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Antibiotics and Periodontal Disease: A Selective Review of the Literature
A S S O C IA T IO N
REPORT
Antibiotics and periodontal disease: a selective review of the literature C o u n c il o n D e n ta l R e s e a r c h
W i llia m A . G ib s o n , DDS, PhD
I
t is now generally accepted that mi croorganisms act as primary etiologic ag e n ts in the vario u s form s of periodontal disease.1'6 Moreover, there is increasing evidence that spe cific kinds of microorganisms may be associated with specific forms of the disease.610 Accordingly, a rationale has developed for the use of antibiotics in the prevention and treatment of periodontal disease. Antibiotics administered systemically to dogs have been found to result in changes in the plaque flora, reduc tion in the signs of gingivitis,11 and a distinct decrease in the progression of alveolar bone loss.12 Investigators using other animal model systems have achieved similar encouraging re sults.13'17 However, the use of antibiotics in humans is associated with a number of problems including induction of resis tant strains of microorganisms and al lergic manifestations ranging from mild reactions to anaphylactic shock, as well as a variety of major and minor side effects.18 Most of these problems are related to the specific antibiotics used, the dosage, the route of adminis tration, and the duration of the treat ment.18 An ideal antibiotic for use in the prevention and treatment of periodon
tal disease would be one that would act specifically on periodontal pathogens, would not be allergenic or toxic, would maintain activity in the oral en vironment or tissue for long periods, would not be in general use for treat ment of other diseases, and would not be prohibitively expensive. However, it is not clear at this time whether a single antibiotic, even if it were ideal, would be equally efficacious in both prevention and treatment. The bacte rial flora associated with gingivitis, for example, has far less specificity than that associated with other forms of periodontal disease.6 In addition, an tibiotics have been incorporated into periodontal dressings19'21 and used as an adjunct to periodontal surgery as a means of reducing sequelae such as in fection, pain, swelling, and delayed healing, with varied results.22'25 Thus, it is obvious that continued research is needed in the microbiology of periodontal disease as well as the evaluation of new and currently avail able antibiotics, with respect to pre vention, treatment, and management of periodontal disease. The following is a review of some of the antibiotics studied thus far. Other reviews have been done by Loesche,26 Johnson and Rozanis,27Parsons,28 and Winer and others.29
P e n icillin P en ic illin , iso lated in 1929 a n d in tro du ced in to clin ic al m e d ic in e in 1941, w as th e first a n tib io tic u se d in h u m ans. A n im al stu d ies by S tah l30'32 an d W ild erm an 33 re su lte d in co n flictin g rep o rts ab o u t th e effects of p e n ic illin o n h e a lin g f o llo w in g p e r io d o n ta l surgery. In h u m a n stu d ies, Dal P ra an d S tra h an 34 an d K idd an d W ade35 fo u n d th a t p a tie n ts g iv e n p e n ic illin afte r p erio d o n tal surg ery ex p e rien c ed less p o s to p e ra tiv e p a in . S im ila r re s u lts w ere ach iev ed in a m ore recen t stu d y by P en d rill an d R ed d y .25 H ow ever, p a ra m e te rs s u c h as in fe c tio n , p la q u e levels, g in g iv itis, an d crev icu lar flu id flow w ere n o t sta tistica lly d ifferen t b e tw e e n th e p e n ic illin - a n d p laceb o treated groups.
As penicillin remains one of the most important antibiotics against many microorganisms that cause seri ous infections in humans, coupled with the high incidence of allergic reactions and frequency with which bacterial resistance develops with its use, there appears little rationale for its routine use after periodontal surgery. Animal and human studies have failed to demonstrate a clear-cut benefit from such use. JADA, Vol. 104, F ebruary 1982 ■ 213
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Erythromycin T h e a n tib a c te ria l sp e c tru m of e ry th ro m y cin closely resem bles th a t of p e n ic illin , b u t b o th b acterial re sist an c e a n d severe to x ic effects o cc u r w ith le ss fre q u en cy . It is th e re fo re often reserv ed for u se in patien ts w ho h a v e d e v e l o p e d a s e n s i t i v i t y to p e n ic illin .18 A lth o u g h L obene a n d o th ers 36 achiev ed a 35% red u c tio n in p la q u e form ation d u rin g a seven-day a d m in is tra tio n o f e ry th ro m y c in in w h ic h subjects rin sed , th en sw allow ed th e p rep a ra tio n four tim es a day, th e ef fect w as short-lived after th e antibiotic w as w ith d raw n . In add itio n , all p artic ip a n ts suffered from gastrointestinal problem s. As is tru e w ith p en icillin , ery th rom ycin sh o u ld be reserved for trea tm e n t of system ic disease.
Kanamycin T h is ra th e r toxic antibiotic is ch e m i c a lly s im ila r to s tr e p to m y c in a n d n e o m y c in .18 It h as b een stu d ie d by L oesche an d associates as a to p ic ally a p p lie d p rep a ra tio n of 5% an tib io tic in O rabase in selected m entally h a n d i c a p p ed subjects for a few w eeks37 an d for one year.38 G ingival h ealth w as ob served to im prove in treated in d iv id u als ev en th o u g h th e re w as no signifi can t re d u c tio n in plaq u e scores. In a m ore rec en t stu d y ,39 a five-day to p ical kan am y cin treatm en t red u ced p la q u e m ass on to o th surfaces com p are d w ith placebo treatm ent. T he re d u c tio n occurred w ith o u t m echanical h y g ien e p ro ced u res an d p ersisted for a t least four w eeks. H ow ever, th e g in g iv itis sc o re s w e re n o t r e d u c e d to m u c h below p retreatm en t levels an d w e re h ig h e r th a n p o s tp r o p h y la x is scores. T he re d u c tio n in plaque m ass w as d eterm in e d to be due to red u c ed n u m b ers of streptococci. T he m arginal r e s u lt s a c h ie v e d w ith k a n a m y c in w o u ld ap p e ar to lim it its use in all b u t a sm all n u m b e r of in d iv id u als w ho are n o t able to m a in ta in th e ir oral hygiene w ith ro u tin e procedures.
Spiramycin S p ira m y c in is a n a n tib io tic a c tiv e a g a in st g ram -positive organism s in c lu d in g S tre p to c o c c u s m u ta n s a n d A c tin o m y c e s v is c o s u s 40 a n d is r e ta in e d in an active state for p ro lo n g ed p erio d s in bone, saliva, an d salivary g la n d s.41'46 K eyes a n d cow orkers15 d e 214 ■ JADA, Vol. 104, February 1982
te rm in ed th a t sp iram y cin w as th e m ost efficacious of n in e agents in red u cin g d en tal p la q u e an d p erio d o n tal lesions in th e ham ster. Investigators in early clin ical trials in h u m an s, rely in g on clin ical im p res sions, g enerally rep o rted favorable re s u lts w ith sp ira m y c in : D a lig la n d 47 c o n d u c te d a th ree -y e ar s tu d y of 90 p e rio d o n ta l p a tie n ts tre a te d for 20 days; H arvey48 gave a d etailed acco u n t of seven of 70 cases treated ; an d Gend ro n 49 a d m in iste re d sp iram y cin b e fore treating 300 p atien ts w ith a w id e variety of oral co n d itio n s. In a m ore co n tro lled stu d y , W iner an d o th ers29 co m p ared th e effect of sp iram y cin an d p lacebo in p erio d o n tal p a t i e n t s w ith a n d w i t h o u t lo c a l therapy. Im p ro v em en t w as rep o rted in p atien ts treated w ith sp iram y cin even w h en local th e ra p y w as n o t ap p lied . M ills a n d o th e r s 50 c o n d u c te d a d o u b l e - b l i n d s t u d y in w h ic h 48 p e rio d o n ta l p a tie n ts w ere ran d o m ly assigned to one of th ree g ro u p s an d given eith er sp iram y cin , erythrom y cin, or a placeb o for five days. E xam i n atio n s c o n d u c te d once a w eek for a m o n th c o n siste d of g in g iv a l in d ex , plaq u e an d p o ck et d ep th s on an terio r teeth, crev icu lar flu id readings, an d w et plaque w eig h t from selected teeth. A n a ly s is b e tw e e n a n d w ith in te s t g roups in d ic ated a m ore favorable re sp o n se w ith th e u se of sp ira m y c in com pared w ith eith er ery th ro m y cin or th e placebo. In a m ore rec en t study, Johnson an d others,51 a n d R ozanis an d o th ers52 co n d u cted d o u b le-b lin d exam inations o n 63 subjects w h o refrain ed from m e chanical o ral h y g ien e p ro ce d u re s for 11 w eeks. T h ey receiv ed cap su les to be tak en four tim es a day for five days. In a ran d o m m an n er, 29 received 500-mg c a p s u le s of sp ira m y c in a n d 34 r e ce iv e d p la ce b o c a p su le s. A lth o u g h plaq u e sam ples tak en from th o se re ceiving th e an tib io tics in d ic ated a re d u ctio n in p la q u e as m easu red by w et w eight, tu rb id ity , an d n itro g e n an d carbohydrate co n ten t lastin g for th ree w eeks, on ly th e m a n d ib u la r p laq u e ind ex at w eek 3 w as sig n ifican tly re duced. T h is m ay in d icate th e relative in se n sitiv ity of th e clin ical p aram e te r.27 In ad d itio n , in in d iv id u als re ceiving antib io tics, th e co u n ts of S m u ta n s a n d S sa n g u is w e re re d u c e d , w h e re a s g r a m -n e g a tiv e o rg a n is m s w ere n o t affected. A lth o u g h th e resu lts o b tain ed th u s
fa r w ith s p ir a m y c in c a n o n ly be ch aracterized as m ild ly en couraging, th ere ap p ears to be su fficien t ev idence to w arran t fu rth e r research. It is partic u la r ly w o rth w h ile b e c a u se sp iram y cin is co n sid ered a safe n o n toxic drug w ith few an d in freq u en t sid e effects18 an d is n o t in g en eral use by th e m ed ical pro fessio n .53
Vancomycin V ancom ycin is a g ly co p ep tid e an tib io tic ac tiv e a g a in st g ram -p o sitiv e o r ganism s. It is asso ciated w ith severe toxic effects w h e n ad m in istered system ically. H ow ever, no ad v erse effects have been rep o rted w h e n u se d to p ic ally .18 In early clin ic al stu d ies by M itchell an d H olm es,54 1% vanco m y cin in an ad h esiv e paste w as a p p lied to p ically to th e teeth an d g in g iv a of an in stitu tio n a liz e d p o p u la tio n o n ce a day for eig h t days. T h is trea tm e n t re su lted in a red u c tio n in p la q u e scores a n d g ingivitis. T hese param eters re tu rn ed to p retrea tm e n t levels in th ree w eeks. In su b seq u en t stu d ies, M itchell a n d c o -w o rk e rs55 re p o rte d th a t 1% v an co m y cin o in tm en t w as effective in red u cin g p laq u e, g in g iv itis, a n d objec tio n ab le oral odors w h e n a p p lied th ree tim es a w eek an d th a t som e p atien ts h ad rec eiv e d su c h tre a tm e n t for as long as eig h t m o n th s w ith o u t observa ble adverse effects. H ow ever, Loe a n d associates56 re p orted o nly a m o d erate re d u c tio n in p laq u e in v o lu n teers as a re su lt of th ree d aily m o u th rin se s w ith a v ancom ycin p rep a ra tio n d u rin g five days w ith o u t o ra l h y g ie n e , a n d J e n s e n a n d cow o rk e rs ,57 in a s im ila r b u t lo n g e r study, fo u n d th a t v an co m y cin failed to sig n ifican tly red u c e p laq u e levels, an d th a t b o th a n tib io tic - a n d p la c e b o trea ted g ro u p s d ev e lo p e d g in g iv itis a fte r th r e e w e e k s. A s in d iv id u a ls treated w ith v an co m y cin h a d a p re d o m in a n tly g ram -n eg ativ e b ac te ria l flora, it w as co n c lu d e d th a t su ch a flora w as cap ab le of form ing p la q u e an d causing g ingival inflam m ation. C ollins,58 u sin g th e earlier p rep a ra tio n of 1% v an co m y cin in an adh esiv e paste, fo u n d th a t its u se sig n ifican tly r e d u c e d p la q u e in p a t i e n t s a f te r p e r io d o n t a l s u r g e r y . M c F a ll a n d o th ers,59 how ever, co u ld fin d no sig n ifican t difference in p la q u e d ep o si tio n w h en a sim ilar p rep a ra tio n an d a placebo o in tm en t w ere a p p lie d to p ar
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tic ip a n ts refrain in g from oral h ygiene p ro ced u res. In a m ore recen t stu d y , K aslick and co-w orkers,60 u sin g 1% v an co m y cin o in tm en t a n d a placebo in a d o u b le b lin d stu d y w ith p a rtic ip a n ts refra in ing from oral h ygiene for six days, re p o rted th at, alth o u g h p la q u e scores w e re s i g n i f i c a n t l y r e d u c e d in an tib io tic-treated subjects, th ere w ere no sig n ific an t d ifferences in th e scores for g ingivitis. It w o u ld a p p e a r th a t, w ith s u c h n eg ativ e resu lts, v an co m y cin w o u ld h a v e lim ite d u s e in p e r io d o n tic s . H ow ever, it sh o u ld be e m p h asized th a t d iffe ren t p re p a ra tio n s a n d d iffe ren t subjects w ere u sed in th e se studies. F u rth e r research , in c lu d in g d o u b le b lin d an d d etailed ex am in atio n s after th e u se of several different p re p a ra tio n s of v anco m y cin in carefu lly ch o s e n p o p u la tio n s o f p a t i e n t s w ith p erio d o n tal disease, n ee d s to be ac co m p lish e d before v an co m y cin can be d ro p p e d from fu rth e r co n sid eratio n .
Tetracyclines T etracy clin es co n sist of a n u m b e r of a n t i b i o t i c c o m p o u n d s o f s i m ila r m o lecu lar stru ctu re an d b ro ad sp e c tru m of a n tib a c te ria l a c tiv ity .18 A l th o u g h th e in c id en c es of b acterial re sistan ce an d h y p erse n sitiv ity are low w h e n a d m in is te r e d s y s te m ic a lly ,18 th e y in crease sig n ific an tly w h e n te tra cy clin es are u se d in to p ic a l p re p a ra tio n .61 In an early clin ic al stu d y , Loe an d co-w orkers56 rep o rted th a t a m o u th w a sh c o n ta in in g 0.5% te tra c y c lin e u se d for five days in subjects w ith o u t m e ch an ical oral h y g ien e pro ced u res resu lted in red u c ed p la q u e levels b u t no sig n ific an t differences in gingival scores co m p ared w ith placeb o co n trols. S tu d ies by B orzelleca a n d Cherr ic k 62 a n d B a d e r a n d G o ld h a b e r 63 d e m o n stra te d th a t sy ste m ic a lly a d m in iste re d tetracy clin es ap p e ared in th e s a liv a a n d g in g iv a l c r e v ic u la r flu id , respectively. M ost su b se q u en t s tu d ie s h av e u sed system ically a d m in istered tetracyclines, alth o u g h th e use in p e r io d o n ta l d r e s s in g s h a s b e e n stu d ied ; lack of foul taste in th e m o u th w as th e o n ly a d v a n ta g e c ite d . N o n s p e c ific s to m a titis , m o n ilia s is , an d u n d esira b le tissu e rea ctio n s oc cu rred as com plications. S u ch topical u s e of te tra c y c lin e s in p e rio d o n ta l d ressin g s is n o t rec o m m en d e d .64
A n u m b e r of an im al m o d el system s h ave b een u se d to stu d y th e effect of sy stem ic te tracy c lin e . W illiam s an d o th e rs12,65 a n d Jeffcoat a n d o th e rs66 re p o rted th a t d aily system ic tetracy clin e sig n ific an tly in h ib ite d th e p ro g ressio n of alveolar b o n e loss in trea ted vs n o n trea ted con tro l beagle dogs. In a n o th er stu d y , L istgarten an d o th e rs11 a d m in iste re d 250 m g of te tra c y c lin e HC1 tw ice d aily for four w eeks to dogs w ith v a ry in g d e g re e s of g in g iv itis , a n d fo u n d th a t p la q u e an d g in g iv al scores im p ro v e d . In a d d itio n , h isto lo g ic a l stu d ies in d ic a te d a re d u c tio n in th e n u m b e r of inflam m ato ry cells, b u t in f la m m a t i o n w a s n o t e l i m i n a t e d . S ip o s67 u se d beagle dogs to s tu d y th e efficacy of to p ically a p p lie d te tracy clin e in th e form of m elo cy clin e in p re v e n tin g th e d ev e lo p m e n t of g in givitis. A fter an in ital p ro p h y lax is an d 19 days of tw ice-d aily b ru sh in g , the an im als w ere assig n ed to one of th ree groups. O ne gro u p w as left u n trea ted , th e s e c o n d w a s tr e a t e d w ith 1% m elo cy clin e cream d aily, a n d th e th ird g ro u p w as tre a te d sim ila rly w ith a placebo cream . A fter fo u r an d seven w eeks of treatm en t, sta tistically sig n if ic a n t d iffe re n c e s c o u ld b e d e m o n strated b etw een u n trea ted an d treated g ro u p s w ith resp e ct to p laq u e, g in givitis, an d b leed in g scores. H ow ever, pocket d ep th s w ere n o t sig n ifican tly different. W einer an d o th e rs17 in d u c e d p e r io d o n titis in th e m a x illa ry le ft segm ents of rats w ith lig atu re w ire a n d a m o d ifie d d ie t. T h e e x p e rim e n ta l an im als w ere given 21 m g of tetracy clin e d aily for te n w eeks in th e d rin k ing w ater. W hen co m p ared w ith co n trols, th e tetracy clin e-treated an im als h ad less reso rp tio n of b u ccal alveolar b o n e , le s s a p ic a l m ig r a tio n of e p ith e liu m o n th e d istal ro o t of th e m axillary first m olar, a n d few er in flam m atory cells. In h u m a n s, Scopp a n d asso ciates68 gave p erio d o n tal p atien ts eith er ca p su les co n tain in g p lacebo or 250 m g of te tracy c lin e to b e tak en every six h o u rs f o r f iv e d a y s a f te r s u r g e r y . In a d o u b le -b lin d ex am in atio n , n o sig n ifi c a n t d if fe r e n c e s w e re d e te c te d in eith er th e am o u n t of p a in or in flam m a tio n p rese n t at th ree a n d sev en days p ostsurgically. In a m ore re c e n t d o u b le-b lin d stu d y , S copp an d co-w orkers69 beg an w ith a ran d o m d iv isio n of 20 p atien ts in to tw o te st groups. O ne gro u p receiv ed tetracy clin e 250 m g fo u r tim es a day
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th e first w eek, th ree tim es a day th e seco n d w eek, an d tw o tim es a day th e th ir d w ee k . T h e c o n tro l g ro u p r e ceiv ed a placeb o in a sim ilar fashion. Both g ro u p s receiv ed id e n tic al clin ic al th e ra p y co n sistin g of root p la n in g an d cu rettag e. A t th e en d of th ree m o n th s, th e g ro u p s w e re s w itc h e d a n d th e s tu d y w as rep e ate d for an a d d itio n a l th r e e m o n th s . N o s ig n if ic a n t d if fe re n c e s w e re d e te c te d b e tw e e n p la c e b o - a n d te tr a c y c lin e - t r e a te d g ro u p s w ith resp e ct to g in g iv al in d ex , d e b ris in d e x , or p a p illa ry b le e d in g d u rin g eith er of th e th ree -m o n th stu d y p erio d s. H ow ever, G enco an d co-w orkers70 a n d R e y n o ld s a n d c o -w o rk e rs71 r e p o rted that, w h en tetracy clin e is u se d as an a d ju n c t to trad itio n al p erio d o n tal p ro ced u res, sig n ifican t en h a n ce m e n t of h ea lin g occurs. In th e latter study, h o w ev er, an in crease in th e n u m b ers of te tra c y c lin e -re sista n t o rg an ism s w as o bserv ed in th e saliva an d p erio d o n tal pockets. L istg arten an d o th e rs72 an d H elld en a n d o th e rs73 u se d h alf-m o u th scalin g an d root p la n in g in tw o g ro u p s of p a tien ts; one g ro u p receiv ed 1 gm te tra c y c lin e a n d th e o th e r w as g iv e n a p lacebo d aily for tw o p erio d s of tw o w eek s se p arate d by a four-w eek in te r val. In all areas of b o th gro u p s, oral h y g ie n e a n d g in g iv al co n d itio n s w ere o b se rv e d to b e im p ro v ed ; h o w ev er, lo w e r p la q u e a n d g in g iv a l in d e x sco res w ere re c o rd e d in th e sc ale d areas co m p ared w ith u n se a le d areas. In th e u n se a le d areas, tetracy c lin e re s u lte d in m o d e st im p ro v e m e n ts in c lin ic al p aram eters th a t w ere n o te d at th e eight-w eek, b u t n o t th e 25-w eek, ex a m in atio n p erio d . T etracy clin e d id n o t re su lt in sig n ifican t im p ro v em en t w h e n s c a le d are a s w e re c o m p a re d w ith u n se a le d areas, w ith th e ex cep tio n of a sm a ll g ain in a tta c h m e n t levels; h o w ev er, th e au th o rs d id agree w ith p rev io u s in v e stig a to rs70,71 th a t th e u se of tetracy clin e en h an ces h e a l ing. S lots an d co-w orkers74 also stu d ie d th e u s e o f a d ju n c tiv e te tr a c y c lin e th e ra p y in p e rio d o n tal p atien ts after a sin g le co u rse of scaling an d root p la n ing. T hey fo u n d th a t th e clin ic al ef fects of ad ju n ctiv e te tracy c lin e in m ost p a tie n ts d id n o t differ sig n ific an tly fro m th o s e a c h ie v e d w ith c o n v e n tio n a l th e ra p y alo n e. H o w ev er, a d ju n c tiv e tetracy c lin e d id re su lt in th e im p ro v e m e n t of tw o p a tie n ts w h o IADA. Vol. 104. February 1982 ■ 21S
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w ere u n resp o n siv e to rep eated con v en tio n al therapy. M ajor differences w ere n o te d in th e am o u n t and com po sitio n of th e pre- an d posttreatm en t su b g in g iv al m icroflora. T his an d other stu d ie s have led to an increasing in te r est in b o th th e long- and short-term ef fects of tetracy clin e on th e subgingival m icroflora. C laiborne an d M cFall75 re p o rted th a t p atien ts taking 250 m g of tetracy clin e a day for at least six w eeks as a trea tm e n t for acne vulgaris ex p eri en ced a decrease in anaerobic gram n eg ativ e ro d s an d gram -positive cocci of 19% an d 11%, respectively, com p are d w ith u n trea ted controls. O sterb erg a n d o th e rs 76 s tu d ie d a s in g le p a tie n t w ith a d v a n c e d p erio d o n tal disease, an d noted th a t a co m plex, largely gram -negative flora w as c h a n g e d to a fa c u lta tiv e , sacch aro ly tic p la q u e of streptococci and actin o m yces w ith in tw o w eeks of tet rac y clin e th e ra p y at 1,000 m g daily. A fter an a d d itio n a l tw o w eeks of 500 m g of tetracy clin e daily, R othia dentocariosa w as th e p re d o m in a n t o r g an ism . A fter th e ra p y , c e rta in p re trea tm e n t organism s retu rn ed , in c lu d in g P e p to stre p to c o c c u s m icros a n d F u so b acteriu m nucleatum . H ow ever, B a c te r o id e s a s a c c h a r o l y t i c u s a n d an aero b ic co rroding bacilli, organism s c o n sid ered su sp e ct in perio d o n tal d is ease, w ere n o t observed to retu rn . In ad d itio n , m an y of th e gram -positive cocci iso lated d uring treatm en t h ad h ig h levels of resistance to te tracy cline. In a n o th e r s tu d y , W illia m s a n d o th e rs77 analy zed th e subgingival m i cro flo ra in p erio d o n tal p a tie n ts u n d erg o in g conv en tio n al th erap y a n d re ceiving eith er 1,000 mg tetracycline a day for tw o w eeks or 100 m g tetracy clin e a day for one w eek follow ed by 250 m g a day for extended periods. P re d o m in a n t o rganism s cu ltu red from b o th trea tm e n t groups w ere species of S trep to coccus an d the gram -positive ro d s, A ctin o m y ces an d R othia.H ow ever, th e m icroflora of th e group re ceiv in g 250 m g a day h ad a greater co m p lexity an d in c lu d ed m any of the o rg an ism s th a t are co n sid ered to be re la ted to th e patho g en esis of p erio d o n ta l d ise a se .6 T etra cy c lin e resistan c e w a s d e m o n s tr a te d c o n s is te n tly in S treptococcus, Veillonella, an d N eis seria, an d A ctinom yces odontolyticus an d , in one instance, in A viscosus strain s. T etra cy c lin e resistan c e w as
216 ■ JADA, Vol. 104, February 1982
a lso d e m o n s tr a te d in a v a r ie ty of gram -negative ro d s iso lated from th e group receiving 250 mg a day. S uch re sistance in c re ase d w ith tim e of trea t m ent. T he au th o rs co n c lu d e d th a t th e p ro longed lo w er dose treatm en t w ith te t racycline w as no m ore effective th a n th e tw o w eek, 100 mg a day trea tm e n t an d th a t it resu lted in th e g en eratio n of greater num b ers of tetracy clin e resis ta n t organism s. T his w as co n sid ered to be related to th e relativ ely lo w co n cen tratio n s of tetracy clin e ach iev ab le in th e crev icu lar flu id su b seq u en t to sys tem ic ad m in istratio n . H ow ever, Gor d o n a n d co-w orkers78 fo u n d th a t sys te m ic a lly a d m in is te re d te tra c y c lin e w as co n cen trated in th e g in g iv al cre vic u lar flu id a n d reach ed levels tw o to te n tim es th a t of serum , an d Ciancio a n d c o - w o r k e r s , 79 i n v e s t i g a t i n g m ino cy clin e, a sem isy n th etic tetracy clin e w ith th e p ro p erty of lip id so lu b il ity, fo u n d levels in gingival crev icu lar flu id five tim es as h ig h as seru m after system ic adm in istratio n . In th e latter study, im p ro v em en ts w ere n o ted in n in e p atien ts receiving 200 mg daily a n d te n p a tie n ts re c e iv in g 150 m g daily for eig h t days w ith resp e ct to gingival an d p laq u e indexes. S ignifi cant re d u c tio n in pocket d ep th s, h o w ever, w ere n o te d o n ly in th o se receiv ing th e h ig h e r dosage. R ecent in te rest h as focused80-83 o n th e local delivery of tetracy lcin e w ith th e u se of h o llo w fiber devices. G oodson an d o th ers80 observed th a t tetracy clin e-filled h o l low fibers p la c e d in th e g ingival su l cus w o u ld p ro v id e th erap y w ith less th a n 1/1,000 th e am o u n t of tetracy clin e u sed in system ic therapy. L in d h e and o th ers83 u se d su ch a d evice in five p a tie n ts w ith ad v an ced p erio d o n tal d is ease. In each p a tie n t th ree sites w ere tr e a te d b y sc a lin g , th r e e by te tr a cy clin e -filled , h o llo w -fib er d ev ices, an d th ree left u n tre a te d as controls. T etracycline w as ad m in istered in th is fashion for tw o, tw o-day p erio d s w ith a four-w eek in terv al in b etw een. Both scaled an d tetracy clin e-treated areas w ere clin ically h e a lth ie r th a n controls; how ever, re d u c tio n in pocket d ep th w as sig n ifican tly greater in th e scaled s ite s c o m p a re d w ith te tr a c y c lin e trea ted sites. T etracy clin e trea tm e n t resu lted in a red u c tio n in th e n u m b ers of sp iro ch e te s a n d o th e r m o tile or ganism s, b u t n o t an elim in atio n as re p o rted by G oodson an d asso ciates.82
Conclusions T here is in creasin g ev id en ce th a t cer ta in specific gram -negative m icro o r ganism s m ay h av e a role as etiologic agents in specific form s of p erio d o n tal disease. T his ev id en ce su g g ests th a t a n tib io tic th e ra p y d ire c te d to w a rd e lim in a tio n of s p e c ific p e rio d o n ta l p ath o g en s m ay be a u se fu l ad ju n ct to c u rre n t tre a tm e n t m o d e s, p ro v id e d th a t su ch treatm en t does n o t le ad to selec tio n of a n tib io tic -re sista n t oral bacteria. A n tib io tic s th a t a re a c tiv e o n ly ag ain st g ram -positive b acteria w o u ld n o t likely be of b en efit in th e trea tm e n t of eith er ad v an ced ch ro n ic p e rio d o n ti tis or p erio d o n to sis. A lth o u g h tetracy clin e th erap y a p pears to offer som e clin ic al b en efit in selected cases, a sig n ifican t am o u n t of se lec tio n for te tra c y c lin e re sista n c e o ccurs am ong gram -negative bacteria. C learly, fu rth e r re se a rc h d ire c te d to w ard s th e ev alu atio n of n ew a n d c u r ren tly available an tib io tics for u se in th e trea tm e n t of p erio d o n tal disease m u st in c lu d e q u an titativ e as w ell as q u alitativ e assessm en ts of ch an g es in th e co m p o sitio n of th e m icrobial flora as w ell as d etailed assessm en ts of p re cise lev els of re sista n c e am ong th e flora after th erap y . R ecent stu d ie s84 in d ic a tin g th a t a n tib io tic resistan c e m ay be g en etically tran sferred by co n ju g atio n b etw een m em bers of different species of b acteria em p h asize th e seri o u sn e ss of u s in g a n tib io tic s in d is crim in ately .85 It sh o u ld be n o te d th a t few of th e cited stu d ies in th is review co u ld be co n sid ered to have an ad eq u ate d e sign. U nfortunately, th is m akes th e in te rp retatio n of th e resu lts of m an y of th ese stu d ies a d ifficu lt an d u n c e rta in task. T h e d esig n of fu tu re an tib io tic c lin i cal stu d ies sh o u ld in c lu d e em p h asis on p erform ance in a d o u b le-b lin d fash io n w ith in c lu sio n of placebo co n tro l g ro u p s, ra n d o m g ro u p assig n m en ts, ad eq u ate len g th s of tim e in p retrea t m e n t, tre a tm e n t, a n d p o sttre a tm e n t p h ases, th e u se of d ifferen t p re p a ra tio n s a n d co n c en tra tio n s of th e a n tib i o tic b e in g e v a lu a te d , a n d th e m o n ito rin g of p a tie n ts for a n y adverse effects.
Dr. Gibson is director of research, Louisiana State University School of Dentistry, New Or leans. This report was given at the 1980 annual
A S S O C IA T IO N
session of the ADA. It was approved by the Coun cil on Dental Research in June 1981. Address re quests for reprints to the Council. 1. Socransky, S.S. Relationship of bacteria to the etiology of periodontal disease. J Dent Res 49;203, 1970. 2. Ellison, S.A. Oral bacteria and periodontal disease. J Dent Res 49:198,1970. 3. Kelstrup, J., and Theilade, E. Microbes and periodontal disease. J Clin Periodontol 1:15,1974. 4. Socransky, S.S., and Crawford, A.C. Recent advances in the microbiology of periodontal dis ease. Current therapy, ed 5. St. Louis, C. V. Mosby, 1977. 5. Theilade, E., and Theilade, J. Role of plaque in the etiology of periodontal disease and caries. Preventive dentistry: nature, pathogenicity and clinical control of plaque. Oral Sci Rev 9:23-63, 1976. 6. Socransky, S.S. Microbiology of periodontal disease—present status and future consid erations. J Periodontol 48:497-504, 1977. 7. Crawford, A.; Socransky, S.S.; and Bratthall, G. Predom inant cultivable microbiota of ad vanced perio d o n titis. J Dent Res 54(A):97, abstract no. 209, 1975. 8. Van Palenstein Halderman, W.H. Total viable count and differential count of vibrio(camfylobacter) sputorum, fusobacterium nucleatum, selenomas sputigena, bacteroides ochraceus and veillonella in the inflamed and non-inflamed gingival crevice. J Periodont Res 10:294-305, 1975. 9. Slots, J. The predominant cultivable micro flora of advanced periodontitis. Scand J Dent Res 85:114-121, 1977. 10. Listgarten, M.A., and Hellden, L. Relative distribution of bacteria at clinically healthy and periodontally diseased sites in humans. J Clin Periodontol 5:155-132,1978. 11. Listgarten, M.A.; Lindhe, J.; and Parodi, R. The effect of systemic antimicrobiol therapy on plaque and gingivitis in dogs. J Periodont Res 14:65-75, 1979. 12. Williams, R.C., and others. Effect of sys tem ic tetracycline on alveolar bone loss in beagles. J Dent Res 57(A); abstract no. 770, 1978. 13. Mitchell, D.F., and Johnson, M. The nature of the gingival plaque in the hamster— production, prevention and removal. J Dent Res 35:651-655, 1956. 14. Shaw, J.H.; Griffiths, D.; and Auskaps, A.M. The influence of antibiotics on the periodontal syndrome in the rice rat. J Dent Res 40:511,1961. 15. Keyes, P.H., and others. Bio-assays of medi caments for the control of dentobacterial plaque, dental caries, and periodontal lesions in Syrian hamsters. J Oral Ther Pharmacol 3:157, 1966. 16. Kornman, K.S.; Caffesse, R.G.; and Nasjleti, C.E. The effects of intensive antibacterial therapy on the su lc u la r environm ent in m onkeys. Changes in the bacteriology of the gingival sul cus. J Periodontol 51:34-38,1980. 17. Weiner, G.S.; DeMarco, T.J.; and Bissada, N.F. Long term effect of systemic tetracycline ad ministration on the severity of induced periodon titis in the rat. J Periodontol 50:619,1979. 18. Kucers, A., and Bennett, N.M. The use of an tibiotics, ed 3. Philadelphia, J. B. Lippincott Co, 1979. 19. Fraleigh, C.M. An evaluation of topical terramycin in postgingivectomy pack. J Periodontol 27:201,1956. 20. Romanow, I. The relationship of moniliasis to presence of antibiotics in periodontal packs. Periodontics 2:298, 1964.
21. Baer, P.N.; Sumner, C.F.; and Miller, G. Periodontal dressings. Dent Clin North Am 13:181-191,1969. 22. Ariaudo, A.A. The efficacy of antibiotics in periodontal surgery: controlled study with lincomycin and placebo in sixty-eight patients. J Periodontol 40:150,1969. 23. Kolmer, J.A. Relation of chemotherapy to dentistry and oral surgery with special reference to antibiotic compounds. JADA 35:12,1947. 24. Arches, H. Penicillin in intraoral lesions. Br Dent J 82:201,1947. 25. Pendrill, K., and Reddy, J. The use of prophylactic penicillin in periodontal surgery. J Periodontol 51:44-48, 1980. 26. Loesche, W.J. Chemotherapy of dental plaque infections. Oral Sci Rev 9:65-107,1976. 27. Johnson, R.J., and Rozanis, J. A review of chem otherapeutic plaque control. Oral Surg 47:136-141, 1979. 28. Parsons, J.C. Chemotherapy of dental plaque: a review. J Periodontol 45:177,1974. 29. Winer, R.A.; Cohen, M.M.; and Chauncey, H.H. Antibiotic therapy in periodontal disease. J Oral Ther Pharmacol 2:404,1966. 30. Stahl, S.S. The influence of antibiotics on the healing of gingival wounds in rats. J Periodon tol 33:261, 1962. 31. Stahl, S.S. The influence of antibiotics on the healing of gingival wounds in rats. J Periodon tol 34:166, 1963. 32. Stahl, S.S.; Soberman, A.; andDeCesare, A. Gingival healing, V. J Periodontal 40:521,1969. 33. Wilderman, M.N. Repair after a periosteal retention procedure. J Periodontol 34:487,1963. 34. Dal Pra, D.J., and Strahan, J. D. A clinical evaluation of the benefits of a course of oral penicillin following periodontal surgery. Aust Dent J 17:219-221, 1972. 35. Kidd, E.A. and Wade, A.B. Penicillin con trol of swelling and pain after periodontal osseus surgery. J Clin Periodontol 1:52,1974. 36. Lobene, R.R.; Brion, M.; and Socransky, S.S. Effect of erythromycin on dental plaque and plaque forming microorganisms. J Periodontol 40:287-291, 1969. 37. Loesche, W.J., and others. Effect of topical kanamycin sulfate on plaque accumulation. JADA 83:1063-1069, 1971. 38. Loesche, W.J., and Nafe, D. Reduction of supragingival plaque accum ulation in in stitutionalized Down’s syndrome patients by periodic treatment with topical kanamycin. Arch Oral Biol 18:1131-1143,1973. 39. Loesche, W.J.; Hockett, R.N.; and Syed, S.A. Reduction in proportions of dental plaque strep tococci following a five-day kanamycin treat ment. J Periodont Res 12:1-10, 1977. 40. Baker, P.J., and others. Antibiotics as in vitro plaque inhibitors. J Dent Res 57(A):246 abstract no. 687, 246, 1978. 41. Pellerat, J., and Maillard, M.A. Etudes sur l ’elimination salivaire de la spiramycine et de di vers antibiotiques. Acta Odontostomatol 61:6572, 1963. 42. Yankell, S.L., and others. Spiramycin excre tion in animals. A single oral dose in rats. J Dent Res 51:712-715, 1972. 44. Yankell, S.L., and others. Spiramycin excre tion in animals. A single oral dose in dogs. J Dent Res 53:364-368, 1974. 45. Tsvetanova, M., and Klein-Genova, S. De posit and length of retention of Rovamycin (spiramycin) in the bones and its level in rats’ blood serum after oral administration. Stomatol (Sofia) 49:261-266, 1967. 46. Tsvetanova, M., and Klein-Genova, S. Com
REPORT
parative studies on the deposition and length of retention of spiramycin, tetracycline and ery thromycin in the serufti, jaw and long bones of white rats. Stomatol (Sofia) 50:364-369,1968. 47. Daligland, P. Paradentosis—results of three years of spiramycin therapy. Stomatol 59:784, 1958. 48. Harvey, R.F. Clinical impressions of a new antibiotic in periodontitis: spiramycin. J Can Dent Assoc 27:576-585, 1961. 49. Gendron, R. L’antibiotherapie en periodontie. J Can Dent Assoc 27:62-65, 1961. 50. Mills, W.H.; Thompson, G.W.; and Beagrie, G.S. Double blind clinical evaluation of spiramy cin and erythromycin in control of periodontal disease. J Dent Res 55(B):abstract no. 806, 1976. 51. Johnson, R.H., and others. The effect of spiramycin on plaque accumulation and gin givitis. J Can Dent Assoc 44:456-460,1978. 52. Rozanis, J., and others. Spiramycin as a selective dental plaque control agent. J Periodont Res 14:55-64,1979. 53. Turnbull, R.S., and Pearson, G.E. The role of spiramycin in the treatment of periodontal dis ease. J Can Dent Assoc 44:313-315,1978. 54. Mitchell, D.F., and Holmes, L.A. Topical an tibiotic control of dentogingival plaque. J Periodontol 36:202-208, 1965. 55. Mitchell, D.F., and others. Topical antibio tic maintenance of oral health. J Oral Therap Pharmacol 4:83-92, 1967. 56. Loe, H., and others. Experimental gingivitis in man. The influence of antibiotics on gingival plaque development. J Periodont Res 2:282-289, 1967. 57. Jensen, S.G., and others. Experimental gin givitis in man. Vancomycin induced changes in bacterial plaque composition as related to devel opment of gingival inflammation. J Periodont Res 3:284-293, 1968. 58. Collins, J.F. Effect of vancomycin on plaque after periodontal surgery. J Dent Res 49:1478, 1970. 59. McFall, W.T.; Shoulars, H.W.; and Carnevale, R.A. Effect of vancomycin on inhibition of bacterial plaque. J Dent Res 47:1195,1968. 60. Kaslick, R.S.; Tuckman, M.A.; and Chasens, A.I. Effect of topical vancomycin on plaque and chronic gingival inflammation. J Periodontol 44:366-368, 1973. 61. Mac Dougall, J.C. Topical application of an tibiotics in dentistry. Dent Pract 13:147,1962. 62. Borzelleca, J., and Cherrick, H.M. Excretion of drugs in saliva. J Oral Therap Pharmacol 2:180, 1965. 63. Bader, H.I., and Goldhaber, P. The passage of intravenously administered tetracycline into the gingival sulcus of dogs. J Oral Therap Phar macol 2:324, 1966. 64. Ciancio, S.G. Tetracycline and periodontal therapy. J Periodontol 47:155-159,1976. 65. Williams, R.C., and others. Effects of tetra cycline on periodontal disease in beagles. Rate of alveolar bone loss. J Dent Res 59(A)abstract no. 1064,1980. 66. Jeffcoat, M.K., and others. Effects of tetracy cline on periodontal disease in beagles. Nuclear medicine studies. J Dent Res 59(A), abstract no. 1065, 1980. 67. Sipos, T. Prevention of gingivitis in beagles with topically applied melocycline. J Dent Res 59(A), abstract no. 1062,1980. 68. Scopp, I.W., and others. Tetracycline— double-blind study to evaluate the effectiveness in periodontal surgery. J Periodontol 48:484-486, 1977.
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69. Scopp, I. W., and others. Tetracycline: a clin ical study to determ ine its effectiveness as long term adjuvant. J Periodontol 51:328-330, 1980. 70. Genco, R., and others. Use of tetracycline in the treatm ent of adult periodontitis. I. Clinical studies. J Dent Res 57(A), abstract no 768, 1978. 71. Reynolds, H .,and others. Use of tetracycline in the treatm ent of adult periodontitis. II. Mi crobiological studies. J Dent Res 57(A), abstract no. 769, 1978. 72. Listgarten, M.A.; Lindhe, J.; and Hellden, L. Effect of tetracyline and/or scaling on hum an periodontal disease. J Clin Periodontol 5:246-271, 1978. 73. Hellden, L.; Listgarten, M.A.; and Lindhe, J. The effect of tetracylcine and/or scaling on hum an periodontal disease. J Clin Periodontol 6:222-230, 1979. 74. Slots, J., and others. Periodontal therapy in hum ans. M icrobiological and clinical effects of a
THE PRESIDENTS
single course of periodontal scaling and root planing, and of adjunctive tetracycline therapy. I Periodontol 50:495-509, 1979. 75. Claiborne, W.J. and McFall, W.T. Tetracy cline: influ en ce on plaq u e co m position and p erio d o n tal h e a lth status. J D ent Res 58(A), abstract no. 770,1979. 76. Osterberg, S.K.; W illiams, B.L.; and Jorgen sen, J. Long-term effects of tetracycline on the subgingival microflora. J Clin Periodontol 6:133140, 1979. 77. W illiams, B.L.; Osterberg, S.K.; and Jorgen sen J. Subgingival microflora of periodontal pa tients on tetracycline therapy. J Clin Periodontol 6:210-221, 1979. 78. Gordon, J.M., and others. Concentration of tetracycline in hum an crevicular fluid after single and m ultiple doses. J Dent Res 59(A), abstract no. 977,1980. 79. Ciancio, S.G.; Mather, M.L.; and McMullen, J.A. An evaluation of m inocycline in patients
w ith periodontal disease. J Periodontol 51:530534, 1980. 80. Goodson, J.M.; Haffajee, A.; and Socransky, S.S. Local drug delivery using hollow fiber de vices. Construction relase and side effects. J Dent Res 57(A), abstract no. 766, 1978. 81. Haffajee, A., and others. Local drug delivery using hollow fiber devices. Effects on the m i crobiota. J Dent Res 57(A), abstract no. 767,1978. 82. Goodson, J.M.; Haffajee, A.; and Socransky, S. S. Periodontal therapy by local delivery of tetra cycline. J Clin Periodontol 6:83-92,1979. 83. Lindhe, J., and others. Local tetracycline de livery using hollow fiber devices in periodontal therapy. J Clin Periodontol 6:141-149, 1979. 84. Researchers find antibiotic resistance is transferred am ong bacteria in the m outh. JADA 99:513, 1979. 85. Sack, R.B. Prophylactic antibiotics? The in dividual versus the com m unity. New Engl J Med 300:1107-1108, 1979.
B. Holly Smith 1899 - 1900
D o cto r S m ith , o f B a ltim o re , w a s e le c te d 3 7 th p re s id e n t o f th e A s s o c ia tio n at th e 1899 m e e tin g at N ia g a ra F alls. T h e S o u th e rn B ra n c h o f th e A sso c ia tio n m et e a rly th a t y e a r in N e w O rle a n s. Doctor Smith received a DDS degree in 1881 and an MD degree in 1883. He practiced dentistry in Baltimore for 37 years. Offices he held included the
presidency of the Southern Dental Association, the Maryland State Dental Association, the Baltimore College of Dental Surgery, and the National Asso ciation of Dental Faculties. Doctor Smith’s special interests included the de velopment of a system of oral hygiene in the Baltimore public schools. He was widely known as an eloquent orator. He was born in Maryland in 1858 and died in 1920. The Open Door policy regarding China was announced by Secretary of State John Hay. Philippine insurrection against the United States began in 1899 and was crushed in 1901 with the capture of the leader, Emilio Aguinaldo. An act of Congress provided for a territorial form of government for the Hawaiian Islands. Each month, The Journal prints the picture of a past president of the American Dental Association w ith a brief biography and a few historical highlights of his presidential year. The series began in February 1979 w ith the first president and is continuing in chronological order.
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REPORT
Antibiotics and periodontal disease: a selective review of the literature C o u n c il o n D e n ta l R e s e a r c h
W i llia m A . G ib s o n , DDS, PhD
I
t is now generally accepted that mi croorganisms act as primary etiologic ag e n ts in the vario u s form s of periodontal disease.1'6 Moreover, there is increasing evidence that spe cific kinds of microorganisms may be associated with specific forms of the disease.610 Accordingly, a rationale has developed for the use of antibiotics in the prevention and treatment of periodontal disease. Antibiotics administered systemically to dogs have been found to result in changes in the plaque flora, reduc tion in the signs of gingivitis,11 and a distinct decrease in the progression of alveolar bone loss.12 Investigators using other animal model systems have achieved similar encouraging re sults.13'17 However, the use of antibiotics in humans is associated with a number of problems including induction of resis tant strains of microorganisms and al lergic manifestations ranging from mild reactions to anaphylactic shock, as well as a variety of major and minor side effects.18 Most of these problems are related to the specific antibiotics used, the dosage, the route of adminis tration, and the duration of the treat ment.18 An ideal antibiotic for use in the prevention and treatment of periodon
tal disease would be one that would act specifically on periodontal pathogens, would not be allergenic or toxic, would maintain activity in the oral en vironment or tissue for long periods, would not be in general use for treat ment of other diseases, and would not be prohibitively expensive. However, it is not clear at this time whether a single antibiotic, even if it were ideal, would be equally efficacious in both prevention and treatment. The bacte rial flora associated with gingivitis, for example, has far less specificity than that associated with other forms of periodontal disease.6 In addition, an tibiotics have been incorporated into periodontal dressings19'21 and used as an adjunct to periodontal surgery as a means of reducing sequelae such as in fection, pain, swelling, and delayed healing, with varied results.22'25 Thus, it is obvious that continued research is needed in the microbiology of periodontal disease as well as the evaluation of new and currently avail able antibiotics, with respect to pre vention, treatment, and management of periodontal disease. The following is a review of some of the antibiotics studied thus far. Other reviews have been done by Loesche,26 Johnson and Rozanis,27Parsons,28 and Winer and others.29
P e n icillin P en ic illin , iso lated in 1929 a n d in tro du ced in to clin ic al m e d ic in e in 1941, w as th e first a n tib io tic u se d in h u m ans. A n im al stu d ies by S tah l30'32 an d W ild erm an 33 re su lte d in co n flictin g rep o rts ab o u t th e effects of p e n ic illin o n h e a lin g f o llo w in g p e r io d o n ta l surgery. In h u m a n stu d ies, Dal P ra an d S tra h an 34 an d K idd an d W ade35 fo u n d th a t p a tie n ts g iv e n p e n ic illin afte r p erio d o n tal surg ery ex p e rien c ed less p o s to p e ra tiv e p a in . S im ila r re s u lts w ere ach iev ed in a m ore recen t stu d y by P en d rill an d R ed d y .25 H ow ever, p a ra m e te rs s u c h as in fe c tio n , p la q u e levels, g in g iv itis, an d crev icu lar flu id flow w ere n o t sta tistica lly d ifferen t b e tw e e n th e p e n ic illin - a n d p laceb o treated groups.
As penicillin remains one of the most important antibiotics against many microorganisms that cause seri ous infections in humans, coupled with the high incidence of allergic reactions and frequency with which bacterial resistance develops with its use, there appears little rationale for its routine use after periodontal surgery. Animal and human studies have failed to demonstrate a clear-cut benefit from such use. JADA, Vol. 104, F ebruary 1982 ■ 213
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Erythromycin T h e a n tib a c te ria l sp e c tru m of e ry th ro m y cin closely resem bles th a t of p e n ic illin , b u t b o th b acterial re sist an c e a n d severe to x ic effects o cc u r w ith le ss fre q u en cy . It is th e re fo re often reserv ed for u se in patien ts w ho h a v e d e v e l o p e d a s e n s i t i v i t y to p e n ic illin .18 A lth o u g h L obene a n d o th ers 36 achiev ed a 35% red u c tio n in p la q u e form ation d u rin g a seven-day a d m in is tra tio n o f e ry th ro m y c in in w h ic h subjects rin sed , th en sw allow ed th e p rep a ra tio n four tim es a day, th e ef fect w as short-lived after th e antibiotic w as w ith d raw n . In add itio n , all p artic ip a n ts suffered from gastrointestinal problem s. As is tru e w ith p en icillin , ery th rom ycin sh o u ld be reserved for trea tm e n t of system ic disease.
Kanamycin T h is ra th e r toxic antibiotic is ch e m i c a lly s im ila r to s tr e p to m y c in a n d n e o m y c in .18 It h as b een stu d ie d by L oesche an d associates as a to p ic ally a p p lie d p rep a ra tio n of 5% an tib io tic in O rabase in selected m entally h a n d i c a p p ed subjects for a few w eeks37 an d for one year.38 G ingival h ealth w as ob served to im prove in treated in d iv id u als ev en th o u g h th e re w as no signifi can t re d u c tio n in plaq u e scores. In a m ore rec en t stu d y ,39 a five-day to p ical kan am y cin treatm en t red u ced p la q u e m ass on to o th surfaces com p are d w ith placebo treatm ent. T he re d u c tio n occurred w ith o u t m echanical h y g ien e p ro ced u res an d p ersisted for a t least four w eeks. H ow ever, th e g in g iv itis sc o re s w e re n o t r e d u c e d to m u c h below p retreatm en t levels an d w e re h ig h e r th a n p o s tp r o p h y la x is scores. T he re d u c tio n in plaque m ass w as d eterm in e d to be due to red u c ed n u m b ers of streptococci. T he m arginal r e s u lt s a c h ie v e d w ith k a n a m y c in w o u ld ap p e ar to lim it its use in all b u t a sm all n u m b e r of in d iv id u als w ho are n o t able to m a in ta in th e ir oral hygiene w ith ro u tin e procedures.
Spiramycin S p ira m y c in is a n a n tib io tic a c tiv e a g a in st g ram -positive organism s in c lu d in g S tre p to c o c c u s m u ta n s a n d A c tin o m y c e s v is c o s u s 40 a n d is r e ta in e d in an active state for p ro lo n g ed p erio d s in bone, saliva, an d salivary g la n d s.41'46 K eyes a n d cow orkers15 d e 214 ■ JADA, Vol. 104, February 1982
te rm in ed th a t sp iram y cin w as th e m ost efficacious of n in e agents in red u cin g d en tal p la q u e an d p erio d o n tal lesions in th e ham ster. Investigators in early clin ical trials in h u m an s, rely in g on clin ical im p res sions, g enerally rep o rted favorable re s u lts w ith sp ira m y c in : D a lig la n d 47 c o n d u c te d a th ree -y e ar s tu d y of 90 p e rio d o n ta l p a tie n ts tre a te d for 20 days; H arvey48 gave a d etailed acco u n t of seven of 70 cases treated ; an d Gend ro n 49 a d m in iste re d sp iram y cin b e fore treating 300 p atien ts w ith a w id e variety of oral co n d itio n s. In a m ore co n tro lled stu d y , W iner an d o th ers29 co m p ared th e effect of sp iram y cin an d p lacebo in p erio d o n tal p a t i e n t s w ith a n d w i t h o u t lo c a l therapy. Im p ro v em en t w as rep o rted in p atien ts treated w ith sp iram y cin even w h en local th e ra p y w as n o t ap p lied . M ills a n d o th e r s 50 c o n d u c te d a d o u b l e - b l i n d s t u d y in w h ic h 48 p e rio d o n ta l p a tie n ts w ere ran d o m ly assigned to one of th ree g ro u p s an d given eith er sp iram y cin , erythrom y cin, or a placeb o for five days. E xam i n atio n s c o n d u c te d once a w eek for a m o n th c o n siste d of g in g iv a l in d ex , plaq u e an d p o ck et d ep th s on an terio r teeth, crev icu lar flu id readings, an d w et plaque w eig h t from selected teeth. A n a ly s is b e tw e e n a n d w ith in te s t g roups in d ic ated a m ore favorable re sp o n se w ith th e u se of sp ira m y c in com pared w ith eith er ery th ro m y cin or th e placebo. In a m ore rec en t study, Johnson an d others,51 a n d R ozanis an d o th ers52 co n d u cted d o u b le-b lin d exam inations o n 63 subjects w h o refrain ed from m e chanical o ral h y g ien e p ro ce d u re s for 11 w eeks. T h ey receiv ed cap su les to be tak en four tim es a day for five days. In a ran d o m m an n er, 29 received 500-mg c a p s u le s of sp ira m y c in a n d 34 r e ce iv e d p la ce b o c a p su le s. A lth o u g h plaq u e sam ples tak en from th o se re ceiving th e an tib io tics in d ic ated a re d u ctio n in p la q u e as m easu red by w et w eight, tu rb id ity , an d n itro g e n an d carbohydrate co n ten t lastin g for th ree w eeks, on ly th e m a n d ib u la r p laq u e ind ex at w eek 3 w as sig n ifican tly re duced. T h is m ay in d icate th e relative in se n sitiv ity of th e clin ical p aram e te r.27 In ad d itio n , in in d iv id u als re ceiving antib io tics, th e co u n ts of S m u ta n s a n d S sa n g u is w e re re d u c e d , w h e re a s g r a m -n e g a tiv e o rg a n is m s w ere n o t affected. A lth o u g h th e resu lts o b tain ed th u s
fa r w ith s p ir a m y c in c a n o n ly be ch aracterized as m ild ly en couraging, th ere ap p ears to be su fficien t ev idence to w arran t fu rth e r research. It is partic u la r ly w o rth w h ile b e c a u se sp iram y cin is co n sid ered a safe n o n toxic drug w ith few an d in freq u en t sid e effects18 an d is n o t in g en eral use by th e m ed ical pro fessio n .53
Vancomycin V ancom ycin is a g ly co p ep tid e an tib io tic ac tiv e a g a in st g ram -p o sitiv e o r ganism s. It is asso ciated w ith severe toxic effects w h e n ad m in istered system ically. H ow ever, no ad v erse effects have been rep o rted w h e n u se d to p ic ally .18 In early clin ic al stu d ies by M itchell an d H olm es,54 1% vanco m y cin in an ad h esiv e paste w as a p p lied to p ically to th e teeth an d g in g iv a of an in stitu tio n a liz e d p o p u la tio n o n ce a day for eig h t days. T h is trea tm e n t re su lted in a red u c tio n in p la q u e scores a n d g ingivitis. T hese param eters re tu rn ed to p retrea tm e n t levels in th ree w eeks. In su b seq u en t stu d ies, M itchell a n d c o -w o rk e rs55 re p o rte d th a t 1% v an co m y cin o in tm en t w as effective in red u cin g p laq u e, g in g iv itis, a n d objec tio n ab le oral odors w h e n a p p lied th ree tim es a w eek an d th a t som e p atien ts h ad rec eiv e d su c h tre a tm e n t for as long as eig h t m o n th s w ith o u t observa ble adverse effects. H ow ever, Loe a n d associates56 re p orted o nly a m o d erate re d u c tio n in p laq u e in v o lu n teers as a re su lt of th ree d aily m o u th rin se s w ith a v ancom ycin p rep a ra tio n d u rin g five days w ith o u t o ra l h y g ie n e , a n d J e n s e n a n d cow o rk e rs ,57 in a s im ila r b u t lo n g e r study, fo u n d th a t v an co m y cin failed to sig n ifican tly red u c e p laq u e levels, an d th a t b o th a n tib io tic - a n d p la c e b o trea ted g ro u p s d ev e lo p e d g in g iv itis a fte r th r e e w e e k s. A s in d iv id u a ls treated w ith v an co m y cin h a d a p re d o m in a n tly g ram -n eg ativ e b ac te ria l flora, it w as co n c lu d e d th a t su ch a flora w as cap ab le of form ing p la q u e an d causing g ingival inflam m ation. C ollins,58 u sin g th e earlier p rep a ra tio n of 1% v an co m y cin in an adh esiv e paste, fo u n d th a t its u se sig n ifican tly r e d u c e d p la q u e in p a t i e n t s a f te r p e r io d o n t a l s u r g e r y . M c F a ll a n d o th ers,59 how ever, co u ld fin d no sig n ifican t difference in p la q u e d ep o si tio n w h en a sim ilar p rep a ra tio n an d a placebo o in tm en t w ere a p p lie d to p ar
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tic ip a n ts refrain in g from oral h ygiene p ro ced u res. In a m ore recen t stu d y , K aslick and co-w orkers,60 u sin g 1% v an co m y cin o in tm en t a n d a placebo in a d o u b le b lin d stu d y w ith p a rtic ip a n ts refra in ing from oral h ygiene for six days, re p o rted th at, alth o u g h p la q u e scores w e re s i g n i f i c a n t l y r e d u c e d in an tib io tic-treated subjects, th ere w ere no sig n ific an t d ifferences in th e scores for g ingivitis. It w o u ld a p p e a r th a t, w ith s u c h n eg ativ e resu lts, v an co m y cin w o u ld h a v e lim ite d u s e in p e r io d o n tic s . H ow ever, it sh o u ld be e m p h asized th a t d iffe ren t p re p a ra tio n s a n d d iffe ren t subjects w ere u sed in th e se studies. F u rth e r research , in c lu d in g d o u b le b lin d an d d etailed ex am in atio n s after th e u se of several different p re p a ra tio n s of v anco m y cin in carefu lly ch o s e n p o p u la tio n s o f p a t i e n t s w ith p erio d o n tal disease, n ee d s to be ac co m p lish e d before v an co m y cin can be d ro p p e d from fu rth e r co n sid eratio n .
Tetracyclines T etracy clin es co n sist of a n u m b e r of a n t i b i o t i c c o m p o u n d s o f s i m ila r m o lecu lar stru ctu re an d b ro ad sp e c tru m of a n tib a c te ria l a c tiv ity .18 A l th o u g h th e in c id en c es of b acterial re sistan ce an d h y p erse n sitiv ity are low w h e n a d m in is te r e d s y s te m ic a lly ,18 th e y in crease sig n ific an tly w h e n te tra cy clin es are u se d in to p ic a l p re p a ra tio n .61 In an early clin ic al stu d y , Loe an d co-w orkers56 rep o rted th a t a m o u th w a sh c o n ta in in g 0.5% te tra c y c lin e u se d for five days in subjects w ith o u t m e ch an ical oral h y g ien e pro ced u res resu lted in red u c ed p la q u e levels b u t no sig n ific an t differences in gingival scores co m p ared w ith placeb o co n trols. S tu d ies by B orzelleca a n d Cherr ic k 62 a n d B a d e r a n d G o ld h a b e r 63 d e m o n stra te d th a t sy ste m ic a lly a d m in iste re d tetracy clin es ap p e ared in th e s a liv a a n d g in g iv a l c r e v ic u la r flu id , respectively. M ost su b se q u en t s tu d ie s h av e u sed system ically a d m in istered tetracyclines, alth o u g h th e use in p e r io d o n ta l d r e s s in g s h a s b e e n stu d ied ; lack of foul taste in th e m o u th w as th e o n ly a d v a n ta g e c ite d . N o n s p e c ific s to m a titis , m o n ilia s is , an d u n d esira b le tissu e rea ctio n s oc cu rred as com plications. S u ch topical u s e of te tra c y c lin e s in p e rio d o n ta l d ressin g s is n o t rec o m m en d e d .64
A n u m b e r of an im al m o d el system s h ave b een u se d to stu d y th e effect of sy stem ic te tracy c lin e . W illiam s an d o th e rs12,65 a n d Jeffcoat a n d o th e rs66 re p o rted th a t d aily system ic tetracy clin e sig n ific an tly in h ib ite d th e p ro g ressio n of alveolar b o n e loss in trea ted vs n o n trea ted con tro l beagle dogs. In a n o th er stu d y , L istgarten an d o th e rs11 a d m in iste re d 250 m g of te tra c y c lin e HC1 tw ice d aily for four w eeks to dogs w ith v a ry in g d e g re e s of g in g iv itis , a n d fo u n d th a t p la q u e an d g in g iv al scores im p ro v e d . In a d d itio n , h isto lo g ic a l stu d ies in d ic a te d a re d u c tio n in th e n u m b e r of inflam m ato ry cells, b u t in f la m m a t i o n w a s n o t e l i m i n a t e d . S ip o s67 u se d beagle dogs to s tu d y th e efficacy of to p ically a p p lie d te tracy clin e in th e form of m elo cy clin e in p re v e n tin g th e d ev e lo p m e n t of g in givitis. A fter an in ital p ro p h y lax is an d 19 days of tw ice-d aily b ru sh in g , the an im als w ere assig n ed to one of th ree groups. O ne gro u p w as left u n trea ted , th e s e c o n d w a s tr e a t e d w ith 1% m elo cy clin e cream d aily, a n d th e th ird g ro u p w as tre a te d sim ila rly w ith a placebo cream . A fter fo u r an d seven w eeks of treatm en t, sta tistically sig n if ic a n t d iffe re n c e s c o u ld b e d e m o n strated b etw een u n trea ted an d treated g ro u p s w ith resp e ct to p laq u e, g in givitis, an d b leed in g scores. H ow ever, pocket d ep th s w ere n o t sig n ifican tly different. W einer an d o th e rs17 in d u c e d p e r io d o n titis in th e m a x illa ry le ft segm ents of rats w ith lig atu re w ire a n d a m o d ifie d d ie t. T h e e x p e rim e n ta l an im als w ere given 21 m g of tetracy clin e d aily for te n w eeks in th e d rin k ing w ater. W hen co m p ared w ith co n trols, th e tetracy clin e-treated an im als h ad less reso rp tio n of b u ccal alveolar b o n e , le s s a p ic a l m ig r a tio n of e p ith e liu m o n th e d istal ro o t of th e m axillary first m olar, a n d few er in flam m atory cells. In h u m a n s, Scopp a n d asso ciates68 gave p erio d o n tal p atien ts eith er ca p su les co n tain in g p lacebo or 250 m g of te tracy c lin e to b e tak en every six h o u rs f o r f iv e d a y s a f te r s u r g e r y . In a d o u b le -b lin d ex am in atio n , n o sig n ifi c a n t d if fe r e n c e s w e re d e te c te d in eith er th e am o u n t of p a in or in flam m a tio n p rese n t at th ree a n d sev en days p ostsurgically. In a m ore re c e n t d o u b le-b lin d stu d y , S copp an d co-w orkers69 beg an w ith a ran d o m d iv isio n of 20 p atien ts in to tw o te st groups. O ne gro u p receiv ed tetracy clin e 250 m g fo u r tim es a day
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th e first w eek, th ree tim es a day th e seco n d w eek, an d tw o tim es a day th e th ir d w ee k . T h e c o n tro l g ro u p r e ceiv ed a placeb o in a sim ilar fashion. Both g ro u p s receiv ed id e n tic al clin ic al th e ra p y co n sistin g of root p la n in g an d cu rettag e. A t th e en d of th ree m o n th s, th e g ro u p s w e re s w itc h e d a n d th e s tu d y w as rep e ate d for an a d d itio n a l th r e e m o n th s . N o s ig n if ic a n t d if fe re n c e s w e re d e te c te d b e tw e e n p la c e b o - a n d te tr a c y c lin e - t r e a te d g ro u p s w ith resp e ct to g in g iv al in d ex , d e b ris in d e x , or p a p illa ry b le e d in g d u rin g eith er of th e th ree -m o n th stu d y p erio d s. H ow ever, G enco an d co-w orkers70 a n d R e y n o ld s a n d c o -w o rk e rs71 r e p o rted that, w h en tetracy clin e is u se d as an a d ju n c t to trad itio n al p erio d o n tal p ro ced u res, sig n ifican t en h a n ce m e n t of h ea lin g occurs. In th e latter study, h o w ev er, an in crease in th e n u m b ers of te tra c y c lin e -re sista n t o rg an ism s w as o bserv ed in th e saliva an d p erio d o n tal pockets. L istg arten an d o th e rs72 an d H elld en a n d o th e rs73 u se d h alf-m o u th scalin g an d root p la n in g in tw o g ro u p s of p a tien ts; one g ro u p receiv ed 1 gm te tra c y c lin e a n d th e o th e r w as g iv e n a p lacebo d aily for tw o p erio d s of tw o w eek s se p arate d by a four-w eek in te r val. In all areas of b o th gro u p s, oral h y g ie n e a n d g in g iv al co n d itio n s w ere o b se rv e d to b e im p ro v ed ; h o w ev er, lo w e r p la q u e a n d g in g iv a l in d e x sco res w ere re c o rd e d in th e sc ale d areas co m p ared w ith u n se a le d areas. In th e u n se a le d areas, tetracy c lin e re s u lte d in m o d e st im p ro v e m e n ts in c lin ic al p aram eters th a t w ere n o te d at th e eight-w eek, b u t n o t th e 25-w eek, ex a m in atio n p erio d . T etracy clin e d id n o t re su lt in sig n ifican t im p ro v em en t w h e n s c a le d are a s w e re c o m p a re d w ith u n se a le d areas, w ith th e ex cep tio n of a sm a ll g ain in a tta c h m e n t levels; h o w ev er, th e au th o rs d id agree w ith p rev io u s in v e stig a to rs70,71 th a t th e u se of tetracy clin e en h an ces h e a l ing. S lots an d co-w orkers74 also stu d ie d th e u s e o f a d ju n c tiv e te tr a c y c lin e th e ra p y in p e rio d o n tal p atien ts after a sin g le co u rse of scaling an d root p la n ing. T hey fo u n d th a t th e clin ic al ef fects of ad ju n ctiv e te tracy c lin e in m ost p a tie n ts d id n o t differ sig n ific an tly fro m th o s e a c h ie v e d w ith c o n v e n tio n a l th e ra p y alo n e. H o w ev er, a d ju n c tiv e tetracy c lin e d id re su lt in th e im p ro v e m e n t of tw o p a tie n ts w h o IADA. Vol. 104. February 1982 ■ 21S
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w ere u n resp o n siv e to rep eated con v en tio n al therapy. M ajor differences w ere n o te d in th e am o u n t and com po sitio n of th e pre- an d posttreatm en t su b g in g iv al m icroflora. T his an d other stu d ie s have led to an increasing in te r est in b o th th e long- and short-term ef fects of tetracy clin e on th e subgingival m icroflora. C laiborne an d M cFall75 re p o rted th a t p atien ts taking 250 m g of tetracy clin e a day for at least six w eeks as a trea tm e n t for acne vulgaris ex p eri en ced a decrease in anaerobic gram n eg ativ e ro d s an d gram -positive cocci of 19% an d 11%, respectively, com p are d w ith u n trea ted controls. O sterb erg a n d o th e rs 76 s tu d ie d a s in g le p a tie n t w ith a d v a n c e d p erio d o n tal disease, an d noted th a t a co m plex, largely gram -negative flora w as c h a n g e d to a fa c u lta tiv e , sacch aro ly tic p la q u e of streptococci and actin o m yces w ith in tw o w eeks of tet rac y clin e th e ra p y at 1,000 m g daily. A fter an a d d itio n a l tw o w eeks of 500 m g of tetracy clin e daily, R othia dentocariosa w as th e p re d o m in a n t o r g an ism . A fter th e ra p y , c e rta in p re trea tm e n t organism s retu rn ed , in c lu d in g P e p to stre p to c o c c u s m icros a n d F u so b acteriu m nucleatum . H ow ever, B a c te r o id e s a s a c c h a r o l y t i c u s a n d an aero b ic co rroding bacilli, organism s c o n sid ered su sp e ct in perio d o n tal d is ease, w ere n o t observed to retu rn . In ad d itio n , m an y of th e gram -positive cocci iso lated d uring treatm en t h ad h ig h levels of resistance to te tracy cline. In a n o th e r s tu d y , W illia m s a n d o th e rs77 analy zed th e subgingival m i cro flo ra in p erio d o n tal p a tie n ts u n d erg o in g conv en tio n al th erap y a n d re ceiving eith er 1,000 mg tetracycline a day for tw o w eeks or 100 m g tetracy clin e a day for one w eek follow ed by 250 m g a day for extended periods. P re d o m in a n t o rganism s cu ltu red from b o th trea tm e n t groups w ere species of S trep to coccus an d the gram -positive ro d s, A ctin o m y ces an d R othia.H ow ever, th e m icroflora of th e group re ceiv in g 250 m g a day h ad a greater co m p lexity an d in c lu d ed m any of the o rg an ism s th a t are co n sid ered to be re la ted to th e patho g en esis of p erio d o n ta l d ise a se .6 T etra cy c lin e resistan c e w a s d e m o n s tr a te d c o n s is te n tly in S treptococcus, Veillonella, an d N eis seria, an d A ctinom yces odontolyticus an d , in one instance, in A viscosus strain s. T etra cy c lin e resistan c e w as
216 ■ JADA, Vol. 104, February 1982
a lso d e m o n s tr a te d in a v a r ie ty of gram -negative ro d s iso lated from th e group receiving 250 mg a day. S uch re sistance in c re ase d w ith tim e of trea t m ent. T he au th o rs co n c lu d e d th a t th e p ro longed lo w er dose treatm en t w ith te t racycline w as no m ore effective th a n th e tw o w eek, 100 mg a day trea tm e n t an d th a t it resu lted in th e g en eratio n of greater num b ers of tetracy clin e resis ta n t organism s. T his w as co n sid ered to be related to th e relativ ely lo w co n cen tratio n s of tetracy clin e ach iev ab le in th e crev icu lar flu id su b seq u en t to sys tem ic ad m in istratio n . H ow ever, Gor d o n a n d co-w orkers78 fo u n d th a t sys te m ic a lly a d m in is te re d te tra c y c lin e w as co n cen trated in th e g in g iv al cre vic u lar flu id a n d reach ed levels tw o to te n tim es th a t of serum , an d Ciancio a n d c o - w o r k e r s , 79 i n v e s t i g a t i n g m ino cy clin e, a sem isy n th etic tetracy clin e w ith th e p ro p erty of lip id so lu b il ity, fo u n d levels in gingival crev icu lar flu id five tim es as h ig h as seru m after system ic adm in istratio n . In th e latter study, im p ro v em en ts w ere n o ted in n in e p atien ts receiving 200 mg daily a n d te n p a tie n ts re c e iv in g 150 m g daily for eig h t days w ith resp e ct to gingival an d p laq u e indexes. S ignifi cant re d u c tio n in pocket d ep th s, h o w ever, w ere n o te d o n ly in th o se receiv ing th e h ig h e r dosage. R ecent in te rest h as focused80-83 o n th e local delivery of tetracy lcin e w ith th e u se of h o llo w fiber devices. G oodson an d o th ers80 observed th a t tetracy clin e-filled h o l low fibers p la c e d in th e g ingival su l cus w o u ld p ro v id e th erap y w ith less th a n 1/1,000 th e am o u n t of tetracy clin e u sed in system ic therapy. L in d h e and o th ers83 u se d su ch a d evice in five p a tie n ts w ith ad v an ced p erio d o n tal d is ease. In each p a tie n t th ree sites w ere tr e a te d b y sc a lin g , th r e e by te tr a cy clin e -filled , h o llo w -fib er d ev ices, an d th ree left u n tre a te d as controls. T etracycline w as ad m in istered in th is fashion for tw o, tw o-day p erio d s w ith a four-w eek in terv al in b etw een. Both scaled an d tetracy clin e-treated areas w ere clin ically h e a lth ie r th a n controls; how ever, re d u c tio n in pocket d ep th w as sig n ifican tly greater in th e scaled s ite s c o m p a re d w ith te tr a c y c lin e trea ted sites. T etracy clin e trea tm e n t resu lted in a red u c tio n in th e n u m b ers of sp iro ch e te s a n d o th e r m o tile or ganism s, b u t n o t an elim in atio n as re p o rted by G oodson an d asso ciates.82
Conclusions T here is in creasin g ev id en ce th a t cer ta in specific gram -negative m icro o r ganism s m ay h av e a role as etiologic agents in specific form s of p erio d o n tal disease. T his ev id en ce su g g ests th a t a n tib io tic th e ra p y d ire c te d to w a rd e lim in a tio n of s p e c ific p e rio d o n ta l p ath o g en s m ay be a u se fu l ad ju n ct to c u rre n t tre a tm e n t m o d e s, p ro v id e d th a t su ch treatm en t does n o t le ad to selec tio n of a n tib io tic -re sista n t oral bacteria. A n tib io tic s th a t a re a c tiv e o n ly ag ain st g ram -positive b acteria w o u ld n o t likely be of b en efit in th e trea tm e n t of eith er ad v an ced ch ro n ic p e rio d o n ti tis or p erio d o n to sis. A lth o u g h tetracy clin e th erap y a p pears to offer som e clin ic al b en efit in selected cases, a sig n ifican t am o u n t of se lec tio n for te tra c y c lin e re sista n c e o ccurs am ong gram -negative bacteria. C learly, fu rth e r re se a rc h d ire c te d to w ard s th e ev alu atio n of n ew a n d c u r ren tly available an tib io tics for u se in th e trea tm e n t of p erio d o n tal disease m u st in c lu d e q u an titativ e as w ell as q u alitativ e assessm en ts of ch an g es in th e co m p o sitio n of th e m icrobial flora as w ell as d etailed assessm en ts of p re cise lev els of re sista n c e am ong th e flora after th erap y . R ecent stu d ie s84 in d ic a tin g th a t a n tib io tic resistan c e m ay be g en etically tran sferred by co n ju g atio n b etw een m em bers of different species of b acteria em p h asize th e seri o u sn e ss of u s in g a n tib io tic s in d is crim in ately .85 It sh o u ld be n o te d th a t few of th e cited stu d ies in th is review co u ld be co n sid ered to have an ad eq u ate d e sign. U nfortunately, th is m akes th e in te rp retatio n of th e resu lts of m an y of th ese stu d ies a d ifficu lt an d u n c e rta in task. T h e d esig n of fu tu re an tib io tic c lin i cal stu d ies sh o u ld in c lu d e em p h asis on p erform ance in a d o u b le-b lin d fash io n w ith in c lu sio n of placebo co n tro l g ro u p s, ra n d o m g ro u p assig n m en ts, ad eq u ate len g th s of tim e in p retrea t m e n t, tre a tm e n t, a n d p o sttre a tm e n t p h ases, th e u se of d ifferen t p re p a ra tio n s a n d co n c en tra tio n s of th e a n tib i o tic b e in g e v a lu a te d , a n d th e m o n ito rin g of p a tie n ts for a n y adverse effects.
Dr. Gibson is director of research, Louisiana State University School of Dentistry, New Or leans. This report was given at the 1980 annual
A S S O C IA T IO N
session of the ADA. It was approved by the Coun cil on Dental Research in June 1981. Address re quests for reprints to the Council. 1. Socransky, S.S. Relationship of bacteria to the etiology of periodontal disease. J Dent Res 49;203, 1970. 2. Ellison, S.A. Oral bacteria and periodontal disease. J Dent Res 49:198,1970. 3. Kelstrup, J., and Theilade, E. Microbes and periodontal disease. J Clin Periodontol 1:15,1974. 4. Socransky, S.S., and Crawford, A.C. Recent advances in the microbiology of periodontal dis ease. Current therapy, ed 5. St. Louis, C. V. Mosby, 1977. 5. Theilade, E., and Theilade, J. Role of plaque in the etiology of periodontal disease and caries. Preventive dentistry: nature, pathogenicity and clinical control of plaque. Oral Sci Rev 9:23-63, 1976. 6. Socransky, S.S. Microbiology of periodontal disease—present status and future consid erations. J Periodontol 48:497-504, 1977. 7. Crawford, A.; Socransky, S.S.; and Bratthall, G. Predom inant cultivable microbiota of ad vanced perio d o n titis. J Dent Res 54(A):97, abstract no. 209, 1975. 8. Van Palenstein Halderman, W.H. Total viable count and differential count of vibrio(camfylobacter) sputorum, fusobacterium nucleatum, selenomas sputigena, bacteroides ochraceus and veillonella in the inflamed and non-inflamed gingival crevice. J Periodont Res 10:294-305, 1975. 9. Slots, J. The predominant cultivable micro flora of advanced periodontitis. Scand J Dent Res 85:114-121, 1977. 10. Listgarten, M.A., and Hellden, L. Relative distribution of bacteria at clinically healthy and periodontally diseased sites in humans. J Clin Periodontol 5:155-132,1978. 11. Listgarten, M.A.; Lindhe, J.; and Parodi, R. The effect of systemic antimicrobiol therapy on plaque and gingivitis in dogs. J Periodont Res 14:65-75, 1979. 12. Williams, R.C., and others. Effect of sys tem ic tetracycline on alveolar bone loss in beagles. J Dent Res 57(A); abstract no. 770, 1978. 13. Mitchell, D.F., and Johnson, M. The nature of the gingival plaque in the hamster— production, prevention and removal. J Dent Res 35:651-655, 1956. 14. Shaw, J.H.; Griffiths, D.; and Auskaps, A.M. The influence of antibiotics on the periodontal syndrome in the rice rat. J Dent Res 40:511,1961. 15. Keyes, P.H., and others. Bio-assays of medi caments for the control of dentobacterial plaque, dental caries, and periodontal lesions in Syrian hamsters. J Oral Ther Pharmacol 3:157, 1966. 16. Kornman, K.S.; Caffesse, R.G.; and Nasjleti, C.E. The effects of intensive antibacterial therapy on the su lc u la r environm ent in m onkeys. Changes in the bacteriology of the gingival sul cus. J Periodontol 51:34-38,1980. 17. Weiner, G.S.; DeMarco, T.J.; and Bissada, N.F. Long term effect of systemic tetracycline ad ministration on the severity of induced periodon titis in the rat. J Periodontol 50:619,1979. 18. Kucers, A., and Bennett, N.M. The use of an tibiotics, ed 3. Philadelphia, J. B. Lippincott Co, 1979. 19. Fraleigh, C.M. An evaluation of topical terramycin in postgingivectomy pack. J Periodontol 27:201,1956. 20. Romanow, I. The relationship of moniliasis to presence of antibiotics in periodontal packs. Periodontics 2:298, 1964.
21. Baer, P.N.; Sumner, C.F.; and Miller, G. Periodontal dressings. Dent Clin North Am 13:181-191,1969. 22. Ariaudo, A.A. The efficacy of antibiotics in periodontal surgery: controlled study with lincomycin and placebo in sixty-eight patients. J Periodontol 40:150,1969. 23. Kolmer, J.A. Relation of chemotherapy to dentistry and oral surgery with special reference to antibiotic compounds. JADA 35:12,1947. 24. Arches, H. Penicillin in intraoral lesions. Br Dent J 82:201,1947. 25. Pendrill, K., and Reddy, J. The use of prophylactic penicillin in periodontal surgery. J Periodontol 51:44-48, 1980. 26. Loesche, W.J. Chemotherapy of dental plaque infections. Oral Sci Rev 9:65-107,1976. 27. Johnson, R.J., and Rozanis, J. A review of chem otherapeutic plaque control. Oral Surg 47:136-141, 1979. 28. Parsons, J.C. Chemotherapy of dental plaque: a review. J Periodontol 45:177,1974. 29. Winer, R.A.; Cohen, M.M.; and Chauncey, H.H. Antibiotic therapy in periodontal disease. J Oral Ther Pharmacol 2:404,1966. 30. Stahl, S.S. The influence of antibiotics on the healing of gingival wounds in rats. J Periodon tol 33:261, 1962. 31. Stahl, S.S. The influence of antibiotics on the healing of gingival wounds in rats. J Periodon tol 34:166, 1963. 32. Stahl, S.S.; Soberman, A.; andDeCesare, A. Gingival healing, V. J Periodontal 40:521,1969. 33. Wilderman, M.N. Repair after a periosteal retention procedure. J Periodontol 34:487,1963. 34. Dal Pra, D.J., and Strahan, J. D. A clinical evaluation of the benefits of a course of oral penicillin following periodontal surgery. Aust Dent J 17:219-221, 1972. 35. Kidd, E.A. and Wade, A.B. Penicillin con trol of swelling and pain after periodontal osseus surgery. J Clin Periodontol 1:52,1974. 36. Lobene, R.R.; Brion, M.; and Socransky, S.S. Effect of erythromycin on dental plaque and plaque forming microorganisms. J Periodontol 40:287-291, 1969. 37. Loesche, W.J., and others. Effect of topical kanamycin sulfate on plaque accumulation. JADA 83:1063-1069, 1971. 38. Loesche, W.J., and Nafe, D. Reduction of supragingival plaque accum ulation in in stitutionalized Down’s syndrome patients by periodic treatment with topical kanamycin. Arch Oral Biol 18:1131-1143,1973. 39. Loesche, W.J.; Hockett, R.N.; and Syed, S.A. Reduction in proportions of dental plaque strep tococci following a five-day kanamycin treat ment. J Periodont Res 12:1-10, 1977. 40. Baker, P.J., and others. Antibiotics as in vitro plaque inhibitors. J Dent Res 57(A):246 abstract no. 687, 246, 1978. 41. Pellerat, J., and Maillard, M.A. Etudes sur l ’elimination salivaire de la spiramycine et de di vers antibiotiques. Acta Odontostomatol 61:6572, 1963. 42. Yankell, S.L., and others. Spiramycin excre tion in animals. A single oral dose in rats. J Dent Res 51:712-715, 1972. 44. Yankell, S.L., and others. Spiramycin excre tion in animals. A single oral dose in dogs. J Dent Res 53:364-368, 1974. 45. Tsvetanova, M., and Klein-Genova, S. De posit and length of retention of Rovamycin (spiramycin) in the bones and its level in rats’ blood serum after oral administration. Stomatol (Sofia) 49:261-266, 1967. 46. Tsvetanova, M., and Klein-Genova, S. Com
REPORT
parative studies on the deposition and length of retention of spiramycin, tetracycline and ery thromycin in the serufti, jaw and long bones of white rats. Stomatol (Sofia) 50:364-369,1968. 47. Daligland, P. Paradentosis—results of three years of spiramycin therapy. Stomatol 59:784, 1958. 48. Harvey, R.F. Clinical impressions of a new antibiotic in periodontitis: spiramycin. J Can Dent Assoc 27:576-585, 1961. 49. Gendron, R. L’antibiotherapie en periodontie. J Can Dent Assoc 27:62-65, 1961. 50. Mills, W.H.; Thompson, G.W.; and Beagrie, G.S. Double blind clinical evaluation of spiramy cin and erythromycin in control of periodontal disease. J Dent Res 55(B):abstract no. 806, 1976. 51. Johnson, R.H., and others. The effect of spiramycin on plaque accumulation and gin givitis. J Can Dent Assoc 44:456-460,1978. 52. Rozanis, J., and others. Spiramycin as a selective dental plaque control agent. J Periodont Res 14:55-64,1979. 53. Turnbull, R.S., and Pearson, G.E. The role of spiramycin in the treatment of periodontal dis ease. J Can Dent Assoc 44:313-315,1978. 54. Mitchell, D.F., and Holmes, L.A. Topical an tibiotic control of dentogingival plaque. J Periodontol 36:202-208, 1965. 55. Mitchell, D.F., and others. Topical antibio tic maintenance of oral health. J Oral Therap Pharmacol 4:83-92, 1967. 56. Loe, H., and others. Experimental gingivitis in man. The influence of antibiotics on gingival plaque development. J Periodont Res 2:282-289, 1967. 57. Jensen, S.G., and others. Experimental gin givitis in man. Vancomycin induced changes in bacterial plaque composition as related to devel opment of gingival inflammation. J Periodont Res 3:284-293, 1968. 58. Collins, J.F. Effect of vancomycin on plaque after periodontal surgery. J Dent Res 49:1478, 1970. 59. McFall, W.T.; Shoulars, H.W.; and Carnevale, R.A. Effect of vancomycin on inhibition of bacterial plaque. J Dent Res 47:1195,1968. 60. Kaslick, R.S.; Tuckman, M.A.; and Chasens, A.I. Effect of topical vancomycin on plaque and chronic gingival inflammation. J Periodontol 44:366-368, 1973. 61. Mac Dougall, J.C. Topical application of an tibiotics in dentistry. Dent Pract 13:147,1962. 62. Borzelleca, J., and Cherrick, H.M. Excretion of drugs in saliva. J Oral Therap Pharmacol 2:180, 1965. 63. Bader, H.I., and Goldhaber, P. The passage of intravenously administered tetracycline into the gingival sulcus of dogs. J Oral Therap Phar macol 2:324, 1966. 64. Ciancio, S.G. Tetracycline and periodontal therapy. J Periodontol 47:155-159,1976. 65. Williams, R.C., and others. Effects of tetra cycline on periodontal disease in beagles. Rate of alveolar bone loss. J Dent Res 59(A)abstract no. 1064,1980. 66. Jeffcoat, M.K., and others. Effects of tetracy cline on periodontal disease in beagles. Nuclear medicine studies. J Dent Res 59(A), abstract no. 1065, 1980. 67. Sipos, T. Prevention of gingivitis in beagles with topically applied melocycline. J Dent Res 59(A), abstract no. 1062,1980. 68. Scopp, I.W., and others. Tetracycline— double-blind study to evaluate the effectiveness in periodontal surgery. J Periodontol 48:484-486, 1977.
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69. Scopp, I. W., and others. Tetracycline: a clin ical study to determ ine its effectiveness as long term adjuvant. J Periodontol 51:328-330, 1980. 70. Genco, R., and others. Use of tetracycline in the treatm ent of adult periodontitis. I. Clinical studies. J Dent Res 57(A), abstract no 768, 1978. 71. Reynolds, H .,and others. Use of tetracycline in the treatm ent of adult periodontitis. II. Mi crobiological studies. J Dent Res 57(A), abstract no. 769, 1978. 72. Listgarten, M.A.; Lindhe, J.; and Hellden, L. Effect of tetracyline and/or scaling on hum an periodontal disease. J Clin Periodontol 5:246-271, 1978. 73. Hellden, L.; Listgarten, M.A.; and Lindhe, J. The effect of tetracylcine and/or scaling on hum an periodontal disease. J Clin Periodontol 6:222-230, 1979. 74. Slots, J., and others. Periodontal therapy in hum ans. M icrobiological and clinical effects of a
THE PRESIDENTS
single course of periodontal scaling and root planing, and of adjunctive tetracycline therapy. I Periodontol 50:495-509, 1979. 75. Claiborne, W.J. and McFall, W.T. Tetracy cline: influ en ce on plaq u e co m position and p erio d o n tal h e a lth status. J D ent Res 58(A), abstract no. 770,1979. 76. Osterberg, S.K.; W illiams, B.L.; and Jorgen sen, J. Long-term effects of tetracycline on the subgingival microflora. J Clin Periodontol 6:133140, 1979. 77. W illiams, B.L.; Osterberg, S.K.; and Jorgen sen J. Subgingival microflora of periodontal pa tients on tetracycline therapy. J Clin Periodontol 6:210-221, 1979. 78. Gordon, J.M., and others. Concentration of tetracycline in hum an crevicular fluid after single and m ultiple doses. J Dent Res 59(A), abstract no. 977,1980. 79. Ciancio, S.G.; Mather, M.L.; and McMullen, J.A. An evaluation of m inocycline in patients
w ith periodontal disease. J Periodontol 51:530534, 1980. 80. Goodson, J.M.; Haffajee, A.; and Socransky, S.S. Local drug delivery using hollow fiber de vices. Construction relase and side effects. J Dent Res 57(A), abstract no. 766, 1978. 81. Haffajee, A., and others. Local drug delivery using hollow fiber devices. Effects on the m i crobiota. J Dent Res 57(A), abstract no. 767,1978. 82. Goodson, J.M.; Haffajee, A.; and Socransky, S. S. Periodontal therapy by local delivery of tetra cycline. J Clin Periodontol 6:83-92,1979. 83. Lindhe, J., and others. Local tetracycline de livery using hollow fiber devices in periodontal therapy. J Clin Periodontol 6:141-149, 1979. 84. Researchers find antibiotic resistance is transferred am ong bacteria in the m outh. JADA 99:513, 1979. 85. Sack, R.B. Prophylactic antibiotics? The in dividual versus the com m unity. New Engl J Med 300:1107-1108, 1979.
B. Holly Smith 1899 - 1900
D o cto r S m ith , o f B a ltim o re , w a s e le c te d 3 7 th p re s id e n t o f th e A s s o c ia tio n at th e 1899 m e e tin g at N ia g a ra F alls. T h e S o u th e rn B ra n c h o f th e A sso c ia tio n m et e a rly th a t y e a r in N e w O rle a n s. Doctor Smith received a DDS degree in 1881 and an MD degree in 1883. He practiced dentistry in Baltimore for 37 years. Offices he held included the
presidency of the Southern Dental Association, the Maryland State Dental Association, the Baltimore College of Dental Surgery, and the National Asso ciation of Dental Faculties. Doctor Smith’s special interests included the de velopment of a system of oral hygiene in the Baltimore public schools. He was widely known as an eloquent orator. He was born in Maryland in 1858 and died in 1920. The Open Door policy regarding China was announced by Secretary of State John Hay. Philippine insurrection against the United States began in 1899 and was crushed in 1901 with the capture of the leader, Emilio Aguinaldo. An act of Congress provided for a territorial form of government for the Hawaiian Islands. Each month, The Journal prints the picture of a past president of the American Dental Association w ith a brief biography and a few historical highlights of his presidential year. The series began in February 1979 w ith the first president and is continuing in chronological order.
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