title: In vivo pharmacodynamics of piperacillin/tazobactam: implications for antimicrobial efficacy and resistance suppression with innovator and generic products.
abstract: Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of β-lactam/β-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>thresholdand TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 β-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>thresholdindex described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10kill. The non-equivalent generic required a longer exposure (fT>threshold33%) to suppress resistance compared with the innovator (fT>threshold22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence.
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia; Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
authors.forename: Maria
authors.initials: M
authors.lastname: Agudelo
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Zuluaga
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia; Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellín, Colombia. Electronic address: omar.vesga@udea.edu.co.
authors.forename: Omar
authors.initials: O
authors.lastname: Vesga
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D051379:Mice; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D012641:Selection, Genetic; D016896:Treatment Outcome; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D016568:Drugs, Generic; D065093:beta-Lactamase Inhibitors; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: Antimicrobial resistance; Generic antibiotics; Pharmacodynamics; Pharmacokinetics; Piperacillin/tazobactam; Therapeutic equivalence