DEBATE: Is it time for a rethink on the use of antibiotics to treat periodontitis?

The use of antibiotics, as an adjunct to mechanical debridement, to treat periodontitis is known to be effective, writes Phoebus Madianos, Chairman, EFP Scientific Affairs Committee.

But it remains controversial because of the wider context of the over-prescription of antibiotics and the rise of antimicrobial resistance (AMR).

In May 2016, Dame Sally Davies, the chief medical officer for England, warned that the threat to humanity from AMR was on a par to that from terrorism and climate change, noting that there are already 50,000 deaths per year in Europe and the USA as the result of antibiotic-resistant infections.

Moreover, according to World Health Organization, in the USA alone the calculated cost of hospitalisation because of AMR is up to $20 billion (€18 billion) per year.

The consensus report of the sixth European Workshop in Periodontology in 2008 was that, in this context, antibiotics should be restricted for use with specific patient groups and conditions, such as in aggressive and severe forms of periodontitis.

Some clinicians have questioned the extent to which the use of antibiotics in periodontal therapy might contribute to the increase in antibiotic resistance.  It is therefore still debatable how the potential added benefits of antibiotic use in periodontics rivals the potential hazards and increased costs stemming from AMR.

Prof Lior Shapira, chairman of the Department of Periodontology in the Dental Faculty of the Hebrew University-Hadassah in Jerusalem and Prof Andrea Mombelli, chair of the Division of Periodontology at the University of Geneva School of Dental Medicine debate the issues.

Lior Shapira: ‘Broad-spectrum antibiotics should be a weapon of last resort in extreme cases only’

The scientific evidence today shows that the use of broad-spectrum antibiotics, in addition to mechanical anti-infection therapy (scaling and root planing), in chronic periodontitis patients achieves superior and significant clinical improvement compared to mechanical therapy alone (comprehensively reviewed by Jepsen & Jepsen, Periodontology 2000, 2016). 

However, in modern medicine we have to consider the pros and cons of every treatment and to evaluate its relevance to each specific patient. Therefore, we have to ask ourselves: do the results justify the use of antibiotics in our patients? 

When evaluating the results of the adjunctive use of antibiotics, we need to take into account that studies are based on a single use and that the follow-up is only short-term.  In two systematic reviews, Sgolastra et al (2012) showed that the beneficial effect on full-mouth pocket depth is approximately 0.5 mm.  In addition, the use of the broad-spectrum antibiotics, such as amoxicillin and metronidazole, have no specific microbiological target and only a small part of the intake dose reaches the target organ. The remaining dose reaches all the other organs and systems in the body, with no beneficial effect and only side-effects.   

So what are the long-term benefits of the adjunctive use of antibiotics? The benefit of anti-malignant medication is calculated by “benefit in survival”, which we can translate in periodontal medicine as “the survival of an affected tooth over and above standard treatment methods.”  However, such data is not available and I have my doubts that we will be able to find any differences between these treatments in the long term. 

The “price” we are paying as a society for the wide use of antibiotics is well-known. The increase in antibiotic resistance may sometimes be life-threatening. Is this a price worth paying?

All health organisations across the globe are calling for a reduction in the worldwide use of antibiotics, urging clinicians to prescribe them only in cases that cannot be resolved by other treatments. “Antimicrobial resistance poses ‘catastrophic threat’”, says the Chief Medical Officer of the UK in her 2011 report.  Paul Cosford, ‎the Director for Health Protection and Medical Director at Public Health England, said in March 2016: “Tackling antimicrobial resistance is rightly a national and international priority. One key action in work to slow resistance is ensuring all antibiotics are appropriately prescribed and that these prescriptions are regularly reviewed.”

Maybe we should listen to this and consider carefully when to use adjunctive antibiotics – and restrict this weapon to a very limited group of our patients.

References

Jepsen, K., Jepsen, S., ‘Antibiotics/antimicrobials: systemic and local administration in the therapy of mild to moderately advanced periodontitis.’ Periodontology 2000, June 2016; 71(1): 82-112.

Sgolastra, F., Gatto, R., Petrucci, A., Monaco, A., ‘Effectiveness of systemic amoxicillin/metronidazole as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis.’ Journal of Periodontology, 2012; 83: 1257-69.

Sgolastra, F., Petrucci, A., Gatto, R., Monaco, A., ‘Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis.’ Journal of Periodontology, 2012; 83: 731-43.

Annual Report of the Chief Medical Officer, Volume Two, 2011: Infections and the rise of antimicrobial resistance.

www.england.nhs.uk/2016/03/antibiotic-overusage/

Andrea Mombelli: ‘There is increasing evidence that systemic antibiotics in the non-surgical treatment phase reduce the need and extent of surgery’

The clinical benefit of antibiotics in the treatment of periodontal diseases – especially the combination of amoxicillin and metronidazole as an adjunct to scaling and root planing (SRP) – is well established (Zandbergen et al, 2016). Indeed, no properly designed clinical trial has demonstrated a superior performance by any alternative approach. There is increasing evidence that systemic antibiotics in the non-surgical treatment phase reduce the need and extent of surgery, and that minimally invasive secondary therapy – carried out in tissues free of infection – has better outcomes(Cortellini 2012; Griffiths et al, 2011; Kaner et al, 2007; Mombelli et al, 2015).

It nevertheless remains a matter of controversy whether this treatment should be restricted to certain individuals, for example those with a specific microbiological profile. Critics warn that the inclusion of antibiotics in routine periodontal protocols may contribute considerably to the development of bacterial antibiotic resistance. However, little evidence supports microbiological testing as a means to obtain better clinical outcomes (Mombelli et al, 2013), and the true impact of antimicrobial periodontal treatments on the development of bacterial antibiotic resistance has yet to be determined.

Such a contribution may be very minor in comparison to the effects of frequent antibiotic prescriptions by doctors for other reasons, whether therapeutic or prophylactic. A recent study found that the use of amoxicillin plus metronidazole in periodontal therapy did not significantly affect the resistance pattern of the viridans group streptococci to penicillin or erythromycin (Mombelli et al, 2016). While other studies have shown a connection between antibiotic use and resistance, these are often confounded by various factors or do not analyse antibiotic exposure and outcome individually for each patient. As a result, these studies at best indicate association, but not causality.

To limit their overuse, we recommend abstention from using antibiotics whenever it is reasonable to assume that thorough non-surgical mechanical debridement alone can resolve the problem – and this is the case for uncomplicated and moderately advanced periodontitis. In patients with advanced defects, especially with lesions on molar teeth, systemic amoxicillin plus metronidazole significantly enhances the effects of SRP, thereby diminishing the need for costlier surgical interventions (Mombelli et al, 2013).

Too many periodontally compromised teeth are extracted today because of a lack of trust in non-surgical cause-related periodontal therapy. Many of these teeth could be saved with a very efficient and efficacious treatment: SRP plus amoxicillin and metronidazole. Ironically, when clinicians subsequently place implants to replace the extracted teeth, they will give their patients antibiotics without hesitation. Rather than using antibiotics according to their main purpose – to fight a disease caused by bacteria – they are prescribed empirically, in the hope that they will prevent a secondary infection. But the evidence to support antibiotics as prophylaxis is minimal, while the evidence for their therapeutic benefit is overwhelming.

While non-surgical periodontal therapy with adjunctive antibiotics meets a lot of scepticism, practitioners nonetheless prescribe antibiotics when half-finished cause-related therapy needs to be completed surgically, when regenerative procedures are carried out to reconstruct tissues, and whenever peri-implantitis needs to be treated. Much of this can be avoided if the bacteria causing the disease are rigorously suppressed in the first place.

References

Cortellini, P., 'Minimally invasive surgical techniques in periodontal regeneration.' Journal of Evidence-Based Dental Practice, 2012;12: 89-100.

Griffiths, G. S., Ayob, R., Guerrero, A., Nibali, L., Suvan, J., Moles, D. R. & Tonetti, M. S., 'Amoxicillin and metronidazole as an adjunctive treatment in generalized aggressive periodontitis at initial therapy or re-treatment: a randomized controlled clinical trial.' Journal of Clinical Periodontology, 2011; 38: 43-49.

Kaner, D., Christan, C., Dietrich, T., Bernimoulin, J. P., Kleber, B. M. & Friedmann, A., 'Timing affects the clinical outcome of adjunctive systemic antibiotic therapy for generalized aggressive periodontitis.' Journal of Periodontology, 2007; 78: 1201-08.

Mombelli, A., Almaghlouth, A., Cionca, N., Courvoisier, D. S. & Giannopoulou, C., 'Differential benefits of amoxicillin-metronidazole in different phases of periodontal therapy in a randomized controlled crossover clinical trial.' Journal of Periodontology, 2015; 86: 367-75.

Mombelli, A., Cionca, N., Almaghlouth, A., Cherkaoui, A., Schrenzel, J. & Giannopoulou, C., 'Effect of Periodontal Therapy With Amoxicillin-Metronidazole on Pharyngeal Carriage of Penicillin- and Erythromycin-Resistant Viridans Streptococci.' Journal of Periodontology, 2016; 87: 539-47.

Mombelli, A., Cionca, N., Almaghlouth, A., Décaillet, F., Courvoisier, D. S. & Giannopoulou, C., 'Are there specific benefits of Amoxicillin plus Metronidazole in Aggregatibacter actinomycetemcomitans-associated periodontitis? Double-masked, randomized clinical trial of efficacy and safety.' Journal of Periodontology, 2013; 84: 715-24.

Zandbergen, D., Slot, D. E., Niederman, R. & Van der Weijden, F. A., 'The concomitant administration of systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating periodontitis: a systematic review.' BMC Oral Health, 2016,  DOI 10.1186/s12903-12015-10123-12906.

Shapira: ‘We need to consider alternatives to antibiotics’

If we look at the accumulated evidence (Jespen & Jespen 2016), we can conclude that the main benefit of the use of adjunctive antibiotics can be found in very severe patients (in which the majority of the pockets are 7 mm or more), with limited to no response to non-surgical intervention, and in young patients with aggressive forms of periodontitis.  This is a very small group of our patients, and the long-term effect of the treatment is still questionable.  Are there alternatives with similar effects?

During the course of periodontal disease, a dysbiosis of the normal oral flora triggers an inflammatory response, which in turn results in periodontal tissue damage.  Since antibiotics change the oral flora in a non-specific manner, alternatives should be considered. 

One recently explored approach is the use of probiotics after non-surgical mechanical periodontal therapy. The idea is to restore the positive bacterial population and to prevent the establishment of pathogens.  Martin-Cabezas et al (2016), in a detailed systematic review, found that the adjunctive use of probiotics can restore the microbial flora and improve the clinical parameters of patients with periodontitis – without the collateral damage caused by antibiotics.  In a short-term controlled study, Teughels et al (2013) showed that the use of adjunctive probiotics can reduce by 50% the “need for surgery”, similar to the results shown previously for adjunctive antibiotics, but without the risks involved.  In addition, probiotics is not a drug and can be adopted for long-term use.

In most of our patients, the majority of the pockets are moderate, and only a limited number of them are deep (7 mm and above). These deep pockets are the ones that are putting the teeth at risk, and are the main challenge to our treatment. In these cases, local sustained-released delivery systems with antimicrobials can be used.  They release their anti-bacterial substance for up to ten days in the target site only, and this treatment can be repeated during supportive periodontal therapy when indicated (Soskolne et al 2003). 

Periodontitis is not an infectious disease.  It is an inflammatory disease which is considered to be initiated by bacteria that are normal habitants of the oral flora.  The tissue damage is caused by the uncontrolled inflammatory response. The use of host-modulating drugs to control periodontitis might be the future, and clinical data is starting to accumulate which support this novel approach.

Researchers have recently shown in several studies that the use of combination of low-dose aspirin with omega-3 derivatives together with non-surgical periodontal therapy is able to improve the results of the mechanical anti-infective treatment, and the results are comparable to the use of adjunctive antibiotics (El Khouli et al 2011; Naqvi et al, 2014; Deore et al, 2014; Elwakeel et al, 2015).  This is a unique anti-inflammatory approach to the treatment of periodontitis, and the promising pilot results need to be established by wider studies and more research centres. This combination lacks the hazards of antibiotic use and can be administrated for lifetime. 

Resolvins are a new class of “inflammation-resolving” drugs from the lipid mediator family. These natural compounds have been found to induce resolution of uncontrolled inflammation in many experimental models of different diseases.  Their positive effect on periodontitis was proven in several animal studies of experimental periodontitis, and they are already being used today in human clinical trials (Gyurko & Van Dyke, 2014, Chun-Teh Lee et al, 2016). 

In summary, it may be possible at present to justify the use of adjunctive antibiotics with a very small number of patients – those with many uncontrolled risk factors (such as uncontrolled diabetes) and those who are not responding favourably to other treatment approaches, in spite of their good compliance. The treatment of those patients should be limited to dentists with adequate training in periodontology, which will allow better control of antibiotic use. 

We are still in the process of looking for a host-modulating approach, directed towards controlling inflammation that will be complementary to the conventional anti-plaque approach. But this approach is very much the future.

References

Martin-Cabezas, R., Davideau, J.L., Tenenbaum, H., Huck, O., ‘Clinical efficacy of probiotics as an adjunctive therapy to non-surgical periodontal treatment of chronic periodontitis: a systematic review and meta-analysis’, Journal of Clinical Periodontology, June 2016: 43(6): 520-30.

Teughels, W., Durukan, A., Ozcelik O., Pauwels, M., Quirynen, M., Haytac, M.C., ‘Clinical and microbiological effects of Lactobacillus reuteri probiotics in the treatment of chronic periodontitis: a randomized placebo-controlled study’, Journal of Clinical Periodontology, November 2013; 40(11): 1025-35.

Soskolne, W.A., Proskin, H.M., Stabholz, A., ‘Probing depth changes following 2 years of periodontal maintenance therapy including adjunctive controlled release of chlorhexidine’, Journal of Periodontology, April 2003; 74(4): 420-7.

Elkhouli, A.M., ‘The efficacy of host response modulation therapy (omega-3 plus low dose aspirin) as an adjunctive treatment of chronic periodontitis (clinical and biochemical study): a randomized, double-blind, placebo-controlled study’, Journal of Periodontal Research, 2011; 46: 261-68.

Naqvi et al, ‘Docosahexaenoic Acid and Periodontitis in Adults: A Randomized Controlled Trial’, Jouranl of Dental Research, 2014; 93(8): 767-73.

Deore et al, ‘Omega 3 fatty acids as a host modulator in chronic periodontitis patients: a randomised, double-blind, palcebo-controlled, clinical trial’, Journal of Periodontal Implant Science, 2014;44: 25-32, http://dx.doi.org/10.5051/jpis.2014.44.1.25.

Elwakeel, N.M., Hazaa, H.H., ‘Effect of omega 3 fatty acids plus low-dose aspirin on both clinical and biochemical profiles of patients with chronic periodontitis and type 2 diabetes: a randomized double blind placebo-controlled study’, Journal of Periodontal Reseach, 2015; doi:10.1111/jre.12257

Gyurko, R., Van Dyke, T.E., ‘The role of polyunsaturated ω-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1) in bone preservation’, Critical Reviews in Immunology, 2014;34(4): 347-57.

Chun-Teh Lee et al, ‘Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis’, Journal of Immunology, due to be published in October 2016.

Mombelli: ‘Costs and benefits of alternative methods are not clear’

With regards to alternative methods, too many patients are submitted to treatments with a poor or unclear cost-benefit ratio. As long as comprehensive evaluations of benefits, risks, and economic aspects are lacking, it does not help our patients to prematurely promote potential novel approaches as an alternative to thoroughly scrutinised protocols.

Nobody supports the routine prescription of systemic antibiotics in all cases of periodontitis. We all agree that simple and moderate cases of periodontitis can, and should, be treated with non-surgical mechanical means only. But in advanced cases – i.e. those where big-flap surgery seems to be indicated – we should consider thorough full-mouth scaling and root planing assisted by amoxicillin and metronidazole as a first treatment. Hopefully, our patients will be protected from the later use of "prophylactic" antibiotics.

Finally, when you eat your next beef steak, you might like to consider the following. The European Medicines Agency reported that 8,421 tonnes of antibiotics were sold as veterinary antimicrobial agents, applicable mainly to food-producing animals, in 25 EU/EEA countries in 2011.

The 1,947 tonnes of penicillin fed to these animals in one year – principally as a growth-promoter rather than for treating infection! – corresponds to the total dose necessary to treat 247 million human cases of periodontitis (375 mg t.i.d. for seven days equals 7,875 g amoxicillin), which is about half the entire population of these 25 countries.

Lior Shapira: Prof. Lior Shapira is the Chairman of the Department of Periodontology in the Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem Israel. He is also the Vice Dean, a full professor in Periodontology, and the “Betty and D. Walter Cohen Chair for Clinical Periodontal Research”.  Prof. Shapira has published over 100 scientific and clinical papers, and he is serving today at the editorial boards of the Journal of Clinical Periodontology and the Journal of Periodontology. Several international awards, including the Teva award (1996), the Rizzo award (1999), the “Sunstar Award” (2003), and the “Distinguished Scientist Award in Periodontal Research” of the IADR (2009) have acknowledged the impact of his research work. 

Andrea Mombelli: Professor and Chair, Division of Periodontology, and director of the post-graduate programme in periodontology at the University of Geneva School of Dental Medicine, Switzerland. He graduated from the University of Bern School of Dental Medicine and completed his post-graduate studies reaching the status of Private Docent in 1992. He has a Swiss Federal diploma in dentistry (D.D.S.), a Doctorate in dentistry (Dr. med. dent.) and is a Swiss board certified periodontist.