Abstract

Periodontal disease is an infectious disease and as any other inflammation, the best approach for treatment are antimicrobial or antibiotics as an adjunct to a conventional periodontal scaling and root planing (SRP). Studies up do date has shown that standard antibiotic therapy of 200 to 300 mg is not effective due to immediate repopulation of bacteria flora in oral cavity and increased chance for resistance. Since the host response is the main issue in destruction of periodontal tissue in periodontal disease, the most effective antimicrobial approach was found to be an administration of subantimicrobial dose of Doxycycline of 20 mg. bid, for a period not shorter than three months that help to suppress host response and decrease even more pocket depths after SRP, but has no effects on present bacterial flora thus removing the possibility of development of resistance to antimicrobials.

Introduction

The aetiology of chronic periodontitis involves complex host-parasite interactions modified by environmental and genetic factors.
The pathophysiology of periodontal disease is characterized by a sequence of events initiated by the presence of bacteria in the gingival sulcus. Since the birth of Dentistry, it was considered that the bacteria were the solo cause of periodontal disease. Major breakthrough was achieved by study done in 2000 by Page, Offenbacher and Schroeder (7) that has shown that the breakdown of periodontal tissues is primarily caused by the response of the host to the presence of bacteria and then as second come bacteria and their endotoxins. The host response results in the stimulation of cells to release a variety of substances like  cytokines and interleukins and prostaglandins, which in turn induce infiltrating and resident cells in periodontium to release enzymes known as matrix metalloproteinases (MMPs).

Periodontal destruction with Matrix Metalloproteinases (MMPs).

MMPs are peptidases that act together as degrading agents of periodontal connective tissue and proteins including collagen. Study done in 1998 by Golub LM, Lee H-M and Ryan ME (5) has shown that prominent amongst the MMPs that promote the breakdown of periodontal supporting structures are neutrophil-derived MMP-8 (collagenase), MMP-9 (gelatinase), and MMP-13 (collagenase which is bone derived).
Elevated levels of activated MMPs progressively destroy the collagenous matrix; degrade the gingiva, the periodontal ligament and supporting alveolar bone. In other words, bacteria and their toxic products cause” direct bone loss”, but ultimately, however, the host’s own immunologic responses to this bacterial infections cause even bigger bone destruction that is referred to as “indirect bone loss”.

Effects of conventional antimicrobial treatment

Traditional nonsurgical treatments such as scaling and root planning (SRP) also known as periodontal debridement mechanically reduce the bacterial load in the oral cavity by removing dental plaque as a major cause of periodontal inflammation, calculus as a contributory cause, and bacterial endotoxins from the root surface of the teeth.
Additional therapies are considered adjunctive and extremely beneficial to mechanical debridement and include systemic and/or locally delivered antimicrobials or antibiotics.
Tetracyclines have been widely used in treatment of periodontal diseases due to their ability to accumulate in gingival crevicular fluid (GCF) and act as a depot medication against present pathogenic bacteria. In doses of 200 or 100 mg/day they are known to act as bacteroistats against major players in Periodontal disease like Prevotella intermedia, Porphyromonas gingivalis, Bacteroides forsytis and Actinobacillus actinomicetemcomitans. But traditional antimicrobial treatments present with three major limitations:

• Total bacterial elimination is impossible, since the ever present oral flora quickly repopulates with minutes of the removal, even in cases of pocket sterilization
• Antimicrobial treatment does not address the “host-response” aspect of the disease and does not affect the activity of MMPs, which are the end products.
• There is a remarkable possibility of development of bacterial resistance to tetracyclines after their long term use in regular antimicrobial doses ( 250 mg /day for 2-7 years)

The novel treatment approach: Tetracyclines as host-modulatory agents and role of subantimicrobial doses of doxycycline (SDD) in the treatment of periodontal disease

Along with their bacteriostatic capabilities, tetracyclines are also known as inhibitors of tissue-destructive MMPs in crevicular fluid including MMP-8, MMP-9 and MMP-13, whereas doxycycline (a semisynthetic tetracycline) has been shown to be the most potent inhibitor of MMP activity. Study done in 1997 by Golub LM, Lee H-M and Greenwald RA (4) acknowledged for the first time in human studies, that subantimicrobial doses doxycycline (SDD), have reduced the elevated levels of specific collagenase (MMP-8) and bone type collagen degradation fragment (MMP-13) in gingival crevicular fluid (GCF), as compared with patients receiving placebo (p<0.05).
In separate study, done by Caton JG in 1999 (1), involving healthy volunteers who received a subantimicrobial dose doxycycline 20 mg twice daily, plasma levels were below the minimum levels required for antimicrobial efficacy. These two studies have confirmed the assumption that the host modulatory effects of 20 mg. of doxycycline are independent of its antimicrobial properties, because the dose of 20 mg is too low to affect bacteria. As results, resistance to this medication has not been seen. This is not case after long term use of tetracycline (250 mg /day for 2-7 years) was found high proportions of tetracycline-resistant gram-negative rods. Therefore, it is not advisable to prescribe long-term regimens of tetracycline because of the possible development of resistant bacterial strains. Study made by Slots J and Rams in 1990 (9) shows that antibiotics as adjunctive therapy to periodontal treatment has it own advantages and disadvantages and specifically deals with development of bacterial resistance to antibiotics after its long term use.
In the late 90’s of the last century, after several studies were done, the US Food and Drug Administration (FDA) approved Periostat (20mg of Doxycycline) for use as an adjunct to SRP in the treatment of adult periodontitis.

Do subantimicrobial doses of doxycycline (SDD) have an antibacterial effect on the subgingival flora?

Multiples studies have failed to identify an antimicrobial effect of SDD on the subgingival microflora. Walker C, Thomas J. and Nango S.  In their study done in 2000 (10) , for instance, found no microbial differences between the study groups, for coccoid forms, motile and non-motile rods, fusiforms and filamentous rods. Only spirochetes were found to be lower in the SDD group as compared to the placebo group.

What are the effects of subantimicrobial doses of doxycycline (SDD) treatment in conjunction with scaling and root planning (SRP) on patients with chronic periodontitis?

The most extensive study was published by Caton JG, Ciancio SG and Blieden in 2000 (2). This study included 190 patients in five dental centers in the United States. All patients received scaling and root planning (SRP) and than they were assigned to receive 20 mg doxycycline or placebo bid. Baseline measurements such as probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP) was monitored every three months up to nine months. The results of this study were significantly reductions in probing depths and increases in clinical attachment levels with adjunctive   doxycycline therapy in conjunction with root planning.

What should be the minimal duration and dosage of subantimicrobial doses of doxycycline (SDD) therapy?

In a unique study, Golub LM, McNamara TF and Ryan ME in 2001 (6), were evaluated 51 patients up to 36 weeks. After supra and subgingival scaling and prophylaxis, the patients were divided in 5 groups:

1. doxycycline 12 weeks 20mg bid
2. doxycycline 12 weeks 20 mg qid
3. doxycycline 4 weeks 20 mg bid then 8 weeks 20mg qid
4. doxycycline 4 weeks 20 mg bid then placebo 8 weeks
5. placebo 12 weeks
   

In all three groups receiving SDD a reduction in GCF collagenases and gain of CAL was observed as compared to the placebo groups.
From this study it appears that the beneficial effect of three months doxycycline 20 mg bid, was not maintained for more than three months without a second course of SDD treatment. All groups maintained stability, if not a gain of CAL in the first three months (12 weeks) after the end of the SDD treatment, which was followed by a rapid loss of CAL from week 12 to week 24.
Another study done by Caton JG, Ciancio SG and Blieden in 2001 (3), examined patients three months after they stopped the SDD and placebo treatment. The results indicated that the initial improvement in PD and CAL remained stable for the additional three months without treatment.
From studies available in the literature so far, it appears to suggest the following treatment approach:

• An initial three months course of subantimicrobial dose of doxycycline 20 mg bid in conjunction with SRP
• Then, evaluation of results
• If patients have been maintaining stable PD and CAL, they should stop with SDD treatment for the following three months, and should be placed on a three months maintenance interval when SRP will be performed and SDD treatment will resume for additional three months.

To date, no study has examined the effect of SDD treatment for a period longer than nine months.

How beneficial is the treatment with subantimicrobial doses of doxycycline (SDD) on smokers

In the study done by Preshaw PM, Bradshaw MH and Hefti AF in 2003 (8), was reported that SDD treatment in conjunction with SRP, for a period of nine months, showed better results as compared to the placebo in both smokers and non-smokers groups. Interestingly in this study is the finding that smokers study group with SDD accomplished more PD reduction and CAL gain when compared to the non-smokers placebo group. The explanation lies in bad effects of smoking to periodontal tissues making their host response weaker, thus reducing the amount of destruction of periodontal tissues.

Summary

The novel approach in antimicrobial therapy as adjunct to conventional SRP using subantimicrobial doses of doxycycline in an amount of 20 milligrams twice per day for a period not less than three months has been shown very beneficial and effective in reduction of pocket depths and clinical attachment loss, and is highly recommended as a tool for Dental Hygienists in ongoing battle against periodontal disease.

References

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