Relevance of various animal models of human infections to establish therapeutic equivalence of a generic product of piperacillin/tazobactam

• Therapeutic equivalence of generic antibiotics should be demonstrated, not assumed.
• Murine models of infection are validated for establishing therapeutic equivalence.
• One investigated generic product was equivalent in murine thigh, lung and brain infection models.

After demonstrating with diverse intravenous antibacterials that pharmaceutical equivalence (PE) does not predict therapeutic equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2 h (thigh and brain) or 14 h (lung) after infection and was administered every 3 h over 24 h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P > 0.21) and were bioequivalent (IC90 83–117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic equivalence of the generic product was proved in every model and against different pathogens.