Maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 5: Lincosamides: lincomycin
2021; Wiley; Volume: 19; Issue: 10 Linguagem: Inglês
10.2903/j.efsa.2021.6856
ISSN1831-4732
AutoresKonstantinos Koutsoumanis, Ana Allende, Avelino Álvarez‐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, E. Liébana, Gloria López‐Gálvez, Paola Manini, Pietro Stella, Luísa Peixe,
Tópico(s)Pesticide Residue Analysis and Safety
ResumoEFSA JournalVolume 19, Issue 10 e06856 Scientific OpinionOpen Access Maximum levels of cross-contamination for 24 antimicrobial active substances in non-target feed. Part 5: Lincosamides: lincomycin EFSA Panel on Biological Hazards (BIOHAZ), Corresponding Author EFSA Panel on Biological Hazards (BIOHAZ) biohaz@efsa.europa.eu Correspondence:biohaz@efsa.europa.euSearch for more papers by this authorKonstantinos Koutsoumanis, Konstantinos KoutsoumanisSearch for more papers by this authorAna Allende, Ana AllendeSearch for more papers by this authorAvelino Alvarez-Ordóñez, Avelino Alvarez-OrdóñezSearch for more papers by this authorDeclan Bolton, Declan BoltonSearch for more papers by this authorSara Bover-Cid, Sara Bover-CidSearch for more papers by this authorMarianne Chemaly, Marianne ChemalySearch for more papers by this authorRobert Davies, Robert DaviesSearch for more papers by this authorAlessandra De Cesare, Alessandra De CesareSearch for more papers by this authorLieve Herman, Lieve HermanSearch for more papers by this authorFriederike Hilbert, Friederike HilbertSearch for more papers by this authorRoland Lindqvist, Roland LindqvistSearch for more papers by this authorMaarten Nauta, Maarten NautaSearch for more papers by this authorGiuseppe Ru, Giuseppe RuSearch for more papers by this authorMarion Simmons, Marion SimmonsSearch for more papers by this authorPanagiotis Skandamis, Panagiotis SkandamisSearch for more papers by this authorElisabetta Suffredini, Elisabetta SuffrediniSearch for more papers by this authorDan I Andersson, Dan I AnderssonSearch for more papers by this authorVasileios Bampidis, Vasileios BampidisSearch for more papers by this authorJohan Bengtsson-Palme, Johan Bengtsson-PalmeSearch for more papers by this authorDamien Bouchard, Damien BouchardSearch for more papers by this authorAude Ferran, Aude FerranSearch for more papers by this authorMaryline Kouba, Maryline KoubaSearch for more papers by this authorSecundino López Puente, Secundino López PuenteSearch for more papers by this authorMarta López-Alonso, Marta López-AlonsoSearch for more papers by this authorSøren Saxmose Nielsen, Søren Saxmose NielsenSearch for more papers by this authorAlena Pechová, Alena PechováSearch for more papers by this authorMariana Petkova, Mariana PetkovaSearch for more papers by this authorSebastien Girault, Sebastien GiraultSearch for more papers by this authorAlessandro Broglia, Alessandro BrogliaSearch for more papers by this authorBeatriz Guerra, Beatriz GuerraSearch for more papers by this authorMatteo Lorenzo Innocenti, Matteo Lorenzo InnocentiSearch for more papers by this authorErnesto Liébana, Ernesto LiébanaSearch for more papers by this authorGloria López-Gálvez, Gloria López-GálvezSearch for more papers by this authorPaola Manini, Paola ManiniSearch for more papers by this authorPietro Stella, Pietro StellaSearch for more papers by this authorLuisa Peixe, Luisa PeixeSearch for more papers by this author EFSA Panel on Biological Hazards (BIOHAZ), Corresponding Author EFSA Panel on Biological Hazards (BIOHAZ) biohaz@efsa.europa.eu Correspondence:biohaz@efsa.europa.euSearch for more papers by this authorKonstantinos Koutsoumanis, Konstantinos KoutsoumanisSearch for more papers by this authorAna Allende, Ana AllendeSearch for more papers by this authorAvelino Alvarez-Ordóñez, Avelino Alvarez-OrdóñezSearch for more papers by this authorDeclan Bolton, Declan BoltonSearch for more papers by this authorSara Bover-Cid, Sara Bover-CidSearch for more papers by this authorMarianne Chemaly, Marianne ChemalySearch for more papers by this authorRobert Davies, Robert DaviesSearch for more papers by this authorAlessandra De Cesare, Alessandra De CesareSearch for more papers by this authorLieve Herman, Lieve HermanSearch for more papers by this authorFriederike Hilbert, Friederike HilbertSearch for more papers by this authorRoland Lindqvist, Roland LindqvistSearch for more papers by this authorMaarten Nauta, Maarten NautaSearch for more papers by this authorGiuseppe Ru, Giuseppe RuSearch for more papers by this authorMarion Simmons, Marion SimmonsSearch for more papers by this authorPanagiotis Skandamis, Panagiotis SkandamisSearch for more papers by this authorElisabetta Suffredini, Elisabetta SuffrediniSearch for more papers by this authorDan I Andersson, Dan I AnderssonSearch for more papers by this authorVasileios Bampidis, Vasileios BampidisSearch for more papers by this authorJohan Bengtsson-Palme, Johan Bengtsson-PalmeSearch for more papers by this authorDamien Bouchard, Damien BouchardSearch for more papers by this authorAude Ferran, Aude FerranSearch for more papers by this authorMaryline Kouba, Maryline KoubaSearch for more papers by this authorSecundino López Puente, Secundino López PuenteSearch for more papers by this authorMarta López-Alonso, Marta López-AlonsoSearch for more papers by this authorSøren Saxmose Nielsen, Søren Saxmose NielsenSearch for more papers by this authorAlena Pechová, Alena PechováSearch for more papers by this authorMariana Petkova, Mariana PetkovaSearch for more papers by this authorSebastien Girault, Sebastien GiraultSearch for more papers by this authorAlessandro Broglia, Alessandro BrogliaSearch for more papers by this authorBeatriz Guerra, Beatriz GuerraSearch for more papers by this authorMatteo Lorenzo Innocenti, Matteo Lorenzo InnocentiSearch for more papers by this authorErnesto Liébana, Ernesto LiébanaSearch for more papers by this authorGloria López-Gálvez, Gloria López-GálvezSearch for more papers by this authorPaola Manini, Paola ManiniSearch for more papers by this authorPietro Stella, Pietro StellaSearch for more papers by this authorLuisa Peixe, Luisa PeixeSearch for more papers by this author First published: 26 October 2021 https://doi.org/10.2903/j.efsa.2021.6856 Requestor: European Commission Question number: EFSA-Q-2021-00505 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. Acknowledgments: 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 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract The specific concentrations of lincomycin 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, it was not possible to conclude the assessment until further experimental data become available. To address growth promotion, data from scientific publications obtained from an extensive literature review were used. Levels of lincomycin in feed that showed to have an effect on growth promotion/increased yield were reported. It was recommended to carry out studies to generate the data that are required to fill the gaps which prevented the calculation of the FARSC for lincomycin. 1 Introduction The European Commission requested the European Food Safety Authority (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.11 Aminoglycosides: 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. 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/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 lincomycin. 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 Lincosamides, together with the structurally unrelated antimicrobials, macrolides and streptogramins are usually grouped into a single family, the macrolides, lincosamides and streptogramins (MLS) family (Schwarz et al., 2016). This classification is justified by a similar, although not identical, mechanism of action. The mode of action of MLS family is via protein synthesis inhibition by binding to the 50S ribosomal subunit. Relevant lincosamides include clindamycin and lincomycin. Chemically lincomycin consists of a non-canonical amino acid linked to a sugar with clindamycin being a chlorinated derivative. Lincosamides bind to the 50S subunit of the ribosome near the peptidyl transferase centre (sharing overlapping binding sites with macrolides) and cause premature peptidyl-tRNA release (Spížek and Řezanka, 2017). Lincosamides are active mainly against Gram-positive bacteria (e.g. staphylococci and streptococci) although not in enterococci, Mycoplasma, anaerobes and protozoans, and the two most widely used clinically are lincomycin and its derivative clindamycin, both of which are used in veterinary medicine. For human infections, only clindamycin is used because of the adverse toxic effects of lincomycin. 1.3.2 Main use22 Antimicrobials 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 use in medicated feed for prophylaxis is to be prohibited under Regulation (EU) 2019/4. Lincomycin is often used in combination with spectinomycin for treatment of Gram-positive and anaerobic respiratory and enteric infections in livestock. This includes Serpulina (formerly Brachyspira) hyodysenteriae (causing dysenteria), Mycoplasma hyopneumoniae (causing pneumonia), M. hyosynoviae (arthritis), Brachyspira pilosicoli (colitis), Lawsonia intracellularis (ileitis) and associated enteropathogens (e.g. Escherichia coli) in pigs, and Mycoplasma gallisepticum, Avibacterium paragallinarum (infectious coryza) and E. coli in poultry. The main administration route for the above is oral except for respiratory infections in large animals, where the primary administration route is intramuscular injection. Lincomycin in combination with neomycin can also be used for intramammary treatment of staphylococcal, streptococcal and mycoplasma mastitis in cattle (Guardabassi et al., 2008). In ruminants, lincomycin may also be used against Staphylocccus aureus associated arthritis, and as a topical treatment of foot lesions in cattle (Guardabassi et al., 2008). 1.3.3 Main pharmacokinetic data Lincomycin is rapidly but incompletely absorbed when administered orally to animals (Papich, 2017). The oral absorption of lincomycin was lower in fed than fasted animals. In fed pigs, the oral bioavailability was found to be 41 ± 23% (Nielsen and Gyrd-Hansen, 1998). Lincomycin is eliminated unchanged or in the form of various metabolites in bile and urine (Giguère, 2013). After absorption, approximately 50% of lincomycin is metabolised in the liver of pigs but high concentrations of the active form are observed in the intestine. A published study showed that 17% of lincomycin was found as the parent drug in the faeces of pigs after oral administration (Hornish et al., 1987). Compared to the parent compound, none of lincomycin metabolites were found to have had any significant antimicrobial activity. Both N-desmethyl and lincomycin sulfoxide have 15–100 times less antimicrobial activity than the parent lincomycin. There was no evidence that the remaining metabolites have any antibacterial activity (EMEA, 1998). 1.3.4 Main resistance mechanisms Lincosamides share several resistance mechanisms with macrolides and streptogramins B, often generating cross-resistance between these drug classes, so-called MLSB resistance (Schwarz et al., 2016). As for macrolides, a common resistance mechanism is by methylation of 23S rRNA by methyl transferases encoded by the large family of different erm genes carried on plasmids and transposons. In addition, the CFR 23S rRNA methylase can provide resistance to lincosamides and several other antimicrobials such as oxazolidinones, phenicols, pleuromutilins and streptogramin A (Shen et al., 2013). Similarly, mutations in 23S rRNA and ribosomal proteins L4 and L22 can result in reduced susceptibility to one or more of the MLSB antimicrobials. The ABC-F proteins (encoded by the vga and other genes) confer resistance by ribosome protection and are thought to act by binding to antimicrobial-inhibited ribosomes and promote dissociation of the drug from its binding site. In addition, resistance to lincosamides can be conferred by a number of different efflux genes. Finally, the lnu genes encode lincosamide nucleotidyltransferases which enzymatically inactivates lincosamides and reduce their activity (Roberts, 2004, 2008; Spížek and Řezanka, 2017; Feßler et al., 2018). 2 Data and methodologies The data sources and methodology used for this opinion are described in a dedicated document, 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 antimicrobial under assessment are shown below. 3.1.1 Resistance development/spread due sub-MIC concentrations of lincosamides including lincomycin: examples 3.1.1.1 Effects of sub-MIC concentrations on selection for resistance and mutagenesis No relevant studies have been found regarding sub-inhibitory effects of lincosamides on resistance selection. 3.1.1.2 Effects of sub-MIC concentrations on horizontal gene transfer and virulence Horizontal gene transfer can be stimulated by lincosamides as shown by the induction of Tn916 transfer in E. faecalis at sub-inhibitory drug concentrations. Thus, at concentrations 10-fold below the MIC of lincomycin and clindamycin, HGT was increased by about three orders of magnitude (Scornec et al., 2017). With regard to virulence-associated factors, lincomycin at sub-inhibitory levels (1/32 of MIC) could stimulate biofilm formation about fivefold in S. suis (Waack and Nicholson, 2018), which could potentially increase persistence and virulence. Studies on other licosamides showed that sub-MIC concentrations of clindamycin, similarly to the macrolides, have been shown to reduce expression of extracellular proteins in several bacterial species, including Panton-Valentine leucocidin, α-haemolysin and protein A in S. aureus (Herbert et al., 2001; Otto et al., 2013; Campbell et al., 2019; Hu et al., 2019), streptolysin S and M protein production in Streptococcus pyogenes (Shibl and Al-Sowaygh, 1979; Gemmell et al., 1981) and lipase production by Cutibacterium (formerly Propionibacterium) spp. (Unkles and Gemmell, 1982). In summary, our understanding of the sub-MIC effects of lincosamides, including lincomycin, is very limited except for a few studies showing effects on virulence-associated functions and one study showing strong stimulation of HGT by lincosamides at concentrations 1/10 of MIC. 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 this value for lincomycin 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) for lincomycin as indicated in Table 1. However, no minimal selective concentration (MSC) data required to do the calculations are available for this substance. Table 1. Calculation of lincomycin predicted minimal selective concentration (PMSC) Antimicrobial (all values in mg/L) MICtest MSCtest MICtest/MSCtest ratio MIClowest Predicted MSC (PMSC) for most susceptible species (MIClowest/MICtest/MSCtest) Lincomycin NA NA NA 0.5 NA MIC: minimum inhibitory concentration; MSC: minimal selective concentration; MSCtest: MSC experimentally determined; MIClowest, lowest MIC data for lincomycin calculated based on data from the EUCAST database as described in Bengtsson-Palme and Larsson (2016), see Methodology Section 2.2.1.3.1.1 in the Scientific Opinion Part 1 (EUCAST database https://mic.eucast.org/search/ last accessed 15 May 2021); NA: not available. Due to the lack of PMSC, no FARSC could be calculated. If PMSC was available, the FARSC (FARSCintestine and FARSCrumen) 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 lincomycin. 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 oral bioavailability of lincomycin was around 41 ± 23% in pigs. However, the low level of absorption through the gut wall is not the only explanation for this bioavailability since only 17% of lincomycin was recovered as the parent drug in the faeces of pigs after oral administration. Hepatic first-pass effect (hepatic metabolism) should also contribute to limit the bioavailability. For the calculations, the factor (1 − F + F × GE), reflecting the fraction available for microorganisms was considered equal to 0.17 in pigs. The potential inactivation of lincomycin by binding to intestinal contents is not described. Table 2. Pharmacokinetic (PK) values used for the calculation of Feed Antimicrobial Resistance Selection Concentration (FARSC) of lincomcyin for the pigs Lincomycin data Scenario #1 Inactive fraction (I) NA Fraction of the dose available for intestinal microorganisms corresponding to (1 − F + F × GE) in pigs 0.17 Inactive fraction (I) is the fraction of antimicrobial that would not have any activity on bacteria. Bioavailability (F) is the fraction of antimicrobial that is absorbed from the digestive tract to the blood. Gastrointestinal elimination (GE) is the fraction of the antimicrobial that is secreted back into the intestinal tract for elimination, after initially being absorbed into the bloodstream. The fraction remaining in the digestive tract and that could be available for the bacteria is equal to (1 – F + F × GE). NA: not available. There are no quantitative data on the fate of lincomycin for other species and no proposal for PK parameter values was done. 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 lincomycin under assessment: MSC data: no data for MSC are available. MIC data: data available only for few bacterial species in EUCAST database. Bioavailability: only bioavailability data for pigs was found. No data were available for other species. Fraction eliminated in gut: several studies suggest an elimination of lincomycin as parent drug and inactive metabolites. However, there are no quantitative data except for pigs (in only one study) to consider this process. Inactive fraction: no data on the possible binding of lincomycin in digestive tract are available. Ruminants: no PK data are available for lincomycin administered to adult ruminants by 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 antimicrobials concentrations in feed which have an effect in terms of growth promotion/increased yield 3.3.1 Lincomycin 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: Methodology, general data gaps and uncertainties' (see also the Virtual Issue), resulted in 399 papers mentioning lincomycin and any of the food-producing animal species considered33 Ruminants: 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); crustaceans; other animal species. and any of the performance parameters identified as relevant for the assessment of the possible growth-promoting effects of lincomycin.44 (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. After removing the reports not matching the eligibility criteria, 46 publications were identified. 3.3.1.2 Evaluation of the studies The 46 publications identified in the literature search were appraised for suitability for the assessment of the effects of lincomycin 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: Methodology, general data gaps and uncertainties'; see also the Virtual Issue).55 The 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)'. A total of 37 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.1 (Table A.1). 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 lincomycin on growth performance and yield Nine publications were considered suitable for the assessment of the effects of lincomycin 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: Methodology, general data gaps and uncertainties' (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 lincomycin 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 pigs In the study of Biehl et al. (1985), a total of 120 pigs for fattening (unspecified breed, both sexes) weighing ca. 20 kg were distributed i
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