Oral diseases affect nearly 3.7 billion people worldwide,¹ with conditions such as untreated dental caries and periodontal diseases impacting more than 2 billion and 1 billion individuals, respectively, thus imposing significant functional, social, and economic burdens.^1-3 Despite the dental profession’s progress in understanding the etiopathogenesis of dental caries and periodontal diseases, the global burden of these disorders remains high, with case numbers increasing due to population growth and aging.^1,2,4 Unfortunately, this trend is expected to continue. Projections for the United Kingdom, for example, suggest that by 2050, over 60% of the adult population aged 60 or older will have untreated dental caries, and more than half will be affected by periodontal diseases.⁴ The expected increase in these conditions poses a threat to dentists’ ability to provide curative care to all affected patients, highlighting the need to focus on actions toward health promotion and disease prevention.

A Complex Interplay

The prevalence of dental caries and periodontal diseases reflects a complex interplay among biological, behavioral, and social determinants. Biologically, supragingival biofilm is the main etiological factor for both dental caries and periodontal diseases.⁵ Contrary to earlier pathogen-specific models, current evidence indicates that the transition from oral health to dental caries or periodontal disease involves dysbiotic changes in the oral microbiome and overgrowth of commensal species with pathogenic potential, as opposed to the acquisition of exogenous pathogens.⁵ This knowledge is key for health promotion and disease prevention, as it implies that regular supragingival biofilm control is paramount to prevent the maturation of supragingival biofilm, a condition required for microorganisms with pathogenic potential to overgrow and switch from a commensal to a pathogenic state.

Disease susceptibility also varies among patients. For instance, the classical “Experimental Gingivitis in Man” study demonstrated that 100% of the participants developed gingivitis in response to 21 days of undisturbed supragingival biofilm accumulation.⁶ However, recent studies reveal individual variations in clinical response to supragingival biofilm accumulation, with some patients being hyperresponsive and others being hyporesponsive.⁷ In addition to developing more intense clinical signs of gingival inflammation, hyperresponsive patients present higher supragingival biofilm formation rates and increased levels of proinflammatory mediators.⁷ Adding to the scenario of individual variations in disease susceptibility, some current lifestyle behaviors, such as high sugar consumption, frequent snacking, and tobacco use, may further predispose to the development of dental caries and periodontal diseases.⁸

Toothbrushing remains the “gold standard” daily practice for supragingival biofilm control. However, even under the ideal and strict conditions of controlled clinical trials, toothbrushing alone removes on average only 42% of the supragingival biofilm and has limited effects on reaching interproximal spaces.^9,10 These limitations are further amplified by aging, disability, and low oral health literacy, which may compromise patient compliance.^11,12 Given these challenges, chemical supragingival biofilm control has emerged as an adjunctive approach to toothbrushing to enhance supragingival biofilm control, especially in patients with inadequate oral hygiene or who are susceptible to periodontal diseases.

Chemical supragingival biofilm control is primarily achieved through the use of antimicrobial mouthwashes or dentifrices. Although both formulations are effective in reducing supragingival biofilm and gingival inflammation, antimicrobial mouthwashes have demonstrated superior results over antimicrobial dentifrices in reducing supragingival biofilm and gingivitis,¹³ making them the preferred option for susceptible patients. Moreover, mouthwashes can access oral niches (eg, tongue, buccal mucosa, palate, and tonsils) that could serve as microbial reservoirs.¹³ Among antimicrobial mouthwashes, chlorhexidine-based rinses are considered the “gold standard” for controlling supragingival biofilm, either as monotherapy when patients are unable to perform mechanical oral hygiene or as an adjunct to toothbrushing.¹⁴ The duration of chlorhexidine use, however, is limited by its associated side-effects.¹⁵ Therefore, alternative mouthwash formulations have been developed for daily use.

Reducing Biofilm Formation

Cetylpyridinium chloride (CPC), a monocationic quaternary ammonium salt, was first described in 1939.¹⁶ Due to its positive charge, CPC is attracted to and binds nonspecifically to negatively charged phosphate groups on microbial cell membranes, disrupting the membrane physical integrity. In turn, this disruption results in increased cellular permeability and the leakage of low-weight microbial intracellular components, causing a reduction in metabolic activity—a bacteriostatic effect that lasts up to 5 hours.¹⁷ At high concentrations, CPC has a bactericidal effect, causing microbial cell lysis, full extravasation of intracellular components, and microbial cell death. In addition to its disruptive effect on microbial cell membranes, CPC also reduces the adherence of early microbial colonizers to the salivary pellicle, an important early event in the process of biofilm formation,¹⁸ thus contributing to a further reduction in biofilm formation.

CPC’s broad-spectrum antimicrobial activity, wide margin of safety for topical use, and high solubility in both aqueous and alcohol solutions¹⁶ have led to the development of aqueous-based CPC mouthwashes for daily use. Since the first study demonstrating the therapeutic effects of CPC mouthwashes was published in 1974, more than 140 clinical studies published in peer-reviewed journals indexed in PubMed have explored CPC effects in reducing the levels of intraoral pathogenic species, controlling supragingival biofilm, gingivitis, peri-implant mucositis, halitosis, and dentin hypersensitivity, preventing drug-influenced gingival enlargement, and promoting the disinfection of root canals, implant surfaces, and toothbrushes. Clinical studies on the use of CPC have also investigated its effects in limiting the generation of contaminated aerosols and symptoms of upper tract infections and its impact on patient safety and adherence profiles.

The impact of CPC in controlling supragingival biofilm and gingivitis has been extensively evaluated. Its effects on these two conditions, however, have shown substantial heterogeneity, with some studies reporting significant clinical improvements and others reporting minimal or no benefits.¹³ A possible explanation for these discrepancies can be attributed to differences in CPC concentrations used across different studies. In support of this hypothesis, a systematic review and meta-analysis revealed that high-concentration CPC mouthwashes (≥0.07%) demonstrated superior outcomes in reducing supragingival biofilm and gingival inflammation compared to low-concentration CPC mouthwashes (≤0.05%).¹³ Based on this evidence, CPC prescriptions must be restricted to high-concentration formulations.

In addition to CPC concentration, CPC bioavailability also impacts its antimicrobial and clinical efficacy. CPC exists in two major forms depending on the excipients in the formulation: free CPC (fCPC), which has the higher antimicrobial activity, and the less active micellized CPC (mCPC). Interplay with common mouthwash constituents, such as preservatives and certain block copolymer surfactants, can reduce the availability of fCPC molecules, limiting the antimicrobial effect of CPC mouthwashes.¹⁹ While some surfactants, such as Cremophor, favor the formation of mCPC, others, like P407, allow the maintenance of CPC in its free form state.¹⁹ Therefore, in addition to having a high CPC concentration, CPC mouthwash formulations should limit the incorporation of constituents known to cause mycelial formation. The CPC formulations discussed within this special issue have been designed using surfactant species at levels that allow CPC to remain in its fCPC form, thus preserving CPC antimicrobial activity and clinical efficacy.

Incorporating Zinc Lactate

The incorporation of zinc lactate into high-concentration CPC mouthwashes brought several improvements in the original CPC formulations. Zinc is an essential antioxidant and antimicrobial agent, often added as zinc lactate, due to its high and stable solubility in aqueous solution, thus avoiding the need for ethanol in the formulation. Direct comparison studies have demonstrated that mouthwashes containing 0.075% CPC and 0.28% zinc lactate have more pronounced effects on supragingival biofilm and gingivitis control, as compared to rinses containing only CPC or alcohol-free essential oil (EO) rinses.^20-22

Notably, the addition of zinc lactate into CPC-containing mouthwash has enhanced the formulation’s antiplaque and antigingivitis effects to levels equivalent to those achieved with the daily use of EO rinses containing 21.6% ethanol.²³ This finding is highly significant as EO rinses with ethanol have long been considered the most efficient daily use formulation for the control of supragingival plaque and gingivitis, with clinical results often superior to those obtained by the use of rinses containing CPC only. Thus, there is now an enhanced CPC formula containing zinc lactate that performs like alcohol-based EO rinses, but without causing the typical burning sensation experienced with the use of alcohol-based EO rinses, which may compromise patient adherence. Unlike alcohol-based EO rinses that are contraindicated for children, individuals with alcohol dependency, and those with soft-tissue lesions, CPC-zinc lactate rinses are considered a safer option for routine use. They are associated with low rates of adverse events¹⁵ and promote shifts in the oral microbiome that favor the restoration of a microbial balance without inducing microbial resistance.^24,25 Also, in the context of infection control, both CPC-zinc lactate and chlorhexidine pre-procedural rinses reduce contaminated aerosols by approximately 70% during aerosol-generating procedures.²⁶

CPC-zinc lactate rinses are also a valuable option for patients with halitosis.²⁷ In addition to its antimicrobial effects, zinc’s organoleptic properties allow it to oxidize thiol groups in precursors of volatile sulfur compounds converting them into non-volatile odorless compounds. Considering that halitosis has a high prevalence, affecting approximately 30% of the adult population,²⁸ and its negative impact on oral-health-related quality of life,²⁹ dental providers should adopt comprehensive treatment approaches that both address the intraoral underlying causes of halitosis and support patients’ overall well-being in their daily life. In this scenario, CPC rinses containing zinc lactate can serve as a valuable adjunctive therapy.

Effectiveness of CPC and Zinc Lactate

This special issue highlights the latest findings on the effectiveness of CPC and zinc lactate mouthwash in controlling supragingival biofilm, gingival inflammation, and oral malodor, while also discussing its impact on the oral microbiome. The evidence presented further supports the recommendation of CPC-zinc lactate rinses for adults with halitosis or periodontal diseases, based on the clinical and microbiological benefits associated with daily use.