Adverse Drug Interactions 2

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236 J ADA, Vol. 130, February 1999

This a rt icle, focusing on ant ibiotics, is the sec-

ond in a five-par t series discussing th e clinicalsignificance of reported drug interactions as they

relate t o dentistr y. While there are numerous an-

tibiotic prepara tions ava ilable for the trea tment

of loca lized an d syst emic infections, relat ively few

a ntibiotic prepa ra tions a re routinely employed in

dentistry (Box, Antibiotics Commonly Used in

Dentistr y). This factor a lone limits the qua ntity

of adverse drug intera ctions seen wit h a ntibiotics

in our profession.

How ever, ant ibiotics a re prescribed for longer

durat ions tha n a re other a gents rout inely a dmin-

istered in dentistry. F or exam ple, local a nesthet-

ics a nd sedat ives usua lly are given in a singlecourse of thera py,1 whereas in most pat ients ana l-

gesics are ta ken for a few da ys on a n a s-needed

ba sis. The typica l a nt ibiotic regimen for an odon-

togenic infection is of a five- to 10-da y d ura tion on

an around-the-clock schedule. This more chronic

dosing sets th e sta ge for some rat her serious a nd

potentia lly life-threa tening dr ug int eractions in-

volving an timicrobial a gents (such as erythro-

mycin, cla rithromycin, ketocona zole a nd itra cona -

zole), wh ich inhibit t he gut w all a nd liver

cytochrome P -450 system w ith a host of oth er

A B S T R A C T

ADVERSE DRUG INTERACTIONS IN DENTAL PRACTICE:INTERACTIONS INVOLVING ANTIBIOTICSPART II OF A SERIES

ELLIOT V. HERSH, D.M.D., M.S., PH.D.

Background. The prudent use of a ntibiotics

is an integral part of dental practice. While these

agents genera lly are considered safe in t he dental set-

ting, their use can result in intera ctions tha t can lead

to serious morbidity in dental patients.

Methods. The faculty of a sym posium entit led

Adverse Drug Intera ctions in D entistry : Separa ting

the Myths From the Facts did an extensive li tera-

tur e review on drug int eractions. Through th is, they

were able to establish a significance rating of alleged

adverse drug interactions a s they relate t o dentistry ,

based on their scientific documenta tion an d severity

of effect. The a uth or of this a rt icle focused on a ntibi-

otics.

Results. Most of th e reported drug int eractions

discussed in this a rticle ar e well-documented by clini-

cal studies. I t is particularly important tha t dentists

be aware of the potentially serious and life-threaten-

ing interactions of the antibiotics erythromycin, clar-

ithromycin and metronidazole, a nd of the ant ifungal

agents ketoconazole and itraconazole, with a host of

other drugs whose metabolism is impaired by these

ant imicrobial a gents. In contra st, th e alleged a bility

of commonly employed antibiotics to reduce the effec-

tiveness of oral contraceptive agents is not adequate-

ly supported by clinical resear ch. It s till is recom-

mended, however, tha t clinician s discuss this possible

interaction w ith their pat ients , as i t might represent

a relatively rare event tha t cannot be discerned in

clinical trials.

Conclusions. P otentia lly serious a dverse

drug interactions can occur between antimicrobial

agents used in denta l practice and other drugs pa -

tients are taking for a variety of medical conditions.

Clinical Implications. I t is importa nt

tha t dentists sta y abreast of potential drug intera c-

tions involving an tibiotics to avoid serious morbidity

am ong their patients .

JA D A

T INU

ING E DU

CAT

I

O

N

ARTICLE 4

Copyright 1998-2001 American Dental Association. All rights reserved.


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drugs that use the same

meta bolic pat hw a y. The a bility of

certain an timicrobial agents to

increase blood levels of other

drugs wit h low t hera peutic in-

dexes is, in fact, t he cause of themost potentially hazardous inter-

a ctions discussed in this a rticle.

The purpose of this a rt icle

a nd t he oth ers in this series is

not simply to list a nd discuss

th e theoretica l basis of pub-

lished adverse drug int erac-

tions. Our ma jor goa l is to ex-

plore the scient ific documen-

ta tion an d the seriousness of

each interaction a s i t relates to

th e pra ctice of dent istry. Ma nyof the interactions th at wil l be

presented in this article are

supported by a n a bunda nce of

scientific dat a . For example,

th ere ar e numerous w ell-de-

signed phar ma cokinetic stu dies

tha t ha ve demonstrat ed clear ly

tha t t he s imulta neous ingestion

of a gents cont a ining divalent or

tr ivalent cations an d tetra cy-

cline ant ibiotics greatly impa ir

th e absorption of this cla ss ofantibiotic agents. On the other

ha nd, a l though case reports

ha ve implicat ed the administra -

tion of penicillins, tetracyclines

a nd other a nt ibiotics used in

dentistry with reduced systemic

absorption and ultimat e fai lure

of ora l contra ceptive agent s,

well-controlled clinical trials

ha ve fai led to demonstrat e this

interaction.

THE SIGNIFICANCERATING SCALE

The significa nce ra ting scale

tha t is a ssigned to each drug in-

teraction with in this ar t icle was

present ed in detail in th e first

a rticle of th is series 1 and is

summa rized in Ta ble 1.

Although a dverse drug int erac-

tions assigned a ra ting of 1 or 2

clea rly sh ould be of concern t o

the practicing dentist, those

given a r a ting of 4 should not be

dismissed completely. A rating

of 4 typically implies th at a few

published report s ha ve suggest-ed an int eraction th at is of

ma jor or moderat e severity, but

th a t scient ific document a tion ei-

th er is lacking or does not sup-

port a n intera ction. Further re-

search is n eeded t o eith er

further establish or refute t he

interaction.

Ta ble 2 summar izes the spe-

cific interactions that are asso-

ciated w ith a ntibiotic therapy in

dentist ry a nd provides the sig-nifican ce ra ting for each.

BACTERICIDALANTIBIOTICS WITHBACTERIOSTATICANTIBIOTICS

Most tea chers of pha rma cology

to predoctoral a nd postgra duat e

dental s t udents preach the cen-

tra l dogma t ha t bacter icidal an-

tibiotics should n ever be com-

bined w ith ba cter iosta tic

J ADA, Vol. 130, February 1999 237

PHARMACOLOGY

Trade Name*

P en-Vee K

Amoxil

Keflex

Duricef

Flagyl

Generic Name

Erythromycin

Cla rithromycin

Azithromycin

Clindam ycin

Tetr a cycline

Doxycycline

Trade Name

Eryc

Biaxin

Zithr oma x

C leocin

Achromycin

Vibra mycin

* The tra de-nam ed bactericidal ant ibiotics are listed only as examples. Manufa cturers are a sfollows: P en-Vee K, Wyeth-Ayerst Labora tories; Amoxil, Smit hKline B eecham ConsumerHealth Care; Keflex, Dista Products and Eli Lilly and Company; Duricef, Bristol-MyersSquibb Company; Flagyl , G .D. Sear le and Company.

The tra de-nam ed bacteriosta tic ant ibiotics are listed only as examples. Manufa cturers areas follows: Eryc, Warn er Chilcott Labora tories; Biaxin, Abbott Laborat ories; Zithromax,Pfizer Incorporated Consumer Health Care Group; Cleocin, Pharmacia and UpjohnCompany; Achromycin, Lederle Laborat ories; Vibramycin, P fizer Incorporated C onsumerHealth Ca re Group.

ANTIBIOTICS COMMONLY USED IN DENTISTRY.

a nt ibiotics (Box, Antibiotics

Commonly U sed in D entis try),

because the lat ter wil l anta go-

nize the a ction of the former. In

reality, there are relatively fewwell-a uth enticat ed clinical ex-

a mples of th is phenomenon.2

In pa tient s with pn eumococ-

cal meningitis, penicillin pro-

duced significa nt ly higher re-

covery rat es and fewer

mortal i t ies when used a lone

tha n w hen combined with a

tetra cycline to treat the same

infection.3,4 A higher ra te of

spont a neous reinfection a lso

ha s been report ed in pat ientswith scar let fever w ho were

treat ed with a penicil lin-tetra -

cycline combina tion th a n in

th ose receiving only penicillin.2

In oth er studies involving scar-

let fever, combined penicillin

an d erythromycin thera py was

slightly less effective tha n

monothera py wit h penicillin,5

an d ant agonism between these

tw o ant ibiotics has been demon-

Generic Name

P enicillin V

Amoxicillin

Cepha lexin

Cefa droxil

Metronida zole

BACTERICIDAL BACTERIOSTATIC



3/16

stra ted in vitro.6

There a re several inst a nces,however, in which bacteriostatic

a nt ibiotics ha ve been su ccess-

fully combined wit h ba ctericidal

a nt ibiotics to prevent t he emer-

gence of resista nt stra ins. Ta ke,

for example, the t riple a nt ibiot-

ic combinat ion of bismuth sub-

sa licyla te (P epto-B ismol,

P rocter & G a mble), tet ra cycline

(a st a tic ant ibiotic) a nd metro-

nida zole (a cida l a nt ibiotic),

wh ich ha s been w idely em-ployed for th e eradicat ion of

H eli cobacter pyloriin pat ients

with gast rointestinal ulcers .7

In dent a l medicine, there is

no ra tiona le for combining ba c-

teriostatic antibiotics with bac-

tericidal ant ibiotics to trea t

odont ogenic infections. These

combina tions a re likely to lead

to great er toxicity tha n tha t of

s ingle-drug t herapy a nd, a t

least w ith penicillins, a diminu-tion of antibiotic effectiveness.

TETRACYCLINES WITHPRODUCTS CONTAININGDIVALENT ANDTRIVALENT CATIONS

The a bility of divalent a nd

triva lent cations such as calci-

u m + + , m agnes iu m + + , bi s-

m u t h+ + , ir on + + , zin c+ + a n d

a luminum+ + (found in da iry

products , a nta cids and vitamin

prepara tions) to mar kedly im-

pair the absorption of tetracy-cline molecules from the gas-

trointestinal tr act is probably

the adverse drug interaction

most widely known among den-

ta l clinicia ns. These intera c-

tions a re well-document ed an d

established through numerous

case reports and well-controlled

clinical studies. 8-15

While the individual tet ra cy-

cline moieties differ with re-

spect to certain cations (for ex-ample, doxycycline and

minocycline a re not a ffected a s

much as oth er tetra cycline moi-

eties with respect t o calcium+ +

and z inc+ + 10,11,15), reduct ions in

serum tet ra cycline concentra -

tions of 20 to 100 percent in t he

presence of these cations often

are so large tha t a ntibiotic lev-

els ca n fa ll below t hose needed

to inhibit bacterial growth).2

The significance rating of 2given to this int eraction reflects

a likely increa se in pa tient m or-

bidity. The simulta neous inges-

tion of tetracycline molecules

a nd mult ica tionic products

should be a voided a bsolutely.

METRONIDAZOLE WITHALCOHOL, LITHIUM

Metronidazole with alcohol.Metronidazole, like disulfira m

(Ant a buse, Wyet h-Ayerst

La bora tories), ha s been shown

in the laboratory to inhibit t he

activity of acetaldehyde dehy-

drogenase, theoretically ca using

an accumulation of acetalde-hyde in patients w ho ingest a l-

cohol concomitantly.16 The clini-

cal a bility of metronida zole to

produce disulfiramlike reac-

tions in alcohol consumers

(Table 2) is supported by sever-

a l s tud ies tha t ha ve shown a n

incidence rang ing from 2 per-

cent to 100 percent of the study

population.2,17-19 While th e rea c-

tion norma lly is more unpleas-

ant and f r ightening than i t i sserious, pat ients should be ad-

vised not t o consume a lcohol

during metronidazole therapy

an d for at least t hree days a f-

terward .20

Metronidazole with lithi-um. Lithium, a monovalentcation, is indicated for th e treat -

ment of bipolar (ma nic-depres-

sive) disorder, most frequently

during the ma nic phase. I t is

given un der close supervisionwith regular monitor ing of

blood concentrations because of

its low th erapeutic index.

Thera peutic blood levels a re in

th e ra nge of 0.8 to 1.5 mil-

liequiva lent per liter during a n

acute man ic at ta ck an d 0.6 to

1.2 mE q/L for ma int ena nce

therapy .2,21 Ea rly signs of lith i-

um int oxica tion can occur at

blood concentrations that are

just a bove thera peutic (in th e1.5-2 mE q/L ra nge) a nd include

letha rgy, muscle weakness and

fine ha nd t remors. More serious

toxicity consistin g of confusion,

nys tagmus and a t axia t yp ica l ly

a re seen at lithium blood con-

centra tions of 2.0 to 2.5 mE q/L.

Life-threatening toxicity (con-

sisting of seizures, coma a nd

circula tory collapse) can occur

with l i thium concentra tions

238 J ADA, Vol . 130, February 1999

PHARMACOLOGY

TABLE 1

1

2

3

4

5

Ma jor

Moderate

Minor

Ma jor or modera te

Minor

All

Est a blished, proba-

ble or suspected


ble or suspected


ble or suspected

P ossible

P ossible

U nlikely

SIGNIFICANCERATING

SEVERITY RATING DOCUMENTATIONRATING

THE DRUG INTERACTION SIGNIFICANCE RATING SCALE.



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a bove 2.5 mE q/L.2 In a ddition,

elevated blood lithium concen-

tra tions can lead to renal dys-

function, often in th e form of

nephrogenic diabetes insipidus,

result ing in excessive excretion

of dilute urine.2,21

Three cas es ha ve been re-

ported in th e litera tur e in wh ich

the a dministra tion of metro-

nida zole for one w eek (500-

1,000 milligra ms da ily) a ppar-

ently induced elevat ions in

lithium blood concentra tions

wit h concomita nt t oxicity. 22,23 In


PHARMACOLOGY

TABLE 2

2

2

2

1

4

1

4

1

Theoretically, ba ctericida l dru gs w ork best

wh en microbes ar e a ctively grow ing. B y inhibit-ing cell growt h, bacteriosta tic agents ma y a n-

ta gonize th e ba ctericida l agent . This intera ction

is not consistent ly demonstra ted clinically.

Tetra cycline molecules chelat e diva lent a nd

triva lent cations, impa iring a ntibiotic a bsorp-tion. In a ddition, ant a cids ca n ra ise the gas-

trointestinal pH, a lso impairing a bsorption.

Serum tet ra cycline levels ca n be reduced 20 to

100 percent, lea ding t o poor a nt ibiot ic effica cy.

Metronida zole produces a disulfiram effect by

inhibiting the enzyme a ceta ldehyde dehydroge-

na se. Aceta ldehyde a ccumulat ion can lea d t o fa-cia l f lushing, hea da che, pa lpita tion and n a usea.

Metronida zole inhibits t he rena l excretion of

lithium, lea ding t o elevat ed lithium blood con-

cent ra tions. Lithium toxicitya s ma nifested byconfusion, at a xia a nd kidney da ma geca n re-

sult.

Metronida zole inhibits t he rena l excretion of

lithium, lea ding t o elevat ed lithium blood con-

cent ra tions. Lithium toxicitya s manifestedby confusion, a ta xia a nd kidney da ma geca n

result. A single ca se report describes eleva ted

lithium blood concent ra tions a nd lithiumtoxicity wit h concomita nt tetra cycline a dminis-

trat ion.25 Anoth er report 26 a nd a clinica l re-

search study27 do not support th e int era ction.

These an tibiotics can reduce the gut flora , in

particular Eubacteri um lentum , wh ich meta bo-lize a significa nt a mount of ora l digoxin in 10

percent of pat ients ta king the drug. E levat ed

concent ra tions of digoxin can occur in such pa -tients, leading to digita lis toxicity, a s ma nifest-

ed by saliva tion, visua l disturba nces and a r-

rhythmias .

B road -spectr um a nt ibiotics are hypothesized to

reduce the gut f lora tha t normally synth esize vi-ta min K, a necessar y cofa ctor for clott ing. Since

war far in s an d a nisindiones anticoagulant

mecha nism involves a n a nta gonism of vita minK-dependent clotting fa ctors, an increa sed risk

of bleeding ma y occur. Int era ction a ppea rs sig-

nifica nt only in pat ients w ith poor vita min K in-

take.

These a nt ibiotics decrease t he met a bolism of

wa rfar in and a nisindione and ca n significa ntlyincrease prothr ombin times an d increa se th e

risk of serious bleeding in a nt icoagula ted pa -

tient s. Signs of th is adverse intera ction includehemat uria, bruising and hemat oma format ion.

POSSIBLE DRUGINTERACTION

SIGNIFICANCERATING

MECHANISM AND CLINICAL PRESENTATION

ADVERSE DRUG INTERACTIONS IN DENTISTRY: ANTIBIOTICS.

Bactericidal antibiotics withbacteriostatic antibiotics

Tetracyclines with productsthat contain divalent ortrivalent cations

Metronidazole with alcohol

Metronidazole with lithium

Tetracyclines with lithium

Erythromycin or tetracy-clines with digoxin

Tetracyclines or otherbroad-spectrum antibioticswith warfarin or anisindione

Erythromycin, cla-rithromycin or metronida-zole with warfarin oranisindione

cont i nu ed on page 240



5/16

one woman, lithium blood con-

cent ra tions increased from 1.3

mE q/L t o 1.9 mEq /L. S he d evel-

oped signs (such as a ta xia, men-

ta l clouding a nd muscle wea k-

ness) of lithium toxicity.22 In

another woman, lithium blood

concentra tions were elevat ed to

a lesser d egree (from 1.1 mE q/L

t o 1.3 mE q/L), but s he devel-

oped persistent polyuria a nd

noctur ia, indica tive of kidney

damage.23 In a third female pa-

tient , lithium blood concent ra -

tions increased dra mat ically

from 0.9 mE q/L to 2.0 m E q/L.

She wa s admitt ed to the hospi-

ta l beca use of severe confusion


PHARMACOLOGY

TABLE 2 CONTINUED

Erythromycin, clarithro-mycin, ketoconazole or itra-conazole with a host ofother drugs that are metab-olized by the CYP3A4 andCYP1A2 system in the gutwall and liver

Astemizole, terfenadineor cisapride

Alfentanil

Bromocriptine

Carbamazepine

Cyclosporine

Felodipine and possiblyother calcium-channelblockers

Methylprednisolone orprednisone

Theophylline

Lovastatin and possiblyother -statins

Triazolam or oralmidazolam

Disopyramide

Penicillins, cephalosporins,erythromycin, cla-rithromycin, tetracyclines,metronidazole with com-bined estrogen and pro-gestin oral contraceptives

Depends on

interacting

dr ug (seebelow )

1

1

1

1

1

1

1

1

1

2

4

4

These an timicrobia l a gents block the

meta bolism a nd th us increase blood levels of a

number of drugs. Severity of th e reactiondepends on th e thera peut ic index of the int er-

a cting drug.

Life-thr eatening ventricula r a rrhyt hmias (tor-sa des de point es). Metr onidazole also increases

cisapr ide blood levels.

En ha nced a nd/or prolonged respirat ory d epres-

sion. Ketocona zole not implicat ed.

Increa sed risk of ad verse centr a l nervous sys-

tem effects, dyskinesias a nd hy potension.

Increa sed risk of a ta xia, vertigo, drowsiness a nd

confusion. Ca rdia c arr est report ed in one child

ta king eryt hromycin.68

En ha nced immunosuppression and nephro-

toxicity.

Increa sed risk of hypotension, t a chycardia a nd

edema .

Increa sed risk of Cushing s syndrome a nd

immunosuppression.

Increa sed risk of ta chyca rdia, cardia c a rrhyt h-

mia s, tremors a nd seizures. Ketoconazole not

implicat ed in this intera ction.

Muscle pa in a nd rh a bdomyolysis (skeleta l mus-cle lysis). P ha rma cokinetic int era ction demon-

stra ted for a zole a ntifungal drugs.

Ma rked increa ses in blood levels of both benzo-

diazepines when t a ken by mouth, lea ding to in-

creases in seda tive depth a nd dura tion.

A few clinica l reports of a rrh yt hmia s or hea rt

block with concurrent eryt hromycin use.Definitive pha rma cokinetic stu dies are needed.

Spora dic ca se report s ha ve implica ted t he con-comita nt ingest ion of a nt ibiotics an d oral con-

tra ceptives wit h unw a nted pregnancies. It is

theorized tha t a ntibiotics, by decimat ing thenormal gut f lora, can int erfere with the entero-

hepa t ic recycling of th e estrogen component of

oral cont ra ceptives, th ereby lead ing to subth era -peutic blood levels an d ovula t ion. With th e ex-

ception of the a nt ituberculosis drug rifa mpin,

clinica l studies ha ve failed t o demonstra te a n

interaction.

POSSIBLE DRUG

INTERACTION

SIGNIFICANCE

RATING

MECHANISM AND CLINICAL PRESENTATION

ADVERSE DRUG INTERACTIONS IN DENTISTRY: ANTIBIOTICS.



6/16

and ataxia. She also developed

hypernatremia and abnormally

dilute urine, consistent w ith a

diagn osis of nephrogenic dia-

betes insipidus, conditions t ha t

persisted for six mont hs.23

While a more definit ive clini-

cal trial exploring the likelihood

of the metronida zole-lithium in-

tera ction ha s not been per-

formed, t hese thr ee ca se reports

a re well-document ed wit h sup-

porting pharma cokinetic data .

A significa nce rat ing of 1 is as-

signed to this a dverse drug in-

tera ction because th e documen-

ta t ion ind ica t es tha t the

interaction is at least suspectedand the severity of the interac-

tion is major. P ra ctitioners

should avoid th e use of metro-

nida zole in pat ients receiving

li thium therapy.

TETRACYCLINESWITH LITHIUM

A wa rning to completely avoid

the concomitan t administra tion

of tetracycline with lithium also

exists in the literature.24

I tstems from a single ca se report

of a 30-year-old woman whose

lithium blood levels ha d ra nged

fr om 0.50 mE q/L t o 0.84 mE q/L

over a three-year period.25 After

a one-week course of tetracy-

cline hydrochloride (250 mg

th ree times per da y), her lithi-

um blood concentra tion in-

creased t o 2.74 mE q/L. S he a lso

developed clinica l signs of lit hi-

um t oxicity: dr owsiness, slurredspeech, fine han d tremors a nd

thirs t .25 However , another a u-

thor ha s reported using th ese

drugs in combina tion in his pa-

tient populat ion w ith n o ob-

served a dverse drug int erac-

tions.26 A clinica l tr ia l in 14

healthy volunteers demonstra t-

ed tha t lith ium blood levels ac-

tua lly decreased slight ly (from

0.51 t o 0.47 mEq /L) aft er t he

a ddition of tetra cycline (1 gram

per da y) for one week.27

While th e severity of th is po-

tentia l a dverse drug int eraction

is severe, its scient ific documen-

ta tion puts i t a t most in thepossible category. We there-

fore assign it a significa nce ra t-

ing of 4.

ERYTHROMYCIN,CLARITHROMYCIN ORTETRACYCLINES WITHDIGOXIN

Digoxin (La noxin, Gla xo

Wellcome In c.) a nd digit oxin

(Cry stodigin, Eli Lilly a nd

Compan y) a re cardia c glyco-

sides indica ted for th e treat -ment of congestive hea rt fa ilure

an d certain ty pes of a tr ia l ar-

rhyt hmia s. They both ha ve low

th erapeut ic indexes, so th a t sig-

nif icant cha nges in their plasma

levels a re likely t o lea d t o se-

vere reactions.1 In a ddition, pa-

tients who are ta king these

agents a re more fragile t h a n

relat ively healthy denta l pa-

tient s beca use of their cardia c

disease.

Digoxin is fa irly w ell-a b-

sorbed (a bout 75 percent) aft er

oral administrat ion.

28

However,a bout 10 percent of people ha r-

bor enteric bacter ia tha t ina cti-

vat e digoxin in t he gut, great ly

reducing t he drug s bioa vaila bil-

i ty and necessitat ing that t hey

receive great er tha n a verage

ma int ena nce doses (Ta ble 2).2

In t hese patients , the a dminis-

tration of certain antibiotics can

decima te th e ent eric bacteria ,

leading to a ma rked rise in

serum digoxin levels.28,29 A dou-

bling of serum digoxin levels

a nd signs of digitalis t oxicity

ha ve been reported in pa tient s

ta king erythromycin s imultan e-

ously for t hree to six day s.29-31 A30 percent rise in ser um dig oxin

levels an d a fall in digoxin

meta bolites ha ve been reported

with s imulta neous t etracycline

administration. 29,32

Although these case reports

do not represent well-cont rolled

clinical st udies, they ar e, in fact,

supported by some rather con-

vincing pha rma cokinetic dat a. A

significance rat ing of 1 is thus

a ssigned to this a dverse drug in-teraction because the documen-

ta tion indicat es that the interac-

tion is at least suspected a nd

th e clinical outcome of digita lis

toxicity is q uite serious an d po-

tent ially life-thr eat ening.

TETRACYCLINES OROTHER BROAD-SPEC-TRUM ANTIBIOTICS WITHORAL ANTICOAGULANTS

P robably the la rgest number of

reported drug int eractions in-volve the oral a nticoagula nts

wa rfar in, dicumar ol and a nisin-

dione. These competitive antag-

onists of vita min K -dependent

clotting factors have a low ther-

apeutic index; administration of

other drugs tha t can increase

these antagonists activity can

lead to serious a nd potentia lly

life-th reat ening bleeding.2

Several a nt ibiotics routin ely

used in dent istry ha ve been im-plica ted in producing t his effect.

I t ha s been hypothesized tha t

broad-spectru m a nt ibiotics su ch

a s tetr a cyclines, a moxicillin and

ampicillin can reduce endoge-

nous vitam in K levels and en-

ha nce the effects of ora l a nt ico-

agula nts by decimat ing the

normal gut f lora tha t produce

vita min K.

There ha ve been severa l case


PHARMACOLOGY

Pract i t ioners sho uld

avoid the use of

metronid azole in

pat ients receiv ing

l i thium therapy.



7/16

reports of increased proth rom-

bin times an d bleeding in pa-

tients taking anticoagulant s and

a variety of tetra cyclines.2,33-35

However, one study demonstra t-

ed tha t t etra cycline had no ef-fect on proth rombin times in a

group of pat ients receiving

chronic warfarin therapy.36 Cas e

reports implica tin g a moxicillin

or ampicillin with enha nced an -

ticoagulant activity also have

a ppea red in the literat ure.2,37

Int erestingly, th ere ha s been at

least one report demonstra ting

tha t a moxicillin slightly lowered

prothr ombin t imes in five pa -

tients .2 I t a ppears tha t th e abili-ty of these ant ibiotics t o en-

han ce an ticoagulant activity is

relatively rare and unpre-

dicta ble, and t ha t it is of most

concern in patients whose di-

etary inta ke of vita min K is

poor.38,39 Concurrent use of these

a ntibiotics wit h oral ant icoagu-

lants (in pat ients w ith normal

vita min K int a ke) need not be

a voided, but pa tients n eed t o be

monitored for signs (such a sbruising, melena , bleeding) of

increased anticoagulant activity.

ERYTHROMYCIN,CLARITHROMYCIN ORMETRONIDAZOLE WITHORAL ANTICOAGULANTS

A marked increase in t he effects

of wa rfar in wit h bleeding ha s

been reported in some pat ients

simulta neously ta king a five- to

eight-day course of erythro-

mycin,

2,30,35,40-45

clarithromycin

2

ormetronidazole.2,46 The r esult s of

a pharmacokinetic study re-

vealed tha t, in some volunteers,

th e ingestion of erythromycin (1

g per day for eight da ys), result-

ed in a 30 percent reduction of

wa rfar in cleara nce.47 Another

clinical investiga tion demon-

strated that metronidazole (750

mg da ily for one w eek) increased

the ha lf-life of wa rfarin by a l-

most one-th ird an d virtua lly

doubled the a nticoagu lant effect

of th e more a ctive (S-) isomer of

war far in .48 While the enha nce-

ment of anticoagulant activity

a ppears in only some people,this potent ially serious int erac-

tion is supported by pharma -

cokinetic da ta . A full course of

thera py with t hese an tibiotics in

a pa tient receiving ant icoagula-

tion thera py requires consulta-

tion w ith the pat ient s physician

before being initiated.49 Warfar-

in is just one of ma ny dr ugs

wh ose meta bolism ca n be inhib-

ited by ant imicrobial a gents

th a t block the cytochrome P -450system.50,51

ERYTHROMYCIN,CLARITHROMYCIN,KETOCONAZOLE ORITRACONAZOLE WITH AHOST OF OTHER DRUGS

The cyt ochrome P -450 sy st em

consists of a large set of similar

enzymes (isoenzymes) th a t a re

responsible for metabolizing a

wide ra nge of drugs.50,51 The

CYP3A4 isoenzyme accounts for60 percent of th e cytochrome

enzymes in t he liver and 70 per-

cent of those in th e enterocyt es

found in th e gut w all .51

Erythromycin, clarithromycin,

ketoconazole (Nizoral, J a nssen

P ha rmaceutica Inc.) an d i tra-

cona zole (Sporan ox, J an ssen

P ha rmaceutica Inc.) are potent

inhibitors of CYP 3A4 and t hus

can significa nt ly increase blood

concentra tions a nd t oxicity ofother drugs tha t use this sys-

tem for detoxification.

The toxicity that one encoun-

ters w ith t hese intera ctions is

simply an extension of the in-

teracting drugs pha rma cologi-

cal effects, a s if an overdose of

the interacting agent h ad been

a dministered. For example, ery-

thromycin or ketoconazole,

when t aken concomitan tly w ith

the nonsedat ing antihis ta mines

terfena dine or a stemizole, ca n

indu ce prolonga tion of th e Q-T

interva l on th e electroca rdio-

gram an d a l ife-threa tening

form of ventr icular arrh ythmia sknown a s torsades de pointes.

These effects are identical to

wha t one would see with a n

overdose of t hese nonsedat ing

antihis tamines. 52,53

The inh ibition of other cy-

tochrome isoenzymes such a s

CYP 1A2 account s for eryt hro-

mycin s abil i ty to greatly en-

hance theophylline blood con-

centrations and toxicity.51 In

a ddition to case report s, all ofthe int eractions a ssigned a s ig-

nifican ce ra tin g of 1 or 2 in

Ta ble 2 a re supported by pha r-

ma cokinetic data consisting of

increased half-lives or plasma

concentra tions of the intera ct-

ing drug.2,50,51,54-94 In some in-

stances, the actual adverse

phar ma codyna mic events pub-

lished in case report s ha ve been

reproduced in clinical st udies.

Typically, t he C YP 3A4 inhibitorhas to be ta ken for a t least t hree

to five days before th e intera c-

tion occurs, although t here ha ve

been reports of exposure t imes

a s short a s one day. Concom-

ita nt u se of these ant imicrobial

drugs with t he interacting drug

should be a voided.

Terfenadine and astemi-zole. The int eraction of th isty pe th a t ha s received the most

at tention over the last s ix yearsinvolves the nonsedating anti-

histam ines ter fenadine

(Seldan e, Hoescht Mar ion

Roussel) and a stemizole

(Hismanal , J annsen

P ha rmaceutica Inc.).2,54-59

Terfenadine is actu a lly a pro-

drug; tha t is , the parent com-

pound undergoes almost com-

plete m eta bolism by CYP 3A4 in

the gut a nd l iver to an a ctive


PHARMACOLOGY



8/16

a cid met a bolite fexofenadine

(Allegra, Hoescht Marion

Roussel), a s shown in Figur e 1.

In fact , i t is highly unusual t o

detect a ny t er fenadine in the

bloodstream of a patient w hoha s ingested the drug.54,58 The

a ctive meta bolite fexofenadine

provides the desired ant ihis-

taminic action.50,51,54 The parent

compound t erfenadine is poten-

tia lly ca rdiotoxic, an d if its

meta bolism by C YP 3A4 is im-

paired, terfenadine can accumu-

late in t he body a nd result in

serious cardiac toxicity, includ-

ing t orsades de pointes.54,55,58,59

Like terfenadine, a stemizolea lso undergoes extensive first-

pass met a bolism by CYP 3A4,

and i t a ppears tha t the parent

astemizole molecule also is car-

diotoxic.51,58 A num ber of well-

cont rolled stu dies ha ve demon-

strated that erythromycin,

clar i thromycin a nd t he a zole

antifungal drugs ketoconazole

and itraconazole cause an accu-

mulat ion of both the parent ter-

fenadine molecule and its a ctivemeta bolite fexofenadine in

healthy volunteers.2,54,55,58,59 In

a ddition, electrocardiographic

cha nges (prolonged Q-T int er-

vals) ha ve been det ected in

some of th e study populat ion.54,59

As terfena dine is the car-

diotoxic entit y, it h a s been re-

moved from t he mar ket a nd re-

placed by fexofenadine, its

noncardiotoxic active met a bo-

lite. Like fexofenadine, lorat a -dine (Cla ritin, Schering

Corpora tion) does not a ppear to

be ca rdiotoxic a nd a ppear s to be

free of this a dverse drug inter-

action with erythromycin, clar-

ithromycin or ketoconazole.51,95

I t a lso appears tha t the relat ed

ma crolide a nt ibiotic azith ro-

mycin does not int eract w ith

terfena dine or a stemizole.50,51,55

Cisapride with CYP3A4

inhibitors.Although t he inter-actions with nonsedating an ti-

histamines a re fa ir ly well-

known a mong dental

practit ioners, serious a nd po-

tentia l ly fa ta l ventr icular a r-

rhyth mias , including torsades

de pointes, a lso have been re-ported in pat ients concomita nt -

ly ta king cisa pride (P ropulsid,

J anssen P harma ceut ica Inc. )

a nd inhibitors of CYP 3A4 (in-

cluding a zole ant i fungal a gents ,

eryth romycin, clarith romycin

a nd met ronidazole).50,51,60-62,96

Cisa pride is a w idely prescribed

gastrointestinal prokinetic

agent, indicat ed for th e treat-

ment of gast roesopha geal reflux

disease. As wit h th e nonsedat -

ing an tihis tam ine interactions,

deaths ha ve been a tt r ibuted to

this interaction.51,60 Studies in

healthy volunteers have demon-

stra ted substant ial increases in

cisapride blood concentrations

a nd prolonga tion of th e Q-T in-terva l on t he electroca rdiogram

wh en cisapride an d ketocona-

zole were ta ken concomita nt ly.62

As w ith a stemizole and ter fena -

dine, the significance ra ting a s-

signed to the intera ction be-

tw een cisapride and th e

a nt imicrobia l agent s in Ta ble 2

is 1.

Triazolam with midazo-lam. Other adverse drug inter-


PHARMACOLOGY

HO-C

HO-C

N-CH2CH2CH2CH C-CH3

CH3

CH3OH

N-CH2CH2CH2CH C-COOH

CH3

CH3OH

Terfenadine

Fexofenadine

Figure 1. Conversion of potentially cardiotoxic terfenadine to fexofena-

dine by CYP3A4. Erythromycin, clarithromycin, ketoconazole and itra-

conazole block this process.



9/16

a ctions involving these an timi-

crobial inhibitors of the cy-

tochrome P-450 system are

summ a rized in Table 2. They

a ll involve the a ccumula tion of

th e int eracting drug . The ad-

verse drug interactions w ith t he

oral a ntia nxiety-sedat ive agents

tr iazolam and midazolam areespecia lly relevant to denta l

practit ioners wh o use ora l seda -

tion techniques. In one ca se re-

port, an 8-year-old child who

wa s premedicat ed with oral m i-

da zola m lost consciousness du r-

ing an eryth romycin infusion.89

His peak midazolam concentra-

tions were double the norma l

values. The child aw a kened

spont a neously 45 minut es later.

In a placebo-controlled studyof 12 health y volunteers, eryt h-

romycin (500 mg t hree t imes a

da y for six days) increased peak

blood levels of a single d ose of

oral midazolam almost th ree-

fold.90 In addition, drowsiness

a nd other indicat ors of psy-

chomotor impa irment w ere far

more intense in subjects ta king

eryth romycin compar ed to a

pla cebo. The effects of ery th -

romycin on blood levels an d

sedat ive effects of intr a venous

mida zola m w ere fa r less pro-

found.90 Another st udy found

th a t even a single 750-mg dose

of eryt hromycin increased t he

sedative effects of a single 10-

mg ora l dose of midazolam. 91

A study of 16 health y sub-jects found th a t 333 mg of

eryth romycin da ily for th ree

da ys decreased t he cleara nce of

a single 0.5 mg dose of triazo-

lam by a bout h alf , and a pproxi-

ma tely doubled tota l tr ia zolam

blood levels (levels in t he a rea

under t he concentra tion

curve).92 Azithromycin seems

free of intera ctions wit h mida -

zolam or t r iazolam .97 Clinical

s tudies have revealed th at keto-cona zole and itr a cona zole have

even more dram a tic effects on

th ese seda tive hypnotics, in-

crea sing t otal blood concent ra -

tions of oral m idazolam an d tr i-

azolam 15- and 27-fold,

respectively, and peak blood

levels three- to fourfold. Intense

a nd prolonged (a s long as 17

hours) psychomotor impa irment

a ccompanied these pha rma coki-

netic cha nges.93,94

Fortunat ely , when ta ken by

mouth, benzodiazepines such a s

midazolam a nd tr iazolam ha ve

enormous t hera peutic indexes

wh en compa red to other cla ssesof antianxiety-sedative drugs.

Overdoses of almost 70-fold

ha ve not resulted in fat al i t ies .98

Thus, t he int eraction betw een

ma crolide ant ibiotics or a zole

an tifungal drugs and midazo-

lam or t r iazolam is given a s ig-

nifica nce rat ing of 2. Overseda -

tion with prolonged and intense

psychomotor impairment is a

likely, alt hough not life-th reat -

ening, outcome.

ANTIBIOTICS WITH ORALCONTRACEPTIVES

Among t he most cont entiously

debat ed adverse drug interac-

tions is the a lleged ability of a

variety of commonly prescribed

a nt ibiotics to reduce blood con-

centra tions and t he ultimate ef-

fectiveness of oral contraceptive

agents . Considering t he rela-

tively high usa ge of theseagents , the a ctua l scienti f ic

document at ion for this intera c-

tion is far from overwhelming.

B efore a discussion of the da ta

or la ck of da ta supporting t his

intera ction, a brief review of

oral contra ceptive pha rma colo-

gy is in order.

The pharmacology of oralcontraceptives.The combina -tion pill is ma de up of tw o com-

ponent s: semisynth etic estro-gens, typically ethinyl estra diol,

or EE, or mestranol , an d

semisynth etic progesterones

known a s progestins (for exam -

ple, norethist erone a nd lev-

onorgestr el). The est rogen com-

ponent ga ins its cont ra ceptive

effica cy by blocking ovula tion

by inhibiting th e release of folli-

cle-stimulating hormone, or

FSH , a nd luteinizing h ormone,


PHARMACOLOGY

2,000

1,500

1,000

500

0

40

30

20

10

0Ethinylestradiol(picogra

m/milliliter)

Norethisterone(nanogra

m/milliliter)

Rifampin Control Rifampin Control

P < .01 P < .01

Figure 2. Blood concentrations (mean + standard error) of ethinyl estra-

diol, or EE, and norethisterone in women taking oral contraceptives inboth the presence and absence of rifampin. Blood levels of both EE and

norhisterone are significantly reduced in the presence of rifampin. Data

from Back and colleagues.107,108



10/16

or LH. The mechanisms of ac-

tion for the progestin compo-

nent include an enha ncement of

th e viscosity of cervical fluid, a

chang e in th e endometria l lin-ing tha t ma kes i t unsuita ble for

egg implanta tion, and some an-

tiovulatory action.99

The components of th e pill

are not w ithout potentia l s ide

effects. The most critical side ef-

fect of th e estrogen component

is a n increased r isk of venous

thromboembolytic disease. The

progestin component h a s been

a ssociat ed with increases in

blood pressure, blood glucosea nd blood lipid levels in some

women. An increased risk of

myocardia l infarction and

stroke ha ve been r eport ed in

oral contraceptive users older

tha n th e age of 35 years w ho

are heavy smokers.99 These

deleterious event s ha ve led t o

th e development of pills con-

ta ining reduced dosag es of both

components. Some a uth ors have

speculated t ha t the w idespread

use of t hese so-called mini-

pills, wh ich ha ve reduced

amounts of both estrogen and

progestin components, increa seth e risk of drug int eractions

a nd cont ra ceptive failure.100

Like any drug, oral contra-

ceptives a re not 100 percent ef-

fective. When taken correctly,

they reduce the chance of be-

coming pregnant to less tha n 1

percent. H owever, the typical

failure rate among American

populat ions is a round 3 percent

per year .101 In t he teenage popu-

lat ion, the fa ilure ra te is report-ed to be as high a s 8 percent ,

proba bly from teens missing a n

a verage of th ree pills per

cycle.102

Interactions with ri-fampin. The antituberculosisdrug r i fampin wa s the f irs t a n-

tibiotic implicated in reducing

th e effectiveness of oral contra -

ceptives. I n 1971, Reimers a nd

J ezek103 reported t ha t 38 of 51

women (75 percent) taking ri-

fampin and oral contraceptives

concomitantly experienced

breakt hrough bleeding, an indi-

cator of ovulat ion. Two y earslater , another report s ta ted tha t

in 88 women, five pregnancies

a nd 66 inst a nces of break-

th rough bleeding were associat -

ed wit h concomita nt use of ri-

fampin and oral contracep-

tives.104 Other reports of preg-

nancy have been associated

with this interaction.105 In fact ,

76 percent of all a lleged a nt ibi-

otic-oral contraceptive interac-

tions involve rifampin.

106

Clinical st udies clearly

demonstra te tha t r i fampin sig-

nifican tly reduces blood levels

of both t he estrogen an d pro-

gestin components of oral con-

traceptives (Figure 2).107,108

Rifam pin is a potent inducer of

th e liver cytochrome P -450 sys-

tem a nd increases the

meta bolism of a number of

drugs, including oral contra cep-


PHARMACOLOGY

EE EE EE EE

EE EE

EE EE

EE EE

EE EE EE EE

EE EE

EE EE EE EE SO4SO4Glucuronic

Acid

Glucuronic

Acid

AntibioticGut

Flora

Intestine

Blood

Intestine

Blood

A B

Figure 3. The proposed ability of antibiotics to inhibit the enterohepatic recirculation of ethinyl estradiol, or

EE. In the absence of antibiotics (A), enteric bacteria hydrolyze glucuronic acid and sulfate groups from EE

molecules liberating the lipid-soluble and active parent compound, which can be readily reabsorbed from the

intestine into the bloodstream. In the presence of antibiotics (B), the enteric bacteria are markedly dimin-

ished, leading to a significant reduction in EE reabsorbed into the bloodstream.



11/16

tives.51,105 At present , rifam pin

remains th e only a ntibiotic tha t

ha s been scient ifica lly demon-

stra ted to interfere with t he ef-

fectiveness of oral contraceptiveagents .

Interactions with otherantibiotics. Ca se reports ofmore commonly prescribed an-

tibiotics interfering with ora l

contraceptive effectiveness

began to surfa ce in 1975. In

tha t year , Dossetor 109 reported

th ree ca ses in her pra ctice in

which pat ients ta king oral con-

tra ceptives apparently ha d be-

come pregnan t w hen givena mpicillin. Five yea rs lat er, an-

other report described a 20-

year -old student wh o claimed to

be total ly complian t with her

oral contra ceptive regimen, but

nevertheless became pregnan t

a fter a five-da y course of tetra -

cycline. 110 In 1982, DeS an o a nd

Hurley111 described 16 pregnan-

cies over a t w o-yea r period in

their private obstetric and gyne-

cologic practices, a ll in pat ients

wh o claimed t o be tota lly com-

plian t with their contra ceptive

regimen but w ho also had con-

sumed additional medications.Antibiotics had been consumed

in 13 of th ese ca ses: a mpicillin

in five, penicillin in th ree, tetra -

cycline in one an d a nt ibiotics

not commonly used in dentist ry

in t he other four. However, four

of th e pa tient s ta king ampicillin

a nd tw o of th ose ta king peni-

cil lin a lso ha d ta ken a va r iety of

other medica tions, including a n-

tihis tam ines, decongesta nts an d

analgesics. All of these case re-ports were, by necessity, u ncon-

trolled, retrospective an d sub-

ject t o reca ll bias. 105

In 1986, a case report of an

a lleged a nt ibiotic-oral contra -

ceptive intera ction a ppea red in

th e denta l literat ure. A 19-year -

old wh o had ta ken a n oral con-

tra ceptive for 18 months r e-

ceived an intra muscular

injection of a long -a cting peni-

cillin combinat ion durin g denta l

impaction surgery. At t he thr ee-

month follow-up, she w a s found

to be pregna nt ; 40 weeks aft er

surgery, she gave bir th t o

hea l thy tw ins.112

P robably th e most compre-

hensive report of potentia l an -

tibiotic-oral contraceptive inter-

actions w as supplied by B ack

a nd colleagues,113 wh o gat hered

dat a from the U nited Kingdom s

Committee on S afety in

Medicines between 1968 and

1984. Du ring th is period, 63

pregna ncies were reported w ith

simulta neous a dministra tion of

oral contraceptives and antibi-otics (excluding rifa mpin).

P enicillins w ere implicated in

32 of these pregna ncies, tet ra cy-

clines in 12, cotrimoxa zole (sul-

famethoxazole an d t r imetho-

prim) in five, metronidazole in

three, erythromycin in t wo a nd

a nt ibiotics not commonly used

in dentistry in the other nine.

The a uth ors tempered th ese

findings by also reporting that

in En glan d between 1973 a nd1984, there wa s a t otal of

159,000,000 prescript ions for

penicillins; 68,000,000 for t etr a -

cyclines; 40,000,000 for cotr i-

moxazole; 31,000,000 for eryth-

romycin; and 6,000,000 for

metronidazole. In addition, they

reported, t here were a pproxi-

mately 2,500,000 regular users

of ora l cont ra ceptives per year

during t his period.114 Thus, the

a ctua l number of reported preg-na ncies in Englan d a l leged to

involve oral cont ra ceptive int er-

actions with antibiotics other

tha n r i fampin might be, in real-

ity, extremely low.

In t he United St at es , 29 re-

ports of unintended pregna ncies

in oral cont ra ceptive users who

received penicillins or tetracy-

clines were listed in th e U.S.

Depar tment of Heal th a nd


PHARMACOLOGY

1,200

1,000

800

600

400

200

0

Control Tetracycline

Day 1

Tetracycline

Days 5-10

Eth

inylestradiol(picogram/m

illiliter)

Figure 4. Blood concentrations (mean + standard error) of ethinyl estra-

diol, or EE, in women taking oral contraceptives in both the absence

and the presence of tetracycline. There was no effect on blood levels of

EE following one day or five to 10 days of antibiotic therapy. Data from

Murphy and colleagues.132



12/16

Huma n S ervices MEDWATCH

Spontaneous Reporting

System.115 These numbers a ga in

must be tempered with the fact

th a t a s of 1994, a pproximat ely

11,000,000 women per yearwere using oral cont ra ceptives

in the Uni ted S ta t es.116

Assumptions in the litera-ture. Although th ese ca se re-ports certa inly should not be ig-

nored an d t heoretically could

indicat e a rar e interaction, a

number of reviews ha ve been

published implying t ha t the

a bility of commonly prescribed

antibiotics to reduce the effec-

tiveness of ora l cont ra ceptives isan esta blished intera ction.117-119

For example, one otherwise ex-

cellent a rticle in th e denta l lit-

erat ure discussing th e impact of

th e 50 drugs most frequent ly

dispensed in clinical practice

conta ins a s ta tement t ha t t he

an tibiotics th at interfere with

th e ovulat ory inhibiting effects

of ora l cont ra ceptives a re peni-

cillin V potassium, amoxicillin,

cepha lexin, tetr a cycline anderythromycins.117 The a uth or

cites a s his evidence one of the

previously described ca se re-

ports112 an d not a ny clinical t r i-

als or pha rmacokinetic data .

In 1991, the ADA Health

Foundation Research Insti tut e

published a st a tement concern-

ing t his issue. A small portion

of the s ta tement read a s fol-

lows: Unfor tunat ely , many a n-

tibiotics commonly used in den-tis try int erfere with the a ction

of ora l cont ra ceptives, resulting

in unexpected pregnan cies.

Fa ilure to inform a patient

using oral cont ra ceptives during

antibiotic therapy resulting in a

birth could leave th e dentist re-

sponsible for da ma gesinclud-

ing child support pa yment s.120

While i t w as very importa nt to

wa rn dentist s of the possibility

of th is int eraction, there were

not enough scientific da ta to

suppor t th e s ta tement t ha t the

interaction w as indeed esta b-

lished. Even t he P hysicians

Desk Reference121 at best de-scribes th e interaction w ith a n-

tibiotics other tha n r i fampin a s

possible. Other authors have

reported one or tw o successful

l i t igat ions aga inst dentis ts .115,122

Unfortunately, these legal pro-

ceedings cann ot be resear ched

or even substa ntia ted.123

The pharmacologicalbasis of the interaction.Antibiotics abil i ty to inhibit the

enterohepat ic recircula tion ofth e estrogen component of th e

oral cont ra ceptive is the t heory

most often mentioned in th e lit-

erat ure to explain th e alleged

interaction 124-126 (Figu re 3). In

huma ns, the bioava ilabili ty of

EE is only a bout 40 percent t o

50 percent beca use of a large

first-pass met abolism in the gut

a nd t he liver. These inactive

conjugated metabolites (50 per-

cent to 60 percent of the pa rentcompound) then are excreted in

th e bile, wh ere the drug w ould

be lost if not for the ba cteria in

th e colon, which are thought to

split th e EE conjugat es. This

libera tes th e active par ent com-

pound, w hich ca n rea dily be re-

absorbed in the int estine and

provide the necessa ry a ddition-

a l blood levels of the dru g.

In t heory, this enterohepat ic

recirculat ion ca n be inhibitedby an tibiotics that kill the

colonic bacteria involved in t he

deconjuga tion process. In fa ct,

s tud ies in ra t s an d rabbi ts do

show tha t pretrea tment w i th

am picil lin interferes with the

enterohepa tic recirculat ion pro-

cess.127-128 How ever, no clinica l

s tudy h as been a ble to demon-

s tra t e tha t a s imi lar scenar io

also occurs in humans.

Proving the interaction. Astudy ma ny reference as scien-

tific proof of an interaction be-

tw een ant ibiotics and oral con-

tra ceptives is one in w hich

treat ment w ith a mpicil lin re-duced endogenous estr ogen con-

centra tions in pregnant pa-

tients .129 However , th is s tudy

did not evalua te t he effects of

a nt ibiotics on t he blood levels of

the estrogen or progestin com-

ponent of ora l cont ra ceptives,

an d any a tt empt to correlate

ampicillin s a bility to reduce en-

dogenous estrogen in pregna nt

patients w ith t he fai lure of oral

contraceptives is scientificallyquestionable.

A number of studies, howev-

er, ha ve looked directly a t ora l

contraceptive blood concentra-

tions both in t he absence a nd

the presence of antibiotics.

St udies showed n o significa nt

decreases in plasma levels of ei-

ther t he EE or the progestin

contraceptive component in

women treated with a mpi-

cillin,130,131

tetracycline,125,132

doxycycline,133 metronidazole,130

erythromycin,125 clarithro-

mycin,134 temafloxacin 135 or flu-

conazole.136 Figure 4 illustrates

th e results of one such study.

The antibiotic cotrimoxazole ac-

tua lly increased E E levels sig-

nificantly, 137 whereas clar-

ithr omycin significa nt ly

reduced FSH a nd LH levels134

a ll of th ese being possible indi-

cators of increased cont ra cep-tive effica cy. In a nother st udy of

22 women ta king ora l contra -

ceptives, n one of the subjects

ovula ted w hile ingesting rox-

ithr omycin (a ma crolide rela ted

to eryt hr omycin), but 11 (50

percent) ovulat ed wh ile ingest-

ing the positive control ri-

fampin.138

There is one potent ial w eak-

ness in all th ese studies: their


PHARMACOLOGY



13/16

relat ively sma ll sample sizes

(ra ngin g from six to 25 w omen).

If th e intera ction occurs rarely,

a s in one in 1,000 people, stud -

ies of th is size may not detect

th e int eraction. It should benoted, however , that these rela-

tively sma ll sample sizes readi-

ly display the rifampinoral

cont ra ceptive intera ction.107,108,138

There are two retrospective

studies, with somewhat larger

databases, that have examined

pregna ncy rates in women wh o

consumed a nt ibiotics as derma -

tologic pat ient s. (The issu e of

potential antibiotic interactions

wit h ora l contra ceptives is ofgreat importance to dermatolo-

gists, beca use they often pre-

scribe a nt ibiotics on a chronic

basis to women of child-bearing

potential.) In the first study,

281 pat ients w ere surveyed; 34

were found t o ha ve used an tibi-

otics a nd low-estrogen cont ra -

ceptives for a combined total of

71 year s.139 One woman who

concurrently took tetra cycline

a nd ora l cont ra ceptives for 12months became pregnant, giv-

ing an overall pregnancy rate of

1.4 percent per year a mong pa-

tients t aking a ntibiotics .

In a larg er study of 356 pa-

tient s with a h istory of com-

bined antibiotic-oral contracep-

tive us e an d of 425 w omen

taking oral contraceptives and

no a nt ibiotics, resea rchers

found a pregnan cy rat e of 1.6

percent in t he a nt ibiotic groupa nd 0.96 percent in t he cont rol

group.101 There w a s no signifi-

cant difference (P= .4) in preg-

na ncy rates betw een the a ntibi-

otic and control groups, an d

both groups had pregnancy

ra tes below t he 3 percent typi-

cally found in th e Unit ed

S ta tes .

Are there any da ta other

tha n case reports tha t support

The fa ilure of ora l cont ra cep-

tives in women simulta neously

ingesting antibiotics may indi-

cate ba ckground noisetha t i s,

the normal fa i lure rat e of these

drugs or a relat ively rare int er-action t ha t can not be detected

by clinica l tria ls. Although t he

intera ction, by definition, ca n-

not be classified a s esta blished,

proba ble or even suspected, t he

philosophy of recommendin g

th e use of additional forms of

birth control for a ll ora l contra -

ceptive users receiving a nt ibiot-

ic thera py, a s a possible protec-

tion of a few of them from

unwa nted pregnancies , s t i l lseems justified.

Of note, however, a re the re-

cently published legal proceed-

ings in which a plainti f f and h er

husba nd sued a gynecologist

an d a n oral surgeon for mal-

practice and wr ongful life

a fter she a llegedly became preg-

na nt either during or shortly

a fter she wa s given a prescrip-

tion for penicillin V.141 B oth doc-

tors had fa i led to wa rn her of apotentia l interaction w ith t he

oral contraceptive she was tak-

ing. She an d her husban d lost

th e case for the following rea -

sons: (1) Her experts cited re-

view a r ticles with no data and

art icles tha t showed no sta tis t i-

cally significan t correlat ion be-

tw een a ntibiotic use an d oral

cont ra ceptive fa ilure; (2) her ex-

perts fa iled to show a scientifi-

cally validated interaction be-tw een penicillin V a nd th e ora l

contraceptive she wa s t aking;

(3) under C a lifornia law , physi-

cia ns do not ha ve to discuss

risks of a very low incidence

(the fai lure rat e would have to

be more tha n double th e norma l

expected r a te); an d (4) her ex-

perts a lso failed to prove tha t

she became pregnan t when she

was taking penicillin.


PHARMACOLOGY

th e possibility of an intera ction

between commonly prescribed

a nt ibiotics and oral cont ra cep-

tives? Shenfield an d G riffin140

presented a sing le ca se study of

an oral contraceptive user whoha d a his tory of breakthrough

bleeding w hile on a nt ibiotics.

While taking minocycline, this

woman displayed lower E E

plasma concentra tions and t hea bolition of two of three plasma

peaks, a s compared with when

she was not ta king the antibiot-

ic.140 I t w as hypothesized tha t

this conceivably could indicate

an antibiotic-induced reduction

of the ent erohepat ic recircula -

tion process in this subject.

One oth er study, w hile re-

vea ling n o effect of a mpicillin on

plasma EE levels of the entire

study populat ion, did identifytw o women in t he sample whose

EE concentra tions were signifi-

cantly reduced while they were

taking ampicillin.131 However,

neither of these women experi-

enced brea kthr ough bleeding or

changes in laborat ory para me-

ters tha t w ould indicat e ovula-

tion.

Interaction vs. normalcontraceptive failure rate.

The fai lure of oral

con tracept ives in

wom en s imul taneous-

ly ingest ing ant ib i -

ot ics may indicate

background noise

that is, the norm alfai lure rate of these

drug s or a relat ively

rare interact ion that

canno t be detected

by cl in ical tr ials.



14/16

CONCLUSION

Adverse drug intera ctions in-

volving antimicrobial agents

can occur in denta l pat ients. Of

part icular significance is theability of certain antimicrobial

agents to cause t he accumula-

tion of a number of drugs tha t

ha ve low t hera peutic indexes. It

is importa nt t hat cl inicians s ta y

abreast of potentia l drug inter-

a ctions t o avoid serious m orbid-

ity a mong their pat ients . s

Dr. H ersh is an a ssociat e professor,University of Pennsylvania, School of DentalMedicine, Department of Oral Surgery a nd

Ph arm acology, 4001 Spruce St., P hiladelphia,Pa. 19104-6003. Address reprint requests toDr. Hersh.

This ar ticle is based on mat erial presentedMarch 4, 1998, in a symposium entitledAdverse Drug Interactions in Dentistry:Separating the Myths From the Facts . D r.Hersh a nd Dr. P aul Moore cochaired thissymposium, which was presented at t he 27thGenera l Session of th e American Associat ionfor Denta l Research in Minnea polis. The sym-posium w as jointly sponsored by theInternational Association for DentalResearch, the American Association of Denta lSchools an d the American Denta l Associationand w as supported in par t by a grant f romWarner Lambert Pha rmaceuticals .

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