This document reviews evidence on potential drug interactions between oral contraceptives and antibiotics that may lead to contraceptive failure. It summarizes several studies, including: - 30 case reports of pregnancies in women taking oral contraceptives and antibiotics like rifampin. - Surveys of women prescribed both oral contraceptives and antibiotics found failure rates of 1.2-1.6%, within the expected range for typical use but higher than perfect use. Common antibiotics included tetracyclines and penicillins. - Adverse event reports linked contraceptive failures to antibiotics like griseofulvin and combinations including penicillins, tetracyclines and sulfonamides. However, failure rates matched

1. REVIEW
Drug Interactions Between Oral Contraceptives and
Antibiotics
Barry D. Dickinson, PhD, Roy D. Altman, MD, Nancy H. Nielsen, MD, PhD, and
Melvyn L. Sterling, MD, for the Council on Scientific Affairs, American Medical Association
OBJECTIVE: To evaluate the evidence on possible drug in-
teractions between antibiotics and oral contraceptives
(OCs) that may lead to OC failure.
DATA SOURCES: MEDLINE and Lexis/Nexis Medical Li-
brary searches for 1966–1999 using the key word “oral
contraceptives,” cross-indexed with the terms “antibiotics,”
“adverse effects,” and “pregnancy,” and MEDLINE search
using the additional MeSH term “drug interactions.” No
language restrictions were used.
METHODS OF STUDY SELECTION: A total of 167 articles were
retrieved for analysis. Another 32 articles were identified
by review of the references cited in these publications.
Articles were selected based on their ability to provide
information on the relationship between antibiotic therapy
and OC efficacy in otherwise compliant users (defined as
women with unplanned pregnancies who reported compli-
ance with their OC regimen). Additionally, studies that
either directly measured the effects of antibiotics on the
pharmacokinetics of OC components, or that analyzed the
effects of antibiotics on measures of ovulation in OC users
were accepted.
TABULATION, INTEGRATION, AND RESULTS: At least 30 cases
have been reported of pregnancies occurring in women
taking OCs and antibiotics, particularly rifampin. Approx-
imately 20% of pregnant women reporting to family plan-
ning or abortion clinics reported concomitant OC and
antibiotic use. Information from adverse event reporting
databases generally mirrors the types of information
gleaned from these case reports and clinical surveys and
accounts for approximately one-third of reported cases.
Retrospective surveys, primarily from dermatology-based
practices, also have reported 24 pregnancies in OC users
who concomitantly received therapy with antibiotics, most
commonly tetracyclines and penicillins. Apparent OC fail-
ure rates in clinical surveys were within the usual range
expected for patterns of typical use. In pooled results ob-
tained from relatively small populations, oral antibiotics,
with the exception of rifampin, have not significantly af-
fected the pharmacokinetics of ethinyl estradiol, levonor-
gestrel, and norethindrone or reduced the serum concen-
trations of gonadotropins. However, individual patients
have been identified who experienced significant decreases
in the plasma concentration of these components of OCs
and who appeared to ovulate.
CONCLUSION: Rifampin impairs the effectiveness of OCs.
Pharmacokinetic studies of other antibiotics have not
shown any systematic interaction between antibiotics and
OC steroids. However, individual patients do show large
decreases in the plasma concentrations of ethinyl estradiol
when they take certain other antibiotics, notably tetracy-
cline and penicillin derivatives. Because it is not possible to
identify these women in advance, a cautious approach is
advised. (Obstet Gynecol 2001;98:853–60. © 2001 by
the American College of Obstetricians and Gynecologists.)
An estimated 10 million women in the United States use
oral contraceptives (OCs) annually, including estrogen–
progestin combinations or progestin-only products.1
Combination products (monophasic, biphasic, or tripha-
sic) pills provide contraception primarily by suppressing
follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) release, thereby inhibiting follicular growth
and development and ovulation. Secondary effects on
cervical mucus and endometrial histology that reduce
the likelihood of fertilization or implantation also may
contribute. Progestin-only products (“minipills”) inhibit
ovulation in less than 50% of users, providing contracep-
tion mainly by thickening cervical mucus and maintain-
ing an endometrial environment that is unsuitable for
implantation and nurturing of a fertilized ovum.
The estrogenic component in virtually all combina-
tion products is ethinyl estradiol; a few products contain
mestranol, which serves as a pro-drug for ethinyl estra-
From the Council on Scientific Affairs, American Medical Association, Chicago,
Illinois.
Members and staff of the Council on Scientific Affairs at the time this report was
prepared were: Myron Genel, MD (Chair), New Haven, CT; Michael A.
Williams, MD (Chair-Elect), Baltimore, MD; Roy D. Altman, MD, Miami, FL;
Scott D. Deitchman, MD, MPH, Duluth, GA; J. Chris Hawk III, MD,
Charleston, SC; John P. Howe III, MD, San Antonio, TX; Hillary D. Johnson,
St. Louis, MO; Nancy H. Nielsen, MD, PhD, Buffalo, NY; John F. Schneider,
MD, PhD, Chicago, IL; Melvyn L. Sterling, MD, FACP, Orange, CA; Zoltan
Trizna, MD, PhD, Galveston, TX; and Donald C. Young, MD, Iowa City, IA.
Staff: Barry D. Dickinson, PhD (Secretary); James M. Lyznicki, MS, MPH
(Assistant Secretary); and Marsha Meyer (Editor), Chicago, IL.
853VOL. 98, NO. 5, PART 1, NOVEMBER 2001 0029-7844/01/$20.00
© 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc. PII S0029-7844(01)01532-0

2. diol. Older progestins used in combination pills are
norethindrone, norethindrone acetate, and ethynodiol
diacetate (estrane derivatives), and the second-genera-
tion agents norgestrel and levonorgestrel. Newer (third-
generation) progestins used in the United States include
desogestrel and norgestimate. These agents may possess
less potent androgenic activity.
Standard drug information and drug interaction data-
bases continue to issue warnings about the possibility of
OC failure in women who are prescribed rifampin,
griseofulvin, penicillins, and tetracyclines.2–4
Addition-
ally, a recent review intended for primary care physi-
cians identifies amoxicillin, ampicillin, metronidazole,
and tetracycline as drugs that may potentially decrease
the effectiveness of OCs, and advises that it may “be
prudent for women to use a back-up contraceptive
method during antibiotic therapy and for 7 days after
completing the antibiotic course or having the last epi-
sode of vomiting and diarrhea.”5
Given the continued concern about this issue among
physicians and the problems posed by unintended preg-
nancies, the American Medical Association’s Council on
Scientific Affairs systematically reviewed the literature
concerning women of childbearing age who became
pregnant after receiving antibiotics while practicing oral
contraception to formulate recommendations for clinical
practice based on the published scientific evidence.
Because there is no evidence that antibiotics affect the
pharmacodynamics of estrogens and progestins, it is
generally believed that any interaction between antibiot-
ics and OCs must be grounded in pharmacokinetic
effects on ethinyl estradiol and/or progestins. Therefore,
the Council also examined studies that either measured
directly the effects of antibiotics on the pharmacokinetics
of OC components, or analyzed the effects of antibiotics
on measures of ovulation in OC users.
SOURCES
Published studies from 1966 through December 1999
were identified through MEDLINE and Lexis/Nexis
Medical Library searches (without language restriction)
using the term “oral contraceptives,” cross-indexed with
“antibiotics,” “adverse effects,” and “pregnancy.” Re-
lated articles in the MEDLINE database using the addi-
tional MeSH term “drug interactions” also were identi-
fied. A total of 167 articles were retrieved for analysis,
and another 32 articles were identified by review of the
references cited in these publications. Articles were se-
lected based on provision of information on the relation-
ship between antibiotic therapy and OC efficacy in oth-
erwise compliant users (defined as women with
unplanned pregnancies who reported compliance with
their OC regimen). Case reports, surveys, and informa-
tion from adverse reaction databases, as well as studies
that either directly measured the effects of antibiotics on
the pharmacokinetics of OC components or analyzed
the effects of antibiotics on measures of ovulation in OC
users were reviewed.
RESULTS
Clinical Reports of Antibiotics Apparently Causing OC
Failure
The first report of potential interactions between anti-
biotics and OCs appeared in 1971 when Reimers and
Jezek6
reported an increased incidence of intermen-
strual breakthrough bleeding in 38 of 51 women
treated concomitantly with OCs and rifampin. Shortly
thereafter, rifampin was implicated in five unplanned
pregnancies among 88 women with tuberculosis who
were taking both rifampin and OCs. Another 62
women suffered from menstrual irregularities.7
Over
the next decade, another 13 reports documented
women with tuberculosis who became pregnant on
OCs with concomitant use of rifampin, often in asso-
ciation with other antitubercular agents, including one
who experienced a second pregnancy under the same
conditions.8 –12
After the reports on rifampin ap-
peared, possible linkages between the use of other
antibiotics and failure of OCs were reported in 12
additional women; the antibiotics included chloram-
phenicol, sulfamethoxypyradizine, ampicillin, oxacil-
lin, penicillin G, tetracycline, oxytetracycline, minocy-
cline, and other “unspecified.”10,13–16
Thus, the total
number of reported pregnancies due to OC failure
associated with antibiotic treatment is 30.
Case reports were also published linking the use of
griseofulvin to the occurrence of oligomenorrhea and
irregular menses in a 32-year-old woman taking a low-
dose, triphasic OC and of unplanned pregnancy in two
other women.17,18
Increasing the estrogen dose to 50 ␮g
restored regular menses. Additionally, 22 case reports of
a possible interaction between griseofulvin and OCs
were compiled in spontaneous adverse reaction reports
(see below).19
Surveys From Office-Based Practice
Four retrospective surveys have been conducted on pa-
tients from office-based practices or outpatient clinics
evaluating possible interactions between antibiotics and
OCs (Table 1).20–23
These surveys found OC failure
rates of 1.2–1.6% (ie, 1.2–1.6 pregnancies per 100 years
of women exposure) in women on OCs who also were
treated with antibiotics. These failure rates are larger
than the ideal failure rates predicted with perfect compli-
854 Dickinson et al OC and Antibiotic Interactions OBSTETRICS & GYNECOLOGY

3. ance, but well within the 1–3% (or larger) range encoun-
tered with patterns of typical use. These studies suffer
from reliance on patient recall and failure to consider the
frequency of sexual intercourse during the period of
possible drug interaction. Also, three studies emanated
from dermatology practices, in which the most common
antibiotic used was erythromycin. This drug is not asso-
ciated with OC failure, and macrolides may actually
Table 1. Surveys of Apparent Oral Contraceptive Failures in Women Taking Oral Antibiotics
Survey Design Subjects Results Conclusion/Comment
Helms et al20
Retrospective cohort
study of 3
dermatology
practices using chart
review and surveys
dependent on patient
recall
356 patients with a
history of
combined OC/
antibiotic use;
425 controls on
OCs alone,
including 263
from the first
groups
5 pregnancies in 311
woman-years in OC/
antibiotics users (1.6%
failure rate)
Combined antibiotic/OC
is associated with a
nonsignificant (P ϭ
0.4) increase in OC
failure rates. This value
is within the expected
range associated with
typical patterns of use
12 pregnancies in 1245
woman-years for OCs
alone (0.96% failure
rate)
Antibiotics were
minocycline and a
“cephalosporin,” which
had been taken for at
least 3 months when
pregnancy occurred.
No individual analysis
by type of OC or
antibiotic used
London et al21
Retrospective survey in
an outpatient
dermatology clinic
dependent on patient
recall
34 patients were
found to have
used oral
antibiotics and
OCs together.
1 pregnancy in 71 woman-
years (1.4% failure rate)
Combined oral
antibiotics/OCs
associated with
nonsignificant increase
in OC failure rate.
The most common
antibiotics were
erythromycin
and tetracycline
Preponderance of
erythromycin
recipients, an antibiotic
not noted for this
potential interaction
DeSano et al22
Retrospective survey of
private obstetrics
practice, dependent
on patient recall
16 apparently
compliant
patients who
became
pregnant while
taking oral
contraceptives
13 of 16 patients recalled
taking antibiotics
during the cycle in
which conception took
place, including
penicillin (3), ampicillin
(5), sulfa antibiotics (3),
tetracycline (1), and
cephalexin (1) (failure
rate N/A)
Antibiotics may cause
OC failure in otherwise
compliant patients;
however, failure rate is
within the range
associated with typical
patterns of use
Hughes et al23
Retrospective survey of
private dermatology
practice dependent
on patient recall
124 patients who
had taken
antibiotics for
acne and OC
simultaneously
2 pregnancies in 163
woman-years (1.2%
failure rate); antibiotics
were minocycline and
oxytetracycline
Antibiotics might cause
OC failure in otherwise
compliant patients;
however, failure rate is
within the range
associated with typical
patterns of use
Most common antibiotic
used was
erythromycin, an
antibiotic not noted for
this potential
interaction
OC ϭ oral contraceptive.
855VOL. 98, NO. 5, PART 1, NOVEMBER 2001 Dickinson et al OC and Antibiotic Interactions

4. increase the plasma concentrations of ethinyl estradiol
and certain progestins.
Interaction Information From Adverse Event Reporting
Databases
The Committee on the Safety of Medicines in the United
Kingdom and the Netherlands Centre for Monitoring of
Adverse Reactions to Drugs received reports on two
women who became pregnant on OCs while receiving
griseofulvin and sulfonamide antibiotics.19
Twenty
other OC users reported experiencing transient inter-
menstrual bleeding or amenorrhea in the first or second
cycle after beginning griseofulvin therapy.19
Inananalysiscoveringtheyears1968–1984,atotalof63
unplanned pregnancies were reported to the Committee on
Safety of Medicines in women taking OCs and concomi-
tant antibiotics.24
Penicillins and tetracyclines were in-
volved in 70% of the reports. Other antibiotics mentioned
were sulfamethoxazole plus trimethoprim, sulfonamides or
trimethoprim, metronidazole, cephalosporins, erythromy-
cin, and fusidic acid. In 51 reports that specified the type of
OC, the largest number of apparent reported failures (n ϭ
33) occurred in women using a low-dose monophasic prod-
uct containing 30 ␮g of ethinyl estradiol. The frequency
with which a particular antibiotic was associated with OC
failure roughly mirrored the volume of prescriptions writ-
ten for that time period, suggesting that the association may
have been by chance.
Pregnant Women Presenting for Family Planning
Services
One study over a 4-year period from November 1981 to
December 1985 documented 163 cases of OC method
failures in reliable OC users who presented for abortion
services.25
In more than one-third of these cases (36%),
there were no predisposing factors. Significant factors
associated with failure were diarrhea and/or vomiting in
35%, and breakthrough bleeding on the combined OC in
21%; 23% of the failures were associated with antibiotic
use, most commonly amoxicillin. These results are sim-
ilar to another study of pregnant women presenting to
family planning or abortion clinics that also discovered
approximately 20% of these women (23 of 113) reported
that conceptions occurred during concurrent use of com-
bination OCs and antibiotics.26
Although the strength of association varies in the
above reports of contraceptive failure in patients treated
concomitantly with various antibiotics, more than 200
occurrences have been noted in anecdotal case reports,
spontaneous adverse-event monitoring systems, and ret-
rospective surveys.
Possible Mechanisms for OC Failure Caused by
Antibiotics
Either pharmacodynamic or pharmacokinetic interac-
tions could theoretically inhibit the efficacy of OCs.
There is no evidence that any antibiotic directly affects
steroid receptor function, or that it serves as a physio-
logic antagonist of estrogens or progestins. It is com-
monly believed that drug interactions with OCs (not
involving steroid receptors) have a pharmacokinetic ba-
sis. Therefore, the pharmacokinetics of the common
estrogen and progestin components of combined OCs
are briefly reviewed. The values reported in the follow-
ing sections were obtained from original studies or pre-
vious reviews on the subject. If such information was
lacking, data was obtained from the manufacturer’s offi-
cial product labeling.
Pharmacokinetics of OC Components
Ethinyl estradiol, the major estrogenic component of
combined OCs, is well absorbed after oral administra-
tion but is subject to a first-pass effect in the gut mucosa
(sulfate conjugation) and liver. Oral bioavailability aver-
ages 38–48%, but great interindividual variability (20–
65%) has been reported.27
Ethinyl estradiol is 97%
bound to serum albumin. Although it is not bound to sex
hormone–binding globulin (SHBG), ethinyl estradiol
induces SHBG synthesis.
The major phase I metabolic reaction undergone by
ethinyl estradiol is aromatic 2-hydroxylation, which is
largely accomplished by the cytochrome P4503A4. This
metabolite is further methylated and conjugated with
glucuronic acid before urinary and fecal excretion. The
parent compound also is subject to direct glucuronida-
tion (and sulfation) at position 3, and possibly position
17 as well. Conjugates of ethinyl estradiol are secreted in
the bile. These conjugates may be hydrolyzed by gut
bacteria to liberate the parent compound, which can then
be reabsorbed (enterohepatic circulation).28
Treatment
with either ampicillin 250 mg four times daily or tetracy-
cline 250 mg four times daily decreases urinary excre-
tion, and increases the fecal excretion of ethinyl estradiol,
while reducing fecal bacterial estradiol-␤-glucuronidase
activity.
At steady state, plasma concentrations of estradiol
sulfate are higher than that of the parent compound.
Other minor hydroxylated metabolites of estradiol are
also formed. The elimination half-life of ethinyl estradiol
in most studies varies between 13 and 27 hours at steady
state.29
Based on in vitro analysis, all progestins in com-
mon use tend to inhibit the hepatic metabolism of ethinyl
estradiol to about the same degree.30
Results of some
studies indicate that the hepatic clearance of ethinyl
856 Dickinson et al OC and Antibiotic Interactions OBSTETRICS & GYNECOLOGY

5. estradiol may be more markedly inhibited by progestin
derivatives such as desogestrel.31
Nevertheless, the
steady state concentrations of ethinyl estradiol demon-
strate considerable interpatient variability, varying eight-
to tenfold.32–34
Levonorgestrel is rapidly and nearly completely ab-
sorbed after oral administration with a bioavailability ap-
proaching 100%. Levonorgestrel undergoes reduction and
hydroxylation in the liver, followed by conjugation with
sulfate and glucuronic acid. The parent compound also
may be subject to sulfation. Levonorgestrel is primarily
bound in serum to SHBG. The elimination kinetics of
levonorgestrel are not dose dependent in users of combina-
tion OCs because ethinyl estradiol induces the synthesis of
SHBG. The elimination half-life of levonorgestrel is vari-
able, averaging 36 Ϯ 13 hours at steady state.32–34
Norgestimate is well absorbed after oral administration
and is converted in part to an active, deacetylated derivative
that has a half-life of 12–30 hours. Various other hydroxy-
lated metabolites and conjugates also are formed.
Norethindrone (acetate) is well absorbed, with a mean
bioavailability of 65% due to presystemic clearance. It
chiefly undergoes reduction of ring A, followed by con-
jugation with glucuronide or sulfate. Some hydroxylated
metabolites also are formed that can undergo conjuga-
tion. Like other progestins, the plasma clearance and
half-life (5–14 hours) of norethindrone exhibit consider-
able interindividual variability. Norethindrone acetate is
completely and rapidly deacetylated to norethindrone
after oral administration.32
Ethynodiol acetate also is
quantitatively metabolized to norethindrone.32
Desogestrel is rapidly and well absorbed, with an oral
bioavailability of about 84%. The parent compound is
converted to an active metabolite, 3-keto-desogestrel,
which is 99% bound to SHBG and has a half-life of
28–38 hours. Other minor inactive hydroxylated metab-
olites also are formed, which may be converted to sulfate
and glucuronide conjugates. As with other progestins,
there is a wide variability in individual clearances, and
elimination may be nonlinear due to induction of SHBG
by ethinyl estradiol.
Enterohepatic circulation is important in the elimina-
tion kinetics of ethinyl estradiol. With the possible ex-
ception of levonorgestrel, other progestins are not sub-
ject to direct conjugation. Rather, they are extensively
reduced to inactive compounds before conjugation. Ethi-
nyl estradiol and all progestins used in OCs are subject to
large interindividual variations in drug disposition.
Pharmacokinetic Interaction Studies of Antibiotics and
OCs
It is well established that drugs that increase the rate of
hepatic drug metabolism (phenobarbital, carbamaz-
epine, phenytoin) can increase the failure rate of OCs.32
Thus, concomitant use of rifampin, which is a potent
inducer of cytochrome P4503A4, is associated with an
increase in OC failure rate. Rifampin also induces
SHBG, which may reduce free plasma concentrations of
progestins. Antibiotics that do not induce cytochrome
P450 may reduce the plasma levels of steroids based on
indirect interference with the enterohepatic circulation of
ethinyl estradiol. With the possible exception of
levonorgestrel, other progestins commonly used in OCs
are not subject to direct conjugation with glucuronic acid
and enterohepatic circulation.
A number of studies have examined the effect of oral
antibiotics on the plasma concentrations of ethinyl estra-
diol and the progestin component, as well as FSH and
LH.35–49
Some studies also evaluated ovulation, either
with ovarian sonography or by measuring progesterone
concentrations. One study indicated that at least one
broad-spectrum antibiotic (sulfamethoxazole and tri-
methoprim) appears to actually increase the plasma con-
centration of ethinyl estradiol, while leaving the concen-
tration of levonorgestrel unchanged.50
In vitro analysis of the oxidation of ethinyl estradiol in
hepatic microsomes prepared from liver biopsies ob-
tained from women (n ϭ 4) treated with rifampin sug-
gests that such treatment increases the initial hydroxyla-
tion rate of ethinyl estradiol about fourfold.51
The effect
of rifampin on the disposition of OCs and the menstrual
cycle have been examined both in women with tubercu-
losis and in healthy volunteers. The majority of these
were open studies.35–40,52
Rifampin (450–600 mg daily
or 8–10 mg/kg) significantly accelerates the elimination
of ethinyl estradiol and various progestin components
that are contained in combination preparations. When
measured, approximately 30–50% of women appeared
to ovulate. Thus, rifampin clearly impairs the efficacy of
monophasic and triphasic preparations containing 30–
50 ␮g of estradiol.
A number of pharmacokinetic studies have been con-
ducted with other antibiotics in small groups of women.
Short-term administration of ampicillin (up to 1.5 g daily
in divided doses) did not significantly affect serum con-
centrations of gonadotropins or OC steroids. Individual
patients, however, exhibited breakthrough bleeding or
elevated FSH concentrations.41–43
Only 3 of 25 women
receiving low-dose monophasic preparations appeared
to ovulate when they were treated briefly with metroni-
dazole (400 mg three times daily for 6–8 days).42
In open studies involving volunteers who served as
their own controls, neither tetracycline nor doxycycline
significantly affected the disposition of monophasic prep-
arations containing 35 ␮g of ethinyl estradiol and nor-
ethindrone.44,45
Large interindividual variation oc-
857VOL. 98, NO. 5, PART 1, NOVEMBER 2001 Dickinson et al OC and Antibiotic Interactions

6. curred but was obscured in the analysis of pooled results.
In studies that examined the effects of fluoroquinolones
on low-dose monophasic preparations containing 30 ␮g
of ethinyl estradiol and levonorgestrel, plasma concen-
trations of LH, FSH, and the latter were largely unaf-
fected, although one woman experienced a large de-
crease in ethinyl estradiol.47–49
Among the macrolides,
roxithromycin does not affect ovulation,39
and dirithro-
mycin decreases the clearance of ethinyl estradiol ap-
proximately 10%, an effect that may be exacerbated
three- to fourfold in individuals with low baseline val-
ues.46
No interaction studies have been conducted using
products containing the newer progestins.
Except for rifampin, antibiotics do not significantly
affect the plasma concentrations of ethinyl estradiol (or
norethindrone and levonorgestrel) based on pooled
data; however, large interindividual variation in plasma
concentrations of ethinyl estradiol and norethindrone
occurred. Some of the large variance noted historically
can be attributed to the variability inherent in older assay
methodologies. In some studies, individual patients: 1)
exhibited large decreases in the plasma concentrations of
ethinyl estradiol; 2) experienced breakthrough bleeding
or rises in plasma estradiol indicating incomplete follicu-
lar suppression; or 3) appeared to ovulate.41–43,46,49
One
woman taking a triphasic OC preparation had a history
of breakthrough bleeding whenever she took antibiotics.
Measurement of plasma hormone concentrations on day
15 showed lower plasma ethinyl estradiol concentrations
with minocycline.52
Moreover, one individual has been
reported who preferentially formed ethinyl estradiol
conjugates because of an apparent inability to form the
2-hydroxy derivative.53
DISCUSSION
Based on retrospective case series (usually without con-
trol groups) and individual case reports, it has long been
suspected that the prescription of oral antibiotics to
women using OCs may occasionally result in OC failure
in otherwise compliant patients. Caution must be exer-
cised in the interpretation of these data because of recall
bias and the possibility that individuals may underreport
poor compliance when they are confronted with an
unplanned (or unwanted) pregnancy or are requesting
abortion services.
These studies have not demonstrated any systematic
interaction between antibiotics and OC steroids, and
clinical pharmacokinetic evidence indicating that antibi-
otics alter blood concentrations of OCs is lacking. Nev-
ertheless, it is possible that certain individuals may be at
risk of this interaction. Although reported cases of OC
failure in women concurrently taking antibiotics are
relatively few in number compared with the extensive
use of these products, the true incidence of such failures
is unknown and cannot be predicted in individual cases.
Because the disposition of OC components is so vari-
able among individuals, some may be more susceptible
to OC failure. Modern OC preparations contain smaller
amounts of estrogen; thus, drug interactions leading to
decreased efficacy of OCs may be more likely.54
How-
ever, with the exception of rifampin (and griseofulvin),
oral antibiotics do not induce hepatic drug metabolism.
In fact, the macrolides and azole antifungals tend to
inhibit the same cytochrome P450 isoform (3A4) that
hydroxylates ethinyl estradiol.
Therefore, clinicians are faced with the task of discuss-
ing risks, benefits, and alternatives—with the added bur-
den of not knowing the magnitude of the risk of OC
failure in patients who are prescribed oral antibiotics,
although the risk appears to be very small. It is so small
that, given the comparatively large range of OC failure
(1% to 3%), under patterns of typical use, it probably
cannot be identified. If women who are at risk are those
who have: 1) very low rates of ethinyl estradiol 2-hy-
droxylation; 2) relatively high rates of hepatic conjuga-
tion; 3) low plasma ethinyl estradiol concentrations; 4)
extensive intestinal hydrolysis of estrogen conjugates;
and 5) gut flora particularly susceptible to the antibiotic
being used, then averaging the results in small numbers
of women could easily fail to detect any interaction.
Under these circumstances, and given the serious conse-
quences of unwanted pregnancy, a cautious approach is
advisable to safeguard the few women using OCs who may
be at risk of OC failure. For those women on short-term
broad-spectrum antibiotic therapy, use of an additional
nonhormonal method of contraception may be justified.
Changing contraceptive methods because of short-term
antibiotic therapy is not advisable and may have negative
effects on contraceptive compliance and efficacy. For those
women on long-term antibiotic therapy, use of an addi-
tional nonhormonal method or alternative method of con-
traception may be justified. The period of risk for drug
interactions is not known during long-term therapy, but
may exist primarily during the first few weeks of therapy or
until gut flora become resistant. An alternative form of
contraception is advised if diarrhea or breakthrough bleed-
ing are noted in women taking OCs who receive antibiotic
therapy,orifthebaselinerateoforalcontraceptionfailureis
unacceptable.
CONCLUSIONS
The following statements, recommended by the Council
on Scientific Affairs, were adopted as American Medical
Association policy in June 2000.
858 Dickinson et al OC and Antibiotic Interactions OBSTETRICS & GYNECOLOGY

7. 1. Women prescribed rifampin concomitantly with
OCs faced significant risk of OC failure and should
be counseled about the additional use of nonhor-
monal contraceptive methods during the course of
rifampin therapy.
2. Women using combined OCs should be informed
about the small risk of interactions with antibiotics
and that it is not possible to identify in advance the
women who may be at risk of OC failure. Women
who are not comfortable with the small risk of inter-
action should be counseled about the additional use
of nonhormonal contraceptive methods. Women
who have had previous OC failures or who develop
breakthrough bleeding during concomitant use of
antibiotics and OCs should be counseled about the
use of alternate methods of contraception if they
engage in intercourse during the period of concomi-
tant use, as they may be part of the subset of women
at high risk of contraceptive failure.
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Address reprint requests to: Barry Dickinson, PhD, Secretary
to the Council on Scientific Affairs, American Medical Associ-
ation, 515 North State Street, Chicago, IL 60610; E-mail:
barry_dickinson@ama-assn.org.
Received November 30, 2000. Received in revised form April 6, 2001.
Accepted June 15, 2001.
860 Dickinson et al OC and Antibiotic Interactions OBSTETRICS & GYNECOLOGY