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antibiotics in perio
- 1. Periodontology 2000, Val. 10, 1996, 45-78 Printed in Denmark . All rights reserved Copyright 0 Munksgaard 1996 PERIODONTOLOGY 2000 ISSN 0906-6713 ARIEJAN VAN WINKELHOFF, THOMAS E. RAMS& J0RGEN SLOTS Gingivitis (inflammation of the gingiva) and peri- odontitis (gingivitis with clinical attachment loss) comprise the two major infections of the periodon- tium. Gingivitis occurs in virtually all humans. Ad- vanced periodontitis is limited to 10-15% of most adult populations. Periodontal diseases also have been described in many animal species (148).Both periodontal diseases are caused by supra- and sub- gingival microbial plaque. The microbial compo- sition of the disease-producing plaque and several putative host susceptibility factors for periodontitis have been elucidated during the last two decades. Inflammatory periodontal diseases are treated pri- marily by supra- and subgingival debridement of affected tooth surfaces. Mechanical and surgical treatment combined with proper oral hygiene meas- ures can arrest or prevent further periodontal attach- ment loss in most individuals. However, despite dili- gent dental therapy, some individuals continue to experience periodontal breakdown. Refractory peri- odontitis may be related to remaining subgingival pathogens (18, 181) and to impaired host resistance (44). Selective antimicrobial therapy may remove persistent periodontal pathogens. Cessation of smoking may reduce the risk of periodontal break- down, but present therapies cannot reduce most host risk factors for periodontitis. The microbial composition of subgingival plaque varies considerably from patient to patient (103,208, 209).Early investigations broadly characterized sub- gingival organisms as being gram-positive and gram- negative and as facultatively anaerobic and anaer- obic species. The description of the Gram stain reac- tion and the anaerobic requirement of the infectious periodontal microbiota provided the first guidelines for selection of antimicrobial therapy. Later studies found some subgingival bacteria, including Actino- bacillus actinomycetemcomitans and Porphyromon- as gingivalis, to be infrequent in periodontal health and able to elicit a marked antibody response in in- fectedperiodontitis patients.Thesebacteria may con- stitute exogenous organisms in subgingival sites and may represent true periodontal infections (205). Atypical (nonoral)pathogenic enteric bacteria can be isolated from some periodontal lesions and may be considered superinfecting organisms. Periodontal in- fections by indigenous organisms may be designated endogenous periodontal infections. Delineation of the type of periodontal infection may be important in selecting a proper strategy for antimicrobial therapy in periodontics (222). Differences in antimicrobial profiles among periodontal pathogens also suggest the use of a variety of antibiotic regimes in treatment of severeperiodontitis (82,200,205). Since the initial microbiological characterization of destructive periodontal diseases in the late 1970s the use of antibiotics in the treatment of periodontal disease has been surrounded by controversy. The value of periodontal antibiotic therapy has fre- quently been misunderstood, overstated or over- simplified. This article provides a critical evaluation of the usefulness of systemic antimicrobial therapies in periodontal treatment. History Microscopic studies from the turn of the century re- vealed large numbers of spirochetes and amoebae in subgingival plaque (84, 165).These microorganisms were considered the cause of periodontal disease (“pyorrhoea”)and treated with neo-salvarsan or em- entin. However, the inorganic arsenic compounds were associated with considerable adverse reactions, proving true the old saying “Gravioraquaedum sunt rernedia periculus” (some remedies are worse than the disease). The next major chemotherapeutic agent to be developed from a synthetic dye was prontosil, a compound converted in the human body to sulfonamide. Sulfonamides and related compounds are still used in antimicrobial therapy. The greatest discovery in the era of antibiotics was 45
- 2. van Winkelhoff et al. Fleming’sfinding of Penicillium notatum producing a substance (“penicillins”)that inhibited the growth of Staphylococcusaureus.Since then, numerous anti- microbial agents have been introduced into medical and dental practice. Today the medical and dental profession benefits tremendously from the develop- ment of antibiotic therapy but also faces the prob- lems of adverse reactions of antibiotics, including drug resistance, toxicity and hypersensitivity reac- tions and interactions with other medications. In periodontics, antibiotics and chemothera- peutics are traditionally prescribed for patients who do not respond to conventional mechanical therapy or as an adjunct to periodontal surgery. The choice of antibiotics was initially based on empirical evi- dence and included mainly penicillins. Tetracycline- HC1 became popular in the 1970s due to its broad- spectrum antimicrobial activity and low toxicity. In the last decade, increased knowledge of the compo- sition of the periodontal microbiota has led to the development of microbiological guidelines for se- lecting antibiotics (205,207).Also, controlled clinical studies on the effectiveness of periodontal antibiotic therapies were initiated in the late 1970s. However, despite intensive research efforts, uncertainty still exists on the most appropriate use of antibiotics in periodontics. Many different antimicrobial regimens have been suggested, with dentists in various coun- tries and even within the same geographical area commonly differing in the selection of antibiotic regimens. Concepts of antimicrobial therapy Periodontal therapy aims to arrest further loss of periodontal attachment and to ensure an aesthetic outcome. Treatment procedures include removal of tooth-borne bacterial plaques and calculus, often in conjunction with periodontal surgery, instruction in oral hygiene procedures and elimination of plaque retention factors. A microbiological approach to periodontal therapy aims primarily at suppressing specific pathogenic bacteria and permitting a sub- sequent recolonization of a microbiota compatible with health. Supragingivalplaque control in the sup- portive periodontal therapy phase helps prevent re- colonization by periodontal pathogens. The concept of antibiotic periodontal therapy re- volves around the drug, the pathogenic microorgan- isms and the host. Systemic periodontal anti- microbial therapy is based on the premise that speci- fic microorganisms cause destructive periodontal disease and that the antimicrobial agent in the peri- odontal pocket can exceed the concentrations necessary to kill the pathogen(s). Compared with mechanical debridement and topical application of antiseptics, systemic antibiotic therapy has certain advantages. Via serum, systemic antibiotics can reach microorganisms at the base of deep peri- odontal pockets and furcation areas and may also affect organisms residing within gingival epithelial and connective tissues. Systemic antibiotics may be capable of eradicating periodontal pathogens colon- izing oral mucosa and other extra-dental sites (132, 133, 157, 226, 245). The possibility of eradicating periodontal pathogens from the entire mouth may reduce the risk for subgingival recolonization of pathogens and for future disease activity (132). Dis- advantages of systemic antibiotic therapy over loc- ally applied antibiotics include adverse drug reac- tions (200) and uncertain patient compliance (99). Periodontal pathogens Rational use of antibiotics in the treatment of peri- odontitis presupposes a thorough knowledge of the periodontal microbiota. An excellent review of the current knowledge on periodontal microbiology has been published recently (61). The periodontal pocket may harbor more than 500 bacterial species (130). It is clear that not all subgingival bacteria are important in the onset and progression of peri- odontitis, as judged from association studies with destructive disease, the effect of elimination, the host response, the presence of virulence factors and the pathogenic potential in animal models (61).Also, periodontitis is usually caused by a constellation of microbial species rather than a single bacterial spe- cies and constitutes a compilation of different infec- tions. Periodontal pathogens belong mostly to gram- negative anaerobic species (Table 1).However, a few gram-positive anaerobic species and some gram- negative facultative rods are considered important pathogens as well. The rather limited number of putative periodontopathic bacterial species com- prises the organisms targeted for periodontal anti- microbial therapy. Types of periodontal infection A functional description of the microbiota of de- structive periodontal disease takes into account both 46
- 3. Systemic antibiotic therapy in periodontics Table 1. Microbial species associated with various clinical forms of periodontitis Localized Failing juvenile Early-onset Adult Refractory guided tissue Species periodontitis periodontitis periodontitis periodontitis regeneration Actinobacillusactinomycetemcomitans +++ ++ ++ ++ ++ Porphyromonasgingiualis f +++ +++ ++ ++ - ~ Prevotella intermedialnigrescens ++ +++ +++ +++ +++ Bacterozdesforsytkhus * ++ +++ ++ ++ Fusobacterzumspecies + ++ +++ ++ +++ Peptostreptococcusmicros f ++ +++ + + I Eubacteriumspecies + ++ + + +++ - -___ - Campylobacterrectus + ++ ++ + +++ - ++ ~- ++ +++ +++ ++ - _ . Treponemaspecies Entericrods and pseudomonads * + f Beta-hemolvticstreptococci ? ++ ++ ++ + - - Candidaspecies - - - - rt -, not elevated in comparison to health +, occasionally isolated; +, < 10%of the patients positive; ++, < 50%of the patients positive; +++, > 50% of the patients positive. Sources: references 38, 103, 144, 145,and 200. - the origin of the microorganisms and the host re- sponse to infection. Delineation of the various types of periodontal infection may help explain why peri- odontal treatment may eliminate some bacteria from the oral cavity but merely reduce the levels of other species. Similar to infections in many nonoral body sites, periodontal pathogens may be divided into endo- genous and exogenous sources of origin (Fig. 1) (229). Endogenous infections are caused by organ- isms present in the healthy host that may overgrow and become pathogenic (commensal organisms). Exogenous infections are caused by organisms ac- quired from outside the oral cavity or the host (pri- mary pathogens). Endogenous infection Endogenous medical and dental infections are caused by microorganisms that are part of the nor- mal human microbiota of the skin, nose, mouth and intestinal and urogenital tracts. Many indigenous 1compromised 1 hqst exogenous organisms i healthy 1 ‘ I ~ , . carrier , . , , , , , i Prevotella intermedia Fusobacteriurn nucleaturn Peptostreptococcus micros Klebsiella Eubacterium spp. Pseudomonas Eikenella corrodens Staphylococcus Campylobacter rectus Candida spirochetes Enterobacter Escherichia coli Ac tinobacillus actinornycetem comitans Porphyromonas gingiva lis Fig. 1. Different types of periodontal infection 47
- 4. van Winkelhoff et al. microbes serve a beneficial role by preventing colon- ization of more pathogenic species. Indigenous bac- teria are nonpathogenic under normal circum- stances, but they may increase to harmful levels after changes in the conditions of the local environment. Indigenous microorganisms can also colonize pre- viously sterile sites of the body and cause infection after propagation to pathogenic levels. Examples are Escherichia coli in urinary tract infection, Bacteroides species in abdominal abscesses and various oral bacteria in sinusitis. Gingivitis is an example of an endogenous dental plaque infection. Maturing dental plaque creates an environment favoring the selective outgrowth of an- aerobic species. These microbial events subsequent- ly lead to inflammation of gingival tissues. Most forms of mild to moderate periodontitis are also as- sociated with bacteria that are part of the oral micro- biota in health. The endogenous type of periodontal infection may, to some extent, comply with the non- specific plaque hypothesis (95). Opportunistic infection Opportunistic infections occur in a systemically or locally impaired host. Most opportunistic pathogens are not highly virulent, but the organisms can cause disease in people whose host defenses are compro- mised by predisposing conditions such as old age, malnutrition, stress, genetic defects, medical pro- cedures and underlying organic disease. A reduced host resistance may be transient or permanent. Some forms of early onset periodontitis have been associated with abnormalities in neutrophil func- tions that may lead to periodontal opportunistic in- fections (188).Periodontal opportunistic infections may also be associated with diabetes mellitus (56, 1171, malignancies (1471, acquired immunodefic- iency syndrome (137), immunosuppressive drugs (124,1801,stress (54, 136),and smoking (15,90, 163). Superinfection The meaning of superinfection is not unequivocal. The term may describe a new infection that compli- cates treatment of an existing infectious process. Su- perinfection is also used to describe a multiple out- burst of an infection caused by the same pathogen. It can be a synonym for a secondary infection by a microorganism on top of a pre-existing infection by another microorganism: for example, Haemophilus infection after viral pneumonia. Superinfection can further represent a complication of an antimicrobial therapy that alters a beneficial microbiota and causes an overgrowth of potentially harmful resident or other opportunistic pathogens. Superinfections may involve indigenous or ex- ogenous microorganisms. Enteric rods, pseudo- monads, staphylococci, beta-hemolytic streptococci and yeasts have been described as superinfecting or- ganisms in periodontitis (41, 168, 177, 202). These organisms commonly occur in combination with classical periodontal pathogens. It is not known whether these species initiate periodontal break- down or appear later in the infectious process. Based on the known pathological potential of superin- fecting organisms in nonoral diseases, it seems plausible that some of these organisms contribute to periodontal disease progression. The subgingival presence of enteric rods and pseudomonads tends to increase with patient age (194)and seems to occur at a high prevalence in periodontitis patients from some developing countries (201). True infection True infections involve organisms that normally do not occur or have a very low carrier rate in healthy individuals. True infections also may encompass or- ganisms that rarely inhabit a given body site in health, e.g., the periodontal ecosystem. Exogenous microorganisms are transmitted from diseased indi- viduals or animals and may cause disease when a required threshold number of organisms is ex- ceeded. Examples of diseases caused by true infec- tious microbes are syphilis, gonorrhea, tuberculosis and plague. A. actinomycetemcomitans and l? gingiualis may be regarded as true infectious agents in periodontal disease. Both bacteria exhibit a low prevalence in periodontal health and gingivitis (91, and the im- mune response towards these bacteria markedly ex- ceeds that characteristic of endogenous infections (198).DNA fingerprinting techniques (36, 104, 105, 162, 217, 218) have provided evidence for these spe- cies being transmitted from parent to child and be- tween spouses (36, 37, 45, 122, 160, 161, 164, 219). Table 13 summarizes studies on transmission of A. actinomycetemcomitans and l? gingivulis among family members. Indirect evidence for the exogenous nature of A. actinomycetemcomitans and P gingivaliscomes from clinical studies showing that long-term elimination of A. actinomycetemcomitans and l? gingiualis is possible after appropriate mechanical treatment and selected antibiotic therapy (157, 167). 48
- 5. Systemic antibiotic therapy in periodontics Treatmentimplications Endogenous periodontal infections are the result of a selective outgrowth of mainly anaerobic bacteria above a certain threshold level in the subgingival ecosystem. Total oral elimination of endogenous putative periodontal pathogens is probably not feas- ible and perhaps not necessary to arrest further peri- odontal breakdown. The major treatment goal of endogenous periodontal infection is reduction of the total bacterial mass and post-treatment colonization by bacteria with low pathogenic potential. Mechan- ical debridement, oral hygiene instruction and sup- portive periodontal therapy possibly combined with antiseptic agents or topical antibiotics constitute the major therapeutic components. Surgical pocket re- duction converts a subgingival environment to a supragingival environment that may further favor the outgrowth of streptococci, Actinomyces species and other health-associated bacteria. Most cases of endogenous periodontal infections do not require systemic antibiotic therapy to arrest disease pro- gression, except in situations involving acute in- flammation and abscess formation. Occasionally, systemic antibiotics may be used to support the mechanical and surgical decrease of pathogenic bac- teria to a level compatible with periodontal health or minimal disease. Due to impaired host resistance in opportunistic periodontal infections, periodontal therapy should reduce pathogens to a level lower than that in an uncompromised host in order to sustain a healthy periodontium. However, the pathogenic bacterial load may be difficult to reduce due to the compro- mised antimicrobial capacity of the host. Prevotella intermedia may overgrow in patients with stress due to the release of stress-related hormones that act as microbial growth factors (SO) and Capnocytophaga species may overgrow in patients with insulin-de- pendent diabetes (56, 117). Meticulous supra- and subgingival debridement, possibly combined with subgingival irrigation with antiseptics along with op- timal oral hygiene and supportive periodontal ther- apy are necessary to control the disease. Some pa- tients may need systemic antibiotic therapy to re- duce subgingival pathogens to levels compatible with periodontal health. Periodontal superinfections may often be the re- sult of previous use of antibiotic or cytotoxic drugs (66, 67, 166). As many as 15% of refractory peri- Table 2. Susceptibility of Actinobacillus actinomycetemcomitans to selected antimicrobial agents No. of study strains References Range MIC,, MICm Antimicrobial agent PgJml W m l pg/ml Penicillin 0.125-8.0 2 4.0 93 150 0.25-4.0 4 . 0 1.o 42 237 0.8-6.25 3.1 6.25 14 69 Amoxicillin 0.06-2.0 1.o 1.o 93 150 cO.25-2.0 <1.0 2.0 43 237 0.4-100 0.8 1.6 14 69 1.0 231 0.5-2.2 Not determined 0.8 50 156 Tetracycline 0.25-1.0 0.5 0.5 93 150 __ Cefime 0.06-16.0 <1.0 8.0 47 231,237 Doxycycline 0.25-2.0 0.4-3.1 1.0 1.6 1.0 3.1 93 150 14 69 Metronidazole 2.0->64 16 32 93 150 2.0-32 16 32 77 75 3.1->lo0 3.1 12.5 14 69 32 231 Ciprofloxacin 150 156 Erythromycin 0.5-8.0 4.0 8.0 93 150 1.0->32 4.0 232 39 237 Azithromvcin 0.25-4.0 <1.0 c2.0 79 151 MIC,,: minimal inhibitoryconcentration for 50%of the strains, MIC,,: minimal inhibitory concentration for 90% of the strains.
- 6. uan Winkelhoff et al. Table 3. Susceptibility of Porphyromonas gingivalis and Prevotella intermediato selected antimicrobial agents Antimicrobial MIC,, No. of study agent d m 1 strains Reference . - . . Penicillin P gingiuulis 0.016 64 149 0.29 11 14 P intermedia 5.0 8 14 8.0 22 73 Amoxicillin I? gingiualis 0.023 64 149 < 1.0 231 8 P intermedia 0.062 2.0 2 231 Doxycycline Metronidazole I? gingivalis 0.047 64 149 P gingivalis 0.023 64 149 2.1 11 14 2.0 231 I? intermedia 1.1 9 14 4.0 231 0.5 8 2 .- ___- Clindamycin P gingivalis 0.016 64 149 < 1.0 231 P intermedia 0.125 22 73 1.o 231 ~~ ~ Table 4. Interactions of antimicrobial agents in the killing of A. actinomycetemcomitans in vitro In combination Hydroxy- with Metronidazole metronidazole __ - penicillin G synergy synergy amoxicillin synergy synergy cefixime synergy synergy moxalactam synergy synergy erythromycin additive additive tetracycline additive additive tobramycin additive additive ciprofloxacin synergy synergy ~~ -___ Source Pdm?ic et a1 (156) odontitis patients in the United States show severe subgingival infections with one or more superin- fecting organisms (195, 202). Control of periodontal superinfection solely by mechanical therapy may be difficult (166, 195).Systemic antibiotic therapy as an adjunct to mechanical therapy may eliminate or markedly reduce the levels of subgingival enteric, pseudomonad and staphylococcal organisms (168, 195). In principle, organisms in true infections can be eradicated by proper antimicrobial therapy. The complete elimination of A. actinomycetemcomitans and I!gingivalis seems to be a prerequisite for arrest- ing ongoing periodontal breakdown in many pa- tients (6, 18,21, 25, 83, 157,227, 241).SubgingivalA. actinomycetemcomituns can be predictably elimin- ated or suppressed for a prolonged period of time by antibiotic therapy combined with mechanical de- bridement (48, 83, 204, 224).Table 2 lists the in vitro susceptibility of A. actinomycetemcomituns to several antimicrobial agents. Subgingival I! gingivalis may be eliminated by mechanical therapy depending on the tooth anatomy and the pocket depth (178, 179). PaviEiC et al. (157) found 89% of patients studied to be free of detectable l?gingivalis after adjunctive sys- temic antibiotic therapy. Table 3 summarizes the in vitro antibiotic susceptibility of l? gingivulis to se- lected antibiotics. In vitro interactionsbetween antibiotics Since the subgingival microbiota in periodontitis often harbors more than one periodontopathic spe- cies that differ in antimicrobial susceptibility,combi- nation drug therapy may be useful in some patients. Metronidazole and its hydroxymetabolite exert syn- ergy in vitro against A. actinomycetemcomitans (75, 155). PaviEiC et al. (159) found that metronidazole susceptibility varied among A. actinomycetemcomit- x ' 1 m 20 c L incubation time (h) Fig. 2. Anaerobic uptake of metronidazoleby 5 strains of A. actinomycetemcomitans. From PaviEiC et al. (159).
- 7. Systemic antibiotic therapy in periodontics 2-4 ~ ---. ___ __. Clindamycin 150 2-3 1-2 1 I Metronidazole 500 6-12 8-10 1-2 6-12 Ciprofloxacin 500 1.9-2.9 ND 1-2 3-6 1 Sources adapred from references 106and 200 ND. not determined. I ans strains (Fig.2) and was associated with the pres- ence of nitro-reductases. Synergyalso exists between metronidazole and amoxicillin as well as between the hydroxy-metabolite of metronidazole and amoxi- cillin and other p-lactani antibiotics (156).The syn- ergisticeffect may be due to the ability of amoxicillin to enhance metronidazole uptake (158). Ciproflox- acin and metronidazole also act synergistically against A. actinomycetemcomitans in vitro (156) (Table 4). It is important to emphasize that some antibiotics in combination can lead to a reduction rather than an increase in their antimicrobial activity.An antag- onistic effect occurs, for example, between bacterio- static tetracyclines and bactericidal p-lactam anti- biotics. From in vitro to in vivo The in vivo efficacy of an antibiotic is determined by pharmacokinetic characteristics and local environ- mental factors (Table5) (152).Extrapolation of in vi- tro susceptibility of periodontal pathogens to in vivo effectiveness must be done with caution. For ex- ample, tetracycline is active against virtually all A. actinomycetemcomitans strains in vitro and appears in gingival crevicularfluid in sufficient concentration to suppress the microorganism. However, tetracy- cline may occur in serum and gingival connective tissues in levels too low to inhibit tissue-invading A. actinomycetemcomitans (191). Consequently, tetra- cycline therapy often fails to eliminate A. actino- mycetemcomitans from the subgingival area (28, 114, 115, 204, 224). Topical administration of tetracy- clines results in an even higher pocket concentration of the drug than with systemic use of tetracyclines. Nevertheless, topical tetracycline seems to reduce A. actinomycetemcomitans levels to only a limited ex- tent (1401,and increased levels of A. actinomycetem- comitans have even been reported after local tetracy- cline therapy (115, 125).Topical tetracycline therapy in conjunction with mechanical treatment also seems to have a limited effect on the occurrence of J? gingivalis (125, 140). These observations contra- dict high expectations based on in vitro susceptibil- ity testing. Factors that may play a role in the efficacy of anti- biotics in the periodontal area include the following: Drug binding to tissues. Tetracycline adheres to root surfaces and is released over an extended period of time (13, 16). Protection of key organisms through binding and/ or consumption of the drug by nontarget micro- organisms. This phenomenon may be significant in periodontal infections with a complex micro- biota. Enterococcus faecalis can protect Bacter- oidesfragilis by inactivating metronidazole, here- by enabling B. fragilis to survive in a mixed niicro- biota of medical importance (138).E. faecalis may inhabit periodontal pockets (169).The ability of the concomitant biota to bind and inactivate me- tronidazole has been proposed as the mechanism of treatment failure in bacterial vaginosis (138) and has been described for oral Fusobacterium nucleatum (87).In addition, different mixtures of facultative and anaerobic bacteria respond dif- ferently to metronidazole monotherapy and com- bination drug therapy (139). Most likely, various mechanisms of inhibition, degradation and inacti- vation of antibiotics occur in the periodontal microbiota containing a mixture of gram-positive Table 5. Characteristics of antimicrobial agents used in the treatment of periodontal disease Serum Crevicular fluid Time to reach Dose concentration concentration peak concentration Half-life in mg (pglml) (pgimll in serum (hours) (hours) Penicillin 500 3 ND 1 0.5 Arnoxicillin 500 8 3-4 1.5-2 0.8-2 Doxycycline 200 2-3 2-8 2 12-22 Tetracvcline 500 3-4 5-12 2-3 2-3 51
- 10. zim Winkelhoff et ul. and gram-negative, facultative and anaerobic bac- teria. Microbial invasion of periodontal tissues and root surfaces may decrease the efficacy of antibiotic therapy,A. actinomycetemcornitans(27)and spiro- chetes (116) are potential invaders of gingival tissues. The total bacterial load in the periodontal pocket in relation to the maximal achievable antibiotic concentration may be too large to allow the elim- ination of key organisms. This phenomenon is known as the inoculum effect. The determination of the minimum inhibitory concentration uses a standardized inoculum of approximately lo5 cells per ml. The minimal inhibitory concentration of tetracycline for lo5 cellsIm1 of A. actinomycetem- comituns is approximately 6 pg/ml and decreases with increasing concentrations of bacterial cells. Since A. actinornycetemcomitans cells in an un- treated deep pocket may be in excess of 107/ml, the number of cells may exceed that which can be controlled by the antibiotic in vivo. In addition, the effect of the many additional pocket bacteria on the inoculum size of a target organism is not known but may further inhibit the killing of the target cells in vivo. The inoculum effect may be most critical for bacteriostatic agents, such as the tetracyclines. However, it may also be applicable to the bactericidal agent metronidazole. Metroni- dazole may reach gingival crevicular fluid concen- trations of 10-12 pg/ml, but since susceptible bac- terial cells in an untreated deep pocket may be as high as lo9,metronidazole may not be able to kill all targeted bacteria in vivo. The bacteriostatic tetracyclines can suppress sus- ceptible periodontal pathogens but are not able to completely eradicate some key subgingival organ- isms. The effectiveness of bacteriostatic anti- biotics strongly depends on the host defense sys- tem, which may be impaired in the periodontal pocket (196). Periodontal pathogens may reside on buccal mu- cosa, tongue tonsils and gingiva (132, 203, 226, 228, 245). These organisms may seed the subgin- gival area after periodontal therapy and may also be transmitted to other individuals. Organisms from extradental sites are usually not affected by scaling and root planing and other periodontal site-specific mechanical tooth cleaning ap- proaches but may be eradicated by appropriate systemic antibiotic therapy. Penicillins and other p-lactam antibiotics may be inactivated by bacterial derived p-lactamases. Sev- era1 periodontal bacteria including Prevotella, Capnocytophaga,l? gingivalis,Eikenella corrodens, Veillonella parvula and streptococci elaborate p- lactamases (71, 79, 233, 238).The levels of p-lacta- mase producing species is significantlyelevated in subjects with recent penicillin exposure (79). The subgingival microbiota can be considered as an adherent layer of bacterial microcolonies (bi- ofilms). Production of glycocalixby plaque organ- isms may induce a biofilm phenomenon. Micro- organisms in biofilms are more resistant to the bactericidal actions of antibiotics in comparison to planktonic cells (7, 8).Biofilm phenomena may also complicate the clinical interpretation of the results of in vitro antimicrobial susceptibility testing. Clinical studies The best evidence of effectiveness of antibiotic ther- apy in periodontics can be derived from controlled clinical studies. Many existing studies are difficult to interpret due to the use of clinically different patient groups, failure to assess periodontitis disease activ- ity, varying antimicrobial regimens, different evalu- ation periods often not exceeding 1year, major dif- ferences in baseline subgingival microbial compo- sition, lack of randomization and double-blind evaluation and insufficient supragingival plaque control. The most commonly used study design evaluates systemic antibiotics as an adjunct to scaling and root planing. This is in agreement with good medical practice that the bacterial load should be reduced as much as possible prior to the institution of antibiotic therapy. This type of study aims to investigate poss- ible additional clinical and/or microbial effects of the antimicrobial drug compared with a placebo medication or no control medication. A second type of study examines the effectiveness of antimicrobial therapy in patients with refractory periodontitis or with recurrent abscess formation. The study patients have experienced further loss of periodontal attachment after thorough conventional mechanical treatment with or without periodontal surgery. The optimal study design for evaluation of the antimicrobial periodontal therapy includes a pro- spective, randomized, placebo-controlled, double- blind investigation (Table6).Uncontrolled longitudi- nal, retrospective and case-report studies provide less reliable information. 34
- 11. Systemic antibiotic therapy in periodontics Clinical studies should be evaluated in the light of these different protocols because evidence of effec- tiveness of a drug in one patient category does not necessarily implicate or deny usefulness in other pa- tient groups. For example, metronidazole, in con- junction with scaling and root planing, may result in additional clinical effects in advancing adult peri- odontitis, whereas it may display little or no benefit in stable, moderate periodontitis (76, 77, 89). Thus, since most clinical trials on antibiotic periodontal therapy have been performed in patients with little or unknown disease activity, and with arbitrary anti- biotic assignment irrespective of the antimicrobial susceptibility of the patient’s subgingivalmicrobiota, the potential value of systemic antibiotics in the treatment of progressive periodontitis is likely greatly underestimated in the present scientific literature. The following discussion separates recent studies into investigations of single antibiotic regimes (Tables6-8) and studies involvingcombination anti- biotic regimens (Table9). Systemicantibiotic studies in localized juvenile periodontitis are summarized in Table 10. Single antibiotic regimens Tetracyclines in adult periodontitis. Tetracycline was one of the first systemic antibiotics for treat- ment of periodontitis that received scientific evalu- ation. In a split-mouth study design, Listgarten et al. (94) and Hellden et al. (65)tested the clinical efficacy of tetracycline in 12 adult periodontitis patients. No statistically significant differences were measured in favor of the tetracycline group, although the mean probing depth and attachment level improved slightly more in the tetracycline group. Slots et al. (199) and Scopp et al. (190)reported similar clinical findings after systemic tetracycline. Nevertheless, several case reports have claimed clinical success with tetracycline therapy (119, 131).In a short-term study, Ciancio et al. (30, 31) found adjunctive mino- cycline to enhance favorable clinical and microbio- logical changes with mechanical treatment, although no significant difference in pocket depth between test and control sites was observed (31).These early studies did not assess the pretreatment disease ac- tivity and the cultivable composition of the pocket microbiota of the study patients. The effects of tetracyclines seem to be optimal in “refractory” adult periodontitis patients. In double- blind studies, Rams & Keyes (170) and McCulloch et al. (120, 1211, found systemic tetracycline to reduce significantly probing pocket depth. McCulloch et al. (121) selected patients on the basis of periodontal disease activity, with active disease being defined as loss of clinical attachment or abscess formation. In comparison to placebo, doxycycline administered for 3 weeks showed significantly more reduction in probing pocket depth and resulted in more gain of probing attachment, but this was only observed at sites with evidence of recent disease activity. The doxycycline regimen reduced the relative risk for periodontal breakdown by 43% over a 7-month period. Even though adjunctive doxycycline therapy was effective in some active periodontitis patients, it failed to prevent periodontal breakdown in 13 of 29 individuals. Recurrent disease activity after systemic tetracycline therapy has also been reported by others (3,48, 224, 2353. The disease progression may have been caused by organisms in the subgingival micro- biota that doxycycline failed to adequately suppress. A. actinomycetemcomitans and E. corrodenswere not markedly suppressed in the doxycycline-treated pa- tients (121). No statistical difference in subgingival microbial composition was found between the pla- cebo and doxycycline patients at 7 months after treatment (85, 12l),indicating that anti-collagenase or other nonantimicrobial mechanisms may have played an important role in disease protection (49). Systemic tetracycline may not suppress subgingi- Val A. actinomycetemcomitans in all patients (133, 135, 224) and may even give rise to an upgrowth of the organism (134). Systemic tetracycline therapy may also lead to colonization of superinfecting and opportunistic pathogens (60, 66, 70, 166). A more predictable outcome of systemic tetracycline therapy in adult periodontitis requires additional studies to determine the subgingival rnicrobiota that is suscep- tible to therapeutic doses of tetracyclines. Tetracyclines in localized juvenile periodontitis. A regime of 1 g/day of tetracycline-HC1 has been shown to enhance the resolution of gingival in- flammation and to support gain of clinical attach- ment and alveolar bone in localized juvenile peri- odontitis (43,91, 142, 143, 199,204). The clinical ef- fect was probably due to the elimination or marked suppression of subgingival A. actinomycetemcomit- ans (29,204).However, tetracyclines as an adjunct to scaling and root planing did not suppress A. actino- mycetemcomituns in all localized juvenile peri- odontitis lesions (204). Periodontal sites with high post-treatment levels of A. actinomycetemcomitans tend to experience further destruction of periodontal 55
- 16. van Winkelhoff et al. I attachment (11,83, 114, 187, 204). Renewed disease activity may occur in 25% of tetracycline-treated lo- calized juvenile periodontitis patients, despite pro- fessional dental cleaning every 3 months (91). Sys- temic tetracycline may not be the best choice of antibiotic in localized juvenile periodontitis patients in terms of predictability and long-term effective- ness. Thus, tetracyclines may provide significant ad- junctive clinical effects to mechanical debridement in some adults with refractory periodontitis (19) and in some localized juvenile periodontitis patients (55, 114). Systemic tetracycline may also support drain- age of periodontal abscesses by suppressing suscep- tible black-pigmented anaerobic species (64). The clinical benefits are likely due to the combined anti- microbial and anti-collagenase effects of the drug. Better guidelines are needed to select patients who would benefit from tetracycline therapy. Metronidazole in adult periodontitis. Systemic me- tronidazole therapy can augment the clinical effect of mechanical periodontal treatment in some peri- odontitis patients. Metronidazole therapy without concomitant scaling and root planing provides very short-lived (up to 1 month) clinical and microbial benefits (92, 239). In a placebo-controlled study, Lindhe et al. (92) observed that metronidazole (200 mg four times daily for 14 days, repeated twice after 2-month intervals) in conjunction with scaling and root planing yielded a slight improvement in gingival status and clinical attachment compared to controls. Deep pockets (27 mm) responded equally well in the test and control group, whereas pockets of 5- 6 mm depth responded better in the metronidazole group. Other researchers have demonstrated adjunc- tive metronidazole therapy to be more effective in adults with deep pockets than with less advanced periodontitis (32,76, 77, 89, 102,210).In conjunction with periodontal surgery, systemic metronidazole has not shown additional clinical effects (113,212). Loesche et al. (98, 101) suggested that systemic metronidazole plus mechanical debridement may decrease the number of teeth in need of periodontal surgery or indicated for extraction due to peri- odontitis. The clinical effect paralleled a slight but statistically significant decrease of subgingival spiro- chetes. Strikingwas the negligibleeffect of metronid- azole on various anaerobes such as l ? gingivafisand Prevotella intermedia, E nucleaturn and Selenomon- as.Presumably,lack of proper oral hygiene or patient compliance in adherence to the drug prescription (99) may explain the minor microbial effects. Later
- 20. van Winkelhofletal. Loesche et al. (97, 98) administered metronidazole or placebo after completion of the mechanical treat- ment and used 20% subgingival spirochetes in at least two subgingival samples to trigger treatment. Again, at 4-6 weeks post-treatment, significantly fewer teeth in the metronidazole group needed peri- odontal surgery. Metronidazole only transiently sup- pressed levels of motile rods, selenomonads, spiro- chetes and P intermedia, and only spirochetes re- mained at reduced proportions at week 6 post- treatment. It may be questioned whether a reduction in subgingival spirochetes from 59% before treat- ment to 22% after debridement provides adequate documentation of the efficacy of systemic metronid- azole. In rapidly progressive periodontitis, metronidazo- le seems to improve healing for up to 6 months com- pared with periodontal scaling alone (211). Gusberti et al. (57) observed statistically significant improve- ment in mean pocket depth, attachment level and percentage of bleeding sites for up to 9 months after a combined therapy of mechanical debridement and systemic metronidazole (250 mg three times daily, 10 days). Using Ornidazole@,Mombelli et al. (127) observed similar effects in patients with recurrent periodontal disease. Metronidazole in localized juvenile periodontitis. Saxh & Asikainen (185, 186) suppressed A. actino- mycetemcomitans in localized juvenile periodontitis patients for up to 18months by mechanical debride- ment plus metronidazole (200 mg three times daily, 10 days). In comparison, systemic tetracycline ther- apy and mechanical treatment alone only eliminated A. actinomycetemcomitans in 44% and 67%of the lo- calized juvenile periodontitis patients, respectively (185, 186).The hydroxy-metabolite of metronidazole may be responsible for the suppression of subgingi- val A. actinomycetemcomitans(75, 156). Thus, systemic metronidazole therapy may result in a marked reduction of anaerobes in the peri- odontal pocket. However, subgingival spirochetes, motile rods, selenomonads, l? intermedia, P gingi- uaEis and E nucleatum tend to reappear after me- tronidazole therapy (57,97, 98, 102, 127).The reason may be an incomplete removal of pathogens at the treated sites or a rapid recolonization of treated sites from other oral sites. Clindamycin and Augmentin@. Clindamycin and Augmentha in treatment of periodontal disease have been investigated in a limited number of studies. Gordon et al. (53) selected 13 periodontitis patients with recent evidence of active disease de- spite conventional periodontal treatment and sys- temic tetracycline therapy. Adjunctive systemic clindamycin and scaling decreased the proportion of active sites per patient per year from 10.7% to 0.5%. During 12 months, 11 of 13 study patients experienced no further loss of clinical periodontal attachment, the percentage of pockets with 1-3 mm depth increased, and the percentage of pockets with more than 6 mm depth significantly decreased. Also, gingival redness, percentage of bleeding sites and sites with suppuration de- creased significantly. At 12 months the percentage of spirochetes remained below 10% of total sub- gingival organisms. At 24 months, a mean gain of clinical attachment of 1.5 mm and a decrease of disease active patients from an annual rate of 8% to 0.5% was found (52). The clinical effects were associated with significant reduction for 1-2 years of spirochetes, motile rods and gram-negative an- aerobic rods including P gingivalis and P interme- dia, and an increase of gram-positive rods and cocci (234). However, clindamycin did not perma- nently suppress subgingival l? gingiualis, which may explain the recurrence of disease activity in some patients. Notably, one study patient developed pseudo- membranous colitis, a gastrointestinal superinfec- tion by Clostridium dificile that may be life-threat- ening. Although they did not perform a double-blind study, Gordon et al. (53) clearly demonstrated the beneficial effect of clindamycin as an adjunct to scal- ing in refractory adult periodontitis. This may in part be related to the use of clindamycin only in patients who harbored a subgingival microbiota susceptible to clindamycin (236). Ohta et al. (146)used clindamycin in five patients with advanced adult periodontitis who received no periodontal therapy with the exception of oral hy- giene instructions. They observed clinical improve- ments and a reduction in the mean percentage of subgingival spirochetes and black-pigmented gram- negative anaerobes for up to 6 months. l? gingivalis appeared particularly susceptible to clindamycin therapy, since this organism remained undetectable for 6 months. A. actinornyceterncornitans and E. corrodenswere resistant to clindamycin and showed a slight increase after 6 months. Magnusson et al. (112)reported on the clinical ef- fects of repeated scaling and root planing in con- junction with either clindamycin or Augmentha in refractory adult periodontitis who in the past had re- ceived periodontal surgery, systemic tetracycline 64
- 21. Systemic antibiotic therapy in periodontics therapy and supportive periodontal therapy. The two systemic antimicrobial therapies were prescribed on the basis of the susceptibility of the whole subgingi- Val microbiota (236). Magnusson et al. (112),over a 2-year evaluation period, found no significant differ- ence in the proportions of sites losing attachment following clindamycin or AugmentinB therapy in comparison to mechanical therapy only. However, the proportion of sites gaining clinical attachment increased from 0.9% before therapy to 5.1% after clindamycin therapy. The authors concluded that ar- rest of further loss of periodontal attachment in re- fractory patients requires repeated mechanical de- bridement and selective antibiotic therapy. Haffajee et al. (59) examined systemic Aug- mentin@, tetracycline-HC1, ibuprofen or placebo therapy given for 30 days in conjunction with sub- gingival debridement and modified Widman flap surgery on adults exhibiting progressive peri- odontitis. Significantlygreater mean gains in clinical periodontal attachment and decreased probing depths were measured at 10 months post-treatment in subjects receiving adjunctive systemic Aug- mentin@or tetracycline therapy as compared with the ibuprofen or placebo regimen. Although de- creases in numbers of subgingival putative peri- odontal pathogens paralleled the marked clinicalim- provements, it is interesting to note that no patho- gen was eliminated from the subgingival microbiota of the study subjects for the length of the 10-month study period. It is also important to note that selec- tion of the antibiotic therapy used in this study was randomly assigned irrespective of the composition or antimicrobial susceptibility of the subject’s sub- gingival microbiota. Thus, it is not likely that optim- ally effective systemic antibiotic regimens were pre- scribed to the study subjects, which suggests that even greater clinical improvements would be ex- pected with individually tailored systemic antibiotic therapy. Overall, monotherapy regimens with various sys- temic antibiotics as adjuncts to mechanical peri- odontal treatment may in some patients induce beneficial microbial effects and decrease the number of periodontal sites with active breakdown. The clin- ical improvement is due to a suppression of the total subgingival bacterial load and a change in the com- position of the subgingival microbiota. However, single antibiotic therapies in adult periodontitis ap- pear unable to predictably eliminate some putative exogenous pathogens. Single antibiotics may be the choice of antimicrobial therapy in many periodontal endogenous infections where the major treatment goal is the establishment of a subgingivalmicrobiota with low levels of putative pathogens. Combination and serial antimicrobial therapy Since the subgingival microbiota in destructive peri- odontal disease consists of various putative patho- gens that may differ in antimicrobial susceptibility, the use of a combination of two or more antibiotics may represent a valuable approach in periodontal chemotherapy. Combination antibiotic therapy may help: to broaden the antimicrobial range of the thera- peutic regimen beyond that attained by any single antibiotic; to prevent or forestall the emergence of bacterial resistance by using agents with overlapping anti- microbial spectra; and to lower the dose of individual antibiotics by ex- ploiting possible synergy between two drugs against targeted organisms. The disadvantages of combination drug therapy are: 0 0 increased adverse reactions; and antagonistic drug interactions with improperly se- lected antibiotics. A bactericidal antibiotic (p-lac- tam drugs or metronidazole) should not be used simultaneously with a bacteriostatic agent (tetra- cyclines)because the bactericidal agent exerts ac- tivity during cell division that is impaired by the bacteriostatic drug. Metronidazole plus amoxicillin,Augmentin@or cip- rofloxacin have been used successfully in the treat- ment of advanced periodontitis, especially with A. actinomycetemcomitans-associated infections (26, 48, 81, 156, 157, 167, 224, 225). Metronidazole and amoxicillin in vitro exert synergistic activity against A. actinomycetemcomitans, and metronidazole/ amoxicillin and metronidazole/Augmentin@ may markedly suppress or eliminate A. actinomycetem- comitans and other subgingival organisms in peri- odontitis lesions (Table 9). Metronidazole/amoxi- cillin has also shown to be effective against nonoral infections associated with oral pathogens (221,223). Metronidazole/ciprofloxacin can be useful with mixed periodontal infections involving anaerobic bacteria, A. actinomycetemcomitans, enteric rods 65
- 22. [JanWinkelhoff et al. Table 11. Selected adverse effects of antibiotics used in the treatment of periodontal diseases Antimicrobial agent Frequent Infrequent Penicillins Hypersensitivity, mainly rashes, nausea, diarrhea Hematological toxicity,encephalopathy, pseudomembranous colitis (ampicillin) Tetracyclines Gastrointestinal intolerance, candidiasis, dental Photosensitivity, nephrotoxicity, intracranial staining and hypoplasia in childhood, nausea, diarrhea hypertension Metronidazole Gastrointestinal intolerance, nausea, diarrhea, Peripheral neuropathy, furred tongue Clindamvcin Rashes, nausea, diarrhea Pseudomembranous colitis, hepatitis unpleasant metallic taste Ciprofloxacin Gastrointestinal intolerance, rashes, unpleasant taste Confusion/convulsions, photosensitivity and pseudomonads (156, 167, 195).Since metronid- azole/ciprofloxacin does not affect most gram-posi- tive facultative bacteria, this combination of anti- microbials may facilitate recolonization of the pocket by facultative streptococci of low peri- odontopathic potential (61). Serial drug regimens studied to date in peri- odontics include systemic doxycycline administered initially and then followed by either Augmentin@or metronidazole (3, 118).The sequential use of drugs overcomes the potential risk of antagonism between bacteriostatic and bactericidal antibiotics. The value of serial antibiotic therapy in the management of ad- vanced periodontitis merits further study. Adverse reactions Table 11 and the article by Walker in this volume (232)list common adverse reactions with antibiotic therapy. Adverse reactions can range from transient adverse reactions to life-threatening hypersensitivity. Most antibiotics comprise low-molecular-weight molecules that, by themselves, are not antigenic. Penicillin (p-lactamantibiotics) exhibiting a molecu- lar weight of about 350 is converted in the body to a molecule that may combine with large serum pro- tein carrier molecules to form an antigenic hapten- carrier complex. Approximately 2.5% of individuals produce antibodies in response to these complexes, resulting in allergic reactions. The formation of anti- penicillin antibodies excludes the future use of peni- cillins in affected individuals. Undesirable discolora- tion of teeth and tissues in adults has been increas- ingly reported following use of systemic tetracycline antibiotics (22, 184). Systemic antibiotictherapyi n periodontal practice Patient selection Systemic antibiotic therapy in periodontics aims to eliminate or markedly suppress specific microorgan- isms with the potential of causing breakdown of periodontal attachment in susceptible patients. Therefore, prime candidates for systemic anti- microbial therapy are patients who exhibit continu- ing breakdown despite diligent conventional mech- anical periodontal therapy. Patients with localized juvenile periodontitis and other types of early-onset periodontitis or with medical conditions predispos- ing for periodontitis should be considered for anti- biotic therapy. Patients with acute or recurrent se- vere periodontal infections (periodontal abscess and acute necrotizing gingivitis and periodontitis) (64) and peri-implantitis also may benefit from antibiotic therapy (128). Patients with stable periodontal or gingivitis lesions derive little or no long-lastingbene- fit from antibiotic therapy. The periodontal disease status may be determined by repeated measure- ments of periodontal attachment level (62, 175),as- sessment of bleeding upon probing (74, 88), meas- urement of pocket temperature (63) and radio- graphic determinations (172). Microbiological analysis Microbiology testing should be performed after completion of conventional mechanical therapy to assess the need for additional antibiotic treatment. Microbial testing should be comprehensive enough to identify the most optimal drug regimen in case
- 23. Systemic antibiotic therapy in periodontics antibiotic therapy is warranted. Microbiology testing might be repeated at 1 to 3 months after the anti- microbial therapy to verify the elimination or marked suppression of the pathogen(s) and to screen for possible superinfecting organisms (45, 174, 205, 229). Ideally, the composition of the sub- gingivalmicrobiota post-treatment should be similar to that in periodontal health (192). Sampling procedure. Microbial sampling sites can include individual pockets with recent disease activ- ity or several pooled subgingival sites. A pooled sub- gingival sample provides useful information on the range of periodontal pathogens to be targeted by the antibiotic therapy. A representative subgingival sample for a patient may be obtained by pooling specimens from one deep bleeding or suppurating periodontal pocket in each quadrant of the mouth (129). Subgingival samples can be collected with either sterile paper points or a curet. With culture, the specimens must be placed in a reduced transport medium to sustain the viability of the sampled microorganisms during shipment to a qualified oral microbiology laboratory for processing (126, 213, 220). tection of periodontal pathogens (197,244).The dis- advantages of these techniques are the limited num- ber of species that can be detected and the inability to determine the antimicrobial susceptibility of sus- pected pathogens. An indirect method to test for E gingivulis, B. for- sythus and some Treponemu species involves the de- tection of a trypsin-like enzyme produced by these organisms (96).However, this method fails to ident- ify or quantify specific microbial species and does not provide antimicrobial sensitivity testing. Antimicrobial susceptibility testing. Table 12A lists the rationale for in vitro antimicrobial determination of putative periodontal pathogens. Table 12B de- scribes techniques to assess the in vitro anti- microbial susceptibility of oral bacteria. In vitro sus- ceptibility testing on primary plaque cultures has been described (202, 236). Isolates of putative peri- odontal pathogens might be tested for susceptibility to metronidazole, amoxicillin, clindamycin, cipro- floxacin, tetracycline and other relevant anti- microbial agents. Several periodontal pathogens Culture methods. Microbial anaerobic culturing provides the most comprehensive assessment of the periodontal microbiota. Total cell counts, the relative proportions of putative periodontal pathogens, and the occurrence of unusual subgingival organisms can be determined (Fig. 1). The determination of relative microbial levels allows a comparison to criti- cal thresholds of the various pathogens (173).Also, culture is currently a prerequisite for in vitro anti- microbial susceptibility testing. The disadvantages of culture are a time-consuming analysis, requirement of technical skills, relatively high costs and limited survival time of the sampled organisms (220). Nonculture techniques. Molecular techniques to de- tect periodontal bacteria include species-specific DNA probes (107) and polymerase chain reaction- based assays (9, 17, 193). These techniques do not require viable cells and can show high sensitivityand specificity. Molecular detection techniques are rela- tively easy, fast and inexpensive to perform. Disad- vantages are the limited number of species that can be detected, the inability to quantify target organ- isms and the inability to perform antimicrobial sen- sitivity testing of target microorganisms. Polyclonal or monoclonal antibodies can be used to stain plaque smears for immunofluorescent de- Table 12A. Rationale for in vitro antimicrobial susceptibility testing of periodontal pathogens in individual patients Thereis a correlationbetween in vitro susceptibility The susceptibilityto any antimicrobialagent varies Antimicrobialresistancecontinues to emerge. There may be regionalvariationsin susceptibility The dentist maywant to know the results in individual results and clinicaloutcome. considerablyamong periodontal species. patterns. patients for medical-legalpurposes. Table 12B. Methods for in vitro susceptibility testing Disk diffusion test: convenient and inexpensive;not applicableto many slow-growing organismsand anaerobes unreliablefor many anaerobes purchased in frozenor lyophilizedform, many fastidiousanaerobes grow poorly in this system Broth disk elution test: convenient and inexpensivebut Broth microdilutiontest: convenient,plates may be Broth macrodilutiontest: labor-intensive Agar dilution test: best supports the growth of E-test:combines disk dilution and minimum inhibitory anaerobes, labor-intensive concentration testing, expensive 67
- 24. van W i n k e l ~ o ~ e t al. (such as I? gingivalis and C. rectus) are usually sus- ceptible to a range of antimicrobial agents and the antimicrobial profiles are quite predictable. In con- trast, strains of I? intermedia, Peptostreptococcus micros, some superinfecting microorganisms and other putative periodontal pathogens may demon- strate resistance to metronidazole, 0-lactam drugs or tetracyclines. Microbial epidemiology. A. actinomycetemcomitans and I? gingiualis can be transmitted from periodontal patients to family members (4,5, 160, 161,164,219). Microbial testing of spouses and children in families with members affected by periodontitis may deter- mine possible transmission of pathogens and form the basis for early disease intervention in susceptible individuals (230) (Table 13). Sequencing of antibiotic therapy. Antibiotics should be considered one of the tools available in peri- odontal therapy and an adjunct to mechanical de- bridement (50, 51, 174, 200, 205). Antibiotic therapy should be reserved for patients with continuing peri- odontal breakdown despite diligent conventional mechanical treatment. Some patient categories with high risk for periodontal breakdown, such asjuvenile periodontitis and other early-onset forms of peri- odontitis, may be treated with antibiotics after the initial mechanical therapy. Use of potent antibiotics without thorough mechanical debridement and without adequate clinical diagnosis, microbiological analysis and susceptibility testing of target organ- isms should be regarded as improper. Fig. 3 presents a practical approach to antibiotic therapy for patients with progressive adult peri- odontitis and early-onset periodontitis. 1. Initial periodontal therapy should include thor- ough mechanical root debridement combined with surgical access if needed. Supplemental sub- gingivally applied broad-spectrum antiseptic agents may be used (176).Periodontal abscesses may develop if systemic antibiotics are adminis- tered without mechanical debridement (68, 215). 2. One to 3 months after completion of the mechan- ical therapy, the clinical response is evaluated. A microbiological examination of the subgingival microbiota is required to determine the presence and the level of remaining putative periodontal pathogens (174, 205). In vitro susceptibility test- ing should ideally be carried out to identify feas- ible systemic antimicrobial therapies. 3. Antibiotics should be prescribed on the basis of the clinical need for further treatment, the micro- biological findings, and the medical status and current medications of the patient (Table 14). Short-term high-dose antibiotic regimens should be favored. 4. At 1 to 3 months after systemic antimicrobial therapy, another microbiological test may be war- ranted to verify the subgingivalelimination of tar- get pathogen(s) and screen for possible superin- Table 13.Selected studies on transmission of putative periodontal pathogens Study Method of Level of Organism(s1 study transmission Zambon et al. (243) A. actinomycetemcomitans Biotyping Identical bio- and serotypes within all 5 families Serotmina Alaluusua et al. (4) A. actinomycetemcomitans Serotyping Children with identical serotypes in 2 of 9 families Alaluusua et al. (5) A. actinomycetemcomitans Ribotyping 2 of 9 spouses showed identical ribotypes, 6 of 9 families children with identical ribohmes as mother/father Petit et al. (160) A. actinomycetemcomitans REA Saarela et al. (183) A. actinomycetemcomitans Ribotyping 2 of 4 couples showed identical A. actinomyceterncomitans Transmission in 8%of spouses and in 15%from proband to children ribotypes I! gingivalis van Steenbergen I! gingivalis Ribotyping 2 of 4 couples showed identical I!gingivalisribotypes REA 6 of 8 married couples showed identical types by all three Ribotyping - et al. (219) methods applied AP-PCR -~ Preus et al. (164) A. actinomycetemcomitans AP-PCR In 6 of 7 families, husband and wife showed different AP-PCR types, children had strainsidentical to one of the parental AP-PCR types. 1of 10 children had a strain from both the mother and father HEA restrict~on endonuclease analysis, AP-PCR polymerase chain reaction with arbitrary primers
- 25. Systemic antibiotic therapy in periodontics diagnosis therapy effective I - ineffective retreatment f 1 1 I maintenance care Fig. 3. Flow chart of periodontal antimicrobial therapy fecting organisms. High levels of viridans strepto- cocci and Actinomyces species are suggestive of periodontal health or minimal disease. 5. After resolution of the periodontal infection, the patient should be placed on an individually tailored maintenance care program. Good patient home plaque control after systemic antimicrobial therapy is essential for long-term treatment suc- cess (58, 82). Recurrence of progressive disease may prompt additional microbiological testing and further therapy targeting the specific peri- odontal pathogens involved. 6. Screening for and eradication of exogenous pathogens (A. actinomycetemcomitans and P gin- gizmlis) in family members might be considered to prevent reinfection and possible recurrence of disease. Selection of antibiotic regimens in periodontal therapy A substantial lack of knowledge exists on the pharmacodynamics of systemic antimicrobial ther- apies in periodontics (152).In the complex subgingi- val microbiota, bacteria not only differ in anti- microbial spectra but are probably also killed or sup- pressed through different mechanisms. Concentration-dependent and time-independent drugs whose activity depends on the ratio between the peak drug concentration (Cp,,) and the mini- mal inhibitory concentration (MIC) of the pathogen include aminoglycosides, metronidazole and the fluoroquinolones. For a concentration-dependent drug, a single dose resulting in a peak-serum con- centration at 8-10 times above the MIC of a patho-
- 26. van Winkelhoff et al. Table 14. Potential drug interactions of selected antimicrobial agents Antimicrobial Contraindications for use Potential drug interaction - - Penicillins Hypersensitivity to peniciIlins Efficacydecrease by bacteriostatic antimicrobial agents, potentiates Effectsof Coumadin (warfarin)and aspirin, probenecid increases Potentiates anticoagulant effects of Coumadin (warfarin) Potentiates toxicity of lithium Potentiates vasoconstrictive effects of ergot alkaloids Potentiates nephrotoxicity of diuretics Decreases bactericidal effects of penicillins Absorption is decreased by magnesium, bismuth, Barbiturates can enhance secretion of tetracyclines Alcohol elicits disulfiram effects (nausea,abdominal cramps,vomiting, Potentiated by chloramphenicol and cimetidine Potentiates phenytoin and phenobarbital Decreases effects of erythromycin, increases effectsof benzoyl peroxide Hypersensitivity to quinilones Bactericidaleffectsreduced by tetracyclines,inhibited by nitrofurantoin Combined liver and kidney diseases Absorption reduced by antacids Reduces metabolism of caffeine Cyclosporins may increase serum levels of ciprofloxacin Interacts with anticoagulants anticoagulants serum half-life . . . Tetracycline Children under 8 years Hypersensitivity to tetracyclines Liver disorders aluminum and iron-containingdrugs -~ ~- Metronidazole Hypersensitivity to nitroimidazoles Potentiates anticoagulant effects of Coumadin (warfarin) Nervous system disorders Blood disorders headache) Clindamycin Hypersensitivity to lincomycins Ciprofloxacin Children under 16years Increases serum levels of theophylline gen may be the optimum dosing strategy. In vitro, doubling the concentration of a concentration-de- pendent drug will kill the same number of organisms in half the time. In a mouse model infected with Pseudornonas aeruginosa, netilmicin 30 mglkg ad- ministered as a single dose appeared more effective in reducing the number of bacteria than two 15mgl kg doses given every 6 hours (34). Apparently, the fraction of killed bacteria increased with an increase in the Cp,,: MIC ratio. This observation may be due to bacteria in the inoculum exhibiting varying sensi- tivity to the drug. Concentration-independent and time-dependent drugs kill microorganisms during time periods where the concentration of unbound drug remains above the MIC. P-Lactams are examples of concen- tration-independent antibiotics. Once a threshold drug concentration has been achieved, no further in- crease in bacterial killing is obtained by increasing the drug concentration. A concentration-indepen- dent drug should be taken frequently to maintain a maximal Cp,,: MIC ratio. The post-antibiotic effect of a drug is also an im- portant factor in periodontal antibiotic therapy (152).The post-antibiotic effect represents the time during which bacterial growth is inhibited after the drug concentration has fallen below the bacterial minimum inhibitory concentration. The post-anti- biotic effect of a given drug differs for gram-positive and gram-negative bacteria. Also, the post-antibiotic effect tends to last longer for antimicrobial agents that inhibit protein synthesis (macrolides and tetra- cyclines)than for p-lactam drugs. Furthermore, anti- microbial combinations may be synergistic, indiffer- ent or antagonistic with regard to the post-antibiotic effect (246). The optimal choice and dosing of antibiotics for various periodontal infections remains to be deter- mined. The reader might consult Tables 6 to 11 and with Slots & van Winkelhoff (205) and van Winkel- hoff et al. (229) to help select proper drug prescrip- tion regimens. Tetracyclines may be indicated for monoinfec- tions of periodontal A. actinomycetemcomitans (19, 821, but may not provide sufficient suppression of subgingival pathogens to arrest destructive disease activity in mixed infections (29, 91, 114, 115, 133, 186, 204, 224). Metronidazole plus amoxicillin provides a rela- tively predictable eradication of periodontal A. acti- nomycetemcomitans and P gingivalis in early-onset forms of periodontitis and in refractory adult peri- 70
- 27. Systemic antibiotic therapy in periodontics odontitis (26, 82, 157, 224, 225). Ciprofloxacin may substitute for amoxicillin in case of allergy to p-lac- tam drugs (156). Metronidazole may arrest disease progression in refractory periodontitis patients with l? gingivalis and/or l? intermedia infections without other poten- tial pathogens (98, 102). Clindamycin has demonstrated efficacy in refrac- tory periodontitis (52, 53, 112).Clindamycin may be considered with periodontal infections comprising high levels of Peptostreptococcus, P-hemolytic streptococci and various oral gram-negative anaer- obic rods (234). Clindamycin should be prescribed with caution due to the potential for pseudomem- branous colitis from superinfections with C. dificile (47). Augmentin@may comprise an alternative to clind- amycin in treatment of periodontitis (33, 111, 112). Also systemic AugmentinB therapy may kill peri- odontal pathogens with guided tissue regeneration procedures and increase the possibility for gain of clinical attachment (144, 145). Ciprofloxacin is effective against enteric rods, pseudomonads, staphylococci, A. actinomycetem- comitans and other periodontal organisms (195).Ci- profloxacinmay be combined with metronidazole or a P-lactam drug for treatment of mixed anaerobic periodontal infections (167,205). Summary and conclusion 1. 2. 3. Periodontal disease may result from endogenous infections (E nucleaturn in gingivitis), opportun- istic infections (P intermedia in insulin-depend- ent diabetes periodontitis), superinfections (Can- dida, enteric rods and Pseudomonas in adult periodontitis) and true infections (A. actinomyce- temcornitans and l? gingivalis in advanced adult periodontitis). Periodontal treatment aims at restoring a micro- biota compatible with periodontal health. Effec- tive therapy implies a reduction of pathogenic levels of indigenous oral microorganisms and an elimination of exogenous pathogens and of or- ganisms outside their ecologicalniche such as en- teric rods and pseudomonads. Since both mi- crobial and host susceptibility factors determine the periodontal health status, the composition and number of subgingival organisms associated with periodontal health may vary from individual to individual. Mechanical periodontal treatment can reduce total supra- and subgingival bacterial mass, but major pathogens may escape the effect of treat- ment due to their ability to invade periodontal tissues or to reside in furcations or other tooth structures outside the reach of periodontal instru- ments, or due to poor host defense mechanisms. Systemic periodontal antibiotic therapy aims to reinforce mechanical periodontal treatment and to support the host defense system in overcoming the infection by killing subgingival pathogens that remain after conventional mechanical peri- odontal therapy. Single antimicrobial drug therapies are able to suppress the number of subgingival indigenous bacteria for a prolonged period of time depending on the host defense and oral hygiene efforts. Combination drug therapies aim at enlarging the antimicrobial spectrum and exploiting synergy between antibiotics and may be indicated with complex mixed subgingival infections. Much has been learned about the microbiological etiology of destructive periodontal disease and the effectiveness of various periodontal therapies. Suc- cessful periodontal treatment depends on proper as- sessment of an individual’s risk for periodontal breakdown which, in turn, depends on the patho- genic characteristics of the periodontal microbiota and the host susceptibility. Therapeutic success in periodontal therapy will undoubtedly increase with improved ability to diagnose the periodontal infec- tion and critical host factors and to apply individu- ally tailored periodontal treatments using an arma- mentarium of locally and systemically applied thera- peutic agents. References 1. 2. 3. 4. 5. Abu-Fanas SH, Drucker DB, Hull PS. Amoxicillinwith cla- vulanic acid and tetracycline in periodontal therapy. J Dent Res 1991: 19: 97-99. Abu-Fanas SH, Drucker DB, Hull PS, Reeder JC, Ganguli LA. Identification and susceptibility to seven anti- microbial agents of 61 gram-negative anaerobic rods for periodontal pockets. J Periodont Res 1991: 19: 46-50. Aitken S, Birek P, Kulkarni GV, Lee W, McCulloch CAG. Serial doxycycline and metronidazole in prevention of re- current periodontitis in high risk patients. J Periodontol Alaluusua S, Asikainen S, Lai CH. Intrafamilial trans- mission of Actinobacillus actinomycetemcomi~ans. J Peri- odontol 1991:62: 207-210. Alaluusua S, Saarela M, Jousimies-Somer H, Asikainen S. Ribotyping shows intrafamilial similarity in Actinobacillus 1992:63: 87-92. 71