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Update on antimicrobial agents and drug-drug interactions
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Although many commonly used antimicrobial agents in the pediatric population do not entail clinically significant risks for drug-drug interactions, some drug classes and specific agents are notable exceptions. As antibiotics and other antimicrobial agents — eg, antifungal agents — are frequently prescribed to infants, children and adolescents, a discussion of this topic is worthy of review.
Fortunately, many children do not have risk factors associated with an increasing likelihood of clinically significant drug-drug interactions. Such risk factors include higher quantity of prescribed medications, underlying hepatic or renal dysfunction, older age/compensated organ function, and need for medications with a narrow therapeutic index, such as warfarin. Some drug classes prescribed in pediatrics do share relatively long lists of potentially interacting drugs, including antifungals, rifamycins and selective serotonin reuptake inhibitors (SSRIs), and are discussed below.
Combined oral contraceptives (COC) are commonly prescribed for the adolescent population, and relatively new data and recommendations indicate that interactions with some antibiotics are not as significant as perhaps once believed.
Edward A. Bell
Drug-drug interactions can result from numerous mechanisms, including alterations in gastrointestinal absorption, renal excretion, or hepatic metabolism. Additive or toxic pharmacologic effect also may occur, such as use of more than one drug with serotonergic activity, potentially resulting in serotonin syndrome. More recently described information on drug-drug interaction mechanism includes alterations of drug transportation out of cells and within physiologic spaces to drug site of action and excretion. Drug transporter interactions are currently under evaluation for P-glycoprotein, organic anion transporter, and other transporter systems.
Alterations in hepatic drug metabolism, the site for most drug metabolism, are likely the most familiar type of drug-drug interaction to health care professionals. Hepatic drug metabolism primarily occurs by phase 1 reactions, mostly by cytochrome P450 enzymes (CYP), many of which have been identified. The sub-class enzymes 2D6 and 3A4 are responsible for the metabolism of many drugs. Drugs may induce or inhibit the hepatic metabolism of other drugs, potentially resulting in clinically significant drug-drug interactions.
Generally, drug-metabolizing inhibition occurs quickly, within hours to days, while drug metabolizing induction requires days to become clinically significant. Several factors can affect the quantity of drug metabolism alteration, including genetics, drug dose and underlying health status, among others. Specific drugs can be described as substrates (its metabolism is affected by another drug), or inhibitors or inducers (affecting the metabolism of another drug), or both.
Interpreting drug-drug interactions for clinical significance is often difficult and involves more than reviewing drug information sources. While drug information sources can be useful, some have criticized drug interaction software programs as overly cautious and unrealistic. While avoiding potentially interacting drugs is generally preferred, this may not always be possible, or necessary. Depending upon the specific interaction, monitoring for increased or decreased therapeutic effect, or adverse effects, may be all that is necessary. Empiric dose alteration (of the substrate) with the addition or discontinuance of an interacting drug may be necessary with other drug-drug interactions.
Oral contraceptives and rifamycins
Some health care professionals may recall being taught that administration of an antibiotic to a female maintained on a combined oral contraceptive product can reduce COC efficacy, substantially increasing the risk for unintended pregnancy. Recently published recommendations from the CDC (US Medical Eligibility Criteria for Contraceptive Use, 2010) and the AAP state that this is unlikely to occur with most antibiotics. Last year the AAP Committee on Adolescence published a document, “Contraception for Adolescents,” with only rifampin listed as an antibiotic that can decrease COC efficacy. Mycobutin (rifabutin, Pharmacia and Upjohn) is described along with rifampin in the document published by the CDC.
A large case-crossover study of 1,330 COC failures from two large databases (more than 15,000 women from each) was recently published, in which the antibiotics most commonly administered to the database patients were amoxicillin, ampicillin, macrolides and sulfonamides. The study authors did not find an association between concomitant antibiotic use and risk for breakthrough pregnancy among COC users. Many anticonvulsants and some antiretroviral agents can significantly reduce COC efficacy by hepatic metabolizing enzyme induction, and are described in these documents. Rifampin (also referred to as rifampicin) is a known potent inducer of CYP enzymes and the P-glycoprotein transport system, characterizing its high potential for significant drug-drug interactions. Rifabutin and Priftin (rifapentine, Sanofi), other rifamycin agents, also induce CYP hepatic enzymes. Use of rifampin, rifabutin, and perhaps rifapentine, are best avoided concomitantly with COC use.
Other than interacting with COCs, rifampin, rifabutin, and rifapentine can substantially increase the hepatic metabolism, with resultant decreased efficacy, of numerous additional medications, including corticosteroids, antiretrovirals, tacrolimus, and cyclosporine, among others. When a rifamycin agent is initiated or discontinued (as the substrate agent dose may then require reduction), it is wise to review the patient’s medication profile carefully.
Linezolid
Linezolid is an oxazolidinone antibiotic and can selectively play a role in the treatment of some infections from MRSA and other gram-positive microbes. Linezolid use has the potential to result in numerous drug-drug interactions, as it is a reversible inhibitor of monoamine oxidase. Product labeling for linezolid warns of the potential for serotonin syndrome when linezolid is used concomitantly with serotonergic agents, such as SSRIs, SNRIs, or bupropion.
Initiating linezolid therapy in a patient receiving an SSRI or SNRI is not as straightforward as simply discontinuing the SSRI or SNRI, as these agents have relatively long elimination half-lives (at least 24 hours). As the list of drugs that can potentially interact with linezolid is relatively lengthy, a review of a patient’s concomitant medications is prudent when considering linezolid use.
Azole antifungal agents
The azole antifungal agents Diflucan (fluconazole, Pfizer), Sporanox (itraconazole, Ortho-McNeil-Janssen Pharmaceuticals), Vfend (voriconazole, Pfizer) and Noxafil (posaconazole, Merck) have numerous uses in pediatrics. Nizoral (ketoconazole, McNeil), also an azole, has very limited use, due to its adverse effect and drug-drug interaction profile, as was described in a 2013 warning by the FDA. All azole agents are moderate-strong inhibitors of hepatic 3A4, and also can inhibit other hepatic CYP450 enzymes. Additionally, the azoles are substrates for several CYP450 enzymes. Several hundred drug-drug interactions are described in drug information sources for the azoles, with many of these interactions listed as contraindicated use. Labeling for itraconazole and ketoconazole includes black box warnings due to the potential for significant drug-drug interactions.
While the prevalence of drug-drug interactions in pediatrics may not be as high as in the adult population, several antimicrobial agents commonly used in children may result in clinically significant interactions. It is prudent for health care providers to reconcile patients’ medication lists at each office visit, and especially before prescribing new medications. Patients can benefit from obtaining all of their medications from one pharmacy alone when possible, to provide an additional means for drug-drug interaction screening. Recognizing specific classes of antimicrobial agents that are more likely to result in drug-drug interactions is helpful. While some drug-drug combinations are contraindicated, others can be managed with empiric dose alterations or careful monitoring for therapeutic efficacy and adverse effects.
References:
Baciewicz AM, et al. Curr Med Res Opin. 2013;doi:10.1185/03007995.2012.747952.
Bruggemann RJM, et al. Clin Infect Dis. 2009;doi:10.1086/598327.
CDC. US Medical Eligibility Criteria for Contraceptive Use, 2010: Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition. MMWR. 2010;59:1-6.
Clark DB, et al. Pharmacotherapy. 2006;doi:10.1592/phco.26.2.269.
Lewis RE. Mayo Clin Proc. 2011;doi:10.4065/mcp.2011.0247.
Ott MA, et al. Pediatrics. 2014;doi:10.1542/peds.2014-2300.
Toh S, et al. Contraception. 2011;doi:10.1016/j.contraception.2010.08.020.
For more information:
Edward A. Bell, PharmD, BCPS, is professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.
Disclosure: Bell reports no relevant financial disclosures.