Systemic antibiotics in the treatment of periodontal disease

Transcription

1 Periodontology 2000, Vol. 28, 2002, Copyright C Munksgaard 2002 Printed in Denmark All rights reserved PERIODONTOLOGY 2000 ISSN Systemic antibiotics in the treatment of periodontal disease JØRGEN SLOTS &MIRIAM TING Periodontitis in many patients is a lifelong disease characterized by periods of exacerbation and remission. In most patients, mechanical debridement and anti-infective chemotherapy can readily control the disease without the need for surgery. A subset of patients with more severe may require surgery, which results in almost complete cure of the infection, at least temporarily. Properly managed, virtually all patients can retain their dentition for a lifetime. Current periodontal therapy strongly emphasizes suppressing or eradicating specific periodontal pathogens (116, 119). However, present treatment modalities differ in their ability to eliminate periodontal pathogens. Nonsurgical scaling and root planing may remove subgingival Campylobacter rectus (94) but is frequently ineffective against Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, staphylococci and enteric rods (27, 68, 87, 92, 106), and may not significantly reduce Actinobacillus actinomycetemcomitans (95, 123, 143) or Peptostreptococcus micros (93). Mechanical debridement may fail to remove pathogenic organisms because of their location in subepithelial gingival tissue (A. actinomycetemcomitans) (16, 86), crevicular epithelial cells (A. actinomycetemcomitans, P. micros, P. intermedia and P. gingivalis) (24, 33, 49, 98), collagenous substrata (P. gingivalis) (75), altered cementum and radicular dentinal tubuli (2, 37), subgingival hard deposits (105) or furcations or other anatomic features complicating adequate instrumentation. Moreover, periodontal pathogens frequently colonize oral mucosa, tongue dorsum, tonsils and other oral domains and may translocate from non-periodontal sites to periodontal crevices (70, 74, 89, 120). During the past two decades, dentists and microbiologists have embraced periodontal antibiotic therapy as the evidence for bacterial specificity in has accumulated and strengthened (108, 110). Antibiotics, defined as naturally occurring or synthetic organic substances that, in low concentrations, inhibit or kill selective microorganisms, are particularly useful in combating severe periodontal infections. 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. Systemic antibiotic therapy can also potentially suppress periodontal pathogens residing on the tongue or other oral surfaces, thereby delaying subgingival recolonization of pathogens (69). Systemic antibiotics may even be required for eradication of periodontal infections by A. actinomycetemcomitans and other pathogens (71). Practitioners have traditionally chosen the antimicrobial agents, route of administration and duration of use based more on personal bias and experience than on data from microbiological studies and rigorous clinical trials. However, because the periodontopathic microbiota includes a variety of microorganisms with differing antimicrobial susceptibility, because clinical disease features can only rarely incriminate the offending bacteria and because 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 (9, 21, 26, 32, 91, 124, 126). 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. Microbiological analysis is particularly advisable in patients who are recalcitrant to conventional periodontal therapy and may harbor a great variety of periodontal pathogens. In addition, the medical status of the patient and potential adverse effects of antibiotics are important therapeutic considerations. Single drug therapies with penicillins, tetracyclines, metronidazole or clindamycin have been used fre- 106

2 Systemic antibiotics in the treatment of periodontal disease quently in periodontal practice. However, since lesions often harbor a mixture of pathogenic bacteria, drug combination therapies have gained increased importance (108, 109). Valuable combination therapies include metronidazole amoxicillin for A. actinomycetemcomitans and various anaerobic periodontal infections (85, 143) and metronidazole ciprofloxacin for mixed anaerobic and enteric rod/ Pseudomonas periodontal infections (111). Knowledge of the efficacy and safety of periodontal antibiotic therapy is growing rapidly, but many important aspects of the choice of medication, mode of delivery, dosage and length of therapy remain to be determined. This chapter therefore attempts to describe the potential of systemic antibiotic therapy to control the periodontopathic microbiota and destructive periodontal disease rather than comprising a comprehensive state-of-the science report that probably soon would be outdated anyway. This chapter evaluates the utility of systemic antibiotics in the treatment of moderate to severe types of adult and of some special clinical situations and makes recommendations for therapy. However, because destructive periodontal disease has variable clinical manifestations and often an unpredictable course, which makes evaluation of case reports and studies with small sample sizes or short duration difficult, and because relatively few antibiotic studies have been placebo-controlled, the specific recommendations for antibiotic periodontal therapy will unquestionably be revised along with the development of even better understanding of the pathogenic periodontal microbiota and the availability of new drugs that are tested in placebo-controlled, long-term studies. General considerations in antibiotic therapy The pharmacological characteristics of antibiotics are critical in deciding their use, dosage and routes and frequency of administration. Important pharmacological determinants include the degree of absorption, rate of metabolism and duration of effective antimicrobial levels at the site of infection. As pointed out by van Winkelhoff et al. (134), a sufficiently high dosage of metronidazole or other antibiotics must be prescribed to ensure efficacy in periodontal treatment. To maintain effective antimicrobial levels after oral administration, penicillins and clindamycin must be taken three times a day, metronidazole, ciprofloxacin and erythromycin twice a day, and doxycycline and azithromycin suffice once a day (Table 1). Tenenbaum et al. (125) showed that 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. Metronidazole can readily attain effective antibacterial concentrations in gingival Table 1. Selected pharmacological features and common adverse reactions of antibiotics Approximate Peak Serum wholesale price % absorption serum half-life Usual adult (generic) for after oral level dosage Most common adverse dosage (oral) in one usual adult Antibiotics administration in mg/ml in hours reactions, % occurrence periodontics dosage Clindamycin Diarrhea: 7% 300 mg three or $3.25 four times daily Metronidazole Nausea/vomiting: 12% 250 three times $0.25 daily or 500 mg twice daily Penicillins Hypersensitivity (rash): 5% mg three $0.25 (amoxicillin) Diarrhea: 5% times daily Tetracyclines Photosensitivity 200 mg once daily $0.10 (doxycycline) (sunscreen advised) (doxycycline) Erythromycins Diarrhea: 8% mg three $0.25 times daily Azithromycin Diarrhea: 5% mg once $6.50 (250 mg) daily Clarithromycin Diarrhea: 3% 500 mg twice daily $3.50 Photosensitivity Fluoroquinolones Nausea/vomiting: 5% 500 mg twice daily $3.75 (ciprofloxacin) Photosensitivity 107

3 Slots & Ting Table 2. Adverse drug reactions in relation to patient age Age Drug Reactions Comments Pregnancy Clindamycin None known Probably safe fetal toxicity Metronidazole Perhaps teratogenic Avoid Penicillins None known Probably safe Tetracyclines Discoloration and hyperplasia of teeth and Contraindicated depressed skeletal growth Erythromycins Chlorithromycin may cause fetal toxicity in primates Avoid Fluoroquinolones Arthropathy in animals Contraindicated Children All antibiotics Adjust dosage to avoid excessive concentrations Tetracyclines Discoloration and hyperplasia of teeth and Contraindicated depressed skeletal growth Fluoroquinolones Cartilage toxicity in young animals Contraindicated Elderly adults All antibiotics Advanced age may be associated with altered pharmacokinetics of antibiotics Clindamycin Increased frequency of pseudomembranous colitis Penicillins Increased frequency of anaphylaxis due to prior exposure tissue and crevicular fluid (13, 51, 129). The macrolide antibiotic roxithromycin (23) and spiramycin and metronidazole, which are combined in Rodogyl A (97), can also reach effective antimicrobial levels in gingival tissue and crevicular fluid. Azithromycin exhibits excellent ability to penetrate into both normal and pathological periodontal tissues (12, 64). Fluoroquinolones also penetrate readily into periodontal tissue and gingival crevicular fluid and may reach even higher concentrations than in serum (10, 20, 43, 84). In contrast to earlier studies, Sakkelari et al. (100) found that the average concentration of systemically administered tetracyclines in gingival crevicular fluid was less than in plasma and varied widely among individuals (between 0 and 8 mg/ml), with approximately 50% of samples not achieving levels of 1 mg/ml, possibly explaining much of the variability in clinical response to systemic tetracyclines observed in practice. Food does not influence the bioavailability of most oral antimicrobial agents, except for tetracyclines, quinolones and azithromycin. These three groups of antibiotics should be given 1 hour before or 2 hours after food intake. Systemic antibiotics can give rise to a number of adverse reactions and should be administered only after proper indication has been determined. Table 1 lists the frequency of the most common adverse reactions of antibiotics used in periodontal treatment. Serious adverse reactions are fortunately rare and are discussed elsewhere (136). Cost can be a determinant in selecting anti- microbial periodontal therapy. Table 1 shows the average wholesale prices in US dollars for antibiotics in the United States in spring Antibiotics in the lower-cost group include tetracyclines, amoxicillin and metronidazole. Antibiotics in the higher cost group include azithromycin, clarithromycin, ciprofloxacin, amoxicillin/clavulanic acid and clindamycin. The possibility of unique age-related adverse effects is an important consideration in prescribing antibiotics. Prescribing antibiotics to pregnant women is a cause for particular concern. Table 2 lists age-related safety issues of antibiotics commonly used in periodontal therapy. Many antibiotics may interact with other drugs and cause clinically significant effects (Table 3). Interaction occurs when one drug alters the other drug s pharmacokinesis with respect to absorption, distribution, metabolism or excretion. The list of drug drug interactions keeps expanding and is too long to be memorized. Patients on long-term medication for cardiovascular disease, asthma, seizures or diabetes are at particularly high risk for drug drug interactions. Effectivess of systemic antibiotics in periodontal therapy This chapter concentrates on studies that have evaluated the utility of systemic antibiotic treatments commonly employed in periodontics. The 108

4 Systemic antibiotics in the treatment of periodontal disease Table 3. Antibiotic drug drug interactions Clinical Antibiotic Interacting drug Effect significance Clindamycin Anti-diarrheal agents (kaolin) Decreased absorption of clindamycin Probable Muscle relaxants (diazepam) Increased frequency and duration of respiratory Probable paralysis Erythromycin Mutual antagonism Probable Metronidazole Barbiturates and hydantoins Decreased effectiveness of metronidazole Probable Oral anticoagulants (warfarin) Increased anticoagulant effect Definite Ethanol Disulfiram-like (Antabuse A ) reaction Probable Disulfiram (Antabuse A ) Acute toxic psychosis Probable Penicillins/ Probenecid Increased levels of penicillins Probable amoxicillin Tetracyclines/ Antacids, aluminum, bismuth, Decreased absorption of tetracyclines due to Probable doxycycline iron, Mg ππ chelation Barbiturates and hydantoins Decreased serum half-life of doxycycline Probable Carbamazepine (Tegretol A ) Decreased serum half-life of doxycycline Probable Digoxin Increased serum levels of digoxin Probable Erythromycins/ Carbamazepine Increased serum levels of carbamazepine: Definite azithromycin/ nystagmus, nausea, vomiting and ataxia clarithromycin Cisapride Increased cisapride concentration, with the risk Definite of life-threatening arrhythmia Cyclosporine Increased serum levels of cyclosporine, Probable with toxic effects Methylprednisolone Increased steroid concentration Definite Nonsedating antihistamines Increased antihistamine concentration, Definite (terfenadine, astemizole) with the risk of life-threatening arrhythmia Theophylline Increased serum levels of theophylline, Definite with nausea, vomiting, seizures and apnea Oral anticoagulants (warfarin) Increased anticoagulant effect Probable Fluoroquinolones Cations (Al πππ,ca ππ,fe ππ, Decreased absorption of fluoroquinolones Definite (ciprofloxacin) Mg ππ,zn ππ ) in antacids, due to chelation vitamins and dairy products Caffeine Increased caffeine concentration Probable Cimetidine Increased serum levels of fluoroquinolones Probable Cyclosporine Increased serum levels of cyclosporine Probable Nonsteroidal Increased risk of central nervous system stimulation Definite anti-inflammatory drugs Probenecid Decreased ciprofloxacin clearance Probable Sucralfate Decreased absorption of fluoroquinolones Definite Theophylline Increased serum levels of theophylline Definite Oral anticoagulants (warfarin) Increased anticoagulant effect Probable studies selected originate from a variety of research centers and include patients with chronic as well as aggressive. Table 4 presents an overview of the antibiotic therapies examined, the study designs and the clinical and microbiological variables studied. Effect of systemic antibiotic therapy on clinical variables Systemic antibiotic therapy does not significantly affect supragingival plaque accumulation (Table 5). Reduction in dental plaque depends mostly on patients oral hygiene efforts. However, Ng & Bissada (76) reported that systemic doxycycline administration for 6 weeks was associated with significantly reduced plaque accumulation at week 12 posttreatment compared with placebo. Systemic antibiotics might not have a significant effect on gingival inflammation, with the possible exception of metronidazole, doxycycline and metronidazole amoxicillin combinations (Table 6). Watts et al. (139) found that 7 days of systemic metronidazole therapy significantly reduced the proportion of gingival bleeding sites compared with 109

5 Slots & Ting Table 4. Overview of study designs on systemic antibiotic periodontal therapy Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Lincosamides Gordon 20 Adult refractory Clindamycin- Patients with history of Number of active Not done et al. (38) (31 69 years) HCl 150 mg, unsuccessful treatment with sites four times daily, scaling, periodontal % active sites per 7 days surgery, tetracycline 250 mg, subject four times daily, days, and at least one % active sites per other antibiotic, including subject per month penicillin V, ampicillin, % sites probing Augmentin A, erythromycin, cephalexin 1 3 mm and metronidazole Patients were treated with scaling and clindamycin therapy Gordon 13 Refractory Clindamycin- History of periodontal Number of active % spirochetes et al. (39) (31 67 years) HCl 150 mg, therapy with extensive sites four times daily, antibiotic therapy including % active sites per 7 days tetracycline-hcl, a subject penicillin compound, erythromycin and % active sites per cephalexin subject per month Patients were treated with scaling and clindamycin Eight patients participated in microbial analysis Side effects: one subject developed pseudomembranous colitis Macrolides Al-Joburi 79 (mean age: Advanced adult Spiramycin Subjects were randomly Plaque Index % spirochetes et al. (4) 46 years) 1,500,000 IU assigned to spiramycin, Number of sites twice daily, tetracycline and placebo. Tetracycline: 27 bleeding on probing 14 days Scaling and root planning Spiramycin: 28 started at baseline Probing depth for: Placebo, four Pockets 4 6 mm Placebo: 24 times daily, Only data for placebo and Pockets Ø7 mm 14 days spiramycin presented Attachment level for: Pockets 4 6 mm For pockets Ø7 mm Periotron readings for gingival crevicular fluid Nitroimidazoles Aitken Doxycycline π Periodontitis Metronidazole Treatment in the previous % subjects with % sites positive for: et al. (3) metronidazole: patients 250 mg, three 7 months included disease recurrence % A. actinomycetemcomitans 11 previously times daily, bimonthly scaling with within 3 months E. corrodens (mean age: treated with 10 days (11 subjects) or without F. nucleatum Gingival 50 years) placebo or (12 subjects) 3 weeks of P. intermedia attachment level doxycycline systemic doxycycline P. gingivalis spirochetes Placebo π 7 months ago metronidazole: All patients received showing 12 thorough subgingival (mean age: continued scaling, root planning and 54 years) attachment loss prophylaxis and oral greater than hygiene instruction 2mm Only data from placebo and metronidazole group presented Clark 23 mentally Destructive Metronidazole Prophylaxis and root Gingival Index % spirochetes et al. (18) retarded periodontal 250 mg, three planning was not done. adolescents disease times daily, Subjects randomly assigned Attachment level excluding acute 7 days to antibiotic group or necrotizing Placebo, three placebo group ulcerative times daily, gingivitis and 7 days juvenile periodontosis 110

6 Systemic antibiotics in the treatment of periodontal disease Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Gusberti 5 Recurrent Metronidazole History of scaling, root Plaque index % A. naeslundii et al. (40) periodontal 250 mg, three planning and modified Bleeding on probing % A. odontolyticus disease times daily, Widman flap surgery % Capnocytophaga spp. 10 days followed by maintenance Probing depth % E. corrodens visits every 3 5 months Attachment level % Fusobacterium spp. Scaling, root planning and % P. gingivalis antibiotic treatment % P. intermedia % spirochetes Jenkins 10 (38 55 years) Advanced adult Metronidazole Supragingival and Plaque index % spirochetes et al. (45) 200 mg, three subgingival debridement Probing depth % streptococci times daily, and, 3 months later, 5 days antibiotic therapy and halfmouth debridement The experimental design allowed comparisons between debridement only, metronidazole only and debridement π metronidazole Attachment level Lindhe 16 (32 48 years) Advanced adult Metronidazole Subjects randomly assigned % sites having: % spirochetes et al. (53) 200 mg, four to antibiotic group or Plaque IndexΩ0 times daily for control group. Subjects Gingival IndexΩ0 three periods of received a series of scaling Probing dept 2 weeks treatments involving only Æ4 mm separated by two quadrants of the intervals of 8 dentition Attachment level weeks Loesche 33 Advanced adult Metronidazole Scaling and root planning, Probing depth: % A. actinomycetemcomitans et al. (57) 250 mg, three antibiotics or placebo For initial % A. naeslundii Test: 15 times daily, probingæ3 mm %A. odontolyticus Need for periodontal : 18 7 days For initial probing % A. viscosus surgery or extraction 4 6 mm % Fusobacterium spp. determined 4 6 weeks after For initial % P. gingivalis initial treatment probingø7 mm %P. intermedia % S. sanguis Attachment level: % S. mutans For initial % Selenomonas spp. probingæ3 mm % Treponema spp. For initial probing % Veillonella spp. 4 6 mm For initial probingø7 mm Number of teeth requiring surgery % teeth requiring surgery Loesche Test: 29 Advanced adult Metronidazole Scaling and root planning Number of teeth Not done et al. (58) (26 77 years) 500 mg, twice followed by random requiring surgery daily, 14 days assignment to control, and extraction Placebo: 33 simultaneously metronidazole or (31 71 years) with placebo, doxycycline group once daily, Only data for the first round 14 days of metronidazole and Placebo, twice control are presented daily, 14 days simultaneously with another placebo, once daily, 14 days Loesche Test: 18 Advanced adult Metronidazole Antibiotic therapy, multiple % teeth requiring Anaerobic species: et al. (59) : mg, three visits for scaling, root surgery % F. nucleatum times daily, planning and oral hygiene Probing depths % P. gingivalis 7 days instruction % P. intermedia Placebo, three Attachment level % Selenomonas spp. times daily, Facultative species: 7 days % A. actinomycetemcomitans % A. naeslundii % A. viscosus % S. sanguis % S. mutans 111

7 Slots & Ting Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Loesche 40 Moderate to Metronidazole All three groups received Number of % A. naeslundii et al. (60) Advanced advanced adult 250 mg, three mechanical debridement pocketsø7 mm per % A. odontolyticus disease test times daily, and oral hygiene subjects % A. viscosus group 7 days instruction Number of sites % Capnocytophaga spp. Placebo, three Advanced disease test with attachment % F. nucleatum Moderate times daily, group received antibiotics lossø7 mm % P. intermedia disease test 7 days % P. gingivalis group Moderate disease test group Pocket depth: % S. mutans Moderate and moderate disease For initial probing % S. sanguis disease placebo placebo group were 4 6 mm % Veillonella spp. group randomly assigned in a For initial probing double-blind fashion to 6 mm receive antibiotics or Attachment level: placebo For initial probing 4 6 mm For initial probing 6 mm Lundström 4 Advanced adult Metronidazole Oral hygiene instruction, Probing depths % spirochetes et al. (63) Sufficient oral 200 mg, three subgingival debridement % bleeding sites hygiene group: 2 times daily, and antibiotic therapy 7 days Poor oral Only data from patients hygiene group: 2 randomly chosen for metronidazole therapy were presented Nieminen 33 Advanced adult Metronidazole After initial nonsurgical Bleeding on probing % subjects, % microflora: et al. (77) 250 mg, three therapy, patients were Number of pockets: A. actinomycetemcomitans Surgery: 15 times daily, randomly assigned to either Probing depthø6 P. gingivalis Metronidazole: 10 days periodontal surgery mm 18 (modified Widman flap) or Probing depth systemic antibiotics Ω4 5 mm Post-treatment % subjects with unresponsive patients attachment loss received surgery or systemic metronidazole, depending on which of the procedures had already been given previously Data for periodontal surgery only and antibiotic therapy only were presented Noyan 10 (35 51 years) Adult Metronidazole Oral hygiene instruction Plaque Index % obligate anaerobes et al. (79) 250 mg, three Test: 5 Patients divided into two Gingival Index times daily, groups (five patients each) : 5 7 days Probing depth consisting of a topical antibiotic group and a Attachment loss systemic antibiotic group. In the systemic antibiotic group, subjects received scaling in two quadrants and no scaling in the remaining two quadrants Only data for systemic antibiotic group (test), and scaling and root planning only group (control) were presented Palmer Test: 31 Moderate to Metronidazole Oral hygiene instruction, % sites with plaque % spirochetes et al. (82) (mean age: advanced adult 200 mg, three ultrasonic instrumentation, 45 years) times daily, followed by random % bleeding sites 7 days assignment to either % sites probing Ø7 : 27 systemic or topical mm (mean age: 51 years) antibiotics or control group Attachment level Only data for systemic antibiotic and control groups were presented 112

8 Systemic antibiotics in the treatment of periodontal disease Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Palmer Smoker Moderate to Metronidazole Oral hygiene instruction Proportion of sites % spirochetes at 6 months et al. (83) treatment advanced adult 200 mg, three and subgingival scaling with plaque groups: times daily, Subjects randomly assigned % sites with plaque test: 10 7 days to three groups: no further at 6 months control: 9 treatment group, systemic Proportion of sites Nonsmoker antibiotics group and with bleeding on treatment topical antibiotics group probing groups: Only data for systemic test: 21 % bleeding sites at 6 antibiotics were presented control: 18 months Probing depth Attachment level Saxén & Asikainen Test: 9 Localized Metronidazole Oral hygiene instruction, % bleeding sites % subjects: (101) (14 25 years) juvenile 200 mg, three scaling and root planning % sites probing A. actinomycetem-comitans : 9 times daily, every 3 months, antibiotic Ø4 mm (14 25 years) 10 days therapy, modified Widman flap surgery performed at 6 Number of sites: months with 25% bone : no medication loss with 25 48% bone Only data for loss metronidazole and control groups were presented Söder et al. (121) Test: 46 Moderate and Metronidazole All patients received oral Mean number of Number of spirochetes per (35 45 years) advanced 400 mg, three hygiene instruction, sites Ø5 mm unit, times daily, professional cleaning and : 46 Mean probing Number of P. gingivalis with more than 7 days deep scaling (35 45 years) depth positive patients three teeth with Placebo, three Reported side effects: 5 mm pockets times daily, Plaque Index Number of Test: 15 patients and radiographic 7 days A. actinomycetemcomitans Placebo: nine patients % subjects having alveolar bone positive sites more than three loss after scaling Gastric discomfort: teeth with pockets and root Test: six patients Ø5 mm planning Placebo: seven patients Severe diarrhea: Test: one patient, metronidazole treatment was discontinued Objection to the taste: Test: eight patients Placebo: one patient Söder et al. (122) 64 (mean age: Advanced adult Metronidazole Comprehensive % teeth with: % subjects: 36 years) 400 mg, three professional prophylactic Plaque Index Ω2 A. actinomycetemcomitans times daily, treatment, including scaling Plaque Index Ω3 P. gingivalis Smokers 7 days and root planning, followed P. intermedia Test: 16 % teeth bleeding on Placebo, three by antibiotics or placebo, % spirochetes Placebo: 21 probing times daily, with or without periodontal Nonsmokers 7 days surgery, and regular Subjects surgically Test: 16 maintenance over 5 years and non-surgically Placebo: 11 treated % teeth with pockets Ø5mm Probing depth Attachment level % bone height von Troil-Lindén 10 (mean age: Advanced Metronidazole Scaling and root planning, % sites with plaque % patients: et al. (135) 56 years) 500 mg, twice soft tissue curettage, % sites with gingival A. actinomycetemcomitans daily, gingivoplasty when bleeding C. rectus 7 days indicated, antibiotic P. gingivalis therapy, twice daily % sites probing P. intermedia/p. nigrescens chlorhexidine rinse and Æ3 mm P. micros chlorhexidine gel in % sites with: interdental areas during and alveolar bone loss an additional week after 1/3 mechanical therapy alveolar bone loss Spouse data were not Ø1/2 presented Walsh et al. (138) Test: 6 Adult Metronidazole Test group: antibiotics only Plaque Index % Fusobacterium spp. (28 59 years) 2 g single dose Scaling group: oral hygiene Bleeding Index % obligate anaerobes Scaling: 6 for treatment of instruction, scaling and root % spirochetes Trichomonas Probing depth (23 53 years) planning vaginalis by Attachment loss : 6 medical staff : no treatment (25 44 years) 113

9 Slots & Ting Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Watts et al. (139) Test: 13 Adult Metronidazole Scaling and root planning % bleeding sites % spirochetes : mg, three followed by random times daily, assignment to either 7 days antibiotic or placebo group Placebo, three times daily, 7 days Winkel 27 (29 64 years) Refractory Metronidazole Supragingival and Plaque Index % subjects, % microflora: et al. (142), 500 mg, three subgingival debridement, Bleeding on probing Posttreatment B. forsythus in culture-positive times daily, antibiotic therapy. pretreatment B. forsythus for B. forsythus 7 days Re-examination at Probing depth positive subjects and culture- 6 months Attachment level Posttreatment P. gingivalis in negative for pretreatment P. gingivalis A. actinopositive subjects mycetemcomitans Posttreatment P. gingivalis in pretreatment P. gingivalis negative subjects Posttreatment P. intermedia in pretreatment P. intermedia positive subjects Posttreatment P. intermedia in pretreatment P. intermedia negative subjects Penicillins Abu Fanas 4 Rapidly Amoxicillin Oral hygiene instruction, % sites bleeding on % F. nucleatum et al. (1) progressive 250 mg with supragingival and probing clavulanic acid subgingival scaling and root Mean probing (125 mg), three planning pocket depth times daily, Supragingival plaque 14 days control was maintained throughout the experimental period, with further scaling and oral hygiene instruction if necessary Collins 30 (23 70 years) Refractory Amoxicillin Patients with history of % sites: % subjects: et al. (19) 250 mg with periodontal treatment Bleeding on probing A. actinomycetemcomitans clavulanic acid (including periodontal Probing 0 3 mm E. corrodens (125 mg), four surgery and antibiotic Probing 4 6 mm F. nucleatum times daily, therapy) and progressive Probing 6 mm Capnocytophaga spp. 14 days attachment loss or repeat C. recta abscess development P. gingivalis The refractory treatment protocol consisted of systemic antibiotic therapy, topical povidone iodine, 3% hydrogen peroxide rinse to remove coronal staining, and twice-daily chlorhexidine (0.12%) rinse All patients had already received periodontal maintenance within the last 3 months and were calculus-free at the initiation of therapy Haffajee 98 (14 71 years) Mild to Amoxicillin Subgingival scaling, Clinical data % sites: et al. (41) moderate 250 mg with modified Widman flap and presented in graphs, A. actinomycetemcomitans clavulanic acid antibiotics mean values not serotype a (125 mg), three Patients with evidence of given A. actinomycetemcomitans times daily, 30 prior attachment loss serotype b days B. forsythus Subjects with localized Placebo 250 mg C. ochracea juvenile or sucrose, three P. gingivalis rapidly progressive times daily, P. intermedia were not 30 days P. nigrescens included 114

10 Systemic antibiotics in the treatment of periodontal disease Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Winkel Test: 10 Generalized Amoxicillin Scaling and root planning, Mean Plaque Index et al. (140) (36 66 years) adult 500 mg with oral hygiene instruction. % subjects, % microflora: Bleeding on probing clavulanic acid Repeated oral hygiene A. actinomycetemcomitans : (125 mg), three instruction, scaling and Gingival Index B. forsythus 11 (28 47 years) times daily, root planning and F. nucleatum Mean probing 10 days antibiotic therapy at 6 P. gingivalis pocket depth weeks after initial therapy P. intermedia Clinical attachment P. micros level spirochetes Tetracyclines Abu Fanas 4 Rapidly Tetracycline-HCl Oral hygiene instruction, % sites bleeding on % F. nucleatum et al. (1) progressive 250 mg, four supragingival and probing times daily, subgingival scaling and Mean probing 14 days root planning pocket depth Supragingival plaque control was maintained throughout the experimental period with further scaling and oral hygiene instruction Al-Joburi 79 (mean age: Advanced adult Tetracycline Subjects were randomly Plaque Index % spirochetes et al. (4) 46 years) 250 mg, four assigned to spiramycin, Number of sites times daily, tetracycline and placebo. Placebo: 24 bleeding on probing 14 days Scaling and root planning Tetracycline: 27 initiated at baseline Probing depth for: Placebo, four Pockets 4 6 mm Spiramycin: 28 times daily, Only data for placebo and Pockets Ø7mm 14 days tetracycline presented Attachment level for: Pockets 4 6 mm Pockets Ø7mm Periotron readings of crevicular fluids Atilla et 21 (37 52 years) Moderate to Minocycline-HCl Oral hygiene instruction at Bleeding Index Not done al. (6) advanced adult 100 mg, once baseline. Patients were Periodontally Mean probing daily, 14 days divided into two groups healthy: 5 depth according to probing depth (39 55 years) (4 to 5 mm and 6 mm). Number of Ø6 mm Each group was further pockets divided, with one group Number of receiving scaling and root epithelial cells planning only and the other group receiving scaling and Salivary protease root planning and activity adjunctive antibiotics Ciancio 19 (22 55 years) Gingivitis and/or Group 1: No information Gingival Index Not done et al. (17) minocycline- Group 1: 9 HCl 100 mg, Plaque Index Group 2: 10 twice daily, 8 days Group 2: minocycline- HCl 50 mg in the morning and 100 mg in the evening for 8 days Feres et al. (30) 20 (Ø20 years) Adult Doxycycline Full-mouth scaling and root % sites with: Clinical data presented in Test: mg the first planning Plaque graphs, mean values not day and 100 mg Early onset and refractory Gingival redness given : 10 each day excluded Bleeding on probing thereafter for Suppuration 14 days Mean pocket depth Mean attachment level Haffajee 98 (14 71 years) Mild to Tetracycline 250 Subgingival scaling, Clinical data % sites: et al. (41) moderate mg, three times modified Widman flap and presented in graphs, A. actinomycetemcomitans daily, 30 days antibiotics mean values not serotype a Placebo: 250 mg Patients with evidence of given A. actinomycetemcomitans sucrose, three prior attachment loss were serotype b times daily, included B. forsythus 30 days C. ochracea Subjects with localized P. gingivalis juvenile or P. intermedia rapidly progressive P. nigrescens were excluded 115

11 Slots & Ting Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Helldén 12 (27 42 years) Advanced adult Tetracycline 250 Subjects were randomly % sites: Not done et al. (42) Test: 6 mg, four times assigned to a test and Plaque IndexΩ0 daily for 2 control group. The test Gingival IndexΩ0 : 6 periods of 14 group received antibiotic days each. The therapy. Oral hygiene Probing depth first period instruction followed by Attachment level extended from scaling and root planning of day 0 to the end one half of the mouth in of week 2 and each subject. Maintenance the other period post-antibiotic therapy from the beginning of week 7 to the end of week 8 Lindhe 14 (37 52 years) Advanced adult Tetracycline 250 Double-blind, split-mouth % sites: % spirochetes et al. (52) Test: 7 mg, four times study. Subjects were Plaque IndexΩ0 daily for the first randomly assigned to two Gingival IndexΩ0 : 7 2 weeks and groups, with one group % sites bleeding on once daily for receiving long-term probing the next antibiotics. Oral hygiene 48 weeks instruction, scaling and % sites root planning of two Probing Æ4mm random quadrants of the Probing Ø7mm mouth Attachment level Listgarten Test: 6 Advanced adult Tetracycline-HCl Oral hygiene instruction, Plaque Index % spirochetes et al. (56) 250 mg, four and scaling and root : 6 times daily, for planning in half the mouth. Gingival Index 2 periods of One group received Probing depth 14 days each antibiotic therapy and one separated by a group no therapy 4-week interval Loesche Test: 32 Advanced adult Placebo, twice Scaling and root planning, Number of teeth Not done et al. (58) (27 72 years) daily for 14 days followed by random requiring simultaneously assignment to control, periodontal surgery Placebo: 33 with doxycycline systemic metronidazole and and extraction (31 71 years) 100 mg, once doxycycline groups daily, 14 days Only data for first round of Placebo, twice systemic doxycycline and daily, 14 days control groups were simultaneously presented. with another placebo, once daily, 14 days Lundström 5 Advanced adult Doxycycline 100 Oral hygiene instruction, Probing depths % spirochetes et al. (63) mg, once daily, professional cleaning, 14 days subgingival debridement % bleeding sites and antibiotic therapy Only data for patients randomly chosen for doxycycline therapy were presented Mandell & 8 (13 22 years) Localized Doxycycline 100 No presurgical initial % sites bleeding on % patients, % sites: Socransky (65) juvenile mg, twice daily therapy or home care probing A. actinomycetemcomitans for the first day, instructions were given to then 100 mg, the patients. Patients Probing depth once daily for received surgical therapy Attachment level 13 days consisting of inverse bevel, full-thickness mucoperiosteal flap without osseous recontouring, and antibiotic coverage. Re-sampling at 3 months Matisko 5 (12 70 years) Refractory Doxycycline 200 Patients were randomly Mean plaque score Mean values not given & Bissada (66) Doxycycline : mg for the first assigned to antibiotic or only (control A. actino- day and then 100 control groups. Each group Mean gingival score group in study) mycetemcomitans mg, once daily, was further subdivided % sites: and/or for 10 days using a split-mouth Bleeding P. gingivalis technique: half of the Suppuration associated mouth received one session Mean probing of root planning; the other pocket depth half received no local therapy. Patient s oral Mean probing hygiene regimen was not attachment level adjusted Only data for antibiotic or control groups were presented 116

12 Systemic antibiotics in the treatment of periodontal disease Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Müller 33 (16 63 years) Advanced Minocycline-HCl Oral hygiene, weekly Bleeding on probing A. actinomycetemcomitans: et al. (72) Localized A. actino- 200 mg, once prophylaxis, reinforcement Probing depth % subjects juvenile mycetemcomitans daily, 21 days of oral hygiene, systemic % sites associated antibiotic, subgingival Attachment loss, % microflora low plaque: 7 scaling and root planning, (mean age: and twice-daily 0.1% 25 years) chlorhexidine digluconate rinse Localized, At sites with 5 mm plaque: 10 remaining depth and (mean age: bleeding on probing, 32 years) mucoperiosteal flaps were elevated and antibiotics Generalized prescribed for another severe 2 weeks, high plaque: 9 Patients were recalled for (mean age: prophylaxis every 35 years) 2 3 months Generalized moderate, low plaque: 6 (mean age: 33 years) Ng & 32 (32 72 years) Generalized Doxycycline 200 Split-mouth design for Plaque Index Not done Bissada (76) moderate adult mg the first day scaling and root planning. and then 100 Subjects were randomly Gingival Index mg, once daily, assigned to the different Probing depth 6 weeks treatment groups Attachment level Ibuprofen 800 mg, once daily, 6 weeks Combined doxycycline (200 mg the first day and 100 mg, once daily, thereafter) and ibuprofen (800 mg), once daily, 6 weeks Placebo, once daily, 6 weeks Preus et al. (88) 10 (35 63 years) Moderate to Minocycline-HCl Scaling, root planning and Not done % colony-forming units: severe adult 50 mg in the systemic antibiotics Aerobic minocycline morning and resistant strains Only data for systemic 100 mg in the antibiotic therapy were Aerobic minocyclineevening for presented resistant strains 10 days Saxén & Test: 9 Localized Tetracycline Oral hygiene instruction, % bleeding sites % subjects: Asikainen (101) (16 24 years) juvenile 250 mg, four scaling and root planning A. actinomycetemcomitans % sites probing times daily, every 3 months, antibiotic : 9 Ø4 mm 12 days therapy, modified Widman (14 25 years) flap procedure performed Number of sites: at 6 months after initial with 25% bone examination loss : no medication with 25 48% bone loss Only data for control and tetracycline were presented Saxén et al. (102) 14 (14 25 years) Localized Doxycycline Test group: oral hygiene % sites probing % sites: Test: 7 juvenile 200 mg the first instruction, scaling and Ø4 mm A. actinomycetemcomitans day, then 100 mg, root planning, doxycycline Placebo: 7 % bleeding sites once daily for 200 mg on the first day, then 14 days 100 mg for 2 weeks Placebo Placebo group: oral hygiene instruction, scaling and root planning and placebo Periodontal surgery performed after 2 months in some patients 117

13 Slots & Ting Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Slots & Rosling 6 (13 17 years) Localized Tetracycline-HCl Oral hygiene instruction, Plaque Index A. actinomycetemcomitans: (117) juvenile 250 mg, four scaling, root planning, Gingival Index % patients times daily, topical Betadine A solution % sites 14 days (10% povidone-iodine) and Probing depth Number of infected deep systemic antibiotics Attachment level and shallow pockets during tetracycline therapy Capnocytophaga spp.: % patients % sites Number of infected deep and shallow pockets during tetracycline therapy Combination therapy: metronidazole and amoxicillin Berglundh 16 (35 58 years) Advanced Metronidazole Oral hygiene instruction, Plaque Index % A. actinomycetemcomitans et al. (11) Test: 8 periodontal 250 mg, three supragingival scaling, Bleeding on probing % P. gingivalis disease times daily π subgingival scaling in only % P. intermedia : 8 amoxicillin 375 one side of the mouth and Pocket depth mg, twice daily, antibiotic or placebo Probing attachment 14 days therapy level Flemmig Test: 18 A. actino- Metronidazole Supragingival and Not reported Number of et al. (35) (mean age: mycetemcomitans 250 mg, three subgingival scaling and root A. actinomycetemcomitans 49 years) and/or times daily π planning, oral hygiene positive subjects: P. gingivalis amoxicillin 375 instruction, together with or Oral cavity : 20 positive mg, three times without systemic Subgingival plaque (mean age: daily, 8 days antibiotics and daily 0.06% Oral mucous membranes 54 years) chlorhexidine digluconate Tongue rinse Tonsils Buccal mucosa Number of P. gingivalis positive subjects: Oral cavity Subgingival plaque Oral mucous membranes Tongue Tonsils Buccal mucosa Flemmig Test: 18 (mean A. actino- Metronidazole Supragingival and Mean incidence (%) Number of patients: et al. (34) age: 49 years) mycetemcomitans 250 mg, three subgingival scaling and root of 2 mm or more of A. actinomycetemcomitans and/or times daily π planning, oral hygiene probing attachment only : 20 P. gingivalis amoxicillin 375 instruction, together with or level gain for A. actinomycetemcomitans (mean age: 54 positive mg, three times without systemic subjects with and P. gingivalis years) daily, 8 days antibiotics and daily 0.06% A. actino- P. gingivalis only chlorhexidine digluconate mycetemcomitans rinse regardless of P. gingivalis Mean incidence (%) of2mmormoreof probing attachment level gain for subjects with P. gingivalis without A. actinomycetemcomitans López & Test: 23 Moderate to Metronidazole Subjects were randomly % sites with plaque % sites: Gamonal (61) (mean age: advanced adult 250 mg, three assigned to receive % sites bleeding on A. actinomycetemcomitans 44 years) times daily π antibiotics or placebo. No probing P. gingivalis Placebo: 21 amoxicillin 375 effort was made to change P. intermedia mg, three times the oral hygiene habits of % active sites (mean age: 44 years) daily, 8 days the patients % sites gaining Active sites are sites losing attachment Ø2 mm in clinical attachment level Probing depth López et al. (62) 40 (36 68 years) Moderate to Metronidazole No effort was made to % sites: Not done Test: 20 advanced adult 250 mg, three change the oral hygiene with plaque times daily π habits of the patients and Bleeding on probing Placebo: 19 with Ø2 mm amoxicillin 500 no additional therapy was Active sites attachment loss mg, twice daily, provided Gaining attachment in Ø2 sites in the 14 days Mean attachment previous Placebo, three level 2 months times daily, Mean probing 7 days depth 118

14 Systemic antibiotics in the treatment of periodontal disease Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Pavičić et al. (85) 48 A. actino- Metronidazole Supragingival and Plaque Index % subjects: mycetemcomitans 250 mg, three subgingival debridement, Bleeding Index A. actinomycetemcomitans associated severe times daily π oral hygiene instruction, P. gingivalis amoxicillin 375 and antibiotic therapy % bleeding sites P. intermedia mg, three times Probing depth daily, 7 days % sites: Probing depth 5 mm Probing depth 5 8 mm Probing depth 9 mm Attachment level van Winkelhoff 22 (14 44 years) A. actino- Metronidazole Subgingival scaling and % sites showing % subjects: et al. (132) Localized mycetemcomitans 250 mg, three antibiotic therapy bleeding on probing A. actinomycetemcomitans juvenile associated times daily π Subjects with prior Probing depth P. gingivalis : 11 amoxicillin 375 periodontal therapy: 14 P. intermedia including mg, three times Rapidly localized daily, 7 days Subjects with no prior progressing juvenile periodontal therapy: 8 : 11 Side effects: and rapidly Severe diarrhea: 2 subjects progressive van Winkelhoff Localized A. actino- Metronidazole Supragingival and Pocket depth % subjects, % microflora: et al. (133) juvenile mycetemcomitans 250 mg, three subgingival debridement, A. actinomycetemcomitans Attachment level : 28 associated times daily π oral hygiene instruction P. gingivalis (mean age: amoxicillin 375 and antibiotic therapy Bleeding index P. intermedia 27 years) including mg, three times localized daily, 7 days Generalized juvenile advanced adult, : 50 generalized (mean age: advanced adult 36 years), Refractory and refractory : 50 (mean age: 37 years) Winkel 22 (29 54 years) A. actino- Metronidazole Oral hygiene instruction, Plaque Index Number of subjects, mean et al. (143) mycetemcomitans 250 mg, three supragingival and % microflora: Bleeding Index positive times daily π subgingival scaling and root A. actinomycetemcomitans amoxicillin 375 planning and antibiotic Suppuration Index B. forsythus with either mg, three times therapy Probing pocket F. nucleatum P. gingivalis, daily, 7 days depth P. gingivalis Number of patients with B. forsythus or P. intermedia adverse effects: P. intermedia Clinical attachment P. micros Any adverse effect: 17 co-infection level Diarrhea: 10 Metallic taste: 4 Headache: 4 Nausea: 3 Winkel 49 (mean age: Generalized Metronidazole Scaling and root planning Plaque Index Number of subjects, mean et al. (141) 42 years) severe adult 250 mg, three with oral hygiene % microflora: Bleeding Index times daily π instruction. Six weeks later, A. actinomycetemcomitans Test: 23 amoxicillin 375 repeat scaling and root Suppuration Index (mean age: B. forsythus 45 years) mg, three times planning, reinforced oral Probing pocket F. nucleatum daily, 7 days hygiene instruction, and depth P. gingivalis Placebo: 26 antibiotic therapy or P. intermedia (mean age: placebo Clinical attachment P. micros 40 years) level Number of placebo group patients with adverse effects: Any adverse effect: 2 Rash on the face: 1 Number of test group patients with adverse effects: Gastrointestinal intolerance: 9 Rash on the face: 1 Rash on the neck: 1 Nausea after alcohol: 1 Diarrhea: 1 119

15 Slots & Ting Table 4. Continued Number Systemic of subjects Periodontal antibiotic Periodontal Clinical Microbiological Study (age) condition regimen treatment variables variables Combination therapy: various combinations Aitken et al. (3) Doxycycline π Active Test: Patients were treated 7 % subjects with % positive tests: metronidazole: doxycycline 200 months prior with disease recurrence A. actinomycetemcomitans 11 mg the first day bimonthly scaling with within 3 months E. corrodens (mean age: and then 100 mg, either 3 weeks of systemic Gingival attachment F. nucleatum 54 years) once daily, doxycycline or placebo. level P. intermedia Placebo π 21 days, and Patients were monitored P. gingivalis metronidazole: metronidazole for recurrent spirochetes mg, three and scaled every 2 months (mean age: times daily, Patients with continued 53 years) 10 days periodontal destruction Placebo: were entered into this lactose- prospective study. These containing patients received placebo, once metronidazole therapy daily, 21 days and metronidazole 250 mg, three times daily 10 days Matisko & 11 (12 70 years) Refractory Test: Patients were randomly Mean plaque score Mean values not given Bissada (66) amoxicillin/ placed into test or control Test: Mean gingival score A. actino- clavulanic acid antibiotic treatment groups. doxycycline and mycetemcomitans 500 mg, three Each group was further % sites: amoxicillin/ and/or P. times daily, subdivided using a splitclavulanate: 6 Bleeding gingivalis 5 days, and then mouth technique: one-half Suppuration : associated doxycycline 200 of each mouth received one Mean probing doxycycline mg the first day session of root planning; the pocket depth only: 5 and 100 mg, once other half mouth received daily, 4 days no local therapy. Patients Mean probing usual oral hygiene regimen attachment level : was not adjusted doxycycline 200 mg the first day and 100 mg, once daily, 10 days controls. Ng & Bissada (76) reported that 6 weeks of systemic doxycycline therapy significantly decreased gingival inflammation compared with placebo. López & co-workers (61, 62) showed that metronidazole amoxicillin combination therapy resulted in less gingival bleeding for up to 12 months compared with placebo. 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. Several systemic antibiotic therapies have no significant impact on periodontal pocket depth compared with controls (Table 7). However, metronidazole and its combination with amoxicillin constitute an important exception (Table 7). Noyan et al. (79) and Elter et al. (29) reported that 7 days of metronidazole therapy reduced pocket depth significantly compared with controls. Winkel et al. (141) showed that 7 days of 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. Loesche et al. (60) also found most probing depth reductions in pockets greater than 6 mm. Sigusch et al. (107) demonstrated a significant decrease in pocket depth after systemic metronidazole and clindamycin therapies. An important study by Collins et al. (19) revealed that 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. Systemic spiramycin as adjunct to scaling and root planing may give rise to significant reduction in probing depth as well (7). Systemic metronidazole and its combinations can significantly improve clinical (probing) attachment level compared with controls (Table 8). Loesche et al. (57, 60) and Elter et al. (29) found that 7 days of metronidazole therapy significantly increased 120