Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics: The Case of Piperacillin-Tazobactam

Abstract

Previous studies have demonstrated that pharmaceutical equivalence and pharmacokinetic equivalence of generic antibiotics are necessary but not sufficient conditions to guarantee therapeutic equivalence (better called pharmacodynamic equivalence). In addition, there is scientific evidence suggesting a direct link between pharmacodynamic nonequivalence of generic vancomycin and promotion of resistance in Staphylococcus aureus. To find out if even subtle deviations from the expected pharmacodynamic behavior with respect to the innovator could favor resistance, we studied a generic product of piperacillin-tazobactam characterized by pharmaceutical and pharmacokinetic equivalence but a faulty fit of Hill’s Emax sigmoid model that could be interpreted as pharmacodynamic nonequivalence. We determined the impact in vivo of this generic product on the resistance of a mixed Escherichia coli population composed of ∼99% susceptible cells (ATCC 35218 strain) and a ∼1% isogenic resistant subpopulation that overproduces TEM-1 β-lactamase. After only 24 hours of treatment in the neutropenic murine thigh infection model, the generic amplified the resistant subpopulation up to 20-times compared with the innovator, following an inverted-U dose-response relationship. These findings highlight the critical role of therapeutic nonequivalence of generic antibiotics as a key factor contributing to the global problem of bacterial resistance.

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

“…The neutropenic murine infection model has recently been used to compare the therapeutic equivalence of generic molecules with respect to innovator piperacillin-tazobactam (Rodriguez et al, 2016). Although a generic in that study did not achieve good results and favored the amplification of resistant microorganisms, the other generics evaluated, including the one analyzed in the present study, showed the same performance as the innovator, supporting the lack of differences in the clinical outcomes in this study (Rodriguez et al, 2016).…”

“…The safety and therapeutic equivalence of generic antibiotics is a controversial issue. However, the data from this study, along with real-world evidence, indicate that its use can be as safe and effective as the innovator, which has been demonstrated for other antimicrobials and other infections, and for different indications, such as cardiovascular (McCormack and Chmelicek, 2014;Rodriguez et al, 2016;Lin et al, 2016;Kesselheim et al, 2016;Jackevicius et al, 2016). In addition, economic analyses have shown that generic antibiotic treatments during a 5-day hospitalization cost on average US$ 45.5-98.2, while the use of innovators can cost US$ 106.2-463.7.…”

“…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). Furthermore, a lack of therapeutic equivalence in murine models for a specific generic molecule of piperacillin-tazobactam was reported recently (Rodriguez et al, 2016).…”

Evaluation of in-vivo and in-vitro microbiological methods for testing the efficacy of parenteral antibiotics: A Review

“…Rodriguez et al 20 have compared the in-vitro activity of an innovator and a generic piperacillintazobactam in a study aimed to determine the impact of therapeutically non-equivalent generics on bacterial resistance. Though there was no significant difference in MIC value for both innovator and generic products, therapeutic non-equivalence was observed in the in-vivo assessment and higher enrichment of resistant sub-populations when exposed to the generic products.…”

In silico Evaluation of Impurities Found in Some Generic Drugs of Piperacillin/ Tazobactam

“…Besides since the particle size of the bulk powder of all imported meropenems is larger than that of the brand drug, this was identified as the cause of being less likely to dissolve. Furthermore, it was reported that generic Piperacillin/ Tazobactam was pharmaceutic difference and therapeutically nonequivalence [5,6]. A generic product is approved as a drug as long as its main ingredient is the same as that of the original drug.…”