Metronidazole Twice Daily: A Pharmacokinetic and Clinical Justification

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This medication is associated with a number of adverse effects, such as gastrointestinal upset and peripheral neuropathies, that may be mitigated by less frequent dosing.

Metronidazole (Flagyl; Pfizer), a widely used nitroimidazole antibiotic for anaerobic infections, is traditionally administered 3 times a day (TID). However, this medication is associated with a number of adverse effects, such as gastrointestinal upset and peripheral neuropathies, that may be mitigated by less frequent dosing.1 A deeper look into the pharmacokinetic rationale and clinical evidence supporting twice daily (BID) dosing could provide the most optimal strategy for various infections.

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Metronidazole, a prodrug, exhibits high bioavailability (>90%) upon oral administration, with extensive distribution into bodily fluids and tissues, excluding adipose and placental tissues. This antimicrobial undergoes hepatic metabolism, producing an active hydroxy metabolite with a half-life comparable to that of the parent compound, approximately 11 to 13 hours for the metabolite and 8 hours for the parent drug. Metronidazole is a concentration-dependent antibiotic that benefits from peak concentrations above an isolate’s minimum inhibitory concentration (MIC).1,2

In a pharmacokinetic study by Earl et al. (1986), the authors revealed comparable peak serum concentrations between oral 400 mg BID and intravenous 500 mg BID administrations. The mean peak concentration observed with oral and intravenous administration of metronidazole in this population was 17.4 mg/L and 23.6 mg/L, respectively.3 Intravenous administration of 500 mg TID results in a maximum metronidazole serum concentration ranging from 15 to 25 mg/L on average.3 The mean peak serum concentration achieved with the BID dosing falls within the range observed with the TID dosing. Moreover, per the Clinical and Laboratory Standards Institute, the metronidazole breakpoint for obligate anaerobes is ≤ 8 mg/L, a threshold that the observed peak levels certainly exceed. Although the pharmacokinetic findings of this study impress upon the adequacy of the 12-hour dosing regimen, it is important to note that serum levels were variably taken anywhere between the third and sixteenth doses of the dosing schedule for each patient.3

Several clinical outcomes studies support BID dosing. Soule et al. (2018) revealed comparable clinical cure rates for presumed anaerobic or mixed anaerobic infections between TID and BID regimens (83% in both groups, p=1.00, not statistically significant), pointing toward non-inferiority between the 2 regimens. Notably, patients receiving the every-8-hour regimen were older (62.5 ± 18.7) compared to those on the 12-hour regimen (53.9 ± 19.6) (p=0.002), but no other baseline characteristics were reported to be statistically significantly different. Additionally, while there was no significant difference in hospital length of stay between the 2 groups, there was a trend towards longer stays in the q12-hour group (5.2% vs. 8.1%, p=0.110), possibly due to a higher percentage of intensive care unit admissions within this group.4 Major consideration points for this study are that only 2 patients had positive cultures for anaerobic bacteria and that patients being treated for C. difficile infections, central nervous system (CNS) infections, and parasitic infections were excluded.4

Shah et al. (2021) found no disparity in mortality between 8-hour and 12-hour dosing in bloodstream infections caused by anaerobes, predominantly Bacteroides fragilis. For the primary outcome of all-cause mortality, no significant difference was found: 15.6% in the 8-hour group versus 9.4% in the 12-hour group.5 Notably, this study excluded patients treated for C. difficile and CNS infections.5

Lloyd et al. (1994) examined postoperative infection incidence within 7 days following mandibular third molar removal when patients were given metronidazole for prophylaxis. Their findings indicated no statistically significant differences in postoperative complications between BID and TID dosing regimens. Notably, a higher incidence of nausea was observed in the TID group, with 15 patients experiencing it in the 8-hour dosing regimen compared to 8 patients in the 12-hour dosing regimen (p < 0.05).6

Metronidazole BID dosing aligns with its pharmacokinetic profile, and it demonstrates clinical non-inferiority compared to TID regimens across various infections. Table 11 summarizes recommended dosing strategies based on infection type, of which several infections already have a BID indication.1 Twice daily dosing of metronidazole offers a rational approach supported by pharmacokinetic principles and clinical data, potentially reducing adverse effects such as nausea and cost. Additionally, implementation of this dosing strategy has been shown to reduce yearly antibiotic expenditure.7 Importantly, clinical data is lacking to support BID dosing for the treatment of C. difficile and CNS infections.5,6 Clinicians should consider this reduced dosing frequency in infections where TID dosing may not confer additional benefit.

Table 1.1 Metronidazole Indications and Dosing Recommendations

Table 1.1 Metronidazole Indications and Dosing Recommendations

References

1. Metronidazole. Lexi-Drugs. [updated 2024 Mar 14; cited 2024 Mar 14] In Lexicomp Online [Internet]. UpToDate. Waltham, MA. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1798773

2. CLSI. M100, 34 ed. CLSI guideline. Clinical and Laboratory Standards Institute; 2024.

3. Earl P, Sisson PR, Ingham HR. Twelve-hourly dosage schedule for oral and intravenous metronidazole. J Antimicrob Chemother. 1989;23(4):619-21. doi: 10.1093/jac/23.4.619.

4. Soule AF, Green SB, Blanchette LM. Clinical efficacy of 12-h metronidazole dosing regimens in patients with anaerobic or mixed anaerobic infections. Ther Adv Infect Dis. 2018;5(3):57-62. doi: 10.1177/2049936118766462.

5. Shah S, Adams K, Merwede J, McManus D, Topal J. Three is a crowd: Clinical outcomes of a twice daily versus a thrice daily metronidazole dosing strategy from a multicenter study. Anaerobe. 2021;71:102378. doi: 10.1016/j.anaerobe.2021.102378.

6. Lloyd CJ, Earl PD. Metronidazole: two or three times daily--a comparative controlled clinical trial of the efficacy of two different dosing schedules of metronidazole for chemoprophylaxis following third molar surgery. Br J Oral Maxillofac Surg. 1994;32(3):165-7. doi: 10.1016/0266-4356(94)90102-3.

7. Jung B, Andrews JD. Effectiveness of an antibiotic cost containment measure. Can J Hosp Pharm. 1990;43(3):116-22.

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