Metronidazole-induced Metallic Taste: A Systematic Review and Meta-Analysis

Aims: This study aimed to estimate the incidence rate of metallic taste side effects in a patient who received metronidazole versus tinidazole and link it to the safety profile for metronidazole. Study Design: Systematic Review and Meta-Analysis. Place and Duration of Study: This study where written and revised in the pharmaceutical care department at general network for healthcare providers Hospital, Jeddah, Saudi Arabia. between Mar 2021 and Dec 2021. Methodology: Literature searches were conducted in the following databases: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Statistical analysis was performed using Review Manager (RevMan) Version 5.4 software. Review Article Karrar et al.; JPRI, 33(58A): 307-317, 2021; Article no.JPRI.79760 308 Results: Our meta-analysis of randomized controlled trials studies confirm that there is a slight increase in the rate of metallic taste adverse effects. Around one-fifth of patients who were treated with tinidazole had developed an incidence rate (5.1%) higher than the patient who treated with metronidazole. Our data shows that the incidence rate of metallic taste adverse effects in patients who received metronidazole was 15.5% (58/373) while the incidence rate in patients who received tinidazole was 20.6% (104/505). But the overall rate of metallic taste adverse effects was not statistically significantly different (RR, 1.07; 95% CI, 0.45 to 2.55; P = 0.87). also, there was statistical heterogeneity in the included studies (I2 = 75%). Conclusion: In our meta-analysis, the incidence rate of metronidazole-associated metallic taste adverse effects was slightly lower than the incidence rate of tinidazole-associated metallic taste adverse effects. It is not statistically significant as the result shows but still shifting the patient to metronidazole instead of tinidazole may decrease the incidence rate of metallic taste by (5.1%) and give good coverage for the microbial than tinidazole.


Results:
Our meta-analysis of randomized controlled trials studies confirm that there is a slight increase in the rate of metallic taste adverse effects. Around one-fifth of patients who were treated with tinidazole had developed an incidence rate (5.1%) higher than the patient who treated with metronidazole. Our data shows that the incidence rate of metallic taste adverse effects in patients who received metronidazole was 15.5% (58/373) while the incidence rate in patients who received tinidazole was 20.6% (104/505). But the overall rate of metallic taste adverse effects was not statistically significantly different (RR, 1.07; 95% CI, 0.45 to 2.55; P = 0.87). also, there was statistical heterogeneity in the included studies (I2 = 75%). Conclusion: In our meta-analysis, the incidence rate of metronidazole-associated metallic taste adverse effects was slightly lower than the incidence rate of tinidazole-associated metallic taste adverse effects. It is not statistically significant as the result shows but still shifting the patient to metronidazole instead of tinidazole may decrease the incidence rate of metallic taste by (5.1%) and give good coverage for the microbial than tinidazole.

INTRODUCTION
Metronidazole is a type of drug that is widely used in medical practice for the treatment of several types of infectious diseases [1, 2]. Metronidazole works by attacking the DNA of bacteria cells and this class of drug is called nitroimidazole [3,4]. Metronidazole is the first nitroimidazole drug that shows useful clinical activity and it is considered as the most widely and used member of the nitroimidazole drug class [5][6][7][8]. Nitroimidazoles drugs consider as prodrugs and they are activating under a low oxygen environment and this occurs through reduction of the nitro group, leading to the formation of imidazole and cytotoxicity. but, still, the metabolism pathway and cytotoxicity of metronidazole are not definitively characterized [ [37][38][39][40][41]. also, it may lead to neurotoxicity, peripheral neuropathy, encephalopathy, and optic neuropathy in some cases [40,[42][43][44][45]. In some patients, it may alter the taste to a metallic taste [46,47]. Metallic taste is highly associated with treatment failure because it may affect the patient's compliance with their medical treatment regimens [48]. Tinidazole is structurally related to metronidazole but its activity is limited to protozoa such as Giardiasis and Amebiasis. also, it covers some bacteria such as Bacterial vaginosis organisms [49][50][51]. Tinidazole has the similar side effect to metronidazole such as GI upset, Metallic taste, diarrhea, and fatigue [52,53], but some studies find that tinidazole has a more favorable side effect profile than oral metronidazole notably with better gastrointestinal tolerability, less metallic taste incidence, less severity and the total number of overall side effect [54][55][56][57]. In this study, we are looking to highlight the incidence rate of metallic taste adverse effect between the metronidazole and the other type of nitroimidazole drugs such as tinidazole and link it with the safety profile of the metronidazole.

Search Strategy
To retrieve as much literature as possible on metronidazole and the incidence rate of metallic taste Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were used in this systematic review and meta-analysis [58]. A literature search was conducted using PubMed, EMBASE, and the Cochrane Library. All relevant articles published up to Nov 2021 were considered for our review.
The search strategy was as follows: We also looked at bibliographies of relevant literature, meta-analyses, and previously published systematic reviews that might be relevant. Literature retrieval was limited to English only and in case of unclear reported data further communication with the original authors was conducted.

Selection Criteria
We performed a comprehensive literature search for studies that compared metronidazole versus tinidazole in the incidence rate of metallic taste adverse events. Inclusion criteria were established a priori to minimize selection bias based on the PICOS (Problem/Patient, Intervention, Comparison, Outcome, Study design) method [59]. We restricted our research to original studies published in English and people have metallic taste side effects related to the use of metronidazole or tinidazole. The evaluation indicators of this systematic review and meta-analysis were the incidence rate of metallic taste adverse events related to metronidazole and tinidazole and the risk ratio (RR). All retrieved studies were loaded into the reference management software Note Express 3.2.0.7276.
The inclusion criteria of the study were based on PICOS: a. Population: any patients who were treated with metronidazole or tinidazole and the drug had to follow well-defined protocols regarding drug type, dosage, frequency, and duration of treatment. b. Intervention/comparison: metronidazole / tinidazole. c. Outcomes: incidence rate of metronidazole compared to tinidazole. d. Study design: Randomized Controlled Trials (RCTs).
The exclusion criteria of the study were as follows: a. Dual therapies were administered. b. non-English studies. c. Duplicate studies. d. case reports.

Data Extraction
Three reviewers (R. Alhendi and M. Nouh and Y.Nouh) used standardized data forms to extract the data we needed and then entered it into an Excel table. Any disagreement was resolved by consensus. The quality of individual studies was assessed through the Cochrane Collaboration's tool for assessing the risk of bias (Fig. 1). The following data were extracted: author information, study names, study design, funding source, study location, number of patients involved, patient characteristic, a drug used, drug strength, duration of treatment, subject ages, and presenting signs and symptoms.

Statistical Analysis
For each trial, the risk ratio (RR) was calculated for the incidence rate in patients who receive metronidazole versus tinidazole. The RR was presented with 95% confidence intervals (95% CIs); a P < .05 was considered significant (Fig.  1). We estimated the degree of heterogeneity among the trial results using the I 2 test (25%, 50%, and 75% represented low, moderate, and high heterogeneity, respectively). Whenever significant heterogeneity (I 2 > 50%) was achieved (Fig. 1). We used a random-effects model to combine the effect sizes of the included studies. Funnel plot was performed for publication bias (Fig. 2). All these operations were implemented through Review Manager (RevMan) Version 5.4 software [60].

Risk of Bias in Individual Studies
Two authors (Y. Alayafi and B. Alharthy) evaluated the risk of bias in individual studies independently using the Cochrane risk of bias tool (60) (Fig. 1). If there was disagreement between the two researchers, the other two researchers (R. Almansour and H. Alshame) were judged again.

Literature Review
A flow diagram of this systematic review and meta-analysis is shown in (Fig. 3). In summary, 214 studies were identified by our literature search. A total of 389 studies were excluded after an initial screening of titles and abstracts. After reviewing the full text of the remaining studies 7 studies including 876 patients met our inclusion criteria for systematic review and metaanalysis (Table 1).

Study Characteristics
Among the 7 studies, 5 studies did not provide baseline diseases [56,[61][62][63][64] ( Table 2). The total daily dose for most studies was 2000 mg for metronidazole and tinidazole [55,56,[61][62][63]. Except 2 studies were the first study the dose was divided into two groups, the first group was given orally in a twice-daily dose of 500mg, and the other group receives 1gram twice daily 400 mg [64]. In the second study, the patient start on intravenous (2-2.5 g/day) then shifted to oral (2-2.4 g/day) for the metronidazole group and the other group they receive (1.6 g/day) intravenous then shifted to oral (2 g/day) [65]. The duration of treatment for most studies was 7 days for metronidazole and 4 days for tinidazole [55,61,62]. Except 4 studies were the first study the duration was 14 days for metronidazole and 5 days for tinidazole [65]. For the rest of the three studies, the duration was 7 days for metronidazole and tinidazole [56,63,64]. All the studies included were randomized controlled trials [55,56,[61][62][63][64][65], two of them were designed to be double-blind [63,64]. Funding statements were not mentioned for all the studies included [55,56,[61][62][63][64][65]. Four of the studies that were included were conducted in India [55,56,61,65]. Except three studies were conducted in other countries, the first one was conducted in Bangladesh [62]. The other one was conducted in England [64]. The last one was conducted in Thailand [63]. The previous information related to study characteristics will be included in (Table 1).

Metallic Taste Incidence Rate
Regarding the 7 studies were included in this study, the incidence rate of metallic taste adverse effects in patients who received metronidazole was 15.5% (58/373). while the incidence rate in patients who received tinidazole was 20.6% (104/505). The rate of metallic taste adverse effects was not statistically significantly different but the incidence rate was slightly higher with the patient who receive tinidazole instead of metronidazole (RR, 1.07; 95% CI, 0.45 to 2.55; P = 0.87). also, there was statistical heterogeneity in the included studies (I 2 = 75%). The metallic taste incidence rates for the different studies were shown in (Fig. 1).

DISCUSSION
A metallic taste side effect is a risk factor for patients incompliant and discontinues the treatment course. The incidence rate of metallic taste adverse effects in patients who received metronidazole was 15.5% (58/373). While the incidence rate in patients who received tinidazole was 20.6% (104/505) (Fig. 1). Metronidazole was used as first-line therapy for decades. however, still, microbial coverage for the eradication of microbes is higher with the metronidazole than tinidazole [5-8]. Our meta-analysis of randomized controlled trials confirms that there is a slight increase in the rate of metallic taste adverse effects, occurring in approximately one-fifth of treated patients with an incidence rate (5.1%) higher in patients treated with tinidazole regimens instead of metronidazole. However, individual studies have described the incidences rate which is ranging from (3% up to 37%). This variability in incidence rate is due to heterogeneous patient populations, ranges of doses used, and the severity of illness differences. In contrast, our analysis mainly identified studies for a patient treated with metronidazole or tinidazole and the drug had to follow well-defined protocols regarding drug type, dosage, frequency, and duration of treatment. In addition, we analyzed only studies that were randomized controlled studies. There are several risk factors related to metronidazole and tinidazole-associated metallic taste adverse effects that are described in the literature. Those that are consistently reported include age, presence with previous signs and symptoms such as fever, dysentery, abdomen pain, and tender hepatomegaly (Table 2) [55,65]. In our analysis, the mean/median age of patients in most included studies was above 31 years of age. Other patient-specific data was not uniformly reported across the included studies. The risk for have metallic taste adverse effects may also be associated with the duration of metronidazole or tinidazole therapy. There are several strengths to our analysis, We only included randomized controlled studies in our article. In addition, metronidazole dosing in most of the included studies was (2000 mg Once Daily) and tinidazole dose was (2000 mg Once Daily) [55,56,[61][62][63]. Except two studies were the first study the dose divided into two groups. The first group was given orally in a twice-daily dose of 500 mg, and the other group receives 1 gram twice daily 400 mg [64]. In the second study, the patient start on intravenous (2-2.5 g/day) then shifted to oral (2-2.4 g/day) for the metronidazole group and the other group they receive (1.6 g/day) intravenous then shifted to oral (2 g/day) [65]. This dosing is expected to produce concentrations associated with the maximal tolerability threshold.
Also, all randomized controlled trials were not funded by any industry, institution, or society. The population was representative of patients from more than 4 continents. Some limitations may affect the validity and limit the generalizability related to this analysis and it is worth to considerate it. First, the studies in this analysis used variable duration for treatment, which can make clinical application challenging. Second, the overall number of patients in our analysis were relatively small. Finally, there was insufficient detail to examine the progression and resolution of metallic taste adverse effects along a continuum among the individual studies.

CONCLUSION
In our meta-analysis, the incidence rate of metronidazole-associated metallic taste adverse effects was slightly lower than the incidence rate of tinidazole-associated metallic taste adverse effects. It is not statistically significant as the result shows but still shifting the patient to metronidazole instead of tinidazole may decrease the incidence rate of metallic taste by (5.1%) and give good coverage for the microbial than tinidazole.

CONSENT AND ETHICAL APPROVAL
It is not applicable.

COMPETING INTERESTS
Authors have declared that no competing interests exist.