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Systemic antibiotic therapy in periodontics

Winkel, E.G.

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Citation for published version (APA):Winkel, E. G. (2000). Systemic antibiotic therapy in periodontics

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Download date: 26 Jun 2018

CHAPTERR 6

ADDITIONALL CLINICAL AND MICROBIOLOGICA L EFFECTS OFF AMOXICILLI N AND METRONIDAZOLE AFTER INITIAL PERIODONTALL THERAPY

E.G.. Winkel1,3, AJ . Van Winkelhoff, and U. Van der Velden3

11 CI in ic for Periodontology Amsterdam, Departments of 2Oral Microbiology and 3Periodontology,, Academic Centre for Dentistry Amsterdam, The Netherlands.

Journall of Clinical Periodontology 1998; 25: 857-864

99 9

Additionall effects of amoxicillin and metronidazole

Abstrac t t

Thee aims of this study were to evaluate the clinical and microbiological effects of initiall periodontal therapy (IT) and to determine the additional effects of systemic amoxicillinn (Flemoxin Solutab®) 375 mg TID plus metronidazole 250 mg TID the-rapy,rapy, in patients with adult Actinobacillus actinomycetemcomitans (Aa) -associa-tedd periodontitis in conjunction with either Porphyromonas gingivalis (Pg), BacteroidesBacteroides forsythus (Bf) and/or Prevotella intermedia (Pi). In addition the adver-see effects of the antimicrobial therapy were also documented. A total of 22 patientss were enrolled. The deepest, bleeding pocket in each quadrant was selectedd and at these 4 experimental sites clinical measurements and microbio-logicall testing was carried out at baseline, after (IT) , i.e., 21 weeks after base-line,, and after antimicrobial therapy (AM), i.e., 35 weeks after baseline. At base-linee the mean plaque index (PI) amounted 0.5, 0.1 after IT and 0.3 after systemic AM.. The mean bleeding index decreased from 1.6 to 1.2 after IT and a further decreasee to 0.7 after AM was noted. Suppuration was completely eliminated afterr AM. The mean change of probing pocket depth (PPD) after IT amounted 1.44 mm and was further reduced with an additional mean change of 1.1 mm after medication.. Clinical attachment gain was 1.1 mm after IT and an additional 0.9 mmm was observed after AM. One of the 22 Aa positive patients and 4 of 17 Pg positivee patients became negative for these species after IT. The number of patientss with detectable Pi decreased from 16 to 10 after IT. After AM, in com-parisonn to baseline, suppression below detection level for Aa was achieved in 19 outt of 22, for Pg in 9 out of 17, for Bf in 13 out of 14, and for Pi in 11 out of 16 patients.. By contrast, higher frequencies of Peptostreptococcus micros and FusobacteriumFusobacterium nucleatum were found after AM. On the basis of the microbiolo-gicall results the study group was separated into 2 subgroups: group A consis-tedd of subjects who had no detectable levels of Aa, Pg, Bf and <5% of Pi after AM.. Group B consisted of those who still showed presence of one of these 3 speciess and/or >5% levels of Pi. After AM, group B had significantly higher PI, BI,, PPD and CAL scores then group A. It is concluded that group A showed low plaquee scores and no detectable periodontal pathogens. This microbiological conditionn has been associated with a long-term stable periodontium.

Introductio n n

Periodontall disease may be thought of as a number of infections caused by bac-teriaa that affect individual or multiple periodontal sites. One aim of periodontal therapyy is to halt further loss of periodontal attachment. This is achieved by meti-culouss supra- and subgingival debridement that results in the reduction of the

101 1

Chapterr 6

totall bacterial load. In addition, suitable supragingival plaque control measures aree important to prevent recolonization of periodontal pathogens (Magnusson et al.. 1984). Thee microflora of deep periodontal pockets may consist of high proportions of spirochetes,, Actinobacillus actinomycetemcomitans, a small nonmotile Gram negativee capnophilic rod and a number of Gram negative anaerobic rods of whichh Porphyromonas gingivalis, Prevotella intermedia and Bacteroides forsyt-hushus ave considered important pathogens (Dzink et al. 1985,1988, Haffajee & Socranskyy 1994, Tanner et al. 1989, American Academy of Periodontology 1996).. Suppression of these bacteria below detection level results in a remarka-blee improvement of clinical parameters (Haffajee et al. 1997, Magnusson et al. 1994,, Winkel et al. 1997). Wennströmm et al. (1987) showed that no clinically significant loss of attachment occurredd during a 1 -year observation period in the absence of A. actinomyce-temcomitanstemcomitans , P. gingivalis and < 5% of P. intermedia. In contrast, in patients withh one or more of these indicator bacteria, 20% of the sites exhibited clinical attachmentt loss of > 2 mm within 1 year. In a 5-year follow-up study, Dahlén et al.. (1996) investigated the association between the recurrence of periodontal pathogenss and recurrent attachment loss. Reappearance of A. actinomycetem-comitans,comitans, P. gingivalis and P. intermedia was observed in 9 of 13 patients. In 6 off these 9 patients further periodontal attachment loss was observed. Patients withoutt detectable subgingival A. actinomycetemcomitans, P. gingivalis, P. inter-mediamedia during the maintenance period of 5 years remained clinically stable. Sincee it has been shown that A actinomycetemcomitans is difficult to eliminate byy mechanical means alone (Christersson et al. 1985, Goené et al. 1990, Kornmann & Robertson 1985, Mombelli et al. 1994a, Renvert et al. 1990b,c), the practicalityy of antibiotics in the treatment of A. actinomycetemcomitans-asso-ciatedd periodontitis may be inferred. In this respect the use of amoxicillin plus metronidazolee after completion of the initial periodontal therapy has been advo-catedd (Van Winkelhoff et al. 1989, 1992). Yet, so far, the additional effects of amoxicillinn plus metronidazole apart from the initial periodontal therapy have not beenn well documented. Thee aims of the present investigation were to evaluate the clinical and microbio-logicall effects of mechanical initial periodontal therapy and to determine the additionall effects of amoxicillin plus metronidazole therapy in patients with adult A.A. actinomycetemcomitans-assoc\ateó periodontitis, in conjunction with either P.P. gingivalis, B. forsythus and/or P. intermedia. Also in this study, the adverse effectss of the antimicrobial therapy were documented.

102 2

Additiona ll effect s of amoxicilli n and metronidazol e

Materiall and Methods

Patient s s

AA total of 22 patients, comprising 7 males and 15 females, were enrolled in this study.. The mean age was 40 years and ages ranged from 29 to 54 years. The inclusionn criteria for participation were: (1) age of over 25 years, (2) a minimum of 44 pockets with probing pocket depths > 6 mm with at least 3 mm of clinical attachmentt loss, (3) no periodontal treatment history, (4) proven subgingival infectionn with A. actinomycetemcomitans in conjunction with either P. gingivalis, B.B. forsythus and/or P. intermedia, (5) no abnormalities in stool, (6) no use of sys-temicc antimicrobial therapy in the previous 3 months. All patients who partici-patedd in this study consented in writing.

Outlin ee of the stud y

Thee outline of the study is shown in Fig. 1. First, a medical history was obtained. Thenn the deepest, bleeding pocket in each quadrant was selected for clinical and microbiologicall evaluation (Mombelli et al. 1991, 1994a, Muller et al. 1990). At thesee 4 experimental sites clinical measurements and microbiological testing wass carried out at baseline, after initial periodontal therapy (IT), i.e. 21 weeks afterr baseline, and after systemic antimicrobial therapy (AM), i.e. 35 weeks after baseline.. IT included oral hygiene instructions and supra- and subgingival sca-lingg and root planing for a maximum of 6 hours and was completed within 15 weekss after baseline. At week 21, only oral hygiene was re-inforced. The antimi-crobiall therapy consisted of amoxicillin 375 mg TID (Flemoxin Solutab®) and metronidazolee 250 mg TID, both drugs for 7 days.

Fig.Fig. 1. Study outline.

Baselin e e Afte rr IT

21 1

writte nn consen t clinica ll measurement s bacteriologica ll sample s star tt initia l treatmen t

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IT:: initial periodontal therapy; AM: amoxicillin and metronidazole.

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103 3

Chapterr 6

Att week 21, information about the patient's stool was gathered concerning any changess or irregularities in the past 3 months. One week after completion of the antimicrobiall therapy, patients were interviewed concerning adverse effects and changess or irregularities of stool. Two questions were asked in order to assess adversee effects using standard phrases (1) "Did anything special occur last week?",, (2)" Was there any change in your stool over the past 2 weeks?"

Clinica ll measurement s

Too record the responses to clinical therapy the following parameters were employedd at the 4 experimental sites. (1)) Plaque index (PI, Sillness & Löe, 1964). (2)) Bleeding index (BI). Bleeding on probing: 0, no bleeding; 1, 'pin prick'

bleeding;; and 2, immediate and overt bleeding. (3)) Suppuration index (SUP). Suppuration: 0, no suppuration; 1, suppura

tion. . (4)) Probing pocket depth (PPD) using a Hu-Friedy PQW probe. (5)) Clinical attachment level (CAL) by subtraction of the distance between

thee gingival margin and the cemento-enamel junction from the recorded probingg pocket depth.

Microbiologica ll procedure s

Afterr removal of supragingival plaque from the 4 experimental sites, a subgingi-vall sample was obtained by using 2 sterile paper points at each site. Paper pointss from all four experimental sites were pooled and collected in reduced transportt fluid (RtF, Syed & Loesche, 1972) and processed within 36 hours (Petit ett al. 1991, Van Steenbergen et al. 1993). Tenfold serial dilutions were prepared inn RTF and aliquots of 0.1 ml were plated onto 5% horse-blood agar plates (Oxoidd no. 2, Basingstoke, England) supplemented with haemin (5 mg/l) and menadionee (1 mg/l) for isolation and growth of obligate anaerobic bacteria, and onn TSBV for selective isolation and growth of A. actinomycetemcomitans (Slots 1982).. Blood agar plates were incubated anaerobically in 80% N2, 10% H2 and 10%% CO2 for up to 14 days and TSBV plates were incubated in air + 5% CO2 for 55 days (Van Steenbergen et al. 1986). Blood agar plates were used for enumera-tionn of dark-pigmented colonies and B. forsythus. Representative dark-pig-mentedd colonies were purified and identified using standard techniques (Van Winkelhofff et al. 1985), including Gram-stain, hemagglutination of 3% sheep erythrocytes,, fermentation of glucose, production of indole from tryptophan and productionn of specific enzymes (Van Winkelhoff et al. 1986). B, forsythus was

104 4

Additionall effects of amoxicillin and metronidazole

identifiedd on the basis of the typical colony morphology, Gram-stain and produc-tionn of a trypsin-like enzyme (Braham & Moncla 1992).

Statistica ll analyse s

Forr analyses of the clinical and microbiological data a "patient level response" variablee was calculated for each parameter by computing the mean value of the scoress assessed at the 4 experimental sites at each assessment. Differences in clinicall and microbiological parameters before initial therapy (baseline), after IT andd after AM, and between selected patient groups were analyzed using an unpairedd Wilcoxon-test. A Fisher's exact test was used to analyze differences in thee frequency of species after each phase of therapy. Values of p<0.05 were acceptedd as statistically significant.

Result s s

Clinica ll effect s

Thee means of the clinical parameters at baseline, after IT and after AM are sum-marizedd in Table 1. All clinical parameters improved after IT and showed further improvementt after AM with the exception of the PI. Thee mean change of PI at the 4 experimental sites decreased 0.4 after IT and increasedd with 0.2 after AM. The mean BI decreased 0.4 after IT and a further decreasee of 0.5 after AM was noted. Suppuration was completely eliminated afterr systemic antibiotic therapy. The mean change of probing pocket depth afterr IT amounted 1.4 mm and was further reduced with an additional mean changee of 1.1 mm after AM. Clinical attachment gain was 1.1 mm after IT and an additionall 0.9 mm was observed after AM.

Microbiologica ll effect s of initia l periodonta l therap y

Thee frequency of detection of the target bacterial species and the corresponding PPDD andd CAL on a patient level is summarized in Table 2. One of the 22 A. acti-nomycetemcomitansnomycetemcomitans patients and 4 of 17 P. gingivalis patients became negative forr these species after IT. The number of patients with detectable P. intermedia decreasedd from 16 to 10 after IT; 2 patients (#12 and 14) became positive for this species.. Four of the 14 initially positive patients became negative for B. forsyt-hushus after IT. One patient (#12) became positive for B. forsythus after IT. We observedd a striking increase in the number of patients with detectable PeptostreptococcusPeptostreptococcus micros (from 4 to 11, p< 0.05) after IT. Also the number of

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Additionall effects of amoxicillin and metronidazole

patientss with detectable subgingival Fusobacterium nucleatum increased post-therapyy (from 3 to 7). All patients but one (#14), positive for P. micros and F. nucleatum,nucleatum, remained positive after mechanical therapy. The mean PPD and the meann CAL had both significantly improved after IT. Nevertheless, 4 patients showedd no clinical attachment gain (#4,6,12,13).

Microbiologica ll effect s of systemi c antimicrobia l therap y

Alll patients completed the systemic antimicrobial therapy. A significant change inn the frequency of the selected species was observed after the additional anti-bioticc therapy. Suppression below detection level was achieved for A actinomy-cetemcomitanscetemcomitans in 18 (p< 0.001) and for P. gingivalis in 9 patients (p< 0.001). Of thee 14 patients at baseline only one (#18) had detectable levels of B. forsythus post-antibioticc therapy. This patient also remained positive for A actinomyce-temcomitans.temcomitans. P. intermedia was found in 11 of the patients post-antibiotic the-rapy.. P. micros and F. nucleatum were found at higher frequency after AM (10 andd 9, respectively) compared to baseline (4 and 3, respectively). In 7 patients, P.microsP.micros and in 10 patients F. nucleatum were not detected at any time during thee study. The mean % recovery of the selected bacteria is summarized in Table 3.. Only minor changes in the mean percentages of A actinomycetemcomitans andd P. gingivalis were observed after initial therapy. By contrast, the mean per-centagee of P. intermedia slightly increased, whereas the mean %'s of FusobacteriumFusobacterium nucleatum decreased gradually. Only the mean percentage of P. microsmicros declined significantly after mechanical therapy. Two of the 3 patients (#17,22),, positive for A actinomycetemcomitans post-antibiotic therapy, had bothh the highest mean plaque index (1.5) at the end of the study period. Patient #177 had the highest mean plaque index ( baseline 2, after IT 1, after AM 1.5) and patientt #22 had the highest mean PPD during the entire study (baseline 11 mm, afterr IT 8.7 mm, after AM 7.5 mm). These 3 A actinomycetemcomitans positive patientss also showed significantly higher levels of P. intermedia (p < 0.05) during thee entire study than the patients who became negative for this species after AM. Inn retrospect, the 4 patients with detectable levels of P. gingivalis post AM had a significantlyy higher suppuration index after IT 3 versus , p-0.04) andd showed a higher plaque index ( p=0.009), more bleeding on probing (p<0.0001),, deeper probing pocket depth (p=0.03) and more clinical attachment losss (p=0.01) by comparison with the patients without detectable P. gingivalis after AM. .

Onn the basis of the microbiological results after AM, the study group was sepa-ratedd into 2 subgroups (Table 4). Group A, representing the patients #1-14 in Tablee 2, consisted of those subjects who after AM had no detectable levels of A

107 7

Chapterr 6

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actinomycetemcomitans,actinomycetemcomitans, P. gingivalis, B. forsythus and showed <5% of P. inter-media.media. Group B showed still presence of one of these 3 species and/or >5% levelss of P. intermedia. The mean age of group A was 37.5 years and for group BB 43.5 years (p=0.05). Group B was characterized by a higher mean PI, BI, PPD andd CAL post AM. In retrospect patients in group B showed more loss of clini-call attachment at baseline. However, after IT, there were no significant differen-cess in clinical parameters between group A and B. After AM, Group B showed a smallerr mean change in PPD and an increase in plaque level.

Advers ee effect s

Alll patients reported normal stool at first interview in week 21, i.e. after initial periodontall therapy and before the medication of amoxicillin and metronidazole. Afterr medication, 17 of the 22 patients experienced adverse effects (Table 5). Ten patientss reported diarrhoea, one had a more frequent stool but without diar-rhoea,, 4 patients reported a metallic taste, 4 patients reported headaches and 3 sufferedd from nausea. The reported events were mild and were tolerated by all patients.. The adverse effects were deemed to relate to the medication.

Discussio n n

Inn this study, we investigated the clinical and microbiological effects of initial periodontall therapy in patients with A. actinomycetemcomitans-assoc\ateö adult periodontitiss and the additional effects of a systemic amoxicillin plus metronida-zolee therapy. Alll clinical parameters improved significantly after the initial periodontal therapy. Thee mean change in clinical attachment level (1.1 mm) concurs with other stu-dies,, while the observed 1.4 mm mean reduction in probing pocket depths in this studyy was moderate (Cobb 1996, Hammerle et al. 1991, 2.1 mm and 2.2 mm, respectively).. A minimal clinical improvement in adult periodontitis patients after initiall periodontal therapy has been related to subgingival persistence of A. acti-nomycetemcomitansnomycetemcomitans and P. gingivalis (Mombelli et al. 1994 a,b, Renvert et al. 19900 a,b, Ali et al. 1992). These observations may, in part, explain our results. However,, due to the selection criteria, the evaluated sites may have comprised aa relative large number of angular bony defects of which it has been shown that gingivall recession will occur to a limited extent (Hellström et al. 1996). The mode-ratee effects of the initial periodontal therapy on the subgingival microflora cannot bee explained by poor supragingival plaque control since a significant reduction off the PI after IT (from 0.5 to 0.1) was achieved in the present study population.

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Additionall effects of amoxicillin and metronidazole

Thee rationale for continuing periodontal therapy is based on observations that suggestt further disease progression when A actinomycetemcomitans, P. ging-ivalisivalis and P. intermedia are still detectable after initial periodontal therapy (Ali et al.. 1992, Bragd et al. 1987, Dahlén et al. 1996, Goené et al. 1990, Wennström et al.. 1987). The choice for periodontal antimicrobial therapy was based on earlier observationss showing that renewed debridement has little or no additional effectt (Badersten et al. 1984). In this study the periodontal therapy was followed byy an additional systemic antimicrobial therapy with amoxicillin plus metronida-zole.. The choice of this systemic antibiotic regime was based on an earlier report showingg predictable and long-term suppression of subgingival A actinomyce-temcomitanstemcomitans and P. gingivalis (Paviöic et al. 1994). Thee results of the additional course of amoxicillin and metronidazole showed a significantt further reduction in mean probing pocket depth, bleeding tendency, suppuration,, and gain of clinical attachment level. By comparison with the base-linee measurements, the reduction of PPD (2.5 mm) and gain of CAL (2 mm) 3 monthss after IT followed by AM, exceeded those reported by Paviöic and co-workerss 1994 (2.3 mm and 1.4 mm, respectively). In the present study the clini-call improvements were parallelled by a major reduction in the isolation frequen-cyy of A. actinomycetemcomitans, P. gingivalis, and B. forsythus. Especially the reductionn of B. forsythus in positive patients was noteworthy and has not pre-viouslyy been reported. Nott all patients were free of putative pathogens after the antibiotic therapy . To studyy the additional effects of antibiotics, no attempt was made to disrupt the subgingivalsubgingival biofilm shortly before the antibiotic therapy was commenced. Therefore,, our treatment may not have been the most effective therapy. The recentt recognition that subgingival plaque is in fact a biofilm in which subgingi-vall bacteria greatly increase their resistance to antibiotics, may explain that some patientss still had detectable levels of periodontal pathogens after therapy (Anwar ett al. 1992, Darveau et al. 1997, Van Winkelhoff et al. 1994, Wright et al. 1997).

Onn the basis of the microbiological data after systemic antimicrobial therapy, the studyy population was divided into 2 subgroups. Group A, patients without A. actinomycetemcomitans,actinomycetemcomitans, P. gingivalis, B. forsythus and < 5% P. intermedia, and groupp B, patients with one or more of these periodontal pathogens and > 5% P. intermediaintermedia (Wennström et al. 1987). After AM, group B had significantly higher PI,, BI, PPD and CAL scores then group A. In retrospect, group B had signifi-cantlyy more clinical attachment loss at baseline than group A. However, after IT, noo significant differences were noted between the 2 subgroups; thus group B respondedd better to IT than group A. This concurs with the studies of Badersten ett al. (1984) and Cobb (1996) who showed that greater gain of clinical attachment

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andd greater reduction of pocket depth can be expected in deeper than in shallo-werr sites after IT. By contrast, after AM the most pronounced improvement of clinicall parameters was noted in group A, the patients with no detectable levels off A actinomycetemcomitans, P. gingivalis, B. forsythus and < 5% P. intermedia. Thee difference in plaque scores after AM in group A as opposed to group B needss further discussion. Several studies have shown that the rate of plaque accumulationn is related to the degree of gingival inflammation, i.e. the more ging-ivitis,, the more rapid plaque formation (Hillam & Hull 1977, Ramberg et al. 1995,1996).. This phenomenon may be explained by the persistence of subging-ivall periodontal pathogens which results in an increase of gingival crevicular fluid (Giedrys-Leeperr et al. 1985) which in turn provides a rich source of nutrients for plaquee formation (Darveau et al. 1997). In this respect it is important to note that certainn extracellular proteases of especially P. gingivalis are able to increase vas-cularr permeability (Imamura et al. 1994). Consequently, the higher plaque scores afterr AM in group B compared to group A may not be the result of a different qualityy of oral hygiene control but may be attributed to the presence of subging-ivall periodontal microflora and continuing inflammatory response. Thee aim of periodontal therapy may be defined as creating a periodontal condi-tionn which shows a long-term stable attachment level. In this respect, it seems likelyy that group A fulfilled the conditions to achieve this goal since the patients involvedd showed low plaque scores and no detectable periodontal pathogens, andd this has been associated with a stable long-term periodontal condition (Dahlénn et al. 1996, Wennström et al. 1987). Consequently, group B did not reach thee endpoint of active periodontal treatment and will probably need additional periodontall therapy (Haffajee et al. 1997, Rams et al. 1996 , Slots 1996, Winkel etal.. 1997).

Acknowledgement s s

Thee authors wish to thank José de Vries-Dubbeldam for her assistance in this project.. The statistical assistance of Mark Timmerman is also greatly apprecia-ted.. The study was supported by Gist Pharma, project number 90-FLM-02.

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