Orofacial infections of odontogenic origin

GUTIÉRREZ-PÉREZ JL, PEREA-PÉREZ EJ, ROMERO-RUIZ MMª, GIRÓN-GONZÁLEZ JA. OROFACIAL INFECTIONS OF ODONTOGENIC ORIGIN. MED ORAL 2004;9:280-7.

ABSTRACT

The polymicrobial nature of the odontogenic infections as well as the variety of associated conditions are a consequence of the diversity of the buccal microbiota and the anatomical and functional complexity of the oral cavity. In addition to this, all these processes can give way to multiple complications which range from the local to the systemic level.
The appropriate choice of antibiotic and posology is crucial in the successful management of these infections. Pharmacodyna-mics provides those parameters that make it possible to assess how antibiotics activity varies in time. As a general rule, the first step in the initial management of orofacial infections in adults, included odontogenic infections, will be the administration of 875 mg of amoxicillin and 125 mg of clavulanic every 8 hours.
Therapeutic compliance is paramount to avoid resistance, therefore patient's acceptance must be sought. In this sense, it has been proved that Augmentine Plus (2000/125) every twelve hours both as profylaxis and as treatment significantly decreases the rate of infective complications associated to extraction of the third molar.

Key words: Odontogenic infections, amoxicillin/clavulanic, MIC, betalactam

INTRODUCTION

The morphological complexity of the oral cavity as well as it being a functional and anatomical crossroads brings about the great variety of conditions classified as "orofacial infections". Thus, we distinguish between multiple and variable forms of odontogenic infection such as periimplantitis, periodontitis, odontogenic infections, etc. The high incidence rate of some of these conditions confers these pathologies great importance and relevance. More specifically, odontogenic infections are specially interesting on account of its intense local symptoms together with associated risks such as tooth loss or retropharyngeal, sinusal, cardiovascular or polyarticular compromise among other distant complications. On those occasions when drug treatment is indicated, this can be limited to a merely palliative approach or seek to control the infectious agent. Ultimately, what provides definite symptomatic relieve is the ethiological and curative approach. Therefore, it is of the utmost importance that odontologists are aware of the microbiological, pharmacokinetic and pharmacodynamic aspects of the antibacterial chemotherapy used to control these infections.

The great anatomical and hystological diversity of the buccal cavity makes it possible for different microbial ecosystems to co-exist; each one possessing specific metabolic and nutritional characteristics and being part of a delicate ecological balance. In addition, the proportion of each bacterial species to the whole varies according to age, diet, buccal hygiene, the occurrence of caries or periodontal disease, previous and/or concomitant antimicrobial treatment, hospitalisation, pregnancy and certain genetic and racial factors (1, 2). Generally, the oral cavity contains an endogenous, saprophytic microbiota which consists of over 500 species (3). The genera Streptococcus, Peptostreptococcus, Veillonella, Lactobacillus, Corynebacte-rium and Actinomyces constitute more than 80% of all cultured strains, several of which are betalactamase-producing organisms (1). The isolation of facultative gram-negative bacteria from healthy adults is not common and its occurrence is usually facilitated by factors such as old age, hospitalisation, immunological compromise, etc (4)

Although all of them can be isolated all about the oral cavity, each species shows preference for particular niches. The accumulation of micro-organisms in the different mouth tissues and the subsequent formation of bacterial plaque depends on various factors. These can be physicochemical, fundamentally qualitative and quantitative features of saliva, mechanical (tooth brushing technique and frequency, buccal hygiene) and host-interaction factors (adhesion to the mucous membrane or enamel, immunological mechanisms...).

The polymicrobial nature of the odontogenic infections increases the chance of bacterial synergism and symbiosis. Generally, the infection is triggered by caries progression through enamel and dentin and, eventually, the invasion of dental pulp. Up until the initiation of pulpitis, all bacteria involved in this process are mainly aerobic. However, anaerobiosis and neurovascular bundle necrosis take place as a result of bacterial accumulation. This generates optimal conditions for the establishment of facultative, and eventually, strict anaerobes, which are responsible for infective processes affecting, among other locations, deep cervicofacial planes.

In order to manage these processes efficiently and opt for the most suitable diagnostic and ethiological approach, it is of paramount importance to compile a correct and complete medical history that provides sufficient information to detect and/or identify any underlying pathology or concomitant silent processes that can worsen or mask the situation in early stages. With regards to the therapeutic aspects, timing the treatment appropriately is also essential because if odontogenic infections become a chronic condition, the therapeutical management of those species that have evolved and generated a strictly anaerobic environment turns out to be far more complex and tedious. The inherent variability and complexity of the bacterial microbiota make the various available therapies subject to completely different conditioning factors depending on which phase the infection is in. Thus, an odontological, pharmacologi-cal or surgical approach, or a combination of the three in different degrees of intensity, can be used.

The polymicrobial character of odontogenic infections makes it advisable to use broad spectrum antibiotics which are active against aerobic and anaerobic bacteria. On occasions, in order to obtain a broader antimicrobial spectrum and one more appropriate for the type of infection occurring, it is necessary to use combined therapies.

Traditionally, penicillin, ampicillin and amoxicillin have been used to treat odontogenic infections on account of the fact that their antibacterial spectrum notably matches those bacteria existing in the buccal cavity, both aerobic and anaerobic (5). However, in view of the emergence over the last years of betalactamase producing strains which explain resistance to betalactam antibiotics and cause treatment failure, these agents are no longer used in isolation (6, 7, 8). The association of a betalactam antibiotic agent with a betalactamase inhibitor, such as amoxicillin plus clavulanic acid, re-establishes the former's activity against these bacteria. (9, 10) Currently, the amoxicillin/clavulanic acid combination is considered as the first line antibiotic in the management of odontogenic infections in view of its broad spectrum (10).

ETHIOPATHOGENESIS AND EVOLUTION OF THE ODONTOGENIC INFECTION

Patients with infection of odontogenic origin show, among others, the following acute symptoms: tumefaction, pain, induration, trismus, odynophagia and even serious systemic complications, if particular infections progress in an uncontrolled manner.

As mentioned above, the most frequent cause of odontogenic infection is caries leading into pulpar necrosis and eventually a periapical abscess or acute apical periodontitis. A less common cause is the invasion of the dental pulp through secondary canaliculus coming from the periodontal ligament or from the area of infection when periodontitis is present. Also important are inoculations of the neurovascular bundle secondary to odontofacial traumatisms, small repeated traumas due to malocclusions or bruxism; these two being more common in the elderly. Once the periapical infection is established, it tends to spread following the path of least resistance. Most frequently, it will spread towards the vestibular cortical bone once the subperiosteal membrane is broken with the subsequent abscess usually originating a vestibular fistula. On occasions, the infectious component spreads towards deep cervicofacial regions through the muscular aponeurosis and soft tissue, a process that results in complications and abscesses at this level. If evolving uncontrolled, this kind of cellulitis can settle and have fatal consequences due to the proximity of the buccal cavity and the swallowing and breathing areas and the mediastinum; which is why these processes require early treatment.

COMPLICATIONS IN THE ODONTOGENIC INFECTION

Odontogenic infections can spread towards adjacent areas or enter the bloodstream and cause systemic complications.

Direct spreading of these infections can originate maxillary sinusitis, intracraneal infections, maxillary osteomielitis, suppurative thrombophlebitis of the yugular vein, carotid erosion, etc depending on the anatomical area involved, being mediastinum infection the one that can eventually be fatal.

More specifically, maxillary osteomielitis can be consequence of an uncontrolled periapical infection, although there are several risk factors, fundamentally those arising from an immunocompromised state, which make patients prone to it.

In the event of mediastinitis or erosion of a carotid artery, a fatal outcome is to be expected, due to the fact that both complications compromise cerebral vascularization as well as the integrity of the airways. Odontological procedures are frequently associated to temporary bacteremia involving germs that can settle on the heart valves or on prothesis, originating endocarditis when these devices are infected. Basically any internal intervention can be associated to bacteriemia, including dental interventions, hence the recommendation of prophylaxis before certain odontological procedures in order to avoid complications through the spreading of the infection in the blood-stream. In fact, temporary bacteremia associated to chewing gum or simple tooth brushing have been reported although they usually have no clinical repercussion.

The standard profilaxis consists of 2 grs of amoxicillin, orally, 60 minutes before any of the above mentioned procedures is performed (11). When oral administration is not possible, it is recommended to inject 2 grs of amoxicillin i.m. in adults or i.v. 30 minutes before the procedure, whereas in patients with hypersensitivity to betalactam antimicrobials, clindamycin, clarithromycin or a cephalosporin such as cephalexin will be the alternative treatment.

If any of the following events occurs, the patient with odontogenic infection must be referred to hospital:

- trismus

- breathing difficulty

- phonatory of swallowing disorders

- compromise of deep anatomical spaces is suspected

- the patient's general status seems to be progressively compromised (high fever and discomfort)

- inadequate response to previous ambulatory treatment

ANTIBIOTIC PHARMACODYNAMICS

Pharmacokynetics is the part of pharmacodynamics that studies the absorption, distribution and elimination of drugs. Together with dosage, these factors determine how the drug concentration in serum and tissues varies with time and, therefore, the intensity and duration of the therapeutical effect. This is also a function of the agent's bioavailability, i.e. the amount of unaltered drug which reaches the systemic circulation after it is administered.

Antibiotic pharmacodynamics studies the relation between the plasmatic concentrations of an antibiotic and its antimicrobial activity against a particular microorganism. When studying and trying to predict antibiotic activity, plasmatic concentration vs time curves are normally used. These curves display the pharmacokinetics of the antibiotic, so that there is not antibiotic in the blood-stream at time "0", then the trace rises after administration until it reaches the maximum concentration plateau. At a certain point, the antibiotic starts being removed from the circulation and subsequently the curve falls until antibiotic levels are non detectable. The "Minimum Inhibitory Concentration" or MIC (12), determined in the microbiology laboratory through various methods, is usually displayed across the concentration-time curve. Thus, these curves may be used to establish to what degree and for how long the plasmatic levels of antibiotic are above the MIC, and produce an initial estimation of the efficiency of penicillins, cephalosporins, erithromicin, chlaritromicin and clindamycin. Two other extraodinarily important parameters used to predict some antibiotics performance are the "Area Under the Curve" and the "Time above MIC". (See Fig. 1, pag. 282)

If the concentration-time curve is notably above the MIC, and assuming a similar kinetic behaviour in the infected point, antibiotics can reasonably be expected to be effective against the pathogen.

Another farmacodynamics variable is the Cmax/MIC ratio. A Cmax/MIC ratio > 8 has been correlated with therapeutical success in treating infections caused by gramnegative bacteria with aminoglycosides and fluoroquinolones.

Once the antibiotic is cleared off the blood stream, the bacterial growth inhibitory effect can remain present over a certain period of time. This phenomenon, known as post-antibiotic effect or PAE (Post Antibiotic Effect), should not be mistaken with the effect produced by sub-inhibitory concentrations of the antimicrobial agent, because the PAE effect occurs afterwards.

The underlying mechanism of PAE is not well understood, is. The longer the microorganism is exposed to the antibiotic and the bigger the concentrations, the longer the PAE will last. Antibiotics with a prolonged PAE can be administered with broader gaps between doses.

The different pharmacodynamic variables related with clinical and anti-bacterial efficiency vary depending on the antibiotic. Considering these variables is important, when selecting the ideal antibiotic and dosage, to maximise erradication and minimise potential development of resistance. Some antibiotics exhibit sustained activity, and therefore, their blood concentration needs not be excessively above the MIC. Others have a characteristically long post-antibiotic effect, extendedly altering the bacterial structures and protein synthesis, so that the inhibitory effect lasts longer.

According to their activity and the duration of their therapeutic effect, antimicrobial agents are classified within two big groups: concentration-dependant and time-dependant.

-Concentration-dependant antimicrobial agents

This group is mainly integrated by aminoglycosides and fluoroquinolones, although ketolides, azithromicine and vancomycin are also included (13).

These antibiotics have a persistent post-antibiotic effect and their maximum bactericide activity is reached when serum concentration is 4 times the MIC.

Their therapeutic effect is maximised with high serum concentration peaks. These are obtained by means of a daily dose, which confers a level of performance comparable to the traditional dosage system but with less cost and toxicity. When treating with members of this group the aim is to achieve antibiotic concentrations at least 10 times as big as the MIC within the first 24 hours.

-Time-dependant antimicrobial agents

This second group contains mainly betalactam antibiotics (penicillins, cephalosporins), although macrolides (erythromicin, clarithromycin) and clindamycin also belong in it.

Their main feature is that serum concentrations are kept slightly above the MIC over the longest possible period. Concentrations 4-5 times higher than the MIC do not generally imply greater bactericide action. Therefore, these agents should be administered according to the farmacodynamic characteristics of the agent, both regarding dosage and posology (14).

Achieving therapeutic success requires prescribing a sustained dose or delayed release system which will guarantee that the antibiotic concentration will stay above the MIC of the pathogen over the interdose gap. If this is achieved for at least 40-50% of the interval between doses, the bactericide effect will be satisfactory, and consequently, pathogen erradication and symptom control will be accomplished.

PERIODONTAL DISEASE

The etiology of both periimplantitis and periodontal disease is of bacterial nature. Thus, the treatment options are the same as for odontogenic infections: odontological, pharmacological (antibiotic) and surgical.

Lodged bacteria generate distant immunopathogenic mechanisms which are associated with diabetes, coronary disease or underweight newborns, which is why an empirical antimicrobial therapy is established initially (15). Subsequent bacterial cultures will make it possible to find out if the administered antibiotic is appropriate and consequently make the appropriate therapeutical choices.

PHARMACOLOGICAL TREATMENT OF THE ODONTOGENIC INFECTION

Buccal samples for culture must be collected as soon as possible in order to find out the microbiological makeup of the infection and the exact identity of those germs. Consequently, the empirical antimicrobial treatment can be confirmed or rectified once it is known whether it is appropriate or not.

Nowadays, amoxicillin/clavulanic acid is the recommended antibiotic in orofacial infections on account of, among other factors, its bacterial spectrum and high degree of user-friendliness, specially against the genus Streptococcus.

As a general rule, the initial management of orofacial infections in adults, including odontogenic infections, involves the administration of 875 mg of amoxicillin maintaining 125 mg of clavulanic every 8 hours, which provides concentrations above the MIC for a longer time and gets a bigger area under the curve and a better patient healing profile, while the generation of resistant strains is kept to a minimum. Augmentine Plus (2000/125) administered every twelve hours, permits taking a smaller number of capsules per day, which improves compliance, as well as achieving more adequate antibiotic concentrations against the odontogenic pathogens. Recently, a study assessing the efficacy of amoxicillin/clavulanic acid 2000/125 mg for the profylaxis of infective complications after extraction of the third molar has been reported. Patients were randomised to receive 2000/125 mg of amoxicillin/clavulanic acid prior to surgery, treatment with 2000/125 mg of amoxicillin/clavulanic acid every 12 hours for 5 days after surgery or placebo. Treatment or profylaxis with 2000/125 mg of amoxicillin/clavulanic acid significantly decreased the rate of infective complications associated to extraction of the third molar compared to placebo (5.3% in the profylaxis arm, 2.7% in the treatment arm and 16% in the placebo arm; p > 0.007). Additionally, patients receiving the drug showed a quicker symptom relieve (p < 0.002) and less analgesic consumption (p < 0.003) (16).

Amoxicilline/clavulanic acid can be administered intravenously to patients with serious infections. In the event of hypersensitivity, the alternative choice would be clindamycin given with an aminoglycoside.

On special occasions, such as when treating pregnant women, the empiric treatment can consist of amoxicilline alone, and add clavulanic acid only when the antibiogram proves it necessary.

Other factors to be considered in the treatment

Further to what has been described so far in this article, it is necessary to take into account each patient's individual characteristics (age, size, weight, immunological status) and the infection location, as both these factors influence the antibiotic concentration.

Another important aspect to be considered is the pathogen's resistance mechanisms, regardless of whether they are being expressed or not, so that potential treatment failure can be anticipated.

Nowadays, there are additional matters of consideration such as the so called social functions. In other words, adverse reactions suffered by the patient and environmental impact should be minimised. As an example, it could be mentioned that quinolones are not transformed by patient's metabolism and therefore they are excreted unaltered. However, betalactam antibiotics are degraded and the resulting effect on the environment is smaller.

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