Managing Oral Health in Context of Antimicrobial Resistance: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Lucinda J. Bessa.

The oral microbiome plays a major role in shaping oral health/disease state; thus, a main challenge for dental practitioners is to preserve or restore a balanced oral microbiome. Nonetheless, when pathogenic microorganisms install in the oral cavity and are incorporated into the oral biofilm, oral infections, such as gingivitis, dental caries, periodontitis, and peri-implantitis, can arise. Several prophylactic and treatment approaches are available nowadays, but most of them have been antibiotic-based. Given the actual context of antimicrobial resistance (AMR), antibiotic stewardship in dentistry would be a beneficial approach to optimize and avoid inappropriate or even unnecessary antibiotic use, representing a step towards precision medicine. 

  • antibiotic resistance
  • antibiotic stewardship
  • dental practice
  • oral infections
  • oral microbiome
  • oral resistome

1. Oral Microbiome

The term microbiome has been connected to various definitions, but it has been recognized that there is a need to converge to a clear and commonly agreed upon definition of the microbiome [2][1]. Considering the recent definition proposed for microbiome by Berg et al. [2][1], it may define the oral microbiome as a dynamic ecosystem composed of the oral microbiota, viruses, their structural elements, and metabolites, as well as molecules produced by the coexisting host and controlled by the surrounding environment. The oral microbiome, like every microbiome, is continuously and functionally evolving due to the microbe–host and inter-species interactions.
In the oral cavity, there are distinctive niches, each with its associated microbiome, including the gingival sulcus, tongue, cheek, hard and soft palate, floor of the mouth, throat, saliva, teeth, and, if present, dental implants [3,14,15,16][2][3][4][5]. The Human Microbiome Project defined nine anatomical locations in the human mouth in a state of health: the tongue dorsum, the hard palate, the tonsils, sub- and supra-gingival plaque on teeth, the keratinized gingiva, the buccal mucosa, the throat, and saliva [17][6].
The microbial oral community shifts constantly throughout an individual’s life due to extrinsic and intrinsic factors [3,18,19,20,21][2][7][8][9][10]. The oral cavity is exposed to exogenous microorganisms mainly through diet, drinking, air, kissing, and lifestyle [18][7]. Changes in oral pH, depressed immune system, presence of chronic diseases, and intake of antibiotics also affect the composition of the oral microbiome [19,21][8][10]. Nonetheless, despite all these factors accounting for inter-individual variability, an oral core microbiome has been pinpointed [14[3][11],22], and it refers to the microbial taxa or the genomic and functional attributes associated with those taxa that are characteristic of the oral cavity under healthy conditions [23,24][12][13].
Quantitative and qualitative variations in the composition of the core microbiome cause dysbiosis, which correlates with the disease state [29,30][14][15]. The taxonomic composition of microbial communities implicated in dental caries, periodontitis, and peri-implantitis has been pinpointed by several studies throughout the years [30,31,32,33,34,35][15][16][17][18][19][20] (Figure 1), which have disclosed that the microbial communities are distinct in those three oral diseases in terms of composition and/or abundance. Nonetheless, the taxonomic composition is unsurprisingly not definite; it is being constantly updated as knowledge and technologies are advancing.
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Figure 1. Characteristic taxa associated with dental caries, periodontitis, and peri-implantitis [30,31,32,33,34,35][15][16][17][18][19][20]. Figure created with BioRender.com.

2. Oral Biofilms and Biofilm-Related Oral Diseases

Bacteria play a major role in biofilm formation as the initial colonizers and in terms of abundance and function in a normal oral microbiome. However, fungi, viruses, archaea, and protozoa are also constituents of the oral community and must be taken into consideration when studying the complete oral microbiome [5][21]. Entamoeba gingivalis and Trichomonas tenax are the most commonly found protozoa in the oral cavity, while Candida species are the most prevalent fungi [18][7].
Bacteria within a biofilm communicate via quorum sensing, through which signaling molecules are produced and detected by neighboring bacteria. This communication system enables bacteria to regulate several bacterial mechanisms, such as the production of virulence factors and biofilm formation [39][22]. In addition, biofilm seems to boost bacterial protection against the host immune system, environmental factors (such as shear stress), and antimicrobial agents [10,11][23][24]. Thus, any biofilm-associated infection, including those of the oral cavity, represents a therapeutic conundrum.
Streptococci and some Actinomyces species are known to be the early colonizers of the salivary pellicle, an organic film composed mostly of proteins on the tooth surface, epithelium, and restorations [32,40][17][25]. The colonization of the salivary pellicle is the starting point for the co-aggregation of new species to previously adhered bacteria and the subsequent formation of a polymicrobial biofilm known as dental plaque, which is a natural phenomenon involved in the physiology and defenses of the host [41][26], as long as a certain degree of stability, known as microbial homeostasis, is maintained despite regular environmental perturbations, such as dietary intake and oral hygiene. Consequently, dysbiotic dental plaque is implicated in the development of common oral diseases, such as erosion, dental caries, periodontal disease, and peri-implantitis [40][25], and is characterized by an imbalance in the biofilm composition favoring oral pathogens to take the lead. It is noteworthy that the appearance and persistence of dysbiosis rely on both microbial changes and host factors, namely the development of inflammation and the intake of dietary sugars [42][27].
Dental caries is a multifactorial oral disease, which is biofilm-mediated and modulated by dietary carbohydrates [43][28]. High and frequent exposure to fermentable carbohydrates is the driver for the development of a supragingival dysbiotic biofilm, where aciduric bacteria prevail and lead to a pH decline that can no longer be buffered by saliva. Therefore, there is a selection for more acid-tolerant microorganisms, which in turn favors the persistence of this acidic environment that enables enamel demineralization [42,44,45][27][29][30]. In early studies, Streptococcus mutans has been recognized as ‘the cariogenic keystone pathogen’; however, next-generation sequencing (NGS) and omics studies have disclosed that dental caries is more a polymicrobial disease based on a variable and diverse pathogenic community that relies on sugar consumption, rather than a classic Koch’s postulate (a single agent related disease) [45,46][30][31]. Despite the substantial inter-individual variability composition of this dysbiotic biofilm in dental caries, different microbial combinations have been identified to have a similar functional profile [47][32]. This suggests that the pathogenesis of dental caries is controlled by complex and intricate host, microbial, and environmental factors and interactions, and for that reason, it remains an entangled research issue [45][30].
Periodontitis and peri-implantitis are also biofilm-mediated oral diseases with marked microbial dysbiosis and inflammation. In both, alveolar bone is lost, in addition to the loss of tooth-supporting tissue in periodontitis and peri-implant tissue in peri-implantitis, respectively [48][33]. If untreated, these oral non-communicable diseases can lead to tooth or dental implant loss. On the one hand, both diseases share many etiological and clinical features. On the other hand, they differ in the microbial community present. This is mostly due to the material (dentin or titanium) that serves as the substratum for biofilm formation and affects bacterial adhesion, determining differences in the type of initial bacterial colonizers and dictating the formation of distinct subgingival biofilms [49][34].

3. Antimicrobial Resistance (AMR) in Dental Practice

Dentists prescribe antibiotics for two purposes: (1) prophylaxis, to improve the outcome success of surgical interventions and reduce complications and symptoms, and (2) therapeutics, for treating oral infections [57][35]. However, in dental practice, antibiotic indication has been long based on personal experience or judgment and on old evidence, rather than on effective diagnosis [58][36]; and it has been mostly an empirical drug prescription, with a predominant choice for broad-spectrum antibiotics [57,59][35][37]. Furthermore, guidelines for the prudent usage of antibiotics were scarce or not generally shared among dental practitioners before [60][38]. 

It is evident that the implementation of antibiotic stewardship programs in the dental setting is of great need [68][39]. Antibiotic stewardship entails a set of coordinated interventions to promote the correct use of antibiotics (optimal selection, dosing, route, and duration of administration), to improve clinical outcomes and minimize side effects to patients, and to reduce the development and spread of multidrug-resistant bacteria [69][40].

A multidisciplinary antibiotic stewardship team, involving the dental team in close collaboration with pharmacists, microbiologists, or other health care professionals, is fundamental to assure the execution of an antibiotic stewardship program in a dental setting [70][41]. A set of antibiotic stewardship interventions recommended for dental practice are compiled in Table 1.

Table 1.
Antibiotic stewardship interventions in dental practice.
• Ponder patient conditions and look for a clear diagnosis before prescribing antibiotics; discuss with peers and other specialists if needed
• Follow updated and standardized guidelines
• Receive feedback on previous acts of antibiotic prescribing
• Warrant ongoing education and appropriate training
• Educate the dental patient and establish good communication to ensure the patient will follow the correct instructions when taking antibiotics
• Audit how appropriately antimicrobials are prescribed
These points have been proposed by recent studies [56,68,70][39][41][42].

Among these interventions, the education of both dentists and patients on the adequate use of antibiotics and the current problem of AMR should be encouraged. Several studies have confirmed the critical need for dental students’ education and specific training in the prescription of antibiotics [71,72,73,74][43][44][45][46]. Educational interventions can include lectures, didactic meetings, workshops, and practice campaigns. A recent study showed that final-year undergraduates from the Glasgow Dental School were enthusiastic about attending a supplemental, yet mandatory, online course on the essential role of dental teams in antimicrobial stewardship and in reducing AMR; the students’ feedback was positive, and they recognized they could play an important role in stewardship [75][47]. 

4. Antibiotic Prophylaxis (AP) and Treatment of Oral Infections

4.1. Recent Changes for AP

The actual tendency, mostly to lessen the development of AMR, is to reduce the use of prophylactic antibiotics. Current evidence has led to the recommendations [61][48] to not use antibiotics to prevent postoperative complications after (1) extraction of impacted wisdom teeth [77][49], (2) surgical extractions of teeth or retained roots, (3) minor surgical removal of soft tissue lesions, and (4) peri-radicular surgery. Moreover, antibiotics are not recommended for the prevention of pain associated with irreversible pulpitis [64][50]. Undergoing AP prior to dental procedures has been a common procedure and is currently indicated by American and European guidelines on the recommended use of antibiotic prophylaxis to prevent infective endocarditis (IE) in subjects undergoing invasive procedures [65][51]. Nowadays, Sweden and the United Kingdom have, however, abandoned the use of AP in dentistry for the prevention of IE [78][52]. A nationwide cohort study conducted in Sweden provided results suggesting that the Swedish recommendation of 2012 to not administer antibiotics in dentistry for the prevention of IE did not cause an increased incidence of oral streptococcal IE among high-risk individuals [78][52].

4.2. Antibiotic Treatment of Dental Caries, Periodontal Diseases, and Peri-Implantitis

The administration of antibiotics in dental care is a common procedure. However, due to the increase in antibiotic resistance and recent advances in scientific knowledge, there has been a transformation in how dentists clinically manage the most common conditions, particularly dental caries, periodontal diseases, and peri-implant conditions. Regarding periodontal diseases, the use of systemic antibiotics become popular in aggressive forms of periodontitis or ulcerative periodontal conditions based on the aggressive clinical progression of these diseases. On the one hand, systemic antibiotics do impact periodontal parameters in the short-term without a significant change in serum markers [89[53][54],90], and with higher side effects [90][54]. However, for long-term follow-up, there is low-certainty evidence that systemic antibiotics could be of help in the treatment of periodontitis [91][55]. Moreover, there is very low-quality evidence on the effects of systemic antibiotics in adults with symptomatic apical periodontitis or acute apical abscess [92][56].  eatment approaches have been used [96][57]. Even if the non-surgical procedures (i.e., mechanical debridement) have been largely used to treat peri-implantitis, it has soon become evident that such an approach is not sufficient by itself to completely remove the biofilm from the implant surface. Therefore, additional/adjunctive treatment approaches have been used, such as topic or systemic antibiotics, photodynamic therapy, or surgical therapy [96,97][57][58]. Despite the use of topical/systemic antibiotics as an adjunctive therapy in peri-implantitis, there is a lack of consensus and evidence regarding their real efficacy in the definitive treatment of the disease [98][59], and thus, their use has not been advised for that purpose.

5. Oral Resistome

The usage of antibiotics is undoubtedly an important driver for the development of antibiotic resistance genes (ARGs). The presence of oral pathogenic bacteria harboring ARGs endangers the success rate of antibiotic treatment recommended for certain oral infections, while commensal bacteria carrying ARGs may be responsible for antibiotic infections at other sites of the human body [27,101][60][61]. Based on that, a broader concept arose which is oral resistome. The term resistome dates back to the year 2006 [102][62], and it is nowadays defined as the collection of all the ARGs and their precursors in pathogenic and nonpathogenic bacteria composing a microbiome [103][63]. As such, examining the composition and changes of the oral resistome holds a promising interest in order to uncover oral antibiotic resistance profiles, circumvent failure of antibiotic treatment, and develop new effective therapies [101][61]. To that end, high-throughput next-generation sequencing technologies, such as metagenomics, are paving the way to an in-depth understanding of the distribution and diversity of ARGs in the oral microbiome, in addition to the disclosure of novel ARGs [26][64]. In particular, shotgun metagenomics is deemed essential to map all the resistance genes in the oral microbiome as well as to predict the function of these genes [104][65]. To date, however, there still is little understanding of the oral resistome, in both health and disease states, with only a few studies providing some insights so far. Since the oral microbiome is a reservoir of antibiotic resistance, it favors the horizontal gene transfer of ARGs and MGEs. Thus, monitoring the oral resistome has huge potential in providing the reference levels for proper antibiotic use and helping the development of new and more effective antimicrobial strategies for the treatment of oral infections, namely periodontitis and peri-implantitis.

6. Current Alternatives to Antibiotics to Prevent and Treat Oral Infections

6.1. Antimicrobial Photodynamic Therapy (APDT)

APDT is an emerging and non-invasive treatment method, involving a photosensitizer and a low-energy laser light in the presence of oxygen to generate reactive oxygen species (ROS) that are responsible for the bactericidal effect [8][66]. The potential use of APDT in dentistry has recently been explored [111][67], with several in vitro and clinical studies being conducted to support the therapeutic application of APDT alone, but mostly as an adjunctive treatment, in dental caries [112[68][69],113], endodontic diseases [114[70][71],115], periodontal diseases [116[72][73],117], and peri-implantitis [118,119][74][75]. There are several synthetic molecules that can be used as photosensitizers (toluidine blue, methylene blue, and indocyanine green) and combined with lasers of various wavelengths. Natural photosensitizers, such as curcumin, chlorella, chlorophyllin, and phycocyanin, among others [120][76], are less toxic and costly than synthetic ones and have also started to be used in APDT against oral pathogenic bacteria, with encouraging in vitro results obtained in many recent studies that stimulate research in this area to be continued and advanced. Moreover, the nanoparticles of these photosensitizers are being developed either to enhance their photosensitivity or to increase their solubility [121,122][77][78].

6.2. Cold Atmospheric Plasma (CAP)

CAP is another innovative strategy showing significant advantages over traditional antibiotic approaches and with good prospects to be adopted for clinical dental applications to control biofilm infections [8][66]. CAP generates reactive oxygen and nitrogen species that diffuse into the biofilm and cause oxidative damage to the bacterial membrane, and to the extracellular DNA and proteins constituting the biofilm [110][79].

6.3. Natural Products

Nature has been a prolific source of antimicrobial compounds, namely antimicrobial peptides. A significant number of natural product drugs/leads are produced by microorganisms and/or microbial interactions; thus, the field of natural product research must continue to be explored as a source of compounds with diverse desirable bioactivities [124][80].

6.4. Antimicrobial Peptides (AMPs)

Another promising alternative to antibiotics in the treatment of microbial infections, including those of the oral cavity, is AMPs. AMPs are oligopeptides with a varying number (usually less than a hundred amino acids) that can be produced by most living organisms, ranging from bacteria to humans, as the first line of defense, but they can also be chemically synthesized [130][81]. In addition to their broad-spectrum activity against many microbes (bacteria, fungi, viruses, and parasites), other activities, such as antioxidant and antitumor activities, have been attributed to these peptides. AMPs can present more than one mechanism of action simultaneously, leading to the direct killing of microorganisms, while also modulating the immune response [131][82]. Having multiple mechanisms of action makes the development of resistance more difficult [132][83].

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