Drug interactions between non-rifamycin antibiotics and hormonal contraception: a systematic review Katharine B. Simmons, MD, MPH; Lisa B. Haddad, MD, MS, MPH; Kavita Nanda, MD, MHS; Kathryn M. Curtis, PhD M illions of women worldwide rely on hormonal contraception (HC) to plan and space pregnancies and to prevent unintended pregnancies. 1 To maximize the reliability of these methods, it is important to understand whether drug interactions could contribute to HC failure or pose safety concerns. Antibiotics commonly are used by reproductive-aged women. Drug interactions between HC and antibiotics, such as induction or inhibition of he- patic enzymes by either drug, theoreti- cally could compromise contraceptive or antibiotic effect. 2 However, clinical con- cerns of drug interactions between anti- biotics and HC are based primarily on case reports of unintended pregnancies in HC users and patient and provider surveys that are limited severely by recall bias. 2 Likewise, although rifamycin an- tibiotics (rifampin, rifabutin) induce hepatic enzymes that are required for HC metabolism, other antibiotics do not; assumption of similar behavior of all antibiotic drugs may be inappropriate. 3 Misconceptions regarding HC and drug interactions are common among women, providers, and pharmacists; a majority of pharmacists recommend backup contraception for women who use antibiotics with HC. 4 Such warnings could result in interruption of a woman’ s HC or poor compliance with antibiotic regimens, which could increase her risk for treatment failure with either drug. If no true drug interaction is present, these risks are assumed unnecessarily. Objectives The purpose of this systematic review was to evaluate published literature on the interaction of non-rifamycin antibi- otics and HC. Specifically, we addressed the following research question: Among women taking HC or non-rifamycin antibiotics, do users who take these drugs together experience decreased contraceptive or antibiotic effectiveness or increased hormonal or antibiotic toxicity compared with users who take each drug alone? Methods This systematic review was conducted according to an a priori protocol with similar methods to previous World From the Division of Reproductive Health, US Centers for Disease Control and Prevention (Drs Simmons, Haddad, and Curtis), and the Department of Gynecology and Obstetrics, Emory University (Dr Haddad), Atlanta, GA; the Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC (Dr Simmons); and FHI 360, Durham, NC (Dr Nanda). The authors report no conflict of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. Corresponding author: Katharine Simmons, MD, MPH. [email protected]0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.07.003 OBJECTIVE: The purpose of this study was to determine whether interactions between non-rifamycin antibiotics and hormonal contraceptives result in decreased effectiveness or increased toxicity of either therapy. STUDY DESIGN: We searched MEDLINE, Embase, clinicaltrials.gov, and Cochrane li- braries from database inception through June 2016. We included trials, cohort, case- control, and pharmacokinetic studies in any language that addressed pregnancy rates, pharmacodynamics, or pharmacokinetic outcomes when any hormonal contra- ceptive and non-rifamycin antibiotic were administered together vs apart. Of 7291 original records that were identified, 29 met criteria for inclusion. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently assessed study quality and risk of bias using the United States Preventive Services Task Force evidence grading system. Findings were tabulated by drug class. RESULTS: Study quality ranged from good to poor and addressed only oral contraceptive pills, emergency contraception pills, and the combined vaginal ring. Two studies demonstrated no difference in pregnancy rates in women who used oral contraceptives with and without non-rifamycin antibiotics. No differences in ovulation suppression or breakthrough bleeding were observed in any study that combined hormonal contra- ceptives with any antibiotic. No significant decreases in any progestin pharmacokinetic parameter occurred during co-administration with any antibiotic. Ethinyl estradiol area under the curve decreased when administered with dirithromycin, but no other drug. CONCLUSION: Evidence from clinical and pharmacokinetic outcomes studies does not support the existence of drug interactions between hormonal contraception and non- rifamycin antibiotics. Data are limited by low quantity and quality for some drug clas- ses. Most women can expect no reduction in hormonal contraceptive effect with the concurrent use of non-rifamycin antibiotics. Key words: antibiotics, contraceptive failure, drug interaction, hormonal contraception, pharmacokinetics Systematic Reviews ajog.org 88 American Journal of Obstetrics & Gynecology JANUARY 2018
Transcript
Systematic Reviews ajog.org
Drug interactions between non-rifamycin
antibiotics and hormonal contraception:a systematic reviewKatharine B. Simmons, MD, MPH; Lisa B. Haddad, MD, MS, MPH; Kavita Nanda, MD, MHS;Kathryn M. Curtis, PhD
OBJECTIVE: The purpose of this study was to determine whether interactions betweennon-rifamycin antibiotics and hormonal contraceptives result in decreased effectivenessor increased toxicity of either therapy.STUDY DESIGN: We searched MEDLINE, Embase, clinicaltrials.gov, and Cochrane li-braries from database inception through June 2016. We included trials, cohort, case-control, and pharmacokinetic studies in any language that addressed pregnancyrates, pharmacodynamics, or pharmacokinetic outcomes when any hormonal contra-ceptive and non-rifamycin antibiotic were administered together vs apart. Of 7291original records that were identified, 29 met criteria for inclusion.STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently assessedstudy quality and risk of bias using the United States Preventive Services Task Forceevidence grading system. Findings were tabulated by drug class.RESULTS: Study quality ranged from good to poor and addressed only oral contraceptivepills, emergency contraception pills, and the combined vaginal ring. Two studiesdemonstrated no difference in pregnancy rates in women who used oral contraceptiveswith and without non-rifamycin antibiotics. No differences in ovulation suppression orbreakthrough bleeding were observed in any study that combined hormonal contra-ceptives with any antibiotic. No significant decreases in any progestin pharmacokineticparameter occurred during co-administration with any antibiotic. Ethinyl estradiol areaunder the curve decreased when administered with dirithromycin, but no other drug.CONCLUSION: Evidence from clinical and pharmacokinetic outcomes studies does notsupport the existence of drug interactions between hormonal contraception and non-rifamycin antibiotics. Data are limited by low quantity and quality for some drug clas-ses. Most women can expect no reduction in hormonal contraceptive effect with theconcurrent use of non-rifamycin antibiotics.
Key words: antibiotics, contraceptive failure, drug interaction, hormonal contraception,pharmacokinetics
illions of women worldwide rely
M on hormonal contraception(HC) to plan and space pregnancies andto prevent unintended pregnancies.1 Tomaximize the reliability of these
From the Division of Reproductive Health, US CenSimmons, Haddad, andCurtis), and the Departmen(Dr Haddad), Atlanta, GA; the Department of ObstCarolina, Chapel Hill, NC (Dr Simmons); and FHI 3
The authors report no conflict of interest.
The findings and conclusions in this report are thosthe official position of the US Centers for Disease C
Corresponding author: Katharine Simmons, MD, M
0002-9378/$36.00 � ª 2017 Elsevier Inc. All rights reser
88 American Journal of Obstetrics & Gynecology
methods, it is important to understandwhether drug interactions couldcontribute to HC failure or pose safetyconcerns. Antibiotics commonly areused by reproductive-aged women. Drug
ters for Disease Control and Prevention (Drst of Gynecology andObstetrics, EmoryUniversityetrics and Gynecology, University of North60, Durham, NC (Dr Nanda).
e of the authors and do not necessarily representontrol and Prevention.
interactions betweenHC and antibiotics,such as induction or inhibition of he-patic enzymes by either drug, theoreti-cally could compromise contraceptive orantibiotic effect.2 However, clinical con-cerns of drug interactions between anti-biotics and HC are based primarily oncase reports of unintended pregnanciesin HC users and patient and providersurveys that are limited severely by recallbias.2 Likewise, although rifamycin an-tibiotics (rifampin, rifabutin) inducehepatic enzymes that are required forHCmetabolism, other antibiotics do not;assumption of similar behavior of allantibiotic drugs may be inappropriate.3
Misconceptions regarding HC anddrug interactions are common amongwomen, providers, and pharmacists; amajority of pharmacists recommendbackup contraception for women whouse antibiotics with HC.4 Such warningscould result in interruption of a woman’sHC or poor compliance with antibioticregimens, which could increase her riskfor treatment failure with either drug. Ifno true drug interaction is present, theserisks are assumed unnecessarily.
ObjectivesThe purpose of this systematic reviewwas to evaluate published literature onthe interaction of non-rifamycin antibi-otics and HC. Specifically, we addressedthe following research question: Amongwomen taking HC or non-rifamycinantibiotics, do users who take thesedrugs together experience decreasedcontraceptive or antibiotic effectivenessor increased hormonal or antibiotictoxicity compared with users who takeeach drug alone?
MethodsThis systematic review was conductedaccording to an a priori protocol withsimilar methods to previous World
Koopmans et al14 Case cross-over Pharmacydispensingdatabase in theNetherlands
Any OC use; anyantibiotic scriptwithin 15 days ofconception
397 Cases; self-matched controls
Odds of antibioticexposure duringconception vscontrol timeperiods in OCfailurepregnancies
4 II-2, Poor
Toh et al13 Case cross-over SloaneEpidemiologyCenter BirthDefects Study andNational BirthDefectsPrevention Study
Any OC use duringmonth ofconception; anyantibiotic use in 4weeks beforeconception
1330 Cases; self-matched controls
Odds of antibioticexposure duringconception vscontrol timeperiods in OCfailurepregnancies
4 II-2, Fair
4, no difference in the outcome between cases and controls; OC, oral contraceptive pill.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
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Health Organization and Centers forDisease Control systematic reviews forcontraceptive guidance5,6 (protocolavailable on request). We report thissystematic review according to PreferredReporting Items for Systematic Reviewsand Meta-Analyses guidelines.7
Eligibility criteria, informationsources, and search strategyTypes of studies.We included randomizedand nonrandomized controlled trials,cohort studies, and case-control studies.Abstracts, case reports and series, cross-sectional studies, editorials, letters, andnonpublished results were excluded. Allincluded studies were required to have acomparison group; therefore, we alsoexcluded prospective observationalstudies without control groups. Forstudies with HC-related outcomes, thecomparison groupwaswomen takingHCwithout concurrent antibiotics. Forstudies of antibiotic-related outcomes,the comparison group was women takingthe antibiotic without HC.
Participants and interventions.Weincluded studies of women taking anymethod of HC (combined pills, patch,ring or injectables; progestin-only pills;ring, injectables, implants orintrauterine-devices, or emergency con-traceptive pills) in combination with anyoral, intravenous, or intramuscular non-rifamycin antibiotic. We excludedstudies of steroid hormones in non-contraceptive formulations, such asintravenous estrogen.
Types of outcomes and data items.Weincluded studies that had at least 1 clin-ical or pharmacokinetic outcome ofinterest. Clinical outcomes of interestincluded (1) pregnancy rates, (2) evi-dence of ovulation by luteal phase serumprogesterone alone or in combinationwith a dominant follicle on ultrasoundimaging, (3) antibiotic effectiveness(treatment response or failure),and (4) adverse health effects (break-through bleeding, drug side-effects,or complications). Pharmacokinetic
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outcomes of interest included areaunder the curve (AUC), maximumserum concentration (Cmax), andsteady-state levels of the contraceptivesteroid hormone or the antibiotic. Weexcluded studies that reported only uri-nary excretion of hormones becausethese were not considered interpretablepharmacokinetic findings.
Search strategy.We searched MEDLINE,Embase, Clinicaltrials.gov, andCochrane libraries from inception toJune 2016 for articles in any languageusing search terms that were developedwith a reference librarian (Appendix A).We scanned reference lists of relevantreview articles to identify additionalstudies that were not captured by oursearch.
Study selectionOne author (K.B.S.) performed thedatabase search in consultation witha reference librarian and screened alltitles and abstracts. Two authors
reviewed the full text of all possiblearticles to determine which articles metinclusion criteria. Non-English articleswere translated as needed. Anydisagreement between authors on in-clusion status was resolved with a thirdauthor.
Data extractionOne author independently extractedrelevant information from each study tocomplete prespecified evidence tables.Tables were reviewed for accuracy by asecond author before study grading(Appendices BeG). We included onlypublished findings and did not contactauthors to obtain additionalinformation.
Assessment of risk of biasWe assigned a quality rating for eachstudy that was based on the overallevidence it provided for its primaryoutcome, according to the United StatesPreventative Services Task Forcegrading scale (good, fair, poor).8 A“good” study has no important limita-tions, and results are considered inter-nally valid; a “fair” study has clearlimitations but no fatal flaws, and a“poor” study has �1 fatal flaws thatmay invalidate results. In determiningthe study quality rating, we assessedrisk of bias using prespecified gradingcriteria. For case-control, cohort studiesand nonrandomized trials with onlyclinical outcomes, grading criteria forrisk of bias included selection bias,appropriateness and generalizability ofparticipants, sample size and power,exposure assessment, timing of anti-microbial use, validation of outcomes,loss to follow up, and confounding.For trials with pharmacokinetic out-comes, we used a previously reportedquality rating system to assess studydesign, sample size, drug exposure andadherence, appropriateness of phar-macokinetic parameters, timing ofblood draws, intersubject variability,steady state of perpetrator drug, andvalidation of assays.9 The quality ofeach study was assigned independentlyby 2 authors. Any differences wereresolved through discussion with athird author.
90 American Journal of Obstetrics & Gynecology
Data synthesisWe synthesized findings descriptively.Observational studies of pregnancy rateswith general antibiotic use weredescribed first, followed by a summary offindings for each class of antibiotic.Metaanalysis could not be conductedbecause of heterogeneity of exposures(different antibiotic drugs, doses, andprogestins) and outcomes (differences inpharmacokinetic parameters andtiming) and limited studies in most drugclasses.
ResultsWe identified 7291 articles and 70 studieson clinicaltrials.gov in our initial searchafter removal of duplicates (Figure). Af-ter review of titles and abstracts, 220 full-text articles were reviewed. Twenty-ninearticles met inclusion criteria, including1 article in German.10 No studies onclinicaltrials.gov met inclusion criteriathat were not already captured by otherdatabases. We first report observationalstudies of pregnancy rates or HC failurewith any antibiotic use (n¼4) and thenreport trials of individual antibioticswith clinical or pharmacokinetic out-comes (n¼25).
Pregnancy rates and antibiotic use(Table 1; Appendix B)Two studies compared pregnancy ratesin women who used HC alone or withan antibiotic.11,12 In a retrospectivecohort study of 3 dermatology prac-tices, Helms et al11 surveyed by mail578 women with a history of concur-rent exposure to oral contraceptive pills(OCs) and antibiotics over 5 years. Of356 women who completed the survey,263 women also had unexposed timeperiods with OC use alone; in-vestigators surveyed an additional 162OC users without a record of concur-rent antibiotic use to complete thecontrol group. Five pregnanciesoccurred among women who wereexposed to HCs and antibiotics (min-ocycline, 3; cephalosporin, 2); 12 preg-nancies occurred in women who wereexposed to OCs alone. There was nodifference in pregnancy rates forwomen who used OCs alone andwomen who used OCs concurrently
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with antibiotics (0.96 and 1.6 per 100women-years, respectively; P¼.4).
Jick et al12 performed a nested casecontrol study to examine risk factors forunintended pregnancy within a databaseof general practitioners in the UnitedKingdom. Cases were women with un-intended pregnancy or pregnancytermination who had a prescription forHC within 4 months before the indexdate (date of diagnosis of unintendedpregnancy; n¼1129). Four women percase who used HC without a docu-mented unintended pregnancy served ascontrol subjects, matched by age, prac-tice, and year. Antibiotic exposure wasdetermined by prescription for an anti-biotic within 16 weeks before the indexdate. The odds of unintended pregnancywere similar, regardless of antibiotic use(odds ratio [OR], 1.0; 95% confidenceinterval [CI], 0.8e1.2).
Two studies examined the odds ofantibiotic use at the time of OC fail-ure.13,14 Toh et al13 used a national birthdefects database to evaluate antibioticuse in 1330 OC failure pregnancies in acase crossover study. Women served astheir own controls, with risk factors forOC failure compared between the timeframe of 0e4 weeks before conception(case period) to 4e8 weeks beforeconception (control period). The rate ofantibiotic use was 4% during the caseperiod and 3.8% during the controlperiod (self-matched OR, 1.08; 95% CI,0.63e1.84). Odds of antibiotic exposurewere also similar with the use of analternate control period (8e12 weeksbefore conception) or restricting to onlyampicillin/amoxicillin use.
Finally, Koopmans et al14 performed acase crossover study using an outpatientpharmacy dispensing database in TheNetherlands. The population includedwomen who presumably became preg-nant while taking OCs (based on pickingup an OC refill within the first 3 monthsof a pregnancy; n¼397). The exposurewindow for any concurrent antibioticprescription was 15 days before and afterprobable conception; the control win-dows were 1-month periods thatoccurred 2 months (period 1) or 1 year(period 2) before the exposure window.Odds of antibiotic use were no higher in
FIGUREPreferred reporting items for systematic reviews and meta-analyses(PRISMA) flow diagram
Number of articles identified in initial database search and excluded at each step of the assessment
process.
HC, hormonal contraception.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
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the exposure window than in controlwindows (control period 1: OR, 2.0; 95%CI, 0.89e4.79; control period 2: OR,1.42; 95% CI, 0.64e3.25).
Penicillins/cephalosporins and OCs(Table 2; Appendix C)Surrogate measures of contraceptive effec-tiveness and adverse health effects. Threesmall trials evaluated luteal progesteronelevels in women taking OCs with andwithout ampicillin; none of the trialsshowed evidence of ovulation in cycleswith concurrent ampicillin, and 1 ovula-tion occurred in a control cycle.15-17 Oneobservational study reported that 2 of20 women with previously normal cycleson OCs experienced breakthroughbleeding after the addition of ampicillin500 mg 4 times daily.10
Pharmacokinetic outcomes. Three smalltrials found no difference in HC phar-macokinetic when administered withampicillin.16-18 A single sequence cross-over study of 6 healthy women examinedethinyl estradiol (EE) and norethindronepharmacokinetic during OC alone andwith ampicillin 500 mg twice daily for5e7 days later in the same cycle.17 EE andnorethindrone AUC and mean plasmalevels were unchanged after the additionof ampicillin. Likewise, a mixed parallelgroup and single sequence crossoverstudy enrolled 11 postmenopausalwomen and administered 3 days ofampicillin (500 mg 4 times day) on days5e8 ofOCs.18 Although no statisticsweregiven, EE/norethindrone steady-stateplasma values that were presented ingraphic form did not decrease frombaseline after ampicillin was added andwere similar to controls. Back et al16
conducted 2 small single sequencecrossover studies of EE/levonorgestrelpharmacokinetic in 13 women takingOCs alone and with ampicillin (500 mg 3times daily for 8 days during cycle 1 or 2).EE and levonorgestrel mean plasmaconcentrations were no different duringcycles with and without ampicillin.
Two studies addressed pharmacoki-netic outcomes for penicillins.19,20 Phi-lipson19 reported plasma ampicillinlevels and AUC in 10 women after asingle 500-mg dose on day 21 of an OC
cycle and again on day 28, after a 7-dayOC washout. Mean ampicillin plasmalevels were lower 1 hour after dosingwhen administered with the OCcompared with without (values notprovided; P<.05), but at all other timepoints were unchanged; the total AUCand Cmax were no different. Authorsconcluded that the difference in ampi-cillin levels did not appear to be clinicallyimportant. Finally, a study of 4 womentaking OCs reported cephaloridine levelsover 8 hours after a 500-mg intramus-cular dose on days 21 (with OC) and 28(after washout).20 Peak serum levels ofcephaloridine were higher on day 28than on day 21 (23.5 vs 18.9 mg/mL, nostatistics given). The clinical significanceof this difference was not described.
Tetracyclines and OCs (Table 2;Appendix D)Three studies demonstrated no differ-ence in surrogate contraceptive effec-tiveness or pharmacokinetic outcomeswith tetracyclines.10,21,22 Murphy et al21
performed a mixed parallel group andsingle-sequence crossover study of 11women to evaluate tetracycline and OCpharmacokinetic when administered
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separately and together. EE AUC andCmax were unchanged before and aftertetracycline (500 mg every 4 hours for 10days); norethindrone AUC24 and Cmaxrose after tetracycline was added (AUC,33.0e57.9 [units not provided]; Cmax,4.5e6.3 ng/mL; P<.01 for both). Tetra-cycline AUC0-4 did not differ with andwithout OCs. Similarly, Neely et al22
performed a single sequence crossoverstudy of 24 women taking OCs for 2cycles, with doxycycline 100 mg twicedaily on days 14e21 during cycle 2.Norethindrone and EE steady-state levelson days 18e20 were unchanged duringthe control and doxycycline cycles. Days18e20 serum progesterone concentra-tions were unchanged and consistentwith anovulation in both cycles. Foradverse health effects, a third study re-ported that 15 women with previouslynormal cycles on OCs reported nobreakthrough bleeding after takingoxtetracycline (500 mg 4 times daily).10
Fluoroquinolones and OCs (Table 2;Appendix E)Surrogate measures of contraceptive effec-tiveness and adverse health effects. Twotrials reported no ovulation by luteal
TABLE 2Summary of evidence from trials with pharmacodynamics or pharmacokinetic outcomes (continued)
Study Study design Interventions Size, n Outcomes Interactiona Quality
Blode et al33 Single sequencecrossover
E2V/DNGErythromycin
12 E2V PKDNG PK
E2V [DNG [
Fair
Fischer et al34 Parallel groups OCs Azithromycin 25 Azithromycin PK Azithromycin [ Poor
Meyer et al30 Single sequencecrossover
LNG/EERoxithromycin
22 Serum PUltrasound
No ovulation Fair
Wermeling et al32 Single sequencecrossover
NET/EE Dirithromycin 15 EE PKSerum P
EE YNo rise in P
Good
Others antibiotics
Hempel et al10 Single sequencecrossover
NET/EETrimethoprim/sulfamethoxazole
21 Bleeding changes 0/21 Control vs 2/21with BTB
Poor
Hempel et al10 Single sequencecrossover
NET/EENitrofurantoin
18 Bleeding changes 0/18 Control vs 0/18with BTB
Poor
Joshi et al35 Parallel groups NET/EE Dapsone 16 NET PKEE PK
NET PK: 4EE PK: [
Fair
Joshi et al17 Single sequencecrossover
NET/EEMetronidazole
25 NET PKEE PKSerum P
NET PK: 4EE PK: 4No difference in P
Fair
Mehrota et al36 Parallel groups Mestranol/EEIsoniazid/streptomycin
83 TB outcomes No difference in TBoutcomes
Poor
Other contraceptiveformulations
Dogterom et al38 Randomizedcrossover
ENG/EE CVRAmoxicillin
16 ENG PKEE PK
ENG PK: 4EE PK: 4
Good
Dogterom et al38 Randomizedcrossover
ENG/EE CVRDoxycycline
16 ENGEE PK
ENG PK: 4EE PK: 4
Good
Pohl et al37 Single sequencecrossover
UPA Erythromycin 18 UPA PK UPA [ Good
a Interaction reflects the outcome with the combination of HC and antibiotic, compared with the outcome drug alone. Direction of interaction represents summary of PK changes to reflect overallexposure.Y, statistically significant decrease in drug exposure; 4, no change in drug exposure; [, statistically significant increase in drug exposure; BTB, breakthrough bleeding; CVR, con-traceptive vaginal ring; DMPA, depo-medroxyprogesterone acetate; DNG, dienogest; DSG, desogestrel; E2V, estradiol valerate; EE, ethinyl estradiol; ENG, etonogestrel; LNG, levonorgestrel; NET,norethindrone; OC, oral contraceptive pill; P, progesterone; PK, pharmacokinetics; TB, tuberculosis; UPA, ulipristal acetate.
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progesterone and no difference inovarian activity by ultrasound scanningin OC cycles with and without cipro-floxacin.23,24 One trial reported nobreakthrough bleeding in OC cycles withand without ciprofloxacin.25 Two addi-tional trials reported no ovulation byserum progesterone and/or monitoringof follicles on ultrasound scanning inOCcycles with and without temafloxacin orofloxacin.26,27
Pharmacokinetic outcomes. Two studiesreported no change to HC pharmaco-kinetic with fluoroquinolones.24,27 In asingle sequence crossover study of 12
women using OCs over 2 cycles, with a7-day course of temafloxacin 600 mgdaily starting in cycle 2, steady-stateplasma levels of EE and levonorgestrelon days 5e8 were no different in thetemafloxacin cycle than with OCsalone.27 Likewise, a double-blind, ran-domized controlled crossover study of24 women using OCs with ciprofloxa-cin 500 mg twice daily or placebo forthe first 10 days of 2 cycles found nodifference in EE AUC24 or Cmax geo-metric mean ratios (GMRs) betweencycles.24
Two studies reported small, but clin-ically unclear, reductions in
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fluoroquinolone pharmacokinetic withOCs.28,29 One parallel group study re-ported trovafloxacin pharmacokineticafter a single 200-mg dose in womenusing HC (OCs or depot medrox-yprogesterone acetate) or non-HC.28
Trovafloxacin Cmax and AUC werelower in the HC group (Cmax, 2.27 vs1.92 mg/L; AUC, 26.7 vs 20.8 mg/L), andclearance was higher (7.62 vs 9.96 L/h; allcomparisons P<.004). A second parallelgroup study reported moxifloxacinpharmacokinetic after a single 400-mgdose for women using OCs or non-HC.29 They observed no difference inCmax between groups, but AUC0-48 was
15% lower (P¼.008), and clearance was20% higher (P¼.015) in the OC group.The clinical significance of these changeswas not addressed in either study.
Macrolides and OCs (Table 2;Appendix F)Surrogate measures of contraceptive effec-tiveness and adverse health effects. Threetrials reported no ovulation by ultra-sound scanning and/or luteal progester-one during OC cycles with and withoutroxithromycin, clarithromycin, or diri-thromycin.30-32 There was also no dif-ference in breakthrough bleedingbetween cycles with and without roxi-thromycin or dirithromycin.30,32
Pharmacokinetic outcomes. Three studiesreported mixed HC pharmacokineticoutcomes with macrolides.31-33 Backet al31 performed a single-sequencecrossover study of 10 OC users andmeasured OC steady-state plasma levelsduring cycles with and without clari-thromycin 250 mg twice daily on days1e7. Day 5e8 EE and levonorgestrelplasma steady-state levels were un-changed between the 2 cycles (P>.1),and 3-ketodesogestrel (the primarymetabolite of desogestrel) increasedslightly with clarithromycin (3.35 vs 1.43ng/mL; P<.02). Wermeling et al32 re-ported day-8 EE pharmacokinetic in asingle sequence crossover study of 15women using OCs alone and with diri-thromycin 500 mg daily during days21e28 of cycle 2 and days 1e8 of cycle 3.They found a small, but significant,decrease in mean EE AUC (7.6%; P¼.03)and an increase in EE clearance (10%;P¼.03) in the dirithromycin cycle, but nochange in Cmax. Blode et al33 reportedpharmacokinetic of estradiol anddienogest in a single sequence crossoverstudy of postmenopausal women takingestradiol valerate (E2V)/dienogest withand without erythromycin (500 mg 3times daily for 5 days; n¼12). Contra-ceptive exposure increased when E2V/dienogest was administered with eryth-romycin; estradiol Cmax and AUC24
GMRs were 151% (95% CI, 136e168%)and 133% (95% CI, 118e150%),respectively; dienogest Cmax and AUC24
GMRs were 133% (95% CI, 123e144%)
94 American Journal of Obstetrics & Gynecology
and 162% (95% CI, 146e180%),respectively.A single paper reported azithromycin
pharmacokinetic in 2 small parallelgroup studies of women using OCs(n¼10) or not (n¼15), taking 500 mgoral azithromycin followed by 250 mgdaily for 4 days.34 The AUC of azi-thromycin was higher for OC users thanfor nonusers (mean difference, 11.4 mg-h/L; 95% CI, 5.7-17.2 mg-h//L), andazithromycin clearance was 38% lowerin OC users. Clinical implications werenot evaluated.
Other antibiotics and OCs (Table 2;Appendix G)One single sequence crossover study of10 women examined metronidazole(400 mg 3 times daily for cycle days7e14) in combination with OCs.17
Compared with a cycle with OCs alone,day 14 EE and norethindrone steadystate, Cmax, and AUC24 were notsignificantly different. In a group of 25women (the original 10 plus an addi-tional 15 women taking the same drugcombination), luteal progesterone wasconsistent with ovulation for 3 of 25metronidazole cycles and 2 of 25 controlcycles.Joshi et al35 reported OC pharmaco-
kinetic for OCs administered withdapsone (100 mg 5 days per week) in 10womenwith leprosy compared with OCsalone in 6 control women. Norethin-drone Cmax and AUC24 were similar inboth groups; EE AUC0-8 was higher indapsone patients than control patients(1041 vs 682 pg/mL/hr; P<.05), and EECmax was not significantly different.In a single sequence crossover study,
Hempel et al10 reported bleeding pat-terns before and after the addition ofsulfamethoxazole/trimethoprim (3times daily) or nitrofurantoin (100 mg 4times daily) to OCs. Compared with ahistory of no disordered bleeding withOCs alone, 2 of 22 women taking sulfa-methoxazole/trimethoprim reporteddisordered bleeding while on the anti-biotic, and none of 18 women onnitrofurantoin reported disorderedbleeding.Finally, Mehrota et al36 followed
tuberculosis disease outcomes in women
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using isoniazid-based antibiotic regi-mens with and without OCs over 1 year.Sputum cultures were negative for all 33women who received OCs and for 32 of34 non-OC patients at the end of theyear.
Other contraceptive formulations(Table 2; Appendix G)Pohl et al37 reported ulipristal acetate(UPA) pharmacokinetic in a singlesequence crossover study of 18 healthywomen with and without erythromycin(500 mg twice daily for 9 days). UPACmax and AUC24 GMRs increased in thepresence of erythromycin (24% [95%CI, 1e52%] and 224%, [95% CI, 175-283%], respectively); the primary UPAmetabolite showed an increase in AUC24
of 62% (43e85%) and a decrease inCmax by 48% (95% CI, 38e56%). UPAwas well tolerated with and withouterythromycin, and no serious adverseevents occurred.
Dogterom et al38 performed 2 ran-domized crossover studies of the EE/etonogestrel contraceptive vaginal ring(CVR) with and without amoxicillin(875mg twice daily days 1e10; n¼16) orwith and without doxycycline (100 mgdaily days 1e10; n¼16) over 2 cycles.With the use of the data in the GMRs and90%CIs, therewas no difference in EE oretonogestrel AUC12 with amoxicillin orAUC24 with doxycycline compared withcontrol cycles.
CommentMain findingsUnintended pregnancy is a great concernfor women taking HC with potentiallyinteracting drugs. In this systematic re-view, 2 studies of fair-to poor qualityfound no increased risk of pregnancy inOC users taking antibiotics (any type),compared with OC users not taking an-tibiotics.11,12 Two additional fair-to-poor quality studies found no higherodds of antibiotic use at the time ofconception in OC-breakthrough preg-nancies than in control time periods.13,14
Although additional older studies thatwere excluded from this review reportedcontraceptive failure in OC users takingantibiotics or reported antibiotic useamong women with pill failures, none of
those studies had comparison groups,which makes it impossible to draw con-clusions on the role of the antibiotic inthose pregnancies.2
Surrogate markers of contraceptiveeffectiveness in this review also supportno interaction between the use of non-rifamycin antibiotics and HC. Althoughmost ovulation outcomes were second-ary and often underpowered(Appendices CeG), no differences inovulation by serum progesterone or ul-trasound scanning were observed in anystudy that combined OCs with ampi-cillin,15-17 doxycycline,22 temafloxacin,27
ofloxacin,26 ciprofloxacin,23,24 clari-thromycin,31 roxithromycin,30 diri-thromycin,32 or metronidazole.17
Likewise, breakthrough bleeding waseither no different than control orinconclusive in combination withampicillin,10 oxtetracycline,10 ciproflox-acin,25 dirithromycin,32 roxi-thromycin,30 nitrofurantoin,10 ortrimethoprim/sulfamethoxazole.10
Finally, pharmacokinetic outcomeswere also reassuring for no interactionbetween HC and non-rifampicin anti-biotics. Importantly, no significant de-creases in any progestin or EE parameteroccurred during co-administration withantibiotics that included ampicillin oramoxicillin (4 good-to-poor qualitystudies),16-18,38 tetracycline or doxycy-cline (3 good-to-poor qualitystudies),21,22,38 temafloxacin or cipro-floxacin (2 good-to-fair qualitystudies),24,27 clarithromycin or erythro-mycin (2 fair-quality studies),31,33 ordapsone or metronidazole (1 fair-qualitystudy each; Table 2).17,35 UPA geometricmean peak levels and AUC increasedduring co-administration with erythro-mycin in 1 good quality study.37
Although there is a wide range in qual-ity and design of these studies, the con-sistency of results is reassuring thatprogestin levels, which are critical tocontraceptive effect, are not reducedwhen co-administered with non-rifamycin antibiotics.
The only statistically significantdecrease in any EE parameter occurredduring co-administration with diri-thromycin (a drug no longer available inthe United States). EE AUC decreased
7.6%, but Cmax was unchanged in 1good-quality study.32 Decreases in sys-temically active EE may result in thedevelopment of a dominant folliclebecause of insufficient suppression offolliculogenesis, but ovulation suppres-sion should still be maintained by sup-pression of luteinizing hormone bythe progestin component.39 An increasein some EE and E2V pharmacokineticparameters occurred with co-administration with dapsone and eryth-romycin, respectively.33,35 Increases inestrogen exposure theoretically couldaffect thrombosis risk, although thisoutcome was not addressed in any study.Combined HCs can also affect meta-
bolism of co-administered antibiotics,potentially altering safety or effectivenessprofiles. EE is a known moderate inhib-itor of several cytochrome P450 (CYP)enzymes and could increase concentra-tions of drugs that are metabolized bythese enzymes.3 Two poor-qualitystudies of cephaloridine and azi-thromycin reported statistical increasesin antibiotic pharmacokinetic parame-ters during co-administration with OCs,which has uncertain clinical significancebut could pose theoretic drug toxicityconcerns.20,34 Although EE is not aknown inducer of CYP enzymes (whichwould reduce levels of co-administereddrugs), 2 fair-to-poor quality studiesreported statistical reductions in sometrovafloxacin and moxifloxacin phar-macokinetic parameters when takenwith OCs, which could pose theoretictreatment concerns if reductions werelarge enough to affect the therapeuticrange.28,29 No change to ampicillinand tetracycline pharmacokinetic pa-rameters was seen in 2 fair-to-poorquality studies with OCs.19,21 None ofthese studies reported toxicity or anti-biotic treatment failure outcomes inconjunction with pharmacokinetic out-comes, limiting their interpretation andutility.
Strengths and limitationsThis systematic review has severalstrengths. Primarily, we used strict in-clusion criteria that required that allstudies include a comparison group.This is important because combined
JANUARY 2018 A
HCs have a typical-use failure rate of9%,40 so it is inappropriate to assumethat combined HC failures in womenwho use antibiotics are due to druginteraction, as was theorized in olderuncontrolled observational studies, caseseries, and guidelines that were based oncase reports.2,41 Likewise, our inclusionof a range of clinical and pharmacoki-netic outcomes allows for evaluation ofconsistency of findings and betterextrapolation to clinical care.
However, this review is limited by thequality and quantity of published evi-dence. The observational studies faceddegrees of misclassification bias ofantibiotic and HC exposures and preg-nancy outcomes (Appendix B). They arealso limited by grouping antibiotics(which may dilute smaller effects), aninability to assess contraceptive adher-ence, and a lack of adjustment for con-founders. Studies that addressedovulation faced limitations thatincluded small sample sizes and infre-quent or poorly timed measurements ofprogesterone, which may have led tomissed ovulations in some cases(Appendices CeG). Few studies usedultrasound scanning to monitor follic-ular development and rupture; serumprogesterone is itself a surrogate markerfor ovulation. Pharmacokinetic studieshad various weaknesses that includednot assessing adherence to 1 or bothdrugs, small sample sizes, use of non-standardized pharmacokinetic parame-ters, the use of statistical comparisonsthat do not take into account thera-peutic bioequivalence, a lack ofrandomization, and a lack of attentionto potential confounders (AppendicesCeG). It is also difficult to draw clin-ical conclusions from pharmacokineticstudies alone because minimum efficacythresholds are not established for EE orprogestins.42 Finally, only 1 studyexamined a non-OC formulation(CVR).38 No data exist on the combi-nation of antibiotics with other non-oral formulations that include thetransdermal patch, injectables, or pro-gestin implants. Studies of OCs includeda range of doses and progestins, butnone included the lowest dose pills (ie,containing <30 mg EE or <150 mg
levonorgestrel). We did not attemptto normalize findings based on EE orprogestin dosing. Therefore, the find-ings of this review may not extrapo-late to the lowest dose pills thatcontain 10e25 mg EE or <150 mglevonorgestrel.
Theoretic mechanisms for contra-ceptive failure with antibiotics includealterations in drug absorption or meta-bolism. Decreases in intestinal bacteria,which transform orally ingested EEbefore absorption and enterohepaticcirculation by the small intestine, couldreduce absorption of contraceptive ste-roids.43 However, enterohepatic circula-tion contributes relatively little tocirculating EE and progestin levels formost women, so its reduction is unlikelyto have a significant effect on systemiclevels.43,44 Metabolismmay be altered byinduction or inhibition of hepatic en-zymes. Rifampin is the only antibioticknown to induce CYP enzymes, whichcould increase the rate of EE and pro-gestin metabolism and potentiallycompromise contraceptive effect.3
Although some antibiotics are knowninhibitors of CYP enzymes (ciprofloxa-cin, clarithromycin, erythromycin,metronidazole, trimethoprim, and tele-thromycin),3 this interaction would in-crease steroid levels, which would notcompromise contraceptive mechanismsbut theoretically could increase side-effects. Studies of UPA and E2V/dieno-gest reported increases in steroidhormones when co-administered witherythromycin, but side-effects did notincrease for UPA and were not reportedfor E2V/dienogest.33,37 Finally, antibi-otics could reduce biologically activeprogestin levels through increasedproduction of sex hormone bindingglobulin, which is an hepatic protein thatbinds progestins. Although rifampininduces the production of sex hormonebinding globulin, other antibiotics donot.2
Despite the reassuring evidence pre-sented in this review, there are individualvariations in CYP metabolism that arebased on genetics and ethnicity, andthere may be a small subset of women(likely <1%) who are more susceptibleto HC failure at baseline because of these
96 American Journal of Obstetrics & Gynecology
factors.44,45 Likewise, enterohepatic cir-culation is altered in obesity, and it isunknown whether obese women aremore susceptible to drug interactions asa result. Contraceptive failure on aparticular method, particularly whencompliance has been good,may suggest ahigher risk of repeat failure on thatmethod, and such women shouldconsider switching to a more effectivemethod or adding backupcontraception.
Comparison with existing literatureOur findings are consistent with currentcontraceptive guidance from the 2016United States Medical Eligibility Criteriafor Contraceptive Use6 and the 2015World Health Organization MedicalEligibility Criteria for ContraceptiveUse,5 which recommend no restrictionfor the use of any method of HC withbroad spectrum antibiotics. Likewise,the most recent guidance for dentalpractitioners46 and from the AmericanAcademy of Dermatology Association47
no longer advise use of additional con-traceptive protection during use of non-rifamycin antibiotics.
Conclusions and implicationsExisting evidence does not support druginteractions between HC and non-rifamycin antibiotics. Data are limitedby insufficient quantity and quality forsome antibiotic drug classes (particularlymetronidazole, sulfa drugs, and nitro-furantoin) and non-OC formulations.Most women can expect no reduction inHC effect with concurrent use of non-rifamycin antibiotics. To maximize theeffectiveness of user-dependent methodslike OCs, providers should encouragecorrect and consistent use at all times,including during illness. -
REFERENCES
1. Trends in contraceptive use worldwide. In:Department of Economic and Social Affairs PD,ed. New York: United Nations; 2015.2. Dickinson BD, Altman RD, Nielsen NH,Sterling ML; Council on Scientific Affairs AMA.Drug interactions between oral contraceptivesand antibiotics. Obstet Gynecol 2001;98:853-60.3. Guidance for industry: Drug interactionstudies - study design, data analysis, implications
JANUARY 2018
for dosing, and labeling recommendations. In:Food and Drug Administration, ed. 2012. Avail-able at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed June 7,2017.4. Masters KP, Carr BM. Survey of pharmacistsand physicians on drug interactions betweencombined oral contraceptives and broad-spectrum antibiotics. Pharm Pract (Granada)2009;7:139-44.5. Medical Eligibility Criteria for ContraceptiveUse: World Health Organization, 2015. Availableat: http://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/. AccessedMay 18, 2017.6. United States medical eligibility criteria forcontraceptive use, 2016. MMWR Morb MortalWkly Rep 65;3:1-103.7. Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA group. Preferred reporting items for sys-tematic reviews and meta-analyses: the PRISMAstatement. PLoS Med 2009;6:e1000097.8. US Preventative Services Task Force. Gradedefinitions. 2016. Available at: https://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions#grade-definitions-after-may-2007. Accessed June 7, 2017.9. Berry-Bibee EN, Kim MJ, Simmons KB, et al.Drug interactions between hormonal contra-ceptives and psychotropic drugs: a systematicreview. Contraception 2016;94:650-67.10. Hempel E, Zorn C, Graf K. Effect ofchemotherapy agents and antibiotics on hor-monal contraception [German]. Z Arztl Fortbild1978;72:924-6.11. Helms SE, Bredle DL, Zajic J, Jarjoura D,Brodell RT, Krishnarao I. Oral contraceptivefailure rates and oral antibiotics. J Am AcadDermatol 1997;36:705-10.12. Jick SS, Hagberg KW, Kaye JA, Jick H. Therisk of unintended pregnancies in users of thecontraceptive patch compared to users of oralcontraceptives in theUKGeneral practice researchdatabase. Contraception 2009;80:142-51.13. Toh S,Mitchell AA, AnderkaM, de Jong-vanden Berg LT, Hernandez-Diaz S; National BirthDefects Prevention S. Antibiotics and oral con-traceptive failure: a case-crossover study.Contraception 2011;83:418-25.14. Koopmans PC, Bos JH, de Jong van denBerg LT. Are antibiotics related to oral combi-nation contraceptive failures in the Netherlands?A case-crossover study. PharmacoepidemiolDrug Saf 2012;21:865-71.15. Friedman CI, Huneke AL, KimMH, Powell J.The effect of ampicillin on oral contraceptiveeffectiveness. Obstet Gynecol 1980;55:33-7.16. Back DJ, Breckenridge AM, MacIver M,et al. The effects of ampicillin on oral contra-ceptive steroids in women. Br J Clin Pharmacol1982;14:43-8.17. Joshi JV, Joshi UM, Sankholi GM, et al.A study of interaction of low-dose combina-tion oral contraceptive with ampicillin andmetronidazole. Contraception 1980;22:643-52.
18. Adlercreutz H, Pulkkinen MO,Hamalainen EK, Korpela JT. Studies on the roleof intestinal bacteria in metabolism of syntheticand natural steroid hormones. J Steroid Bio-chem 1984;20:217-29.19. Philipson A. Plasma and urine levels pro-duced by an oral dose of ampicillin 0.5 Gadministered to women taking oral contracep-tives. Acta Obstet Gynecol Scand 1979;58:69-71.
20. Wise R, Reeves DS. Two aspects of theavailability of cephalosporins after intramuscularinjection. J Antimicrob Chemother 1975;1:47-52.21. Murphy AA, Zacur HA, Charache P,BurkmanRT. The effect of tetracyclines on levelsof oral contraceptives. Am J Obstet Gynecol1991;164:28-33.22. Neely JL, Abate M, Swinker M, D’Angio R.The effect of doxycycline on serum levels ofethinyl estradiol, norethindrone, and endoge-nous progesterone. Obstet Gynecol 1991;77:416-20.23. Droppert RA, Scholten PC, Zwinkels M,Hoepelman IM, Te Velde ER. Lack of influence ofciprofloxacin on the effectiveness of oral con-traceptives. Drugs 1993;46:286-7.24. Scholten PC, Droppert RM, Zwinkels MGJ,Moesker HL, Nauta JJP, Hoepelman IM. Nointeraction between ciprofloxacin and an oralcontraceptive. Antimicrob Agent Chemother1998;42:3266-8.25. Maggiolo F, Puricelli G, Dottorini M,Caprioli S, Bianchi W, Suter F. The effect ofciprofloxacin on oral contraceptive steroidtreatments. Drugs Exp Clin Res 1991;17:451-4.26. Csemiczky G, Alvendal C, Landgren BM.Risk for ovulation in women taking a low-doseoral contraceptive (microgynon) when receivingantibacterial treatment with a fluoroquinolone(ofloxacin). Adv Contracept 1996;12:101-9.27. Back DJ, Tjia J, Martin C, et al. The lack ofinteraction between temafloxacin and combined
oral contraceptive steroids. Contraception1991;43:317-23.28. Amsden GW, Mohamed MA,Menhinick AM. Effect of hormonal contracep-tives on the pharmacokinetics of trovafloxacin inwomen. Clin Drug Investig 2001;21:281-6.29. Shain CS, Whitaker AM, Amsden GW.Effects of oral contraceptives on the phar-macokinetics of moxifloxacin in premeno-pausal women. Clin Drug Investig 2002;22:429-34.30. Meyer B, Muller F, Wessels P, Maree J.A model to detect interactions between roxi-thromycin and oral contraceptives. Clin Phar-macol Ther 1990;47:671-4.31. Back DJ, Tjia J, Martin C, Millar E, Salmon P,OrmeM. The interaction between clarithromycinand combined oral-contraceptive steroids.J Pharm Med 1991;1:81-7.32. Wermeling DP, Chandler MH, Sides GD,Collins D, Muse KN. Dirithromycin increasesethinyl estradiol clearance without allowingovulation. Obstet Gynecol 1995;86:78-84.33. Blode H, Zeun S, Parke S, et al.Evaluation of the effects of rifampicin, ke-toconazole and erythromycin on the steady-state pharmacokinetics of the componentsof a novel oral contraceptive containingestradiol valerate and dienogest in healthypostmenopausal women. Contraception2012;86:337-44.34. Fischer JH, Sarto GE, Habibi M, et al. Influ-ence of body weight, ethnicity, oral contracep-tives, and pregnancy on the pharmacokinetics ofazithromycin in women of childbearing age.Antimicrob Agents Chemother 2012;56:715-24.35. Joshi JV, Maitra A, Sankolli G, Bhatki S,Joshi UM. Norethisterone and ethinyl estradiolkinetics during dapsone therapy. J Assoc Phy-sicians India 1984;32:191-3.36. Mehrotra ML, Gautam KD, Pande DC, et al.Compatibility of oral contraceptive with anti-tubercular chemotherapy in female pulmonary
JANUARY 2018 A
tuberculosis patients. Indian J Med Res1974;62:1782-6.37. Pohl O, Osterloh I, Gotteland JP. Effects oferythromycin at steady-state concentrations onthe pharmacokinetics of ulipristal acetate. J ClinPharm Ther 2013;38:512-7.38. Dogterom P, Van Den Heuvel MW,Thomsen T. Absence of pharmacokinetic in-teractions of the combined contraceptivevaginal ring NuvaRing with oral amoxicillin ordoxycycline in two randomized trials. Clin Phar-macokinet 2005;44:429-38.39. Fritz MA, Speroff L. Clinical gynecologicendocrinology and infertility, 8th ed. Philadel-phia: Lippincott Williams & Wilkins; 2011.40. Trussell J. Contraceptive failure in the UnitedStates. Contraception 2011;83:397-404.41. American Dental Association Council onScientific Affairs. Antibiotic interference with oralcontraceptives. J AmDent Assoc 2002;133:880.42. Cherala GE, Edelman AB, Dorflinger L,Stanczyk FZ. The elusive minimum thresholdconcentration of levonorgestrel for contracep-tive efficacy. Contraception 2016;94:104-8.43. Edelman AC, Cherala GE, Stanczyk FZ.Metabolism and pharmacokinetics of contra-ceptive steroids in obese women: a review.Contraception 2010;82:314-23.44. Weisberg E. Interactions between oralcontraceptives and antifungals/antibacterials. Iscontraceptive failure the result? Clin Pharmaco-kinet 1999;36:309-13.45. Goldzieher JS, Stanczyk FZ. Oral contra-ceptives and individual variability of circulatinglevels of ethinyl estradiol and progestins.Contraception 2008;78:4-9.46. Taylor J, Pemberton MN. Antibiotics andoral contraceptives: new considerations fordental practice. Br Dent J 2012;212:481-3.47. Hormonal agents: Recommendations:American Academy of Dermatology Associa-tion. Available at: https://www.aad.org/practicecenter/quality/clinical-guidelines/acne/hormonal-agents. Accessed June 13, 2017.
Appendix A Search strategyMEDLINE: (Contraceptive Agents, Fe-male/ OR exp Contraceptives, Oral/ ORexp Intrauterine Devices, Medicated/)OR ((Levonorgestrel/ OR EthinylEstradiol-Norgestrel Combination/ ORexp Progesterone/ OR exp Progestins/)and (contracept* OR birth con-trol).ti,ab,kf,hw.) OR ((progest* OR Le-vonorgestrel OR ethinylestradiol ORestradiol OR Norgestrel OR etonogestrelOR oral OR pill OR tablet OR hormon*OR steroid OR inject* OR depo*OR medroxyprogesterone OR dmpa ORnet-en OR norethisterone enanthateOR patch* OR transdermal OR implant*OR long acting OR intravaginal ORintra-vaginal OR ring* OR post coitalOR postcoital) AND (contracept* ORbirth control)).ti,ab,kf,hw. OR (nor-plant* OR (intrauterine ADJ2 device*)OR (intra-uterine ADJ2 device*) OR(intrauterine ADJ2 contracept*) OR(intrauterine ADJ2 system*) OR (intra-uterine ADJ2 contracept*) OR (intra-uterine ADJ2 system*) OR LNG-IUS ORIUD? OR IUS OR IUCD? OR ((intra-vaginal OR intra-vaginal OR vaginal)ADJ2 ring*)).ti,ab,kf,hw.
ANDExp anti-infective agents/ or exp anti-
bacterial agents/ or exp antifungal agents/or exp anti-infective agents, local/ or expantiparasitic agents/ or antiviral agents/OR (Anti-infective OR anti-microbial ORantimicrobial OR antiinfective OR anti-biotic* ORmicrobicide*OR antiviral* ORanti-viral* OR anti-fungal* OR anti-fungal* OR fungicide* OR antimalarial*OR anti-malarial* OR antiparasitic* ORanti-parasitic* OR antibacterial* OR anti-bacterial* OR bacteriocid* OR anti-mycobacterial* OR anti-mycobacterial*OR antiparasitic* OR anti-parasitic* ORparasiticide*).ti,ab,kf,hw.
OR injectable contraceptive agent/or postcoitus contraceptive agent/)OR ((Levonorgestrel/ OR EthinylEstradiol-Norgestrel Combination/ ORexp Progesterone/ OR exp Progestins/)and (contracept* OR birth control).ti,ab.)OR ((progest* OR Levonorgestrel ORethinylestradiol OR estradiol OR Norges-trel OR etonogestrel OR oral OR pill ORtablet OR hormon* OR steroid OR inject*OR depo* OR medroxyprogesterone ORdmpa OR net-en OR norethisteroneenanthate OR patch* OR transdermal ORimplant* OR long acting OR intravaginalOR intra-vaginal OR ring* OR post coitalOR postcoital) AND (contracept* ORbirth control)).ti,ab. OR (norplant* OR(intrauterine ADJ2 device*) OR (intra-uterine ADJ2 device*) OR (intrauterineADJ2 contracept*) OR (intrauterine ADJ2system*) OR (intra-uterine ADJ2 contra-cept*) OR (intra-uterine ADJ2 system*)OR LNG-IUS OR IUD? OR IUS ORIUCD?OR((intravaginalOR intra-vaginalOR vaginal) ADJ2 ring*)).ti,ab.
ANDantiinfective agent/ OR exp quinoline
derived antiinfective agent/ OR anti-bacterial agents/ OR antifungal agents/OR antiparasitic agent/ OR antibioticagent/ OR (Anti-infective ORanti-microbial OR antimicrobial ORantiinfective OR antibiotic* OR micro-bicide* OR antiviral* OR anti-viral* ORanti-fungal* OR antifungal* OR fungi-cide* OR antimalarial* ORanti-malarial* OR antiparasitic*OR anti-parasitic* OR antibacterial* ORanti-bacterial* OR bacteriocid* ORantimycobacterial* OR anti-mycobacterial* OR antiparasitic* ORanti-parasitic* OR parasiticide*).ti,ab.
Cochrane: ([mh “ContraceptiveAgents, Female”] OR [mh “Contracep-tives, Oral”] OR [mh “Intrauterine De-vices, Medicated”]) OR (([mhLevonorgestrel] OR [mh “EthinylEstradiol-Norgestrel Combination”] OR
[mh Progesterone] OR [mh Progestins])and (contracept* OR birth con-trol):ti,ab) OR ((progest* OR Levonor-gestrel OR ethinylestradiol OR estradiolOR Norgestrel OR etonogestrel OR oralOR pill OR tablet OR hormon* OR ste-roid OR inject* OR depo* OR medrox-yprogesterone OR dmpa OR net-en ORnorethisterone enanthate OR patch* ORtransdermal OR implant* OR longacting OR intravaginal OR intra-vaginalOR ring OR post coital OR postcoital)AND (contracept* OR birth con-trol)):ti,ab OR ((intrauterine NEAR/2device*) OR (intra-uterine NEAR/2 de-vice*) OR (intrauterine NEAR/2 con-tracept*) OR (intrauterine NEAR/2system*) OR (intra-uterine NEAR/2contracept*) OR (intra-uterine NEAR/2system*) OR LNG-IUS OR IUD? ORIUS OR IUCD? OR ((extrauterine ORextra uterine) NEAR/2 coil*)OR ((intravaginal OR intra-vaginal ORvaginal) NEAR/2 ring*)):ti,abAND[mh “anti-infective agents”] OR [mh
“anti-bacterial agents”] OR [mh “anti-fungal agents”] OR [mh “antiparasiticagent”] OR [mh “anti-infective agents,local”] OR [mh “antiviral agents”] OR(Anti-infective OR anti-microbial ORantimicrobial OR antiinfective OR anti-biotic* OR microbicide* OR antiviral*OR anti-viral* OR anti-fungal*OR antifungal* OR fungicide* OR anti-malarial* OR anti-malarial* OR anti-parasitic* OR anti-parasitic* ORantibacterial* OR anti-bacterial* ORbacteriocid* OR antimycobacterial*OR anti-mycobacterial* OR antipara-sitic* OR anti-parasitic* ORparasiticide*):ti,abClinicaltrials.gov: “antimicrobial and
contraception” “antibiotic andcontraception”Simmons. Antibiotics and hormonal
contraception. Am J Obstet Gynecol2018.
Systematic Reviews ajog.org
97.e1 American Journal of Obstetrics & Gynecology JANUARY 2018
Study andfunding Study design Population Exposures Confounders Outcomes Results Strengths Weaknesses
Qualityrating
Helms et al(1997);fundingnot stated
Retrospectivecohort
Antibiotic exposed:578 women withconcurrent antibiotic/OC prescriptions in 3dermatologypractices over 5years; 356 of thesewomen completedsurveys and includedin analysis.Unexposed:162women in samepractices who tookOCs withoutantibiotics, plus 263exposed women withcontrol periods of noantibiotic use
From medicalrecords: OC use (anyactive prescription);any antibiotic use inrecord during OC use(confirmedconcurrent use bysurvey)
Age, marital status,particular antibioticand OC length ofcombined exposure,sexual activity duringcombined exposure,and use of barriercontraception;adjusted only for age
Pregnancy: Noted inmedical record orreported by surveyand confirmed bytelephone call.Powered to detectdifference of 2pregnancies per 100woman-years
Pregnancyrates:Antibiotics andOCs:1.6/100 woman-years.OCs alone: 0.96/100woman years (p¼.4).Five pregnancies onconcurrent antibiotics(n¼3 minocyclineand 2¼cephalosporin), someof these had missedOC doses and alsohad pregnancieswhile on OCs alone
Adjusted for age;excluded women notat risk of pregnancyor using othercontraception;performed subgroupanalyses for 2 controlgroups with sameresults
Control group older;antibiotics groupedtogether; did notadjust for pillcompliance;exposure/outcomeassessment limitedby survey/chartreview; possiblemisclassification ifantibiotics used butnot prescribed by thispractice; 62%response rate
II-2;Fair
Jick et al(2009);fundedby OrthoMcNeilJanssen
Nested casecontrol
Database of 300general practitionersin United Kingdom.Cases: Unintendedpregnancy indatabase with scriptfor HC within 4 mo(n¼1129), verified asample of these bymedical record.Control subjects: 4Control subjects percase matched by age,practice, and year, onHC with no pregnancy(n¼4374)
HC: Script indatabase for OC orpatch. Antibiotic: Anyscript within 16weeks of indexpregnancy
Collected data onbody mass index,smoking, duration ofcontraceptive use,previous abortionsand deliveries,sexually transmittedinfection history,alcohol/drug use,postpartum status,and use of antibioticsand anticonvulsantsfor case control
Pregnancy: By codesfor unintendedpregnancy ortermination ofpregnancy. Reviewedmedical records tovalidate diagnosisand timing ofexposure/outcome
Antibiotic use notassociated withunintendedpregnancy: OR, 1.0(95% CI, 0.8e1.2).Adjustment forlikelihood of exposure(based on timing ofantibiotic use) did notchange the OR
Low risk of selectionbias; examinedmultiple potentialconfounders; largesample size;subgroup analyses bylikelihood and timingof exposure allconsistent
Did not examineantibiotics as a riskfactor for pills andpatch separately; didnot assesscompliance;attempted to validateexposure status byproviderquestionnaire butonly surveyed 8%; upto 36% of pill usercases not exposed,and up to 59% ofpatch users notexposed;misclassificationbias; outcomeassessment mayhave missedpregnancies notcoded as unplanned
II-2;Poor
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018. (continued)
APPENDIX BEvidence from observational studies (continued)
Study andfunding Study design Population Exposures Confounders Outcomes Results Strengths Weaknesses
Qualityrating
Koopmanset al (2012);fundingnot stated
Case cross-over study
Mothers 15e49years old, livingwith their child,identified througha pharmacydispensingdatabase in theNetherlands.Cases: Pregnanciesin OC users (n¼397)
OC: OC scriptpicked up from anoutpatient pharmacyin first 3 mo ofpregnancy (not firsttime users).Antibiotic: Any scriptfor antibiotic duringexposure window
Self-control Odds of exposureto antibiotic duringexposure/controlwindow. EW: 15 daysbefore and afterprobable conception(DOB - 270 days). CW1: month starting2 mo before EW;CW 2: monthexactly 1 yearbefore EW. Subgroupanalysis: broadspectrum antibiotics
Breakthroughpregnanciesaccounted for1.3% of totalpregnancies indatabase. Casecrossover OR: 2.00(95% CI, 0.89e4.79)for control window 1and OR, 1.42 (95% CI,0.64e3.25) forcontrol window 2.Sensitivity analysis:Broad spectrum abs:OR, 0.86 (95% CI,0.24e2.98) for CW1and OR, 0.71 (95% CI,0.18e2.61) for CW2
No selection bias withself-controls;sensitivity analysiswith same conclusion
Database limited towomen living withtheir child (estimated35% pregnanciesexcluded); exposure/outcomes limitedentirely to database;no externalvalidation; proportionof breakthroughpregnancies only1.3%, which seemslow and suggestsmisclassification
II-2;Poor
Toh et al(2011);unfunded
Case cross-over study
Unplannedpregnancies in theSloane Epi CenterBirth Defects Studyand National BirthDefects PreventionStudy, bothinterview-baseddatabases. Cases:1330 Reportedunplannedpregnancies whileon OCs
OC: Use of OCs themonth before andduring conception (asrecorded indatabase). Antibiotic:Any antibiotic use indatabase duringreference timeperiods
Rate of antibiotic usewas 4% during caseperiod and 3.8%during control period.Self-matched OR,1.08 (95% CI, 0.63e1.84) for womenwho took antibiotic inonly 1 of the 2 timeperiods. Adjusting forurinary tract infectionof upper respiratoryinfection, OR, 1.1(95% CI, 0.63e1.93)No diff by smoking,alcohol use bodymass index. Alternatecontrol period: OR,1.45 (95% CI, 0.85e2.5) for antibioticoverall and OR, 1.55(95% CI, 0.72e3.3)for ampicillin/amoxicillin
Did not control forsexual activity,backupcontraception;uncleargeneralizability;databases useprimarily women withbirth defects whomay have recall biasabout medication use
II-2;Fair
abs, antibiotics; CW, control window; DOB, date of birth; EW, exposure window; HC, hormonal contraception; OC, oral contraceptive pill; OR, odds ratio.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
Adlercreutz et al(1984); Fordfoundation, SingridJuselius Foundation,Yrjo JahnssonFoundation, MedicalResearch Council ofthe Academy ofFinland
PK; singlesequencecrossover/parallelgroups
11 Healthy post-menopausal women(hospital employees);ages and BMI notreported
1: 10 mg NET for 10d (n¼3), 5 mgNET for 10 d(n¼1), then10 mg NET (n¼2) or 5mg NET (n¼1) for 13 d2: 50 mg EE, 250 mglynestrenol or 50 mg EEwith 2 mg NET daily(n¼4). Oral ampicillin500 mg 4 times daily,days 5e8
1: Daily serumlevels (Cmin) andday 4 and 8 PK.2: Day 8 PK
1: No change to NETlevels with NET/ampicillin co-administration.2: No change to EE withampicillin co-administration (valuesand statistics notreported)
Perpetratordrug at steadystate
Not randomized; noclear study design;small sample size;adherence notassessed; PKparameters and timingnot uniform; noinformation on potentialconfounders;postmenopausalpopulation withuncertaingeneralizability
Poor
Back et al (1982);supported by MRC,WHO, Mersey Health,Wellcome trust,Wyeth
PK and PD;singlesequencecrossover
Group 1: 7 womenwith UTI or URI takingOCs for at least 3 mo,ages 19e27 y, BMInot reported. Group2: 6 healthy womentaking OCs at least 3mo, ages 21e24 y,BMI not reported
G1: OCs with 30 mg EEand 250 mg LNG (n¼5);30 mg EE and 150 mgLNG (n¼1); 50 mg EEand 1 mg NET (n¼1).G2: OCs with 30 mg EEand 250 mg LNG (n¼5),30 mg EE and 150 mgLNG (n¼1). Ampicillin500 mg 3 times daily for8 days during eithercycle 1 or 2
EE and progestin PK ondays 5e8 cycle 1 andcycle 2.Group 2 only: ovulationby serum P days 21 and23, break-throughbleeding
Not randomized; smallsample size; PK lookingonly at steady state 12and 24 hr after dose; noinformation on potentialconfounders; ampicillinnot detected in serum of4 of 7 G1 patients,which raises question ofvalidity of results
Poor
Friedman et al(1980); funded bySearle and Co
PD; singlesequencecrossover
11 Healthy women;ages 21e39 y, BMInot reported
OC with 50 mg EE and 1mg ethynodiol acetatefor 3 cycles. Ampicillin250 mg or placebo 4times daily on days 1e16 for 2 consecutivecycles
Serum P on days 13 and19; side-effects andbreak-through bleeding
P levels under lutealphase levels in allcycles; 2 women hadbreakthrough bleedingin ampicillin cycle, 1 inthe placebo cycle
Both drugs atsteady state
Not randomized; smallsample size; adherencenot assessed; noinformation on potentialconfounders; P4 levelsmeasured on day 19,which may have missedpeak
Poor
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018. (continued)
20 Healthywomenwith regularmenstrual cycles;age and BMInot reported
OC with 50 mg EEand 1 mg NET for atleast 6 mo. Ampicillin500 mg 4 times daily(duration not stated)
Frequency of bleedingirregularities
0/20 with disorderedbleeding by historicalreport; 2/20 withbreakthrough bleeding;1/20 with no withdrawalbleeding after additionof ampicillin
Retrospective controlperiod; no justificationof sample size;adherence notassessed; noinformation on potentialconfounders; noinformation on outcomeassessment
Poor
Joshi et al (1980);supported bySchering, WorldHealth Organization
PK andPD;singlesequencecrossover
6 Healthy women,ages 20e36 y, BMInot reported
OC with EE 30 mgand NET 1 mg.Ampicillin 500 mgtwice dailyfor 5e7 daysstarting day 6e7of OC
EE and NET PK beforestart of ampicillin andagain on last day oftreatment; ovulationby serum P on days19e23
OCs with 50 mg EEand 0.25 mg LNG(n¼8), 50 mg EE and 0.5mg LNG (n¼1), 50 mgEE and 2.5 mglynestrenol (n¼1). Onedose 500 mg ampicillinon day 21 and 28 ofcycle
15 Healthy womenwith regularmenstrual cycles;age and BMI notreported
OC with 50 mg EEand 1 mg NET for atleast 6 mo;oxtetracycline500 mg 4 timesdaily, durationnot stated
Frequency ofbleedingirregularities
0/15 with disorderedbleeding by historicalreport; 0/15 withbreakthrough bleedingwith oxtetracycline
None Retrospective controlperiod; no justificationof sample size;adherence notassessed; noinformation on potentialconfounders; noinformation on outcomeassessment
Poor
Murphy et al (1991);National Institutes ofHealth, NationalInstitutes of ChildHealth and HumanDevelopment
PK; singlesequencecrossover/parallelgroups
7 Healthy women(antibiotic group), 4healthy controls; ages18e35 y, BMI notreported
OC with 35 mg EEand 1 mg NET;tetracycline 500 mgevery 4 hr for5e10 d, startingday 2 of OC
EE and NET PK day0 and between days5 and 10; tetracyclineAUC on day 1 andbetween days5 and 10
EE: No significantchanges in AUC orCmax with tetracycline.NET: AUC and Cmaxrose over time (days 0eday) whenadministered withtetracycline (P<.01).Tetracycline: Nodifference intetracycline Cmax andAUC 0-4 with OCs vs 4control subjects(parallel analysis)
Adherence assessedwith pill counts, PKparametersappropriate,perpetrator drug atsteady state
Not randomized; smallsample size; timing ofPK measurementsvariable and withinsubject comparisonsmade at different timesof same cycle; noinformation on potentialconfounders
Poor
Neely et al (1991);supported by WestVirginia FacultySenate and Johnsonand Johnson
PK and PD;singlesequencecrossover
24 Women takingOCs; ages 18e35 y,BMI not reported
OC with 35 mg EEand 1 mg NET for 2cycles; doxycycline,100 mg twice dailydays 14e21 incycle 2
EE and NET steady-state levels on days18-20; serum Pon days 18, 19,20 of both cycles
EE: No significantdifferences inserum EE with/withoutdoxycycline (P¼.49);NET: No significantdifferences in serumNET with/withoutdoxycycline (P¼.36).None of the women hadP >0.8 ng/mL and nodifference in P betweencycles (P¼.32)
Sample sizereasonable, adherenceassessed with pillcounts, PK parametersand timing appropriate,minimized intersubjectvariability, perpetratordrug at steady state
Not randomized;included ovulation asan outcome, but timingof serum P not likely tobe relevant, givenmid-cycleadministration ofdoxycycline
Fair
AUC, area under the curve; BMI, body mass index; Cmax, maximum serum concentration; EE, ethinyl-estradiol; HC, hormonal contraception; NET, norethindrone; OC, oral contraceptive pill; P, progesterone; PD, pharmacodynamics; PK, pharmacokinetic.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
Study and funding Study design PopulationExposure(HC and antibiotic) Outcomes Results Strengt
Quality
Amsden et al (2001);support by BassettHealthcare
PK; parallelgroups
Controls: 10 Whitewomen, mean age33 � 7.4 y, usingnon-HC. HC: 10 Whitewomen, mean age 31� 7.4 y taking HC for atleast 3 mo. All normalweight
OCs (n¼9); DMPA(n¼1); single dose200 mg trovafloxacin
Trovafloxacin PKover 24 hr
Both groups did nottolerate medicine infasted state withneurologic orgastrointestinalsymptoms in 80%control, 90% HC. Cmax:No HC 2.27 vs HC 1.92mg/L (P¼.03).Clearance: No HC 7.62vs HC 9.96 L/h(P<.004). AUC: No HC26.7 vs HC 20.8 mg/L-h(P<.004)
PK paratiming alimited ivariabili
Back et al(1991); supportedby Abbot
PK and PD;singlesequencecrossover
12 Healthy womenon OCs at least6 mo withoutbreakthroughbleeding, ages22e32 y, weightrange 44e79 kg
OC with 30 mgEEþ150 mg LNG(n¼11); 30 mgEE and 250 mg LNG(n¼1); temafloxacin600 mg daily � 7d start of cycle 2
EE and progestinlevels on days 5e8cycles 1 and 2;ovulation by serum Pdays 19e21
EE concentration 61.4� 21.1 pg/mL incontrol cycle and 68.5� 26.6 pg/mL intemafloxacin cycle(NS). LNGconcentration 2.07ng/mL in control cycleand 1.89 intemafloxacin cycle(NS). Plasma Pconcentration <1.0 ng/mL in both control andtemafloxacin cycles
PD;randomizedcrossover(each with 2cyclesplacebo and2 cyclesantibiotic)
20 Healthy womenon OCs at least 3 mo,mean age 28.2 y,mean BMI 22.1 kg/m2
OC with 30 mgEEþ150 mg LNG;ofloxacin 200 mg orplacebo twice dailyfor first 7 d of eachcycle
P on days 19e21(<3 nmol/L);ultrasound 4 timesper cycle for follicle>15 mm
No difference inovarian activitybetween placebo andofloxacin cycles; 3women had follicularactivity (follicle >15mm) and high estradiollevels in both placeboand ofloxacin cycles; nowomen ovulated basedon serum P
Randomblind, addiary cacounts;of obserof P meapproprclear; mfollow u
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
ajog.o
rg
JANUARY2018
American
JournalofObstetrics
&Gynecology
97.e8
hs Weaknesses rating
meters andppropriate;ntersubjectty
Not randomized;parallel design; smallsample size; adherencenot assessed; unclearwhether HC at steadystate because time ofcycle not stated; pooled2 hormonal methods
Poor
ce measuredcard andacin levels;omes andppropriate;ntersubjectty; both drugsy state
Not randomized;sample size marginal;data combined frommultiple pillformulations
Fair
ized, doubleherence byrd and tabletmultiple cyclesvation; timingasurementiate; exposureinimal loss top (n¼1)
Method ofrandomizationunclear; no mentionof allocationconcealment;sample sizecalculations notmentioned
APPENDIX EEvidence for fluoroquinolones (continued)
Study and funding Study design PopulationExposure(HC and antibiotic) Outcomes Results Strengths Weaknesses
Qualityrating
Droppert et al (1993),funding not stated
PD;randomizedcrossover
24 Healthy women,ages and weightsnot provided
30 mg EE, 150desogestrel;ciprofloxacin 500 mgtwice daily or placebodays 8e17 duringcycle 1 and cycle 3
Ovulation byultrasound(follicle >18 mm)and P4 at unspecifiedtimes (<2 ng/mL)
No ovulations noted byP; in 4 placebo and 4Cipro cycles, follicles>10 mm seeneincomplete ovariansuppression; 2 placebocycles had follicles>18 mm
Randomized,double blind
Unclear method ofrandomization; nomention of allocationconcealment; samplesize small for clinicaloutcome; adherencenot assessed; timing ofovulation assessmentnot described; nodescription of subjects
Poor
Maggiolo et al (1991);supported by Bayer
PD;randomizedcrossover
10 Healthy volunteerstaking long-termOCs, mean age27.4 y; mean weight61.4 kg, height163.1 cm
OCs: EE 20e40mgþgestodene 75 mg,LNG 50e150 mg, ordesogestrel 150 mg (no.not stated);ciprofloxacin 500 mg orplacebo twice daily forfirst 7 d of cycles2 and 3
Scholten et al (1998);assistance fromOrganon personnel
PK and PD;randomizedcrossover
24 Healthy womenusing OCs for 3 mo;ages 19e32 y; normalweight
OC with 30 mgEEþ150 mgdesogestrel;ciprofloxacin500 mg or placebotwice daily days1e10 of cycles1 and 3
EE PK on days 11,16;ovulation by serum P(days 16, 20, 24, 28)and ultrasound offollicles on days 8, 10,12, 14 (follicle >18mm)
EE PK: Geometricmean ratios forAUC0-12, Cmax, andt1/2 with and withoutCipro were within 80e125% on days 11and 16, consideredbioequivalent; noP >2 ng/mL; 2 withsustained folliculargrowth (>10 mm) onplacebo withoutovulation
Randomized; samplesize adequate;adherence measuredby Cipro levels; PKparameters and timingappropriate; minimizedintersubject variability;drugs at steady state
APPENDIX EEvidence for fluoroquinolones (continued)
Study and funding Study design PopulationExposure(HC and antibiotic) Outcomes Results Strengths Weaknesses
Qualityrating
Shain et al (2002);supported by Bayer
PK; parallelgroups
Control: 15 Healthywomen, meanage 37.6 � 7.2 y. HC:15 Healthywomen, meanage 31.1 � 8.6 y usingOC for at least 3 mo,normal weight
Unspecified OCs;single dose 400 mgmoxifloxacin
MoxifloxacinPK over 48 hr
Moxifloxacin PK: NSdifference in Cmax,Tmax, half-lifewith and without OC.AUC0-48: OC 34.5mg*h/L vs non-OC40.4 mg*h/L,P¼.008. Clearance:OC 191.3 vs non-OC159.9 mL/min,P¼.015; side-effectscommon
Not randomized; OCadherence notassessed; OC typeunspecified; timing ofmoxifloxacin duringcycle not specified;unclear whether OC atsteady state
Fair
AUC, area under the curve; BMI, body mass index; Cmax, maximum serum concentration; DMPA, depo-medroxyprogesterone acetate; EE, ethinyl-estradiol; HC, hormonal contraception; L-h, liters per hour; LNG, levonorgestrel; NS, not significant; OC, oralcontraceptive pill; P, progesterone; PD, pharmacodynamics; PK, pharmacokinetic; Tmax, time to maximum serum concentration.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
OC with estradiolvalerate 2 mg/DNG3 mg days 1e14,erythromycin 500 mg3 times daily ondays 8e14
E2V and DNG PK,antibiotic PK
E2: GMR of Cmax with/without erythromycin:151% (136e168%),AUC0-24 133% (118e150%). DNG: Cmax133% (123e144%),AUC0-24 162 (146e180%). Steady stateexposure up to 33% forE2 and 62% for DNG
Sample sizereasonable; PKparameters and timingappropriate; minimizedintersubject variability;both drugs at steadystate
Not randomized;adherence notassessed; populationnot reproductiveaged but explanationprovided
Fair
Fischer et al (2012);Office of Women’sHealth, US Food andDrug Administration;National Institutes ofHealth
PK; parallelgroups
25 Healthy women, 10used OCs, ages >18 y,weight within 25% ofideal body weight
15 Healthy womenusing OCs, ages18e40 y, weightwithin 15% of idealbody weight
OC with 35 mg EE and0.5/0.75/1 mg NET,dirithromycin 500 mgdaily for 14 days (day21 of cycle 2 throughday 8 of cycle 3)
EE PK on day 8 of bothcycles, ovulation byserum P on day 21 ofcycle 3 and ultrasound,breakthrough bleeding
EE: AUC decreased7.6%with dirithromycin(P¼.03); clearanceincreased 10%(P¼.03). No differenceto Cmax, Tmax, half-life. No womanovulated in eithercycle. Intermenstrualbleeding: 2 women withOC alone but not withdirithromycin 1; womanwith dirithromycin butnot OC alone
Sample sizereasonable;adherence assessedwith pill diaries; PKparameters and timingappropriate; minimizedintersubject variation;both drugs in steadystate
Not randomized Good
AUC, area under the curve; BMI, body mass index; Cmax, maximum serum concentration; DNG, dienogest; E2, estradiol; E2V, estradiol valerate; EE, ethinyl estradiol; FSH, follicle-stimulating hormone; GMR, geometric mean ratio; HC, hormonal contraception;IUD, intrauterine device; LNG, levonorgestrel; NET, norethindrone; OC, oral contraceptive pill; P, progesterone; PD, pharmacodynamics; PK, pharmacokinetic; Tmax, time to maximum serum concentration.
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018.
Trimethoprim/sulfamethoxazole 2/21with disorderedbleeding. Nitrofurantoin0/18 with disorderedbleeding
Retrospective controlperiod; no justification ofsample size; adherencenot assessed; noinformation onconfounders; noinformation on outcomeassessment
Poor
Joshi et al (1984);supported bySchering
PK; parallelgroups
10 Female leprosypatients on dapsone, 6healthy controls, ages19e38 y, normal weight
One OC (1 mgnorethisterone and 30mg EE) at 9 AM. Dapsone100 mg 5 days per week(long-term use)
NET and EE PK NET: Cmax Dapsone14.6 vs 12.4 ng/mLcontrol; AUC0-24Dapsone 88.8 vs 67.1ng/mL/hr control; all NSEE: AUC0-8 Dapsone1041 vs 681 pg/ml/hr(P<.05); Cmax 184dapsone vs 128 pg/mLcontrol (NS)
PK parameters andtiming appropriate;Dapsone at steady state
Not randomized; smallsample size; adherenceto Dapsone notassessed; minimalattempt to minimizeintersubject variation
Fair
Joshi et al (1980);supported bySchering, WorldHealthOrganization
PK and PD;singlesequencecrossover
10 Healthy women(PK and PD), 15healthy women (PDonly), ages 20e36 y,BMI notstated
OC with EE 30 mgþNET1 mg. Metronidazole400 mg 3 times dailyfor 6e8 days startingcycle 2 day 7
EE and NET PK (beforeand after completion ofantibiotic); ovulation byserum P on days 19e23
EE AUC0-6 and NETAUC0-24 did not changesignificantly afteraddition ofmetronidazole. OCs didnot alter levels ofmetronidazole. 3/25Women onmetronidazole/OC hadovulatory level P; 2/25had high P duringcontrol cycle
Borderline sample size;PK parameters andtiming reasonable; bothdrugs at steady state
Not randomized;adherence to OCsassessed, but by recallonly; minimal data onintersubject variation;multiple ovulations inboth groups concerningfor poor adherence orassay problem
Fair
Mehrota et al(1974); fundingnot stated
Clinical;parallelgroups
83 Female patients withpulmonary TB butotherwise healthy, with<15 d of treatment,ages 16e40 y, BMI notstated
OCs: OC with 0.1 mgmestranol and 1 mgethynodiol diacetate.Antibiotics: 300 gisoniazidþ150 mgthiacetazone daily, plusstreptomycin 1ginjection twice weeklyfor first 12 wk
TB status and safetyoutcomes in eachgroup after 1 y
1 Patient died ofpulmonary TB in the noOC group; 1 woman diedof other causes in OCgroup. Sputum culture:negative for 100% of OCusers at 1 year, andnegative for 94% of noOC group
Randomized; groupshad similar diseasestatus at baseline by x-ray and sputum cultures
Not blinded; noinformation onrandomization scheme;unclear power foroutcomes; adherencenot assessed; close to20% LTFU in bothgroups
Poor
Simmons. Antibiotics and hormonal contraception. Am J Obstet Gynecol 2018. (continued)
16 Healthy women perdrug, ages 18e40 y,BMI 18e30 kg/m2
Combined vaginal ring(15 mg EEþ120 mg ofENG daily) for 21 dayswith amoxicillin 875 mgtwice daily ordoxycycline 100 mgdaily on days 1e10 orplacebo during cycles2 and 3
EE and ENG PK No differences inetonogestrel or EEsteady-state levels orAUC between subjectsusing CVR with orwithout eitherantibiotic (GMRsbetween 0.8and 1.25)
Randomized with detailson randomizationscheme; adequate SS;PK measures and timingappropriate; adherencemonitored; minimizedintersubject variability;both drugs at steadystate
None identified Good
Pohl et al(2013); fundedby Preglem SA
PK; singlesequencecrossover
18 Healthy women,mean age 26.4 y(range, 19e41 y),BMI 18.5e25 kg/m2
20 mg UPA on days 1and 13. Erythromycin500 mg twice daily ondays 9e17
UPA PK on days1 and 13
Cmax increased by24% (GMR, 1.24(90% confidenceinterval, 1.01e1.52);AUC0-24 of UPAincreased 3.24 (2.75e3.83; up 224%); nochange to Tmax orhalf-life. For PGL4002(UPA metabolite)half-life doubled, Cmaxdown by 48% (GMRpoint estimate 0.523[95% CI 0.44e0.62])but AUC increased by62% (GMR pointestimate 1.62 [95% CI1.43-1.85]); no changeto Tmax
