title: Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment.
abstract: Combination treatment is increasingly used to fight infections caused by bacteria resistant to two or more antimicrobials. While multiple studies have evaluated treatment strategies to minimize the emergence of resistant strains for single antimicrobial treatment, fewer studies have considered combination treatments. The current study modeled bacterial growth in the intestine of pigs after intramuscular combination treatment (i.e. using two antibiotics simultaneously) and sequential treatments (i.e. alternating between two antibiotics) in order to identify the factors that favor the sensitive fraction of the commensal flora. Growth parameters for competing bacterial strains were estimated from the combined in vitro pharmacodynamic effect of two antimicrobials using the relationship between concentration and net bacterial growth rate. Predictions of in vivo bacterial growth were generated by a mathematical model of the competitive growth of multiple strains of Escherichia coli.
  
  
  
  Simulation studies showed that sequential use of tetracycline and ampicillin reduced the level of double resistance, when compared to the combination treatment. The effect of the cycling frequency (how frequently antibiotics are alternated in a sequential treatment) of the two drugs was dependent upon the order in which the two drugs were used.
  
  
  
  Sequential treatment was more effective in preventing the growth of resistant strains when compared to the combination treatment. The cycling frequency did not play a role in suppressing the growth of resistant strains, but the specific order of the two antimicrobials did. Predictions made from the study could be used to redesign multidrug treatment strategies not only for intramuscular treatment in pigs, but also for other dosing routes.
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 8, DK-1870, Frederiksberg C, Denmark. amaisahmad@gmail.com.
authors.forename: Amais
authors.identifier: 0000-0002-8615-3117
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Zachariasen
authors.affiliation: Department of Applied Mathematics and Computer Science, Technical University of Denmark, Richard Petersens Plads, 2800, Lyngby, Denmark.
authors.forename: Lasse Engbo
authors.initials: LE
authors.lastname: Christiansen
authors.affiliation: Department of Applied Mathematics and Computer Science, Technical University of Denmark, Richard Petersens Plads, 2800, Lyngby, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Græsbøll
authors.affiliation: National Veterinary Institute, Section of Epidemiology, Technical University of Denmark, Bulowsvej 27, DK-1870, Frederiksberg C, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Toft
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health, Institute for Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Matthews
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: John Elmerdahl
authors.initials: JE
authors.lastname: Olsen
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 8, DK-1870, Frederiksberg C, Denmark.
authors.forename: Søren Saxmose
authors.initials: SS
authors.lastname: Nielsen
mesh_terms: D000667:Ampicillin / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development; D058491:Bacterial Load / Q000187:drug effects; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D007273:Injections, Intramuscular; D007422:Intestines / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D013552:Swine; D013752:Tetracycline / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin; D013752:Tetracycline
keywords: Ampicillin; Antimicrobial resistance; Bacterial growth; Dosing strategies; Pharmacodynamic; Pig; Tetracycline