Complications After Lower Third Molar Surgery

Efficacy of the Application of Moxifloxacin and Cefixime in Reduction of Inflammatory Sequelae and Complications After Mandibular Third Molar Surgery

Surgical removal of impacted mandibular wisdom teeth is a frequent intervention, usually accompanied by unpleasant sequelae (pain, swelling and trismus) in the postoperative period, sometimes even with possibly serious complications (dry socket/alveolar osteitis and postoperative infection at the surgical site - SSI). It is therefore advisable to use various medications and procedures to prevent or alleviate the occurrence of these sequelae and complications. Accordingly, there is a debate in the literature on the expedience of perioperative (prophylactic) use of antibiotics. It is interesting that numerous articles recommending perioperative (prophylactic) antibiotic use to patients undergoing the impacted mandibular third molar surgery may be found, as well as those providing arguments for the disagreement with such an approach, considering that its benefits do not outweigh the risks of adverse side effects, especially due to growing resistance of microorganisms towards antibiotics, which is a possible serious threat to global health. Concerning the perioperative (prophylactic) use of antibiotics for this indication, consensus has not yet been reached, and neither of the views has been verified by convincing scientific evidence. Having the aforementioned dilemma in mind, the main endpoint of the study was to determine the validity of perioperative (prophylactic) use of antibiotics as to alleviate customary sequelae and possible complications after surgical removal of impacted mandibular third molars and, at the same time, the effectiveness of newer antibiotics (moxifloxacin and cefixime) when used for this purpose. Moreover, microbiological investigations of susceptibility of the isolated microorganisms to antibiotics used in this research were performed, which could verify the clinically obtained results. With this in mind, two major contributions, based on scientifically verified results, could be expected from the research: (1) confirmation or refuting the validity of perioperative (prophylactic) antibiotic use to control sequelae or complications that could follow the impacted mandibular third molar surgery; and (2) confirmation of the efficacy of fluoroquinolones (moxifloxacin) and cephalosporins (cefixime) in controlling odontogenic infections.

Clinical research was conducted at the Oral Surgery Department of the Dental Clinic of Vojvodina, Novi Sad, Serbia, adopting the double-blind prospective clinical study design. Microbiological studies were performed at the Center for Microbiology of the Institute of Public Health of Vojvodina, Novi Sad, Serbia, on swab samples obtained from the surgical wounds of patients with postoperative infection or the exudate (pus) obtained from the peri-coronal space of patients with pericoronitis or history of pericoronitis. The susceptibility of isolated microorganisms to moxifloxacin, cefixime and other antibiotics commonly used in oral & maxillofacial surgery (penicillin and its derivatives, erythromycin, azithromycin, clindamycin and tetracycline) was tested microbiologically. Patients ≥18 years, indicated for surgical removal of the impacted mandibular third molars, with good systemic health - patients classified as American Society of Anesthesiologists (ASA) classification of Physical Health is a grading system for preoperative health of the surgical patients - ASA I and ASA II were included in the study. Evaluation of the effects of the applied medication was performed on the basis of postoperative sequelae or complications. Complications, including dry socket/alveolar osteitis (AO) and postoperative infection at the surgical site (SSI), and inflammatory sequelae - pain, swelling and trismus (limited mouth opening), were evaluated postoperatively. In the case of pericoronitis or a history of pericoronitis, with the presence of exudate or pus, as well as in the case of postoperative infection, a swab was taken from the operative wound or pericoronary space, and the punctate of exudate or pus was sent for microbiological analysis. The main goal of this analysis was to establish the susceptibility of microorganisms not only to antibiotics used in this study, but also to antibiotics, which are the "gold standard" in the treatment of odontogenic infections, as well as other commonly used antibiotics in the treatment. Analyses were performed by standard bacteriological techniques (seeding the material on appropriate nutrient media and incubating them at 35-37 °C for 18-24 h) to isolate the bacteria. Identification of bacterial species was performed by classical bacteriological methods (morphological, cultural and physiological-biochemical), as well as by the automated system Matrix Assisted Laser Desorption Ionization - Time of Flight (MALDI-TOF), Germany. After identification, susceptibility testing of isolated bacterial species to antimicrobial drugs was performed by standard disk-diffusion method according to Kirby-Bauer, Mueller-Hinton agar and blood Mueller-Hinton agar (HiMedia, India), depending on which bacterial species was in question in line with European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Clinical & Laboratory Standards Institute (CLSI) Guidelines. Discs from Bio-Rad, France, were used to perform the microbiological analyses. All surgical interventions were performed under local anesthesia, using 2% lidocaine with adrenaline 1: 80,000 in a total 4 ml volume (2 ml solution for injection contained 40 mg lidocaine hydrochloride in the form of lidocaine hydrochloride monohydrate and 0.025 mg adrenaline in the form of adrenaline tartrate: Lidocaine 2% - adrenaline, 40 mg +0.025. In all patients, the surgery involved a triangular mucoperiosteal flap design, sutured using synthetic poly-filament non-resorptive suture material (3-0). Patients were advised to take an analgesic containing 200 mg ibuprofen and 325 mg acetaminophen. In accordance with known ethical principles and in accordance with the principles of Good Clinical Practice (GCP), care for the well-being of the patients was maximally respected, in accordance with the latest revision of the Declaration of Helsinki and accepted principles that apply to clinical trials on humans. The holder of the protection of the patients in this clinical trial was the principal researcher, who cooperated with the Ethics Committee of the Dental Clinic of Vojvodina, University of Novi Sad. The patients written Informed Consent implied that the patient had received full information about the research, and was stressed that they had the right to decide independently to participate, without coercion and external influences, or any harmful consequences if they refused to participate.

Postoperative Complications, Antibiotic Reaction, Antibiotic Side Effect, Antibiotic Resistant Infection, Antibiotic Resistant Strain, Infection, Bacterial, Infection, Laboratory

Molar, Third; Moxifloxacin; Cefixime; Placebo, Postoperative Complications; Antibiotic Prophylaxis, Drug Resistance; Microbial Sensitivity Tests

Patients were randomly and equally assigned to treatment groups. The study was planned as a double-blind. Thus, neither the patients nor the researchers knew whether the patients were prescribed antibiotics or placebo tablets, because the tablets were marked with a label that was in the formed codebook. All the film-coated tablets used were of the same appearance (both the antibiotics and the placebo). There was 157 participants, patients and the same oral surgeon.

Patients orally received film-coated tablets with either 400 mg of moxifloxacin. Film-coated tablets were administered for the first five days postoperatively, once a day, in a double-blind manner. All patients were evaluated at the postoperative follow-ups on the first, second and seventh postoperative day.

Patients orally received film-coated tablets with either 400 mg of cefixime. Film-coated tablets were administered for the first five days postoperatively, once a day, in a double-blind manner. All patients were evaluated at the postoperative follow-ups on the first, second and seventh postoperative day.

One third of patients received placebo-tablets containing indifferent substances with no antimicrobial action (99% microcrystalline cellulose, 0.5% silicon dioxide and 0.5% magnesium stearate, which were of the same colour and overall appearance as the used antibiotics. Film-coated tablets were administered for the first five days postoperatively, once a day, in a double-blind manner. All patients were evaluated at the postoperative follow-ups on the first, second and seventh postoperative day.

All used film-coated tablets (400 mg moxifloxacin) were administered for the first five days postoperatively, once a day, after the lower third molar surgery.

All used film-coated tablets (400 mg cefixime) were administered for the first five days postoperatively, once a day, after the lower third molar surgery.

All used film-coated placebo-tablets were administered for the first five days postoperatively, once a day, after the lower third molar surgery.

Signs of postoperative infection were registered clinically, based on the presence of local signs of inflammation and general signs of intoxication (elevated body temperature, accelerated erythrocyte sedimentation, leucocytosis, the level of C-reactive protein, etc. ).

The dry socket (alveolar osteitis) was diagnosed based on reported severe pain in the wound area, accompanied by specific local clinical appearance of the operative wound and absence of pus.

The postoperative pain was assessed using a visual analogue scale (VAS). VAS represents a horizontally drawn length of 100 mm, the beginning of which indicates a pain-free state on the left side, and the end on the right side the state of the strongest pain imaginable. All patients, by placing a dash on the scale, indicated the intensity of pain that, on the appropriate day in the postoperative period, they felt in its strongest intensity. The intensity of pain was determined by measuring the distance of the marked place on the scale from the beginning of the scale on the left side and expressed in millimeters.

The postoperative swelling (oedema) coefficient was obtained by measuring the preoperative and postoperative distance between specific reference points in millimetres. The reference points were: the outer corner of the eye and the angle of the lower jaw; lip corner and tragus; and chin tip and tragus.

The degree of postoperative trismus was assessed by measuring the distance between mesio-incisal angles of the upper and lower central incisors at the maximum mouth opening ability.

The postoperative pain was assessed using a verbal rating scale (VRS). VRS involves a numerical assessment of pain intensity based on six degrees (1-6) - no pain, barely sensitive pain, mild pain, moderate pain, severe pain and very strong, almost unbearable pain.

In each patient, the moment of postoperative pain, its intensity at the indicated observation times was registered, and the need for additional analgesics was registered (patients recorded the number of analgesics consumed daily from the completed surgical intervention to suture removal in the postoperative pain monitoring protocol).

Rate of antibiotic susceptibility and resistance of isolated microorganisms in vitro (microbiological assessment).

The sensitivity of isolated microorganisms to moxifloxacin, cefixime and other antibiotics commonly prescribed in oral and maxillofacial surgery was tested microbiologically. Regarding the susceptibility to antimicrobial drugs, bacteria were classified according to the growth inhibition zone, into three categories: susceptible (S), intermediate (I) and resistant (R).

During the study, any adverse event to drugs used in the clinical study will be recorded in accordance with the GCP.

Inclusion Criteria: patients ≥18 years, indicated for surgical removal of the impacted mandibular third molars, with good systemic health (patients classified as ASA I and ASA II) were included in the study. Exclusion Criteria: hypersensitivity to study drugs; history of systemic antibacterial therapy within 6 months prior to randomization; pregnancy or breastfeeding; fluoroquinolone-related tendon disorder; clinically relevant cardiac conditions or QT interval prolonging drugs; severe hepatic insufficiency (Child-Pugh C). Also, criteria for not including the patients in the study were cases where, in addition to removing the impacted mandibular third molar, some other oral surgical procedure was performed, as well as patients with currently present pericoronitis.

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