Odontogenic infections are one of the most prevalent diseases worldwide and the principal reason for seeking dental care. Dental prescriptions account for nearly 7% to 11% of all common antibiotic prescriptions [
Odontogenic infections are mostly polymicrobial and frequently encountered odontopathogens are
Recently, published evidence suggests that penicillin and amoxicillin are being rendered increasingly less effective because of beta-lactamase producing bacteria. More than half of the Gram-negative anaerobic bacilli (including
Clindamycin is a broad-spectrum antibiotic with activity against aerobic, anaerobic bacteria including coverage against beta-lactamase producing pathogens [
Despite published evidence evaluating different oral formulations of amoxicillin/clavulanic acid in dental infections, there is limited published data on the use of twice daily dosing of 875/125 mg in odontogenic infections. Available evidence suggests that twice daily dosing with 875/125 mg amoxicillin/clavulanic acid results in a successful clinical outcome, better patient compliance, and less gastrointestinal upset, due to a reduction in the dose of clavulanic acid [
AUG117044 was a phase IV, randomised, parallel group, comparative, observer blind study to evaluate efficacy, safety, and tolerability of amoxicillin/clavulanic acid (875 mg/125 mg) and clindamycin (150 mg) in the treatment of acute odontogenic infection with or without abscess. The study was conducted in fifteen centres across four countries with four centres each in Malaysia, Philippines, and Vietnam and three in Thailand.
The study protocol, the informed consent, and other information that required preapproval were reviewed and approved by a national, regional, or investigational centre ethics committee or institutional review board, in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The study was conducted in accordance with ICH GCP and all applicable subject privacy requirements and the ethical principles that are outlined in the Declaration of Helsinki 2008.
A total of 472 subjects were randomised in a 1 : 1 ratio in each of the treatment arms. The study included a one-day screening period followed by a treatment period of five days that could be extended to seven days based on clinical response. Standard surgical intervention for odontogenic infection was permitted only before commencing study treatment. Eligible subjects were randomized on the day of their screening visit or within a day of screening. Efficacy and safety evaluations were performed on Day 2, Day 5, and/or Day 7 (based on treatment duration) (Figure
Study schema. Note: the study had a 1-day screening period (Day 1 to Day 0) during which eligibility was assessed and laboratory tests were performed. Randomisation occurred within 24 hours of screening at baseline (Day 0). Further visits (Day 2, Day 5, and Day 7) were calculated from the baseline/randomisation visit (Day 0).
Inclusion criteria: the study enrolled subjects ≥18 years of age with a diagnosis of acute odontogenic infections (periapical abscess, acute periodontitis, and pericoronitis) that required antibiotic therapy. Radiographic evidence of odontogenic infection and dental pain on mastication were mandatory diagnostic criteria for enrollment. Exclusion criteria: subjects presenting with complicated odontogenic infections (such as osteomyelitis, dentocutaneous and dentoalveolar fistula, and facial-space swelling) or odontogenic infections secondary to traumatic injury or requiring hospitalisation, aggressive intravenous antimicrobial therapy, or local application of antimicrobials for the treatment of odontogenic infection were excluded. Further, patients with other key exclusion criteria such as conditions prone to infective endocarditis and those treated with systemic antibiotics within two weeks before the study of drug administration or injectable long acting antibiotics administered four weeks prior to study of drug administration were also excluded from study.
The primary objective of the study was the comparison of clinical efficacy of amoxicillin/clavulanic acid with clindamycin in subjects with acute odontogenic infection with or without abscess. This efficacy endpoint was based on the percentage of subjects achieving clinical success (cure or improvement) at the end of treatment (Day 5 or 7). The secondary endpoints of the study included percentage of subjects achieving clinical success at Day 5 and change in the VAS score for pain and swelling from baseline to Days 2, 5, and 7. Safety assessments included monitoring of adverse events (AEs) and serious adverse events (SAEs) from the start of study treatment until the end of study treatment. The antibiotic susceptibility of bacterial isolates obtained from pus specimens was recorded at baseline.
A sample size of 205 evaluable subjects in each of the treatment arms provided 90% power to assess noninferiority for the primary endpoint. This was based on a noninferiority margin of 10%, assuming clinical success response rate in the comparator arm (clindamycin 150 mg) of 90% and a one-sided
The per-protocol (PP) population was a subset of Intent-to-Treat (ITT) population that had a postbaseline clinical success response assessment and did not report major protocol deviation(s). However, those subjects who discontinued from the study without any postbaseline assessment and where the reason for discontinuation was documented as “Lack of Efficacy” or “Treatment Failure” were included in the PP population with clinical success outcome treated as “Clinical Failure.” For noninferiority analysis, the PP population using observed case (OC) method was treated as the primary dataset. The assessment of noninferiority for clinical success response was based on two-sided 95% confidence interval (CI); the upper limit of two-sided 95% CI of the difference of proportion between the two treatments of less than 0.10 (10%) was set to conclude the noninferiority between the treatment arms. The analysis of the Intent-to-Treat-Efficacy (ITT-E) population (all randomised subjects with at least one postbaseline assessment of clinical success response) using the OC dataset was provided as a sensitivity analysis for the primary endpoint and was also used to evaluate secondary endpoints. The ITT population (all randomised subjects who received at least one dose of study medication) was the safety dataset for the study.
The investigator’s judgment was considered decisive for the assessment of clinical improvement in a subject. In the event that the main signs and symptoms were cured or improved (complete resolution of fever and >70% reduction in swelling and pain) and there was “no change” or “worsening from baseline” in other signs and symptoms (such as increased leucocyte count/tooth mobility/lymphadenopathy), the investigator’s opinion was sought as to whether additional antimicrobial therapy was required. Subjects that required no additional antimicrobial therapy per the investigators judgment were considered a “success” while those requiring additional antimicrobials were deemed as “failures.” The analysis based on the investigator’s judgment of clinical success or failure was considered as the primary analysis for testing of noninferiority between the treatment groups and the analysis excluding the investigator’s assessment for clinical success was presented as supportive analysis.
For sensitivity analysis, all subjects with an assessment of cure or improvement (complete resolution of fever, >70% reduction in swelling and pain) but with “no change” or “worsening from baseline” in other signs and symptoms (increased leucocyte count/tooth mobility/lymphadenopathy) were considered as “Clinical Failures” irrespective of the clinical judgment of investigator.
Clinical laboratory assessments were summarized on ITT population using OC approach for missing values. Liver function tests (LFTs) values were summarised after values were normalised. Any LFT parameter which was out of reference range for that particular laboratory was considered an adverse event (AE). However, AST, ALT, and alkaline phosphatase values >3 × upper limit of reference range (ULRR) and total bilirubin >1.5 × ULRR were considered to be of potential clinical concern (PCC) as defined by sponsor.
A total of 510 subjects were screened for a planned enrollment of 472 subjects. Amongst the 472 randomised subjects, 235 (46.1%) subjects were randomised to the amoxicillin/clavulanic acid arm and 237 (46.5%) to the clindamycin arm. However, a total of 236 subjects received amoxicillin/clavulanic acid and 235 subjects received clindamycin (one subject randomised to the amoxicillin/clavulanic acid arm did not receive any study drug and two subjects randomised to the clindamycin arm incorrectly received amoxicillin/clavulanic acid). A similar proportion of enrolled subjects completed the study in both the treatment arms (223 (94.9%) in the amoxicillin/clavulanic acid arm and 229 (96.6%) in the clindamycin arm). A total of 11 (4.7%) subjects in the amoxicillin/clavulanic acid arm and 8 (3.4%) subjects in the clindamycin arm discontinued before study completion and the main reasons for discontinuations were as follows: AEs (one and two in amoxicillin/clavulanic acid and clindamycin arms, resp.), protocol noncompliance (one and four in amoxicillin/clavulanic acid and clindamycin arms, resp.), and meeting the withdrawal criteria (nine and two in amoxicillin/clavulanic acid and clindamycin arms, resp.).
Subjects recruited in the study were South East Asian in origin with similar age and sex distribution across both treatment arms. Periapical abscess was the predominant odontogenic infection across both arms (56.8% and 54.9% subjects in the amoxicillin/clavulanic acid and clindamycin arms, resp.). There was no significant difference in baseline characteristics such as pain, swelling, radiographic evidence of dental infection, and medical history/preexisting conditions between the treatment arms (Table
Summary of demographics and baseline characteristics (ITT population).
Characteristic | Statistic | Randomised treatment arm | |
---|---|---|---|
Amoxicillin/clavulanic acid |
Clindamycin | ||
Gender | |||
Male |
|
99 (42.3%) | 94 (39.7%) |
Female |
|
135 (57.7%) | 143 (60.3%) |
Geographic ancestry | |||
Asian: Central/South Asian heritage |
|
0 | 1 (0.4%) |
Asian: East Asian heritage |
|
1 (0.4%) | 4 (1.7%) |
Asian: South East Asian heritage |
|
233 (99.6%) | 232 (97.9%) |
Age (years) |
|
234 (0) | 237 (0) |
Mean (SD) | 33.1 (12.8) | 32.6 (12.0) | |
Median | 29.2 | 28.9 | |
(Min, max) | (18.0, 74.8) | (18.1, 69.0) | |
Type of odontogenic infection | |||
Periapical abscess |
|
133 (56.8%) | 130 (54.9%) |
Acute periodontitis |
|
40 (17.1%) | 37 (15.6%) |
Pericoronitis |
|
62 (26.5%) | 73 (30.8%) |
Diagnostic criteria fulfilled | |||
Dental pain which is increased on mastication |
|
234 (100.0%) | 237 (100.0%) |
Swelling on alveolar mucosa |
|
226 (96.6%) | 227 (95.8%) |
Redness over involved region |
|
215 (91.9%) | 219 (92.4%) |
Increased tooth mobility |
|
82 (35.0%) | 75 (31.6%) |
Fever |
|
5 (2.1%) | 5 (2.1%) |
Malaise |
|
17 (7.3%) | 21 (8.9%) |
Cervical lymphadenopathy |
|
27 (11.5%) | 26 (11.0%) |
Elevated leucocyte count |
|
37 (15.8%) | 37 (15.6%) |
Baseline VAS score | |||
Dental pain |
|
234 (0) | 237 (0) |
Mean (SD) | 6.5 (2.1) | 6.5 (2.1) | |
Median | 7.0 | 6.5 | |
(Min, max) | (1.0, 10.0) | (0.5, 10.0) | |
Swelling |
|
226 (8) | 227 (10) |
Mean (SD) | 4.2 (1.9) | 4.5 (2.1) | |
Median | 4.0 | 4.0 | |
(Min, max) | (0.6, 10.0) | (0.1, 10.0) | |
Surgical intervention required prior to study treatment |
|
55 (23.5%) | 55 (23.2%) |
Percentage is calculated based on number of subjects in ITT population for each treatment arm and by actual randomised arm. As per randomisation, there were 234 subjects in amoxicillin/clavulanic acid arm and 237 in clindamycin arm but due to wrong randomisation process, two subjects were administered amoxicillin/clavulanic acid instead of clindamycin. Hence as per actual treatment received, there were 236 subjects in amoxicillin/clavulanic acid arm and 235 subjects in clindamycin arm.
The primary efficacy analysis using the PP population demonstrated that the clinical efficacy of amoxicillin/clavulanic acid was noninferior to clindamycin, since the upper limit of two-sided 95% CI was within the protocol specified noninferiority margin of 10%.
The percentage of subjects achieving clinical success using the primary analysis population was 88.2% (95% CI: 83.0%, 92.2%) in the amoxicillin/clavulanic acid arm and 89.7% (95% CI: 84.6%, 93.5%) in the clindamycin arm. The treatment difference between the treatment arms was 1.5% (95% CI: −4.7%, 7.7%) using Miettinen and Nurminen method, 1.5% (95% CI: −4.9%, 8.0%) using Farrington and Manning method, and 1.5% (95% CI: −4.5%, 7.6%) using a two-sample proportion test. Since the upper limit of the two-sided 95% CI for between-group percentages differences was less than the prespecified noninferiority margin of 10%, noninferiority of amoxicillin/clavulanic acid to clindamycin with respect to clinical success was demonstrated. This result was also corroborated by sensitivity analysis using the ITT-E population (Table
Primary efficacy endpoint: clinical success outcome at the end of the study.
Population | Clindamycin [% (95% CI)] | Amoxicillin/clavulanic acid [% (95% CI)] | Treatment difference | ||
---|---|---|---|---|---|
Miettinen and Nurminen method (primary) [% (95% CI)] | Farrington and Manning method [% (95% CI)] | Two-sample proportion test [% (95% CI)] | |||
PP | 89.7% |
88.2% (83.0%, 92.2%) | 1.5% ( 95 CI: −4.7%, 7.7%) | 1.5% |
1.5% (−4.5%, 7.6%) |
|
|||||
ITT-E | 86.4% |
85.5% (80.3%, 89.8%) | 0.9% (−5.5%, 7.3%) | 0.9% |
0.9% (−5.5%, 7.2%) |
|
|||||
ITT (randomised treatment arm) | 85.7% |
83.3% (77.9%, 87.9%) | 2.3% (−4.3%, 9.0%) | 2.3% |
2.3% (−4.2%, 8.9%) |
A slightly higher percentage of subjects achieved clinical success in the amoxicillin/clavulanic acid arm by Day 5 [76.8% (95% CI: 70.7%, 82.2%)] than the clindamycin arm [69.1% (95% CI 62.7%, 75.0%)] possibly indicating a faster response in subjects receiving amoxicillin/clavulanic acid arm as compared to subjects who received clindamycin.
The least square mean change in the VAS score for pain (using ITT-E dataset with OC approach) was maximum at Day 7 (6.38 and 6.34 in the amoxicillin/clavulanic acid and clindamycin arms, resp.) compared to Day 5 (5.49 and 5.38 in the treatment arms, resp.) and Day 2 (3.34 and 3.07, resp.) and it was similar between the treatment arms at each time point. Similar results were also noted for swelling (Table
Secondary endpoint: change in VAS scores for pain and swelling from baseline.
Secondary endpoint: change in VAS from baseline | |||||
---|---|---|---|---|---|
Assessment | Day |
Statistic | Amoxicillin/clavulanic acid |
Clindamycin |
Treatment difference |
Change in pain at Day |
|
227 ( |
233 ( |
— | |
Day 2 | Least square mean | 3.34 | 3.07 | 0.27 | |
Two-sided 95% CI (LCL, UCL) | (3.08, 3.61) | (2.81, 3.33) | (−0.10, 0.64) | ||
|
219 ( |
228 ( |
— | ||
Day 5 | Least square mean | 5.49 | 5.38 | 0.11 | |
Two-sided 95% CI (LCL, UCL) | (5.27, 5.71) | (5.16, 5.60) | (−0.20, 0.42) | ||
|
57 (0) | 71 (0) | — | ||
Day 7 |
Least square mean | 6.38 | 6.34 | 0.04 | |
Two-sided 95% CI (LCL, UCL) | (6.02, 6.74) | (6.02, 6.66) | (−0.44, 0.53) | ||
|
|||||
Change in swelling at Day |
|
219 ( |
225 ( |
— | |
Day 2 | Least square mean | 1.92 | 1.61 | 0.31 | |
Two-sided 95% CI (LCL, UCL) | (1.72, 2.11) | (1.42, 1.80) | (0.04, 0.57) | ||
|
214 ( |
223 (3) | — | ||
Day 5 | Least square mean | 3.68 | 3.60 | 0.08 | |
Two-sided 95% CI (LCL, UCL) | (3.51, 3.85) | (3.43, 3.76) | (−0.16, 0.32) | ||
|
55 (0) | 68 (0) | — | ||
Day 7 |
Least square mean | 4.21 | 4.61 | −0.39 | |
Two-sided 95% CI (LCL, UCL) | (3.94, 4.49) | (4.36, 4.86) | (−0.77, −0.02) |
Note: change from baseline in VAS for assessment of pain and swelling was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood and an unstructured covariance matrix. The baseline VAS score was used as a covariate. Treatment groups and nominal days (visits) were considered as fixed effects and interaction effect was considered between treatment and visit (days). Data for “Day 7” is summarised for subjects who continued the study up to Day 7. OC method was used for missing values where the missing value was kept as missing except for early withdrawal.
“
LCL: lower confidence limit, UCL: upper confidence limit.
Pus specimens were obtained in 58 subjects who consented to microbiological sampling including two who were screen failures (25 in the amoxicillin/clavulanic acid arm and 31 in the clindamycin arm; the 2 screen failures were excluded). A total of 61 isolates were obtained from 56 samples, 26 in the amoxicillin/clavulanic acid arm and 35 in the clindamycin arm. Organisms isolated in both the treatment arms were similar and predominantly viridans streptococci group ((
A total of 243 treatment emergent AEs (TEAEs) were reported in 123 subjects in the amoxicillin/clavulanic acid arm and 236 events were reported in 124 subjects in the clindamycin arm. The most frequently observed TEAEs with frequency ≥3% were abdominal discomfort, raised liver enzymes (AST, ALT, and bilirubin), diarrhoea, dizziness, headache, increased appetite, and somnolence (Table
Summary of commonly observed treatment emergent AEs (≥3% in either of the arms).
MedDRA preferred term | Amoxicillin/clavulanic acid |
Clindamycin |
---|---|---|
Total number of treatment emergent AEs | 243 | 236 |
Subjects who experienced at least one AE | 123 (52.1%) | 124 (52.8%) |
Abdominal discomfort | 11 (4.7%) | 7 (3.0%) |
Alanine aminotransferase increased | 26 (11.0%) | 24 (10.2%) |
Aspartate aminotransferase increased | 24 (10.2%) | 20 (8.5%) |
Blood bilirubin increased | 12 (5.1%) | 13 (5.5%) |
Diarrhoea | 19 (8.1%) | 28 (11.9%) |
Dizziness | 18 (7.6%) | 14 (6.0%) |
Headache | 8 (3.4%) | 14 (6.0%) |
Increased appetite | 20 (8.5%) | 15 (6.4%) |
Nausea | 7 (3.0%) | 4 (1.7%) |
Somnolence | 19 (8.1%) | 17 (7.2%) |
Scatter plot of LFT with respect to baseline and end of study by treatment. Normalised value = laboratory value/upper limit of normal reference range of the respective local laboratory.
The primary treatment in acute odontogenic infections is surgical drainage while antibiotics are an adjunct in patients showing signs of systemic involvement [
Amoxicillin/clavulanic acid (875 mg/125 mg) was administered twice daily for 5–7 days and was found to be noninferior or “comparable” to clindamycin (150 mg) administered four times daily. The overall clinical success seen with amoxicillin/clavulanic acid in the study (88.2% (95% CI: 83.0%, 92.2%)) was similar to results seen in other published studies. Success rates of 87% with amoxicillin/clavulanic acid 1 g twice daily and 96% with amoxicillin/clavulanic acid 625 mg thrice daily have been previously reported in other studies [
Safety of the subjects, assessed throughout the study, showed that the overall incidences of TEAEs were similar across both the treatment arms. These were mainly events such as abdominal discomfort, diarrhoea, and raised liver enzymes. As per the available safety information of amoxicillin/clavulanic acid 875/125 mg, nausea and diarrhoea are commonly reported events [
One of the main limitations of the study was the use of an outcome measure based on a subjective score (VAS score) to assess pain and swelling to derive the composite clinical outcome. However, to overcome the subjectivity of the VAS score and to reflect real world practice, only subjects demonstrating >70% reduction in pain and swelling were considered for calculating clinical success response. Another limitation was not having a planned follow-up visit for the subjects after the end of the study visits. As a result, ongoing AEs typically key laboratory parameters such as liver enzymes could not be followed until resolution; however, most were mild and transient in nature.
Amoxicillin/clavulanic acid (875 mg/125 mg) administered twice daily was found to be comparable to clindamycin (150 mg) administered four times daily in achieving clinical success in acute odontogenic infections with or without abscess. It was also found to be well tolerated with a safety profile consistent with the known pharmacologic effects of amoxicillin/clavulanic acid and with that described in the global prescribing information.
Archiel Launch Tancawan, Maria Noemi Pato, Khamiza Zainol Abidin, A. S. Mohd Asari, and Tran Xuan Thong declare no conflict of interests regarding the publication of this paper. Puja Kochhar, Chandra Muganurmath, Monique Twynholm, and Keith Barker are employees of GlaxoSmithKline and hold stocks/shares in GlaxoSmithKline. Archiel Launch Tancawan, Maria Noemi Pato, Khamiza Zainol Abidin, A. S. Mohd Asari, and Tran Xuan Thong were principal investigators in AUG117044 study.
Nooraini Bt Osman (Putrajaya Dental Clinic, Malaysia), Christopher Vincent (Selayang Hospital, Malaysia), Haidee Daphnee Digma (Southern Philippines Medical Center, Philippines), Margarita Oasin (Rizal Medical Center, Philippines), Ngo Thi Quynh Lan (University of Medicine and Pharmacy, Vietnam), Huynh Dai Hai (Odonto-Maxillo-Facial Hospital, Vietnam), Dao Thi Dung (Vietnam-Cuba Friendship, Hanoi), Tanakrit Noppakunwijai (Tanarat Fort Hospital, Thailand), Prisana Pripatnanont (Prince of Songkla University, Thailand), and Nipon Chaisrisookumporn (Lampang Regional Hospital, Thailand) were principal investigators. Gandhali Paranjape and Kavitha Rangappa (DiagnoSearch Life Sciences Pvt. Ltd.) were responsible for editorial assistance; Boshi Mohala (GlaxoSmithKline) was responsible for safety review; Jie Ding (GlaxoSmithKline) and Varsha Parulekar (DiagnoSearch Life Sciences Pvt. Ltd.) were responsible for statistical support. Study was funded by GlaxoSmithKline Pharmaceuticals Ltd. and editorial assistance was provided by DiagnoSearch Life Sciences Pvt. Ltd.