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International Scholarly Research Network ISRN Dentistry Volume 2012, Article ID 581207, 11 pagesdoi:10.5402/2012/581207

Research Article Antimicrobial or Subantimicrobial AntibioticTherapy as an Adjunct to the Nonsurgical PeriodontalTreatment: A Meta-Analysis

Ana Patricia Moreno Villagrana and Jose Francisco Gomez Clavel

Carrera de Cirujano Dentista, FES-Iztacala, Universidad Nacional Aut onoma de M exico, Tlalnepantla, MEX 54090, Mexico

Correspondence should be addressed to Jose Francisco Gomez Clavel, [email protected]

Received 1 July 2012; Accepted 24 July 2012

Academic Editors: M. Behr, I. Magnusson, and S. E. Widmalm

Copyright © 2012 A. P. Moreno Villagrana and J. F. Gomez Clavel. This is an open access article distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

The use of antibiotics in nonsurgical periodontal treatment is indicated in cases in which scaling and root planing presentimportant limitations. However, their use is controversial due to the secondary eff ects associated with them and the disagreementsregarding their prescription. The aim of this study is to determine the eff ectiveness of systemic antibiotics in the managementof aggressive and chronic periodontitis. The study was based on a search of randomized, controlled clinical trials. Common datawere concentrated and evaluated by means of an analysis of variance (ANOVA), and a meta-analysis of the results was performed.The meta-analysis (P < 0.05, 95% confidence interval, post hoc Bonferroni) determined that the supplementation of nonsurgicalperiodontal therapy with a systemic antibiotic treatment—amoxicillin with clavulanic acid and metronidazole or subantimicrobialdose doxycycline—provides statistically significant results in patients with aggressive or chronic periodontitis under periodontaltreatment, whilst increasing the clinical attachment level of the gingiva and reducing periodontal probing depth.

1. Introduction

It is now recognized that the majority of connective tissueand bone destruction in periodontal tissues occurs indirectly as a result of an excessive immunoinflammatory response inthe host to the presence of bacterial plaque in susceptible

individuals. Although bacterial pathogens initiate the peri-odontal inflammation, the host response to these pathogensis equally if not more important in mediating connectivetissue breakdown, including bone loss [1, 2]. The host-derived enzymes known as matrix-degrading metallopro-teinases (MMPs) as well as changes in osteoclast activity driven by cytokines and prostanoids catalyze the breakdownof proteins, including collagen, gelatin, proteoglycan coreprotein, fibronectin, laminin, and elastin, located eitheron the cell plasma membrane or within the extracellularmatrix [3–6]. Pathologically excessive levels of activity of the various MMPs degrade all of the major componentsof the extracellular matrix in the gingiva, the periodontal

ligament, and the alveolar bone, including the collagen fibers(mostly type I and III), proteoglycans, ground substance, andbasement membranes [7–9].

The standard treatment for periodontitis remains highly nonspecific, consisting of the mechanical debridement of theaff ected root surface in order to reducethe total bacterial load

and change the environmental conditions of these microbialniches [19]. However, not all patients nor all sites responduniformly and favorably to conventional mechanical therapy,and a small although relevant proportion of sites and patientsdo not respond adequately to this therapy. The reducedeff ectiveness of the therapy may be explained by a seriesof patient-related factors (local or generalized), the extentand nature of attachment loss, local anatomic variations, theform of the periodontal disease, and the composition andpersistence of periodontal pathogens [20–22]. Based on this,numerous authors have hypothesized that purely mechanicaltreatment may not be eff ective for certain patients, that is,patients with aggressive forms of periodontitis or associated

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with predisposed medical conditions, in whom additionalantimicrobial therapy would improve their clinical outcomeand would even be essential for successful treatment [23, 24].

Several studies have evaluated the use of antibiotics tostop or reduce the progression of periodontitis. Systemically administered antibiotics penetrate the periodontal tissues

via the serum. There, they can reach microorganisms thatare inaccessible to scaling instruments and local antibiotictherapy [23]. This antibiotic therapy also has the potential tosuppress any periodontal pathogenic bacteria colonizing thedeep crevices of the tongue, as well as clinically nondiseasedsites that could cause chronic reinfection. According to theAmerican Academy of Periodontology, the patients who arelikely to benefit from antibiotics are those for whom con-ventional mechanical treatment has proven ineff ective, thosesuff ering from acute periodontal infections (necrotizingperiodontal disease and periodontal abscesses) or aggressiveperiodontitis, certain medically compromised patients, andpatients who smoke [25]. Furthermore, periodontitis causedby Aggregatibacter actinomycetemcomitans often requiresantibiotic treatment because this bacterium is found on allmucous membrane surfaces of the oral cavity and is capableof invading all soft tissues. These recommendations are inline with those of the French Health Products Safety Agency (AFSSAPS) [4].

The main approaches to systemic antibiotic therapy for periodontal treatment are based on monotherapy [26].Amoxicillin with clavulanic acid is a broad-spectrum drugthat shows low concentrations in gingival crevicular fluid(GCF). Metronidazole is an eff ective agent for treatingrefractory periodontitis involving Porphyromonas gingivalisand/or Prevotella intermedia [27, 28]; it is conducive toeff ective antibacterial concentrations in gingival tissuesand GCF, but its oral administration seems to have littleimpact on oral and intestinal microflora. Tetracyclines(doxycycline and minocycline) are active against importantperiodontal pathogens such as A. actinomycetemcomitans[10, 29]; they also have anticollagenase properties and canreduce tissue destruction and bone resorption, althoughsystemically administered tetracyclines reach relatively highconcentrations in GCF. Clindamycin is eff ective in thetreatment of refractory periodontitis and against Gram-positive cocci and Gram-negative anaerobic rods but shouldbe prescribed with caution because of the risk of overgrowthof Clostridium di fficile, which could result in pseudomem-branous colitis [23]. Ciprofloxacin is eff ective against several

periodontal pathogens, including A. actinomycetemcomitans;this antibiotic eff ectively penetrates the diseased periodontaltissues and can reach higher concentrations in GCF thanin the serum [23, 30]. As periodontal lesions host avariety of periodontal pathogenic bacteria, it has becomeincreasingly common to treat aggressive periodontitis usinga combination of antibiotics. Such combinations includemetronidazole and amoxicillin for A. actinomycetemcomitansinfections and metronidazole and ciprofloxacin for mixedperiodontal infections or for patients who are allergic toamoxicillin. Conversely, antagonistic eff ects are observedbetween certain antibiotics, for example, tetracyclines andcertain β-lactams [23, 24, 26].

Several studies have been devoted to pharmacologictherapies that modulated host responses to periodonto-pathic bacteria. The purpose of host modulatory therapy (HMT) is to restore the balance of proinflammatory ordestructive mediators and anti-inflammatory or protectivemediators to that seen in healthy individuals. The only

MMP inhibitor that has been approved for clinical use inthe US, Canada, and Europe and tested for the treatmentof periodontitis is subantimicrobial dose doxycycline orSDD. A number of studies have shown that the therapeuticeff ects of tetracycline antibiotics are to inhibit collagenolyticMMPs, to reduce connective tissue degradation, and todiminish bone resorption [31]. SDD, 20 mg twice daily for2 weeks, significantly reduced collagenase activity in theGCF and gingival tissues of patients with adult periodontitis[32]. In another study, SDD was shown to improve certainclinical parameters (attachment level and probing depth)when administered to patients periodically over a 6-monthperiod [33]. Evidence indicates that SDD also contributesto decreased connective tissue breakdown by downregulatingthe expression of proinflammatory mediators and cytokines(Interleukin-1 and tumoral necrosis factor-α) and increasingcollagen production, osteoblast activity, and bone formation[7, 8, 11, 12, 18].

The aim of this study is to determine the eff ectivenessof systemic antibiotics as an adjunctive treatment in adultperiodontitis therapy.

2. Materials and Methods

2.1. Search Strategy. An initial search was conducted of Else-vier, EBSCO, Wiley, PROQUEST, EJS, BIOMED, PubMed,

Medline, and Ovid journals based on a combination of the following medical subject headings: periodontal dis-ease, antibiotic therapy in periodontal treatment, antibioticprophylaxis in periodontal treatment, antibiotic therapy inscaling and root planing, and periodontal microbiology.

2.2. Inclusion and Exclusion Criteria. Both English and non-English articles were included in the search of the literature.Articles that met the following criteria were reviewed andincluded in the meta-analysis.

(1) Involves systemic antibiotic therapy (prophylactic,postoperatory, and HMT) as an adjunctive treatmentin periodontal instrumentation (scaling and rootplaning).

(2) Is described as a randomized double-blind clinicaltrial.

(3) Includes a control group.

(4) Includes clinical outcomes: gingival attachment leveland periodontal probing depth.

(5) Published between 2001 and 2011.

Studies that did not fulfill all of the aforementioned inclusioncriteria were excluded from this paper. Clinical case reports,literature reviews, and in-vitro studies were also excluded.

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T a b

l e 2 : O u t c o m e s m e a s u r e d i n s y s t e m i c a n t i b i o t i c t r e a t m e n t a s a n a d j u n c t i v e t h e r a p y i n s c a l i n g a n d r o o t p l a n i n g .

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G o l u b e t a l .

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N o v a k e t a l .

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5 [ 1 4 ]

R e i n h a r d t e t a l .

2 0 0 7 [ 1 5 ]

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l i c a c t i v i t y i n G C F g i n g i v a l c r e v i c u l a r fl u i d .

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T a b l e 3 : C l i n

i c a l o u t c o m e s r e p o r t e d i n r a n d o m i z e d c o n t r o l l e d t r i a l s e v a l u a t i n g t h e e ffi c a c y o f a d j u n c t i v e a n t i b i o t i c t r e a t m e n t i n S R P .

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r e d u c t i o n

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A g g r e s s i v e p

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t i m i c r o b i a l d o s e d o x y c y c l i n e , 2 0 m g / 1 2 h r s ; A M

O X I - M E T R O : a m o x i c i l l i n - m e t r o n i d a z o l e , 5 0 0

m g o f e a c h / 8 h r s / 7 d a y s .

∗ T o o t h s i t e s w e r e s t r a t i fi e d a c c o r d i n g t o t h e d

e g r e e o f d i s e a s e s e v e r i t y ( m a g n i t u d e o f P D ) e v i d e n t a t b a s e l i n e . T o o t h s i t e s w i t h a b a s e l i n e P D

o f 0 t o 3 m m w e r e c o n s i d e r e d n o r m a l , t o o t h s i t e s w i t h a b a s e l i n e P D o f

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7 m m w e r e c o n s i d e r e d s e v e r e l y d i s e a s e d .

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Table 7: Forest plot (meta-analysis, random eff ect model) indicating the cumulative eff ect sizes for percentage of sites with clinicalattachment level gain at sites with severe periodontitis (≥7 mm).

Percentage of sites with CAL gain at sites with severe periodontitis (≥7mm)Std diff in means and 95% CI

Study Antibiotic Placebo Std diff in means

95% Cl Z value P value

Caton et al., 2000 [10] 90 93 0.244 1.647 0.1

−1 −0.5 0 0.5 1

Favours antibioticFavours placebo

Preshaw et al., 2004 [12] 10 10 0.178 1.283 0.199

Novak et al., 2002 [11] 107 102 0.775 1.672 0.094

Mohammad et al., 2005 [8] 66 76 0.530 3.096 0.002

Guerrero et al., 2005 [14] 20 21 −0.615 −1.925 0.054

Needleman et al., 2007 [16] 16 18 0.200 0.582 0.561

Synthesis 309 320 0.244 3.035 0.002

CAL: clinical attachment level, P < 0.05, confidence level 95%.

Table 8: Forest plot (meta-analysis, random eff ect model) indicating the cumulative eff ect sizes for probing depth reduction at sites withmoderate periodontitis (4–6 mm).

PD reduction at sites with moderate periodontitis (4–6 mm)Std diff in means and 95% CI



Caton et al., 2000 [10] 90 93 0.244 1.647 0.100

−1 −0.5 0 0.5 1


Preshaw et al., 2004 [12] 10 10 0.081 0.584 0.560

Novak et al., 2002 [11] 107 102 1.296 2.634 0.008

Mohammad et al., 2005 [8] 66 76 0.530 3.096 0.002

Guerrero et al., 2005 [14] 20 21 0.787 2.426 0.015

Needlerman et al., 2007 [16] 16 18 −0.44 −1.275 0.202Synthesis 309 320 0.277 3.435 0.001

PD: probing depth, P < 0.05, confidence level 95%.

Table 9: Forest plot (meta-analysis, random eff ect model) indicating the cumulative eff ect sizes for percentage of sites with probing depthreduction at sites with moderate periodontitis (4–6 mm).

Percentage of sites with PD reduction at sites with moderate periodontitis (4–6 mm)Std diff in means and 95% CI



Caton et al., 2000 [10] 90 93 0.244 1.647 0.100

−1 −0.5 0 0.5 1


Preshaw et al., 2004 [12] 10 10 0.081 0.584 0.560

Novak et al., 2002 [11] 107 102 1.296 2.634 0.008

Mohammad et al., 2005 [8] 66 76 0.530 3.096 0.002

Guerrero et al., 2005 [14] 20 21 0.797 2.426 0.015

Reinhardt et al., 2007 [15] 64 64 0.045 0.254 0.800

Griffitz et al., 2011 [17] 20 21 0.526 1.656 0.098

Synthesis 377 387 0.282 3.865 0.000

PD: probing depth, P < 0.05, confidence level 95%.

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[35] J. Lindhe and R. Palmer, “Group C summary,” Journal of Clinical Periodontology , vol. 29, no. 3, pp. 160–162, 2000.

[36] J. B. Payne, J. A. Stoner, P. V. Nummikoski et al., “Subantimi-crobial dose doxycycline eff ects on alveolar bone loss in post-menopausal women,” Journal of Clinical Periodontology , vol.34, no. 9, pp. 776–787, 2007.

[37] J. B. Payne and L. M. Golub, “Using tetracyclines to treat

osteoporotic/osteopenic bone loss: from the basic sciencelaboratory to the clinic,” Pharmacological Research, vol. 63, no.2, pp. 121–129, 2011.

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