A 2016 poster abstract details a retrospective chart review (N= 81) comparing metronidazole 500 mg twice daily (BID) versus three times daily (TID) for appendicitis or diverticulitis. Clinical outcomes and readmission rates were assessed at 30 days follow-up. Patients were excluded if they had concomitant infection, fistula, or chronic appendicitis. The authors did not find a statistical difference in resolution rates (values unspecified). The 30-day readmission rates were similarly nonsignificant with only 1 or 0 patients in the appendicitis or diverticulitis BID and TID groups being readmitted (p= 1 when comparing appendicitis and p= 0.417 when comparing diverticulitis). Yet, due to the small sample size and retrospective nature of the study, stronger evidence is needed to confirm these findings. [1]
Despite the limited clinical outcomes regarding Q12H vs Q8H metronidazole dosing, relatively dated pharmacokinetic (PK)/pharmacodynamic (PD) studies have observed efficient blood levels at 12 h post-administration. In 18 healthy volunteers who were randomly assigned to 3 doses of intravenous (IV) metronidazole (500 mg Q8H, 1,000 mg/day, 1,500 mg/day) and 8 critically ill patients who received 500 mg Q8H, the researchers observed an attainment of the target pharmacodynamic parameter (AUC/MIC ratio ≥ 70) against B. fragilis isolates is > 99% when MICs are <2 mg/L, irrespective of the dosing interval of 24 h. In multiple PK/PD studies, the elimination half-life ranges from 6 to 10 h for metronidazole and from 8.5 to 19.2 h for its active hydroxy metabolite (antimicrobial activity ~30 to 65% that of metronidazole) in patients with normal renal function. [2], [3]
According to an institutional therapeutic policy, a Canadian health system (Northern Health) advocates a transition from Q8H to Q12H metronidazole dosing for non-C. difficile infections, non-pseudomembranous colitis and non-CNS indications. This recommendation is mainly based on the presence of active metabolites and favorable ratio of serum levels to minimum inhibitory concentration (MIC) without clearly referenced efficacy data regarding patient outcomes. [4]
A 2024 systematic review and meta-analysis evaluated the clinical outcomes associated with dosing metronidazole every 8 hours versus every 12 hours among hospitalized adolescents and adults with anaerobic infections. Two retrospective cohort studies met inclusion criteria, representing a total sample of 285 patients from US-based healthcare institutions. The included studies compared oral or intravenous metronidazole administered on an every-8-hour or every-12-hour schedule. In the 2018 single-center cohort analysis, 200 hospitalized patients with presumed anaerobic or mixed infections received either 8- or 12-hour dosing. No statistically significant differences were observed between the groups in primary outcomes including clinical cure (83% vs. 83%; p= 1.00), mortality (2% vs. 3%; p= 0.65), duration of metronidazole therapy, or hospital length of stay. A second multisite cohort study evaluated 85 patients with culture-confirmed anaerobic bacteremia and similarly found no significant differences in 30-day mortality (15.6% vs. 9.4%; p= 0.49), post-infection length of hospitalization (median 9 vs. 8 days; p= 0.27), or need for antibiotic escalation (12.5% vs. 5.7%; p= 0.47). A fixed-effects meta-analysis demonstrated no statistically significant difference in the risk of antibiotic escalation between dosing intervals (pooled RR 1.87; 95% CI 0.52–6.65; p= 0.34). These findings collectively suggest that metronidazole dosed every 12 hours may be clinically non-inferior to the traditional every-8-hour regimen for select anaerobic infections. See Table 1 (Soule) and Table 2 (Shah) for summary of the individual studies. [5]