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

Pharmacodynamics of nine generic products of amikacin compared with the innovator in the neutropenic mouse thigh infection model

“…Here, our results with amikacin indicate that almost all generics (eight of nine products) failed therapeutic equivalence in a head-to-head in vivo comparison with the innovator, independently of their pharmaceutical equivalence. These data are similar to previous results with other antibiotics [ 13 , 15 , 17 ], reinforcing the idea that therapeutic equivalence of generic antimicrobials cannot be predicted from pharmaceutical equivalence or in vitro testing and therefore requires in vivo studies [ 11 , 12 ].…”

“…This approach has certainly rendered the desired economic results [ 9 ], but at the price of neglecting solid evidence documenting the clinical failure of intravenous generics of vancomycin and cefuroxime [ 10 ]. Besides, an animal infection model was validated by our group to determine the therapeutic equivalence of antimicrobials [ 11 , 12 ], in which many generic products of vancomycin [ 13 ], oxacillin [ 14 , 15 ], gentamicin [ 16 ], meropenem [ 17 ], lincomycin [ 18 ], ampicillin [ 19 ], and penicillin G [ 20 ] failed to kill the same number of microorganisms as the innovators. Of great concern, those generics of vancomycin that failed therapeutic equivalence selected the resistant subpopulation of Staphylococcus aureus [ 21 ], whilst therapeutically equivalent generics of ciprofloxacin were indistinguishable from the innovator in terms of selection of resistant Pseudomonas aeruginosa [ 22 ].…”

Results of the effectiveness of two piperacillin–tazobactam molecules in the real world

“…Some of these patterns exhibited statistically significant differences, and this approach could have altered the conclusions to some extent, despite the fact that the outcomes in the multivariate analyses were adjusted. The differences can be explained by possible physician fear regarding use of the generic antibiotic in complicated infections, although in clinical and in vitro studies, it has not been demonstrated that the results are different in terms of the resolution of morbidity or mortality (Agudelo et al, 2015;Charoenpong et al, 2013;Araya et al, 2015).…”

“…Through in vitro studies, murine models, and observational investigations, it has been shown that the generic form of piperacillin-tazobactam is bioequivalent to the innovator molecules, with no significant difference in pharmacokinetic, effectiveness, or safety parameters (Agudelo et al, 2015;Tschudin-Sutter et al, 2011;Charoenpong et al, 2013;Araya et al, 2015). However, the quality of the generic presentations has been questioned, with some studies reporting that they present lower in vitro activity (Jones et al, 2008;Jones et al, 2013).…”

A strain-independent method to induce progressive and lethal pneumococcal pneumonia in neutropenic mice

“…Recently, we demonstrated the relevance of the pneumonia model in neutropenic mice to predict the biologic response [ 26 ]. Since the host’s immune system enhances significantly the efficacy of most antimicrobials, its elimination is necessary to determine the intrinsic bactericidal activity in vivo [ 19 , 27 ].…”