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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.

Background The wetlands used for some agricultural activities constitute productive breeding sites for many mosquito species. Thus, the agricultural use of insecticide targeting other pests may select for insecticide resistance in malaria mosquitoes. The purpose of this study is to clarify some knowledge gaps on the role of agrochemicals in the development of insecticide resistance in malaria vectors is of utmost importance for vector control. Methods Using the CDC bottle test and the log-probit analysis, we investigated for the first time the resistance levels of Anopheles coluzzii mosquitoes to neonicotinoids, insecticides used exclusively for crop protection in Côte d’Ivoire. The study was conducted in two agricultural regions (Tiassale and Gagnoa) and one non-agricultural region (Vitre) between June and August 2017 using clothianidin, acetamiprid and imidacloprid. Results Mosquito populations from Tiassale and Gagnoa (agricultural settings) were determined to be resistant to acetamiprid with mortality rates being < 85% at 24 h post-exposure. In Vitre (non-agricultural area) however, the mosquito population was susceptible to acetamiprid. In all three localities, mosquito populations were resistant to imidacloprid (mortality rates were 60% in Vitre, 37% in Tiassale, and 13% in Gagnoa) and completely susceptible to clothianidin (100% mortality). An. coluzzii represented 100% of mosquito collected in Gagnoa, 86% in Tiassale and 96% in Vitre. Conclusions This study provides strong evidence that agricultural use of insecticides can cause insecticide resistance in malaria vector populations. Insecticide resistance driven by agrochemical usage should be considered when vector control strategies are developed.

The plant bug Lygus pratensis Linnaeus (Hemiptera: Miridae) is an important insect pest of alfalfa in grassland farming in northern China. A field population of L. pratensis was selected in the laboratory for 14 consecutive generations with lambda-cyhalothrin to generate 42.555-fold resistance. Selection also induced low cross-resistance to imidacloprid and beta-cypermethrin, and medium cross-resistance to deltamethrin. Realized heritability (h2) of lambda-cyhalothrin resistance was 0.339. Susceptible baselines of L. pratensis were established for five insecticides using the glass-vial method, the values of which were 6.849, 3.423, 8.778, 3.559, and 117.553 ng/cm2 for phoxim, methomyl, imidacloprid, lambda-cyhalothrin, and avermectin, respectively, along with the calculated LC99 diagnostic doses. This resistance risk assessment study suggests that a high risk of lambda-cyhalothrin resistance exists in the field. In addition, a 5-year field investigation of resistance monitoring of L. pratensis was conducted in seven alfalfa regions in farming-pastoral ecotones in northern China. The resistance levels of most populations were very low for phoxim, methomyl, and avermectin, with an upward trend for lambda-cyhalothrin resistance in the DK (Dengkou County), TKT (Tuoketuo County), XL (Xilinhot), and LX (Linxi County) populations during 2015–2019, and medium resistance level to imidacloprid in the TKT population in five years we sampled. The study provided information on chemical control, lambda-cyhalothrin resistance development, baseline susceptibility, and the status of resistance to five commonly-used insecticides against L. pratensis.These results could be used to optimize pyrethroid insecticide use as part of a pest integrated resistance management strategy against this key insect pest of alfalfa.

Background There are several indications that pesticides used in agriculture contribute to the emergence and spread of resistance of mosquitoes to vector control insecticides. However, the impact of such an indirect selection pressure has rarely been quantified and the molecular mechanisms involved are still poorly characterized. In this context, experimental selection with different agrochemical mixtures was conducted in Anopheles gambiae . The multi-generational impact of agrochemicals on insecticide resistance was evaluated by phenotypic and molecular approaches. Methods Mosquito larvae were selected for 30 generations with three different agrochemical mixtures containing (i) insecticides, (ii) non-insecticides compounds, and (iii) both insecticide and non-insecticide compounds. Every five generations, the resistance of adults to deltamethrin and bendiocarb was monitored using bioassays. The frequencies of the kdr (L995F) and ace1 (G119S) target-site mutations were monitored every 10 generations. RNAseq was performed on all lines at generation 30 in order to identify gene transcription level variations and polymorphisms associated with each selection regime. Results Larval selection with agrochemical mixtures did not affect bendiocarb resistance and did not select for ace1 mutation. Contrastingly, an increased deltamethrin resistance was observed in the three selected lines. Such increased resistance was not majorly associated with the presence of kdr L995F mutation in selected lines. RNA-seq identified 63 candidate resistance genes over-transcribed in at least one selected line. These include genes coding for detoxification enzymes or cuticular proteins previously associated with insecticide resistance, and other genes potentially associated with chemical stress response. Combining an allele frequency filtering with a Bayesian FST-based genome scan allowed to identify genes under selection across multiple genomic loci, supporting a multigenic adaptive response to agrochemical mixtures. Conclusion This study supports the role of agrochemical contaminants as a significant larval selection pressure favouring insecticide resistance in malaria vectors. Such selection pressures likely impact kdr mutations and detoxification enzymes, but also more generalist mechanisms such as cuticle resistance, which could potentially lead to cross-tolerance to unrelated insecticide compounds. Such indirect effect of global landscape pollution on mosquito resistance to public health insecticides deserves further attention since it can affect the nature and dynamics of resistance alleles circulating in malaria vectors and impact the efficacy of control vector strategies.

Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%-100%) than during 2002-2005 (94.7%; 95% CI 91.9%-96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance-associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.

The aim of this study is to describe the phenotypic and genetic properties of oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) isolates and their beta-lactam resistant derivatives obtained after selection with oxacillin. A collection of hospital- (HA-) and community-acquired (CA-) MRSA was screened for oxacillin susceptibility. Antibiotic susceptibility testing, population analysis profile (PAP), mecA expression analysis, and whole genome sequencing (WGS) were performed for 60 mecA -positive OS-MRSA isolates. Twelve high-level beta-lactam resistant derivatives selected during PAP were also subjected to WGS. OS-MRSA were more prevalent among CA-MRSA (49/205, 24%) than among HA-MRSA (11/575, 2%). OS-MRSA isolates belonged to twelve sequence types (ST), with a predominance of ST22-t223-SCC mec  IVc and ST59-t1950-SCC mec  V lineages. OS-MRSA were characterized by mecA promoter mutations at − 33 (C→T) or − 7 (G→T/A) along with PBP2a substitutions (S225R or E246G). The basal and oxacillin-induced levels of mecA expression in OS-MRSA isolates were significantly lower than those in control ST8-HA-MRSA isolates. Most of the OS-MRSA isolates were heteroresistant to oxacillin. High-level beta-lactam resistant OS-MRSA derivatives selected with oxacillin carried mutations in mecA auxiliary factors: relA (metabolism of purines), tyrS , cysS (metabolism of tRNAs), aroK , cysE (metabolism of amino acids and glycolysis). Cefoxitin-based tests demonstrated high specificity for OS-MRSA detection. The highest positive predictive values (PPV > 0.95) were observed for broth microdilution, the VITEK® 2 automatic system, and chromogenic media. Susceptibility testing of CA-MRSA requires special attention due to the high prevalence of difficult-to-detect OS-MRSA among them. Mis-prescription of beta-lactams for the treatment of OS-MRSA may lead to selection of high-level resistance and treatment failures.

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC50) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC50 values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC50, 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1.

The seasonal distribution and dynamic evolution of antibiotics in wastewater from main treatment areas and in sludge and their resistance selection potential and ecotoxicological risk were studied at a municipal wastewater treatment plant in Jinan, East China. Ten antibiotics were selected, and all were detected in wastewater and sludge samples, with fluoroquinolones showing the highest detection concentrations and frequencies. Seasonal fluctuations in the antibiotic concentrations in the influent, effluent, and sludge were observed, with the highest values in winter in most cases. The dynamic evolution of antibiotics during the treatment process differed among the seasons. The antibiotic removal efficiencies were incomplete, ranging from − 40.47 to 100%. Mass balance analysis showed that sulfonamides, roxithromycin, and metronidazole were mainly removed through biological processing, whereas fluoroquinolones, doxycycline, and chloramphenicol were removed through sludge adsorption. Levofloxacin, as well as a mixture of the 10 antibiotics from the effluent, could pose a low ecotoxicological risk to Daphnia in the receiving waters. Additionally, levofloxacin and ciprofloxacin in the effluent and ciprofloxacin and metronidazole in the sludge may facilitate the selection of antibiotic-resistant bacteria in the environment.

The cotton aphid, Aphis gossypii Glover, is among the most economically significant sap-sucking insect pests, inflicting substantial economic losses worldwide. Insecticides such as thiamethoxam, bifenthrin, and flonicamid are commonly used to manage this pest, despite the inherent risk of developing resistance. In this study, we investigated the evolution of insecticide resistance in A. gossypii after continuous selection with thiamethoxam, bifenthrin, and flonicamid over more than ten generations in a controlled laboratory environment. We assessed the fitness of resistant strains using an age-stage, two-sex life table approach, comparing them to a susceptible population. The results indicated that A. gossypii achieved resistance levels of 158.60-fold against thiamethoxam, 129.18-fold against bifenthrin, and 104.75-fold against flonicamid. Furthermore, life table analyses revealed that the developmental stages were significantly extended, while longevity decreased in all resistant strains compared to the susceptible population. Additionally, the net reproductive rate (R0), fecundity, and reproductive days were notably reduced in the resistant cohorts when compared to the susceptible strain. Overall, these findings provide valuable insights into the laboratory-induced evolution of insecticide resistance and the associated fitness costs in A. gossypii when feeding on cotton plants. This information could be instrumental in formulating effective resistance management strategies to control this significant pest.

Antimicrobial residues excreted in the environment following antimicrobial treatment enhance resistant microbial communities in the environment and have long-term effects on the selection and maintenance of antimicrobial resistance genes (AMRGs). In this study, we focused on understanding the impact of antimicrobial use on antimicrobial residue pollution and antimicrobial resistance (AMR) in the environment of horse-breeding farms. Rhodococcus equi is an ideal microbe to study these associations because it lives naturally in the soil, exchanges AMRGs with other bacteria in the environment, and can cause disease in animals and humans. The environment is the main source of R. equi infections in foals; therefore, higher levels of multidrug-resistant (MDR) R. equi in the environment contribute to clinical infections with MDR R. equi. We found that macrolide residues in the environment of horse-breeding farms and the use of thoracic ultrasonographic screening (TUS) for early detection of subclinically affected foals with R. equi infections were strongly associated with the presence of R. equi carrying AMRGs in the soil. Our findings indicate that the use of TUS contributed to historically higher antimicrobial use in foals, leading to the accumulation of antimicrobial residues in the environment and enhancing MDR R. equi.