Impact on resistance of the use of therapeutically equivalent generics: the case of ciprofloxacin

Abstract

Therapeutic nonequivalence of generic antibiotics may lead to treatment failure and enrichment of resistance. However, there has been no demonstration that an equivalent generic displays the same resistance selection profile as the innovator drug. We aimed to test this hypothesis with five generic versions of ciprofloxacin by assessing their pharmaceutical equivalence with microbiological assays and their efficacy against Pseudomonas aeruginosa PAO1 in the neutropenic murine thigh infection model. One equivalent generic was selected for analysis by high-pressure liquid chromatography-tandem mass spectrometry (LC-MS/MS), to confirm chemical identity, and resistance selection experiments in a hollow-fiber (HF) system simulating two clinical dosing regimens. Total and resistant populations were measured, and the MICs of the resistant cells with and without an efflux pump inhibitor were determined. LC-MS/MS found no differences between products, and the innovator and the generic selected resistance with the same magnitude and mechanism after 7 days of treatment in the HF system, supporting the fact that a generic with demonstrated equivalence in vivo is also equivalent regarding resistance selection.

FIG 1

In vivo exposure-response relationship of ciprofloxacin against P. aeruginosa PAO1, comparing the innovator and four generic products. Global CFA indicated that all data belonged to the same population and could be described by a single curve, confirming the therapeutic equivalence of the generics. Stasis was achieved with a fAUC/MIC value of ∼27 and 99.9% kill with a fAUC/MIC value of ∼75.

FIG 2

LC-MS/MS analysis. The innovator (blue spectrum) and the generic (red spectrum) displayed the same major peaks at almost identical times. The peak corresponding to ciprofloxacin appeared between 7 and 8 min, with equal abundances for the two products.

FIG 3

Resistance selection in the hollow-fiber system during 7 days of exposure to innovator and generic ciprofloxacin. Solid lines, total populations; dashed lines, resistant subpopulations; green lines, group exposed to the innovator; red lines, group exposed to the generic; black lines, untreated controls. (A) 800-mg/day group. (B) 400-mg/day group. In both cases, the resistant cells took over the population after day 1, with overlapping lines until day 7.