ReviewInteraction between broad-spectrum antibiotics and the combined oral contraceptive pill: A literature review
Introduction
The combined oral contraceptive pill (COCP) is among the most popular methods of contraception worldwide. It is easy to use and extremely effective. Failure rates in clinical trial settings are as low as 0.1 per 100 women-years. In typical use, however, few populations of women will achieve such low failure rates and up to 5% of women will have an unintended pregnancy during the first year of use of the COCP.1 One factor with potential impact on both ease of use and reliability of combined oral contraceptives is their postulated interaction with broad-spectrum antibiotics. It is widely believed that concurrent use of the COCP and broad-spectrum antibiotics may reduce contraceptive efficacy, leading to bleeding irregularities and even unwanted pregnancies. There is little consistent evidence for this, either from pharmacokinetic studies or in clinical practice. The international literature contains many reports of alleged antibiotic-induced COCP failures. There are, however, relatively few prospective studies of the pharmacokinetics of concurrent COCP and antibiotic use and few, if any, demonstrate a convincing basis for any reduced contraceptive efficacy. Rifampicin and griseofulvin do appear to have a genuine interaction with the COCP leading to reduced efficacy. The position with the broad-spectrum antibiotics is less clear. Not surprisingly, there are variable and conflicting opinions on the best way of dealing with periods of simultaneous COCP and antibiotic use. Not all authorities advocate additional contraceptive precautions. Those who do, give a somewhat complicated series of instructions that may lead to patient confusion, poor compliance, and a higher “user failure” rate of the COCP.
The British National Formulary (BNF), a refence source updated quarterly and available to all doctors in the UK,2 states that “rifampicin and griseofulvin induce hepatic enzyme activity … additional contraceptive precautions should be taken whilst taking the enzyme-inducing drug and for at least seven days after stopping it; if these seven days run beyond the end of a packet the new packet should be started immediately without a break (in the case of every day tablets, the inactive ones should be omitted) … rifampicin is such a potent enzyme-inducing drug that even if a course lasts less than seven days, the additional contraceptive precautions should be continued for at least four weeks after stopping it.” In the case of long-term administration of rifampicin, an alternative method of contraception (such as an IUD) is always recommended. If this is not possible, the BNF advises an oral contraceptive containing ethinyl estradiol ≥50 μg, which should be taken for 63 days followed by a break of only 4 days.
The BNF also advises that some broad-spectrum antibiotics (eg, ampicillin) may interfere with estrogen absorption and that additional contraceptive precautions should be taken while taking a short course of broad-spectrum antibiotics and for 7 days after stopping. If these 7 days run beyond the end of a packet, the next packet should be started without a break (in the case of every day [ED] tablets the inactive ones should be omitted). If the course exceeds 2 weeks, resistance to this interference develops, and additional precautions are said to become unnecessary.
Interestingly, the manufacturers’ data sheets (label) in the UK are not all in agreement with each other or with the above guidelines. Each company generally issues the same guidelines for all the COCP manufactured, regardless of hormone dose or whether monophasic or multiphasic preparation. Schering and Wyeth broadly echo the above FPA guidelines. The guidelines issued by Searle note that “some drugs modify metabolism” of COCP and, therefore, mechanical contraception “during concurrent use” of antibiotics is suggested. There is no recommendation to continue this for 7 days after stopping antibiotic treatment or to omit any imminent pill-free week. Jansen-Cilag in its data sheets merely notes that concurrent broad-spectrum antibiotic use may cause irregular cycles and decreased reliability of the COCP but does not suggest any form of additional contraceptive precautions.
In the US, some COCP data sheets mention that “reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with the concomitant use of rifampicin. A similar association, though less marked, has been suggested … with anti-convulsant drugs … and possibly with griseofulvin, ampicillin, and tetracycline.” There are no suggestions for additional contraceptive measures.
In light of the lack of consensus, a literature review (using MEDLINE and searching on the key words oral contraceptive, antibiotics, and drug interaction) was undertaken, to assess the strength of evidence for significant drug interactions and to look at the range of advice for clinical practice.
Section snippets
Mechanisms of COCP–antibiotic interaction
There are several known potential mechanisms of interaction between COCP and other drugs. These mechanisms include: 1) liver enzyme induction (this has been shown to apply to rifampicin and possibly griseofulvin, see below), and 2) reduced enterohepatic recirculation of estrogen.
Ethinyl estradiol undergoes a considerable first-pass metabolism in the gut wall and liver. Inactive, unabsorbable ethinyl estradiol conjugates are excreted in bile. Enzymatic activity of gut flora can deconjugate the
Antibiotic–COCP interactions
The extensive literature on antibiotic–COCP interactions falls broadly into three categories. First, there are retrospective case series, usually without control groups, and varying in size, down to individual case reports. Such reports should be considered in the light of likely recall bias and under-reporting of poor pill compliance in the inevitably emotive areas of unwanted pregnancy and requests for termination of pregnancy. Second, there are prospective, controlled studies assaying plasma
Advisory letters, articles, and editorials
On the basis of this rather unsatisfying literature (as well as personal experience), many have written cautionary advice, warning colleagues of the potential hazards of antibiotics in women taking the combined oral contraceptive pill. Dental and dermatologic journals seem particularly to abound in advice, by no means consistent. The dermatologists have the particular problem of long-term antibiotic administration, often tetracycline for resistant acne. In theory, emergence of resistant gut
Conclusion
The antifungal medication griseofulvin and the broad-spectrum antibiotic rifampicin have been convincingly shown to induce hepatic enzymes and to have significant interaction with the combined oral contraceptive pill. When either of these two antimicrobials is used by women taking the COCP, additional or alternative contraceptive protection is certainly advisable.
Uncertainty persists with respect to the other broad-spectrum antibiotics. Medical and dental journals continue to publish rare but
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