Comparison Between Two Different Antibiotic Regimens for the Placement of Dental Implants
Condition: Dental Implants
Study type: Interventional
Phase: Phase 1

Summary: 
      In order to prevent infections and complications, it has been initially established with the
      dental implant placement protocol that pre- and post-operative antibiotics should be
      prescribed to the patient receiving dental implants. There have been many antibiotic regimens
      used in the attempt to minimize the risks of infections and consequently, increasing the
      survival rate of dental implants placement procedures. However, issues about bacterial
      resistance have been raised recently concerning the extensive use of antibiotics. The primary
      objective of this study is to find out whether giving antibiotics before or after implant
      placement would significantly influence crestal bone loss around dental implants. One study
      group will receive one dosage of antibiotics before implant placement followed by
      post-operative intake of antibiotics for 7 days. Another group will receive the antibiotics
      in one single preoperative dose followed by an identical placebo for 7 days. Questionnaires
      for pain and interference with daily activities assessment to be filled for the first
      postoperative week will be distributed to participants. Signs of postoperative morbidity will
      be recorded at 1 and 3 weeks following the surgery, and both clinical and radiographic data
      will be collected at 4 months postoperative to assess the implants status. A radiographic
      follow-up will be done 1 year after the surgery. Peri-implant crevicular fluid levels of 3
      known immunological markers for bone loss (MMP-8, sRANKL and OPG) will be measured at 1-, 3-
      and 16-weeks follow-ups. The findings from this study might allow clinicians to establish the
      ideal antibiotic regimen with minimal risk exposure to bacterial resistance.
    

Detailed description: 
      Introduction

      After the discovery of penicillin as an antimicrobial agent in 1928, and later methicillin,
      an important improvement of the prognosis of antimicrobial therapies occurred. However, an
      increased trend in antibiotic resistance among community-acquired pathogens has been observed
      over the past two decades (1, 2). For example, over a short period of time, S. aureus
      developed resistance to the β-lactam compounds found in penicillin families, and by 2003,
      more than 50% of S. aureus isolates recovered in U.S. hospitals were methicillin-resistant
      Staphylococcus aureus (3). When a resistant bacterium is involved in any clinical infection,
      the prognosis of the antimicrobial treatment drops significantly and the patient affected
      might not always survive such infection. As health care professionals, it is important to
      minimize the exposure of our patients to antibiotics since the emergence of resistance in the
      oral microflora has started to become a threat in our modern society. This could be explained
      by the improper use of antibiotics, in terms of either dosage (duration of treatment too long
      or dose too weak) or indication (4, 5). To support this statement, three studies have shown
      that low dosage and/or long treatment duration increase the risk of carriage of
      antibiotic-resistant strains (6-8).

      The demand for dental implants has been increasing in the population due to their high
      success rate and significant improvements in the quality of life. On the other hand, the use
      of antibiotics is very common in the practice of oral implantology. In order to prevent
      infections, it has been initially established in the implant placement protocol that pre- and
      postoperative antibiotics should be prescribed to the patient receiving dental implants 9.
      There have been many antibiotic regimens used in the attempt to minimize the risks of
      infections and consequently, increasing the survival rate of dental implants. Initially, it
      was recommended to give antibiotics at least 1 hour before implant placement followed by
      daily doses for 10 days (9). Later on, a retrospective study demonstrated that there were no
      advantages in giving antibiotics 1 hour before implant placement and post-operatively for 10
      days regarding the implant survival rates (10). A multicenter retrospective study of 2,973
      implants showed a significant higher survival rate in patients who had received preoperative
      antibiotics (11). The subjects were followed up to 36 months after implant placement. In that
      study, 96% of cases received post-operative antibiotics and that decision to prescribe
      antibiotic coverage and the regimen to follow were left to the discretion of the surgeons.
      Another retrospective study found that there were no significant differences in failure rates
      between implants placed in patients receiving a 1-day single-dose administration of
      antibiotic and those placed in patients taking a 1-week post-operative regimen of antibiotics
      (12). The authors also stated that a single dose of antibiotics to prevent dental implant
      infections was efficient enough to prevent the risks of the emergence of
      antimicrobial-resistant bacterial strains. Two recent meta-analyses of 4 randomized clinical
      trials comparing implants placed in patients who received antibiotics pre- and/or
      post-operatively showed a statistically significant higher number of patients experiencing
      implant failures in the group not receiving any antibiotics (13, 14). To illustrate the
      controversy surrounding antibiotic prophylaxes for dental implant patients, a survey of
      private dental practices in UK found that there was a wide variation of antibiotic regimens:
      prophylactic, postoperative, and combination of both pre- and postoperative antibiotics (15).
      Consequently, in order to prevent the overuse of antibiotics and the potential emergence of
      drug resistant bacteria, it would be advisable to find an optimal protocol including an
      antibiotic therapy with a minimal duration while the implant survival rate would remain
      unchanged.

      Very few clinical trials have looked at the patient-based outcomes. Indeed, the patients'
      pain and discomfort experience has not been taken into account in most of dental implant
      clinical trials and little is known about its prevalence and intensity after surgery,
      especially with regard to different antibiotics regimens. Moreover, it was shown that
      individuals taking postoperative antibiotics exhibited less crestal bone loss 6 months after
      implant placement when compared to those who did not take any antibiotics postoperatively
      (16). However, no information is available on the effect of antibiotics on crestal bone loss
      with the newer design of implants exhibiting the platform switching concept. Crestal bone
      loss around dental implants was recently associated with higher peri-implant crevicular fluid
      (PICF) concentration of biomarkers (pg/μL) involved in the bone metabolism such as
      metalloproteinases (MMPs), and osteoprotegerin (OPG)(17, 18). The membrane bound and soluble
      RANKL (sRANKL) was found in significantly higher PICF levels in peri-implantitis sites
      compared to healthy sites (19). To our knowledge, no prospective study in oral implantology
      comparing two antibiotics regimens has looked at subject-based outcomes, clinical,
      radiographic and immunological outcomes simultaneously.

      Therefore, the aim of this prospective two-arm randomized clinical trial is to compare the
      crestal bone loss, the PICF concentration of three selected biomarkers for bone loss, pain
      experience and interference with daily activities, and the postoperative morbidity (swelling,
      bruising, wound dehiscence and suppuration) between 2 different antibiotics regimens in
      patients undergoing dental implant surgery.

      Hypothesis and Specific aims

      The study's null hypothesis is that there is no difference in crestal bone loss around
      implants between the 2 different antibiotics regimens.

      The primary objective of this study is:

        1. To find out whether giving pre- and/or postoperative antibiotics after implant placement
           would significantly change the crestal bone loss around implants.

           The secondary objectives are:

        2. To assess the patient's perception of the post-operative healing process for each
           antibiotic regimen.

        3. To assess the surgeon's perception of the post-operative healing process for each
           antibiotic regimen.

      Materials & Methods

      Study design Subjects in this randomized controlled clinical trial will be divided in two
      groups: one group will receive 2 g of amoxicillin 1 h prior the surgery and 500mg three times
      a day for 7 days; the second group will receive only 2 g of amoxicillin 1 h prior the surgery
      and an identical placebo three times a day for 7 days.

      Participants

      Fifty patients attending the undergraduate implantology clinic at the Faculté de Médecine
      Dentaire of the Université de Montréal will be invited to participate in this study (see
      Appendix II for detailed sequence of appointments). The following inclusion criteria for this
      study will be:

        -  Periodontally healthy remaining dentition or presenting with mild gingivitis with
           adequate oral hygiene.

        -  Presence of a partially edentulous alveolar ridge that is planned to be restored with no
           more than 2 implants.

        -  To have 1 or 2 implants restored with a crown or fixed bridge.

        -  Presence of a non-infected site.

        -  Presence of enough bone and soft tissue for the implant to be placed without additional
           bone augmentation in a 1-stage approach (with healing abutment).

        -  Implants 8mm long or longer.

        -  Subjects able and willing to provide written informed consent and comply with study
           procedures.

      The exclusion criteria will be the following:

        -  Subjects taking regular analgesics or antidepressants.

        -  Smoking 10 cigarettes/cigars or more per day.

        -  Drug abuse.

        -  Completely edentulous individuals.

        -  Pregnant and nursing women.

        -  Allergies to amoxicillin, cephalosporin, and/or non-steroidal anti-inflammatory
           analgesics.

        -  To have active peptic ulcers or to have a susceptibility to peptic ulcers.

        -  Any systemic or local immunodeficiency.

        -  Any blood coagulation impairment.

        -  Presence of uncontrolled periodontitis or poor oral hygiene.

        -  Presence of any acute oral infection.

        -  Presence of uncontrolled diabetes or other systemic diseases.

        -  Previous radiation therapy in the head and neck area.

        -  Intravenous bisphosphonates.

        -  Oral bisphosphonates intake for more than 3 years.

        -  Long-term intake of corticosteroids.

        -  Need for routine prophylactic antibiotics prior dental surgery.

      Prior to data collection, a consent form approved by the institutional review board of the
      Université de Montréal (Comité d'éthique de la recherché en santé) will be presented to
      participants during initial consultations. All study procedures will be undertaken with the
      understanding and written consent of each participant and according to ethical principles
      including the World Medical Association Declaration of Helsinki.

      Medical and socio-demographic data collection An investigator or a research assistant, who is
      not one of the surgeons, will approach and recruit individuals who had accepted a treatment
      plan for dental implant(s) to restore a partially edentulous jaw at the implant dentistry
      clinic of the Faculty of Dentistry (CRIP). Medical history, smoking habits (smokers,
      non-smokers), ethnicity, gender and age will be obtained through the medical questionnaire
      used at the Faculty of Dentistry and will be included in the statistical analysis.

      Clinical procedures and data collection

      Dental implant(s) (Osseospeed™ TX or Osseospeed™ TX Profile, Astra Tech Implant System™,
      Dentsply Implants, Mölndal, Sweden) will be placed in a one stage procedure, without
      simultaneous bone grafting, and will be inserted at the implantology clinic of the Université
      de Montréal - Faculty of Dentistry (CRIP) by one of three board-certified specialists and
      experienced implant surgeons (RD, RV, PB; minimum of 10 years of experience). All
      participants will be instructed to rinse with chlorhexidine gluconate 0.12% for 1 min. just
      before surgery and to take 1 hour before surgical appointment 2 g of amoxicillin. A third
      party will give an envelope to the patient containing the antibiotic to be taken
      postoperatively and the patient's study number so the surgeon will be unaware of the
      antibiotic regimen. Subjects will be randomly distributed to one of the two study groups:

        -  2 g amoxicillin taken 1 hour preoperatively then 500mg of identical placebo three times
           per day for 7 days;

        -  2 g amoxicillin taken 1 hour preoperatively then 500mg amoxicillin taken three times per
           day for 7 days.

      Subject's allocation will be done in blocks of 4 subjects by a computer-generated sequence
      and sealed in consecutively numbered opaque envelopes. The subjects will receive from a
      research assistant the envelopes containing either one of the antibiotics regimen with
      specific instructions on how to take the medication. The participants will have to take the
      antibiotics under the supervision of the research assistant. Additional measures of asepsis
      will include the use of sterile drapes around the patient's head and over the supine body of
      the patient. Screw-type, root-form, two-pieces rough surfaced dental implants will be placed
      using a standard surgical protocol, following the manufacturers' recommendations.
      Mucoperiosteal flaps will be used to access underlying alveolar bone for all implant
      surgeries. The healing abutment will be inserted instead of the cover screw, and soft tissues
      will be sutured with interrupted sutures (4-0 silk, Perma Sharp®, Hu-Friedy Mfg Co., Chicago,
      U.S.A.). A standardized radiograph will be taken perpendicular to the crestal bone to assess
      the baseline crestal bone level on the mesial and distal aspects of the implant using a bite
      registration material (Blu-Mousse®, Parkell Inc., Edgewood, U.S.A.) adapted to a paralleling
      device (XCP film holding system, Dentsply Rinn, Elgin, U.S.A.) for each participant. The
      customized bite registration will be kept for each patient in a cool room in a locked cabinet
      with the participant study identification number for the subsequent 4 months and 1-year
      radiographic evaluations. The duration of the surgery and length of the incision will be
      recorded by the surgeon. The participants will be asked to refrain from performing mechanical
      plaque control in the surgical area and be advised to remain on a soft diet during the first
      postoperative week. To minimize the influence of independent variables, they will be
      prescribed 600mg of ibuprofen to take every 4 hours for the first 48 hours with a maximum of
      4 tabs per day. They will also be prescribed an emergency analgesic (500mg acetaminophen) to
      take if needed and a 0.12% chlorhexidine gluconate rinse to use twice daily until the sutures
      are removed 1 week later. After receiving the standardized verbal and written post-operative
      instructions, participants will be given questionnaires to assess postoperative pain and
      interference with daily activities for the first postoperative week. The patient will be
      asked to keep a pain medication diary to keep track of the number of analgesics (ibuprofen
      and acetaminophen) taken for the first postoperative week. The patient will be asked to
      record his/her experience with the interference with their daily activities using a 10-cm VAS
      questionnaire with end points being "none" and "extremely much" (20) and will have to
      attribute a numerical value to his/her pain intensity experienced using the Numerical Rating
      Scale (NRS-11), with 0 representing "no pain" and 10 "intolerable". The patient's pain
      experience will also be assessed with the daily pain medication intake diary. Daily
      activities will include their ability to chew foods they want to eat, to open their mouth
      wide, talk, sleep, go to school or work, carry on a regular social life and participate in
      their favorite recreational activities. The subjects will be asked to bring back to the
      research assistant the pain and daily interference questionnaires as well as the envelope and
      drug containers to ensure their compliance with the prescriptions. At the end of the first
      postoperative control appointment, one of the two calibrated examiners unaware of the
      antibiotics regimen prescribed will be asked to fill a questionnaire to evaluate swelling,
      bruising, pus exudate and wound dehiscence as described elsewhere 20. Postoperative swelling
      will be graded as follows: 0 = No swelling, 1 = Mild swelling, 2 = Moderate swelling, 3 =
      Severe swelling. Postoperative bruising, suppuration and wound dehiscence will be evaluated
      using Boolean variables: 0 = None; 1 = Present. The examiner will measure the modified plaque
      index (PI) (21) at four sites per implant (mesial, distal, buccal, lingual). The PI is graded
      as follows: 0 = no detection of plaque, 1 = Plaque only detected by running a probe
      (PCP-UNC15; Hu-Friedy Mfg Co., Chicago, U.S.A.) along the smooth surface of the healing
      abutment, 2 = Plaque can be seen by the naked eye, 3 = Abundance of soft matter. The PI will
      be also measured at the 3-weeks and 16-weeks examinations. He will then collect PICF samples
      to detect the presence of MMP-8, sRANKL and OPG from the mesial surface of each implant at
      this first postoperative appointment and also at the 3-weeks and 16-weeks examinations.
      Briefly, supragingival plaque if present, will be removed gently with a gauze. The sampling
      site will be isolated with cotton rolls and carefully dried. A filter strip (PerioPaper,
      Oraflow Inc., Smithtown, NY, U.S.A.) will be placed 30 s in the peri-implant sulcus. The
      collected samples will be immediately transferred into sterile 1 ml tubes containing 100 μl
      phosphate buffered saline, centrifuged for 10 min, and stored at - 80 °C for further
      analysis. At the laboratory, the enzyme-linked immunosorbent assay (ELISA) will be used to
      assess PICF levels of MMP-8 (Quantikine-Human Total MMP-8 Immunoassay, R&D Systems Inc.,
      Minneapolis, U.S.A), and sRANKL and OPG (Biomedica, Gruppe, Vienna). At the 3-weeks
      appointment, postoperative swelling, bruising, suppuration and wound dehiscence will be
      evaluated as well as the modified PI. PICF samples will be also collected. At the 16-weeks
      evaluation, the implants will be re-assessed both clinically and radiographically to confirm
      osseointegration and the modified PI and PICF samples will be collected again. This
      appointment will coincide with the impression for restoration of the implant. The same
      calibrated examiner unaware of the antibiotics regimen taken will verify if the implants are
      osseointegrated by taking a standardized periapical radiograph to verify the presence or
      absence of infection and evaluate crestal bone loss using the standardized bite registration
      and paralleling device. The examiner will also assess implant mobility using the handles of
      two blunt dental instruments (22) (osseointegration = immobile, failure = mobile) and the
      presence or absence of any symptom related to infection (suppuration), inflammation
      (erythema, bleeding on probing) or neuropathy (paresthesia, dysesthesia, anesthesia) (23).
      Four months and one year after the implant placement, a standardized radiograph will be taken
      to measure crestal bone loss. Subtraction radiographic analysis will be done using a software
      (Image J, National Institutes of Health, Bethesda, U.S.A.) to measure mean mesial and distal
      bone loss around the implants by one investigator who is unaware of the antibiotic regimen
      taken by the participants.

      Ethical issues

      To make sure patients at the implantology clinic do not feel obligated to participate to this
      study, a research assistant will give to potential participants written information about the
      ongoing study at our clinic ("Feuille d'information et de recrutement"). The patients will be
      told they can read that information while they are waiting on the dental chair for their
      treatments to be finished or at home and let know their dental care provider their decision
      once they are sure they are willing to participate. The provider will then notify the
      research assistant of the patient's interest in participating in the study if it is indeed
      the case. At that time, the information and consent form will be presented to the patient who
      is interested in participating in the study.

      Since the dental record number of each participant will be written on the questionnaires for
      identification purposes, a third party (research assistant) will remove the dental record
      number and replace it with a study code prior to data analysis. The third party will then
      place the questionnaires in a folder containing only the study number of each participant.
      The folders containing the research data will be kept in the locked office of the principal
      investigator at the Université de Montréal. The principal investigator will ensure during the
      entire process of data collection that the research team follows the rules of ethics and that
      only members of the research team will have access to the room where the data is kept. Only
      the third party will have possession of the sheet where dental record numbers are matched
      with study codes.

      Sample size calculation

      Assuming that the difference in crestal bone loss between the study groups would be 0.5 mm
      with a standard deviation of 0.5mm, the sample size of 17 participants in each group would
      provide a power of 80% to reject the null hypothesis of absence of between-group differences
      if it is indeed false, at an alpha level of 5%. This difference of 0.5 mm is generally
      considered to be clinically significant (24).

      Outcome measures

      The primary outcome measures will be crestal bone loss at the mesial and distal aspects of
      each implant. The secondary outcomes will be the presence or absence of peri-implant
      radiolucency, patient's pain experience (intensity (VAS) and number of analgesics taken),
      surgeon's perception of healing (intensity of swelling and presence/absence of bruising, pus
      exudate and wound dehiscence), PICF levels of MMP-8, sRANKL, and OPG, modified PI, presence
      or absence of implant mobility, presence or absence of pain, infection, neuropathies, and pus
      exudate.

      Statistical analyses

      Two trained and calibrated examiners will perform all clinical measurements and take the
      radiographs. An intra- and inter-reliability study will be done to compare with a gold
      standard examiner. One calibrated examiner with extensive experience will perform the
      radiographic analysis. Cohen's kappa, intraclass correlation coefficient and Bland and Altman
      graphs will be used to evaluate reliability. Normality of data distribution will be assessed
      using the Shapiro-Wilk test. Normalization will be used in case of non-normal distribution.
      Crestal bone loss, PICF levels and patient's pain perception (VAS) will be analyzed with
      repeated measures ANOVA, with time as a repeated measure (7 days) and groups as a between
      group measure. Groups will be compared regarding postoperative swelling with Kruskall-Wallis
      one-way ANOVA and Mann-Whitney U test. Groups will be compared regarding implant survival at
      4 months, bruising, suppuration, wound dehiscence, mobility, presence of pus exudate,
      presence of peri-implant radiolucency on the radiographs, and presence of persistent
      signs/symptoms with the Fisher's exact test. Analyses will be conducted in conformity of the
      intention to treat principles.

      Relevance of results

      To our knowledge, this will be the first prospective randomized controlled clinical trial to
      compare the crestal bone loss between two different antibiotic regimens including
      simultaneously patient-based outcomes, clinical, immunological and radiographic measures. The
      results from this study might allow dentists and oral surgeons to establish an optimal
      antibiotic regimen and to minimize patient exposure to potential stimulation of bacterial
      resistance by reducing antibiotic intake.
    

Intervention name(s): Amoxicillin
Intervention type(s): Drug
Intervention MeSH terms: Amoxicillin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: dental implants; wound healing; amoxicillin; pain