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ARTICLE 4

ADVERSE DRUG INTERACTIONS IN DENTAL PRACTICE:

INTERACTIONS INVOLVING ANTIBIOTICS
PART II OF A SERIES
ELLIOT V. HERSH, D.M.D., M.S., PH.D.

Background. The prudent use of antibiotics

is an integral part of dental practice. While these
agents generally are considered safe in the dental setting, their use can result in interactions that can lead
to serious morbidity in dental patients.
Methods. The faculty of a symposium entitled
Adverse Drug Interactions in Dentistry: Separating
the Myths From the Facts did an extensive literature review on drug interactions. Through this, they
were able to establish a significance rating of alleged
adverse drug interactions as they relate to dentistry,
based on their scientific documentation and severity
of effect. The author of this article focused on antibiotics.
Results. Most of the reported drug interactions
discussed in this article are well-documented by clinical studies. It is particularly important that dentists
be aware of the potentially serious and life-threatening interactions of the antibiotics erythromycin, clar-

This article, focusing on antibiotics, is the sec-

ond in a five-part series discussing the clinical

significance of reported drug interactions as they
relate to dentistry. While there are numerous antibiotic preparations available for the treatment
of localized and systemic infections, relatively few
antibiotic preparations are routinely employed in
dentistry (Box, Antibiotics Commonly Used in
Dentistry). This factor alone limits the quantity
of adverse drug interactions seen with antibiotics
in our profession.
However, antibiotics are prescribed for longer
durations than are other agents routinely admin-

236

ithromycin and metronidazole, and of the antifungal

agents ketoconazole and itraconazole, with a host of
other drugs whose metabolism is impaired by these
antimicrobial agents. In contrast, the alleged ability
of commonly employed antibiotics to reduce the effectiveness of oral contraceptive agents is not adequately supported by clinical research. It still is recommended, however, that clinicians discuss this possible
interaction with their patients, as it might represent
a relatively rare event that cannot be discerned in
clinical trials.
Conclusions. Potentially serious adverse
drug interactions can occur between antimicrobial
agents used in dental practice and other drugs patients are taking for a variety of medical conditions.
Clinical Implications. It is important
that dentists stay abreast of potential drug interactions involving antibiotics to avoid serious morbidity
among their patients.

istered in dentistry. For example, local anesthetics and sedatives usually are given in a single
course of therapy,1 whereas in most patients analgesics are taken for a few days on an as-needed
basis. The typical antibiotic regimen for an odontogenic infection is of a five- to 10-day duration on
an around-the-clock schedule. This more chronic
dosing sets the stage for some rather serious and
potentially life-threatening drug interactions involving antimicrobial agents (such as erythromycin, clarithromycin, ketoconazole and itraconazole), which inhibit the gut wall and liver
cytochrome P-450 system with a host of other

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PHARMACOLOGY
drugs that use the same
metabolic pathway. The ability of
certain antimicrobial agents to
increase blood levels of other
drugs with low therapeutic indexes is, in fact, the cause of the
most potentially hazardous interactions discussed in this article.
The purpose of this article
and the others in this series is
not simply to list and discuss
the theoretical basis of published adverse drug interactions. Our major goal is to explore the scientific documentation and the seriousness of
each interaction as it relates to
the practice of dentistry. Many
of the interactions that will be
presented in this article are
supported by an abundance of
scientific data. For example,
there are numerous well-designed pharmacokinetic studies
that have demonstrated clearly
that the simultaneous ingestion
of agents containing divalent or
trivalent cations and tetracycline antibiotics greatly impair
the absorption of this class of
antibiotic agents. On the other
hand, although case reports
have implicated the administration of penicillins, tetracyclines
and other antibiotics used in
dentistry with reduced systemic
absorption and ultimate failure
of oral contraceptive agents,
well-controlled clinical trials
have failed to demonstrate this
interaction.
THE SIGNIFICANCE
RATING SCALE

The significance rating scale

that is assigned to each drug interaction within this article was
presented in detail in the first
article of this series1 and is
summarized in Table 1.
Although adverse drug interactions assigned a rating of 1 or 2
clearly should be of concern to

ANTIBIOTICS COMMONLY USED IN DENTISTRY.

BACTERICIDAL

BACTERIOSTATIC

Generic Name

Trade Name*

Generic Name

Trade Name

Penicillin V

Pen-Vee K

Erythromycin

Eryc

Amoxicillin

Amoxil

Clarithromycin

Biaxin

Cephalexin

Keflex

Azithromycin

Zithromax

Cefadroxil

Duricef

Clindamycin

Cleocin

Metronidazole

Flagyl

Tetracycline

Achromycin

Doxycycline

Vibramycin

* The trade-named bactericidal antibiotics are listed only as examples. Manufacturers are as
follows: Pen-Vee K, Wyeth-Ayerst Laboratories; Amoxil, SmithKline Beecham Consumer
Health Care; Keflex, Dista Products and Eli Lilly and Company; Duricef, Bristol-Myers
Squibb Company; Flagyl, G.D. Searle and Company.

The trade-named bacteriostatic antibiotics are listed only as examples. Manufacturers are
as follows: Eryc, Warner Chilcott Laboratories; Biaxin, Abbott Laboratories; Zithromax,
Pfizer Incorporated Consumer Health Care Group; Cleocin, Pharmacia and Upjohn
Company; Achromycin, Lederle Laboratories; Vibramycin, Pfizer Incorporated Consumer
Health Care Group.

the practicing dentist, those

given a rating of 4 should not be
dismissed completely. A rating
of 4 typically implies that a few
published reports have suggested an interaction that is of
major or moderate severity, but
that scientific documentation either is lacking or does not support an interaction. Further research is needed to either
further establish or refute the
interaction.
Table 2 summarizes the specific interactions that are associated with antibiotic therapy in
dentistry and provides the significance rating for each.
BACTERICIDAL
ANTIBIOTICS WITH
BACTERIOSTATIC
ANTIBIOTICS

Most teachers of pharmacology

to predoctoral and postgraduate
dental students preach the central dogma that bactericidal antibiotics should never be combined with bacteriostatic

antibiotics (Box, Antibiotics

Commonly Used in Dentistry),
because the latter will antagonize the action of the former. In
reality, there are relatively few
well-authenticated clinical examples of this phenomenon.2
In patients with pneumococcal meningitis, penicillin produced significantly higher recovery rates and fewer
mortalities when used alone
than when combined with a
tetracycline to treat the same
infection.3,4 A higher rate of
spontaneous reinfection also
has been reported in patients
with scarlet fever who were
treated with a penicillin-tetracycline combination than in
those receiving only penicillin.2
In other studies involving scarlet fever, combined penicillin
and erythromycin therapy was
slightly less effective than
monotherapy with penicillin,5
and antagonism between these
two antibiotics has been demon-

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237

PHARMACOLOGY
TABLE 1

THE DRUG INTERACTION SIGNIFICANCE RATING SCALE.

SIGNIFICANCE
RATING

SEVERITY RATING

DOCUMENTATION
RATING

Major

Established, probable or suspected

Moderate

Established, probable or suspected

Minor

Established, probable or suspected

Major or moderate

Possible

Minor

Possible

All

Unlikely

strated in vitro.6
There are several instances,
however, in which bacteriostatic
antibiotics have been successfully combined with bactericidal
antibiotics to prevent the emergence of resistant strains. Take,
for example, the triple antibiotic combination of bismuth subsalicylate (Pepto-Bismol,
Procter & Gamble), tetracycline
(a static antibiotic) and metronidazole (a cidal antibiotic),
which has been widely employed for the eradication of
Helicobacter pylori in patients
with gastrointestinal ulcers.7
In dental medicine, there is
no rationale for combining bacteriostatic antibiotics with bactericidal antibiotics to treat
odontogenic infections. These
combinations are likely to lead
to greater toxicity than that of
single-drug therapy and, at
least with penicillins, a diminution of antibiotic effectiveness.
TETRACYCLINES WITH
PRODUCTS CONTAINING
DIVALENT AND
TRIVALENT CATIONS

The ability of divalent and

trivalent cations such as calcium++, magnesium++, bismuth++, iron++, zinc++ and
aluminum++ (found in dairy
products, antacids and vitamin
238

preparations) to markedly impair the absorption of tetracycline molecules from the gastrointestinal tract is probably
the adverse drug interaction
most widely known among dental clinicians. These interactions are well-documented and
established through numerous
case reports and well-controlled
clinical studies. 8-15
While the individual tetracycline moieties differ with respect to certain cations (for example, doxycycline and
minocycline are not affected as
much as other tetracycline moieties with respect to calcium++
and zinc++10,11,15), reductions in
serum tetracycline concentrations of 20 to 100 percent in the
presence of these cations often
are so large that antibiotic levels can fall below those needed
to inhibit bacterial growth).2
The significance rating of 2
given to this interaction reflects
a likely increase in patient morbidity. The simultaneous ingestion of tetracycline molecules
and multicationic products
should be avoided absolutely.
METRONIDAZOLE WITH
ALCOHOL, LITHIUM

Metronidazole with alcohol.

Metronidazole, like disulfiram

(Antabuse, Wyeth-Ayerst
Laboratories), has been shown
in the laboratory to inhibit the
activity of acetaldehyde dehydrogenase, theoretically causing
an accumulation of acetaldehyde in patients who ingest alcohol concomitantly.16 The clinical ability of metronidazole to
produce disulfiramlike reactions in alcohol consumers
(Table 2) is supported by several studies that have shown an
incidence ranging from 2 percent to 100 percent of the study
population.2,17-19 While the reaction normally is more unpleasant and frightening than it is
serious, patients should be advised not to consume alcohol
during metronidazole therapy
and for at least three days afterward.20
Metronidazole with lithium. Lithium, a monovalent
cation, is indicated for the treatment of bipolar (manic-depressive) disorder, most frequently
during the manic phase. It is
given under close supervision
with regular monitoring of
blood concentrations because of
its low therapeutic index.
Therapeutic blood levels are in
the range of 0.8 to 1.5 milliequivalent per liter during an
acute manic attack and 0.6 to
1.2 mEq/L for maintenance
therapy.2,21 Early signs of lithium intoxication can occur at
blood concentrations that are
just above therapeutic (in the
1.5-2 mEq/L range) and include
lethargy, muscle weakness and
fine hand tremors. More serious
toxicity consisting of confusion,
nystagmus and ataxia typically
are seen at lithium blood concentrations of 2.0 to 2.5 mEq/L.
Life-threatening toxicity (consisting of seizures, coma and
circulatory collapse) can occur
with lithium concentrations

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PHARMACOLOGY

TABLE 2

ADVERSE DRUG INTERACTIONS IN DENTISTRY: ANTIBIOTICS.

POSSIBLE DRUG
INTERACTION

SIGNIFICANCE
RATING

MECHANISM AND CLINICAL PRESENTATION

Bactericidal antibiotics with

bacteriostatic antibiotics

Theoretically, bactericidal drugs work best

when microbes are actively growing. By inhibiting cell growth, bacteriostatic agents may antagonize the bactericidal agent. This interaction
is not consistently demonstrated clinically.

Tetracyclines with products

that contain divalent or
trivalent cations

Tetracycline molecules chelate divalent and

trivalent cations, impairing antibiotic absorption. In addition, antacids can raise the gastrointestinal pH, also impairing absorption.
Serum tetracycline levels can be reduced 20 to
100 percent, leading to poor antibiotic efficacy.

Metronidazole with alcohol

Metronidazole produces a disulfiram effect by

inhibiting the enzyme acetaldehyde dehydrogenase. Acetaldehyde accumulation can lead to facial flushing, headache, palpitation and nausea.

Metronidazole with lithium

Metronidazole inhibits the renal excretion of

lithium, leading to elevated lithium blood concentrations. Lithium toxicityas manifested by
confusion, ataxia and kidney damagecan result.

Tetracyclines with lithium

4

Erythromycin or tetracyclines with digoxin

Tetracyclines or other
broad-spectrum antibiotics
with warfarin or anisindione

Erythromycin, clarithromycin or metronidazole with warfarin or

anisindione

above 2.5 mEq/L.2 In addition,

elevated blood lithium concentrations can lead to renal dysfunction, often in the form of
nephrogenic diabetes insipidus,

Metronidazole inhibits the renal excretion of

lithium, leading to elevated lithium blood concentrations. Lithium toxicityas manifested
by confusion, ataxia and kidney damagecan
result. A single case report describes elevated
lithium blood concentrations and lithium
toxicity with concomitant tetracycline administration.25 Another report26 and a clinical research study27 do not support the interaction.
These antibiotics can reduce the gut flora, in
particular Eubacterium lentum, which metabolize a significant amount of oral digoxin in 10
percent of patients taking the drug. Elevated
concentrations of digoxin can occur in such patients, leading to digitalis toxicity, as manifested by salivation, visual disturbances and arrhythmias.
Broad-spectrum antibiotics are hypothesized to
reduce the gut flora that normally synthesize vitamin K, a necessary cofactor for clotting. Since
warfarins and anisindiones anticoagulant
mechanism involves an antagonism of vitamin
K-dependent clotting factors, an increased risk
of bleeding may occur. Interaction appears significant only in patients with poor vitamin K intake.
These antibiotics decrease the metabolism of
warfarin and anisindione and can significantly
increase prothrombin times and increase the
risk of serious bleeding in anticoagulated patients. Signs of this adverse interaction include
hematuria, bruising and hematoma formation.

resulting in excessive excretion

of dilute urine.2,21
Three cases have been reported in the literature in which
the administration of metro-

continued on page 240

nidazole for one week (5001,000 milligrams daily) apparently induced elevations in
lithium blood concentrations
with concomitant toxicity.22,23 In

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239

PHARMACOLOGY
TABLE 2 CONTINUED

ADVERSE DRUG INTERACTIONS IN DENTISTRY: ANTIBIOTICS.

POSSIBLE DRUG
INTERACTION

SIGNIFICANCE
RATING

Erythromycin, clarithromycin, ketoconazole or itraconazole with a host of

other drugs that are metabolized by the CYP3A4 and
CYP1A2 system in the gut
wall and liver

Depends on
interacting
drug (see
below)

These antimicrobial agents block the

metabolism and thus increase blood levels of a
number of drugs. Severity of the reaction
depends on the therapeutic index of the interacting drug.

Astemizole, terfenadine
or cisapride

Life-threatening ventricular arrhythmias (torsades de pointes). Metronidazole also increases

cisapride blood levels.

Alfentanil

Enhanced and/or prolonged respiratory depression. Ketoconazole not implicated.

Bromocriptine

Increased risk of adverse central nervous system effects, dyskinesias and hypotension.

Carbamazepine

Increased risk of ataxia, vertigo, drowsiness and

confusion. Cardiac arrest reported in one child
taking erythromycin.68

Cyclosporine

Enhanced immunosuppression and nephrotoxicity.

Felodipine and possibly

other calcium-channel
blockers

Increased risk of hypotension, tachycardia and

edema.

Methylprednisolone or
prednisone

Increased risk of Cushings syndrome and

immunosuppression.

Theophylline

Increased risk of tachycardia, cardiac arrhythmias, tremors and seizures. Ketoconazole not
implicated in this interaction.

Lovastatin and possibly

other -statins

Muscle pain and rhabdomyolysis (skeletal muscle lysis). Pharmacokinetic interaction demonstrated for azole antifungal drugs.

Triazolam or oral
midazolam

Marked increases in blood levels of both benzodiazepines when taken by mouth, leading to increases in sedative depth and duration.

Disopyramide

A few clinical reports of arrhythmias or heart

block with concurrent erythromycin use.
Definitive pharmacokinetic studies are needed.

Sporadic case reports have implicated the concomitant ingestion of antibiotics and oral contraceptives with unwanted pregnancies. It is
theorized that antibiotics, by decimating the
normal gut flora, can interfere with the enterohepatic recycling of the estrogen component of
oral contraceptives, thereby leading to subtherapeutic blood levels and ovulation. With the exception of the antituberculosis drug rifampin,
clinical studies have failed to demonstrate an
interaction.

Penicillins, cephalosporins,
erythromycin, clarithromycin, tetracyclines,
metronidazole with combined estrogen and progestin oral contraceptives

one woman, lithium blood concentrations increased from 1.3

mEq/L to 1.9 mEq/L. She developed signs (such as ataxia, mental clouding and muscle weakness) of lithium toxicity.22 In
240

MECHANISM AND CLINICAL PRESENTATION

another woman, lithium blood

concentrations were elevated to
a lesser degree (from 1.1 mEq/L
to 1.3 mEq/L), but she developed persistent polyuria and
nocturia, indicative of kidney

damage.23 In a third female patient, lithium blood concentrations increased dramatically

from 0.9 mEq/L to 2.0 mEq/L.
She was admitted to the hospital because of severe confusion

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PHARMACOLOGY
and ataxia. She also developed
hypernatremia and abnormally
dilute urine, consistent with a
diagnosis of nephrogenic diabetes insipidus, conditions that
persisted for six months.23
While a more definitive clinical trial exploring the likelihood
of the metronidazole-lithium interaction has not been performed, these three case reports
are well-documented with supporting pharmacokinetic data.
A significance rating of 1 is assigned to this adverse drug interaction because the documentation indicates that the
interaction is at least suspected
and the severity of the interaction is major. Practitioners
should avoid the use of metronidazole in patients receiving
lithium therapy.
TETRACYCLINES
WITH LITHIUM

A warning to completely avoid

the concomitant administration
of tetracycline with lithium also
exists in the literature.24 It
stems from a single case report
of a 30-year-old woman whose
lithium blood levels had ranged
from 0.50 mEq/L to 0.84 mEq/L
over a three-year period.25 After
a one-week course of tetracycline hydrochloride (250 mg
three times per day), her lithium blood concentration increased to 2.74 mEq/L. She also
developed clinical signs of lithium toxicity: drowsiness, slurred
speech, fine hand tremors and
thirst.25 However, another author has reported using these
drugs in combination in his patient population with no observed adverse drug interactions.26 A clinical trial in 14
healthy volunteers demonstrated that lithium blood levels actually decreased slightly (from
0.51 to 0.47 mEq/L) after the

addition of tetracycline (1 gram

per day) for one week.27
While the severity of this potential adverse drug interaction
is severe, its scientific documentation puts it at most in the
possible category. We therefore assign it a significance rating of 4.
ERYTHROMYCIN,
CLARITHROMYCIN OR
TETRACYCLINES WITH
DIGOXIN

Digoxin (Lanoxin, Glaxo

Wellcome Inc.) and digitoxin
(Crystodigin, Eli Lilly and
Company) are cardiac glycosides indicated for the treatment of congestive heart failure
and certain types of atrial arrhythmias. They both have low
therapeutic indexes, so that significant changes in their plasma

Practitioners should
avoid the use of
metronidazole in
patients receiving
lithium therapy.
levels are likely to lead to severe reactions.1 In addition, patients who are taking these
agents are more fragile than
relatively healthy dental patients because of their cardiac
disease.
Digoxin is fairly well-absorbed (about 75 percent) after
oral administration.28 However,
about 10 percent of people harbor enteric bacteria that inactivate digoxin in the gut, greatly
reducing the drugs bioavailability and necessitating that they
receive greater than average
maintenance doses (Table 2).2
In these patients, the administration of certain antibiotics can
decimate the enteric bacteria,
leading to a marked rise in

serum digoxin levels.28,29 A doubling of serum digoxin levels

and signs of digitalis toxicity
have been reported in patients
taking erythromycin simultaneously for three to six days.29-31 A
30 percent rise in serum digoxin
levels and a fall in digoxin
metabolites have been reported
with simultaneous tetracycline
administration.29,32
Although these case reports
do not represent well-controlled
clinical studies, they are, in fact,
supported by some rather convincing pharmacokinetic data. A
significance rating of 1 is thus
assigned to this adverse drug interaction because the documentation indicates that the interaction is at least suspected and
the clinical outcome of digitalis
toxicity is quite serious and potentially life-threatening.
TETRACYCLINES OR
OTHER BROAD-SPECTRUM ANTIBIOTICS WITH
ORAL ANTICOAGULANTS

Probably the largest number of

reported drug interactions involve the oral anticoagulants
warfarin, dicumarol and anisindione. These competitive antagonists of vitamin K-dependent
clotting factors have a low therapeutic index; administration of
other drugs that can increase
these antagonists activity can
lead to serious and potentially
life-threatening bleeding.2
Several antibiotics routinely
used in dentistry have been implicated in producing this effect.
It has been hypothesized that
broad-spectrum antibiotics such
as tetracyclines, amoxicillin and
ampicillin can reduce endogenous vitamin K levels and enhance the effects of oral anticoagulants by decimating the
normal gut flora that produce
vitamin K.
There have been several case

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241

PHARMACOLOGY
reports of increased prothrombin times and bleeding in patients taking anticoagulants and
a variety of tetracyclines.2,33-35
However, one study demonstrated that tetracycline had no effect on prothrombin times in a
group of patients receiving
chronic warfarin therapy.36 Case
reports implicating amoxicillin
or ampicillin with enhanced anticoagulant activity also have
appeared in the literature.2,37
Interestingly, there has been at
least one report demonstrating
that amoxicillin slightly lowered
prothrombin times in five patients.2 It appears that the ability of these antibiotics to enhance anticoagulant activity is
relatively rare and unpredictable, and that it is of most
concern in patients whose dietary intake of vitamin K is
poor.38,39 Concurrent use of these
antibiotics with oral anticoagulants (in patients with normal
vitamin K intake) need not be
avoided, but patients need to be
monitored for signs (such as
bruising, melena, bleeding) of
increased anticoagulant activity.
ERYTHROMYCIN,
CLARITHROMYCIN OR
METRONIDAZOLE WITH
ORAL ANTICOAGULANTS

A marked increase in the effects

of warfarin with bleeding has
been reported in some patients
simultaneously taking a five- to
eight-day course of erythromycin,2,30,35,40-45 clarithromycin2 or
metronidazole.2,46 The results of
a pharmacokinetic study revealed that, in some volunteers,
the ingestion of erythromycin (1
g per day for eight days), resulted in a 30 percent reduction of
warfarin clearance.47 Another
clinical investigation demonstrated that metronidazole (750
mg daily for one week) increased
the half-life of warfarin by al242

most one-third and virtually

doubled the anticoagulant effect
of the more active (S-) isomer of
warfarin.48 While the enhancement of anticoagulant activity
appears in only some people,
this potentially serious interaction is supported by pharmacokinetic data. A full course of
therapy with these antibiotics in
a patient receiving anticoagulation therapy requires consultation with the patients physician
before being initiated.49 Warfarin is just one of many drugs
whose metabolism can be inhibited by antimicrobial agents
that block the cytochrome P-450
system.50,51
ERYTHROMYCIN,
CLARITHROMYCIN,
KETOCONAZOLE OR
ITRACONAZOLE WITH A
HOST OF OTHER DRUGS

The cytochrome P-450 system

consists of a large set of similar
enzymes (isoenzymes) that are
responsible for metabolizing a
wide range of drugs.50,51 The
CYP3A4 isoenzyme accounts for
60 percent of the cytochrome
enzymes in the liver and 70 percent of those in the enterocytes
found in the gut wall.51
Erythromycin, clarithromycin,
ketoconazole (Nizoral, Janssen
Pharmaceutica Inc.) and itraconazole (Sporanox, Janssen
Pharmaceutica Inc.) are potent
inhibitors of CYP3A4 and thus
can significantly increase blood
concentrations and toxicity of
other drugs that use this system for detoxification.
The toxicity that one encounters with these interactions is
simply an extension of the interacting drugs pharmacological effects, as if an overdose of
the interacting agent had been
administered. For example, erythromycin or ketoconazole,
when taken concomitantly with

the nonsedating antihistamines

terfenadine or astemizole, can
induce prolongation of the Q-T
interval on the electrocardiogram and a life-threatening
form of ventricular arrhythmias
known as torsades de pointes.
These effects are identical to
what one would see with an
overdose of these nonsedating
antihistamines.52,53
The inhibition of other cytochrome isoenzymes such as
CYP1A2 accounts for erythromycins ability to greatly enhance theophylline blood concentrations and toxicity.51 In
addition to case reports, all of
the interactions assigned a significance rating of 1 or 2 in
Table 2 are supported by pharmacokinetic data consisting of
increased half-lives or plasma
concentrations of the interacting drug.2,50,51,54-94 In some instances, the actual adverse
pharmacodynamic events published in case reports have been
reproduced in clinical studies.
Typically, the CYP3A4 inhibitor
has to be taken for at least three
to five days before the interaction occurs, although there have
been reports of exposure times
as short as one day. Concomitant use of these antimicrobial
drugs with the interacting drug
should be avoided.
Terfenadine and astemizole. The interaction of this
type that has received the most
attention over the last six years
involves the nonsedating antihistamines terfenadine
(Seldane, Hoescht Marion
Roussel) and astemizole
(Hismanal, Jannsen
Pharmaceutica Inc.).2,54-59
Terfenadine is actually a prodrug; that is, the parent compound undergoes almost complete metabolism by CYP3A4 in
the gut and liver to an active

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PHARMACOLOGY
acid metabolite fexofenadine
(Allegra, Hoescht Marion
Roussel), as shown in Figure 1.
In fact, it is highly unusual to
detect any terfenadine in the
bloodstream of a patient who
has ingested the drug.54,58 The
active metabolite fexofenadine
provides the desired antihistaminic action.50,51,54 The parent
compound terfenadine is potentially cardiotoxic, and if its
metabolism by CYP3A4 is impaired, terfenadine can accumulate in the body and result in
serious cardiac toxicity, including torsades de pointes.54,55,58,59
Like terfenadine, astemizole
also undergoes extensive firstpass metabolism by CYP3A4,
and it appears that the parent
astemizole molecule also is cardiotoxic.51,58 A number of wellcontrolled studies have demonstrated that erythromycin,
clarithromycin and the azole
antifungal drugs ketoconazole
and itraconazole cause an accumulation of both the parent terfenadine molecule and its active
metabolite fexofenadine in
healthy volunteers.2,54,55,58,59 In
addition, electrocardiographic
changes (prolonged Q-T intervals) have been detected in
some of the study population.54,59
As terfenadine is the cardiotoxic entity, it has been removed from the market and replaced by fexofenadine, its
noncardiotoxic active metabolite. Like fexofenadine, loratadine (Claritin, Schering
Corporation) does not appear to
be cardiotoxic and appears to be
free of this adverse drug interaction with erythromycin, clarithromycin or ketoconazole.51,95
It also appears that the related
macrolide antibiotic azithromycin does not interact with
terfenadine or astemizole.50,51,55
Cisapride with CYP3A4

Terfenadine

OH
HO-C

N-CH2CH2CH2CH

CH3
C-CH3
CH3

Fexofenadine

OH
HO-C

N-CH2CH2CH2CH

CH3
C-COOH
CH3

Figure 1. Conversion of potentially cardiotoxic terfenadine to fexofenadine by CYP3A4. Erythromycin, clarithromycin, ketoconazole and itraconazole block this process.

inhibitors. Although the interactions with nonsedating antihistamines are fairly wellknown among dental
practitioners, serious and potentially fatal ventricular arrhythmias, including torsades
de pointes, also have been reported in patients concomitantly taking cisapride (Propulsid,
Janssen Pharmaceutica Inc.)
and inhibitors of CYP3A4 (including azole antifungal agents,
erythromycin, clarithromycin
and metronidazole).50,51,60-62,96
Cisapride is a widely prescribed
gastrointestinal prokinetic
agent, indicated for the treatment of gastroesophageal reflux

disease. As with the nonsedating antihistamine interactions,

deaths have been attributed to
this interaction.51,60 Studies in
healthy volunteers have demonstrated substantial increases in
cisapride blood concentrations
and prolongation of the Q-T interval on the electrocardiogram
when cisapride and ketoconazole were taken concomitantly.62
As with astemizole and terfenadine, the significance rating assigned to the interaction between cisapride and the
antimicrobial agents in Table 2
is 1.
Triazolam with midazolam. Other adverse drug inter-

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243

2,000

1,500
P < .01

1,000

500

0
Rifampin Control

N orethisterone (nanogram/milliliter)

Ethinyl estradiol (picogram/milliliter)

PHARMACOLOGY

40

30
P < .01

20

10

0
Rifampin Control

Figure 2. Blood concentrations (mean + standard error) of ethinyl estradiol, or EE, and norethisterone in women taking oral contraceptives in
both 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

actions involving these antimicrobial inhibitors of the cytochrome P-450 system are
summarized in Table 2. They
all involve the accumulation of
the interacting drug. The adverse drug interactions with the
oral antianxiety-sedative agents
triazolam and midazolam are
especially relevant to dental
practitioners who use oral sedation techniques. In one case report, an 8-year-old child who
was premedicated with oral midazolam lost consciousness during an erythromycin infusion.89
His peak midazolam concentrations were double the normal
values. The child awakened
spontaneously 45 minutes later.
In a placebo-controlled study
of 12 healthy volunteers, erythromycin (500 mg three times a
day for six days) increased peak
blood levels of a single dose of
oral midazolam almost threefold.90 In addition, drowsiness
and other indicators of psychomotor impairment were far
more intense in subjects taking
erythromycin compared to a
placebo. The effects of eryth244

romycin on blood levels and

sedative effects of intravenous
midazolam were far less profound.90 Another study found
that even a single 750-mg dose
of erythromycin increased the
sedative effects of a single 10mg oral dose of midazolam.91
A study of 16 healthy subjects found that 333 mg of
erythromycin daily for three
days decreased the clearance of
a single 0.5 mg dose of triazolam by about half, and approximately doubled total triazolam
blood levels (levels in the area
under the concentration
curve).92 Azithromycin seems
free of interactions with midazolam or triazolam.97 Clinical
studies have revealed that ketoconazole and itraconazole have
even more dramatic effects on
these sedative hypnotics, increasing total blood concentrations of oral midazolam and triazolam 15- and 27-fold,
respectively, and peak blood
levels three- to fourfold. Intense
and prolonged (as long as 17
hours) psychomotor impairment
accompanied these pharmacoki-

netic changes.93,94
Fortunately, when taken by
mouth, benzodiazepines such as
midazolam and triazolam have
enormous therapeutic indexes
when compared to other classes
of antianxiety-sedative drugs.
Overdoses of almost 70-fold
have not resulted in fatalities.98
Thus, the interaction between
macrolide antibiotics or azole
antifungal drugs and midazolam or triazolam is given a significance rating of 2. Oversedation with prolonged and intense
psychomotor impairment is a
likely, although not life-threatening, outcome.
ANTIBIOTICS WITH ORAL
CONTRACEPTIVES

Among the most contentiously

debated adverse drug interactions is the alleged ability of a
variety of commonly prescribed
antibiotics to reduce blood concentrations and the ultimate effectiveness of oral contraceptive
agents. Considering the relatively high usage of these
agents, the actual scientific
documentation for this interaction is far from overwhelming.
Before a discussion of the data
or lack of data supporting this
interaction, a brief review of
oral contraceptive pharmacology is in order.
The pharmacology of oral
contraceptives. The combination pill is made up of two components: semisynthetic estrogens, typically ethinyl estradiol,
or EE, or mestranol, and
semisynthetic progesterones
known as progestins (for example, norethisterone and levonorgestrel). The estrogen component gains its contraceptive
efficacy by blocking ovulation
by inhibiting the release of follicle-stimulating hormone, or
FSH, and luteinizing hormone,

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

PHARMACOLOGY

B
EE EE

EE

Glucuronic
Acid

EE

SO4

EE

EE

EE

Glucuronic
Acid

EE

SO4
Antibiotic

Gut
Flora

EE

EE

EE

EE

EE

EE

Intestine

Intestine

Blood

Blood

EE

EE

EE

EE

EE

EE

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

or LH. The mechanisms of action for the progestin component include an enhancement of
the viscosity of cervical fluid, a
change in the endometrial lining that makes it unsuitable for
egg implantation, and some antiovulatory action.99
The components of the pill
are not without potential side
effects. The most critical side effect of the estrogen component
is an increased risk of venous
thromboembolytic disease. The
progestin component has been
associated with increases in
blood pressure, blood glucose
and blood lipid levels in some
women. An increased risk of
myocardial infarction and
stroke have been reported in
oral contraceptive users older
than the age of 35 years who
are heavy smokers.99 These
deleterious events have led to
the development of pills containing reduced dosages of both
components. Some authors have

speculated that the widespread

use of these so-called minipills, which have reduced
amounts of both estrogen and
progestin components, increase
the risk of drug interactions
and contraceptive failure.100
Like any drug, oral contraceptives are not 100 percent effective. When taken correctly,
they reduce the chance of becoming pregnant to less than 1
percent. However, the typical
failure rate among American
populations is around 3 percent
per year.101 In the teenage population, the failure rate is reported to be as high as 8 percent,
probably from teens missing an
average of three pills per
cycle.102
Interactions with rifampin. The antituberculosis
drug rifampin was the first antibiotic implicated in reducing
the effectiveness of oral contraceptives. In 1971, Reimers and
Jezek103 reported that 38 of 51

women (75 percent) taking rifampin and oral contraceptives

concomitantly experienced
breakthrough bleeding, an indicator of ovulation. Two years
later, another report stated that
in 88 women, five pregnancies
and 66 instances of breakthrough bleeding were associated with concomitant use of rifampin and oral contraceptives.104 Other reports of pregnancy have been associated
with this interaction.105 In fact,
76 percent of all alleged antibiotic-oral contraceptive interactions involve rifampin.106
Clinical studies clearly
demonstrate that rifampin significantly reduces blood levels
of both the estrogen and progestin components of oral contraceptives (Figure 2).107,108
Rifampin is a potent inducer of
the liver cytochrome P-450 system and increases the
metabolism of a number of
drugs, including oral contracep-

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245

Ethinyl estradiol (picogram/milliliter)

PHARMACOLOGY

1,200
1,000
800
600
400
200
0

Control

Tetracycline Tetracycline
Day 1
Days 5-10

Figure 4. Blood concentrations (mean + standard error) of ethinyl estradiol, 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

tives.51,105 At present, rifampin

remains the only antibiotic that
has been scientifically demonstrated to interfere with the effectiveness of oral contraceptive
agents.
Interactions with other
antibiotics. Case reports of
more commonly prescribed antibiotics interfering with oral
contraceptive effectiveness
began to surface in 1975. In
that year, Dossetor109 reported
three cases in her practice in
which patients taking oral contraceptives apparently had become pregnant when given
ampicillin. Five years later, another report described a 20year-old student who claimed to
be totally compliant with her
oral contraceptive regimen, but
nevertheless became pregnant
after a five-day course of tetracycline.110 In 1982, DeSano and
Hurley111 described 16 pregnancies over a two-year period in
their private obstetric and gyne246

cologic practices, all in patients

who claimed to be totally compliant with their contraceptive
regimen but who also had consumed additional medications.
Antibiotics had been consumed
in 13 of these cases: ampicillin
in five, penicillin in three, tetracycline in one and antibiotics
not commonly used in dentistry
in the other four. However, four
of the patients taking ampicillin
and two of those taking penicillin also had taken a variety of
other medications, including antihistamines, decongestants and
analgesics. All of these case reports were, by necessity, uncontrolled, retrospective and subject to recall bias.105
In 1986, a case report of an
alleged antibiotic-oral contraceptive interaction appeared in
the dental literature. A 19-yearold who had taken an oral contraceptive for 18 months received an intramuscular
injection of a long-acting peni-

cillin combination during dental

impaction surgery. At the threemonth follow-up, she was found
to be pregnant; 40 weeks after
surgery, she gave birth to
healthy twins.112
Probably the most comprehensive report of potential antibiotic-oral contraceptive interactions was supplied by Back
and colleagues,113 who gathered
data from the United Kingdoms
Committee on Safety in
Medicines between 1968 and
1984. During this period, 63
pregnancies were reported with
simultaneous administration of
oral contraceptives and antibiotics (excluding rifampin).
Penicillins were implicated in
32 of these pregnancies, tetracyclines in 12, cotrimoxazole (sulfamethoxazole and trimethoprim) in five, metronidazole in
three, erythromycin in two and
antibiotics not commonly used
in dentistry in the other nine.
The authors tempered these
findings by also reporting that
in England between 1973 and
1984, there was a total of
159,000,000 prescriptions for
penicillins; 68,000,000 for tetracyclines; 40,000,000 for cotrimoxazole; 31,000,000 for erythromycin; and 6,000,000 for
metronidazole. In addition, they
reported, there were approximately 2,500,000 regular users
of oral contraceptives per year
during this period.114 Thus, the
actual number of reported pregnancies in England alleged to
involve oral contraceptive interactions with antibiotics other
than rifampin might be, in reality, extremely low.
In the United States, 29 reports of unintended pregnancies
in oral contraceptive users who
received penicillins or tetracyclines were listed in the U.S.
Department of Health and

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PHARMACOLOGY
Human Services MEDWATCH
Spontaneous Reporting
System.115 These numbers again
must be tempered with the fact
that as of 1994, approximately
11,000,000 women per year
were using oral contraceptives
in the United States.116
Assumptions in the literature. Although these case reports certainly should not be ignored and theoretically could
indicate a rare interaction, a
number of reviews have been
published implying that the
ability of commonly prescribed
antibiotics to reduce the effectiveness of oral contraceptives is
an established interaction.117-119
For example, one otherwise excellent article in the dental literature discussing the impact of
the 50 drugs most frequently
dispensed in clinical practice
contains a statement that the
antibiotics that interfere with
the ovulatory inhibiting effects
of oral contraceptives are penicillin V potassium, amoxicillin,
cephalexin, tetracycline and
erythromycins.117 The author
cites as his evidence one of the
previously described case reports112 and not any clinical trials or pharmacokinetic data.
In 1991, the ADA Health
Foundation Research Institute
published a statement concerning this issue. A small portion
of the statement read as follows: Unfortunately, many antibiotics commonly used in dentistry interfere with the action
of oral contraceptives, resulting
in unexpected pregnancies.
Failure to inform a patient
using oral contraceptives during
antibiotic therapy resulting in a
birth could leave the dentist responsible for damagesincluding child support payments.120
While it was very important to
warn dentists of the possibility

of this interaction, there were

not enough scientific data to
support the statement that the
interaction was indeed established. Even the Physicians
Desk Reference121 at best describes the interaction with antibiotics other than rifampin as
possible. Other authors have
reported one or two successful
litigations against dentists.115,122
Unfortunately, these legal proceedings cannot be researched
or even substantiated.123
The pharmacological
basis of the interaction.
Antibiotics ability to inhibit the
enterohepatic recirculation of
the estrogen component of the
oral contraceptive is the theory
most often mentioned in the literature to explain the alleged
interaction124-126 (Figure 3). In
humans, the bioavailability of
EE is only about 40 percent to
50 percent because of a large
first-pass metabolism in the gut
and the liver. These inactive
conjugated metabolites (50 percent to 60 percent of the parent
compound) then are excreted in
the bile, where the drug would
be lost if not for the bacteria in
the colon, which are thought to
split the EE conjugates. This
liberates the active parent compound, which can readily be reabsorbed in the intestine and
provide the necessary additional blood levels of the drug.
In theory, this enterohepatic
recirculation can be inhibited
by antibiotics that kill the
colonic bacteria involved in the
deconjugation process. In fact,
studies in rats and rabbits do
show that pretreatment with
ampicillin interferes with the
enterohepatic recirculation process.127-128 However, no clinical
study has been able to demonstrate that a similar scenario
also occurs in humans.

Proving the interaction. A

study many reference as scientific proof of an interaction between antibiotics and oral contraceptives is one in which
treatment with ampicillin reduced endogenous estrogen concentrations in pregnant patients.129 However, this study
did not evaluate the effects of
antibiotics on the blood levels of
the estrogen or progestin component of oral contraceptives,
and any attempt to correlate
ampicillins ability to reduce endogenous estrogen in pregnant
patients with the failure of oral
contraceptives is scientifically
questionable.
A number of studies, however, have looked directly at oral
contraceptive blood concentrations both in the absence and
the presence of antibiotics.
Studies showed no significant
decreases in plasma levels of either the EE or the progestin
contraceptive component in
women treated with ampicillin,130,131 tetracycline,125,132
doxycycline,133 metronidazole,130
erythromycin,125 clarithromycin,134 temafloxacin135 or fluconazole.136 Figure 4 illustrates
the results of one such study.
The antibiotic cotrimoxazole actually increased EE levels significantly,137 whereas clarithromycin significantly
reduced FSH and LH levels134
all of these being possible indicators of increased contraceptive efficacy. In another study of
22 women taking oral contraceptives, none of the subjects
ovulated while ingesting roxithromycin (a macrolide related
to erythromycin), but 11 (50
percent) ovulated while ingesting the positive control rifampin.138
There is one potential weakness in all these studies: their

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247

PHARMACOLOGY
relatively small sample sizes
(ranging from six to 25 women).
If the interaction occurs rarely,
as in one in 1,000 people, studies of this size may not detect
the interaction. It should be
noted, however, that these relatively small sample sizes readily display the rifampinoral
contraceptive interaction.107,108,138
There are two retrospective
studies, with somewhat larger
databases, that have examined
pregnancy rates in women who
consumed antibiotics as dermatologic patients. (The issue of
potential antibiotic interactions
with oral contraceptives is of
great importance to dermatologists, because they often prescribe antibiotics on a chronic
basis to women of child-bearing
potential.) In the first study,
281 patients were surveyed; 34
were found to have used antibiotics and low-estrogen contraceptives for a combined total of
71 years.139 One woman who
concurrently took tetracycline
and oral contraceptives for 12
months became pregnant, giving an overall pregnancy rate of
1.4 percent per year among patients taking antibiotics.
In a larger study of 356 patients with a history of combined antibiotic-oral contraceptive use and of 425 women
taking oral contraceptives and
no antibiotics, researchers
found a pregnancy rate of 1.6
percent in the antibiotic group
and 0.96 percent in the control
group.101 There was no significant difference (P = .4) in pregnancy rates between the antibiotic and control groups, and
both groups had pregnancy
rates below the 3 percent typically found in the United
States.
Are there any data other
than case reports that support
248

the possibility of an interaction

between commonly prescribed
antibiotics and oral contraceptives? Shenfield and Griffin140
presented a single case study of
an oral contraceptive user who
had a history of breakthrough

The failure of oral

contraceptives in
women simultaneously ingesting antibiotics may indicate
background noise
that is, the normal
failure rate of these
drugs or a relatively
rare interaction that
cannot be detected
by clinical trials.
bleeding while on antibiotics.
While taking minocycline, this
woman displayed lower EE
plasma concentrations and the
abolition of two of three plasma
peaks, as compared with when
she was not taking the antibiotic.140 It was hypothesized that
this conceivably could indicate
an antibiotic-induced reduction
of the enterohepatic recirculation process in this subject.
One other study, while revealing no effect of ampicillin on
plasma EE levels of the entire
study population, did identify
two women in the sample whose
EE concentrations were significantly reduced while they were
taking ampicillin.131 However,
neither of these women experienced breakthrough bleeding or
changes in laboratory parameters that would indicate ovulation.
Interaction vs. normal
contraceptive failure rate.

The failure of oral contraceptives in women simultaneously

ingesting antibiotics may indicate background noisethat is,
the normal failure rate of these
drugs or a relatively rare interaction that cannot be detected
by clinical trials. Although the
interaction, by definition, cannot be classified as established,
probable or even suspected, the
philosophy of recommending
the use of additional forms of
birth control for all oral contraceptive users receiving antibiotic therapy, as a possible protection of a few of them from
unwanted pregnancies, still
seems justified.
Of note, however, are the recently published legal proceedings in which a plaintiff and her
husband sued a gynecologist
and an oral surgeon for malpractice and wrongful life
after she allegedly became pregnant either during or shortly
after she was given a prescription for penicillin V.141 Both doctors had failed to warn her of a
potential interaction with the
oral contraceptive she was taking. She and her husband lost
the case for the following reasons: (1) Her experts cited review articles with no data and
articles that showed no statistically significant correlation between antibiotic use and oral
contraceptive failure; (2) her experts failed to show a scientifically validated interaction between penicillin V and the oral
contraceptive she was taking;
(3) under California law, physicians do not have to discuss
risks of a very low incidence
(the failure rate would have to
be more than double the normal
expected rate); and (4) her experts also failed to prove that
she became pregnant when she
was taking penicillin.

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

PHARMACOLOGY
CONCLUSION

Adverse drug interactions involving antimicrobial agents

can occur in dental patients. Of
particular significance is the
ability of certain antimicrobial
agents to cause the accumulation of a number of drugs that
have low therapeutic indexes. It
is important that clinicians stay
abreast of potential drug interactions to avoid serious morbidity among their patients.
Dr. Hersh is an associate professor,
University of Pennsylvania, School of Dental
Medicine, Department of Oral Surgery and
Pharmacology, 4001 Spruce St., Philadelphia,
Pa. 19104-6003. Address reprint requests to
Dr. Hersh.
This article is based on material presented
March 4, 1998, in a symposium entitled
Adverse Drug Interactions in Dentistry:
Separating the Myths From the Facts. Dr.
Hersh and Dr. Paul Moore cochaired this
symposium, which was presented at the 27th
General Session of the American Association
for Dental Research in Minneapolis. The symposium was jointly sponsored by the
International Association for Dental
Research, the American Association of Dental
Schools and the American Dental Association
and was supported in part by a grant from
Warner Lambert Pharmaceuticals.
The drugs listed by brand name in this article are given as examples only. Their listing
does not imply any endorsement.
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PHARMACOLOGY
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