title: Impact on resistance of the use of therapeutically equivalent generics: the case of ciprofloxacin.
abstract: Therapeutic nonequivalence of generic antibiotics may lead to treatment failure and enrichment of resistance. However, there has been no demonstration that an equivalent generic displays the same resistance selection profile as the innovator drug. We aimed to test this hypothesis with five generic versions of ciprofloxacin by assessing their pharmaceutical equivalence with microbiological assays and their efficacy against Pseudomonas aeruginosa PAO1 in the neutropenic murine thigh infection model. One equivalent generic was selected for analysis by high-pressure liquid chromatography-tandem mass spectrometry (LC-MS/MS), to confirm chemical identity, and resistance selection experiments in a hollow-fiber (HF) system simulating two clinical dosing regimens. Total and resistant populations were measured, and the MICs of the resistant cells with and without an efflux pump inhibitor were determined. LC-MS/MS found no differences between products, and the innovator and the generic selected resistance with the same magnitude and mechanism after 7 days of treatment in the HF system, supporting the fact that a generic with demonstrated equivalence in vivo is also equivalent regarding resistance selection.
authors.affiliation: GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, School of Medicine, University of Antioquia, Medellin, Colombia Department of Pharmacology, School of Medicine, University of Antioquia, Medellin, Colombia.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, School of Medicine, University of Antioquia, Medellin, Colombia Department of Pharmacology, School of Medicine, University of Antioquia, Medellin, Colombia Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellin, Colombia.
authors.forename: Maria
authors.initials: M
authors.lastname: Agudelo
authors.affiliation: GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, School of Medicine, University of Antioquia, Medellin, Colombia Department of Pharmacology, School of Medicine, University of Antioquia, Medellin, Colombia.
authors.forename: Andres F
authors.identifier: http://orcid.org/0000-0001-5656-4153
authors.initials: AF
authors.lastname: Zuluaga
authors.affiliation: GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, School of Medicine, University of Antioquia, Medellin, Colombia Department of Pharmacology, School of Medicine, University of Antioquia, Medellin, Colombia Department of Internal Medicine, School of Medicine, University of Antioquia, Medellin, Colombia Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellin, Colombia omar.vesga@udea.edu.co.
authors.forename: Omar
authors.initials: O
authors.lastname: Vesga
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016568:Drugs, Generic / Q000627:therapeutic use*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013810:Therapeutic Equivalency
chemical_list: D000900:Anti-Bacterial Agents; D016568:Drugs, Generic; D002939:Ciprofloxacin