Role of antibiotics in generalized aggressive periodontitis: A review of clinical trials in humans.

BACKGROUND: It is well-recognized fact that periodontal diseases are caused by multifactorial etiologies, in which microorganisms play an important role. An essential component of therapy is to eliminate or manage these pathogens. This has been traditionally accomplished through mechanical means by scaling and root planning which is ineffective in some of the aggressive periodontal diseases. These aggressive diseases involve particular groups of microorganisms which are not eliminated by mechanical means; and they require anti-infective therapy, which includes local and systemic antimicrobials. This approach of therapy is of interest to periodontist due to the aforementioned shortcomings of conventional methods.
MATERIALS AND METHODS: A manual and electronic search was made for human studies up to March 2011 that presented clinical and microbiological data for the efficacy of a systemic antibiotics in generalized aggressive periodontitis along with scaling and root planning. A systematic approach was followed by two independent reviewers and included eligibility criteria for study inclusion, quality assessment, and determination of outcome measures, data extraction, data synthesis, and drawing of conclusion.
RESULTS: Only three randomized controlled human trials qualified, and they concluded that both scaling and root planing (SRP) mono-therapy and SRP with antibiotics proves beneficial in improving clinical and microbiological parameters in aggressive periodontitis. Better results were seen in SRP with antibiotic groups as compared with SRP alone.
CONCLUSION: Because of the insufficient quantity and heterogenecity of studies, no adequate evidence could be gathered to use the beneficial effects of these antibiotics along with SRP in aggressive periodontitis compared with SRP alone.

INTRODUCTION

It is a well-established fact that various periodontal diseases are caused by bacterial infections. Over the time, this microbial plaque becomes more complex, so systemic administration of antibiotics may be necessary adjunct in controlling bacterial infections because bacteria can invade periodontal tissues, making mechanical therapy alone sometimes ineffective.[1] Although oral bacteria are susceptible to many antibiotics, no single antibiotic at concentration achieved in body fluids inhibit all putative periodontal pathogens.[2] Indeed, a combination of antibiotics may be necessary to eliminate all putative pathogens from some periodontal pockets;[3] it has been suggested that antibiotic strength of 500 times greater than the usual therapeutic dosage is needed to be effective against bacteria arranged in biofilms.[4] Therefore, it is logical to treat periodontal pockets by mechanical disruption of the subgingival plaque along with antibiotics. Systemic antibiotic therapy combined with mechanical therapy appears valuable in the treatment of recalcitrant periodontal infections and localized aggressive periodontitis (LAP) infections.[5] Rams and Slots reviewed combination therapy using systemic metronidazole (MTZ) along with amoxicillin (AMX); this combination provides excellent elimination of many organisms in adult and LAP.[6] These drugs have additive effects regarding suppression of microflora involved in aggressive periodontitis. Thus, this review discusses the role of scaling and root planing (SRP) with or without antibiotics (AMX and MTZ) in generalized aggressive periodontitis.

MATERIALS AND METHODS

Rationale

This review evaluates literature-based evidence in an effort to determine the efficacy of currently available systemic anti-infective agents, with or without conventional SRP, in controlling generalized aggressive periodontitis.

Focused question

The question addressed in this systematic review was: “In patients with generalized aggressive periodontitis, what is the effect of systemic antibiotics with scaling and root planning compared to scaling and root planning alone, on clinical and microbiological parameters.”

Search protocol

Data sources and search strategies

A search of MEDLINE, the Cochrane central trials register, and web of science was conducted up to March 2011. The review and all associated searches were confined to studies published in English language. The MEDLINE and Cochrane Library database were searched from 1950 till March 2011 using the following Medical subject headings (MeSH): Aggressive Periodontitis, Juvenile periodontitis, MTZ and AMX, scaling, and root planning. Following completion of MEDLINE- and Cochrane-controlled trials registry searches and web of science, a supplementary search was conducted in each of this database to include systemic MTZ and AMX with or without SRP, to assure consistency with the study protocol. A total of 497 studies [Figure 1] were identified addressing the use of MTZ and AMX systemically in generalized aggressive periodontitis. The studies were examined by 2 independent reviewers (AA, CSB) to select studies relevant to the specific question posed in this review. Based on the study titles and abstracts, we selected four studies which fulfilled the inclusion criteria.

Figure 1

Search strategy

Inclusion criteria

Types of studies included were randomized, double-blinded, placebo-controlled clinical trials of 6-month duration on human beings

Publication in peer-reviewed international journals published in English

Studies with clearly stated objectives of the research and/or hypothesis to be tested

Required therapeutic interventions were (1) SRP (2) Systemic antimicrobial therapy with SRP 3) Systemic antimicrobials alone in patients with generalized aggressive periodontitis

Exclusion criteria

The studies which do not fulfill the inclusion criteria, non-randomized clinical trials without placebo-controlled trials, case reports, and split mouth designs were excluded.

Clinical patient outcome

The primary outcome measured included changes in probing depth, clinical attachment level, Bleeding On Probing. Surrogate secondary outcome measures included change in subgingival microbial flora.

Data collection and analysis

Initially, titles and abstracts of studies identified by the previously described search strategies were screened independently by two reviewers (AA and CSB) to determine if they should be included in the review. Selected studies were independently reviewed by the reviewers using the criteria defined above. Study selection criteria were applied to a subset of relevant studies in order to calibrate the reviewers and to offer practical application of the selection criteria.

Quality assessment and ranking of selected studies

The methodology quality of the studies was evaluated on the basis of modifications made in CAMARADES criteria.[7]

Primary quality criteria

Clear objectives and methodology of the proposed study

Randomization to treatment or control

Masked assessment of outcome

Exclusion of patients with syndromes, pregnant, and lactating mothers

Dosage and duration of drug

Toxicity/side effects evaluation of drugs

Sample size adequacy

Secondary quality criteria

Publication in peer-reviewed journal

Statement of compliance with regulatory requirements

Statement regarding possible conflicts of interest. Each quality criteria carried a score of one point for a possible total of 10 points. Studies were graded as high quality = all primary and secondary criteria were met. High moderate quality->4 and<8 primary criteria and all secondary criteria were met. Low moderate quality=>4 primary criteria were met and ≥1 secondary criteria were not met; Poor quality =≤4 primary criteria and all secondary criteria were met. Very poor quality =≤4 primary criteria were met and ≥1 secondary criteria were not met.

RESULTS OF THREE INCLUDED STUDIES

Study selection and description: The MEDLINE and CENTRAL literature searches resulted in 497 hits [Figure 1]. After the first selection step based on the title of the collected studies, 63 articles were included for further analysis. The second step based on the abstract screening resulted in 12 studies. From these studies, three studies which completely fulfilled the inclusion criteria were selected. Nine studies were excluded at the last step, and the reason for exclusion is presented in Table 1. The articles that remained after the third selection (n = 3) are presented in Table 2.

Table 1

Abstracts excluded after text screening for not fulfilling inclusion criteria n=9

Table 2

Abstracts included after text screening which fulfilled inclusion criteria of randomized placebo-controlled double-blinded clinical trials of 6-month duration

Of these selected studies, one of these articles[8] assessed the effects of AMX and MTZ with or without SRP in generalized aggressive periodontitis, both clinically and microbiologically. Subjects received systemic AMX (500 mg) + MTZ (250 mg) or placebo, T.I.D. for 10 days. It was randomized, double-blinded, placebo-controlled clinical trial for 6-month duration on 31 study population. In the second article,[9] patients received “full-mouth disinfection” followed by staged SRP with or without systemic antimicrobials AMX (500 mg ) + MTZ (250 mg) TID for 10 days. It was randomized, double-blinded, placebo-controlled clinical trial for 6-month duration on 35 study population.

And, in the third study[10] included in this systematic review, full-mouth non-surgical periodontal treatment was delivered over a 24-hour period using machine-driven and hand instruments. Test subjects received an adjunctive course of systemic antibiotics consisting of (500 mg) AMX and (500 mg) MTZ three times a day for 7 days. It was randomized, double-blinded, placebo-controlled clinical trial for 6-month duration on 41 study population. All these included studies showed statistically significant improvement in clinical parameters when SRP is done along with systemic administration of antibiotics [Table 2].

Qualitative data synthesis

Because of the limited number of studies, the heterogeneity of the study design, dosage and duration of MTZ and AMX administered, and the inability to retrieve the result data from the published articles, no study data could be pooled for statistical process to decipher the efficacy (in terms of changes in outcome measures) of these antibiotics prescribed along with SRP against aggressive periodontitis in human beings.

DISCUSSION

The present review attempted to systematically evaluate any available randomized, controlled human study on the effect of AMX and MTZ in aggressive periodontitis published up to March 2011. The focus was on finding sufficient evidence from existing clinical studies to explore the effectiveness of antibiotics along with SRP in aggressive periodontitis. Quality assessment of included studies was based on the checklist obtained by modifying the popular CAMARADE 10-item checklist[7] designed by Macleod et al., for evaluating the quality of animal experiments conducted for stroke drugs.

All three included studies are double blinded and of 6-month duration, and compared SRP with AMX and MTZ: and SRP with placebo medications. These three included studies matched each other in duration of the study, but they are heterogenic in design, dosage of antibiotics administered, outcome measured, sample size; and compared SRP with or without antibiotics. The critical question addressed in this review was-does the use of systemic anti-infective drug therapy in conjunction with SRP add to the beneficial clinical and microbiological outcome achievable with SRP alone in generalized aggressive periodontitis? The number of studies qualified are three [Table 1], but their heterogenecity did not allow to subject them to statistical analysis to draw a conclusion, whether SRP along with antibiotics proves beneficial in treating generalized aggressive periodontitis compared with SRP alone or antibiotics as monotherapy. It is noteworthy that all of the studies qualified in this systematic review had small sample size, and severity of the included aggressive periodontitis, genetic variations, and exclusion of patients with syndromes is not mentioned. Treatment outcome in aggressive periodontitis patient may be dependent on patient's hereditary background, their immunity component, and underlying systemic diseases; and effectiveness of antibiotics is also dependant on these factors. In this systematic review, though statistical analysis was not possible due to heterogenecity of studies, the administration of antibiotics along with SRP proved beneficial. It is well-established fact that diseases caused by microbial biofilm like aggressive periodontitis are extremely difficult to treat. Tissue-penetrating bacteria seen in aggressive periodontitis make it even more difficult. The scientific rationale of adding systemic antimicrobial agents theoretically is to reduce the left-out bacteria after SRP. Although SRP proves beneficial in disrupting subgingival deposits and removes bacteria, recolonization of bacteria left after SRP is fast and recurrence of disease in inevitable; hence, adjunctive role of antibiotics would be beneficial.

CONCLUSION

This systematic review did not assess statistical analysis due to heterogenecity of the included studies; though use of antibiotics along with SRP proved beneficial in some patients, question regarding whether adjunctive role of antibiotics along with SRP could prove beneficial in treating generalized aggressive periodontitis and what is an effective dose and duration of antibiotic administration was not drawn.

Characteristics of the included studies (n=3)

Included studies were divided into (1) only clinical, (2) clinical and microbiological studies. Table 2 lists the included studies n=3 which were divided (1) only clinical, (2) clinical and microbiological studies.

Characteristics of excluded studies (n=9)

Table 1 lists the excluded studies (These studies are excluded because they are non-randomized controlled trials).