiotics on chickens infected with Eimeria tenella . Poultry Science, 55, 660–665. 10.3382/ps.0550660 [PubMed] [CrossRef] [Google Scholar]
  • Ojimelukwe AE, Emedhem DE, Agu GO, Nduka FO and Abah AE, 2018. Populations of Eimeria tenella express resistance to commonly used anticoccidial drugs in southern Nigeria. International Journal of Veterinary Science and Medicine, 6, 192–200. 10.1016/j.ijvsm.2018.06.003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Osman N, Abdel‐Kawy M, Shibat El‐hamed DMW, Ibrahim A, Al‐Amgad Z and Ahmed MS, 2020. Comparative study between the prophylactic impact of amprolium, diclazuril, and vaccination against chicken coccidiosis. Journal of Experimental and Applied Animal Sciences, 3, 82–96. 10.20454/jeaas.2020.1618 [CrossRef] [Google Scholar]
  • Patton WH, Schwartz LD, Babish JG and Lisk DJ, 1984. Use of amprolium for the control of coccidiosis in pheasants. Avian Diseases, 28, 693–699. 10.2307/1590237 [PubMed] [CrossRef] [Google Scholar]
  • Pop LM, Varga E, Coroian M, Nedisan ME, Mircean V, Dumitrache MO, Farczádi L, Fülöp I, Croitoru MD, Fazakas M and Gyorke A, 2019. Efficacy of a commercial herbal formula in chicken experimental coccidiosis. Parasites and Vectors, 12. 10.1186/s13071-019-3595-4 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Riddell C and Classen HL, 1992. Effects of increasing photoperiod length and anticoccidials on performance and health of roaster chickens. Avian Diseases, 36, 491–498. 10.2307/1591739 [PubMed] [CrossRef] [Google Scholar]
  • Ruff MD, Chute MB and Garcia R, 1991. Supplemental use of liquid amprolium in skip‐a‐day feeding of replacement pullets. Poultry Science, 70, 515–520. 10.3382/ps.0700515 [PubMed] [CrossRef] [Google Scholar]
  • Selvarani R, Raman M and Gomathinayagam S, 2014. In‐vivo evaluation of anti‐coccidial efficacy of salinomycin and amprolium in commercial chicken. Indian Journal of Veterinary and Animal Sciences Research, 10, 169–173. [Google Scholar]
  • Silzell SA, Kegley EB, Coffey KP, Hellwig DH, Daniels LB and Beers K, 2001. Thiamin status and growth performance of cattle new to the feedlot environment as affected by amprolium and supplemental dietary thiamin. Professional Animal Scientist, 17, 202–207. 10.15232/S1080-7446(15)31623-5 [CrossRef] [Google Scholar]
  • Spencer GK and Waldroup PW, 1985. The influence of amprolium and butynorate on growth rate and feed utilization by large white turkeys. Poultry Science, 64, 610–615. 10.3382/ps.0640610 [PubMed] [CrossRef] [Google Scholar]
  • Talmon P, Jager LP, de Leeuw WA and Timmer WJ, 1989. Coccidiosis in lambs: observations in the preventive use of an amprolium‐containing medicated feed. Tijdschrift Voor Diergeneeskunde, 114, 611–617. [PubMed] [Google Scholar]
  • VKM , 2015. The risk of development of antimicrobial resistance with the use of coccidiostats in poultry diets. Opinion of the Panel on Animal Feed of the Norwegian Scientific Committee for Food Safety, ISBN: 978‐82-8259‐185-0, Oslo, Norway. [Google Scholar]
  • Waibel PE, Halvorson JC, Noll SL, Hoffbeck SL and Daniels H, 1991. Influence of virginiamycin on growth and efficiency of large white turkeys. Poultry Science, 70, 837–847. 10.3382/ps.0700837 [PubMed] [CrossRef] [Google Scholar]
  • Zaman MA, Iqbal Z, Abbas RZ and Khan MN, 2012. Anticoccidial activity of herbal complex in broiler chickens challenged with Eimeria tenella . Parasitology, 139, 237–243. 10.1017/S003118201100182X [PubMed] [CrossRef] [Google Scholar]
Articles from EFSA Journal are provided here courtesy of Wiley
-