Antibiotics and Dental Caries - Advances in Chemistry (ACS

5 Antibiotics and Dental Caries BASIL G. BIBBY

Downloaded by UNIV OF PITTSBURGH on August 18, 2015 | http://pubs.acs.org Publication Date: June 1, 1970 | doi: 10.1021/ba-1970-0094.ch005

Eastman Dental Center, Rochester, Ν. Y . 14603

When

fed in water or diet, penicillin

biotics

consistently

applications Clinical

on animals'

teeth

studies in human

frices or as prophylaxis

in animals.

seem to have

against

rheumatic

to the manner

of use rather than the absence

long-range ecological

an important

ill effects may balance

findings

result

of the oral

are probably of

consideration

from

effect.

in denti

fever gave

While

properties,

negative

anti Topical

some

subjects using antibiotics

sistent results. cariostatic

The

and some other

limit caries activity

disturbance

incon related inherent is of

that the

flora.

i n i t i a l studies o n t h e relationships b e t w e e n a n t i b i o t i c s a n d d e n t a l caries w e r e d e s i g n e d to i n d i c a t e t h e i m p o r t a n c e of b a c t e r i a o r c e r t a i n

b a c t e r i a l g r o u p s i n its e t i o l o g y . T h e r e a f t e r , attempts w e r e m a d e t o estab l i s h t h e usefulness

of c e r t a i n a n t i b i o t i c s i n caries p r e v e n t i o n i n m a n .

R e c e n t l y they h a v e b e e n u s e d a g a i n i n caries research f o r e v a l u a t i n g t h e i m p o r t a n c e of specific b a c t e r i a l types a n d testing n e w ideas i n caries etiology. T w e n t y years ago, t h e b e l i e f that g r a m p o s i t i v e b a c t e r i a , s u c h as t h e streptococci,

w e r e t h e a c t i v a t i n g agents of d e n t a l d e c a y w a s n o t as

g e n e r a l l y a c c e p t e d as i t is t o d a y , a n d some d e n t a l investigators b e l i e v e d that i n a d e q u a t e n u t r i t i o n m i g h t h a v e e q u a l i m p o r t a n c e .

O n e w a y of

settling this q u e s t i o n w a s t o a d d a n agent, s u c h as p e n i c i l l i n , w h i c h w o u l d d e s t r o y a c i d - p r o d u c i n g g r a m p o s i t i v e organisms, to a d i e t w h i c h w a s k n o w n to cause d e n t a l d e c a y i n rats, a n d see w h e t h e r i t w o u l d p r o t e c t the a n i m a l s against caries.

I n s u c h a n experiment, i t w a s f o u n d

(29)

that rats e a t i n g a c a r i e s - p r o d u c i n g d i e t w i t h 75 u n i t s of p e n i c i l l i n p e r g r a m of f o o d o r w a t e r d e v e l o p e d n o d e n t a l d e c a y , w h e r e a s a n i m a l s e a t i n g t h e p e n i c i l l i n - f r e e c o n t r o l d i e t d e v e l o p e d caries as u s u a l . T h e l a c t o b a c i l l i , w h i c h at that t i m e w e r e b e l i e v e d to b e causative agents of caries, h a d b e e n e l i m i n a t e d f r o m t h e m o u t h s of t h e p e n i c i l l i n g r o u p . F o l l o w i n g this a p p r o a c h , S t e p h a n et al. (36, 37)

tested t h e effect of p e n i c i l l i n , A u r e o 46

In Dietary Chemicals vs. Dental Caries; Harris, R.; Advances in Chemistry; American Chemical Society: Washington, DC, 1970.

5.

Antibiotics

BiBBY

and

Dental Caries

47

mycin, bacitracin, Chloromycetin, streptomycin, Terramycin,

cephalo

s p o r i n , a n d p o l y m y x i n o n rat caries for the d o u b l e p u r p o s e of d e t e r m i n i n g the r e l a t i v e effectiveness of these agents i n p r e v e n t i n g caries a n d i n d i c a t i n g w h i c h spectra of m i c r o o r g a n i s m s p l a y e d the most i m p o r t a n t p a r t i n its etiology. T h e i r findings s h o w e d that o n l y c e p h a l o s p o r i n a n d p o l y m y x i n f a i l e d to r e d u c e caries, a n d that n o n e of the b r o a d - s p e c t r u m a n t i b i o t i c s w a s a n y m o r e effective t h a n p e n i c i l l i n i n this respect. T h e f a i l u r e of c e p h a l o s p o r i n , w h i c h is effective against most g r a m p o s i t i v e organisms


except some s t r e p t o c o c c i a n d l a c t o b a c i l l i , t o r e t a r d caries i n d i c a t e d the i m p o r t a n c e of these b a c t e r i a l types i n caries.

T h e n e g a t i v e results w i t h

p o l y m y x i n l i k e w i s e s h o w e d that g r a m n e g a t i v e organisms h a d n o signifi c a n c e i n the c a u s a t i o n of rat caries. Fitzgerald and Jordan

(5)

tested 10 units or 10 μξ

p e r g r a m of

several different a n t i b i o t i c s i n c a r i o g e n i c diets i n a rat s t u d y .

A l l the

agents s i g n i f i c a n t l y r e d u c e d the caries score b e l o w that g i v e n b y control diet.

the

P e n i c i l l i n w a s m o s t effective, w i t h o n l y one t h i r d of t h e

a n i m a l s s h o w i n g caries, f o l l o w e d i n o r d e r b y o r y t h r o m y c i n , z i n c b a c i tracin, carbomycin, and neomycin. I n a s t u d y of the m e c h a n i s m s of caries p r e v e n t i o n b y v a r i o u s agents, M c C l u r e et al

(28)

f o u n d that p e n i c i l l i n at 10 u n i t s p e r g r a m of d i e t w a s

m o r e effective i n p r e v e n t i n g caries i n w h i t e rats t h a n 50 p p m of s o d i u m fluoride

o r i o d o a c e t i c a c i d or a h i g h - m i n e r a l diet. T h e y i n t e r p r e t e d this

to m e a n that b a c t e r i a l a c t i v i t y o n the teeth w a s of p r i m a r y i m p o r t a n c e i n c a u s i n g caries. I n e n d e a v o r i n g to d e t e r m i n e w h i c h types of b a c t e r i a p r o d u c e d caries i n t h e i r caries-susceptible

s t r a i n of rats, R o s e n et al

(33)

f o u n d that

w h e n 500 units o f p e n i c i l l i n or 0 . 0 2 5 % T e r r a m y c i n p e r g r a m of d i e t w e r e f e d , n o caries o c c u r r e d i n the p e n i c i l l i n rats, b u t a l l t h e i r T e r r a m y c i n rats s h o w e d caries.

S i n c e b o t h a n t i b i o t i c s are effective

against

g r a m p o s i t i v e organisms, they c o n c l u d e d that some u n r e c o g n i z e d types of b a c t e r i a m u s t b e r e s p o n s i b l e f o r caries i n t h e i r a n i m a l s . S h a w a n d S w e e n e y (34)

u s e d c o t t o n rats, w h i t e rats, a n d d e s a l i v a t e d

w h i t e rats i n a c o m p a r i s o n of the effectiveness of different levels of a v a r i e t y o f a n t i b i o t i c agents o n caries, a n d also c o m p a r e d t h e i r in effectiveness against a h u m a n a n d rat strain of Lactobacillus

P e n i c i l l i n w a s the m o s t effective i n r e d u c i n g caries i n b o t h species. mycin, Chloromycetin, streptomycin, and Terramycin were

vitro

acidophilus. Aureo-

moderately

effective, whereas p a n t h e n o l , t y r o t h r i c i n , s u b t i l i n , a n d b a c i t r a c i n

gave

o n l y s l i g h t or n o p r o t e c t i o n . N o c o r r e l a t i o n w a s f o u n d b e t w e e n effective ness i n r e d u c i n g a n i m a l caries a n d the a b i l i t y to p r e v e n t a c i d f o r m a t i o n i n the l a c t o b a c i l l u s cultures.

F a l l a a n d S h a w (4)

s h o w e d that

injected

p e n i c i l l i n w o u l d r e d u c e caries i n rats, b u t to b e effective, levels t w i c e as h i g h as i n the f o o d h a d to b e u s e d .


48

DIETARY

C H E M I C A L S

VS.

D E N T A L

U s i n g a 15-day, rather t h a n the u s u a l 80- to 100-day, p e r i o d , M u h l e m a n n et al. (31) a d d i t i o n s of 0.01 to 0 . 2 %

CARTES

experimental

m a d e a n extensive c o m p a r i s o n of d i e t a r y

of a n t i b a c t e r i a l a n d a n t i f u n g a l a n t i b i o t i c s a n d

other a n t i b a c t e r i a l c h e m i c a l a n d cariostatic agents o n the i n i t i a t i o n of rat caries.

T h e a n t i b a c t e r i a l agents u s e d w e r e p e n i c i l l i n , A u r e o m y c i n ,

D e c l o m y c i n , erythromycin, O l e a n d o m y c i n , novobiocin, thiostrepton, bacitracin,

dihydrostreptomycin, and

chloramphenicol.

The

antimycotic

agents u s e d w e r e n y s t a t i n , g r i s e o f u l v i n , a m p h o t e r i c i n B , e c h i n o m y c i n ,


usnic acid, and penicillin,

flavofungin.

T h e antibiotics w i t h gram positive s p e c t r a —

Oleandomycin, erythromycin, and

novobiocin—were

most

effective i n p r e v e n t i n g e a r l y caries, a n d t h e i r b r i e f l y - p r e s e n t e d

results

c a n b e i n t e r p r e t e d as s h o w i n g caries r e d u c t i o n s of f r o m 85 to 9 0 %

below

t h e w a t e r controls.

Tetracyclines—Aureomycin, Tetracyn, and Declo-

m y c i n — g e n e r a l l y gave r e d u c t i o n s i n the 6 0 % w e r e c o m p a r a b l e i n effectiveness t o s o d i u m

range a n d i n this respect fluoride,

as w e r e the a n t i -

b i o t i c s w i t h b o t h g r a m p o s i t i v e a n d g r a m negative spectra. a n t i m y c o t i c s n o r the disinfectants r e d u c e d caries.

N e i t h e r the

F r o m these results, it

w a s c o n c l u d e d that the a n t i b i o t i c s w e r e the most effective agents against rat caries. T h e o b v i o u s c o n c l u s i o n f r o m a l l of these studies is that a n t i b i o t i c s are c a p a b l e of p r e v e n t i n g d e n t a l d e c a y i n a n i m a l s . S e v e r a l o f t h e m are v e r y potent, a n d t h e i r effectiveness seems to b e r e l a t e d to t h e

capacity

to interfere w i t h the g r o w t h of g r a m p o s i t i v e b a c t e r i a i n g e n e r a l , rather t h a n the l a c t o b a c i l l i i n p a r t i c u l a r . T h e d e m o n s t r a t e d effectiveness of antibiotics i n p r e v e n t i n g a n i m a l caries l e d to a c o n s i d e r a t i o n of their use to c o m b a t d e n t a l d e c a y i n m a n . A s a result, b o t h in vitro a n d a n i m a l caries studies w e r e u n d e r t a k e n , w i t h a v i e w to d e v e l o p i n g p r o p h y l a c t i c p r o d u c t s for h u m a n use. T h e in vitro experiments w e r e b a s e d o n the k n o w l e d g e that d e n t a l caries results f r o m d e c a l c i f i c a t i o n of teeth b y acids f o r m e d b y b a c t e r i a l f e r m e n t a t i o n of c a r b o h y d r a t e s , a n d , therefore, a n y agent w h i c h w o u l d effectively interfere w i t h the p r o d u c t i o n of a c i d w o u l d b e l i k e l y to p r e vent tooth decay.

U s i n g this a p p r o a c h , large n u m b e r s of

antibacterial

agents a n d e n z y m e i n h i b i t o r s h a v e b e e n tested i n several w a y s to i n d i c a t e t h e i r p o t e n t i a l usefulness i n p r e v e n t i n g caries.

Zander and B i b b y

(44)

m e a s u r e d r e d u c t i o n of a c i d f o r m a t i o n f r o m glucose i n s a l i v a , F o s d i c k

(9)

c a l c i u m loss f r o m e n a m e l i n a s a l i v a r y f e r m e n t a t i o n system, a n d M a h l e r a n d M a n l y (27) p a c k e d organisms

acid formation i n an "artificial plaque" composed obtained b y centrifuging m o u t h washings.

In

of our

experiments, a n d F o s d i c k ' s , p e n i c i l l i n w a s the most effective of the m a n y agents tested.

F o s d i c k c o n c l u d e d that since p e n i c i l l i n w a s a b s o r b e d i n

p r o t e i n films, a n d other e n z y m e i n h i b i t o r s w e r e not, i t w o u l d h a v e

a

l a s t i n g effect o n the c a r i e s - p r o d u c i n g a c t i v i t y of the b a c t e r i a l p l a q u e s o n


5.

Antibiotics

BIBBY

the t o o t h surface.

and

Dental

49

Caries

H o w e v e r , i n M a h l e r a n d M a n l y ' s (27)

experiments,

i n w h i c h p a c k e d m i c r o o r g a n i s m s w e r e u s e d rather t h a n

suspensions,

p e n i c i l l i n w a s ineffective i n c h a n g i n g the course of a c i d p r o d u c t i o n . T h i s finding

o n short-term a c i d f o r m a t i o n i n " a r t i f i c i a l p l a q u e " w a s e x t e n d e d

i n t o the m o u t h b y B r u d e v o l d a n d H a w e s ' (3)

finding

that p e n i c i l l i n d i d

not interfere w i t h a c i d f o r m a t i o n i n p l a q u e s o n h u m a n t o o t h surfaces. A different sort of in vitro e v i d e n c e o n the effectiveness of p e n i c i l l i n i n p r e v e n t i n g caries w a s offered b y Z a n d e r a n d B i b b y (44),

w h o showed


t h a t s a l i v a c o l l e c t e d f r o m h u m a n m o u t h s 2 h o u r s after a p e n i c i l l i n rinse s t i l l l a c k e d the a b i l i t y to f e r m e n t glucose. W h i l e a t t e n t i o n has b e e n c e n t e r e d o n p e n i c i l l i n , other g i v e c o m p a r a b l e i n h i b i t i o n of a c i d f o r m a t i o n i n in vitro Brudevold and B i b b y (2)

antibiotics

tests (2,

29).

f o u n d that a m o n g e x p e r i m e n t a l l y d e v e l o p e d

a n t i b i o t i c s that the m a n u f a c t u r e r s d e e m e d u n s u i t a b l e f o r systemic a d m i n i s t r a t i o n there w e r e some w h i c h w e r e e q u a l l y as effective as p e n i c i l l i n i n reducing acid production b y m o u t h bacteria.

F r o m this, i t m a y b e s u g -

gested that the l o n g - r a n g e p o s s i b i l i t i e s of u t i l i z i n g a n t i b i o t i c s i n caries c o n t r o l m i g h t w e l l d e p e n d u p o n the selection o f types w h i c h w o u l d n o t b e e m p l o y e d f o r a n y other m e d i c a l p u r p o s e . S e v e r a l a n i m a l - f e e d i n g studies d e s i g n e d to s u p p l e m e n t those a l r e a d y c i t e d h a v e b e e n c a r r i e d out to select a n d evaluate a n t i b i o t i c s f o r i n c l u s i o n i n d e n t i f r i c e s i n t e n d e d f o r caries p r e v e n t i o n i n m a n . finding

L o o k i n g towards

the lowest effective c o n c e n t r a t i o n of p e n i c i l l i n w h i c h w o u l d b e

effective against caries, W e b m a n et al.

(40)

s h o w e d that as l i t t l e as 2

units of p e n i c i l l i n a d d e d to a c a r i e s - p r o d u c i n g d i e t r e d u c e d d e n t a l d e c a y i n rats b y almost a t h i r d , a n d that a r e d u c t i o n of l a c t o b a c i l l u s c o u n t a n d a n increase

of g r a m negative organisms also o c c u r r e d i n the

m o u t h s . V o l k e r et al. (38)

animals'

c o m p a r e d the effect of p e n i c i l l i n , a m e r c u r i c

benzoate, a n d a sarcosinate, a l l of w h i c h i n h i b i t e d a c i d p r o d u c t i o n b y s a l i v a r y b a c t e r i a a n d w e r e r e t a i n e d o n the t o o t h surface, o n

hamster

caries. T h e y f o u n d p e n i c i l l i n to b e the most effective u n d e r the t w o test c o n d i t i o n s u s e d . I n another c o m p a r i s o n of the effectiveness of p e n i c i l l i n a n d other cariostatic agents, P i n d b o r g (32)

f o u n d that 20 m g of p r o c a i n e

p e n i c i l l i n p e r k g of d i e t ( t h e e q u i v a l e n t of 20 i n t e r n a t i o n a l u n i t s p e r g r a m of d i e t ) r e d u c e d d e n t a l d e c a y b y 8 1 % , whereas 10 p p m of s o d i u m fluoride

or of stannous

fluoride

a d d e d to the same d i e t gave

caries

r e d u c t i o n s of o n l y 31.6 a n d 28.9, respectively. Another type

of

experiment,

i n w h i c h antibiotic mixtures

were

b r u s h e d o n a n i m a l teeth, has b e e n u s e d to p r e d i c t t h e p o t e n t i a l effectiveness of a n t i b i o t i c dentifrices i n m a n . I n the first e x p e r i m e n t of this sort, Z a n d e r a n d B i b b y (44)

b r u s h e d a s o l u t i o n c o n t a i n i n g 500 u n i t s of p e n i -

c i l l i n p e r c c o n t h e t e e t h of hamsters

w h i c h were kept on a

caries-

p r o d u c i n g d i e t f o r 40 days. I n e i g h t animals w h o s e teeth w e r e b r u s h e d


50

DIETARY

C H E M I C A L S

VS.

D E N T A L

CARIES

w i t h p e n i c i l l i n , there was less t h a n one c a v i t y p e r a n i m a l , whereas i n the w a t e r - b r u s h e d c o n t r o l g r o u p , the a n i m a l s h a d a n average of seven cavities. I n another hamster e x p e r i m e n t ( 4 5 ) , solutions c o n t a i n i n g v a r i o u s c o n c e n trations of p e n i c i l l i n , A u r e o m y c i n , a n d t y r o t h r i c i n w e r e b r u s h e d o n the teeth.

P e n i c i l l i n w a s most effective.

testing i n c h i l d r e n , Shiere ( 3 5 )

T o select a d e n t i f r i c e f o r c l i n i c a l

b r u s h e d five different t y r o t h r i c i n d e n t i -

frices a n d a c o n t r o l o n hamster teeth.

T h e one w h i c h gave the m a x i m a l

caries

c o n t r o l , was

reduction, 25.6%

b e l o w the

subsequently

found


e q u a l l y effective i n m a n . T h e a c c u m u l a t e d e v i d e n c e that p e n i c i l l i n w o u l d interfere w i t h a c i d formation b y salivary bacteria and w o u l d unquestionably prevent dental caries i n a n i m a l s l e d to tests of its caries-preventive effect i n m a n . B e f o r e m e n t i o n i n g the findings i n the c l i n i c a l tests w h i c h h a v e b e e n c a r r i e d o u t u s i n g a n t i b i o t i c dentifrices, it s h o u l d b e p o i n t e d out

that

m a n y v a r i a b l e s b e y o n d that of the agent u s e d c o m p l i c a t e the o b t a i n i n g of r e l i a b l e results i n h u m a n studies.

F o r instance, a n agent w h i c h is

effective i n a n i m a l s m a y not b e of a n y use i n m a n , or one e x a m i n a t i o n a n d r e c o r d i n g p r o c e d u r e m a y f a i l to s h o w differences w h i c h w o u l d a p p e a r i f another w e r e u s e d , b u t m o s t i m p o r t a n t l y , the w h o l e result is g o i n g to d e p e n d u p o n the extent to w h i c h the instructions o n the use of the test d e n t i f r i c e are f o l l o w e d . O b v i o u s l y , n o t h e r a p e u t i c agent c a n b e expected to p r o d u c e benefit as l o n g as it r e m a i n s i n its container. S e v e r a l c l i n i c a l tests o n the effect of a n t i b i o t i c dentifrices o n caries have been reported.

T h e first s t u d y , that of H i l l et al.

(15),

used a

p o w d e r c o n t a i n i n g 500 units of p e n i c i l l i n p e r g r a m a n d p r o d u c e d n o a p p a r e n t r e d u c t i o n i n d e n t a l decay, a l t h o u g h a r e d u c t i o n i n s a l i v a r y l a c t o b a c i l l u s c o u n t was o b s e r v e d .

H o w e v e r , since the test subjects w e r e

8- to 16-year-old boys w h o s e u n s u p e r v i s e d b r u s h i n g habits

are

most

u n p r e d i c t a b l e , the negative result c o u l d h a v e b e e n the result of l i m i t e d use of the d e n t i f r i c e .

I n another

study, Zander

(43)

found a

55%

r e d u c t i o n i n d e n t a l d e c a y i n 6- to 14-year-old c h i l d r e n i n the first year, a n d a 57.6%

r e d u c t i o n i n the s e c o n d y e a r w h e n a p o w d e r c o n t a i n i n g

500 units of p e n i c i l l i n p e r g r a m w a s b r u s h e d o n the teeth u n d e r superv i s i o n five times p e r w e e k i n school. I n the t h i r d test of a n a n t i b i o t i c d e n t i f r i c e ( 1 6 ) , 1000 units of p e n i c i l l i n p e r g r a m i n a n a n h y d r o u s c r e a m y base was used under supervised brushing.

It w a s o n l y s l i g h t l y effective i n

r e d u c i n g d e n t a l d e c a y a n d d i d not r e d u c e the l a c t o b a c i l l u s c o u n t i n the s a l i v a . T h e l a c k of success i n this instance c o u l d h a v e b e e n c a u s e d b y the p e n i c i l l i n not b e i n g l i b e r a t e d f r o m the d e n t i f r i c e r a p i d l y e n o u g h i n the m o u t h . I n a s m a l l test ( 3 9 )

w i t h a p o w d e r c o n t a i n i n g 100 units of

p e n i c i l l i n p e r g r a m , o r p h a n a g e c h i l d r e n s h o w e d n o s l o w i n g of the caries attack o r r e d u c t i o n of the

l a c t o b a c i l l u s c o u n t as c o m p a r e d w i t h

the

controls. I n the o n l y d e n t i f r i c e s t u d y w i t h a n a n t i b i o t i c other t h a n p e n i -


5.

BIBBY

Antibiotics

and

Dental

51

Caries

c i l l i n ( 3 5 ) , a t y r o t h r i c i n d e n t i f r i c e w h i c h h a d b e e n s h o w n to b e effective against hamster caries gave a 2 6 %

reduction i n dental decay w h e n com-

p a r e d w i t h a c o n t r o l paste. Using

only lactobacillus

counts

and acid formation by

m o u t h organisms to assess caries a c t i v i t y , L u d w i c k et al

(26)

aciduric compared

different concentrations of several a n t i b i o t i c s a n d other agents over 6- to 7-week p e r i o d s . T h e y f o u n d that a p o w d e r c o n t a i n i n g 0.07%

penicillin

was m o r e effective t h a n p o w d e r s c o n t a i n i n g t y r o t h r i c i n , s t r e p t o m y c i n ,


g r a m i c i d i n , b a c i t r a c i n , a n d other anticaries agents. T h e effect of a n a n t i b i o t i c i n a m o u t h w a s h o n caries seems to h a v e b e e n tested o n l y o n c e ( 2 3 ) , i n w h i c h a 1-year t r i a l of b a c i t r a c i n i n a m o u t h w a s h f a i l e d to r e d u c e caries.

W h i l e p e n i c i l l i n has b e e n i n c o r p o r a t e d i n t o c h e w i n g g u m a n d

troches f o r other o r a l uses, t h e r e does not seem to h a v e b e e n a n y o r g a n i z e d s t u d y of t h e i r effect o n d e n t a l caries. R e a s o n f o r b e l i e v i n g that p e n i c i l l i n is c a p a b l e of r e d u c i n g d e n t a l d e c a y i n h u m a n subjects has c o m e f r o m another t y p e of use.

Many

c h i l d r e n are p l a c e d o n p r o p h y l a c t i c p e n i c i l l i n f o r the c o n t r o l of r h e u m a t i c fever or as a means of c o m b a t t i n g c h r o n i c p u l m o n a r y

diseases.

S e v e r a l c o m p a r i s o n s h a v e b e e n m a d e of patients u n d e r s u c h t h e r a p y .

In

one of these ( 2 5 ) , r h e u m a t i c f e v e r patients w h o h a d b e e n o n p r o p h y l a c t i c p e n i c i l l i n f r o m the age of 7 years h a d a p p r o x i m a t e l y 4 0 %

f e w e r carious

teeth t h a n c h i l d r e n of c o m p a r a b l e age w i t h o u t a n t i b i o t i c experience.

In

a later s t u d y ( 1 3 ) , 75 a n d 74 c h i l d r e n w h o r e c e i v e d d a i l y o r a l p e n i c i l l i n , r e s p e c t i v e l y , 200,000 u n i t s f o r the p r e v e n t i o n of r e c u r r e n t fever

and

1-3,000,000 units w i t h

occasional

tetracycline

rheumatic for

chronic

r e s p i r a t o r y diseases, s h o w e d o n l y one t h i r d of the caries i n c r e m e n t

of

c o n t r o l subjects. T h e in vitro

a n d a n i m a l studies, together w i t h p r e l i m i n a r y c l i n i c a l

e v i d e n c e of caries r e d u c t i o n i n m a n , r e s u l t e d i n the b r i e f a p p e a r a n c e o n the m a r k e t of t w o p e n i c i l l i n dentifrices. their disappearance.

S e v e r a l reasons c o n t r i b u t e d to

O n e o f these w a s that c o m p e t i n g t h e r a p e u t i c d e n t i -

frices w i t h greater cosmetic a p p e a l w e r e offered at a b o u t the same t i m e . A n o t h e r is that t h e y w e r e treated w i t h s u s p i c i o n b y b o t h the m e d i c a l a n d d e n t a l professions, w h i c h , as experience g r e w , a t t a c h e d i n c r e a s i n g w e i g h t to the dangers of d e v e l o p i n g p e n i c i l l i n - r e s i s t a n t organisms a n d a l l e r g i c states. T h e e v i d e n c e o n this latter subject rests i n some

demonstrations

that the m o u t h s of c h i l d r e n u s i n g p e n i c i l l i n dentifrices c o n t a i n e d i n creased p o p u l a t i o n s of g r a m n e g a t i v e organisms i n t w o studies (14,

42).

C h i l d r e n u s i n g Z a n d e r s 500-unit p e n i c i l l i n p o w d e r f o r 1£ years d i d not s h o w a n increase i n p e n i c i l l i n - r e s i s t a n t l a c t o b a c i l l i (8) a n d s t a p h y l o c o c c i (22),

or

streptococci

b u t after 3 years m o r e p e n i c i l l i n - r e s i s t a n t strep-

t o c o c c i , m i c r o c o c c i , a n d neisseria w e r e f o u n d (21,

41).

I n patients o n

200,000-3,000,000 units of o r a l p e n i c i l l i n p e r d a y , a s l i g h t increase


in

52

DIETARY

C H E M I C A L S

VS.

D E N T A L

CARIES

a n t i b i o t i c resistance w a s n o t e d w i t h o u t a n y significant change i n b a c t e r i a l e c o l o g y of the m o u t h ( I I ) .

H o w e v e r , f a i l u r e to establish the safety of

p e n i c i l l i n i n the f a c e of i n d i c a t i o n s of increases i n the n u m b e r of p e n i cillin-resistant b a c t e r i a l types r e s u l t e d i n u n f a v o r a b l e o p i n i o n f r o m a n A d H o c C o m m i t t e e of the F e d e r a l F o o d a n d D r u g A d m i n i s t r a t i o n

(24),

a n d l i k e w i s e , the C o u n c i l o n D e n t a l T h e r a p e u t i c s of t h e A m e r i c a n D e n t a l A s s o c i a t i o n offered a c r i t i c a l o p i n i o n ( 1 7 ) , r e c o m m e n d i n g that " p e n i c i l l i n dentifrices

s h o u l d not

be

d i s t r i b u t e d . . . except

on

a

prescription


basis." I n a n y case, w h e t h e r i t w a s f o r this or other reasons, the p e n i c i l l i n d e n t i f r i c e s d i d not c o n t i n u e o n the m a r k e t . A p a r t f r o m c o m m e r c i a l c o n siderations, this m a y h a v e b e e n a p r e m a t u r e d e v e l o p m e n t b e c a u s e e v e n i f p e n i c i l l i n c o u l d not b e u s e d i n e v e r y d a y d e n t i f r i c e s , a p e n i c i l l i n d e n t i f r i c e m i g h t h a v e h a d some usefulness i n s h o r t - t e r m treatment of patients w i t h o t h e r w i s e u n c o n t r o l l a b l e d e n t a l d e c a y . It is also possible that u s i n g a n t i b i o t i c s i n other w a y s m i g h t b e justified i n p h y s i c a l l y h a n d i c a p p e d or m e n t a l l y deficient patients, w h e r e o r d i n a r y m e t h o d s of caries c o n t r o l cannot be used. T h e last phase of e x p e r i m e n t a t i o n w i t h a n t i b i o t i c s has b e e n d i r e c t e d m a i n l y t o w a r d s i n v e s t i g a t i n g the r o l e of i n f e c t i o n w i t h specific m i c r o organisms i n e x p e r i m e n t a l caries. F o l l o w i n g the finding t h a t t r a n s m i s s i o n of m i c r o o r g a n i s m s w a s i m p o r t a n t i n i n i t i a t i n g a c t i v e caries i n a n i m a l s , i t b e c a m e i m p o r t a n t to establish the s p e c i f i c i t y of the b a c t e r i a l types i n volved.

A f t e r i t w a s f o u n d that the caries seemed to result f r o m o r a l

c o n t a m i n a t i o n w i t h the streptococcus

f r o m the feces, K e y e s (18)

was

a b l e to demonstrate that p e n i c i l l i n a n d e r y t h r o m y c i n w h i c h e l i m i n a t e d s u c h s t r e p t o c o c c a l types f r o m the m o u t h also p r e v e n t e d caries. T o d e m onstrate the s p e c i f i c i t y of specific strains of organisms, test s t r e p t o c o c c i w e r e m a d e streptomycin-resistant so that they c o u l d b e u s e d as m a r k e r s a n d i d e n t i f i e d i n the presence

of other s t r e p t o c o c c a l types

(8).

This

m a d e i t possible to s h o w that the m a r k e d types w e r e t r a n s m i t t e d f r o m one a n i m a l to another (6)

a n d to i d e n t i f y t h e m as t h e i n f e c t i v e agents

w h i c h p r o d u c e caries i n o t h e r w i s e caries-free a n i m a l s . This technique

of d e v e l o p i n g s t r e p t o m y c i n resistance

strains of s t r e p t o c o c c i w a s u s e d b y K r a s s e et al. (20)

i n specific

to s t u d y " i n f e c t i o n "

of h u m a n m o u t h s w i t h exogenous c a r i o g e n i c streptococci.

H e demon-

strated l o n g - t e r m s u r v i v a l of a h u m a n c a r i o g e n i c streptococcus i m p l a n t a t i o n i n m o u t h s i n w h i c h it w a s p r e v i o u s l y absent.

after

Cariogenic

h a m s t e r s t r e p t o c o c c i s u r v i v e d for shorter p e r i o d s . A n o t h e r w a y i n w h i c h the a n t i b i o t i c s h a v e b e e n u s e d t o i n d i c a t e the c a r i o g e n i c i t y of specific b a c t e r i a l types is b y u s i n g t h e m as G u g g e n h e i m et al.

(10)

h a v e d o n e to depress t h e u s u a l o r a l flora to p r o d u c e a

p a r t i a l gnotobiosis so that t h e i n t r o d u c e d test t y p e w i l l f a c e a less c o m p e t i t i v e struggle f o r existence a n d b e c o m e established i n a s i t u a t i o n i n



5.

BIBBY

Antibiotics and Dental Caries

53

which it would not otherwise survive. Using a similar approach, Bowen (I) was able to show that an erythromycin-resistant streptococcus from human teeth could be established i n the mouths of monkeys rendered partially gnotobiotic by administration of erythromycin. A further use for antibiotics i n caries research has been to indicate the importance of bacterial polysaccharides i n the sticky masses or plaques which form on the tooth surfaces of rats and hamsters on a sucrose diet (19). Since tooth destruction occurs under these plaques, agents which w i l l inhibit the streptococci responsible for their formation would have potential importance i n the prevention of caries i n man. Keyes (19) has shown that i n rats and hamsters daily short applications of penicillin, erythromycin, streptomycin, tetracycline, and speramycin are very effective i n preventing plaque formation and subjacent tooth decalcification. Vancomycin was somewhat less so, and neomycin, bacitracin, and thiostrepton without effect. W h i l e caution cannot be too strongly emphasized i n projecting animal findings to conditions i n man, Mitchell and Holmes (30) have demonstrated that frequent applications of vancomycin w i l l prevent the development of one type of plaque deposit in human mouths. In conclusion, a final question has to be faced—that is, whether repeated use i n the mouth of a therapeutic vehicle containing a "safe" antibiotic free of a l l medical hazards would be wise. If it killed a wide spectrum of oral bacterial types, its use would not be without danger because elimination of the predominant bacterial types i n the mouth might allow other organisms, such as fungi, to become established, with possible unfortunate pathological effects. The perfect anticaries antibiotic w i l l need to have preferential antagonism for only those types which are particularly important i n caries causation and no effect on other types. Achieving this goal should not be beyond the possibilities of future research.

Literature Cited (1) (2) (3) (4) (5) (6) (7) (8)

Bowen, W., personal communication, 1968. Brudevold, F., Bibby, B. G., unpublished findings. Brudevold, F., Hawes, R. R.,J.Dental Res. 1952, 31, 474. Falla, W . S., Shaw, J. H . , Arch. Oral Biol. 1965, 10, 537. Fitzgerald, R. J., Jordan, H . J., J. Dental Res. 1955, 34, 685. Fitzgerald, R. J., Keyes, P. H . , Am. J. Pathol. 1963, 42, 7. Fitzgerald, R. J., Keyes, P. H . , J. Am. Dental Assoc. 1960, 61, 9. Fitzgerald, R. J., Zander, H . A., Jordan, H. J., J. Am. Dental Assoc. 1950, 41, 62. (9) Fosdick, L . S., Ludwick, W . E., J. Dental Res. 1950, 29, 664. (10) Guggenheim, B., Konig, K . G., Muhlemann, H. R., Helv. Odont. Acta 1965, 9, 121. (11) Handelman, S. L . , Hawes, R. R., Arch. Oral Biol. 1965, 10, 353.



54

DIETARY C H E M I C A L S VS. D E N T A L CARIES

(12) Handelman, S. L., Hawes, R. R.,J.Oral Therap. Pharmacol. 1964, 1, 23. (13) Handelman, S. L., Mills, J. R., Hawes, R. R., J. Oral Therap. Pharmacol. 1966, 2, 338. (14) Hawes, R. R., Thesis, University of Rochester, Rochester, Ν. Y., 1951. (15) Hill, T. J., Kniesner, A. H . , J. Dental Res. 1948, 27, 267. (16) Hill, T. J., Sims, J., Newman,M.,J.Dental Res. 1953, 32, 448. (17) J. Am. Dental Assoc. 1952, 45, 466. (18) Keyes, P. H . , Arch. Oral Biol. 1960, 1, 304. (19) Keyes, P. H., J. Oral Therap. Pharmacol. 1966, 3, 157. (20) Krasse, B., Edwardsson, S., Svensson, I., Trell, L . , Arch. Oral Biol. 1967, 12, 231. (21) Lind, H . E., Antibiot. Chemotherapy 1954, 4, 161. (22) Lind, H . E., Zander, Η. Α., J. Dental Res. 1950, 29, 667. (23) Law, F . E . , Wallace, D . R., Spitz, G. S., Public Health Rept. 1961, 76, 1094. (24) Lewis, Charles N., M.D., personal communication, 1952. (25) Littleton, N . W., White, C. L., J. Am. Dental Assoc. 1964, 68, 520. (26) Ludwick, W . E . , Fosdick, L. S., Schantz, C. W., J. Am. Dental Assoc. 1951, 43, 285. (27) Mahler, I. R., Manly, R. S.,J.Am. Dental Assoc. 1958, 56, 854. (28) McClure, F . J., Falk, J. E . , Rust, J. D., J. Am. Dental Assoc. 1956, 53, 1. (29) McClure, F. J., Hewitt, W . L., J. Dental Res. 1946, 25, 441. (30) Mitchell, D . F., Holmes, L. Α.,J.Periodont. 1965, 36, 202. (31) Muhlemann, H. R., Meyer, R. W., Konig, K. G., Marthaler, T. M., Helv. Odont. Acta 1961, 5, 18. (32) Pindborg, J. J., Acta Odont. Scand. 1958, 16, 383. (33) Rosen, S., Ragheb, C. Α., Hoppert, C. Α., Hunt, H . R., J. Dental Res. 1956, 35, 399. (34) Shaw, J. H., Sweeney, Ε. Α., J. Dental Res. 1957, 36, 349. (35) Shiere, F. R., J. Dental Res. 1957, 36, 237. (36) Stephan, R. M., Fitzgerald, R. J., McClure, F . J., Harris, M . R., Jordan, H . J., J. Dental Res. 1952, 31, 421. (37) Stephan, R. M., Harris, M . R., Fitzgerald, R. J., J. Dental Res. 1952, 31, 475. (38) Volker, J. F., Apperson, L. D., King, W . J., J. Dental Res. 1955, 34, 733. (39) Walsh, J. P., Smart, R. S., New Zealand Dental J. 1951, 47, 118. (40) Webman, H . , Kniesner, A. H., Hill, T. J., J. Dental Res. 1948, 27, 258. (41) Welsh, H . , Randall, W . Α., Buckman, L . E . , Hendrix, F. D . , Antibiot. Chemotherapy 1952, 2, 249. (42) White, B. J., Kniesner, A . H . , Hill, T. J., J. Dental Res. 1949, 28, 267. (43) Zander, Η. Α., J. Am. Dental Assoc. 1950, 40, 569. (44) Zander, Η. Α., Bibby, B. G., J. Dental Res. 1947, 26, 365. (45) Zander, Η. Α., Lisanti, V . F., Shiere, F . R., J. Dental Res. 1951, 30, 139. RECEIVED October 27, 1969.


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