Simulating an intravenous-to-oral cefotaxime-to-cefditoren/cefuroxime switch: an in vitro pharmacodynamic approach against selected Streptococcus pneumoniae strains with defined susceptibility profiles.

INTRODUCTION

The lack of oral equivalent for third-generation IV cephalosporins challenges sequential cephalosporin therapy for pneumococcal infections. This in vitro study combined the previously reported pharmacokinetics of IV cefotaxime (CTX) and oral cefditoren (CDN) or cefuroxime (CXM) to simulate an intravenous-to-oral switch and explore the pharmacodynamic activity against S. pneumoniae.

METHODS

We used an in vitro PK/PD system to expose four Streptococcus pneumoniae strains (serotype/MICCTX mg/L): 1S (23B/0.25), 2S (6A/0.5), 3I (35B/1), and 4I (11A/1), to free serum concentrations simulating an initial IV dose of 1,000 mg CTX, followed by two oral doses of 400 mg CDN bid (CTX-to-CDN) or 500 mg CXM bid (CTX-to-CXM) over 36 h. Reference regimens included a single-dose CTX regimen and a full 1,000 mg bid CTX regimen (CTX-IV). Bacterial growth (K) was used as a control.

RESULTS

Against strain 1S, both oral cephalosporins sustained bactericidal activity in the model, similar to the complete CTX-IV regimen. For strain 2S, CTX-to-CDN maintained bactericidal efficacy comparable to CTX-IV, while CTX-to-CXM showed with counts at 36 h similar to initial inoculum. Against strain 3I, CTX-to-CDN exhibited a bacteriostatic effect, whereas CTX-to-CXM was equivalent to the growth control. Strain 4I was associated with regrowth in both sequential regimens. The CTX-IV regimen was bacteriostatic against strains 3I and 4I.

DISCUSSION: Overall, despite the limitations of the proposed model in reproducing the antimicrobial activity of agents with high plasma protein binding, such as CDN, greater in vitro pharmacodynamic activity was observed with CDN than with CXM in the simulated sequential regimens against the four strains tested, particularly against CTX-susceptible strains. These findings warrant confirmation in clinical studies before any therapeutic recommendation could be made.