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P. gingivalis, T. denticola and T. forsythensis are classified as anaerobes because they are killed by the levels of oxygen present in air. In the mouth they can grow in the sub-gingival plaque in the periodontal pocket because the oxygen levels in the pocket are about 1% (there is 20% oxygen in air). As an overgrowth of these BANA positive germs are found in most forms of periodontal disease, including chronic, and aggressive periodontitis we consider these clinical conditions to be anaerobic infections.

Figure shows clinical cases of chronic and aggressive periodontitis, as well as an acute form of periodontal disease called acute necrotizing ulcerative gingivitis (ANUG), or trench mouth.

We based our treatment approach on the usage of antimicrobial agents which are able to kill anaerobic germs. While many antibiotics, such as penicillin, will kill anaerobes, they will also kill germs that can grow in the presence of oxygen. These other germs would be facultative germs of the type that seem to dominate in plaques when there is periodontal health. Thus most antimicrobial agents will kill both “bad” germs as well as “good” germs. But there are a few antimicrobial agents such as metronidazole, which specifically kills anaerobic germs and do not kill the facultative germs. Metronidazole would selectively kill only those bacteria that seem to be involved with periodontal inflammation, and leave behind those germs that are associated with periodontal health.

This assumes that there are no medical contra-indications to using metronidazole, such as allergies and drug interactions. All prescriptions of metronidazole carry a label warning the user not to consume alcoholic drinks while on this medication, because a few individuals can experience an acute nausea. We prescribe metronidazole 500 mg twice a day (1,000 mg) for one or two weeks, depending on the severity of the periodontal condition. The dosage would be reduced or increased depending on the patient’s weight, i.e., we would reduce the dosage to 750 mg for people weighing under 100 pounds, and increase it 250mg for each 50 pounds that an individual is over 200 pounds.

For patients not willing to abstain from alcohol, other antibiotics such as doxycycline or azithromycin may be substituted for metronidazole. Doxycycline (100 mg per day for 2 to 3 weeks) and azithromycin (250 mg once a day for 4 or 5 days) need to be taken only once a day, which greatly improves patient compliance. Doxycycline may cause the emergence of antibiotic resistant organisms, and a transient diarrhea, problems that are rarely seen with metronidazole. Azithromycin is an important medical antibiotic and its usage in periodontal infections may compromise its subsequent usage in more serious infections.

Metronidazole would be the preferred agent because it selectively kills the anaerobic gram negative members of the plaque flora, and leaves behind the facultative flora which has been shown to be associated with periodontal health. Thus when metronidazole is stopped, the remaining flora consists of those very facultative species that are considered to be members of the “normal flora”.

Combination Therapy (Patients have a Choice)

Systemic antimicrobials such as metronidazole, doxycycline or azithromycin should not be used without first cleaning the teeth of bacterial accumulations (debridement procedures). This is because the numbers of bacteria in a single periodontal pocket can be as high as 500,000,000 cells. It would be difficult to deliver enough antimicrobial agent via a pill or tablet that is swallowed (systemic route), and expect that enough of the agent would enter the pocket via the gingival crevicular fluid so as to kill this large number of bacteria. Debridement becomes essential, as a skilled clinician can probably reduce the numbers of bacteria by 99%, leaving behind 5,000,000 bacteria. While this is still a large number, it is within the killing range of a systemically delivered antimicrobial agent. Thus Combination Therapy is the preferred approach to the treatment of advanced forms of periodontal disease.

We have conducted four double-blind studies involving combination therapy, that have been funded by the National Institute of Dental Research. It was necessary to obtain federal money because metronidazole is a generic drug that is not owned by any pharmaceutical company. While this means that the cost of treatments employing metronidazole will be low, relative to the surgical approach, there is a downside as in the absence of marketing no one hears of the results. A recent review in the medical literature states "if metronidazole were a patented antibiotic, the manufacturer would almost certainly be willing to put substantial marketing resources into convincing the clinical community that antibiotic treatment of periodontal disease was less invasive, cost-effective, cosmetically superior, and less risky than surgery" (Hay and Yu, 1999).

In each of these studies, we have shown that debridement plus one week of unsupervised usage of systemic metronidazole was superior to debridement plus the usage of placebo (the standard of care). We have in the last three studies, used the reduced need for periodontal surgery as our primary treatment outcome, and were able to show that the combination treatment always significantly reduced the need for periodontal surgery. In a 1996 study, we were curious as to how much of the surgical procedures could be avoided if we retreated the patient, or the involved teeth. We found that about 80% of the patients did not need periodontal surgery, and that those 20% who still needed surgery, the number of teeth needing surgery was reduced from the initial levels. We found that combination therapy, involving sometimes retreatment with the antimicrobial agents, resulted in a 92%

reduction in the need for access surgery about individual teeth, and in a 66% reduction in the number of teeth that needed extraction. These extracted teeth did not even need surgery.

It was possible that the benefits seen in this study would not persist over the next few years. Accordingly we have followed these patients for over five years and have seen no relapse of the initial surgical spearing effect of the Combination Therapy. Figure 1 shows that initially the patients had an average of 8.6 teeth needing surgery or extraction and that after treatment this number was reduced to an average of 1.2 teeth. Five years later, among those patients who returned to have their teeth cleaned in the maintenance phase of therapy, the average number of teeth needing surgery was 2.4 teeth, indicating that for most patients the need for surgery was not postponed, but rather prevented.

A summary of these four double blind studies in which the metronidazole plus scaling and root planing treatment was compared to placebo medication plus scaling and root planing is shown in the following table. In each of these studies the standard debridement procedures (scaling and root planing) plus the use of a placebo medication gave results that were statistically inferior in improving the patient’s periodontal health when compared to those obtained when the same debridement procedure was combined with metronidazole. In terms of clinical significance these patients were spared the cost and discomfort of periodontal surgery and in some cases tooth extractions. Using the traditional approach periodontal surgery would most likely be recommended to the patient, whereas, in the case of the metronidazole treated group, most of the surgical procedures were avoided.

Summary of Four Double Blind Studies Which Demonstrate Superiority of Combination Therapy (Metronidazole) to Debridement Alone

Clinical Outcome

Combination Therapy

Debridement

Significance

Reference

Change in Sites with

Probing depth > 5 mm

Attachment level > 5 mm

Reduced Need for Surgery

No. of teeth

-3.19 mm

1.42 mm

6.2

8.4

6.8

-1.55 mm

0.23 mm

2.5

2.6

4.8

p=0.03

p=0.05

p=0.01

p=0.04

1. Loesche, W.J., Syed, S.A., Morrison, E.C., Kerry, G.A., Higgins, T. and Stoll, J. Metronidazole in Periodontitis. I. Clinical and Bacteriological Results after 15 to 30 weeks. J. Periodontol. 1984;55:325-335

2. Loesche, W.J., Schmidt, E., Smith B.A., Morrison E.C., Caffesse R., and Hujoel P.P. Effect of metronidazole on periodontal treatment needs. J. Periodontol. 1991; 62:247-257

3. Loesche, W.J., Giordano, J.R., Hujoel, P.P., Schwarcz, J., and Smith, B.A. Metronidazole in periodontitis. Reduced need for surgery. J. Clin. Periodontol. 1992;19: 103-112

4. Loesche WJ, Giordano J, Soehren S, Hutchinson R, Rau CF, Walsh L, Schork MA. The non-surgical treatment of periodontal patients. Oral Med Oral Surg Oral Path. 1996;81:533-43

5. Loesche WJ, Giordano JR, Soehren S, Kariocoti N. The nonsurgical treatment of periodontal disease. Results after 5 years. J. Am Dent Assoc 2002,133:311-320

*Before Treatment with Metronidazole

*After Treatment with Debridement and Metronidazole

*Clinical photos courtesy of Dr. Randy Valentine, Erie, PA.

We have conducted four double-blind studies involving combination therapy, that have been funded by the National Institute of Dental and Cranial-facial Research. In each of these studies, we have shown that debridement plus one week of unsupervised usage of systemic metronidazole was superior to debridement plus the usage of placebo. We have in the last three studies, used the reduced need for periodontal surgery as our primary treatment outcome, and were able to show that the combination treatment always significantly reduced the need for periodontal surgery. In a 1996 study, we were curious to see how many surgical procedures could be avoided if we retreated the patient, or the involved teeth. We found that about 80% of the patients did not need periodontal surgery, and that those 20% who still needed surgery, the number of teeth needing surgery was reduced from the initial levels. We found that combination therapy, involving sometimes retreatment with the antimicrobial agents, resulted in a 92% reduction in the need for access surgery about individual teeth, and in a 66% reduction in the number of teeth that needed extraction. Amazingly, those teeth previously requiring extraction now did not even require surgery!

A summary of four double-blind studies in which the metronidazole plus scaling and root planing treatment was compared to placebo medication plus scaling and root planing is shown in the following table. In each of these studies the standard debridement procedures (scaling and root planing) plus the use of a placebo medication, gave results that were statistically inferior in improving the patient's periodontal health, when compared to those obtained when the same debridement procedure was combined with metronidazole. Using the traditional approach, periodontal surgery would most likely be recommended to the patient, whereas, in the case of the metronidazole-treated group, most of the surgical procedures were avoided.