Abstract
BackgroundOxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence. We tested the assumption that pharmaceutical equivalence predicts therapeutic equivalence by comparing 11 generics with the innovator product in terms of concentration of the active pharmaceutical ingredient (API), minimal inhibitory (MIC) and bactericidal concentrations (MBC), and antibacterial efficacy in the neutropenic mouse thigh infection model.MethodsThe API in each product was measured by a validated microbiological assay and compared by slope (potency) and intercept (concentration) analysis of linear regressions. MIC and MBC were determined by broth microdilution according to Clinical and Laboratory Standard Institute (CLSI) guidelines. For in vivo efficacy, neutropenic ICR mice were inoculated with a clinical strain of Staphylococcus aureus. The animals had 4.14 ± 0.18 log10 CFU/thigh when treatment started. Groups of 10 mice per product received a total dose ranging from 2.93 to 750 mg/kg per day administered q1h. Sigmoidal dose-response curves were generated by nonlinear regression fitted to Hill equation to compute maximum effect (Emax), slope (N), and the effective dose reaching 50% of the Emax (ED50). Based on these results, bacteriostatic dose (BD) and dose needed to kill the first log of bacteria (1LKD) were also determined.Results4 generic products failed pharmaceutical equivalence due to significant differences in potency; however, all products were undistinguishable from the innovator in terms of MIC and MBC. Independently of their status with respect to pharmaceutical equivalence or in vitro activity, all generics failed therapeutic equivalence in vivo, displaying significantly lower Emax and requiring greater BD and 1LKD, or fitting to a non-sigmoidal model.ConclusionsPharmaceutical or in vitro equivalence did not entail therapeutic equivalence for oxacillin generic products, indicating that criteria for approval deserve review to include evaluation of in vivo efficacy.
Highlights
Oxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence
Penicillinase-resistant penicillins, including the isoxazolyl penicillin oxacillin (OXA), have been the mainstay treatment of β-lactamase producing Staphylococcus aureus infections since the 1960s, their usefulness is nowadays reduced by the emergence and worldwide dissemination of methicillin-resistant strains (MRSA) [1]
The Eagle effect displayed by OXA-SER explains its Gaussian pharmacodynamic pattern (Figure 3), described at the beginnings of the antibiotic era for penicillins and later for other antibacterials [18]. This case was unique among oxacillin generics; OXA-SER probably had degradation products in its formulation that competed with the active pharmaceutical ingredient (API) for the molecular target, as we described recently with generics of vancomycin [19]
Summary
Oxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence. Penicillinase-resistant penicillins, including the isoxazolyl penicillin oxacillin (OXA), have been the mainstay treatment of β-lactamase producing Staphylococcus aureus infections since the 1960s, their usefulness is nowadays reduced by the emergence and worldwide dissemination of methicillin-resistant strains (MRSA) [1]. The patents of these drugs expired long ago and many generic products are currently available while the innova-. Our aim was to challenge the assumption that pharmaceutical equivalence is a surrogate predictor of therapeutic equivalence for generic oxacillin, comparing with the innovator product concentration and potency of the active pharmaceutical ingredient (API), in vitro activity, and in vivo efficacy against a clinical strain of S. aureus in the neutropenic mouse thigh infection model (NMTIM). Preliminary results of this work were presented at the 44th ICAAC [5]
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