Antibiotics in Dentoalveolar Surgery, a Closer Look at Infection, Alveolar Osteitis and Adverse Drug Reaction

Simra Azher, BBiomed, DDS,* and Amish Patel, BDS, MBBS, MFDS(Eng)y

ABSTRACT

Purpose: To execute an evidence-based review answering the following questions: “What antibiotic type and mode of delivery are most effective at reducing inflammatory complications in third molar and dental implant surgery? What are the types and rates of antibiotic-related adverse reactions in the context of third molar surgery, infective endocarditis, medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN)?”
Material and Methods: We performed a comprehensive literature review of peer-reviewed studies using MEDLINE/PubMed, Cochrane, Scopus/Elsevier, Google Scholar, and Wiley online library databases.
Results: Twenty-five studies were reviewed for third molar surgery. Although there is some evidence that systemic antibiotics reduce inflammatory complications (infection and alveolar osteitis), routine use is not recommended for third molar surgery. For at-risk cases, a single preoperative dose of amoxicillin is preferred. Clindamycin, amoxicillin-clavulanic acid and erythromycin have a high adverse risk profile. Eight studies were reviewed for dental implant surgery. Antibiotics with dental implant placement showed little reduction in post surgery infection and minimal improvement in long-term success. A comprehensive search found limited data on antibiotic-related adverse effects in the context of infective endocarditis, MRONJ and ORN.
Conclusions: A set of clinical recommendations are presented to better guide evidence-based and standardized antibiotic usage on the basis of the literature discussed in this review. This review highlights the need for further research focusing on antibiotic type and timing of delivery with adverse drug reaction as a primary outcome measure when assessing treatment outcomes and complications in dentoalveolar surgery. This will better elucidate the risks vs benefits of antibiotic in dentoalveolar surgery.

Antibiotics are used in dental practice prophylactically or therapeutically. Prophylactic use prevents pathogen entry into the body, especially in patients with medical conditions increasing susceptibility to pathogenic infections. In contrast, antibiotic therapy is for the treatment of already established infection.1 Prescriptions for dental infection accounts for 10% of all antibiotic prescription.2 Wound infection postthird molar extraction has been reported to range between 0 to 27%.3 Postoperative infection is higher in the mandible and related to the depth of impaction, intraoperative hemostatic treatment, and simultaneous bilateral removal.4 Parameters used to assess for postoperative infection include pain, purulent discharge, trismus, swelling, temperature, C-reactive protein levels (indicate tissue damage) and salivary neutrophil counts.5
Alveolar osteitis is another common complication typically occurring 3 to 7 days postextraction due to premature blood clot loss with alveolar bone exposure.6 Pain, foul taste, halitosis, activity reduction, and additional return visits are common presentations. The reported incidence is from 2.3 to 19.14%.7-Proposed risk factors include smoking, oral contraceptives, menstruation cycle, surgery length, surgeon experience, surgical trauma, inappropriate intraoperative irrigation, and cartridge number needed for anesthesia.7,8,10 It is debated whether antibiotics reduce alveolar osteitis risk.9
Furthermore, antibiotics have been suggested to reduce dental implant failure, infective endocarditis, medication-related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis (ORN). However, this is controversial due to limited data. Moreover, the ideal method of delivery as a single preoperative dose or postoperative course is also debated. Other considerations with antibiotic use are microbial resistance emergence, toxicity, secondary infection and allergic reactions 6 to 7% of patients.3,11
Amoxicillin is the most frequently used antibiotic due to its pharmacologic properties and broad coverage of oral bacteria.12 Its adverse reactions include skin reactions (rashes) in 87% of cases, gastrointestinal effects (nausea, diarrhea, vomiting, cramps, and stomach pain) in 7% and hematologic complications (leukopenia, thrombocytopenia, liver reactions, and drug-induced fevers) in 1%.13 Anaphylaxis is a severe life-threatening hypersensitivity potentially associated with antibiotics. Augmentin (amoxicillin plus clavulanic acid) is another antimicrobial used in dental practice. Its adverse effects include diarrhea, nausea, candidiasis and hypersensitivity reactions. Pseudomembranous colitis is a key adverse outcome of clindamycin with an incidence of 2 to 10%.
Metronidazole has been implicated in seizures, taste disturbances, anesthesia or paresthesia of the limbs and is incompatible with alcohol ingestion causing nausea, severe stomach cramps, vomiting, flushing, and headaches.2 Furthermore, aminoglycosides and tetracyclines antibiotics are contraindicated in pregnancy as Category D with teratogenic risks. Patients with reduced kidney and liver function may also require adjusted dosing due to toxicity susceptible from inefficient antibiotic metabolism and excretion.2 Overall, amoxicillin has the highest safety level with the lowest adverse reactions. Clindamycin has the highest risk profile.14 Probiotics, especially those containing Lactobacilli strains have shown to reduce incidence rates of antibiotic-associated and Clostridium difficile-associated diarrhea.15
This literature review aims to discuss current research on the effects of antibiotic treatment on infection, alveolar osteitis, and adverse reaction rates in the context of surgical third extraction, dental implants, infective endocarditis, MRONJ, and ORN. The impact of antibiotic type and mode of delivery, preoperative, postoperative, and combined pre- and postoperative, will also be discussed.

SURGICAL EXTRACTIONS AND ANTIBIOTICS – INFECTION, ALVEOLAR OSTEITIS, AND ADVERSE DRUG REACTION

Published data is conflicting on antibiotic-related reduction in infection and alveolar osteitis rates and occurrence of adverse reactions. A large-scale systemic review found antibiotics reduce infection risk by 70% and alveolar osteitis by 38% in patients undergoing third molar extraction. Mild and transient adverse reactions were found for every 21 people treated.16 Furthermore, it has been suggested that regardless of type, frequency, dose or delivery pattern, any antibiotic can reduce the risk of inflammatory complications after third molar removal.17 However, due to the adverse profile variability among different types, this efficacy needs reviewing on an individual antibiotic level.

ANTIBIOTIC TYPES

AMOXICILLIN

A systematic review and meta-analysis found no statistically significant reduction in infection rates or increased risk of adverse reactions with amoxicillin given preoperatively or postoperatively in healthy individuals undergoing third molar extraction.12 These findings are supported by other studies where preoperative amoxicillin was not beneficial in improving soft-tissue edema, pain, mouth opening, presence of purulent secretion and alveolitis (Table 1).3,7,18-40 In contrast, Monaco et al20 found significantly lower wound infection rates, pain, swelling, fever, and analgesic consumption with preoperative amoxicillin. Comparison of preoperative amoxicillin against metronidazole,21 and postoperative amoxicillin against clindamycin,22 yielded no significant difference in surgical site infections. Adverse effects associated with these antibiotics were not assessed. Moreover, due to limited sample sizes and conflicting results in the discussed studies (Table 1), amoxicillin prescription is not indicated in all clinical conditions. Its use should be evaluated on the basis of patient systemic health, operator skill, and surgical environment contamination.22

AMOXICILLIN-CLAVULANIC ACID

Overall, amoxicillin-clavulanic acid may be effective in reducing postoperative infection after third molar surgery, however, the data is conflicting. There is also limited data on its effect on alveolar osteitis rates (Table 1). Collectively, routine oral antibiotic prophylaxis in third molar surgery is not recommended and if antibiotics are required then a single preoperative dose of amoxicillin-clavulanic acid is advised rather than extended postoperative therapy.23,24 The risk of adverse effects is significantly higher with amoxicillin-clavulanic acid, especially diarrhea with prolonged postoperative intake.25 Other studies comparing amoxicillin-clavulanic acid with metronidazole and azithromycin found none to be significantly better than the other in preventing infections after third molar surgery.41 These therapies may be used for prophylaxis when amoxicillin and clindamycin are unavailable.

CLINDAMYCIN

The effect of clindamycin on third molar inflammatory complications have not been researched extensively in existing literature, despite being commonly used as an alternative in penicillin-allergic patients. Earlier studies report a reduction from 15-31% to 0.65% in alveolar osteitis rates with clindamycin use after surgical third molar removal.42 However, recent evidence highlights minimal benefits of preoperative or postoperative clindamycin in reducing trismus, facial swelling, lymphadenopathy, subjective pain at 1st and 2nd-day postsurgery or alveolar osteitis.26 Moreover, 3% of the patients were excluded from the trial due to stomach pain and diarrhea with extended clindamycin administration (Table 1).26 Recent evidence also implicates clindamycin with a higher adverse-effect profile than amoxicillin;14 however, not significantly different from amoxicillin-clavulanic acid.27

METRONIDAZOLE

Similarly, routine use of metronidazole in healthy third molar surgery patients is not recommended. Recently published data found 40 patients require treatment to prevent 1 case of surgical site infection, 20 patients to prevent 1 alveolar osteitis and a higher adverse reaction incidence with extended use.11 These results have been corroborated by other studies on metronidazole (Table 1).28-30 This is despite earlier studies reporting a reduction in alveolar osteitis rates from 4.2 to 1% with metronidazole use postoperatively due to its anaerobic coverage.7

TETRACYCLINE

The effect of tetracycline on alveolar osteitis rates has been a subject of debate. Intraalveolar tetracycline medicament in the form of oxytetracyclineimpregnated drain decreased alveolar osteitis incidence after third molar surgery.43 Similarly, intrasocket tetracycline powder placement immediately after extraction also reduced alveolar osteitis incidence from 28.7 to 14.6%.44 However, in another study, intraalveolar tetracycline placement postsurgically did not affect the incidence of dry socket.45 Hence, although an emerging area of interest, it is not considered routine practice to use intra-socket antibiotic products for reducing inflammatory complications.

Timing of Antibiotic Delivery

If a surgeon chooses to utilize antibiotics in the context of third molar surgery, then a single preoperative antibiotic dose is preferred. The single preoperative dosage has shown similar or improved impacts on infection, alveolar osteitis, and clinically recovery compared with 3-5-day postoperative and combined preoperative with 3-5- day postoperative therapy (Table 1). Single preoperative dosage also averts issues with patient compliance, reduces financial cost, and risk of bacterial resistance development associated with extended therapy.31 Prolonged therapy, especially with combined preoperative and postoperative administration, seems to be associated with a greater risk of adverse side effects such as diarrhea, nausea, vomiting, and stomach pain.24-26,32 Furthermore, a controlled aseptic chain has been recommended instead of extended antibiotic use.46 Nevertheless, it is important to highlight that evidence to the contrary exists. Lopez-Cedrun et al33 found amoxicillin administration before or after the procedure achieved lower wound infection, swelling, pain, temperature, trismus, and dysphagia.33 The postoperative protocol achieved the best results with lower side effects. Due to these discrepancies, evaluation of the effectiveness of antibiotic administration in third molar surgery with further randomized clinical trials and larger sample sizes is warranted.

DENTAL IMPLANTS AND ANTIBIOTICS − ADVERSE DRUG REACTION

The use of antibiotics to promote the success of dental implant treatment is a controversial practice. A success rate of 92% has been shown with no antibiotic use, 96% with preoperative, 97% with postoperative and 96% with combined pre- and postoperative antibiotics. Hence, there is no significant increase in implant success rates with antibiotics (Table 2).47,48-Similar findings have also been reported in a systematic review by Braun et al56 where a single preoperative 1 g amoxicillin dose or extended postoperative use showed no significant difference in pain, purulence, swelling, and wound dehiscence or side effects.56 Although most studies report no significant adverse effects findings (Table 2), Arduino et al48 report higher adverse events with postoperative use, suggesting extended antibiotic use should be avoided.48 Furthermore, postoperative amoxicillin therapy has been implicated in altering the early bacterial colonization of the peri-implant sulcus. Resistant anaerobes are increased and sensitive facultative bacteria and facultative gram-positive cocci are decreased.57 Furthermore, some studies suggest that antibiotics may improve short term implant survival by lowering mobility, peri-implant transparencies, lack of osseointegration and reduce daily activity interference due to pain. However, they do not reduce postoperative infection.49,58-60 Hence, existing research negates the use of antibiotics for dental implants as there is little supportive evidence for an increase in long term implant success or reduction in postoperative infection.

OTHER CONTEXTS FOR ANTIBIOTIC USE – ADVERSE DRUG REACTION

Infective Endocarditis

Infective endocarditis is an infection of the heart valves or endocardium lining of the heart chambers typically due to oral streptococci. Restricted prophylaxis for invasive dental procedures is recommended for at-risk patients.61 This is due to evidence showing amoxicillin efficacy in preventing bacteremia after dental procedures.61 However, this has not been proven for other antibiotics and transient bacteremia also occurs with tooth brushing in patients with poor oral hygiene.61
Hence, it is hotly debated whether antibiotic prophylaxis can prevent bacterial endocarditis as its absolute risk is 1 of 14,000,000 and occurrence is rare. Antibiotics provide a 49% protective efficacy for firstever endocarditis occurring in only 13% of patients with a predisposing heart lesion.62 Hence, suggesting little benefit from prophylaxis in decreasing the total endocarditis burden within the community. Furthermore, anaphylactic allergic reactions to prophylactic amoxicillin63,64 and pseudomembranous colitis after clindamycin use before dental treatment have been reported.65 In another study, almost half of the 60 patients receiving prophylactic erythromycin to reduce bacteremia with dental treatment had adverse gastrointestinal side effects such as nausea, diarrhea, and stomach pains, as well as headaches.66

Medication Related Osteonecrosis of Jaw

MRONJ is a complication localized exclusively to the jaws. Its postulated pathogenesis is altered bone remodeling, angiogenesis inhibition, microtrauma, innate or acquired immunity suppression, inflammation, and infection. Although local tissue infection is not considered its primary etiology, bacterial colonization of the exposed bone is a common occurrence. Patients with established MRONJ may have infectionassociated exposed bone, fracture, fistula or osteolysis. The objective for established MRONJ is to control infection, minimize necrosis, and support tissue healing.67,68
Some studies have shown antibiotic therapy to be beneficial in controlling infection in established MRONJ cases with penicillin, metronidazole, quinolones, clindamycin, erythromycin, and doxycycline being used successfully.67-69 However, Bermudez- Bejarano et al1 highlight the controversy associated with antibiotic therapy as conservative management for MRONJ due to a lack of clinical trials. Moreover, adverse effects from antibiotics used for MRONJ prevention and treatment have not been reported in the existing literature, making it difficult to assess the risk/benefit ratio.1,67,69-72

Osteoradionecrosis

Another context for antibiotic use in dentoalveolar surgery is ORN of the jaw after radiation therapy first reported by Regaud in 1922.73 The currently accepted pathophysiology is Delanian’s fibro-atrophic theory where fibroblast dysregulation results in inadequate healing response leading to fibrous atrophy and tissue breakdown with minimal mechanicaltrauma.73,74 The outcome is bone exposure with pain and fistulation.73 Despite infection not being its primary etiology, antibiotics are often used prophylactically before dental extractions in an attempt to lower ORN rates.75
Prophylactic antibiotics are further debated as they only lower ORN incidence by 6% and are insufficient for prevention of delayed healing complications.76-78 A retrospective study of 830 head and neck tumor patients found only 40% of patients with established ORN could be completely healed through surgery and antibiotic medication.79 Hence, antibiotics use in ORN cases is controversial as little benefit has been shown in the existing literature.80
Furthermore, in the United Kingdom (UK), prophylactic antibiotic use for ORN at-risk patients is not standardized, being recommended by 16% of dentists and 81% of maxillofacial units.81 This highlights a lack of consensus in clinical practice. There is also little data on the adverse effects of such antibiotic use,78- found no adverse reaction although it was still not the primary outcome measured.75
In conclusion, there is a lack of standardization of antibiotic prescribing practices among dentists and surgeons. Often postoperative antibiotics are given when preoperative antibiotics are indicated potentially due to timing, logistics or lack of clinical knowledge regarding dental guidelines.84 Interestingly, the use of prophylactic antibiotics for third molar removal under local anaesthesia is not routine practice. However, preoperative intravenous antibiotic use is common when the same procedure is conducted under general anaesthesia. We have proposed the after recommendations on the basis of the evidence discussed in this review to better inform standardised practice:
• Routine use of antibiotics is not recommended and should be considered for at-risk cases only such as impaired systemic health, operative difficulty, and surgical field contamination. Otherwise, an aseptic chain is preferred to minimize overall antibiotic use.
• Amoxicillin is the antibiotic of choice for dentoalveolar surgery due to its broad oral bacteria coverage and safer adverse risk profile.
• Clindamycin and amoxicillin-clavulanic acid have higher gastrointestinal adverse risk profiles compared with amoxicillin. Concurrent, Lactobacilli probiotic use may be considered to reduce diarrhoeal complications.
• Amoxicillin-clavulanic acid, metronidazole, and azithromycin may be used as alternatives when amoxicillin and clindamycin are unavailable. Erythromycin should be used with caution due to higher reported adverse reaction rates. There is some evidence that systemic antibiotics reduce inflammatory complications with third molar surgery. Use should not be routine and limited to at-risk cases with a single preoperative dose being the preferred mode of delivery over extended multi-day therapy. Patients should be warned regarding mild/transient gastrointestinal upset.
• Intra-socket antibiotic products for the reduction of inflammatory complications; including alveolar osteitis are not recommended.
• Antibiotics are not recommended with dental implant placement due to little evidence for the reduction of postoperative infection and increase of long-term success.
• A limitation in the literature that has been highlighted by this review is the low number of existing third molar studies assessing adverse reactions and insufficient sample sizes. A large-scale clinical trial assessing infection, alveolar osteitis, and adverseeffect rates collectively as primary outcomes in third molar removal with different antibiotic types is warranted.
The use of antibiotics to prevent MRONJ, ORN, and infective endocarditis is controversial due to minimal clinical trials. Including antibiotic-related adverse reaction as a primary outcome measure in future research on these topics will help to clarify the debate. Future studies assessing antibiotic use in dentoalveolar surgery must incorporate adverse drug reactions as a primary outcome measure, detail antibiotic type utilized and timing of delivery when assessing the impact on inflammatory complications. This will better inform the risk vs benefit ratio of antibiotic use in dentoalveolar surgery and further guide standardization of prescription practices.

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