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Background:
Systematic Review

Efficacy of Antimicrobial Agents in Dentifrices: A Systematic Review

by
Vanessa Teixeira Marinho
,
Andréa Cândido dos Reis
and
Mariana Lima da Costa Valente
*
Department of Dental Materials and Prosthodontics, Ribeirão Preto Dental School, University of São Paulo (USP), Ribeirão Preto 14040-904, Brazil
*
Author to whom correspondence should be addressed.
Antibiotics 2022, 11(10), 1413; https://doi.org/10.3390/antibiotics11101413
Submission received: 16 September 2022 / Revised: 6 October 2022 / Accepted: 11 October 2022 / Published: 14 October 2022
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Review Reports Versions Notes

Abstract

:
The aim of this systematic review was to verify if the presence of different antimicrobial agents in dentifrices is effective in reducing the number of microorganisms for disease prevention. This review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and was registered with the Open Science Framework (OSF). A search was conducted in the PubMed, Embase, Scopus, and Web of Science databases. Two independent authors reviewed the titles and abstracts according to the inclusion criteria, which comprised in vitro studies published in English that evaluated the efficacy of antimicrobial agents in dentifrices and their antimicrobial activity. A total of 527 articles were found. Of these, 334 were included for reading of the title and abstract, and 69 were selected for reading in full. In the end, 39 articles remained in this review. Triclosan, sodium fluoride, and sodium monofluorophosphate were the most commonly used chemical antimicrobial agents. Among the herbal agents, miswak extract and neem extract were the most commonly used. The presence of antimicrobial agents in dentifrice formulations can promote the reduction of the number of microorganisms involved in oral diseases, but with variations in their effectiveness, depending on the agent used and the microorganism evaluated.

1. Introduction

The human oral cavity is a complex environment composed of a variety of microorganisms, including commensal bacteria that are part of the healthy oral microbiota and are important for physiology, and pathogenic microorganisms, which are responsible for various infections, the most common and prevalent of which are dental caries and periodontal diseases [1]. When the balance of an individual’s oral microbiota is lost, opportunistic pathogens can proliferate, resulting in the development of diseases [2].
Several microorganisms are involved in the progression of oral pathologies. Streptococcus mutans is a Gram-positive bacteria frequently found in the human oral cavity and one of the main microorganisms involved in the etiology of dental caries, along with Lactobacillus spp. [3,4,5]. Candida albicans is the most commonly commensal fungal species from the oral cavity, and under conditions of dysbiosis, can favor the appearance of oral candidiasis, an opportunistic infection, and is also associated with active caries lesions and promotes negative influences on tissue [6,7]. Staphylococcus aureus is another Gram-positive bacterium capable of causing opportunistic infections [8]. On the other hand, periodontal diseases are mainly caused by streptococci and spirochetes [6].
Caries is a multifactorial disease characterized by unbalanced mineralization and demineralization of teeth. S. mutans acts in the fermentation of carbohydrates from food, and this process produces acids that demineralize and degrade the dental element [6]. Biofilm accumulation and cariogenic microbiota are closely related to disease progression [9]. Periodontal diseases include gingivitis and periodontitis, which affect the tissue and structures that protect and support the teeth, respectively. Periodontitis, the most severe form of the disease, can result in loss of the dental element [6]. Biofilm accumulation also plays an important role in this infection [10].
Tooth brushing with dentifrice is one of the most frequently used oral hygiene practices in the world and is an essential measure for the maintenance of oral health [11,12,13]. Through it, it is possible to mechanically remove biofilm and consequently reduce the number of microorganisms [1]. However, it is not always properly performed. Therefore, the incorporation of antimicrobial agents in dentifrices is a prophylactic method of great importance to help control the number of microorganisms present in the oral cavity and thus reduce the chances of occurring infections. They act by slowing the microorganisms’ multiplication, preventing bacterial aggregation and rupture of the pathogens’ cell walls [14]. Antimicrobial agents such as sodium fluoride and triclosan have as their mechanism of action the inhibition of the activity of different enzymes [15,16]. In addition, herbal dentifrices contain phytochemicals, which are the substances responsible for their antimicrobial and anti-inflammatory effects [17].
Currently, there are several components present in dentifrice formulations with antimicrobial properties, such as triclosan and fluoride agents. However, some chemical antimicrobial agents can cause adverse effects [1,18]. Therefore, natural herbal dentifrices have emerged as a safer alternative to control and reduce the risk of infections and improve oral health. Herbal extracts have phytochemical components, which have antimicrobial and anti-inflammatory properties [17].
Most dentifrices are claimed to have antimicrobial properties, but comparative information on their efficacy is needed. There is a wide variety of dentifrices currently available, with various active substances, especially with the popularization of phytotherapeutic agents. Therefore, the aim of this systematic review was to verify if the presence of different antimicrobial agents in dentifrices is effective in reducing the number of microorganisms involved in oral diseases.

2. Materials and Methods

This systematic review was structured in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and was registered with the Open Science Framework (OSF). The question of the present review was formulated based on the PICOS: “Is the presence of antimicrobial agents in dentifrices really effective in reducing the number of microorganisms?” In this case, the population was formed by dentifrices without type restriction, the intervention was the presence of antimicrobial agents, the comparison was made with a group without the presence of antimicrobial agents, and the outcome was the evaluation of efficacy through antimicrobial activity, with the study focus being in vitro studies.
The electronic search for articles was conducted in November 2021 in the PubMed, Embase, Scopus, and Web of Science databases. The search was performed using the following terms: (dentifrices OR toothpastes) AND (“anti-infective agents” OR “anti-bacterial agents” OR “antimicrobial agents”) AND (“antibacterial activity” OR “antimicrobial activity”). The articles found were exported to Rayyan digital platform (Qatar Computing Research Institute, Doha, Qatar). Table 1 summarizes the database search strategy.
The initial selection was performed by two independent authors. In it, articles were selected based on titles and abstracts, and for studies with insufficient data, the manuscript was obtained and read in full. Studies that did not meet the established eligibility criteria were excluded. The second selection was made by reading the full text. Disagreements in the selection of articles were resolved through discussion between independent authors.
Eligibility criteria included in vitro studies published in English that evaluated the efficacy of antimicrobial agents in dentifrices and their antimicrobial activity. The exclusion criteria were applied to studies that did not evaluate dentifrices and studies that did not evaluate antimicrobial activity. Furthermore, in vivo studies, observational studies, studies that used clinical samples, reviews, book chapters, conference abstracts, case reports, surveys, and letters to the editor were also excluded.
Data from the included studies were extracted in a table in a Word document (Microsoft Corporation, Redmond, USA) with the following information: (1) authors and year of publication; (2) antimicrobial agents; (3) dentifrices used; (4) microorganisms evaluated; (5) method of antimicrobial activity evaluation; and (6) main conclusions (Table 1).
The methodological quality and risk of bias of the included studies were assessed by two authors by the Joanna Briggs Institute quasi-experimental study assessment tool, which was adapted for systematic review of in vitro studies. Each study was classified as low risk, uncertain risk, or high risk.

3. Results

Figure 1 depicts the study selection strategy. A total of 527 articles were identified in the initial search, of which 193 were duplicates. After analyzing the inclusion and exclusion criteria, 69 articles were selected for full-text reading. Of these, 30 were excluded, resulting in the selection of 39 relevant articles.
All selected articles evaluated the efficacy of different antimicrobial agents present in dentifrice formulations. Ten authors [9,19,20,21,22,23,24,25,26,27] evaluated dentifrices with chemical antimicrobial agents, nine authors [1,28,29,30,31,32,33,34,35] evaluated dentifrices with herbal antimicrobial agents and twenty authors [2,6,11,12,18,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50] evaluated both chemical and herbal agents.
The main antimicrobial agents present in the formulations of the studied dentifrices were sodium fluoride [2,6,12,18,20,21,22,24,25,26,27,36,41,42,43,44,45,46,47,48] and triclosan [2,6,11,12,18,20,21,22,24,26,27,37,42,43,44,45,46,47]. The antimicrobial agent sodium monofluorophosphate was also present in several formulations [6,18,20,21,22,24,37,38,43,45,46,47,49]. Regarding herbal antimicrobial agents, miswak [6,32,37,44,45,46,47] and neem [37,44,45,46,47] extracts were the most commonly used. In addition, some authors [18,21,22,24] reported that sodium lauryl sulfate, usually added to dentifrices due to its detergent properties, is also capable of producing antimicrobial activity. In general, among the antimicrobial agents, the dentifrice formulations that have triclosan as the active agent showed the most significant antimicrobial effect. In the studies of Evans et al. [22], Anushree et al. [37], Ali et al. [12] and Sadeghi et al. [21], a larger mean diameter of inhibition zone of triclosan-containing dentifrice (44.6 mm, 40.67 mm, 38 mm and 20.4 mm, respectively) was observed compared to sodium fluoride-containing dentifrice (8.4 mm, 18 mm, 12.4 mm and 14.3 mm, respectively) against S. mutans.
Some authors [39,41,45,47,48] demonstrated that certain herbal dentifrice formulations can be as effective as dentifrice formulations with chemical antimicrobial agents. Furthermore, in five studies [6,32,37,46,47] which evaluated the antimicrobial action of dentifrices in different dilutions, it was observed that the diameter of the inhibition zones decreased with increasing dentifrice dilution.
The most investigated microorganisms were Streptococcus mutans, Candida albicans and Staphylococcus aureus, respectively. In general, most antimicrobial agents were able to reduce the amount of S. mutans, but with great variations in their effectiveness. The largest diameter of the inhibition zones for this microorganism were 5.12 mm, 22 mm, 30 mm and 44.6 mm in the studies of Thounaojam et al. [39], Leite et al. [38], Babu et al. [32] and Evans et al. [22], respectively. The same was observed for S. aureus, where the largest diameter of the inhibition zones were 7 mm, 16.5 mm, 29.67 mm and 49 mm in the studies of Shaheena et al. [28], Leite et al. [38], Anushree et al. [37] and Ali et al. [12], respectively. In five studies [6,29,35,38,48], C. albicans did not show zones of inhibition or showed greater resistance to growth inhibition by plant extracts compared to chemical agents. However, another five studies [2,37,41,43,45] showed better results for some herbal dentifrices compared to chemical antimicrobials.
Figure 2 and Figure 3 summarize the results of the quality evaluation of the studies. The risk of bias was evaluated with the use of an adapted quasi-experimental studies appraisal tool by the Joanna Briggs Institute. Of the 39 studies included in this systematic review, most had a low risk of bias. The exception was the criteria “Were outcomes measured in a reliable way?”, which showed a high risk of bias. The studies did not report whether the trials were performed by the same technician or the number of raters.
Another criterion that showed a higher risk of bias was “Was appropriate statistical analysis used?” This result is justified by the absence of the statistical methods used [19,20,23,24,25,26,30,31,32,33,35,40,45]. Finally, some studies [20,22,26,31,32,43,46] had a high risk of bias for the criterion “Was there a control group?” because they had no control group, but rather just compared groups. Because the studies showed heterogeneity in antimicrobial agents, dentifrices used and microorganisms evaluated, statistical analysis or meta-analysis was not possible.

4. Discussion

The addition of antimicrobial agents to oral care products has been suggested as an important strategy to assist in the control and reduction of microorganisms involved in various diseases, in order to improve oral health. This systematic review investigated the effectiveness of different antimicrobial agents in toothpaste formulations and found that the presence of these components can promote a real reduction in the number of microorganisms involved in oral diseases, but with varying levels of effectiveness.
Fluoride agents were the most frequently used, such as sodium fluoride (NaF) and sodium monofluorophosphate (MFP). Besides acting in the tooth remineralization process and helping to prevent dental caries, fluoride is capable of interfering with bacterial metabolism through the inhibition of enzymes, such as enolase [15]. However, fluoride agents at high levels can cause adverse effects. Excessive exposure to fluoride in children during the formation of permanent teeth can lead to enamel mineralization defects, characterizing dental fluorosis [51]. In a study by Haraszthy et al. [52], the analyzed fluoride-containing dentifrices showed different antimicrobial effects. In most of the studies included in this review that compared fluoride dentifrices, the diameter of their zones of inhibition also varied [6,12,18,21,22,37,41,43,45,46]. Fluoride is more active and has a greater capacity to interfere with microorganism proliferation under low pH conditions [22]. Since some culture media used have a neutral pH, such as Mueller–Hinton agar, the action of fluoride may have been affected. In in vivo studies, considering the pH conditions of the oral cavity, it is possible to observe a reduction in the plaque index when this antimicrobial agent is used. Binney et al. [53] performed a clinical trial that evaluated the plaque inhibitory properties of five dentifrices, all containing fluoride agents. There was a reduction in the participants’ plaque index, which ranged from 2.49 to 2.24 among the dentifrices over a 4-day period. Similarly, in a clinical study by Gupta et al. [54], participants used a fluoride dentifrice and achieved a plaque score reduction ranging from 1.86 to 1.28 over a 4-week period.
Triclosan is a non-ionic phenolic derivative with antimicrobial properties that has also been widely used. In a study by McMurry et al. [16], triclosan showed antimicrobial activity through inhibition of the enzyme enoyl-acyl reductase (ENR) transporter protein, which participates in the synthesis of fatty acids. It also has anti-inflammatory effects, as it acts in the inhibition of the cyclooxygenase/lipoxygenase pathways [55]. Furthermore, triclosan and fluoride are able to damage the bacterial inner membrane [12]. However, great attention has been paid to the possible long-term side effects that this antimicrobial agent can cause [18], including the increase in resistance of microorganisms [22,56]. Some commercial dentifrices have a combination of triclosan and copolymer of maleic acid and polyvinyl methyl ether (PVM/MA), in order to improve its retention in the oral cavity and its solubility in water, resulting in greater substantivity [57,58]. A commercial dentifrice formulation containing triclosan and sodium fluoride has been used in several studies as a positive control and has been shown to be effective in the formation of inhibition zones of various microorganisms [2,11,42,44]. In only three studies in this review [27,43,45] were other dentifrice formulations more effective than those containing triclosan. In the results of Benlatef et al. [43] and Gibraiel et al. [45], herbal dentifrice formulations were more effective than triclosan. Fernández et al. [27], on the other hand, demonstrated that dentifrices containing sodium fluoride and stannous fluoride were more effective. In nine other studies [6,12,18,20,21,22,24,37,46], dentifrices containing combinations of triclosan and sodium fluoride or sodium monofluorophosphate were more effective than the other compared dentifrices that did not have triclosan in their composition. Similarly to these findings, Haraszthy et al. [52] and Forbes et al. [59] reported that dentifrices containing triclosan as the active agent showed greater antimicrobial activity than the others, such as sodium fluoride. In a study by Haraszthy et al. [52], the minimum inhibitory concentration (MIC) of dentifrice containing only sodium fluoride as an antimicrobial agent was 30 µg/mL for S. mutans, 30 µg/mL for S. aureus, and 75 µg/mL for C. albicans. In contrast, the MIC of the dentifrice containing triclosan and sodium fluoride was 7.5 µg/mL for S. mutans, 15 µg/mL for S. aureus, and 30 µg/mL for C. albicans, showing better results. The minimum inhibitory concentration is the lowest concentration of a substance that inhibits microbial growth. In addition, in a study by Forbes et al. [59], the minimum bactericidal concentration (MBC) against anaerobic bacteria of dentifrice containing only sodium fluoride as antimicrobial agent was 3.3 to 12.5 mg/mL, while the MBC of dentifrice containing triclosan and sodium fluoride was 1.6 to 6.3 mg/mL, the latter being more effective at lower concentrations.
Phytotherapeutic antimicrobial agents can be an alternative to the use of chemical agents in children and adults, in view of the possible adverse effects they can cause. Several studies [2,18,32,37,48] have demonstrated that the antimicrobial activity of herbal dentifrices containing different extracts shows a wide variation. In this review, miswak (Salvadora persica) and neem (Azadirachta indica) extracts were the most present in natural dentifrice formulations. Miswak is obtained from the branches of the Salvadora persica tree and has been used as an oral hygiene device since antiquity [60]. In studies by Mohammed [60], Sivakumar et al. [61] and Adwan et al. [62], dentifrices containing miswak extract showed antimicrobial action against different microorganisms, which is in agreement with the studies evaluated in this review [32,37,44,45,47]. Azadirachta indica, known as neem, is a plant that belongs to the Meliaceae family found in Asia and Africa [63]. From it, a stick is made that is also used as an oral hygiene tool by some Asian and African countries [64]. In a study by Jenner et al. [65], the dentifrice containing neem extract was the most effective among those evaluated. Shafiq et al. [66] reported that dentifrice containing neem extract showed inhibitory activity. In the present review, some included studies [37,44,45,47] also demonstrated antimicrobial activity in dentifrices containing neem extract. Prasanth [6] and Anushree et al. [37] reported that dentifrice containing Azadirachta indica and Salvadora persica extracts formed halos of inhibition, but smaller in comparison to dentifrice containing triclosan. It is important to emphasize that most herbal dentifrices do not contain only one extract, but a combination of them. Thus, the variations in efficacy between herbal dentifrices probably occurs because of the difference between the components present in each brand.
Most of the assays were performed using the agar diffusion test, used to compare the antimicrobial activity of the products. In this method, the physicochemical properties of each antimicrobial agent, such as the diffusion coefficient and solubility, have an influence on its diffusion through the agar matrix and, consequently, on the results obtained [14,18]. However, this is a good option as a screening before performing in vivo studies. The test can be done using paper disks containing the agent or in drilled wells, where the agents are introduced. The disk diffusion method is appropriate for fluid products, but it has been widely used to evaluate the antimicrobial activity of dentifrices, which are semi-solid, but become fluid upon contact with water or saliva [67].
Another point to be considered is the interaction between the different components of dentifrices. The presence of some substances in the formulation of dentifrices can either increase or decrease the substantivity and clinical activity of some component [68]. In a study by Sadeghi and Assar [21], two commercial dentifrices had triclosan and sodium monofluorophosphate as antimicrobial agents, but they differed in other components. Although the antimicrobials used were the same, the antimicrobial activity of the dentifrices was different. Thus, the synergistic interactions between the various ingredients present in the formulations are an important factor not to affect the effectiveness of the product [38]. Sadeghi and Assar [21] observed that the antimicrobial action against the microorganisms evaluated was greater in dentifrices that contained more than one antimicrobial agent in their formulation. Following the same reasoning, in a study by Ali et al. [12], commercial dentifrices that already contained antimicrobial agents showed larger zones of inhibition after the addition of Piper betle extract. Oluwasina et al. [41] reported that dentifrice formulations containing a mixture of three or two extracts showed greater bioactivity. In this study, the dentifrice containing three extracts, Dennettia tripetala, Syzygium aromaticum, and Jatropha curcas latex showed inhibition zones against several microorganisms ranging from 10 to 18.3 mm, while the dentifrice containing two extracts, Syzygium aromaticum and Jatropha curcas latex, showed zones ranging from 9 to 16 mm. In contrast, the dentifrice containing only one extract, Jatropha curcas latex, exhibited inhibition zones ranging from 0 to 10 mm. Also, the dentifrice containing only Dennettia tripetala showed zones of inhibition ranging from 0 to 8 mm, demonstrating the greater efficacy of dentifrices containing three and two extracts.
In addition, five authors [6,32,37,46,47] evaluated dentifrices in different dilutions and reported that the diameter of the inhibition zones decreased with increasing dilution of the dentifrice, which suggests that the efficacy of the antimicrobial agent may be reduced when it is diluted. The evaluation of dentifrice at various concentrations is of interest, since under in vivo conditions, saliva is able to dissolve the product.

5. Conclusions

Based on the results of this systematic review, some conclusions were established.
  • The presence of antimicrobial agents in dentifrice formulations can promote the reduction of the number of microorganisms involved in oral diseases, but with variations in their effectiveness, depending on the agent used and the microorganism evaluated.
  • Some dentifrice formulations with herbal ingredients, such as miswak and neem extracts, can be as effective as dentifrice formulations with chemical antimicrobial agents, such as sodium monofluorophosphate and sodium fluoride.
  • The antimicrobial activity of a dentifrice with antimicrobial agents can be reduced when it is diluted.
  • The interaction between the different components of a dentifrice can influence the effectiveness of its antimicrobial activity, and thus the synergism between the ingredients is of great importance.

Author Contributions

Conceptualization, V.T.M. and M.L.d.C.V.; methodology, V.T.M., A.C.d.R. and M.L.d.C.V.; formal analysis, V.T.M., A.C.d.R. and M.L.d.C.V.; investigation, V.T.M. and M.L.d.C.V.; writing—original draft preparation, V.T.M.; writing—review and editing, A.C.d.R. and M.L.d.C.V.; supervision, A.C.d.R. and M.L.d.C.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Antibiotics 11 01413 g001 550
Figure 1. Flowchart summarizing the phases of the systematic review.
Figure 1. Flowchart summarizing the phases of the systematic review.
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Antibiotics 11 01413 g002 550
Figure 2. Risk-of-bias graph of included studies.
Figure 2. Risk-of-bias graph of included studies.
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Figure 3. Risk-of-bias summary of included studies.
Figure 3. Risk-of-bias summary of included studies.
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Table
Table 1. Summary of included studies.
Table 1. Summary of included studies.
Material/Antimicrobial Agent Dentifrices Used Organisms Method of Antimicrobial Activity EvaluationMain Conclusions Ref.
Cinnamon, rosemary, nutmeg, orange, mint, ginger, oregano, thyme, clove, eucalyptus, tangerine, lime and tea tree oil18 dentifrices formulated with essential oils of cinnamon, clove, oregano and thymeStaphylococcus aureus, Streptococcus mutans, Lactobacillus lactis and Enterococcus faecalisHole-plate diffusion method
Broth microdilution method (MIC)		In general, the best results were obtained with cinnamon essential oil and dentifrice against S. mutans[1]
Triclosan, bee propolis and plant extracts, such as Peelu, neem, licorice, pomegranate rind, clove, Persian walnut, cinnamon, peppermint, echinacea, grapefruit seed, among others14 dentifrices:
Acu-Herb, Auromere Herbal Toothpaste, Dental Gel, Dental Herb (powder), Dentifrico de Echinacea, Healthy Mouth, Herbal Brite, Nature’s Gate Natural Toothpaste, Nutrismile C, Peelu, Pink Toothpaste with Myrrh, Pure Herb, Sea Fresh and Tom’s of Maine Natural Toothpaste		Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus and Candida albicansStandard diffusion method6 herbal dentifrices were effective in inhibiting the growth of microorganisms
Only one herbal dentifrice showed consistent antimicrobial activity against all 4 microorganisms (Dental Gel)		[2]
Triclosan, sodium monofluorophosphate, sodium fluoride and herbal products, such as Salvadora persica, Azadirachta indica, Babhul, among others5 dentifrices (A, B, C, D and E) and 5 mouthwashesStreptococcus mutans, Escherichia coli and Candida albicansModified agar well diffusion methodTriclosan containing dentifrice formulations were more effective compared to non-triclosan containing synthetic dentifrices
Herbal dentifrices exhibited lower efficacy compared to the others		[6]
Nanosilver, chitosan and fluoride3 dentifrices: containing nanosilver (TruCare Nanosilver); containing chitosan (Conybio Plus Chitosan); and containing fluoride (Oral B Pro-Health)Streptococcus mutansModified agar well diffusion methodThe dentifrice containing nanosilver has the highest antibacterial efficacy against S. mutans, followed by the dentifrice containing fluoride and chitosan[9]
Rosemary extract, propolis, mauve, cinnamon, peppermint, triclosan and sodium fluorideDentifrices based on rosemary (TR) and propolis (TH—Sorriso Herbal com Própolis) and Colgate Total 12 (TPC)Streptococcus mutans, Streptococcus oralis and Lactobacillus rhamnosusMacrodilution method
Standardized single disk method		The antimicrobial activity of rosemary-based dentifrice (TR) was similar to the commercial dentifrice (TH)
For the inhibition of L. rhamnosus, the propolis-based commercial dentifrice was more effective than TR dentifrice		[11]
P. betle extract, triclosan, sodium fluoride, sodium bicarbonate, corn mint, peppermint, sage oil and coneflower3 dentifrices: Colgate Total, Paradontax and DarlieEscherichia coli, Staphylococcus aureus, Streptococcus mutans, Streptococcus salivarius and Candida albicansStandard procedure for determining MIC
Agar disk diffusion assay		A statistically significant increase in the zone of inhibition after addition of P. betle extract was observed with all 3 dentifrices on all pathogens tested[12]
Triclosan, sodium monofluorophosphate, sodium fluoride, sodium lauryl sulfate and plant extracts, such as peppermint, eucalyptus, cinnamon, clove, Carum petroselinum (parsley), among others15 dentifrices and a stannous fluoride gel:
Sensodyne Repair, Sensodyne
Total Care, Pronamel, Colgate Pro Relief, Colgate Sensitive Multi, Colgate Total, Colgate Neutrafluor 5000 plus, Colgate Sparkling Gel, Alfree, Macleans Advanced Enamel Lock, Gel Kam, Herbal Brite, Herbal Fresh, Grants and Woolworthse Select		Streptococcus mutansAgar diffusion methodColgate Total has the greatest effect and Colgate Gel Kam has the least. Only two herbal toothpastes showed antimicrobial activity (Herbal Fresh and Macro)
Most of the antimicrobial activity against S. mutans depends on the presence of non-fluoride agents, such as triclosan and sodium lauryl sulfate		[18]
Silver and gold nanoparticlesRoyal Denta dentifrice containing silver and gold nanoparticlesStaphylococcus aureus, Enterococcus faecalis,
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis,
Pseudomonas aeruginosa, Bacillus cereus and Candida albicans		Agar diffusion methodSilver in dentifrice has a greater antimicrobial effect than gold, but its effect is still lower than that of a chemical antimicrobial agent[19]
Sodium fluoride, sodium monofluorophosphate and triclosan3 desensitizing dentifrices (Colgate Sensitive Pró-Alívio, Sensodyne Rápido Alívio and Oral B Pro Sensitive) and a common dentifrice (Colgate Total 12 Professional Clean)Candida albicans, Streptococcus mutans and Staphylococcus aureusMicrodilution method (MIC)Colgate dentifrice was able to eliminate all microorganisms evaluated at lower concentrations compared to Colgate Sensitive and Oral B Sensitive
C. albicans was the least resistant to the dentifrices. S. aureus was the most resistant.		[20]
Sodium monofluorophosphate, sodium lauryl sulfate, triclosan, bromochlorophene and sodium fluoride10 Iranian-made dentifrices: Paveh, Saviz, Latifeh II, Bath, Darugar II, Darugar I, Close up, Tage, Pooneh III and NasimStreptococcus mutans, Streptococcus sanguis, Actinomyces viscosus and Candida albicansAgar diffusion methodAll dentifrices showed antimicrobial activity. Those containing more than one antimicrobial showed higher activity
The antimicrobial property of Pooneh III was similar and Bath higher than the positive control		[21]
Sodium monofluorophosphate, stannous fluoride and sodium fluoride in various concentrationsDentifrices with low fluoride concentration: Colgate My First, Oral B Stages and Macleans Milk Teeth
Dentifrices with standard fluoride concentration for adults:
Colgate Total, Oral B Tooth and Gums, Macleans Extreme Clean, Colgate Sensitive Pro Relief and Oral B Pro Health
Dentifrice with high fluoride concentration:
Colgate Neutrafluor 5000		Streptococcus mutans, Streptococcus sanguinis and Lactobacillus acidophilusAgar diffusion assayDentifrices containing 1450 ppm fluoride produced greater growth inhibition of S. mutans and S. sanguinis than those with <500 ppm
Colgate Total produced the highest average growth inhibition on S. mutans and S. sanguinis. Colgate Pro Relief produced the lowest		[22]
Stabilized chlorine dioxideClōSYS oral care products: two mouth rinses, one oral spray and one fluoride dentifriceSARS-CoV-2, SARS-CoV, human coronavirus (HCoV) 229E, influenza A (H3N2), rhinovirus type 14, adenovirus type 5 and herpes simplex virus (HSV) type 1 and 2In vitro suspension virucidal assaysStabilized chlorine dioxide contained in oral care products reduced the viral load of several viruses[23]
Sodium monofluorophosphate, sodium fluoride, triclosan and zinc citrate5 dentifrices: Colgate Regular, Macleans Anti-plaque Formula, Mentadent P Gum Health Formula, Crest Gum Health and Colgate Gum Protection17 bacterias: A. actinomy-cetemcomitans (2), A. odontolyticus, A. viscosus, C. rectus, C. orchracea, Capnocytophaga species, E. timidum, S. oralis, P. anaerobius, P. micros, P. gingivalis, P. intermedia (2), S. constellatus, V. parvula and Veillonella speciesAgar dilution method
Maximum inhibitory dilution (MID)		Mentadent Gum Health Formula, which contains triclosan and zinc citrate, had the highest antimicrobial activity of the dentifrices containing triclosan
Crest Gum Health was generally less active than all other dentifrices, including Colgate Regular, except against A. actinomycetemcomitans		[24]
Stannous fluoride, sodium fluoride and stannous pyrophosphate2 stannous fluoride dentifrices (SF1, SF2), 2 experimental dentifrices with SF and stannous pyrophosphate (SFSP1, SFSP2), a gel with SF (G) and a dentifrice with NaF (C)20 species:
Actinobacillus actinomycetemcomitans (2), Campylobacter rectus, Capynocytophaga sputigena, Capynocytophaga species, Fusobacterium nucleatum, Porphyromonas gingivalis (2), Prevotella nigrescens, Prevotella intermedia, Veillonella parvala, Veillonella species, Actinomyces viscosus, Actinomyces odontolyricus, Eubacterium timidum, Peptostreptococcus anaerobius, Peptostreptococcus micros, Streptococcus constellatus, Streptococcus mutans and Streptococcus oralis		Maximum inhibitory dilution (MID)All formulations showed antimicrobial activity with the average order of highest activity descending being C, SF2, SF1, SFSP1, SFSP2 and G
SF1 containing stannous fluoride was less active than C, a conventional dentifrice containing sodium fluoride (NaF)		[25]
Triclosan and fluorideColgate Total dentifriceKlebsiella pneumoniae, Streptococcus mutans, Candida albicans, Porphyromonas gingivalis and Fusobacterium nucleatumMicrobial kill time assay
European suspension test method		In antimicrobial assays, the dentifrice was effective against bacteria, but not against C. albicans[26]
Sodium fluoride, triclosan and stannous fluoride4 commercially available dentifrices, 2 containing sodium fluoride (NaF) at different concentrations (1450 and 2500 ppm) and 2 NaF with triclosan or stannous fluorideStreptococcus oralis, Actinomyces naeslundii, Veillonella parvula, Fusobacterium nucleatum, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitansSubgingival biofilm
model		Dentifrices containing NaF and stannous fluoride demonstrated higher antimicrobial activity for A. actinomycetencomitans, P. gingivalis, and F. nucleatum when compared to those containing NaF and triclosan, 1450 ppm NaF, or 2500 ppm NaF[27]
Guava leaf extractThree prepared toothpaste formulations varying in ingredient concentrations (F1, F2 and F3)Bacillus subtilis, Proteus vulgaris, Staphylococcus aureus, Streptococcus mutantes and Streptococcus oralisWell diffusion methodF3 was very effective against the bacteria tested, followed by F2 and F1
The highest zone of inhibition was observed against P. vulgaris and B. subtilis and the lowest was observed against S. aureus		[28]
Solanum tuberosum powderExperimental dentifrice containing Solanum tuberosum (Tocosh)Staphylococcus aureus, Streptococcus mutans, Streptococcus mitis and Candida albicansAgar diffusion methodDentifrice with Tocosh has an antibacterial effect against S. aureus, S. mutans and S. mitis. No antimicrobial effect was found against C. albicans[29]
Pomegranate peel, lemon peel and mango peel extract, mint oil and sodium lauryl sulfateA polyherbal dentifrice containing pomegranate, lemon and mango peel methanolic extract formulated in different concentrations (100, 250 and 500 mg/mL)Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosaDisk-diffusion methodThe polyherbal dentifrice has promising antimicrobial effects against Gram-positive and Gram-negative organisms, and may be safer compared to a synthetic dentifrice
S. aureus was the most sensitive, followed by E. coli, B. cereus and P. aeruginosa		[30]
Propolis (10% ethanol solution)Yamada Yohojo Propolis Hamigaki dentifrice, which contains an ethanolic solution of 10% propolis sample at a concentration of 2% (w/w)20 strains representing 12 species:
S. mutans (3), S. sobrinus (3), S. cricetus, S. rattus, S. sanguis (2), S. oralis, S. gordonii, S. mitis (2), S. salivarius,
A. naeslundii, A. viscosus (3) and
L. casei		Minimum inhibitory concentration (MIC)The propolis-containing dentifrice inhibited the growth of 20 bacterial strains in a concentration range of 3–7 mg/mL[31]
Ingredients not specified6 dentifrices:
Ayush, Dant kanti, Colgate vedshakti, Meswak, Dantajeevan and Dabur red		Streptococcus mutans and Candida albicansAntibiotic susceptibility testing
Agar disk-diffusion method		The herbal dentifrice formulations were effective in controlling the oral microflora
For S. mutans, the zone of inhibition is greatest in Ayush. For C. albicans, the zone of inhibition is greatest in Ayush and Dant kanti		[32]
Green tea ethanolic extract and sodium lauryl sulfateTwo experimental dentifrice formulas containing 5% green tea extract in a gel base. Formula A was enriched with 30% CaCO3 as an abrasive. Formula B was made without CaCO3Streptococcus mutans and Lactobacillus acidophilusAgar diffusion methodIn comparison with herbal dentifrice patent containing a combination of green tea extract and P. bettle leaves extract, this had higher antibacterial activity against S. mutans than the green tea dentifrice, but not against L. acidophilus[33]
G. kola extract, sodium lauryl sulfate and sodium bicarbonate
Close up, Aquafresh and Colgate do not have their ingredients specified		Experimental dentifrice containing G. kola extract, Close up, Aquafresh and ColgateEscherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Bacillus subtilis, Staphylococcus aureus, α-haemolytic, Streptococcus pneumoniae, Streptococcus pyogenes and Candida albicansStandard agar diffusion and broth dilution methodsAll microorganisms were significantly susceptible to the extract and the dentifrice
The herbal dentifrice inhibited all tested microorganisms, while none of the commercial dentifrices used showed any antimicrobial activity		[34]
Herbal extracts, such as Stevia rebaudiana leaves (SR), Azadirachta indica bark (AZ), Piper longum fruit (PL), Curcuma longa rhizome (CL), Salvadora persica bark (SP), among othersPolyherbal dentifrice (formulations 1, 2 and 3), Herbodent and ApolloStreptococcus mutans, Streptococcus oralis, staphylococcus aureus, Candida albicans and Lactobacillus acidophilusAgar well diffusion method
Serial micro dilution method (MIC)		The methanol extract of polyherbal formulation 1 and 3 showed lower activity when compared to polyherbal formulation 2. However, the activity was lower than gentamicin[35]
Calendula extracts, sage clay, sodium fluoride and sodium lauryl sulfate2 dentifrices:
Iranian herbal dentifrice and Iranian chemical dentifrice		Streptococcus mutans, Lactobacillus and Candida albicansAgar disk-diffusion methodAt the total concentration, herbal and chemical dentifrices have the same antimicrobial effect, but when reducing the concentration, the effect of the herbal dentifrice is reduced compared to the chemical one[36]
Triclosan, sodium monofluorophosphate and plant extracts, such as miswak, neem, Babool, Pudina, Long, Vajradanti, turmeric, calendula, eucalyptus, and others9 dentifrices in three groupsEscherichia coli, Staphylococcus aureus, Streptococcus mutans and Candida albicansAgar well-diffusion methodOf the herbal groups, the only dentifrice containing several phytochemicals was found to be significantly effective and comparable to the triclosan and fluoride formulation.
Homeopathic products showed lower antimicrobial activity		[37]
Ricinus communis, sodium, monofluorophosphate, chloramine T and sodium bicarbonateExperimental dentifrice based on Ricinus communis
Colgate, Corega Brite and Trihydral commercial toothpastes 		Staphylococcus aureus, Escherichia coli, Streptococcus mutans, Enterococcus faecalis, Candida albicans and Candida glabrataMicrodilution technique in 96-well plates (MIC)
Well agar diffusion method		Comparing the experimental dentifrices, the product with 10% R. communis produced the largest inhibition halos and showed antimicrobial activity similar to commercial dentifrices, except against S. aureus
None of the dentifrices were effective against E. coli		[38]
Fluoride and herbal extractsHerbal dentifrices:
Himalaya herbals (A1) and
Dabur red (A2)
Conventional dentifrices:
Colgate super shakti (B1) and
Pepsodent complete germicheck (B2)		Streptococcus mutans and Candida albicansDisk-diffusion methodHerbal dentifrices are equally and sometimes better than conventional ones
At 50% concentration, B2 showed the maximum zone of inhibition for S. mutans, while at 100% concentration A1 showed better effects. For C. albicans, A2 was the most effective		[39]
Nanohydroxyapatite (nanoHAP) and Curcuma aeruginosa extract20 dentifrices with different concentrations of nanoHAP and C. aeruginosa, plus OF1 and OF2Streptococcus mutansAgar diffusion and microdilution methodsMost of the dentifrice formulations showed antibacterial activity. OF1 and OF2 were shown to have antibacterial activity comparable to that achieved with the control[40]
Ethanolic extracts of Dennettia tripetala seeds, Syzygium aromaticum buds, Jatropha curcas latex, sodium fluoride and Aloe vera3 commercial dentifrices labeled Com A, Com B and Com C
The formulated dentifrices were labeled DenSyzJat, DenSyz and SyzJat		Escherichia coli, Bacillus sp., Staphylococcus aureus, Staphylococcus aureus resistente à meticilina, Staphylococcus epidermidis, Micrococcus luteus, Streptococcus mutans, Streptococcus pyogenes, Lactobacillus acidophilus, Candida albicans and Pseudomonas aeruginosaAgar well diffusion method
Minimum inhibitory concentration (MIC)		The formulated dentifrices exhibited antimicrobial property against all tested microorganisms and showed better and significant antimicrobial effect when compared to commercial dentifrices
The dentifrice formulated with S. aromaticum extract alone seems to be much more active among the 3 bioactive materials used for formulation		[41]
Origanum dubium and Cinnamomum cassia oils, triclosan, sodium fluoride, sodium bicarbonate and plant extracts, such as Calendula officinalis, Aloe barbadensis and Melaleuca alternifolia oil4 dentifrices: Splat Organic, Splat Biocalcium, Jack N ‘Jill and Colgate TotalStreptococcus mutansAgar diffusion method in disk (pure oil) and well (dentifrice) The antibacterial activity of the dentifrices was higher than positive control
Herbal dentifrices showed higher antibacterial activity than their initial forms after the addition of essential oils. C. cassia showed higher antibacterial activity than O. dubium		[42]
Sodium monofluorophosphate, sodium fluoride, triclosan, sodium lauryl sulfate, herbal extracts and oils, such as Clinacanthus nutans, Streblus asper and Murraya paniculata leaves, peppermint oil, eucalyptus oil, among others6 dentifrices: Darly, Close up, Systema, Herbal Twin Lotus, Salz and ColgateCandida albicansAgar diffusion assay
Broth microdilution technique (MIC and MFC)		All dentifrices inhibited the growth of C. albicans with a mean range of the zone of inhibition between 8 and 16.92 mm
Herbal Twin Lotus showed the largest mean zone of inhibition. Saltz showed the lowest mean zone of inhibition		[43]
Triclosan, sodium fluoride and herbal extracts such as neem, chamomile, Babul and Miswalk6 dentifrices: neem, Vicco Vajradanti, Himalaya Herbal, Colgate Herbal, Dabur Red and Dabur BaboolStreptococcus mutans and Lactobacillus acidophiluswell method of microbial cultureHerbal dentifrices are more effective against lactobacilli organisms at the same level as conventional dentifrice and less effective for S. mutans when compared to non-herbal dentifrices[44]
Triclosan, sodium monofluorophosphate, sodium bicarbonate, sodium lauryl sulfate, sodium fluoride and plant extracts, such as Anacyclus pyrethrum, Azadirachta indica (neem), Acacia arabica (Babool), Salvadora persica (miswak), Pudina, among others7 dentifrices (A, B, C, D, E, F, and G) and 2 mouthwashes (H and I)Escherichia coli and Candida albicansModified agar well diffusion methodThe formulations containing natural antimicrobials were more effective compared to dentifrices containing synthetic antimicrobials
The antibacterial activity of A is lower compared to formulation B at higher dilutions		[45]
Sodium monofluorophosphate, triclosan, zinc sulfate, sodium lauryl sulfate, amine fluoride, sodium fluoride and plant extracts, such as neem and miswak7 commercial dentifricesStreptococcus mutans, Escherichia coli and Candida albicansWell agar diffusion assayDentifrice formulations containing triclosan are more effective
The zone of inhibition decreases with increasing dilution		[46]
Sodium fluoride, triclosan, sodium monofluorophosphate, sodium lauryl sulfate, eugenol, clove oil and plant extracts, such as miswak and neem,6 dentifrices: 3 fluoride (Colgate Total, Fresh and White and Safi–clove) and 3 3 non-fluoride dentifrices (Mukmin, Halagel and Pureen)Streptococcus mutansStandard disk diffusion methodAll dentifrices showed antibacterial activity at both concentrations tested, but better results at full strength compared to the diluted. The antibacterial activity of the non-fluoridated toothpastes is as good as the fluoridated ones[47]
Cashew extract, mango extract, calendula extract (Callendula officinalis), Aloe vera, natural banana, natural apple, sodium fluoride and sodium lauryl sulfate6 infant dentifrices: experimental cashew-based dentifrice; experimental mango-based dentifrice; experimental dentifrice without plant extract and fluoride; First Teeth dentifrice; Weleda dentifrice; and Tandy dentifriceStreptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus and Candida albicansAgar plate diffusion testFirst Teeth, Weleda, mango-based dentifrice and dentifrice without plant extract showed no antimicrobial effect against any of the microorganisms tested
The cashew dentifrice showed significant antimicrobial activity against S. mutans, S. sobrinus and L. acidophilus. Tandy had antimicrobial activity against all microorganisms 		[48]
Sodium monofluorophosphate, sodium lauryl sulfate, and herbal extracts, such as maricha, pippali, sunthi, kapor, akarkara, khadir, lawang, among othersMarketed allopathic powdered toothpastes (brand I and II) and herbal powdered toothpastes (brand III and IV)Staphylococcus sorbinus, Staphylococcus salivarius and Lactobacillus acidophilusAgar well diffusion methodThe diameter of the zone of inhibition observed in brands I and II for test microorganisms was not significantly different from the diameter observed in brands III and IV[49]
Propolis and chlorhexidine3 dentifrices (with propolis, without propolis and with chlorhexidine) and 2 mouthwashes (with propolis and chlorhexidine)Actinomyces naeslundii, Veillonella dispar, Fusobacterium nucleatum, Streptococcus mutans, Streptococcus oralis and Candida albicansIn vitro multispecies biofilm modelPropolis seems to have no effect in respect to reducing CFU in the supragingival biofilm model used, neither in the dentifrice nor in the mouthwash[50]
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Marinho, V.T.; dos Reis, A.C.; da Costa Valente, M.L. Efficacy of Antimicrobial Agents in Dentifrices: A Systematic Review. Antibiotics 2022, 11, 1413. https://doi.org/10.3390/antibiotics11101413

AMA Style

Marinho VT, dos Reis AC, da Costa Valente ML. Efficacy of Antimicrobial Agents in Dentifrices: A Systematic Review. Antibiotics. 2022; 11(10):1413. https://doi.org/10.3390/antibiotics11101413

Chicago/Turabian Style

Marinho, Vanessa Teixeira, Andréa Cândido dos Reis, and Mariana Lima da Costa Valente. 2022. "Efficacy of Antimicrobial Agents in Dentifrices: A Systematic Review" Antibiotics 11, no. 10: 1413. https://doi.org/10.3390/antibiotics11101413

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