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The ideal time of systemic metronidazole and amoxicillin administration in the treatment of severe periodontitis: study protocol for a randomized controlled trial. Trials volume 19 , Article number: 201 ( 2018 ) Cite this article. The combination of systemic metronidazole (MTZ) and amoxicillin (AMX) with scaling and root planing (SRP) has shown to be an effective periodontal treatment. However, some essential issues associated with the use of these antibiotics remain unanswered, such as the ideal time of administration during the course of periodontal treatment. Although these agents are often prescribed after the healing phase of the SRP procedure, there is biological plausibility to support its use in conjunction with the mechanical treatment. However, to date, amoxicillin in no placebo controlled randomized clinical trial (RCT) has directly compared these two protocols.

Therefore, the aim of this RCT is to compare the clinical, microbiological and immunological effects of the adjunctive systemic MTZ + AMX administered in different phases of the treatment of severe periodontitis.

Subjects with severe periodontitis ( n = 180) are being randomly assigned into three groups ( n = 60/group): (i) SRP-only (control group), SRP in combination with 400 mg MTZ + 500 mg AMX, starting (ii) at the first SRP session (active phase group), or (iii) after 3 months of its completion (healing phase group). All volunteers are receiving clinical and microbiological evaluation at baseline, 3, 6 and 12 months, and immunological assessment at baseline and 12 months post-therapy.

Nine subgingival biofilm samples are being collected per subject and analyzed for counts and proportions of 40 bacterial species by checkerboard DNA-DNA hybridization, and six gingival crevicular fluid samples are being collected and analyzed for the levels of 20 chemokines by multiplex immunoassay. The primary outcome variable is the number of volunteers reaching the clinical endpoint for treatment (? 4 sites with probing depth ?5 mm) at 1 year post-therapy.

Differences in clinical, microbiological and immunological parameters among groups and over time will be evaluated using analysis of variance, analysis of covariance and the Chi-square and Tukey tests.

Microbiological and immunological analyses will be performed using adjustments for multiple comparisons.

Periodontitis is an infectious-inflammatory disease triggered by oral microorganisms organized in biofilms, resulting in loss of periodontal bone support and, in amoxicillin angina many cases, in tooth loss [1, 2]. The standard care for periodontitis consists of oral hygiene instruction (OHI) and mechanical debridement of the root surfaces (i.e., scaling and root planing (SRP)), aiming to remove calculus and biofilm.

Although this is a very effective approach in many cases [3], it has inherent limitations, especially in patients with advanced disease.

As a result, SRP may be not sufficient to change the bacterial profile associated with periodontitis to a profile compatible with periodontal health [4].

For this reason, other treatments, such as adjunctive systemic antibiotics, have been advocated.

There is strong evidence to support the use of systemic antibiotics as adjuncts to SRP in the treatment of severe periodontitis [4,5,6,7,8,9]. Over the course of recent decades, a diverse range of antimicrobials has been used as adjuncts to nonsurgical periodontal treatment. Among these, the association of metronidazole (MTZ) and amoxicillin (AMX) has shown to be effective in the treatment of severe periodontitis in adults [5, 10,11,12,13,14].

However, in spite of the evidence supporting the efficacy of adjunctive systemic antimicrobials, there is a lack of evidence to support well-defined clinical protocols [5] and some questions remain unanswered, such as: “Which is the best timing for the administration of the antibiotics, during the active phase of therapy or on re-evaluation (3 months after active treatment)?” Some biologic concepts support the use of antibiotics during the active phase of therapy [5], together with SRP treatment. Previous authors have suggested that mild and sequential disturbances of the biofilm structure may not be sufficient to alter its highly stable climax community. On the other hand, rapid and striking reductions of the subgingival microbiota could result in a more beneficial recolonization of the periodontal pockets [15, 16]. Thus, the association between SRP and systemic antibiotics during the initial therapy would amoxicillin mk have a greater potential to create an entirely new and stable climax community, similar to that observed in health.

In addition, since recolonization is normally achieved at 3 months after SRP, there is a possibility that antimicrobials administered at re-evaluation would work almost as a maintenance scaling. Furthermore, if antibiotics are given during the active phase of the therapy, periodontal tissue inflammation will be more intense, which would allow a higher concentration of antibiotic delivered to the subgingival area, as a result of the increased levels of gingival crevicular fluid (GCF) and greater permeability of capillaries, leading to greater antibiotic uptake [17].

Despite the biological plausibility associated with antibiotic intake in the active phase of periodontal treatment, clinicians tend to postpone the decision whether to use these agents to the re-evaluation phase.

Therefore, in daily clinical practice, antibiotics are more likely to be used at 3–6 months after mechanical treatment. So far, only two investigations - one retrospective study [17] and a randomized clinical trial (RCT) on aggressive periodontitis [18] - have investigated the best time for the administration of systemic antibiotics. The results of both studies suggest greater clinical benefits when MTZ and AMX were prescribed at the initial phase of therapy.

It should be noticed, however, that the study of Griffiths et al. [18] was not designed to compare the effectiveness of the antibiotics given in different phases of treatment.

The study was designed to test MTZ + AMX in the active phase and the control group took the agents after 6 months.

Thus, up to now, no RCT has directly addressed the question of which is the best time for the administration of antibiotics in patients with severe periodontitis. The aim of this study is to compare the effectiveness of the two following protocols of MTZ plus AMX, used as adjuncts to SRP in the treatment of severe periodontitis: (i) MTZ + AMX administered at the active phase of the periodontal treatment (together with SRP) or (ii) after the healing phase (3 months after SRP). In order to address this aim, we designed a double-blinded, three-armed, placebo-controlled and bi-centric RCT, which is being conducted at Guarulhos University (UNG; Guarulhos, SP, Brazil) and University of Sao Paulo (USP-SP; Sao Paulo, SP, Brazil).

The protocol was elaborated according to the Standard Protocol Items: Recommendations for Interventional Studies (SPIRIT) guidelines and using the SPIRIT checklist (Additional file 1) [19], and was registered at ClinicalTrials.gov (NCT02954393). The study acronym (M.O.M.E.N.T) stands for “Amoxicillin and Metronidazole Before or After Mechanical Periodontal Treatment”. This trial is being conducted according to the principles of the Declaration of Helsinki for studies in humans.

The protocol was approved by the Institutional Review Board of UNG (Clinical Research Ethics Committee, CAAE: 32.465.714.4.1001.5506) and USP-SP (USP Ethics Committee, CAAE: 32.465.714.4.2001.0075).

All eligible volunteers are informed about the nature, potential risks and benefits of their participation in this study and sign an informed consent form. Subject population and inclusion/exclusion criteria. Systemically healthy volunteers with untreated severe periodontitis are being selected from the Center for Clinical Trials of UNG and Periodontal Clinic of USP-SP. Subjects are being selected according to the following inclusion criteria: ? 35 years of age, presence of at least 15 teeth (excluding third molars and teeth with advanced decay referred for extraction), a minimum of 6 teeth with at least one site each with probing depth (PD) and clinical attachment level (CAL) ?5 mm and at least 30% of the sites with PD and CAL ?4 mm (mm) and bleeding on probing (BOP). Exclusion criteria are as follows: pregnancy, breastfeeding, current smokers and former smokers within the past 5 years, systemic diseases that could affect the progression of periodontitis (e.g. diabetes mellitus, immunological disorders, osteoporosis), SRP or antibiotic therapy in the previous 6 months, long-term intake of anti-inflammatory medications, need for antibiotic pre-medication

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At baseline, all volunteers fulfill a structured questionnaire comprising information about demographic, oral and general health data. Subsequently, they are submitted to a complete periodontal clinical assessment, collection of subgingival biofilm and GCF samples, OHI, supragengival scaling with ultrasonic scaler (Cavitron® Select™ Ultrason Scaler, Denstply, New York, USA) and curettes (Millenium, GOLGRAN, Sao Caetano do Sul , SP, Brazil).

Subsequently, each volunteer is randomly allocated to one of the following therapeutic groups: (i) control ( n = 60) - SRP + placebo concomitant to SRP and at 3 months post-SRP; (ii) active phase group (n = 60) - SRP + AMX (500 mg) + MTZ (400 mg) concomitant to SRP and placebo at 3 months post-SRP; and (iii) healing phase group (n = 60) - SRP + placebo concomitant to SRP and AMX(500 mg) + MTZ(400 mg) at 3 months post-SRP (Fig.

CLIN: clinical assessment; MICRO: microbiological assessment; IMMUNO: immunological assessment; OHI: oral hygiene instruction; SRP: scaling and root planing; MTZ: metronidazole (400 mg/thrice daily); AMX: amoxicillin (500 mg/TID); PMT: periodontal maintenance therapy.

All medications and placebos are given thrice a day (TID) for 14 days and placebo medications include two tablets, one of MTZ and one of AMX. In the active phase of treatment, the medications (antibiotics or placebos) start immediately after the first SRP session.

At 3 months post-therapy (after the healing phase) the medications start immediately after the maintenance appointment. Antibiotics and placebos are being specially prepared for this study by the same pharmacy ( Gallen Pharmacy and Manipulation Ltda , Maringa, PR, Brazil).

All tablets have the same color and size, and are stored in properly coded opaque plastic bottles, with 22 units.

Volunteers, personnel (researchers responsible for the treatment) and the examiners are blind to the intervention.

Volunteers use 21 tablets in the first week and 21 in the second week.

They are not informed about the total number of tablets in each bottle (22 capsules). They return the bottles at the second week of treatment and receive new ones containing the same amount of medication for the second week.

Thus, it is possible to count the number of capsules ingested and the residual capsule (22nd) left in the bottle, in order to monitor compliance.

In addition, they are also monitored every 2 days, personally (during the SRP treatment) or via telephone. At the end of the medication period (14th day), in the active phase and in the healing phase, volunteers respond to a questionnaire about any self-perceived side effects.

SRP is performed using Gracey curettes (conventional and mini-fives) numbers 5/6, 7/8, 11/12 and 13/14 under local anesthesia, and the treatment is completed in four to six sessions of approximately 1 h, distributed over a period of 14 days.

At the

end

and L.S.), one from each center (UNG and USP-SP), perform the clinical evaluations and sample collection. The following parameters are evaluated during clinical examination: visible plaque [20], gingival bleeding (0/1), BOP (0/1), suppuration (0/1), PD (mm) and CAL (mm) at six sites per tooth (mesiobuccal, buccal, distobuccal, distolingual/palatal, lingual/palatal and mesiolingual/palatal) in all teeth, excluding third molars.

PD and CAL measurements are rounded to the nearest millimeter using a North Carolina periodontal probe (Hu-Friedy, Chicago, IL, USA).