SYSTEMIC ANTIBIOTICS IN THE TREATMENT OF PERIODONTAL DISEASE

SYSTEMIC ANTIBIOTICS IN THE TREATMENT OF PERIODONTAL DISEASE Jørgen Slots & Miriam Ting

Periodontitis 1. Lifelong disease characterized by periods of exacerbation and remission.

Non surgical scaling and root planing 1. May remove subgingival Campylobacter rectus but is frequently ineffective against Porphyromonas gingivalis, Protevolla intermedia, Bacteroides forsythus, staphylococci and enteric rods, and may not significantly reduce Actinobacillus actinomycetemcomitans or Peptostreptococcus micros.

Non surgical scaling and root planing 2. Mechanical debridement may fail to remove pathologic organisms because of their location in subepithelial gingival tissue (A. actinomycetemcomitans), crevicular epithelial cells (A. actinomycetemcomitans, P. micros, P. intermedia and P. gingivalis), collagenous substrata (P. gingivalis), altered cementum and radicular dentinal tubuli, subgingival hard deposits or furcations or other anatomic features complicating adequate instrumentation.

Microbiology in oral cavity and systemic antibiotics 1. Moreover, periodontal pathogens frequently colonize oral mucosa, tongue dorsum, tonsils and other oral domains and may translocate from non-periodontal sites to periodontal crevices. 2. Systemic antibiotics enter the periodontal tissues and the periodontal pocket via serum and can affect organisms outside the reach of cleaning instruments or topical anti-infective chemotherapeutics.

Microbiology in oral cavity and systemic antibiotics 3. Systemic antibiotic therapy can also potentially suppress periodontal pathogens residing on the tongue or other oral surfaces, thereby delaying subgingival recolonization of pathogens. Müller et al. JPR 1998 4. Systemic antibiotics may even be required for eradication of periodontal infections by A. actinomycetemcomitans and other pathogens. Müller et al. JPR 1998

Antibiotic-resistant bacteria 1. Inappropriate antibiotic therapy may adversely affect human microbial ecology and give rise to resistance development among serious pathogens, microbiological analysis and antimicrobial susceptibility testing should ideally form the basis for selecting the optimal antimicrobial therapy.

Antibiotic-resistant bacteria 2. Antibiotic-resistant bacteria can emerge by acquiring new genes via transposons or horizontal gene transfer or by selection of resistant variants or naturally resistant strains. 3. Microbiological analysis is particularly advisable in patients who are recalcitrant to conventional periodontal therapy and may harbor a great variety of periodontal pathogens.

Periodontitis and systemic antibiotic therapy 1. Since periodontitis lesions often harbor a mixture of pathogenic bacteria, drug combination therapies have gained increased importance. 2. Valuable combination therapies include metronidazoleamoxicillin for A. actinomycetemcomitans and various anaerobic periodontal infections and metronidazoleciprofloxacin for mixed anaerobic and enteric rod/ Pseudomonas periodontal infections.

General considerations in antibiotic therapy

Dug dosage and administration 1. Penicillin and clindamycin : three times a day 2. Metronidazole, ciprofloxacin and erythromycin : twice a day 3. Doxycycline ad azithromycin : once a day

Systemic antibiotics and gingival crevicular level 1. Effective levels of amoxicillin and clavulanic acid in the gingival crevicular fluid, well above the minimal inhibitory concentrations of some periodontopathic bacteria (P. intermedia), could be achieved after multiple drug applications. 2. Metronidazole can readily attain effective antibacterial concentrations in gingival tissue and crevicular fluid.

Systemic antibiotics and gingival crevicular level 3. The macrolide antibiotic roxithromycin and spiramycin and metronidazole, which are combined in Rodogyl®, can also reach effective antimicrobial levels in gingival tissue and crevicular fluid. 4. Azithromycin exhibits excellent ability to penetrate into both normal and pathological periodontal tissues.

Systemic antibiotics and gingival crevicular level 5. Fluoroquinolones also penetrate readily into periodontal tissue and gingival crevicular fluid and may reach even higher concentrations than serum. 6. The average concentration of systemically administered tetracyclines in gingival crevicular fluid was less than in plasma and varied widely among individuals, possibly explaining much of the variability in clinical response to systemic tetracyclines observed in practice.

Systemic antibiotics and Food 1. Food does not influence the bioavailability of most oral antimicrobial agents, except for tetracyclines, quinolones and azithromycin. 2. These three groups of antibiotics should be given 1 hour before or 2 hours after food intake.

Antibiotics and interactions with each other 1. Many antibiotics may interact with other drugs and cause clinically significant effects. 2. Interaction occurs when one drug alters the other drug’s pharmacokinesis with respect to absorption, distribution, metabolism or excretion.

Effectiveness of systemic antibiotics in periodontal therapy

Effect of systemic antibiotic therapy on clinical variables

Systemic doxycycline 1. Administration for 6 weeks was associated with significantly reduced plaque accumulation at weeks 12 posttreatment compared with placebo.

Systemic antibiotics and gingival inflammation 1. 7 days of systemic metronidazole therapy significantly reduced the proportion of gingival bleeding sites compared with controls. Watts et al. JCP 1986 2. Metronidazole-amoxicillin combination therapy resulted in less gingival bleeding for up to 12 months compared with placebo. López et al. JP 1998, JP 2000

Systemic antibiotics and gingival inflammation 3. It might be that systemic antibiotic therapy is ineffective against gingival inflammation related to supragingival plaque but may help decrease gingivitis caused by susceptible subgingival microorganisms.

Systemic antibiotics and pocket depth 1. 7 days of systemic metronidazole therapy reduced pocket depth significantly compared with controls. Noyan et al. JCP 1997; Elter et al. JPR 1997 2. 7 days of systemic metronidazole-amoxicillin combination therapy produced greater probing depth reduction than did control medication, especially in pockets having initial depths greater than or equal to 7 mm. Winkel et al. JCP 2001

Systemic antibiotics and pocket depth 3. Found most probing depth reductions in pockets greater than 6 mm. Loesche et al. JP 1984 4. Demonstrated a significant decrease in pocket depth after systemic metronidazole and clindamycin therapies. Sigusch et al. JP 2001

Systemic antibiotics and pocket depth 5. A comprehensive anti-infective therapy, including a 2 week regimen of amoxicillin/clavulanic acid in conjunction with professional, subgingival delivery of povidone-iodine, and chlorhexidine mouthwash rinses twice daily, was effective at reducing probing pocket depth with a 56% decrease in the number of pockets greater than 6 mm at 6 weeks posttreatment. Collins et al. JP 1993

Systemic antibiotics and pocket depth 6. Systemic spiramycin as adjunct to scaling and root planing may give rise to significant reduction in probing depth as well.

Systemic antibiotics and clinical attachment levels 1. Systemic metronidazole and its combinations can significantly improve clinical (probing) attachment level compared with controls. 2. 7 days of systemic metronidazole therapy significantly increased attachment levels in periodontal pockets with greater than 4 -6 mm depth. Noyan et al. JCP 1997; Elter et al. JPR 1997

Systemic antibiotics and clinical attachment levels 3. Metronidazole-amoxicillin combination therapy for 714 days significantly increased the proportion of periodontal sites gaining clinical attachment compared with controls. López et al. JP 1998, JP 2000; Winkel et al. JCP 2001 4. Demonstrated most clinical attachment gain in periodontal pockets probing greater than 6 mm. Berglundh et al. JCP 1998

Systemic antibiotics and clinical attachment levels 5. Found significant gain in clinical attachment level after systemic metronidazole and clindamycin therapy. Sigusch et al. JP 2001 6. Systemic doxycycline therapy for 3 weeks followed by systemic metronidazole for 10 days resulted in improved attachment levels and reduced disease recurrence compared with metronidazole treatment alone. Aitken et al. JP 1992

Systemic antibiotics and clinical attachment levels 7. Amoxicillin/clavulanic acid along with subgingival povidon-iodine therapy resulted in clinical attachment gain of at least 1 mm in 41% deep sites at 3 years posttreatment. Collins et al. JP 1993 8. Systemic tetracycline administered during a 3 -week period concomitant with nonsurgical treatment led to almost three times greater gain in clinical attachment than occurred in an age- and sex-matched control group. Ramberg et al. JCP 2001

Systemic antibiotics and radiographic bone level 1. 7 -day systemic metronidazole therapy led to increased alveolar bone height compared with baseline. Söder et al. JP 1999 2. In early lesions of juvenile periodontitis, 1 g of systemic tetracycline per day for 6 weeks resulted in marked gains in clinical attachment and almost complete repair of alveolar bony defects, and the clinical outcome remained stable up to 4 years following the antibiotic therapy. Novak et al. JP 1991

Systemic antibiotics and disease activity 1. Compared with pre-antibiotic findings, clindamycin. HCl therapy for 7 days caused a decrease in the proportion of disease-active sites per subject per month. Gordon et al. JP 1985, JP 1990 2. Metronidazole-amoxicillin combination therapy for 1 week may significantly decrease periodontal disease activity compared with placebo medication. López et al. JP 1998, JP 2000;

Systemic antibiotics and surgical needs 1. Systemic metronidazole for 7 days reduced the number of teeth assigned to surgery more than in control groups with or without the use of placebo. Loesche et al. JCP 1992; JP 1991 2. Systemic doxycycline therapy for 14 days might reduce the need for periodontal surgery, although this finding was statistically nonsignificant compared with controls. Loesche et al. OSOMOPORE 1996

Systemic antibiotics and other clinical variables 1. After 14 days of systemic minocycline therapy, significant decreases in the number of epithelial cells and salivary protease activity in periodontal pockets greater than 6 mm was found. Atilla et al. JP 1996 2. 14 days of systemic spiramycin therapy or 14 days of systemic tetracycline therapy may diminish the rate of gingival fluid flow. Al-Joburi et al. JP 1989

Effect of systemic antibiotic therapy on microbiological variables

Systemic antibiotics and A. Actinomycetemcomitans 1. A. A. is considered an exogenous oral pathogens, and treatment aims at completely removing the organism from the oral cavity. 2. Many systemic antibiotic therapies are unable to consistently suppress subgingival A. A. to undetectable levels.

Systemic antibiotics and A. Actinomycetemcomitans 3. Single systemic therapies by metronidazole or tetracycline may markedly reduce oral A. A. but not eradicate the organism. 4. Strains of A. A. serotype b, which seems to constitute the most periodontopathic serotype in some populations (Asikainen et al. Oral Microbiol. Immunol. 1991), may be more resistant to antibiotic therapy than A. A. serotype a (Haffajee et al. JCP 1996).

Systemic antibiotics and A. Actinomycetemcomitans 5. Periodontal surgery together with systemic tetracycline -HCl was able to decrease periodontal A. A. to below detectable levels in about 50% of the study patients. Slots & Rosling JCP 1983 6. Systemic ofloxacin, 200 mg twice daily for 5 days, in conjunction with open flap surgery was able to suppress A. A. below detectable levels in 22 study patients for a period of 12 months.

Systemic antibiotics and A. Actinomycetemcomitans 7. Systemic ofloxacin therapy can also resolve periodontal A. A. infection in Papillon-Lefèvre syndrome patients. Ishikawa et al. JP 1994 8. Systemic minocycline was unable to eliminate A. A. from buccal mucosa and saliva. Müller et al. JP 1993

Systemic antibiotics and A. Actinomycetemcomitans 9. Periodontal surgery together with systemic minocycline caused a marked suppression of A. A. in virtually all infected localized periodontitis lesions but was not as predictable in severe and generalized types of periodontitis; 10. However, the organism reappeared in some localized periodontitis lesions at 6 months posttreatment. Müller et al. JP 1993

Systemic antibiotics and A. Actinomycetemcomitans 11. The combination of metronidazole (250 mg) and amoxicillin (375 mg), three times daily for 8 days comprises an effective and low-cost therapy against A. A. in localized juvenile periodontitis, Papillon-Lefèvre syndrome periodontitis, adult-type periodontitis, rapidly progressive periodontitis, generalized advanced periodontitis and refractory periodontitis. Eickholz et al. JP 2001; van Winkelhoff et al. JCP 1989, JP 1992

Systemic antibiotics and A. Actinomycetemcomitans 12. Metronidazole-amoxicillin combination therapy may reduce to below detection levels in subgingival plaque for at least 2 years and in oral mucous membranes, tongue dorsum and tonsils for at least 1 year. Flemmig et al. JCP 1998

Systemic antibiotics and A. Actinomycetemcomitans 13. The failure to remove oral A. A. from all patients may be due to lack of patient compliance with the prescribed antibiotic regimen, due to biofilm effect or other microbial factors impeding the effectiveness of antibiotic therapy, or due to reinfection from other individuals.

Systemic antibiotics and A. Actinomycetemcomitans 14. Dentists should not rely solely upon systemic antibiotic therapy for eradicating A. A. from periodontal sites and the entire mouth but, might benefit from combining systemic metronidazole-amoxicillin therapy with mechanical debridement and topical antiseptic treatment.

Systemic antibiotics and P. gingivalis 1. P. gingivalis appears also to be an exogenous oral pathogen, but the organism is difficult to eradicate from subgingival sites by antibiotic therapy alone. 2. Systemic metronidazole for 10 days may suppress subgingival P. gingivalis to very low levels for over 6 months in some patients (Gusberti et al. JCP 1988; Kleinfelder et al. JCP 2000) but not in all cases (Nieminen et al. JCP 1996).

Systemic antibiotics and P. gingivalis 3. Differences in treatment outcome may be partly due to biofilm-associated P. gingivalis that can be resistant to metronidazole at concentrations that are usually attained by systemic administration. 4. Single antibiotic therapy by amoxicillin/clavulanic acid for 10 days may reduce subgingival levels of P. gingivalis and the number of P. gingivalis-infected patients, but not significantly compared with placebo. Kleinfelder et al. JCP 2000; Winkel et al. JCP 1999

Systemic antibiotics and P. gingivalis 5. Metronidazole-amoxicillin therapy for 7 -8 days can reduce subgingival levels of P. gingivalis, although not consistently to below detectable levels. Winkel et al. JCP 2001; JCP 1998 6. Subgingival scaling together with systemic metronidazole-amoxicillin for 14 days caused more suppression of P. gingivalis for 12 months than scaling without metronidazole or metronidazole with scaling. Berglundh et al. JCP 1998

Systemic antibiotics and P. gingivalis 7. Metronidazole-amoxicillin seems to be most effective in suppressing P. gingivalis in rapidly progressive adult periodontitis. van Winkelhoff et al. JCP 1989 8. Almost completely eradication of subgingival P. gingivalis after comprehensive subgingival scaling and systemic metronidazole or clindamycin therapy. Sigusch et al. JP 2001

Systemic antibiotics and P. gingivalis 9. It may be that predictable and long-term eradication of subgingival P. gingivalis from deep periodontal sites requires a combined approach of systemic antibiotic therapy, careful root debridement possibly in conjunction with periodontal surgery and professional and self-care administration of subgingival antiseptics. Slots et al, Periodontol 2000

Systemic antibiotics and B. forsythus 1. Systemic metronidazole, amoxicillin/clavulanic acid, tetracycline and metronidazole-amoxicillin combined therapy may reduce subgingival levels of B. forsythus. 2. However, compared with placebo, the proportional occurrence of B. forsythus and number of infected subjects were significantly reduced only immediately after the termination of the metronidazole-amoxicillin therapy. Winkel et al JCP 2001

Systemic antibiotics and P. intermedia 1. P. intermedia is an indigenous organism that can not be expected to be eradicated from the oral cavity. van Winkelhoff et al. Periodontol 2000. 2. Subgingival P. intermedia seems to be most effectively reduced by metronidazole with or without amoxicillin.

Systemic antibiotics and P. intermedia 3. Metronidazole single drug therapy for 7 -10 days may reduce subgingival P. intermedia counts. Aitken et al. JP 1992; Kamma JP 2000; Loesche et al JCP 1992, JP 1991, JP 1984; Winkel et al. JCP 1997 4. Metronidazole-amoxicillin for 7 days may significantly decrease the proportion of P. intermedia-infected sites. López et al. JP 1998

Systemic antibiotics and P. intermedia 5. Amoxicillin without metronidazole or combined with clavulanic acid was not effective in decreasing subgingival P. intermedia levels. Haffajee et al. JCP 1996; Winkel et al. JCP 1999 6. Doxycycline used in combination with metronidazole caused an increase rather than a decrease in subgingival P. intermedia counts. Aitken et al. JP 1992

Systemic antibiotics and spirochetes 1. Most systemic antibiotics can reduce levels of subgingival spirochetes but not permanently eradicate the organisms. 2. Clindamycin for 7 days (Gordon et al. JP 1985) and metronidazole for 7 -10 days (Clark et al. JP 1983; Gusberti et al. JCP 1988) can also significantly decrease subgingival spirochete counts.

Systemic antibiotics and spirochetes 3. Systemic metronidazole without scaling did not significantly reduce subgingival spirochetes compared with baseline. Lindhe et al. JCP 1983 4. Tetracycline-HCl for two periods 14 days separated by a 4 -week interval (Listgarten et al. JCP 1978) and tetracycline for 1 year (Lindhe et al JCP 1983) suppressed spirochetes below detectable levels.

Systemic antibiotics and spirochetes 5. Doxycycline for 14 days reduced spirochetes in advanced periodontitis lesions to below detectable levels for at least 3 months. Lundström et al. JCP 1984 6. Azithromycin in doses of 500 mg once daily for 3 days can also significantly decrease subgingival spirochete counts. Sefton et al. JCP 1996

Systemic antibiotics and other periodontopathic bacteria 1. Metronidazole can reduce levels of total obligate anaerobes, Fusobacterium species, Selenomonas species, Eikenella corrodens, Campylobacter rectus and Peptostreptococcus micros. 2. The effect of metronidazole on Veillonella, a nonperiodontopathic species, is not consistent.

Systemic antibiotics and other periodontopathic bacteria 3. Amoxicillin with clavulanic acid may reduce subgingival levels of Capnocytophaga, Fusobacterium nucleatum, E. corrodens and C. recta and increase levels of Capnocytophaga ochracea and P. micros. 4. Tetracyclines may decrease subgingival Fusobacterium nucleatum and C. ochracea

Systemic antibiotics and other periodontopathic bacteria 5. The metronidazole –amoxicillin combination but apparently not amoxicillin-clavulanic acid has the potential of reducing subgingival levels of F. nucleatum.

Systemic antibiotics and antibiotic-resistance 1. Metronidazole for 7 -10 days increased subgingival proportions of Streptococcus sanguis and Streptococcus mutans and of Actinomyces naeslundii, Actinomyces odontolyticus and Actinomyces viscosus.

Systemic antibiotics and antibiotic-resistance 2. Subgingival overgrowth of periodontally harmless bacteria may occupy niches previously inhabited by periodontal pathogens and, because of antagonistic bacterial interactions (Chen and Slots, Curr. Opin. Periodontol. 1993), delay or prevent major pathogens from re-colonizing subgingival sites.

Systemic antibiotics and antibiotic-resistance 3. However, overgrowth of mutans streptococci on exposed root surfaces might also increase the risk of dental caries and argue for prophylactic application of topical fluoride concomitant with anti-infective periodontal surgery.

Conclusion and Recommendations

1. Systemic antibiotics may inhibit or kill periodontal pathogens located subgingivally outside the reach of dental instruments and topical antiseptics as well as pathogens invading gingival tissues or residing in nonperiodontal sites of the oral cavity. 2. Decreasing periodontal pathogens counts in the entire oral cavity may delay subgingival recolonization of pathogens and ensure prolonged prophylactic benefits.

3. Tetracyclines have the additional advantages of inhibiting collagenases. 4. Indiscriminate antibiotic administration is contrary to sound clinical practice and unnecessarily increases in vivo resistance to antimicrobial agents that are valuable in potentially fatal medical infections or may cause overgrowth of intrinsically resistant pathogens.

5. Empirical antibiotic therapy may be used for periodontal diseases with known microbial causes, such as acute necrotizing ulcerative gingivitis, which is caused by anaerobic organisms and can be cured by metronidazole, and early localized juvenile periodontitis, mostly involving A. A. , which can be controlled or eradicated by systemic metronidazoleamoxicillin combination therapy.

6. Since the group of periodontal pathogens exhibits diverse antimicrobial susceptibility, microbiological analysis is sometimes necessary for proper selection of antibiotic therapy. 7. If microbiological testing is unavailable, metronidazoleamoxicillin combination therapy (250 -500 mg of each, three times daily for 8 days) may be a reasonable antibiotic first choice in periodontics.

8. However, the metronidazole-amoxicillin combination does not affect Pseudomonas or enteric gram (-) rods that inhabit approximately 14% of advanced periodontitis lesions in the United States and more in developing countries.

9. Another valuable systemic antibiotic therapy in periodontics is the combination of metronidazole and ciprofloxacin (500 mg of each, twice daily for 8 days), which can cure anaerobic, enteric rod and A. A. periodontal infections and promote subgingival overgrowth of streptococci able to inhibit gram (-) pathogens.

10. However, if potentially pathogenic beta-hemolytic streptococci colonize subgingival sites, their overgrowth after antibiotic therapy might lead to recurrence of disease. 11. Some of the inherent risks with antibiotic-resistant pathogens may be partly overcome by concomitant subgingival administration of antiseptic agents capable of suppressing antibiotic-resistant pathogenic organisms.

12. Management of severe types of periodontitis should not rely solely on systemic antibiotics but upon a combination of mechanical debridement possibly in conjunction with surgery, subgingival administration of antiseptics by dental professionals and patients, patients’ oral hygiene efforts and effective and safe systemic antibiotics.