DISCUSSION
death, nausea, diarrhea, abdominal pain, TEAEs, liver injury, headache, SAD
DISEASE
The data described in this study after single and multiple twice-daily oral ceftibuten administered to healthy adult subjects at doses of 400 mg is consistent with previously published data for Previous studies have explored the PK of ceftibuten after single oral doses of 25, 50, 100, 200, 300, 400, and 800 mg (To the best of our knowledge, this is the first study to report In our study, we observed a higher ceftibuten exposure than reported by Lin et al. (The accumulation ratios of The present study found that ceftibuten was well tolerated when administered in all studied single and multiple doses. There were no serious, severe, life-threatening TEAEs, or TEAEs resulting in death reported throughout the study (SAD and MAD periods).In the SAD period of the study, at ceftibuten doses up to 800 mg, the majority of TEAEs were mild in severity and there was no evidence of increasing incidence or severity of TEAEs with increasing dose. In the MAD period of the study, at ceftibuten doses up to 800 mg twice-daily for 7 days, the frequency of TEAEs was similar among all dose levels; however, the number of subjects reporting TEAEs in the total ceftibuten group was approximately twice that of the pooled placebo group. Mild ALT increases occurred in all cohorts with an increase in the incidence with increasing doses of ceftibuten. Approximately 30% of subjects in the 600 and 800 mg cohorts had an increase in their ALT, all of which were less than three times the upper limit of normal of 51 IU/L. ALT increases were initially observed 4–5 days after initiation of dosing and were maximal 3 days after the completion of dosing. All increases were asymptomatic, resolved spontaneously over the follow-up period and were not associated with bilirubin or alkaline phosphatase increases. No subjects discontinued dosing due to ALT increases. Oral cephalosporins have been linked to slight elevations in ALT and alkaline phosphatase levels, which are typically mild, temporary, and not accompanied by any symptoms or progression to more severe liver injury. The reported frequency of these elevations can reach up to 11%, although this rate varies based on factors such as the frequency of monitoring, duration of treatment, and nature and severity of the underlying disease (Overall, the most commonly reported TEAEs were headache, nausea, diarrhea, and abdominal pain, the majority of which were mild in severity. The TEAEs observed in this study are similar to those reported with ceftibuten (Based on recent publications, the pharmacodynamic target for ceftibuten is free ceftibuten concentrations above the minimum inhibitory concentration (MIC) for 60%–67% of the dosing interval (