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.
Highlights
The rise of antimicrobial resistance is a public health emergency that is threatening the conquests of modern medicine with potentially dire consequences for humankind if not addressed promptly [1,2,3,4]
I.e., if a generic antibiotic without therapeutic equivalence would favor resistance in a higher degree than the innovator, we studied in vivo the therapeutic equivalence of four generic products of piperacillin-tazobactam (TZP) against Escherichia coli ATCC 35218, a strain producing the plasmidic class A TEM-1 β-lactamase
We have previously demonstrated that the pharmaceutical equivalence of generic products of oxacillin, vancomycin, gentamicin and meropenem, among other antibiotics, does not assure their therapeutic equivalence in the validated neutropenic thigh infection model [11,12,13,14, 16]
Summary
The rise of antimicrobial resistance is a public health emergency that is threatening the conquests of modern medicine with potentially dire consequences for humankind if not addressed promptly [1,2,3,4]. The widespread use and misuse of antibiotics has exerted an enormous selective pressure on microorganisms, leading to the emergence of resistance to every single known antibacterial drug [5], especially in Gram negative bacilli, for which very few antibiotics have been approved in the last decades [6]. Besides factors like prescription without indication [7], unjustified prolonged therapies, inappropriate dosing, disregard of the pharmacodynamics, poor adherence, and abuse of PLOS ONE | DOI:10.1371/journal.pone.0155806.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
