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Opportunistic Prevotella and the Odontogenic Infection: A Case Series and Review of the Literature

Submitted:

31 July 2024

Posted:

05 August 2024

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Abstract
After 29 years of clinical practice treating odontogenic infections of the head, neck and oral cavity, my co-contributors and I sought to determine by a review of the literature and three clinical cases if Prevotella species were significant opportunistic pathogens in odontogenic infections of all kinds in the oral and maxillofacial region. We performed a PubMed review of 40 articles using terms associated with odontogenic infections, pericoronitis, Prevotella and antibiotics used to treat common oral and maxillofacial infections. Three cases were reported, and the treatment was discussed. An additional 26 articles were reviewed to describe the pathogenesis of Prevotella. Given the opportunity to become virulent—such as post-extraction wound healing of an extraction site adjacent to an intact dentition, excessive plaque and calculus, nearby gingivitis or periodontitis, or an immunocompromised host—we wondered if Prevotella could be targeted with antimicrobials mitigating, or even resolving, odontogenic infections in those cases refractory to conservative surgical therapy that includes source control. We found that Prevotella is a significant opportunistic pathogen in odontogenic infections. Prevotella is susceptible to Metronidazole (Flagyl), and it is effective in mitigating the disease process when basic principles of the treatment of odontogenic infections are employed. Infections not responsive to this empiric therapy should be cultured to determine the opportunistic organism’s sensitivity and susceptibility to specific antibiotic therapy.
Keywords: 
Prevotella
;  
odontogenic infection
;  
metronidazole(flagyl)
;  
pericoronitis
Subject: 
Public Health and Healthcare  -   Public Health and Health Services

Introduction

Prevotella species are inhabitants of the periodontal sulcus living in the crevicular fluid and in the dental biofilm attached to hard tissue surfaces (teeth) and mucosa. These obligate anaerobic Gram-negative rods are part of the normal oral microbiome and do not prove to be opportunistic in the immunocompetent host [1].
Principles of source control include decreasing the bacterial load by incision (opening the wound introduces air, changing the environment from anaerobic to aerobic, killing obligate anaerobes), drainage (decompressing the swelling, releasing purulent exudate, and promoting the blood supply), irrigation (washing out bacteria, bacterial toxins and inflammatory by-products), and tooth extraction [2]. Empiric antibiotics are used in immunocompromised hosts, severe infections, and infections refractory to surgery targeted at opportunistic Prevotella species.
Mixed infections comprising anaerobic, facultative anaerobic, and aerobic bacteria colonize perialveolar and fascial spaces contributing to odontogenic infections of the head and neck that can progress to life- threatening circumstances, including bacteremia, sepsis, airway compromise and death [3,4]. Pericoronitis, perialveolar infections (sometimes called subperiosteal infections), and multi-space odontogenic infections all show evidence of Prevotella species as isolates in the mixed oral flora. Antibiotic agents targeting Prevotella species will be reviewed with the goal of identifying the narrowest spectrum antibiotics—both bactericidal and bacteriostatic—as well as combination antibiotic agents available to treat opportunistic Prevotella and its bacterial collaborators in odontogenic infections.
Odontogenic infections are infections of tooth-related origins usually relating to endodontic or periodontal sources [5,6]. Possible etiologies can include necrotic pulp from carious or fractured teeth, pericoronitis, or deep periodontal pockets where bacteria can harbor and cause infections [7]. Anaerobic and aerobic bacteria are implicated in 50–60% of odontogenic infections, with the most commonly isolated facultative anaerobic organisms being Viridans streptococci, and the most commonly isolated obligate anaerobic bacteria include Bacteroides spp, Prevotella spp, and Peptostretpococcus spp [5].
Pericoronitis is an infection of the soft tissue around the crown of a partially erupted tooth and is usually caused by normal microorganisms that inhabit the oral cavity [5]. Bacterial plaque can accumulate underneath the soft tissue which may lead to the inflammatory process [8]. The bacteria that are found at the highest levels in symptomatic pericoronitis include Actinomyces oris, Eikenella corrodens, Eubacterium nodatum, Fusobacterium nucleatum, Treponema denticola, Eubacterium saburreum, and various Streptococcus species [9]. With proper oral hygiene and strong host defenses, most patients can eliminate the bacteria that are trapped under the operculum without leading to further complications or infections. If the bacteria are not removed under the operculum, pericoronitis can lead to jaw inflammation and phlegmon [10]. If the infection ensues, it may spread, causing a multi-space infection of the head and neck regions.
Management of infections in the oral cavity requires the clinician to have fundamental knowledge of the anatomy of the head and neck region, specifically the fascial planes through which infections can spread. Odontogenic infections typically begin as vestibular space abscesses where the infection is localized and treated easily [5]. The infection, when localized, may present as an abscess, swelling, cellulitis, and trismus. If the infection persists and spreads, the infection will take the path of least resistance, potentially leading to life-threatening complications. Management of odontogenic infection includes controlling the source of the infection by surgical removal, establishing drainage, and mobilizing the host defense system to fight the infection.
Chlorhexidine (CHX) is a broad-spectrum antimicrobial agent commonly used by dental practitioners and the public due to its effectiveness in limiting plaque and biofilm formation. If plaque and biofilm are allowed to flourish and grow, this could result in caries and gingivitis which could progress to periodontitis. The mechanism of action of chlorhexidine is disrupting cellular membranes to kill microorganisms that inhabit the oral cavity. There is some evidence that illustrates that the use of CHX post operatively can reduce the likelihood of post-op infections. Additionally, if CHX is used as a pre-operative rinse, post-operative bacteremia is decreased [11].
The generally accepted standard of care in microbiology labs for susceptibility testing is that if a specimen is considered to be contaminated with indigenous flora, susceptibility testing is not necessary, as the results could be misleading. The minimum bactericidal concentration (MBC) is the minimum concentration of antimicrobial capable of inactivating 99.9% of the bacteria present.
The minimum inhibitory concentration (MIC) of an antibiotic is the lowest concentration of the drug that inhibits the growth of the microorganism [12]. For a bactericidal antibiotic, the minimum bactericidal concentration (MBC) is close to the MIC. For a bacteriostatic antibiotic, the MBC is usually much higher than the MIC, and thus it may not be safe to administer such high doses [12].

Prevotella Pathogenesis

The Prevotella species, P. buccae, P. intermedia, P. loescheii, P. melaninogenica, P. nigrescens are pleomorphic, strict anaerobes, and form black-pigmented colonies. They can convert glucose into acetic acid and succinic acid, and require vitamin K and hemin for growth. P. intermedia is [normally] associated with chronic periodontitis and endodontic infections. Its virulence factors include phospholipase A, IgA/IgG proteases, mercaptans, and hydrogen sulfide [12].
P. intermedia is one of the microorganisms in the “orange complex,” as decribed by Socransky et al. [13] Increasing the colonization of periodontal plaque with microorganisms in this group, which also includes Fusobacterium nucleatum and Peptostreptococcus micros, leads to more sites being colonized by Tannerella forsythia, Porphyromonas gingivalis and Treponema denticola, which are, in turn, characterized as the “red complex” [12,13].
In 1990, the moderately saccharolytic and predominantly oral species, Bacteroides oralis and B. melaninogenicus, were reclassified in the genus Prevotella [14], and the genus name Bacteroides was restricted to Bacteroides fragilis and closely related species, including B. thetaiotaomicron.
Several strains of P. intermedia were found to inhibit the mitogen-or antigen-induced proliferation of B-cells and T-cells, suggesting that immunosupression mediated by periodontal bacteria may contribute to the pathogenesis of periodontal disease [15]. P. intermedia can bind to the basement membrane protein, laminin, which is abundant in the periodontal pocket [16]. It ferments glucose and sucrose, hydrolyzes starch, and produces various acids as metabolic end products, including acetic and succinic acids [17].
P. intermedia expresses a 65 kD molecule that acts as a receptor for the Fc region of human IgG, thereby shielding the bacterium from the humoral response of the host [18]. A 38 kD cysteine protease of P. intermedia completely degrades IgG, IgA and IgM within 24 h [19]. P. intermedia has hemolytic activity that enables it to acquire iron for its metabolism [20]. It also has hemoglobin receptors that can bind hemoglobin with a Kdiss of 2.5x10-8 M [21], and has hemagglutination activity associated with its fimbriae [21].
Another virulence factor of P. intermedia is interpain A, which degrades the C3 component of complement, synergistically with gingipains [22]. Interpain A can also activate the C1 complex in serum, which results in the deposition of C1q on inert and bacterial surfaces. Endodontic pathogens, particularly P. intermedia, can kill infiltrating neutrophils, which may be a mechanism by which endodontic infections get established [23]. P. intermedia has the highest DNA degradation ability among periodontopathogenic bacteria, which may explain its ability to escape neutrophil extracellular traps [24].
P. intermedia lipopolysaccharide (LPS) can induce IL-8 gene expression in human dental pulp fibroblasts. This ability appears to be specific to P. intermedia LPS, since synthetic LPS and Salmonella LPS do not increase IL-8 mRNA levels in the host cells [25]. P. intermedia LPS stimulates the production of tumor necrosis factor-alpha (TNF-α) in monocyte-derived macrophages by activating the three types of mitogen-activated protein kinases (MAPKs), ERK1/2, JNK1/2 and p38 [26].
The adhesion of P. intermedia to HEp-2, KB and HeLa cells and fibroblasts is inhibited by lactoferrin in a dose-dependent manner [27].
In patients with advanced periodontal disease, systemic administration of metronidazole plus amoxicillin inhibits the growth of Aggregatibacter actinomycetemcomitans, P. gingivalis and P. intermedia, and causes a reduction in the inflammatory lesion [28]. The MIC for metronidazole against P. intermedia was found to be about 1 µg/mL [29].
Among other bacteria, P. buccae was found in peri-implant bone defects [30], periodontitis [31,32], root canal infections [33], and radicular cysts [34].

Metronidazole

Metronidazole is a commonly used antibiotic and antiprotozoal medication belonging to the nitroimidazole class. It is synthetically derived from azomycin which was originally detected in Streptomyces spp. in the 1950s [35]. In 1962, it was used for the treatment of vaginitis due to Trichomonas vaginalis and has also been effective in treating patients with gingivitis. Metronidazole is the first choice in the treatment of Clostridium difficile [35].
Metronidazole exerts its antimicrobial effects through a stepwise mechanism. It is first taken into the microorganism by diffusion across the cell membranes of anaerobic pathogens [36]. It exerts its antimicrobial effects after the reduction of its nitro group through the transfer of an electron, activating the prodrug and creating reactive intermediates and radicals that are toxic to the microorganisms, leading to the inhibition of growth or outright killing by the breaking of DNA strands [35].
Metronidazole is absorbed rapidly by the gastrointestinal tract often bypassing the enterohepatic circulation, as observed in studies with mice and rats [35]. The liver breaks down metronidazole into 5 metabolites. The hydroxy metabolite has a longer half-life than its parent compound. The majority of metronidazole and the metabolites are excreted in the subject’s urine and feces, with approximately 12% being excreted unchanged [37].

Metronidazole Disulfiram-Like Reaction

There is a commonly known association of a disulfiram-like reaction with the use of metronidazole and alcohol. Disulfiram is a medication commonly used to treat alcohol dependence. Its mechanism of action is to inhibit the enzyme aldehyde dehydrogenase thus leading to the accumulation of acetaldehyde [38]. Metronidazole has a similar mechanism. While it does not inhibit aldehyde dehydrogenase, it does inhibit alcohol dehydrogenase. When alcohol is mixed with disulfiram or metronidazole there are a range of unpleasant symptoms that accompany the build-up of acetaldehyde. Common symptoms include nausea, vomiting, abdominal pain, flushing of the face, tachycardia, throbbing headaches, and syncope. In more severe cases some of these symptoms may include respiratory depression, cardiovascular collapse, arrhythmias, convulsions, and death [39].
While Prevotella has been shown to be highly susceptible to metronidazole, the symptoms associated with the disulfiram-like reactions are a contributing factor for health care providers not wanting to prescribe this antibiotic.

Methods

We performed a comprehensive search of the medical literature to review the information regarding Prevotella’s relationship to odontogenic infections and the antibiotics used to mitigate its opportunity to become virulent. The PubMed database was searched using the following terms: “Prevotella AND Odontogenic Infection AND (OR Amoxicillin OR Clindamycin OR Metronidazole OR Flagyl)”. We identified 46 articles from 1996 to 2024 of which 40 were published in English. Twenty-five additional references were used to develop the section on Prevotella pathogenesis, and other publications were cited within the paper. A total of 76 references were reviewed and cited. Foreign language papers were excluded from our study. Observational/retrospective studies, literature reviews, and randomized controlled trials were reviewed.

Case Series

CASE 1: Perialveolar Infection

A 25-year-old female presented for extraction of teeth numbers 1, 16, 17, and 32. Her medical history was unremarkable. The surgery was performed with removal of bone, sectioning of teeth and irrigation with dilute Chlorhexidine 0.12% mouthwash and sterile saline. The surgical sites were closed with 4.0 chromic gut sutures. She returned to the office for a post-operative visit one week later that revealed pink healthy healing mucosa in four quadrants. There was no erythema, edema or exudate. The sockets were irrigated with sterile saline alone, and there was no evidence of food impaction. The sutures were removed at this visit. She was told to return to the office if she exhibited any subjective signs of pain or swelling.
21 days after surgery, she returned to the office with concern of yellow fluid in the socket of tooth #17, swelling and mild pain. The floor of mouth and buccal space were not involved. The socket was gently opened with cotton pliers and irrigated with 20 ml of dilute Chlorhexidine 0.12% mouthwash mixed with sterile saline. A prescription was given for Amoxicillin 500 mg, 15 tablets, take one by mouth three times a day until completed. An empiric antibiotic approach with conservative irrigation and drainage was performed as in many perialveolar infections we have treated before.
29 days after surgery she returned to the office with concern of yellow fluid in the socket of tooth #32, swelling and mild pain. The floor of mouth and buccal space were not involved. The socket was gently opened with cotton pliers and irrigated with 20 ml of dilute Chlorhexidine 0.12% mouthwash and sterile saline. A prescription was given for Chlorhexidine 0.12% mouthwash and the patient was instructed to irrigate the socket twice a day with Chlorhexidine 0.12% mouthwash alone for one week. A new prescription was given for Clindamycin 300 mg, 20 tablets, take one by mouth four times a day until gone.
The patient returned on Day 36 for follow-up and the #32 socket was irrigated with dilute Chlorhexidine 0.12% and sterile saline without evidence of purulent exudate.
On day 45, the patient called the weekend on-call doctor and reported there was exudate coming from the #32 socket again. The doctor explained to the patient that tissue levels of the antibiotic were never achieved and prescribed Amoxicillin 500 mg, 40 tablets, “take one by mouth three times a day until gone.”
On day 47, we saw the patient, concerned that there was a resistant bacterium colonizing the #32 space. The #17 space was without evidence of erythema, edema or exudate at this time. Incision and drainage were performed at this site and there was no evidence of purulent exudate. Cultures were taken at the #32 site for anaerobic and aerobic bacteria, a Gram stain and antibiotic sensitivity testing were requested. The socket of #32 revealed caseous material and shiny white collagen-like tissue. The area was irrigated with 60 ml of dilute Chlorhexidine 0.12% mouthwash and sterile saline. The patient continued taking the Amoxicillin.
On day 50, after completing the Amoxicillin prescription, the patient called and reported that the #17 site was draining purulent exudate. The Gram’s stain results for the #32 socket reported, “No white blood cells. No organisms seen.” The aerobic culture reported at day 51 revealed, “Moderate growth of normal oral flora from the #32 extraction wound.” The anaerobic culture reported at day 53 revealed, “Prevotella buccae isolated with heavy growth.” (Table 1).
The #17 site was opened with cotton pliers, irrigated with 20 ml dilute Chlorhexidine 0.12% and sterile saline, and the fluid was cultured again. Only one report was filed by the hospital microbiology department, “Moderate growth of mixed oropharyngeal flora was isolated. Final report.”
Based on the anaerobic culture and sensitivity results from the day 50 surgery, Metronidazole 500 mg, 40 tablets, “take one by mouth four times a day until gone,” was prescribed. The patient continued to irrigate the #17 socket at home with dilute Chlorhexidine 0.12% and water. The patient was followed weekly for improvement and there was no recurrence of the perialveolar infections at the #17 or #32 sockets.
We had never treated a refractory perialveolar infection like this in 18 years of private practice. Therefore, it is important to emphasize careful follow-up and repeated surgical interventions to mitigate these odontogenic infections.

CASE 2: Multi-space Odontogenic Infection

A 23-year-old male patient presented from the hospital emergency department to the lead author’s private office to be evaluated for an oral infection. His medical history was unremarkable. Six days prior, he was treated for a carious impacted tooth #32 by a community dental provider and the tooth was removed. An Amoxicillin prescription was given upon discharge. He was given intravenous Clindamycin at the hospital.
Upon examination, his temperature was 99.4° F and he was trismatic to 1 cm of mouth opening. The perialveolar, buccal and sublingual spaces exhibited moderate edema. There was purulent exudate expressed from the socket of tooth #32. Nitrous oxide-Oxygen sedation was used to facilitate oral opening to approximately 3 cm. Incision and drainage surgery was performed with full thickness mucoperiosteal flap, 5 ml of purulent exudate was removed, and the space was irrigated with dilute Chlorhexidine 0.12% mouthwash and sterile saline. The surgical site was left open for continued drainage. Cultures of the extraction socket of #32 were taken for Gram’s stain, aerobic bacteria, and anaerobic bacteria and sent to the hospital. The patient returned to the hospital for intravenous blood testing and observation.
A Complete Blood Count with differential analysis was ordered and the results revealed “White blood cells 12.4K, 86% Neutrophils.” The Gram’s stain revealed, “Moderate white blood cells, few Gram-positive cocci, few Gram-negative rods, and rare Gram-positive rods.” The aerobic culture revealed, “Light growth Eikenella corrodens, light growth normal oral flora, rare growth Streptococcus anginosus (S. milleri group).”
We recommended the hospitalist send him home with Metronidazole 500 mg, 40 tablets, take one tablet every six hours until gone.
The patient was followed in the private office the next day with improvement of trismus, swelling and pain. He was instructed to rinse with Chlorhexidine 0.12% diluted with water at home for one week. At day 3 post incision and drainage, the anaerobic culture was returned and revealed, “Mixed varieties of Prevotella species isolated. Light growth of mixed anaerobic flora including Prevotella buccae.” CLSI standards lead the microbiology laboratory to not do antibiotic sensitivity testing as no bacteria revealed itself in high quantities outside the expected mixed odontogenic normal flora.
The patient was seen again in the lead author’s office at post operative day 8 with resolution of his infection.

CASE 3: Severe Pericoronitis

A 42-year-old male presented to the office with acute pericoronitis, trismus and pain. The patient had an unremarkable medical history. His vital signs were BP 160/110 with a HR of 90. His BMI was 33. Upon oral evaluation, he exhibited a severe pericoronitis associated with tooth #17 which had extended into the left buccal space. There was no floor of mouth raise or purulent exudate present. He was trismatic to approximately 2 cm of oral opening. After he was examined in the private office, he was sent to the hospital for impending surgery and intravenous antibiotics. He was advised to have nothing to eat or drink (NPO) until surgery in the operating room under general anesthesia. We prescribed Unasyn (ampicillin-sulbactam) 3 g intravenously upon arrival at the hospital, due to trismus and the suspicion of an advancing polymicrobial infection.
Surgery was performed in the operating room under oral-endotracheal general anesthesia. A full thickness mucoperiosteal was elevated and tooth #17 was extracted with removal of alveolar bone, and the space was irrigated with Chlorhexidine 0.12% mouthwash diluted with sterile saline, approximately 60 ml. There was serosanguinous fluid in the buccal space without the presence of purulence indicative of cellulitis. The wound was left open to promote drainage. Cultures were taken for aerobic and anaerobic bacteria, and a Gram Stain was requested from the laboratory. The Gram Stain revealed, “Many white blood cells, moderate Gram-positive cocci, and few Gram-negative rods.” The aerobic culture revealed, “Moderate growth of mixed skin flora, light growth of Klebsiella oxytoca, light growth of Streptococcus anginosus (S. Milleri group).” Three days later, the anaerobic culture revealed, “Heavy Fusobacterium, moderate growth Parvimonas micra (Peptostreptococcus micros), and moderate growth of mixed varieties of Prevotella species including Prevotella intermedia.”
The patient was discharged that day with a prescription for Metronidazole 500 mg, 28 tablets, take one tablet four times a day until gone; Augmentin 875 mg, 14 tablets, take one tablet twice a day until gone; Chlorhexidine 0.12% mouthwash, rinse ½ oz. twice a day and spit out, for one week. We also prescribed an opioid-containing analgesic as needed for pain.
The patient was followed in the office the next day for improvement and his symptoms had subsided by the one-week post-operative examination.
Table 2. Susceptibility Testing for Prevotella intermedia and Fusobacterium species.
Table 2. Susceptibility Testing for Prevotella intermedia and Fusobacterium species.
Susceptibility
Prevotella intermedia
Antibiotic Interpretation Value Comment (μg/mL)
Ampicillin + Sulbactam Susceptible <=0.03
Clindamycin Susceptible <=0.03
Meropenem Susceptible 0.06
Metronidazole Susceptible 0.12
Fusobacterium Species
Ampicillin + Sulbactam Susceptible <=0.03
Clindamycin Susceptible 0.06
Meropenem Susceptible 0.03
Metronidazole Susceptible <=0.03

Results of the Literature Review and Discussion

The microbiome of the oral cavity is one of the most varied floras in the human body. The variety of bacteria in the oral cavity is a result of the many microenvironments, caused by the various surfaces of teeth, the gingival sulcus, buccal mucosa, and tongue [40]. Each organism has a unique set of conditions that allows the bacteria to survive in that region. Each location in the oral cavity has appropriate nutrients and oxygen tension or physical protection from unfavorable conditions [40]. Plum et al. have proposed that Streptococcus salivarius and Veillonella spp. often colonize the tongue and buccal surfaces; Actinomycetes and Streptococcus spp often colonizes the enamel of teeth; and Fusobacterium, Prevotella, Porphyromonas, and Spirochetes colonize gingival surfaces [41]. When managing odontogenic infections it is important to understand the nature of the flora and the environment – specifically analyzing the organism’s oxygen requirement, which will be crucial when identifying the possible bacteria and how to treat the infection. The most common causes of odontogenic infections include caries (65%), pericoronitis (36%) and periodontitis (21%) [42,43]. The teeth most commonly implicated in these infections are those located in the lower posterior segments, according to Sanchez et al. Approximately 61.5% of the cases studied had involvement of the mandibular premolars and molars, followed by the second most frequent causal tooth–the mandibular third molars at 26.6% [44]. The suspected reason for the mandibular molars being the teeth most commonly implicated is due to the teeth lying below the mylohyoid line. The mylohyoid line is a bony ridge to where the mylohyoid muscle attaches and forms the floor of the mouth. The mylohyoid line runs just above the roots of the mandibular molar. Should these teeth develop infections and spread beyond the tooth itself, the infection can extend into the most frequently involved space, the submandibular space, with the potential of spreading further into the deeper neck spaces [2,45,46]. Deep fascial space infections of the neck are most frequently odontogenic in origin and can be life-threatening if the mandibular abscess extends to the adjacent fascial space [47,48]. Severe complications with the spread of odontogenic infection into the deep fascial spaces include descending necrotizing mediastinitis, orbital cellulitis, septic cavernous sinus thrombosis, cerebral abscess, meningitis, necrotizing fasciitis, Lemierre’s syndrome, osteomyelitis, endocarditis, and sepsis [40,49,50]. To prevent the dissemination of bacteria into deep fascial spaces, antibiotics are commonly prescribed to aid in treating the odontogenic infection [6].
In line with recent studies addressing the treatment of odontogenic abscesses, the most prevalent anaerobic bacteria were: Prevotella spp. Peptostreptococcus (Micromonas micros), Bacteroides, and different species of Actinomyces, F. nucleatum comprised 53% of the anaerobes [40,42,44,49,50,51,52]. The aerobic and facultative anaerobes found in high count include: Viridans streptococci, alpha-hemolytic streptococci, S. aureus, and E. coli. [40,42,50,53,54] Fungi have also been collected in small cultures [44]. When addressing larger odontogenic infections, the bacteria involved are more pathogenic than those predominantly isolated from smaller odontogenic infections [55].
Of the cases studied, one-third of the patients were successfully treated solely with incision and drainage. Penicillin has been the antibiotic of choice for uncomplicated dental infections because of its activity against many facultative and anaerobic organisms recovered from these mixed infections [51]. Only in severe abscesses is penicillin prescribed following surgical incision and drainage [53]. The administration of the penicillin drug class is considered to be useful for the empirical management of odontogenic infections, as described by other studies published in Spain [44]. The advantages of such treatment are based upon the bacteria susceptibility to the antibiotic as well as the low cost [44,56,57,58]. However, some authors have found that PEN-resistant organisms are increasingly isolated from abscesses of odontogenic origin due to the production of β-lactamase which restricts the effectiveness of the penicillin [10,42,54,58,59,60]. The ability of species to synthesize β-lactamase should be determined before treating with β-lactam antibiotics to avoid potential antibiotic resistance [61]. Patel et al. found Prevotella to be the most prevalent in producing β-lactamase, followed by Capnocytophaga, Veillonella and Bacteroides [62]. The β-lactamase produced protects the bacteria and other surrounding bacteria in the polymicrobial niches against antibiotic activity [63]. There are several mechanisms through which microorganisms can gain resistance to β-lactam antibiotics. These include alteration in penicillin-binding proteins, and barriers to target sites, and the ability to inactivate the antibiotic through production of β-lactamase. Prevotella’s resistance to β-lactam antibiotics results from the expression of β-lactamase genes. Kuriyama et al. have found Prevotella to have many β-lactamase positive strains. When considering penicillin use, it is important to ascertain whether the patient has allergies to this or other antibiotics.
Other antibiotics that have proven to be effective include penicillinase-resistant penicillin, clindamycin, or a combination of metronidazole plus amoxicillin or a macrolide [51]. Metronidazole has been studied extensively and has been seen to have excellent activity (100%) against all the anaerobic isolates, but possesses little to no activity against aerobes [42,64]. Chan et al. have found there to be a possible decrease in therapeutic effectiveness when metronidazole is used alone [65]. Ciprofloxacin, amoxicillin with a beta-lactam inhibitor like clavulanic acid and clindamycin were also effective [42,66]. Maestre et al. found that Prevotella isolates were susceptible to amoxicillin-clavulanic acid, while amoxicillin alone exhibited resistance rates ranging from 17.1% in P. buccae to 26.3% in P. denticola. In all Prevotella species, resistance rates to metronidazole was below 6%, and clindamycin resistance ranged from 0%–21.1% [67]. When looking at P. buccae, P. denticola, and P. intermedia, resistance rates were found to range from 9.1% to 21% for clindamycin, 0% to 5.9% for metronidazole, and 5.9% to 36.4% for tetracycline [67].
In a study from Central India published in 2018, the effectiveness of different antibiotics on anaerobic isolates was examined. Their results found 0/8 susceptible to penicillin, 6/8 susceptible to CLI, 8/8 AMOX + Cl, and 8/8 Metronidazole [42]. For those who have PEN allergies, Sobotka et al. found clindamycin (CLI), erythromycin, tetracyclines, and levofloxacin (LVX) to be adequate alternative regimens [54]. The family of tetracycline antibiotics has been available and commonly prescribed since the mid-1950s [65]. Because of its widespread use and emergence of drug-resistant microorganisms, a culture and sensitivity test should be performed prior to prescribing tetracycline or its derivatives to ensure its effectiveness.
There has been some discussion of the use of combination therapy. Alou et al. found eradication of β-lactamase producing strains to be achieved quicker by the use of combination therapy of amox/clav + tinidazole and by clindamycin + tinidazole than by a β-lactam antibiotic alone.
Based upon literature researched and clinical cases, when a specimen contains a single organism considered to be an opportunistic pathogen, or if there is a clear predominance of growth in a mixed culture, then susceptibility testing is performed on that organism. Occasionally, however, when known empiric therapies are found to be effective, such antibiotics will be prescribed without susceptibility testing. For example, a culture with Eikenella sp. and S. anginosus found in small quantities among other indigenous flora of the oral cavity, no susceptibilities would be performed. For Eikenella, oral therapy with Amoxicillin/clavulanate (Augmentin) is a well-accepted treatment. This would also cover S. anginosus as well as much of the indigenous flora. Even for anaerobic infections—these are often polymicrobial and often do not require susceptibility testing—empiric therapy including surgery is usually curative [46]. If susceptibility testing is needed for anaerobic organisms such as Prevotella, Metronidazole is reliable as the first line of empiric treatment, as resistance in these organisms to Metronidazole is uncommon [45]. Meropenem is used by Kaiser Permanente as it tends to be a standard antibiotic used for anaerobic susceptibility testing.
To aid in the antimicrobial effectiveness, determination of the breakpoint values are important in analyzing susceptibility data for different species of organisms. The breakpoint value is used to categorize bacteria as susceptible, intermediate, or resistant to that specific antibiotic. In the present study, the susceptibility breakpoints were determined by NCCLS (National Committee for Clinical Laboratory Standards ) criteria. Breakpoints are determined based on data concerning the clinical outcome, the pharmacology of the agents, which includes the tissue and serum concentrations, the degree of protein-binding, and the susceptibility of bacteria to antimicrobial agents. When antibiotics are administered, concentrations of antibiotics in oral and maxillofacial regions are much smaller than those found in serum samples. This could be a result of the various factors of pharmacokinetics including absorption, distribution, metabolism and excretion. Additionally, in specific sites there may be barriers that limit the ability for the antibiotic to penetrate through membranes resulting in lower concentrations than serum levels.
The Clinical and Laboratory Standards Institute (CLSI) publishes standards for susceptibility testing and an antibiogram for anaerobic organisms (Table 4). The table shows that 99% of Prevotella samples tested were susceptible to Metronidazole. Other than Clindamycin and Moxifloxacin, most oral and IV therapies have excellent Prevotella coverage. The table also reports that approximately 30% of Prevotella spp. are resistant to Clindamycin.
What we have observed over 29 years of clinical practice is that Prevotella is often resistant to β-lactam antibiotics. We see refractory infection when Amoxicillin is given, and we see those patients that continue to be reinfected after Cleocin is given as well. We see more of these refractory infections, as Amoxicillin has become more popular as an antimicrobial used to treat odontogenic infections. We believe Amoxicillin became popular in light of Viridans group streptococcal (VGS) infective endocarditis (IE) prophylaxis for dental procedures, its minimal side effects, and for its improved absorption from the gastrointestinal tract, providing higher and more sustained serum concentrations. Viridans group streptococci are common to the oral microbiome and have been shown to be antagonistic to periodontal pathogens such as Prevotella and other obligate anaerobes. Opportunistic bacterial pathogens have also been shown to begin to mutate after just days of antibiotic administration used for both prophylaxis against surgical wound infections or for the treatment of established oral and maxillofacial infections.
We are surprised that Penicillin has been reported as 100% effective in killing Prevotella according to the CLSI table. We also suspect that we did not see Prevotella becoming an opportunistic pathogen in light of the old-fashioned “Penicillin plus Flagyl” regimens for odontogenic infections, as the Flagyl (Metronidazole) was bactericidal for Prevotella. Metronidazole certainly fell out of fashion because of the Disulfiram-like reaction and its poor tolerance due to gastrointestinal upset. It is of interest to note that many antibiotics in the table are intravenous (IV) only. Community providers need a cost-effective and available oral (PO) medication.
The old “Penicillin plus Flagyl” regimen might be the first empiric line, if Prevotella is the suspected actor in a mixed flora multispace odontogentic infection or cellulitis. Surgery and Metronidazole alone seems adequate in treating mild to moderate odontogenic infections in the immunocompetent host.

Conclusions

Prevotella, Eikenella, Fusobacterium and other anaerobic Gram-negative organisms (including Viridans streptococci, Neisseria, Klebsiella and other facultative anaerobes) are frequently mitigated by surgery and common orally administered antibiotics used to treat odontogenetic infections, including Amoxicillin, Penicillin, Augmentin, and Clindamycin (Table 4). These organisms live as part of the normal oral microbiome and biofilm—with facultative anaerobic and aerobic organisms—but they can become virulent given the opportunity in odontogenic infections. Although any antibiotic can contribute to pseudomembranous colitis, the use of Clindamycin continues to decrease due to its contribution to this disease.
Perioperative irrigation of dilute Chlorhexidine 0.12% mouthwash during dentoalveolar surgery seems to prevent both perialveolar infections and alveolar osteitis. Repeated use of Chlorhexidine in the presence of mixed flora odontogenic infections and pericoronitis may lead to disruption of a protective microbiome—resulting in the selection of resistant microorganisms—giving an opportunity for Prevotella to become virulent. Its use is meant to be adjunctive to surgery and systemic antibiotic administration, killing opportunistic bacteria on contact during surgical procedures.
Infections refractory to surgery and empiric antibiotics should be cultured to identify opportunistic organisms. CLSI guidelines should be followed except in light of recurrent infections where Prevotella isolates have been identified. Prevotella buccae is resistant to both beta lactam antibiotics and Clindamycin. Prevotella buccae and other empiric antibiotic-resistant Prevotella species remain part of the oral microbiome and must be ruled out as an opportunistic pathogen in the mixed contaminated isolate.
The principles of surgery including incision, drainage (removing the source of the infection often including tooth extraction, exposing the area to air which kills exposed obligate anaerobes, and decompressing the swelling), and irrigation (decreasing the bacterial load and removing bacterial inflammatory byproducts) will often cure an odontogenic infection in the immunocompetent host.
Metronidazole is bactericidal at appropriate MBC to treat all Prevotella species. Multispace odontogenic infections with mixed flora isolates that include obligate anaerobic organisms can be very dangerous. Early surgery prior to infections spreading through fascial spaces causing trismus and airway compromise is necessary, as these infections can cause morbidity and mortality.
If treatment of these infections is late in the course of the disease, radiographs including CT scans and infectious disease specialist consultation may be indicated. A polypharmaceutical approach to serious odontogentic infections of the head and neck may be needed to supplement appropriate surgery of the infected areas. Culture and sensitivity testing can guide antibiotic susceptibility choices and MBCs.
Metronidazole seems to be the only oral antibiotic able to kill Prevotella buccae and other antibiotic resistant Prevotella species, as well as a majority of obligate anaerobes [7]. Tolerance to the disulfiram-like reaction and stomach upset remain side effects of Metronidazole, limiting its use in some patients. Access to intravenous agents killing Prevotella species resistant to oral antibiotics often require hospitalization for administration and access to the drugs (Table 5).
A quality comprehensive history and physical exam is essential to diagnosing odontogenic infections. We are suggesting the following treatment algorithm based on our case series and literature review:
Mild Odontogenic Infection (e.g., mild pericoronitis, perialveolar infection, chronic or acute suppurative periodontitis, periapical abscess)
a)
Surgery alone in the immunocompetent host without comorbid disease
b)
Surgery plus Metronidazole in patients who are immunocompromised or have comorbid disease
Moderate Odontogenic Infection (e.g., single fascial space involvement, trismus)
a)
Surgery plus Metronidazole
b)
Surgery, Metronidazole, Aminopenicillin with β-lactamase inhibitor.
c)
Culture and sensitivity guidance to identify specific opportunistic pathogens at appropriate MBC
Advanced Odontogenic Infection (e.g., multiple fascial spaces, airway compromise, reinfection refractory to initial surgical and antibiotic treatment)
a)
Surgery, Metronidazole, Aminopenicillin with β-lactamase inhibitor
b)
Culture and sensitivity antibiotic guidance at appropriate MBC
c)
Additional surgery for reinfection or non-improvement of symptoms
d)
Infectious Disease Physician consultation and antibiotic treatment guidance
In patients allergic to β-lactam antibiotics, Clindamycin, Macrolides, Fluoroquinolones, and Aminoglycosides have been effective in mitigating the growth of opportunistic bacterial pathogens in odontogenic infections. These agents have been used in combination to treat the Viridans Streptococci and anaerobic bacteria that contribute to mixed flora odontogenic infections.
We adhere to the principles of antibiotic administration that includes using appropriate MBC, short duration antibiotic therapy to prevent resistant strains of bacteria in oral disease. We look forward to research that isolates Prevotella species in odontogenic infections and determines its ability to be mitigated by antibiotics that kill Prevotella species resistant to β-lactam antibiotics and Clindamycin. Traditional surgical treatment is always the standard of care in odontogenic infections, with or without adjunctive antibiotics.

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Table 1. MBC for Prevotella buccae (anaerobic gram-negative rod).
Table 1. MBC for Prevotella buccae (anaerobic gram-negative rod).
Anaerobic Gram-negative rods
MBC (μg/mL)
Ampicillin + Sulbactam 1 Susceptible
Clindamycin 256 Resistant
Meropenem 0.25 Susceptible
Metronidazole 0.5 Susceptible
Table 4. Anaerobic Organisms Other Than Bacteroides spp. and Parabacteroides spp. Reprinted with permission from Clinical and Laboratory Standards Institute from: CLSI. Performance Standards for Antimicrobial Susceptibility Testing.30th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2020. (With permission).
Table 4. Anaerobic Organisms Other Than Bacteroides spp. and Parabacteroides spp. Reprinted with permission from Clinical and Laboratory Standards Institute from: CLSI. Performance Standards for Antimicrobial Susceptibility Testing.30th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2020. (With permission).
Ampicillin-Sulbactam Pipercillin-tazobactam Imipenem Meropenem
Anaerobic Organisms # of strains %S %R # of strains %S %R # of strains %S %R # of strains %S %R
Prevotella spp. 29 97 3 63 100 0 29 100 0 92 98 0
Fusobacterium spp 20 100 0 55 96 2 75 95 4 20 100 0
Anaerobic gram positive cocci - - - 1853 99 1 134 99 0 1647 100 0
Clostridium perfringens 15 100 0 410 100 0 23 100 0 417 100 0
Clostridioides 76 99 0 542 93 0 480 69 4 609 99 0
Clostridium spp. - 439 94 1 71 99 0 390 100 0
Penicillin Clindamycin Moxifloxacin Metronidazole
Anaerobic Organisms # of strains %S %R # of strains %S %R # of strains %S %R # of strains %S %R
Prevotella spp. 63 100 0 29 69 28 92 66 25 92 99 0
Fusobacterium spp - - - 75 77 21 75 68 23 75 95 5
Anaerobic gram positive cocci 1647 100 0 1826 97 3 300 72 21 0 100 0
Clostridium perfringens 402 90 4 425 83 12 23 83 9 425 100 0
Clostridioides 533 6 37 1013 32 38 480 74 25 1343 100 0
Clostridium spp. 390 69 13 461 67 25 71 62 35 461 100 [i]
Table 5. The number of resistant isolates and the percentage of resistance against different antibiotics and the prevalence of the corresponding resistance genes in Prevotella isolates. A.C.M. Veloo, W.H. Baas, F.J. Haan, J. Coco, J.W. Rossen. Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates, Clinical Microbiology and Infection, Volume 25, Issue 9, 2019, Pages 1156.e9-1156.e13, ISSN 1198-743X, https://doi.org/10.1016/j.cmi.2019.02.017. (With permission).
Table 5. The number of resistant isolates and the percentage of resistance against different antibiotics and the prevalence of the corresponding resistance genes in Prevotella isolates. A.C.M. Veloo, W.H. Baas, F.J. Haan, J. Coco, J.W. Rossen. Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates, Clinical Microbiology and Infection, Volume 25, Issue 9, 2019, Pages 1156.e9-1156.e13, ISSN 1198-743X, https://doi.org/10.1016/j.cmi.2019.02.017. (With permission).
Resistant strains (n[%])
Amoxicillin Meropenem Clindamycin Metronidazole
Species
Breakpoint (mg/L) R>2 R>8 R>4 R>4
P. baroniae (n=2) 1 (50.0) 0 0 0
P. bergensis (n=3) 2 (66.7) 0 2 (66.7) 0
P. bivia (n=17) 9 (52.9) 0 2 (11.8) 1 (5.9)
P. buccae (n=13) 5 (38.5) 0 0 0
P. buccalis (n=3) 0 0 0 0
P. copri (n=2_ 1 (50.0) 0 1 (50.0) 0
P. denticola (n=7) 4 (57.1) 0 0 0
P. disiens (n=4) 1 (25.0) 0 2 (50.0) 0
P. histicola (n=2) 1 (50.0) 0 0 0
P. intermedia (n=4) 1 (25.0) 0 0 0
P. jejuni (n=2) 2 (100) 0 0 0
P. melaninogenica (n=21) 14 (66.7) 0 1 (4.8) 1 (4.8)
P. nigrescens (n=4) 3 (75.0) 0 1 (25.0) 0
P. oris (n=2) 2 (100) 0 0 0
P. timonensis (n=6) 1 (16.7) 0 1 (16.7) 0
Prevotella spp. (n=7) 1 (14.3) 0 0 0
Total, n (%) 48 (48.5) 0 10 (10.1) (2.0)
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