{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:28:04Z","timestamp":1789003684098,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SulTAn","award":["JPIAMR2022-007"],"award-info":[{"award-number":["JPIAMR2022-007"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/X03173X\/1"],"award-info":[{"award-number":["MR\/X03173X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013281","name":"Joint Programming Initiative on Antimicrobial Resistance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Trimethoprim (TMP) and sulphonamides are widely used in combination to treat many conditions, including porcine respiratory infections caused by Actinobacillus pleuropneumoniae (APP), yet the pharmacodynamic basis of their synergy remains unclear. This study investigated the interactions between TMP and three sulphonamides (sulfamethoxazole, sulfadiazine, and sulfadimethoxine) against APP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Interactions were evaluated against three APP strains using MIC determination, static time-kill assays of individual drugs across five TMP: sulphonamide ratios (1:4, 1:19, 1:99, 1:499, 1:999), and semi-mechanistic pharmacodynamic modelling. Single-drug models showed greater TMP potency than sulphonamides (median EC50 0.018\u00a0\u00b5g mL\u22121\u00a0vs \u223c3\u201310\u00a0\u00b5g mL\u22121). A General Pharmacodynamic Interaction model identified a unidirectional interaction in which TMP enhanced sulphonamide potency by reducing their EC50 at sub-MIC TMP concentrations (\u223c22-fold below the MIC), consistent with indirect antifolate action requiring folate depletion. Delayed sulphonamide effects and density-dependent growth limitation improved model performance. Maximal synergy, defined as the relative increase in bacterial killing rate, was 110\u2013115% for all sulphonamides and occurred at a pharmacodynamic ratio of 1:250 (0.002\u00a0\u00b5g mL\u22121 TMP with 0.5\u00a0\u00b5g mL\u22121 sulphonamide). This represents a PD ratio and should not be confused with the classical 1:19 TMP: sulphonamide ratio reported for clinical effectiveness. Simulations using median porcine pharmacokinetics predicted rapid initial bacterial killing across intravenous and oral regimens despite pharmacokinetic ratio drift. However, sustained efficacy was regimen-dependent, with only the TMP-sulfadimethoxine combination achieving eradication, whereas others showed regrowth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings provide a mechanistic explanation of TMP\u2013sulphonamide synergy against APP and highlight the value of semi-mechanistic PK\/PD modelling for optimising veterinary combination therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jambio\/lxag106","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:47:04Z","timestamp":1777031224000},"source":"Crossref","is-referenced-by-count":2,"title":["Pharmacodynamic interaction between trimethoprim and sulphonamides for\n                    <i>A. pleuropneumoniae<\/i>\n                    : synergistic ratios, optimal potentiation, and dynamic responses assessed via time-kill curves"],"prefix":"10.1093","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3550-3030","authenticated-orcid":false,"given":"Andrew","family":"Mead","sequence":"first","affiliation":[{"name":"Pathobiology and Population Sciences (PPS), APPRAISE laboratory, The Royal Veterinary College , Hatfield AL9 7TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6930-9327","authenticated-orcid":false,"given":"Alexis","family":"Viel","sequence":"additional","affiliation":[{"name":"ANSES, CiMMEx Unit, Foug\u00e8res laboratory , 35306 Foug\u00e8res ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Boulanger","sequence":"additional","affiliation":[{"name":"ANSES, CiMMEx Unit, Foug\u00e8res laboratory , 35306 Foug\u00e8res ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Overesch","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Bacteriology, Vetsuisse Faculty, University of Bern , Postfach 8466 Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Louis","family":"Toutain","sequence":"additional","affiliation":[{"name":"INTHERES, Universit\u00e9 de Toulouse, INRAE, ENVT , 31076 Toulouse cedex 03 Toulouse ,","place":["France"]},{"name":"Comparative Biomedical Sciences, APPRAISE, The Royal Veterinary College , Hatfield AL9 7TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aude","family":"Ferran","sequence":"additional","affiliation":[{"name":"INTHERES, Universit\u00e9 de Toulouse, INRAE, ENVT , 31076 Toulouse cedex 03 Toulouse ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Pelligand","sequence":"additional","affiliation":[{"name":"Comparative Biomedical Sciences, APPRAISE, The Royal Veterinary College , Hatfield AL9 7TA ,","place":["United Kingdom"]},{"name":"Clinical Services and Sciences, The Royal Veterinary College , Hatfield AL9 7TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"2026062605472386900_bib1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1046\/j.1365-2885.2001.00337.x","article-title":"Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim (trimazin 30%) after oral administration in non-fasted young pigs","volume":"24","author":"Baert","year":"2001","journal-title":"J Vet Pharmacol Ther"},{"key":"2026062605472386900_bib2","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1208\/s12248-009-9112-5","article-title":"Handling data below the limit of quantification in mixed effect models","volume":"11","author":"Bergstrand","year":"2009","journal-title":"The AAPS journal"},{"key":"2026062605472386900_bib3","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1111\/j.1744-7348.1939.tb06990.x","article-title":"The toxicity of poisons applied jointly 1","volume-title":"Ann Appl Biol","author":"Bliss","year":"1939"},{"key":"2026062605472386900_bib4","doi-asserted-by":"publisher","first-page":"104200","DOI":"10.1016\/j.psj.2024.104200","article-title":"Pharmacokinetic modeling of sulfamethoxazole-trimethoprim and sulfadiazine-trimethoprim combinations in broilers","volume":"103","author":"Boulanger","year":"2024","journal-title":"Poult Sci"},{"key":"2026062605472386900_bib5","doi-asserted-by":"publisher","first-page":"2565351","DOI":"10.1080\/01652176.2025.2565351","article-title":"Population pharmacokinetic modeling of sulfadimethoxine, sulfadiazine and sulfamethoxazole combined to trimethoprim in pigs","volume":"45","author":"Boulanger","year":"2025","journal-title":"Vet Q"},{"key":"2026062605472386900_bib6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1128\/aac.02307\u201318","article-title":"Generating robust and informative nonclinical in vitro and in vivo bacterial infection model efficacy data to support translation to humans","volume":"63","author":"Bulitta","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026062605472386900_bib7","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/j.1476-5381.1968.tb00475.x","article-title":"Trimethoprim, a sulphonamide potentiator","volume":"33","author":"Bushby","year":"1968","journal-title":"British journal of pharmacology and chemotherapy"},{"key":"2026062605472386900_bib8","doi-asserted-by":"publisher","first-page":"S442","DOI":"10.1093\/infdis\/128.Supplement_3.S442","article-title":"Trimethoprim-sulfamethoxazole: in vitro microbiological aspects","volume":"128","author":"Bushby","year":"1973","journal-title":"J Infect Dis"},{"key":"2026062605472386900_bib9","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1124\/pharmrev.124.000951","article-title":"Drug-drug interactions and synergy: from pharmacological models to clinical application","volume":"76","author":"Calzetta","year":"2024","journal-title":"Pharmacol Rev"},{"key":"2026062605472386900_bib10","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.cmi.2018.03.047","article-title":"Pharmacokinetics\/pharmacodynamics characterization of combined antimicrobial agents: a real challenge and an urgent need","volume":"24","author":"Couet","year":"2018","journal-title":"Clin Microbiol Infect"},{"key":"2026062605472386900_bib11","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.vetmic.2014.04.008","article-title":"Antimicrobial susceptibility monitoring of respiratory tract pathogens isolated from diseased cattle and pigs across Europe: the VetPath study","volume":"172","author":"De\u00a0Jong","year":"2014","journal-title":"Vet Microbiol"},{"key":"2026062605472386900_bib12","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1002\/vms3.763","article-title":"The disposition of trimethoprim and sulfadiazine in neonatal foals after intravenous administration","volume":"8","author":"Ekstrand","year":"2022","journal-title":"Vet Med Sci"},{"key":"2026062605472386900_bib13","author":"EUCAST"},{"key":"2026062605472386900_bib14","volume-title":"Trisulmix: Summary of Product Characteristics (SPC)","author":"EUROPEAN MEDICINES AGENCY"},{"key":"2026062605472386900_bib15","volume-title":"Adjusol: Summary of Product Characteristics (SPC)","author":"EUROPEAN MEDICINES AGENCY"},{"key":"2026062605472386900_bib16","volume-title":"Diatrim: Summary of Product Characteristics (SPC)","author":"EUROPEAN MEDICINES AGENCY"},{"key":"2026062605472386900_bib17","volume-title":"T.S.-sol 20\/100: Summary of Product Characteristics (SPC)","author":"EUROPEAN MEDICINES AGENCY"},{"key":"2026062605472386900_bib18","volume-title":"Lidoprim: Summary of Product Characteristics (SPC)","author":"EUROPEAN MEDICINES AGENCY"},{"key":"2026062605472386900_bib19","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.2215\/CJN.08140718","article-title":"Clinical Pharmacology of Antibiotics","volume":"14","author":"Eyler","year":"2019","journal-title":"Clin J Am Soc Nephrol"},{"key":"2026062605472386900_bib20","article-title":"Levers to Improve Antibiotic Treatment of Lambs via Drinking Water in Sheep Fattening Houses: the Example of the Sulfadimethoxine\/Trimethoprim Combination","volume":"9","author":"Ferran","year":"2020","journal-title":"Antibiotics (Basel)"},{"key":"2026062605472386900_bib21","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1111\/j.1749-6632.1971.tb31171.x","article-title":"Folate antagonists as antibacterial and antiprotozoal agents","volume":"186","author":"Hitchings","year":"1971","journal-title":"Ann NY Acad Sci"},{"key":"2026062605472386900_bib22","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/BF02353466","article-title":"Three new residual error models for population PK\/PD analyses","volume":"23","author":"Karlsson","year":"1995","journal-title":"J Pharmacokinet Biopharm"},{"key":"2026062605472386900_bib23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.3390\/antibiotics13060549","article-title":"Stability Studies of the Dilution Series of Different Antibiotic Stock Solutions in Culture Medium Incubated at 37\u00b0C","volume":"13","author":"Kerek","year":"2024","journal-title":"Antibiotics"},{"key":"2026062605472386900_bib24","doi-asserted-by":"publisher","first-page":"105640","DOI":"10.1016\/j.jevs.2025.105640","article-title":"Pharmacokinetics\/pharmacodynamics analysis of trimethoprim and sulfamethoxazole for methicillin-resistant Staphylococcus aureus infection after intravenous and per os administration in Thoroughbred horses","volume":"152","author":"Kuroda","year":"2025","journal-title":"Journal of Equine Veterinary Science"},{"key":"2026062605472386900_bib25","doi-asserted-by":"publisher","first-page":"770518","DOI":"10.3389\/fphar.2021.770518","article-title":"Limitations of antibiotic MIC-based PK-PD metrics: looking back to move forward","volume":"12","author":"Landersdorfer","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026062605472386900_bib26","doi-asserted-by":"publisher","first-page":"e0216721","DOI":"10.1128\/aac.02167-21","article-title":"In Vitro Time-Kill Studies of Trimethoprim\/Sulfamethoxazole against Stenotrophomonas maltophilia versus Escherichia coli Using Cation-Adjusted Mueller-Hinton Broth and ISO-Sensitest Broth","volume":"66","author":"Lasko","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2026062605472386900_bib27","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.micpath.2011.02.002","article-title":"Analysis on Actinobacillus pleuropneumoniae LuxS regulated genes reveals pleiotropic roles of LuxS\/AI-2 on biofilm formation, adhesion ability and iron metabolism","volume":"50","author":"Li","year":"2011","journal-title":"Microb Pathog"},{"key":"2026062605472386900_bib28","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.vetmic.2015.02.033","article-title":"Actinobacillus pleuropneumoniae two-component system QseB\/QseC regulates the transcription of PilM, an important determinant of bacterial adherence and virulence","volume":"177","author":"Liu","year":"2015","journal-title":"Vet Microbiol"},{"key":"2026062605472386900_bib29","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/j.1574-6968.2002.tb10981.x","article-title":"Studies on the production of quorum-sensing signal molecules in Mannheimia haemolytica A1 and other Pasteurellaceae species","volume":"206","author":"Malott","year":"2002","journal-title":"FEMS Microbiol Lett"},{"key":"2026062605472386900_bib30","volume-title":"Biaprim: Summary of Product Characteristics (SPC)","author":"MED-VET"},{"key":"2026062605472386900_bib31","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1023\/A:1010660319832","article-title":"Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after oral single-and multiple-dose administration to healthy pigs","volume":"25","author":"Mengelers","year":"2001","journal-title":"Vet Res Commun"},{"key":"2026062605472386900_bib32","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1111\/j.1365-2885.1995.tb00588.x","article-title":"Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs","volume":"18","author":"Mengelers","year":"1995","journal-title":"J Vet Pharmacol Ther"},{"key":"2026062605472386900_bib33","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/s41467-018-03447-x","article-title":"Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole","volume":"9","author":"Minato","year":"2018","journal-title":"Nat Commun"},{"key":"2026062605472386900_bib34","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1124\/pr.111.005769","article-title":"Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs","volume":"65","author":"Nielsen","year":"2013","journal-title":"Pharmacol Rev"},{"key":"2026062605472386900_bib35","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1128\/AAC.00604-06","article-title":"Semimechanistic pharmacokinetic\/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments","volume":"51","author":"Nielsen","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2026062605472386900_bib36","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.3389\/fmicb.2019.01237","article-title":"Semi-Mechanistic Modeling of Florfenicol Time-Kill Curves and in silico Dose Fractionation for Calf Respiratory Pathogens","volume":"10","author":"Pelligand","year":"2019","journal-title":"Front Microbiol"},{"key":"2026062605472386900_bib37","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1111\/j.2042-7158.1996.tb06017.x","article-title":"Mechanism for synergism between sulphonamides and trimethoprim clarified","volume":"48","author":"Richards","year":"1996","journal-title":"J Pharm Pharmacol"},{"key":"2026062605472386900_bib38","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/jvp.12894","article-title":"Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison)","volume":"44","author":"Ronaghinia","year":"2021","journal-title":"J Vet Pharmacol Ther"},{"key":"2026062605472386900_bib39","first-page":"110784","article-title":"Minimum inhibitory concentrations of sulfonamides and trimethoprim for veterinary pathogens: new data for old antibiotics","author":"Ruchti","year":"2025","journal-title":"Vet Microbiol"},{"key":"2026062605472386900_bib40","doi-asserted-by":"publisher","first-page":"105182","DOI":"10.1016\/j.prevetmed.2020.105182","article-title":"Prevalence and antimicrobial resistance of opportunistic pathogens associated with bovine respiratory disease isolated from nasopharyngeal swabs of veal calves in Switzerland","volume":"185","author":"Sch\u00f6necker","year":"2020","journal-title":"Prev Vet Med"},{"key":"2026062605472386900_bib41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/978-3-319-46718-4_24","article-title":"Sulfonamides and trimethoprim","volume":"Volume 1","author":"Sk\u00f6ld","year":"2017","journal-title":"Antimicrobial Drug Resistance: Mechanisms of Drug Resistance"},{"key":"2026062605472386900_bib42","doi-asserted-by":"publisher","first-page":"S498","DOI":"10.1093\/infdis\/128.Supplement_3.S498","article-title":"Nature of the bactericidal action of sulfonamides and trimethoprim, alone and in combination","volume":"128","author":"Then","year":"1973","journal-title":"J Infect Dis"},{"key":"2026062605472386900_bib43","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1007\/s40262-018-00733-1","article-title":"Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children","volume":"58","author":"Thompson","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"2026062605472386900_bib44","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.vetmic.2011.10.022","article-title":"Antimicrobial resistance of Actinobacillus pleuropneumoniae isolated from swine","volume":"156","author":"Vanni","year":"2012","journal-title":"Vet Microbiol"},{"key":"2026062605472386900_bib45","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1038\/s41467-017-01929-y","article-title":"A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions","volume":"8","author":"Wicha","year":"2017","journal-title":"Nat Commun"},{"key":"2026062605472386900_bib46","first-page":"1042","article-title":"a pragmatic approach to handling censored data below the lower limit of quantification in pharmacokinetic modeling","volume":"14","author":"Wijk","year":"2025","journal-title":"CPT: Pharmacometrics & Systems Pharmacology"},{"key":"2026062605472386900_bib47","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1016\/j.chemosphere.2007.07.045","article-title":"A mechanistical model for the uptake of sulfonamides by bacteria","volume":"70","author":"Zarfl","year":"2008","journal-title":"Chemosphere"},{"key":"2026062605472386900_bib48","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13567-023-01173-x","article-title":"The morphology and metabolic changes of Actinobacillus pleuropneumoniae during its growth as a biofilm","volume":"54","author":"Zhang","year":"2023","journal-title":"Vet Res"},{"key":"2026062605472386900_bib49","volume-title":"Diseases of swine","author":"Zimmerman","year":"2012"},{"key":"2026062605472386900_bib50","doi-asserted-by":"crossref","DOI":"10.1016\/B978-1-4557-4801-3.00033-3","article-title":"33\u2013Sulfonamides and Trimethoprim","volume-title":"Mandell, Douglas, and Bennett\u2019s Principles and Practice of Infectious Diseases","author":"Zinner","year":"2015","edition":"Eighth Edition"}],"container-title":["Journal of Applied Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jambio\/advance-article-pdf\/doi\/10.1093\/jambio\/lxag106\/68159255\/lxag106.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jambio\/article-pdf\/137\/5\/lxag106\/68159255\/lxag106.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jambio\/article-pdf\/137\/5\/lxag106\/68159255\/lxag106.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:51:41Z","timestamp":1782467501000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jambio\/article\/doi\/10.1093\/jambio\/lxag106\/8662448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jambio\/lxag106","relation":{},"ISSN":["1365-2672"],"issn-type":[{"value":"1365-2672","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,4,25]]},"article-number":"lxag106"}}