What is the data regarding metronidazole q12H dosing (and/or other extended intervals) versus q8H (three times daily) dosing?

Comment by InpharmD Researcher

Limited data compare clinical outcomes of using metronidazole for extended intervals such as every 12 hours (BID) versus the standard dosing of every 8 hours (TID). The available evidence, mostly dated before 2000, is primarily from single-center, cohort studies with small sample sizes that include patients with various types of infections. A more recent 2018 retrospective study found no difference in clinical cure rates in patients with anaerobic infections receiving BID versus TID dosing.

Background

A 2016 poster abstract details a retrospective chart review (N= 81) comparing metronidazole 500 mg twice daily (BID) regimen versus three times daily (TID) regimen 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 re-admitted (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]

A prospective, randomized study examined the efficacy and tolerability of novel, once-daily therapies in patients with Helicobacter pylori (H. pylori; N= 160) infection in 1999. Patients were randomized (1:1:1:1) to omeprazole 80 mg daily and metronidazole extended-release 750 mg daily for 10 days (OM); OM plus amoxicillin 1.5 g daily for 10 days (OMAm); OM plus azithromycin 500 mg daily for 7 days (OMAz); or OM plus clarithromycin g daily for 10 days (OMCl). The eradication rate with OM dual therapy was only 8%; however, cure with OMAm was significantly higher than OM (p <0.01). Eradication rates of OMAz vs OMCl were not significantly different (p= 0.32). The authors concluded that while metronidazole 250 mg TID is shown to be effective in H. pylori treatments in other studies, this pilot study revealed that extended-release metronidazole 750 mg for 10 days can be utilized once daily rather than two to three times daily (standard dose) with an eradication rate of approximately 80%. Additionally, the authors noted that the extended-release formulation might offer an advantage for a more constant blood level and suggest a potential for reduced side effects. [2]

References:

[1] Béïque L, Tsang C, Geertsema S, et al. Comparison of metronidazole q12h to q8h in combination with other antibiotics on the clinical outcome and readmission rate of patients with appendicitis and diverticulitis. Open Forum Infectious Diseases. 2016;3(suppl_1):1037.
[2] Laine L, Estrada R, Trujillo M, et al. Once-daily therapy for H. pylori infection: a randomized comparison of four regimens. Am J Gastroenterol. 1999;94(4):962-966. doi:10.1111/j.1572-0241.1999.995_r.x
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the data regarding metronidazole q12H dosing (and/or other extended intervals) versus q8H (three times daily) dosing?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Clinical efficacy of 12-h metronidazole dosing regimens in patients with anaerobic or mixed anaerobic infections

Design

Retrospective, single-center, pre–post-intervention study

N= 200

Objective

To evaluate the frequency of clinical cure among patients who received metronidazole every 12 h compared with those who received an every 8 h frequency

Study Groups

Q8h (n= 100)

Q12h (n= 100)

Inclusion Criteria

Aged ≥ 18 years; received metronidazole for at least 3 days for a presumed anaerobic or mixed anaerobic infection

Exclusion Criteria

C. difficile infection; central nervous system (CNS) infection; parasitic/amoebic infection; use of metronidazole for surgical prophylaxis; receipt of antibiotics with anaerobic coverage for greater than 24 h before the initiation of metronidazole; use of a concurrent medication with anaerobic coverage; those with an organism not susceptible to initial antibiotic selection; pregnant

Methods

From June 2014 to June 2015, all patients received metronidazole using the traditional 8-h dosing frequency. In July 2015, an every 12-h dosing was utilized for all indications except for C. difficile, CNS, or parasitic/amoebic infections. Clinical cure was defined as improvement or resolution of the principle sign/symptom of infection with normalization of white blood cells (WBCs > 4,000 and < 12,000 cells/µL) and temperature (> 96.8°F and < 100.4°F) at the end of therapy or at discharge. Clinical failure was defined by the presence of any of the following parameters: no resolution of the principle sign/symptom, escalation of antibiotics, or no microbiological cure.

Duration

June 2014 to July 2016

Outcome Measures

Primary: clinical cure

Secondary: duration of antibiotics, hospital length of stay, escalation of antibiotic therapy, microbiologic cure, and mortality

Baseline Characteristics

  

Q8h (n= 100)

Q12h (n= 100)

 p-value

Age, years

62.5 ± 18.7

53.9 ± 19.6

 0.002

Male

44 40 0.567

Body mass index, kg/m2

Underweight

Normal

Overweight

Obese

Morbidly obese

 

4%

33%

28%

29%

6% 

 

4%

30%

33%

24%

9%

0.804

-

-

-

-

-

Intensive care unit (ICU) admission

 5% 10% 0.179

Liver dysfunction*

 6% 9% 0.421

Infection type

Abdominal

Skin/soft tissue

Pneumonia

Other

 

89%

4%

0

7%

 

79%

6%

2%

13%

0.187

-

-

-

-

Concurrent antibiotic therapy

Ciprofloxacin

Ceftriaxone

Other

None

93%

67%

17%

9%

7%

95%

46%

32%

17%

5%

0.552

-

-

-

-

Signs of infection

Abdominal pain

Elevated temperature

Elevated white blood cells

Radiographic confirmation

 

73%

18%

51%

77%

 

64%

23%

53%

74%

 

0.171

0.381

0.777

0.622

Underweight, < 18.5; normal, 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; morbidly obese, > 40

*The metabolism of metronidazole is decreased in patients with hepatic impairment. Dose reductions of 50% may be needed for Child-Pugh Class C.

Results

Endpoint

Q8h (n= 100)

Q12h (n= 100)

p-value

Clinical cure

 83% 83% 1

Escalation of all antibiotic therapy

Duration of all antibiotic therapy, days

Duration of metronidazole, days

Hospital length of stay, days

1

5.8 ± 4

4.8 ± 2.8

6.7 ± 5.2

1

5.9 ± 4.3

4.9 ± 2.4

8.1 ± 7

1

0.891

0.827

0.11

Death

 2% 3% 0.651

Adverse Events

Not disclosed

Study Author Conclusions

No differences in clinical outcomes for patients receiving every 12-h metronidazole dosing interval were identified among patients receiving metronidazole for presumed anaerobic or mixed anaerobic infections. These findings validate existing pharmacokinetic data and add to the limited clinical literature that currently exists for this dosing strategy. In addition to effectively treating infections, utilizing a 12-h dosing interval has the potential to reduce drug costs, adverse drug effects, and antibiotic resistance.

InpharmD Researcher Critique

This study has some limitations including the single-center and retrospective design; however, given the relatively large sample size of the study, it was powered to detect a difference in clinical cure between the different dosing groups. Since more patients required initial admission to ICU in the 12-h group vs the 8-h group, patients in the 12-h group may have had more severe infections and possible comorbidities upon initial presentation vs the 8-h group. 



References:

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

 

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

Design

Single-blind, single-center, prospective, randomized trial

N= 57

Objective

 To compare the incidence of post-surgical complications with varying dosage schedules of metronidazole

Study Groups

Twice daily (n= 30)

Three times daily (n= 27)

Inclusion Criteria

 Age 18 to 32 years; surgical excision of both mandibular third molars under general anesthesia

Exclusion Criteria

 Any other surgical removals of maxillary third molars; adverse medical history; acute infection; receiving concurrent antibiotics

Methods

Patients were randomized to receive metronidazole 400 mg PO two or three times daily for 5 days postoperative. Patients were given a prescription of acetaminophen-codeine compound for analgesia but could use others for pain control. Patients and the operative procedures by four different clinicians were blinded, but not the investigators.

Duration

 Follow-up: 7 days

Outcome Measures

 Postoperative complications; reported side effects

Baseline Characteristics

No statistical differences in baseline characteristics (specifics not provided) or surgeon performing the procedure.

Results

Endpoint

Three times daily (n= 27)

Twice daily (n= 30)

Postoperative complications

Swelling

Wound erythema

Wound breakdown

Wound discharge

 

23

14

5

2

 

21

16

3

3

Side effect

Nausea

Vomiting

Abdominal discomfort

Diarrhea

Constipation

Drowsiness

Headache

Dizziness

Change in urine color

 

15*

6

2

1

3

9

7

6

8

 

8

7

3

3

6

11

10

8

7

*p < 0.05 versus three times daily group

Three patients admitted to not being compliant with prescribed metronidazole. Compliance variation was not analyzed between groups.

Study Author Conclusions

 It would appear that a 12-hourly dose interval of metronidazole is no different from an 8-hourly dose interval, in the prevention of local wound infection following minor oral surgery.

InpharmD Researcher Critique

This is an older study and may not be reflective of current clinical practices. The setting is specific to the removal of molars and is not applicable to all clinical scenarios. Patients had confessed not to be fully compliant with metronidazole therapy. Therefore, the true comparative efficacy and safety between dosing intervals of metronidazole remain uncertain.



References:

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):165-167. doi:10.1016/0266-4356(94)90102-3

 

Comparison of Single-Dose vs One-Week Course of Metronidazole for Symptomatic Bacterial Vaginosis

Design

Prospective, single-blind, randomized study

N= 82

Objective

To evaluate the effectiveness of a single 2 g oral dose of metronidazole (MET) in treating symptomatic bacterial vaginosis as compared with the proven seven-day regimen

Study Groups

Single-dose MET (n= 46)

BID-MET (n= 36)

Inclusion Criteria

Nonpregnant women; 18 to 45 years of age; came to the Wyoming Family Practice Clinic at Casper with symptomatic bacterial vaginosis 

Exclusion Criteria

Treatment with antibiotics or vaginal cream in the previous 30 days; history of allergy to metronidazole; did not meet criteria for bacterial vaginosis, or had evidence of Trichomonas or yeast on their wet preparations, or had cultures positive for gonorrhea 

Methods

Eligible patients were randomized to a single 2-g dose of metronidazole (single-dose MET) or 500 mg metronidazole BID (BID-MET) for 7 days. Half of the single-dose MET group and half of the BID-MET group were randomly selected for treatment of the woman's sexual partner with the same dose and regimen as the patient in that group received. Each woman was re-evaluated at one week and three weeks after treatment.

Duration

21 days after treatment

Outcome Measures

Cure rate at 7 to 10 days, cure rate at 21 days (cure defined as G. vaginalis not isolated on culture and symptoms had markedly improved or been eliminated)

Baseline Characteristics

  

All patients

(N= 102)

 

  

G vaginalis isolated on pre-treatment cultures

 86/98 (88%)    

Symptomatic

 98/98 (100%)     

Results

Endpoint

Single Dose MET (n= 46)

BID-MET (n= 36) 

p-value

Cure Rate at 7-10 Days

 40/46 (86%) 35/36 (97%) > 0.1
 

Single Dose MET (n= 34)

 BID-MET (n= 30)   

Cure Rate at 21 Days

 16/34 (46%) 26/30 (86%)  < 0.05 

Clue cells at 21 Days

 18/34 (53%) 4/30 (13%) < 0.02

Amine order at 21 Days

 17/34 (50%) 4/30 (13%) < 0.02

Those who were selected to have sexual partners treated had no significant difference in cure rate at 7 to 10 days or 21 days versus those randomized to the same treatment but without treatment of sexual partners (p > 0.1). 

Adverse Events

Common Adverse Events: Unpleasant taste (53% vs. 47%), nausea (29% vs. 47%), darkened urine (18% vs. 33%); comparison of overall side effects between the two groups did not show a significant difference.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: Two participants in the BID-MET group discontinued due to nausea and palpitations.

Study Author Conclusions

By 21 days after therapy, the single 2 g dose is significantly less effective than the proven seven-day regimen. 

InpharmD Researcher Critique

Since the sample size was small, the study may not be powered to show a significant result for the cure rate. Additionally, researchers did not disclose demographic details of the participants, details of statistical methods used, and details of the analysis of sexual partners. 



References:

Swedberg J, Steiner JF, Deiss F, Steiner S, Driggers DA. Comparison of single-dose vs one-week course of metronidazole for symptomatic bacterial vaginosis. JAMA. 1985;254(8):1046-1049.