A Prospective, Observational Study Evaluating the Incidence of Metallic Taste, Compliance, and Clinical Outcomes with Metronidazole Extended-release 600 mg Compared to Immediate-release Formulations (MERIT STUDY)

Abstract

Background

Metronidazole remains a cornerstone in the management of anaerobic bacterial and protozoal infections. However, its clinical utility is often limited by adverse effects such as a metallic taste (dysgeusia), which can negatively impact treatment adherence. Extended-release (ER) formulations have been developed to optimize pharmacokinetic profiles and improve tolerability.

Objective

To evaluate the incidence of metallic taste, patient compliance, clinical outcomes, and safety of metronidazole ER 600 mg compared with immediate-release (IR) formulations.

Materials and methods

This prospective, observational, multi-center study included 200 adult patients who were prescribed either metronidazole ER 600 mg (n = 102) or IR formulations [200/400 mg; (n = 98)]. The primary endpoint was the incidence of metallic taste. Secondary endpoints included patient-reported compliance, clinical outcomes, and safety. Assessments were conducted at baseline and on days 3 and 5.

Results

The incidence of metallic taste was significantly lower in the ER group compared to the IR group (8.82 vs 19.39%; p = 0.0134), representing a 54% relative risk (RR) reduction. Compliance was significantly higher in the ER group (91.18 vs 80.61%; p = 0.0241). Clinical cure rates were comparable (95.10 vs 90.82%; p = 0.2377). Both formulations were well tolerated, with only mild adverse events reported.

Conclusion

Metronidazole ER 600 mg significantly improved tolerability and adherence while maintaining comparable efficacy and safety. It offers a clinically meaningful advantage in enhancing patient compliance for the treatment of anaerobic infections.

Introduction

Metronidazole is an extensively used nitroimidazole antimicrobial agent that plays an important role in the management of infections caused by anaerobic bacteria and protozoa.¹ Due to its broad antimicrobial spectrum and favorable pharmacokinetic properties,² it remains a cornerstone therapy for a variety of clinical conditions, including gastrointestinal, dental, and gynecological infections.³ After oral administration, metronidazole demonstrates rapid and almost complete absorption, with bioavailability exceeding 90%. The drug is extensively distributed into body tissues and fluids, including saliva, cerebrospinal fluid, and breast milk. It undergoes hepatic metabolism to form an active hydroxy metabolite that contributes to its antimicrobial activity.² The antimicrobial effect of metronidazole results from intracellular reduction of the nitro group, producing reactive metabolites that disrupt microbial deoxyribonucleic acid (DNA) synthesis and ultimately lead to cell death.⁴

Although metronidazole has proven efficacy and is widely used in clinical practice, its use is frequently associated with adverse effects that may reduce patient's acceptability. Among these, metallic taste (dysgeusia) is one of the most commonly reported adverse effects. Patients reporting this taste disturbances usually describe a persistent unpleasant metallic sensation in the mouth, which may be accompanied by nausea, reduced appetite, or discomfort during food intake. Even though this adverse effect is not generally severe, it can negatively impact the overall treatment experience and may lead to poor adherence to the prescribed antibiotic regimen.⁵

The success of antimicrobial therapy mainly depends on medication adherence. Incomplete pathogen eradication, prolonged infection, and an increased risk of antimicrobial resistance are the result of poor compliance with antibiotic therapy.⁶ Taste disturbances have been identified as an important contributor to reduced treatment adherence, particularly in outpatient settings.⁷ A meta-analysis on metronidazole-induced metallic taste highlighted a 15.5% incidence rate of metallic taste adverse effect, showing clinical relevance of this adverse effect and the need for interventions to improve treatment tolerability.⁵

Metronidazole is available in different oral formulations, including extended-release (ER) and immediate-release (IR) tablets. Extended-release formulations are designed to release the drug gradually, maintaining steady plasma concentrations over time and allowing for reduced dosing frequency, whereas IR formulations release the active drug rapidly following administration, resulting in higher peak plasma concentrations and requiring multiple daily dosing. Therefore, the pharmacokinetic profile of the ER formulation may improve tolerability and patient convenience while maintaining therapeutic efficacy.⁸

Previous studies have illustrated that ER metronidazole formulations exhibit bactericidal activity comparable to that of conventional IR formulations; also, the antimicrobial activity of different dosing regimens have shown similar bacterial killing rates against anaerobic pathogens, suggesting that ER formulations can maintain therapeutic effectiveness while potentially improving patient tolerability.⁹ However, despite these pharmacokinetic and pharmacodynamic advantages, clinical data directly comparing the incidence of metallic taste between metronidazole ER and IR formulations remain limited.

Therefore, the present study was conducted to evaluate and compare Metronidazole Extended-release and Immediate-Release Tablet formulation for the incidence of metallic taste and compliance (MERIT Study) in adult patients receiving treatment for dental, gastrointestinal, and gynecological infections. Additionally, the study aimed to assess clinical outcomes and safety associated with both formulations in routine clinical practice.

Materials and Methods

Study Design and Population

This prospective, observational study was registered prospectively, CTRI registration number: CTRI/2025/06/088246 [Registered on: 04/06/2025]. The study was conducted at two different sites in India, namely Aatman Hospital, Ahmedabad, Gujarat and Makhija Dental Care, Ahmedabad, Gujarat, India. The trial was conducted between July 2025 and September 2025.

The prospective, observational, real-world surveillance study included a total of 200 male or female patients aged ≥18 years who were prescribed Metrogyl® 600 ER [(metronidazole 600 mg ER formulation (Manufactured by: JB Chemicals & Pharmaceuticals Ltd.)] (study group) or metronidazole IR (200/400 mg; reference group) tablets for any indication at the physician's discretion. Ethics Committee approval was obtained at both the participating sites [Aatman Hospital (Registration no. ECR/1565/Inst/GJ/2021 & Approval date: 20/05/2025); Makhija Dental Care (Approval date: 20/05/2025)] before initiation of the study and enrolment of patients.

Inclusion Criteria

• Male and female patients aged ≥18 years.

• Patients prescribed with metronidazole ER or IR tablets for any indication at the physician's discretion.

• Patients willing to provide written informed consent and comply with study procedures.

Exclusion Criteria

• Known hypersensitivity or allergy to metronidazole tablets or any component of the formulation.

• History of significant gastrointestinal [e.g., gastroesophageal reflux disease (GERD), peptic ulcers, and inflammatory bowel disease] or neurological disorders (e.g., peripheral neuropathy, stroke, and Parkinson's disease) that may affect drug absorption or taste perception.

• Patients requiring hospitalization for their primary condition.

• Patients currently on medications that may interact with metronidazole or those on concurrent medications that could interfere with the study outcomes.

• History of substance abuse (including alcohol, tobacco, or illicit drugs) within the past 3 months, as it may impact compliance, taste perception, and study outcomes.

• Pregnant or breastfeeding women, or women of childbearing potential.

• Participation in another clinical trial within the last 30 days.

• Not willing to comply with the study requirements.

Study Assessments

The assessments were done at baseline or day 0, screening, eligibility assessment, vitals, and demographic data evaluation was carried out (assessment 1), day 3 (assessment 2), and day 5 for final safety and efficacy monitoring (assessment 3).

Outcome Measures

Primary Endpoint

• Incidence of metallic taste with metronidazole ER tablets and metronidazole IR tablets during the treatment, assessed using 5-point grading criteria.

Secondary Endpoints

• Patient-reported compliance with metronidazole ER and IR tablets during the treatment, was assessed using investigator-defined 5-point categories.

• Change in symptoms and improvement in the underlying condition with metronidazole ER or IR during the treatment.

• Incidence of adverse effects associated with metronidazole ER and metronidazole IR during the treatment.

Sample Size

The sample size was calculated to compare the incidence of metallic taste between the metronidazole ER and IR treatment groups. Assuming an incidence of 21% in the ER group and 40% in the IR group, with a two-sided significance level of 5 and 80% power, the required sample size was estimated using a two-sample comparison of proportions. The calculated sample size was approximately 90 subjects per group, resulting in a total of 180 subjects. To account for a 10% dropout rate, the sample size was inflated to 200 subjects.

Statistical Analysis

All statistical analyses were performed using R software. Continuous variables are presented as mean ± standard deviation (SD), while categorical variables are summarized as frequencies and percentages. Ninety-five percent confidence intervals (CIs) were calculated where applicable. Comparisons between groups for categorical variables were performed using the Chi-square or Fisher's exact test, as appropriate. The strength of association between groups was expressed using relative risk (RR) with corresponding 95% CIs. For continuous or ordinal data not meeting normality assumptions, the Wilcoxon rank-sum test was used to assess differences between groups. Correlation between variables was evaluated using appropriate correlation coefficients (Pearson or Spearman), along with tests of statistical significance. All statistical tests were two-sided, and a p-value < 0.05 was considered statistically significant.

Results

Study Population and Baseline Characteristics

A total of 200 adult patients aged ≥18 years were enrolled in the study with a mean age of 32.75 ± 10.63 years and weight of 66.16 ± 8.45 kg. The study population comprised 121 females (60.5%) and 79 males (39.5%), with a mean age of 32.75 ± 10.63 years. Of these, 102 patients (51.0%) were prescribed metronidazole ER 600 mg, and 98 patients (49.0%) were prescribed metronidazole IR 400 or 200 mg group (Fig. 1). Metronidazole was prescribed for gastrointestinal infections in 22.5% of patients, dental infections in 37.5%, and gynecological infections in 40.0%. Table 1 presents the demographic and baseline characteristics of the enrolled patients.

Fig. 1.

Study flow diagram

Table 1.

Demographic and baseline characteristics of the enrolled patients

Parameters	Total (N = 200)
Gender#
Female	121 (60.50%)
Male	79 (39.50%)
Age (year)#
≥18 years	200 (100%)
Patient assigned to#
Test: Metronidazole ER 600 mg tablets	102 (51.00%)
Reference: Metronidazole IR 400 or 200 mg tablets	98 (49.00%)
Primary infection for which metronidazole is prescribed#
Gastrointestinal infection	45 (22.50%)
Dental infection	75 (37.50%)
Gynecological infection	80 (40.00%)
Age (year)*	32.75 ± 10.63 (31.28–34.22)
Height (cm)*	161.96 ± 6.86 (161.01–162.91)
Weight (kg)*	66.16 ± 8.45 (64.98–67.33)
BMI (kg/m2)*	25.27 ± 3.27 (24.81–25.72)
Systolic blood pressure (mm Hg)*	121.03 ± 3.12 (120.6–121.46)
Diastolic blood pressure (mm Hg)*	70.17 ± 5.83 (69.36–70.98)

^#Data presented as n (%); *Data presented as mean ± SD (95% CI)

Primary Outcome

Incidence of Metallic Taste during Treatment

The primary endpoint was the incidence of metallic taste associated with metronidazole ER compared with metronidazole IR. By day 3, metallic taste was reported by eight patients (7.84%) in the study group compared with 17 patients (17.35%) in the reference group. This difference was statistically significant (p = 0.0421), corresponding to an RR of 0.45 (95% CI: 0.20–1.00). Over the entire treatment duration, the total incidence of metallic taste was 8.82% (9/102) in the study group compared with 19.39% (19/98) in the reference group. This reduction was statistically significant (p = 0.0134), with an RR of 0.46 (95% CI: 0.22–0.96), corresponding to relative risk reduction of 54% with the ER formulation (Table 2).

Table 2.

Incidence of metallic taste with metronidazole ER tablets as compared to metronidazole IR tablets during the treatment

Assessment of metallic taste	Metronidazole ER (N = 102)*	Metronidazole IR (N = 98)*	p-value $	RR (95% CI) ^
Incidence of metallic taste till assessment 2 (day 3)	8 (7.84%)	17 (17.35%)	0.0421	0.45 (0.20, 1.00)
Total incidence of metallic taste during treatment	9 (8.82%)	19 (19.39%)	0.0134	0.46 (0.22, 0.96)

*Data presented as n (%); ^$p-value as based on (Fisher's exact test); ^{^}Relative risk in metronidazole ER vs metronidazole IR as RR (95% CI)

Secondary Outcomes

Patient-reported Compliance

In the study group, 91.18% of patients were fully compliant, compared with 80.61% in the IR group. Moderate or poor compliance was reported in 1.96 and 0% of metronidazole ER-treated patients, respectively, vs 7.14 and 3.06% in the reference group. No patient in either group discontinued therapy due to severe metallic taste. Patient-reported compliance was significantly better with metronidazole ER compared to IR tablets (p = 0.0241). These findings suggest improved adherence with the ER formulation (Table 3).

Table 3.

Patient reported compliance with metronidazole ER tablets and metronidazole IR tablets during the treatment

Patient reported compliance	Metronidazole ER (N = 102)*	Metronidazole IR (N = 98)*	p-value $
Non-compliant	0 (0.0%)	0 (0.0%)	0.0241
Poorly compliant	0 (0.00%)	3 (3.06%)
Moderately compliant	2 (1.96%)	7 (7.14%)
Highly compliant	7 (6.86%)	9 (9.18%)
Fully compliant	93 (91.18%)	79 (80.61%)

*Data presented as n (%); ^$p-value as based on (Wilcoxon rank sum test). Non-compliant – discontinued due to severe metallic taste, poorly compliant – missed multiple doses due to taste disturbance, moderately compliant – missed some doses but tolerated, highly compliant – completed treatment with minor difficulty, fully compliant – no or minimal impact on adherence

Clinical Outcomes at End of Treatment

At the end-of-treatment assessment (minimum day 5), clinical cure was achieved in 95.10% of patients receiving metronidazole ER and 90.82% receiving IR therapy. Clinical improvement was observed in 4.90 and 9.18% of patients in the study and reference groups, respectively. No cases of treatment failure or clinical worsening were reported in either group. However, the difference between groups was not statistically significant (p = 0.2377), indicating comparable therapeutic efficacy (Table 4).

Table 4.

Patient's clinical status at assessment 3 (end of the treatment) – minimum day 5

Clinical outcome**	Metronidazole ER (N = 102)*	Metronidazole IR (N = 98)*	p-value $
Cure	97 (95.10%)	89 (90.82%)	0.2377
Improvement	5 (4.90%)	9 (9.18%)
No improvement	0 (0.0%)	0 (0.0%)
Worsening	0 (0.0%)	0 (0.0%)

*Data presented as n (%); ^$p-value as based on (Wilcoxon rank sum test); **Cure (complete resolution of signs and symptoms), improvement (partial resolution with some persistent symptoms), no improvement (no significant change in symptoms), or worsening (symptoms persisted or worsened despite treatment) in both groups

Adverse Events

Both formulations were generally well tolerated. Adverse events were infrequent and mild in nature. In the study group, nausea was reported in two patients (1.96%), diarrhea in one patient (0.98%), and dry mouth in one patient (0.98%). In the reference group, nausea occurred in two patients (2.04%), loss of appetite in one patient (1.02%), and dry mouth in one patient (1.02%). No serious adverse events were reported during the study (Table 5).

Table 5.

Adverse events

Adverse event	Metronidazole ER (N = 102) #	Metronidazole IR (N = 98) #	Total (N = 200) #
Nausea	2 (1.96%)	2 (2.04%)	4 (2.00%)
Loss of appetite	0 (0.00%)	1 (1.02%)	1 (0.50%)
Diarrhea	1 (0.98%)	0 (0.00%)	1 (0.50%)
Dry mouth	1 (0.98%)	1 (1.02%)	2 (1.00%)

^#Data presented as n (%)

Discussion

The present study evaluated the incidence of metallic taste associated with metronidazole ER tablets compared with metronidazole IR tablets in patients with gastrointestinal, dental, and gynecological infections (Table 1).¹⁰ The results demonstrated a statistically significant reduction in metallic taste incidence with the ER formulation (8.82%) vs the IR formulation (19.39%) (Table 2; p = 0.0134; RR = 0.46, 95% CI: 0.22–0.96), suggesting improved gastrointestinal tolerability.¹⁰

Metallic taste is among the most frequently reported adverse sensory effects of metronidazole, primarily attributed to diffusion of its active metabolites into salivary secretions and interaction with taste receptors.^11,12 Although non-serious, this side effect is a well-recognized cause of treatment discontinuation or nonadherence in antimicrobial therapy.¹³ The ER formulation maintains effective plasma concentrations with reduced peak levels, minimizing sharp fluctuations that enhance mucosal exposure and sensory irritation.¹⁴ This pharmacokinetic advantage plausibly explains the improved tolerability observed with metronidazole ER formulation.^15,16

Results across infection types consistently favored the ER formulation, though differences were not statistically significant, likely due to smaller sample sizes. Importantly, treatment compliance was significantly higher in the ER group (91.18% fully compliant vs 80.61% in IR; Table 3; p = 0.0241). These findings align with evidence linking simplified dosing schedules and improved palatability to better adherence.^17,18 A significant negative correlation between metallic taste and compliance (r = −0.537 for ER; r = −0.64 for IR; p < 0.05) underscores the impact of taste disturbances on treatment persistence.^19,20

Both formulations achieved comparable clinical cure/improvement rates (95.1% ER vs 90.8% IR; Table 4; p = 0.2377), confirming that enhanced tolerability does not compromise efficacy.²¹ Safety profiles were similar, with mild adverse events (nausea, dry mouth) at low, comparable frequencies (Table 5).²²

These results align with studies showing ER nitroimidazoles improve tolerability and satisfaction without compromising antimicrobial efficacy.^23,24 The present findings support metronidazole ER formulations clinical utility for enhancing adherence in prolonged-therapy infections.^17,24 By minimizing metallic taste—a common adherence barrier—the ER formulation addresses a key determinant of real-world treatment success.^14,19

Limitations

Our study had limitations; it was an open-label, study with a modest sample size per group; confounding patient expectations or center-specific practices cannot be excluded. Multicenter trials would strengthen generalizability. Despite this, the primary endpoint achieved statistical significance, supporting the tolerability advantage.

Conclusion

In this prospective, observational, multicenter, study, metronidazole ER tablets demonstrated significantly lower metallic taste incidence and superior compliance vs IR tablets, with equivalent efficacy and safety. The ER profile likely limits peak-related taste disturbances. These findings position metronidazole ER as a patient-friendly alternative enhancing adherence without compromising outcomes in real-world clinical settings. However, multicenter studies with larger cohorts are warranted to validate these observations for broader adoption.

Clinical Significance

Metronidazole remains a widely prescribed antimicrobial agent across gastrointestinal, dental, and gynecological infections; however, treatment adherence is often compromised by the occurrence of metallic taste. The findings of the MERIT study demonstrate that the ER formulation significantly reduced the incidence of metallic taste by approximately 54% compared with IR formulations, while maintaining comparable clinical efficacy and safety. Improved tolerability translated into significantly higher patient compliance, an important determinant of successful antimicrobial therapy. These results suggest that metronidazole ER may offer a clinically meaningful advantage in routine practice by enhancing treatment adherence and patient satisfaction without compromising therapeutic outcomes. Adoption of the ER formulation could therefore contribute to improved real-world effectiveness of metronidazole therapy, particularly in patients where tolerability-related noncompliance is a concern.

Declarations

Ethics Approval and Consent to Participate

This study was performed in line with the principles of the Declaration of Helsinki. Ethics Committee approval was obtained at both the participating sites [Aatman Hospital (Registration no. ECR/1565/Inst/GJ/2021 & Approval date: 20/05/2025); Makhija Dental Care (Approval date: 20/05/2025)]. Written informed consents were obtained from all study participants.

Artificial Intelligence (AI) Disclosure

Author's state that no AI is used in the study performed.

Acknowledgments

The authors would like to thank Dr Hasnat Khan, Mr Taasin Shah and Dr Parikshit Mishra, Medical Affairs, JB Chemicals & Pharmaceuticals Ltd., Mumbai, India for providing medical writing assistance and review of the final manuscript. The authors would also like to thank Dr Jayesh Sanmukhani, Director – Medical Services, Clinexcel Research, an independent contract research organization, for protocol writing, study monitoring, data management, and statistical analysis conducted in accordance with Good Clinical Practice guidelines.

Authors' Contributions

Chintan Patel: Conceptualization, planning, design, study conduct, and data collection; Hasnat Khan: Writing-original draft; and Jay Savai and Kapil Mehta: Supervision, review of protocol, and manuscript. All authors critically reviewed the manuscript and approved the final version.

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.