Do Antibiotics Interact With Combination Oral Contraceptives?

Ben M. Lomaestro, BS, PharmD

Disclosures

August 27, 2009

Question

Do antibiotics reduce the efficacy of combination oral contraceptives?

Response from Ben M. Lomaestro, BS, PharmD
Senior Clinical Pharmacy Specialist in Infectious Diseases, Department of Pharmacy, Albany Medical Center Hospital, Albany, New York

Oral contraceptives (OCs) available in the United States include estrogen-progestin monophasic, biphasic, or triphasic combination products and progestin-only products.[1] Reports and concerns exist regarding the hypothesis that oral antibiotics can reduce the efficacy of combination OCs.

Case reports of antimicrobial-induced OC failure may represent the normal 1% to 3% rate of pregnancy which occurs with typical OC use.[1,2,3,4] Recall bias and underreporting of poor compliance (when confronted with an unwanted pregnancy) may complicate an assessment of interaction incidence.[1,5]

Ethinyl estradiol, the estrogen component usually used in OCs, is about 40% to 50% absorbed systemically in the unchanged active form with marked variability between individuals.[1,2,3,5] The remainder undergoes significant first-pass metabolism in the gut wall and liver via cytochrome P450 3A4.[1] Inactive ethinyl estradiol conjugates are excreted in bile. Bacterial estradiol-beta-glucuronidase of gut flora can deconjugate the metabolites, releasing active ethinyl estradiol for reabsorption in the small intestine through an enterohepatic mechanism.[1,2,5] Progestins are very well absorbed, with no intestinal wall metabolism and minor first-pass hepatic metabolism.[2]

Many proposed mechanisms for interaction between antimicrobials and OCs exist. Examples include decreased absorption, decreased enterohepatic circulation, increased hepatic enzymatic competition, hepatic enzyme degradation or induction, increased elimination, antibiotic-induced diarrhea, increased serum protein binding, and displacement of contraceptive steroid from its receptor site.[1,2,3,4,5,6] There is no evidence that antimicrobials affect steroid receptor function or act as an antagonist of estrogens or progestins.[1] Some studies suggest that because modern preparations contain smaller amounts of estrogen (< 35 μg), the interaction with antibiotics may be more likely.[1,4,6]

Antibiotics, such as ampicillin (eg, Principen®), are also proposed to reduce the quantity of intestinal bacterial flora involved in the hydrolysis of estrogen conjugates in the gastrointestinal tract.[2] Pharmacokinetic studies in small groups of women found that breakthrough bleeding or elevated follicle-stimulating hormone concentrations can occur with short-term ampicillin use. However, this was not associated with changes in hormonal concentrations.[1] Some antibiotics, such as trimethoprim-sulfamethoxazole (eg, Bactrim®), may actually increase plasma levels of ethinyl estradiol.[1,2]

Certain drugs can reduce the efficacy of combination OCs. Drugs that increase hepatic drug metabolism (eg, phenobarbital, carbamazepine [Tegretol®], phenytoin [Dilantin®]) can increase the failure rate of combination OCs.[1] Antimicrobials that are enzyme inducers include rifampin (eg, Rifadin®) and griseofulvin (eg, Fulvicin®).[1,2,5] Rifampin can decrease the levels of both ethinyl estradiol and norethindrone by its potent enzyme inducing activity.[2]

Few studies on this exist[6] and many of the data are conflicting and inconclusive, making it difficult to discuss risks with patients.[3] Clinical pharmacokinetic data suggesting that antimicrobials alter blood concentrations of OCs are lacking (with the exception of rifampin and griseofulvin).[1,2] Potentially, women at risk include those with low rates of ethinyl estradiol hydroxylation, high rates of conjugation, low concentrations of plasma ethinyl estradiol, extensive intestinal hydrolysis of estrogen conjugates, and gut flora highly susceptible to the particular antibiotic.[1]

Women taking antibiotics who do not feel well may be more likely to forget to take or decide not to take their OC if experiencing adverse effects such as vomiting and diarrhea.[2] Medication adherence and different timing of pill taking or meals may contribute to an interaction.[1,5]

The American College of Obstetricians and Gynecologists concluded that tetracycline (Sumycin®), doxycycline (Vibramycin®), ampicillin, metronidazole (Flagyl®), fluconazole (Diflucan®), and fluoroquinolones do not affect OC steroid levels in women taking combination OCs.[7] Reviewers of the literature have suggested that a second form of contraception is not necessary unless rifampin is coadministered with OCs.[4] Griseofulvin would probably also merit such a recommendation. However, given the serious consequences of unwanted pregnancy (and the low but unpredictable incidence of antimicrobial-induced contraceptive failure), others have advised a more cautious approach to safeguard the few women who may be at risk for contraceptive failure.[1,6]

The risk for interaction with chronic low-dose antimicrobials (such as for acne) is unknown but may be most likely during the first weeks of antimicrobial therapy or until gut flora become resistant to the antimicrobial.[1] For those on long-term antibiotic therapy, a nonhormonal or alternative method of contraception may be justified.[1]

Alternative forms of contraception should be recommended for women in whom the baseline rate of OC failure is unacceptable.[1] Women should also be counseled not to stop their OC while on antimicrobials to avoid interaction.[5] Alternative contraception has been recommended if diarrhea or breakthrough bleeding are noted in women taking OCs who receive antibiotics (even though breakthrough bleeding is now recognized as a false marker of lessened contraceptive efficacy).[1,2]

For those on short-term antimicrobials, additional nonhormonal contraception may be justified at initiation and for the duration of antimicrobial therapy (or 14 days, whichever is longer), plus 7 more days after completion of antimicrobial therapy.[6]

With many well-known references suggesting alternative contraception during antimicrobial therapy, it is important to inform all female patients of possible interaction, even if the actual incidence is rare.[5,6]

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