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Department of PeriodontologySchool of Dental MedicineUniversity of Zagreb This paper presents a critical evaluation of the use of systemic antimi- crobial treatment in periodontal disease. Recognizing specific types ofperiodontal infections can significantly influence the choice of antimicro-bial treatment. Therapy should be tailored to differences in antibioticsusceptibility between various periodontal pathogens.
Many different antibiotic regimens have been described in the liter- ature, making the choice in clinical practice difficult. Numerous stud-ies have examined the impact of systemic antibiotic treatment in stop-ping the progression of periodontal diseases. Major candidates forantibiotic therapy are patients whose disease continues to progressdespite conventional mechanical treatment. Antibiotics can also be usedin patients with localized aggressive or other early developed forms of periodontitis, as well as in patients with systemic diseases affecting the course of periodontitis. They have proven to be beneficial as anadjunct to standard therapy. Serious side-effects of systemic antibiotic treatment, such as development of resistance and increase in opportunis-tic microorganisms, do not justify their use in the treatment of chron- ic, slowly-progressive forms of periodontal diseases.
Zavod za ParodontologijuStomatoloπkog fakulteta Key words: periodontitis, antimicrobial therapy, antibiotics, subgin- related to active destructive periodontal disease.
Some of the periodontally pathogenic bacteria are: Gingivitis and periodontitis are the two most Actinobacillus actinomycetemcomitans, Porphyro- common infectious periodontal diseases. Gingivi- monas gingivalis, Prevotella intermedia, Bacteroi- tis occurs in almost all individuals. Advanced peri- des forsythus, Peptostreptococcus micros, Campy- odontitis is found in 10-20 % of the adult popula- lobacter rectus, Eikenella corrodens, Fusobacteri- tion. Both diseases are primarily caused by supra- um nucleatum, Treponema denticola, certain Enter- and subgingival microbial plaque, possessing the obacteriaceae species and staphylococci (1-3).
properties of a biofilm. Microbial composition of Elimination or adequate suppression of periodon- pathogenic plaque has been studied over the last two tal pathogens in the subgingival microflora is essen- to three decades. A higher percentage of certain tial for periodontal healing to take place. Antimicro- microbial species in the subgingival plaque has been bial therapy in periodontology includes mechani- Acta Stomatol Croat, Vol. 38, br. 1, 2004. Antimicrobial Treatment of Periodontal Diseases cal debridement of the root surfaces, oral hygiene bial periodontal therapy (24). Antibiotic therapy of measures and local and systemic antimicrobial severe periodontitis forms should be adapted to the differential antimicrobial susceptibility of the peri- Inflammatory periodontal diseases are primari- ly treated with supra- and subgingival scaling of the Microbiological analysis revealed that subjects affected tooth surfaces. Clinical improvement is with the same clinical form of the disease have dif- directly related to the reduction or removal of the ferent bacterial composition of subgingival plaque, subgingival pathogenic plaque (4-6). The majority and that the same bacteria can be found in different of subgingival bacteria is sensitive to the antimi- clinical forms of the disease. Consequently, it is not crobial effect of mechanical therapy (7). Mechani- possible to relate specific bacteria to specific clini- cal and surgical treatment, combined with proper cal appearance, or discern between periodontitis oral hygiene, in most cases arrests further periodon- forms on the basis of microbiological isolates. This tal attachment loss. However, despite well performed conclusion is in accordance with modern under- mechanical treatment, in some individuals the clin- standing of periodontal disease as a result of the ical attachment destruction cannot be stopped.
interaction between microorganisms and different Refractory periodontitis and diminished immune host factors. The same microorganisms can lead to host response (8) can be related to residual subgin- different clinical forms of the disease (26).
gival pathogens (9, 10). Numerous studies have Starting with the first investigations in the late shown that mechanical debridement cannot effec- 1970s, the use of antibiotics in periodontal therapy tively eliminate A. actinomycetemcomitans, P. gin- has been controversial. The value of antibiotic ther- givalis, P. intermedia, B. forsythus, P. micros, enter- apy has often been misinterpreted, overestimated or obacteria and some other bacterial species (5, 6, 11, over-simplified. In this article we will survey mod- 12-14). The reason is the ability of the mentioned ern concepts of systemic antimicrobial therapy in bacterial species to invade gingival epithelial cells the treatment of periodontal diseases.
and subepithelial connective tissue (15-18). Cer-tain periodontal pathogens possess the ability torecolonise the tooth surfaces from the tongue, ton- sillae and buccal mucosa which act as reservoirs(19). Targeted antimicrobial therapy could perhaps Microscopic studies at the beginning of the last suppress or eliminate residual periodontal pathogens, century revealed the presence of large numbers of and thus serve as an adjunct to conventional mechan- spirochetes and amoebas in subgingival plaque (27, 28). These microorganisms were held responsible Microbial composition of subgingival plaque can for the initiation of periodontal disease, and subse- differ greatly between individual patients (21, 22).
quently neo-salvarsan and ementin were used as Recent studies have shown that some subgingival treatment. These anorganic arsenic drugs had very bacteria, including Actinobacillus actinomycetem- dangerous side effects. After them appeared pron- comitans and Porphyromonas gingivalis, relatively tosil, chemotherapeutic derived from artificial dyes, rarely occur in healthy periodontium, and are able one of its metabolites being sulfonamide. Sulfon- to stimulate production of specific antibodies in amides are still being used in medicine. The begin- patients with periodontitis. These bacteria are exoge- ning of the antibiotic era was Flemming's discov- nous microorganisms and could represent true peri- ery of Penicillium notatum mould producing a sub- odontal infections (23). Atypical (non-oral) patho- stance which inhibits Staphylococcus aureus growth.
genic enteric bacteria were isolated from some peri- Since then numerous antibiotics have been discov- odontal lesions, and present superinfections. Peri- ered, which are used in medical or dental practice.
odontal infections caused by oral microorganisms Although the advantages of antibiotic use in fight- can be considered endogenous periodontal infec- ing bacterial infection are huge, unwanted effects tions. Knowing the type of periodontal infections such as resistance, toxicity, sensitivity and interac- is important when choosing appropriate antimicro- tion with other medications are often encountered.
Acta Stomatol Croat, Vol. 38, br. 1, 2004. Antimicrobial Treatment of Periodontal Diseases Traditionally, in periodontics antibiotics were Most of the clinical studies only tested one prescribed to patients not responding to conventional antibiotic, instead of comparing different kinds of mechanical treatment, or as an adjunct for peri- antibiotics. Therefore it is very difficult to give one- odontal surgical procedures. Initially, the choice of sided, on scientific evidence-based recommendation antibiotics was based on clinical experience and for the choice of antibiotic treatment of certain peri- mostly penicillins were used. Tetracycline hidrochlo- ride became widely used during the 1970s, and theadvantages of its usage were its broad antimicrobialspectrum and low systemic toxicity. First controlled clinical studies testing the effectiveness of antibi-otic therapy started in the late 1970s. Despite numer-ous investigations, it is still not clear which is the most effective antibiotic in periodontology. In the Tetracyclines are a group of broad-spectrum, bac- literature, many different forms of antibiotic thera- teriostatic antibiotics. They are the first antimicro- py have been described, making the choice of antibi- bial drugs which have been scientifically investi- gated in periodontology. This group includes tetracy-cline hydrochloride, minocycline and doxycycline.
In their double-blind clinical studies, Rams and Keyes (36) and McCulloch et al. (37), showed that The aim of antimicrobial therapy is to stop peri- systemic intake of tetracyclines statistically signifi- odontal attachment loss, and as far as possible, to cantly reduced probing pocket depth. The risk of the maintain the soft tissue esthetics. This includes occurrence of periodontal destruction after 7 months removal of bacterial plaque and calculus from the was decreased by 43%, and destruction was not root surfaces, surgical access if needed, and oral stopped in more than one third of the patients. Some hygiene instructions and removal of local plaque authors described the reappearance of the disease after systemic tetracycline therapy (38, 39). Possi-ble cause of further disease progression are microor- Systemic antimicrobial therapy in periodontol- ganisms inadequately suppressed by tetracycline, ogy is based on the fact that specific bacterial species such as A. actinomycetemcomitans (40). Tetracycline cause periodontal destruction and that it is possible therapy could lead to superinfection with enteric bac- to achieve bactericidal or bacteriostatic concentra- teria, staphylococci or with Candida albicans (41-43).
tions of the antimicrobial substance in the peri-odontal pocket (29). In comparison with mechani- It seems that the older studies showed benefi- cal treatment or local delivery, systemically adminis- cial effect against A. actinomycetemcomitans, while tered antibiotics have several advantages. Through newer studies do not support this. This can partly be serum it is possible to influence microorganisms explained by the higher resistance to these antibi- (Table 1) in the furcation area, or at the bottom of otics. Besides this, positive effects were observed in a deep periodontal pocket, perhaps even bacteria studies conducted in North america, where different present in the epithelial or connective tissue of the A. actinomycetemcomitans serotypes are present gingiva (30), or bacteria colonising oral mucosa or with different virulence factors, than in Europe. We extraoral locations (31, 32). Disadvantages of antibi- did not find studies in the literature by European otic therapy are possible adverse effects (Table 2) authors showing beneficial effect of tetracyclines Since periodontal disease is not caused by one Concerning the choice of tetracyclines, the advan- microorganism, antibiotic usage for elimination of tages of doxycycline are one daily dosage, rare gas- one pathogenic species is not possible. In the best trointestinal adverse effects, as well as normal cal- case, antibiotics will suppress some subgingival bac- cium absorption. Especially interesting is the usage teria over a limited period of time (35).
of low-dosage doxycycline (20-30 mg) during 6-9 Acta Stomatol Croat, Vol. 38, br. 1, 2004. Antimicrobial Treatment of Periodontal Diseases months. Clinical attachment gain has been proved, without resistance occurrence or changes in normal A member of the fluorquinolones, it is used in the periodontal microflora (44). Besides the antimicro- therapy of urinary infections. Ciprofloxacin is also bial effect, doxycycline inhibits collagenase and effective in the treatment of periodontal superinfec- other matrix metalloproteinases, enzymes respon- tions caused by enteric bacteria, pseudomonas or sible for collagen degradation during periodontal staphylococci. Clinical isolates of A. actinomyce- infection, so its efficacy is partly due to this mech- temcomitans are highly sensitive to ciprofloxacin (49). Another positive aspect is its inactivity towards Minocycline, as an adjunct to mechanical thera- streptococci, whose presence in the subgingival area py failed to eliminate A. actinomycetemcomitans in is associated with periodontal health. Heightened all patients, and the disease reoccurred in 25% of streptococcal counts can postpone recolonisation of the test subjects, despite regular check-ups every 3 the pathogenic bacterial species (50).
It seems that the effect of tetracyclines is opti- mal in patients with 'refractory' chronic periodon- Azithromycin is an antibiotic from the macrolide titis, while it is not the best choice for treatment of group, it exerts bacteriostatic activity by blocking localised aggressive periodontitis, due to the weak of bacterial proteins synthesis. The spectrum is broad effect on A. actinomycetemcomitans the antibiotics and covers gram-negative bacteria, including enteric bacteria. Assessment of availability in periodontaltissues showed extremely high values in periodon- tal tissues, crevicular fluid and saliva. Periodontal-ly inflamed tissues exhibit concentrations signifi- Metronidazole is a synthetic nitroimidazole. Its cantly higher than healthy periodontal tissues, which action is bactericidal, acting on anaerobic bacteria, is a very convenient characteristic of this antibiotic including gram-negative rods and spirochetes, through (51). Data from clinical investigations support the DNA synthesis blocking. Due to the susceptibility use of azithromycin in the treatment of advanced of the spirochetes, it is effective in cases of necrotis- chronic, or aggressive periodontitis (52).
ing periodontal diseases. It seems relatively ineffec-tive in the suppression of A. actinomycetemcomi- tans. Periodontal abscesses can be successfuly treat- Clindamycin is a pyranoside antibiotic similar to ed with metronidazole, while for aggressive peri- macrolides, with a broad antimicrobial spectrum.
odontitis treatment its antimicrobial spectrum is not Efficacy of clindamycin has been tested in several clinical studies (53, 54). This drug has stopped attach-ment loss in a high number of patients and increased the number of sites with the attachment gain, even Penicillins inhibit bacterial cell-wall synthesis, in patients who had already undertaken unsuccess- and the antimicrobial spectrum of natural penicillins ful antibiotic therapy. Resistance to clindamycin of is narrow. Amoxicillin is a semi-synthetic penicillin certain A. actinomycetemcomitans and P. gingivalis with broadened antimicrobial spectrum, and is used serotypes was described (55). Because of the pos- in periodontology because it is effective against sibility of dangerous side-effects, as well as the occur- some subgingival bacterial species such as P. micros rence of resistance of certain subgingival microor- and A. actinomycetemcomitans as well. It can be used ganisms to this medicaton, it is not the first-choice in cases of acute infections, although it is most com- antibiotic used in the treatment of periodontal dis- monly used in combination with metronidazole.
Amoxicillin in combination with clavulonic acid is It can be concluded that antibiotic monothera- indicated in the presence of oral bacteria capable py, with one medication as an adjunct to the mechan- ical therapy, has a favourable influence on the com- Acta Stomatol Croat, Vol. 38, br. 1, 2004. Antimicrobial Treatment of Periodontal Diseases position of bacterial microflora and reduction in the apy, or in cases of disease reactivation during the number of active periodontal pockets. Clinical im- supportive phase of therapy, occurring despite good provement is a result of the total bacterial load sup- oral hygiene and repeated mechanical subgingival pression, and the changes in the composition of the instrumentation. One of the combinations effective subginigival bacterial microflora. Due to the complex in the prevention of recurrent periodontitis in high- composition of the subgingival bacterial microflo- risk individuals is doxycycline and metronidazole ra, such a form of antibiotic therapy is often ineffec- tive in eliminating exogenous bacterial pathogens.
Systemic antimicrobial therapy in periodontal Subgingival microflora in periodontal diseases The main candidates for antibiotic therapy are includes different pathogenic bacteria possessing periodontal patients, in which conventional mechan- differential sensitivity to antimicrobials, so the use ical therapy does not arrest further disease progres- of two or more antibiotics presents a useful option sion. The use of antibiotics is also indicated in patients in the treatment of these diseases. The advantages with localised aggressive periodontitis or other forms of combined antibiotic therapy are broadened spec- of early-onset disease, as well as in patients with sys- trum of antimicrobial activity, occurence od syner- temic disease influencing the periodontitis. In patients gistic activity (Table 3) (56) and prevention of bac- with acute or recurrent periodontal infections, like terial resistance development. Disadvantages of such periodontal abscesses, acute necrotizing gingivitis a treatment are elevated incidence of adverse effects.
or periodontitis (62) or periimplantitis (63), systemic Metronidazole in combination with amoxicillin medication of antibiotics can lead to clinical improve- or ciprofloxacin has been successfuly used in the ment. Patients with stable periodontitis can profit treatment of advanced periodontitis, especially infec- from antimicrobial therapy minimally or for a short tions with A. actinomycetemcomitans (9, 39, 57, 58).
Metronidazole and amoxicillin in vitro act synergis- Microbiological analysis should be performed tically on A. actinomycetemcomitans. Combination after conventional mechanical therapy has been fin- of metronidazole with amoxicillin or amoxicillin and ished, in order to assess the need for antibiotic ther- clavulonic acid can eliminate A. actinomyctemco-mitans and other periodontal pathogens from the apy. It should include antimicrobial susceptibility periodontal pockets for at least two years (57, 59).
testing on specific antimicrobials. The microbial test- Metronidazole and ciprofloxacin can be effective in ing should be repeated 1-3 months after the antibi- mixed periodontal infections, such as the presence otic administration, not only to check if elimination of anaerobes, A. actinomycetemcomitans, enteric bac- or marked suppression of the pathogens occurred, teria and pseudomonades (58, 59). As this combina- but also to monitor for possible superinfections (23, tion is ineffective against most gram-positive, fac- ultative anaerobic bacteria, it can facilitate strepto- Microbial sampling of individual or several com- coccal colonisation of the pockets which have no bined active pockets is conducted. The sample com- periodontally pathogenic potential (60).
bined from more pockets gives a better insight in the Serial use of antibiotics is indicated for a combi- spectrum of periodontal pathogens that need to be nation of antibiotics, in which one has bactericidal acted upon through antimicrobial therapy. Repre- and the other bacteriostatic activity. Combined admin- sentative subgingival sample is obtained by com- istration would lead to antagonistic effects and ther- bining samples from the deepest pocket bleeding apeutical failure. This form of systemic antimicro- or showing suppuration, from each quadrant (66). The bial therapy should be used in especially severe cases samples can be taken by means of sterile curettes of recurrent or refractory periodontitis, where attach- or paper points, and the samples should immediately ment loss was not arrested despite careful initial ther- be put into the reduced transport media (67).
Acta Stomatol Croat, Vol. 38, br. 1, 2004. Antimicrobial Treatment of Periodontal Diseases of the disease. Systemic antimicrobial therapy isindicated in cases of disease where the periodontal The value of systemic antibiotic use in arresting destruction continued, despite thoroughly performed disease progression has been investigated in numer- mechanical therapy. In patients from high-risk groups, ous studies. It was shown that it can improve the such as aggressive forms of periodontitis or peri- treatment outcome, as an adjunct to therapy. Seri- odontitis as a manifestation of systemic disease, the ous adverse effects such as the development of antibi- use of antibiotics is indicated as an adjunct to scal- otic resistance and growth of opportunistic microor- ing and root planing. Antibiotics are never indicat- ganisms do not support the concept of routine use ed in the treatment of chronic gingivitis.
of antibiotics in the treatment of chronic, adult forms Acta Stomatol Croat, Vol. 38, br. 1, 2004.

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