Background
About the Authors
Hayley Hamilton, PharmD, is a clinical pharmacist at Ascension Sacred Heart Medical Group in Pensacola, Florida.
Randi Silcox, PharmD, BCPS, is a clinical pharmacist at Ascension Sacred Heart Hospital in Pensacola, Florida.
Sasha Ward, PharmD, BCPS, BCIDP, is a regional clinical pharmacy manager at Ascension Sacred Heart Hospital in Pensacola, Florida.
Laura Comalander, PharmD, is a clinical pharmacist at Ascension Sacred Heart Hospital in Pensacola, Florida.
Emily Plauche, PharmD, BCIDP, AAHIVP, is a clinical pharmacist at Visante in St Paul, Minnesota.
Disclosures
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to report.
Metronidazole is the antibiotic of choice for anaerobic infections due to its effectiveness against gram-positive and gram-negative anaerobes, minimal adverse effect profile, and affordability.1 Its pharmacokinetic properties support twice-daily dosing despite the traditional dosing scheme of thrice-daily dosing. The half-life of metronidazole is 6 to 10 hours, with studies showing adequate levels to reach and exceed the minimum inhibitory concentration of common anaerobic bacteria at 12 hours following the dose. Metronidazole is metabolized by the liver to form 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (HM), 1-acetic acid-2-methyl-5-nitroimidazole, and glucuronide metabolites. HM is the major metabolite and has 30% to 65% of the biological activity of the parent drug. The half-life of the HM metabolite exceeds that of the parent drug, ranging from 9.5 to 19.2 hours in patients with normal kidney function.2 Few studies have evaluated clinical outcomes of twice-daily dosing regimens versus thrice-daily dosing in both confirmed anaerobic bloodstream infections and presumed anaerobic infections.3,4 One study conducted by Soule et al3 found no significant differences in clinical cure for twice-daily versus thrice-daily dosing regimens in presumed anaerobic and mixed anaerobic infections. Another study conducted by Shah et al found no significant difference in mortality, length of hospital stay, or escalation of therapy between the dosing strategies in patients with confirmed anaerobic bacteremia.4
Based on this literature and the pharmacokinetic properties of metronidazole, along with limited ability to obtain intravenous (IV) metronidazole due to shortage, Ascension Sacred Heart updated the standard dosing of metronidazole from 500 mg thrice daily to 500 mg twice daily for most indications. This study aimed to evaluate the effectiveness of this change of dosing schemes in confirmed anaerobic infections.
Objectives
The primary objective of this study was to evaluate the frequency of clinical cure in patients who received metronidazole twice daily versus thrice daily. Secondary end points included hospital length of stay, inpatient mortality rate, need for escalation of therapy, hospital readmission rates within 30 days of discharge due to the same infection, and metronidazole spend.
Definitions
Clinical cure was a composite end point defined as improvement or resolution of the principal sign or symptom of infection with normalization of white blood cells (WBCs > 4000 and < 12,000 cells/µL) and temperature (> 96.8 °F and < 100.4 °F) at the end of therapy or at discharge, whichever occurred first. Escalation of antibiotics was defined as changing to a broader-spectrum IV antibiotic with anaerobic coverage. If broader coverage was warranted due to other organisms growing in the culture, it was not deemed an escalation.
Methods
Study Design
This multisite, retrospective, quasi-experimental study was conducted at 2 sites within a community teaching hospital system within the Ascension network. It was deemed exempt from institutional review board approval. The preintervention period observed in this study occurred from January 1, 2022, to April 30, 2023, during which time thrice-daily dosing of metronidazole was the standard. In June 2023, the standard dosing of metronidazole was updated from 500 mg thrice daily to 500 mg twice daily by the Antimicrobial Stewardship Committee, and updates to the electronic health record software went live in October 2023. The postintervention period observed in this study occurred from November 1, 2023, to June 30, 2024. All data were collected retrospectively.
Patient Selection
Patients with cultures positive for anaerobes were identified using clinical surveillance software Sentri7 and reports from Ascension Sacred Heart’s microbiology laboratory. To be included, patients must have received at least 72 hours of metronidazole therapy and have a confirmed anaerobic infection, defined as an identified anaerobe in blood, fluid, tissue, surgical, or bone culture(s). Patients with central nervous system infections, Clostridioides difficile infections, parasitic or amoebic infections, or Helicobacter pylori infections were excluded since these indications were listed as exceptions in the metronidazole dosing policy update. Additionally, patients were excluded if they received metronidazole for surgical prophylaxis. Patients could not have received metronidazole twice daily during the preintervention period or thrice daily during the postintervention period, unless they switched from thrice-daily to twice-daily dosing within 24 hours during the postintervention period. Patients also could not have received more than 72 hours of nonmetronidazole anaerobic coverage in the 7 days before starting metronidazole, concomitant antimicrobials that cover anaerobes, or have an anaerobe identified in a blood culture that was deemed a contaminant. A blood culture was considered a contaminant if a single specimen was positive for a common commensal organism defined by the Centers for Disease Control and Prevention and/or if the primary team deemed it a contaminant.5 Two of 2 positive blood cultures were considered contaminated if the following criteria were met: there is no source of infection identified, 2 of the blood culture specimens were positive for a likely contaminant organism, and if repeat blood cultures were collected prior to administration of an agent that the organism is susceptible to, have no bacterial growth or if 2 of the blood culture specimens were positive for a likely contaminant organism and the provider states it is a contaminant in the patient’s electronic health record. Metronidazole spend was determined by the cost of each dose of IV ($1.16) and oral ($0.52) metronidazole at Ascension Sacred Heart during the study period.
Statistical Analysis
Baseline characteristics were analyzed using the Wilcoxon rank-sum test instead of t tests, as none of the variables met the normality assumption. Chi-square and Fisher exact tests were applied to categorical variables. Continuous variables were assessed using the Wilcoxon rank-sum test.
Results
Of the 1242 patients screened, 77 patients were included in the study: 43 patients in the preintervention group and 34 in the postintervention group. Most patients screened did not receive at least 72 hours of metronidazole or received more than 72 hours of nonmetronidazole anaerobic coverage in the 7 days before starting metronidazole; therefore, they were not included. Baseline characteristics are reported in the Table. No significant differences in baseline characteristics were identified between groups. The most common type of confirmed anaerobic infection in both groups was skin and soft tissue infection, followed by intra-abdominal infection. The most common causative anaerobic organisms were Bacteroides fragilis (n = 24), followed by Bacteroides spp(n = 14) and Bacteroides thetaiotaomicron (n = 12). The primary end point of clinical cure occurred more frequently in the postintervention group compared with the preintervention group but was not statistically significantly different (71% versus 58%, respectively; P = .37; Figure). Rates of improvement or resolution of the principal sign of infection along with normalization of temperature were similar between the twice-daily and thrice-daily dosing groups (94% versus 93% [P > .99] and 91% versus 93% [P > .99], respectively). Normalization of WBCs throughout treatment was slightly higher in the postintervention group but was not statistically significantly different (76% versus 65%, respectively; P = .41).
No patients in the preintervention group and 1 patient in the postintervention group died during hospitalization. This patient was critically ill in the intensive care unit setting throughout their hospitalization, with the primary cause of death being sepsis with organ failure. At the time of death, the patient had been off metronidazole for 2 weeks and had been transitioned to meropenem based on culture results; therefore, metronidazole treatment failure was unlikely to have been a contributing factor. There was also a similar hospital length of stay (9 days versus 11 days, respectively; P = .18) between the 2 groups, and no patients in either group were readmitted to the hospital within 30 days due to the same infection. Escalation of therapy was low in both the twice-daily and thrice-daily dosing groups (2 patients [6%] versus 1 patient [2%], respectively; P = .58). The most common antibiotic that metronidazole was escalated to in both groups was meropenem. One patient in the postintervention group was escalated to piperacillin-tazobactam after concomitant use of cefepime and metronidazole. The total cost of metronidazole was significantly lower in the twice-daily dosing group compared with the thrice-daily dosing group ($378.72 vs $827.92, respectively; P < .001). Differences in total metronidazole spend, total doses of IV metronidazole, and total doses of metronidazole were statistically significant.
Discussion
The findings of this study support the use of twice-daily metronidazole dosing, similar to other studies, but address confirmed anaerobic infections outside of solely anaerobic bacteremia. In this study, patients who received twice-daily dosing had similar rates of clinical cure, and all subcomponents of the primary end point either favored twice-daily dosing or results were similar between the 2 groups. Escalation of therapy was also similar between the 2 groups. Notably, most patients in both groups achieved adequate source control while receiving metronidazole therapy. Patients who received twice-daily dosing also had a shorter hospital length of stay and overall lower median and total metronidazole spend compared with the thrice-daily dosing group. The lower spend is to be expected based on the less frequent dosing, somewhat shorter time in the hospital, and slightly fewer patients included in the postintervention group. Overall mortality rates were low in both groups.
Strengths of this study include that this is one of the only studies assessing effectiveness of metronidazole in confirmed anaerobic infections. Some previously published studies looked at presumed anaerobic infections or confirmed anaerobic bloodstream infections only. This study also included patients from multiple hospital sites from 2022 to 2024. Limitations of this study include the retrospective nature of the study design. This could be a limitation due to the possibility of recall bias and the difficulty of controlling confounding variables. Patients were also included if they received fewer than 72 hours of inpatient therapy but were discharged home on metronidazole therapy. However, adherence to the outpatient regimen could not be assessed; therefore, it could not be determined whether those select patients achieved clinical cure after completion of therapy. Another limitation of this study is that IV metronidazole was in short supply during the preintervention study period, which may have contributed to fewer patients meeting inclusion criteria for the study.
Conclusion
No significant differences in clinical outcomes were found between patients receiving twice-daily metronidazole dosing and those receiving the traditional thrice-daily dosing for confirmed anaerobic infections. These results align with existing pharmacokinetic data and contribute to the limited clinical literature that currently exists supporting twice-daily dosing.
REFERENCES
Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis. 2010;50(Suppl 1):S16-S23. doi:10.1086/647939
Lau AH, Lam NP, Piscitelli SC, Wilkes L, Danziger LH. Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. Clin Pharmacokinet. 1992;23(5):328-364. doi:10.2165/00003088-199223050-00002
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
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
Blood Culture Contamination: An Overview for Infection Control and Antibiotic Stewardship Programs Working with the Clinical Laboratory. Centers for Disease Control and Prevention. Accessed November 2, 2026. https://www.cdc.gov/antibiotic-use/media/pdfs/fs-bloodculture-508.pdf
