A recently published meta-analysis compared the efficacy of intravenous or oral metronidazole administration at every 8-hour versus every 12-hour intervals. The study highlighted that metronidazole's long elimination half-life, favorable ratio of steady-state serum levels to minimum inhibitory concentration (MIC), and presence of active metabolites suggest the consideration of using metronidazole at 12-hour dosage intervals. The final analysis incorporated two prospective cohort studies: one involving 200 patients at a single site (Table 1) and another multisite study with 85 patients (Table 2). The findings from the single-site study conducted by Soule et al. revealed no statistically significant between-group differences in primary outcomes, including clinical cure (8-hour: 83% vs. 12-hour: 83%, p= 1.00) and mortality (8-hour: 2% vs. 12-hour: 3%, p= 0.651). Additionally, there were no statistically significant differences in secondary clinical outcomes, such as the duration of antibiotic therapy (8-hour: 5.8 ± 4 vs. 12-hour: 5.9 ± 4.3, p= 0.891), duration of metronidazole use (8-hour: 4.8 ± 2.8 vs. 12-hour: 4.9 ± 2.4, p= 0.827), or hospital length of stay (LOS) in days (8-hour: 6.7 ± 5.2 vs. 12-hour: 8.1 ± 7, p= 0.110). Similarly, the multisite study conducted by Shah et al. indicated that patients who received metronidazole every 8 hours, compared to those who received it every 12 hours, had no statistically significant differences in all-cause 30-day mortality (8-hour: 15.6% vs. 12-hour: 9.4%, p= 0.492), median post-infection days of hospitalization (8-hour: 9 days, interquartile range [IQR]: 6 to 12.8 days vs. 12-hour: 8 days, IQR: 4 to 10 days, p= 0.271), or 30-day readmission due to infection (8-hour: 3.1% vs. 12-hour: 1.9%, p= 0.999). All patients who had repeat blood cultures showed sterile results (8-hour: 56% vs. 12-hour: 88.7%, p= 0.999). The meta-analysis concerning the need to escalate antibiotic therapy revealed no statistically significant difference (95% confidence interval [CI] 47.6% lower to 6.4 times higher risk; p = 0.342). These findings collectively suggest that dosing metronidazole every 12 hours is as effective as dosing every 8 hours for anaerobic infections. As a result, healthcare systems may consider adopting the every 12-hour metronidazole dosing regimen while continuing to evaluate patient outcomes. [1]
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. [2]
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 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. [3], [4]
A 1983 review of metronidazole PK profile also discusses that Q12H dosing interval would generate corresponding concentrations of ~ 5 to 20 mcg/mL, which should be sufficient against most of the anaerobes and infections caused by Bacteroides, Fusobacteria, and Clostridia species. However, these MICs and susceptibility may not reflect antibiograms in current practice. [5]
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 MIC without clearly referenced efficacy data regarding patient outcomes. [6]
Two randomized, controlled trials published in 2022 evaluated the efficacy of metronidazole twice daily as part of combination regimens for treating Helicobacter pylori infections. The first study compared esomeprazole 20 mg QID and amoxicillin 750 mg QID versus esomeprazole 20 mg BID, amoxicillin 1000 mg BID, and either clarithromycin 500 mg BID, metronidazole 400 mg BID, or levofloxacin 500 mg daily. All regimens were given for 14 days. Eradication of H. pylori with the two-drug regimen was found to be 84.9% compared to 83.6% in the patients that received triple therapy. There was no mention of how many patients in the triple therapy group received metronidazole, but 50% of specimens were found to be resistant to metronidazole therapy. [7]
Another randomized, controlled trial compared quadruple therapy (pantoprazole 40 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours) for 14 days versus 14 days of high-dose dual therapy consisting of esomeprazole 40 mg BID and amoxicillin 1g TID. Eight weeks after the end of treatment, H. pylori eradication was found to be 88.6% in the quadruple therapy group compared to 82.2% in the dual therapy group (p= 0.19). [8]
A 2010 review indicates metronidazole is effective for the management of anaerobic infections, such as intra-abdominal infections, gynecologic infections, septicemia, endocarditis, bone and joint infections, central nervous system infections, and oral/dental infections. Metronidazole is also commonly used for prophylaxis before abdominal and gynecological surgical procedures to reduce the risk of postoperative anaerobic infection. For the treatment of severe intra-abdominal and pelvic infections, a retrospective chart review published in 2007 observed 1 g of metronidazole given intravenously once daily to have pharmacokinetic and pharmacoeconomic advantages over treatment administered every 6 to 8 hours. There is noted to be an increasing number of clinical failures reported with metronidazole treatment of Clostridioides difficile (C. diff). However, the appropriate frequency of metronidazole administration for the treatment of C. diff is not addressed. [9]