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Home , Cefepime, Cefotaxime

Ritu Banerjee, MD, PhD,​a Cary W. Thurm, PhD,​b Erin R. Fox, PharmD,c​ Adam L. Hersh, MD, PhDc Shortages in Pediatrics MEDICATION SHORTAGES ARE INCREASING NATIONWIDE

Medication shortages are increasingly common and severe in the United States and are a serious health threat. Medication shortages occur when reduced supply of a drug influences how1 it is prepared, dispensed, or prescribed by pharmacies or providers. According to the US Food and Drug Administration (FDA), most shortages are caused by quality and 2 aVanderbilt University Medical Center, Nashville, Tennessee; manufacturing problems. Consequences of shortages include rationing bChildren’s Hospital Association, Lenexa, Kansas; and cUniversity of Utah, Salt Lake City, Utah limited supplies, delays in therapy,3 medication errors, use of less- efficacious alternatives, and death. Recently, critical drugs like sodium Drs Banerjee and Hersh conceptualized and designed chloride and amino acids have been on shortage, exacerbated by damage the study, drafted the initial manuscript, and reviewed to manufacturing plants by natural disasters like Hurricane Maria. and revised the manuscript; Dr Thurm collected the data, Although shortages have affected virtually all classes of medications, performed the initial analyses, and reviewed and revised the antimicrobial shortages are common and account for 15% of all drug manuscript; Dr Fox critically reviewed the manuscript for 1,4​ important intellectual content and revised the manuscript; shortages. and all authors approved the final manuscript as submitted ANTIMICROBIAL SHORTAGES CAN CAUSE HARM TO PATIENTS, AND THEIR and agree to be accountable for all aspects of the work. IMPACT ON CHILDREN IS NOT WELL STUDIED DOI: https://​doi.​org/​10.​1542/​peds.​2018-​0858 Accepted for publication Jul 30, 2018 Address correspondence to Ritu Banerjee, MD, PhD, Medication shortages can force clinicians to treat patients with Vanderbilt University Medical Center, 1161 21st Ave, Nashville, suboptimal therapy, which, in turn, can lead to poor outcomes. Examples TN 37232. E-mail: [email protected] relating to antimicrobial agents are when a shortage led PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098- to usePneumocystis of second-line jiroveci therapies for neurosyphilis, an intravenous 4275). trimethoprim-sulfamethoxazole shortage led to alternative therapies Copyright © 2018 by the American Academy of Pediatrics for infections, an acyclovir shortage led to use FINANCIAL DISCLOSURE: The authors have indicated they of alternative antiviral therapy for herpes encephalitis, and shortage have no financial relationships relevant to this article to of amikacin led to alternative antibiotic combinations for multidrug- disclose. resistant Gram-negative infections. Most infectious disease physicians FUNDING: No external funding. surveyed through the Emerging Infections Network reported that POTENTIAL CONFLICT OF INTEREST: Vizient pays Dr Fox’s antibiotic shortages had adversely affected patient outcomes in their1 affiliation, the University of Utah Drug Information Service, practice because of use of inferior, more-toxic, or costly alternatives. A to provide them with drug shortage data; no funds are recent shortage of - affected 88 of 107 hospitals directly paid to Dr Fox; and Drs Banerjee, Thurm, and Hersh have indicated they have no potential conflicts of interest to in the MedMined Clinic Research Database and led many institutions5 to disclose. prescribe alternativeClostridium difficile in place of piperacillin-tazobactam. Hospitals that used more alternative antibiotics had higher rates of5 hospital-onset infection among adult patients. Few To cite: Banerjee R, Thurm CW, Fox ER, et al. Antibiotic evaluations of the impact of antimicrobial shortages on children have Shortages in Pediatrics. Pediatrics. 2018;142(5):e20180858 been performed. During a recent shortage, many pediatric institutions recommended the use of piperacillin-tazobactam in place of Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 5, November 2018:e20180858 PEDIATRICS PERSPECTIVES ’ cefepime. At 1 children s hospital, this resulted in higher rates of acute kidney injury, which is associated with piperacillin-tazobactam and 6 combination therapy. THE SHORTAGE IS AN EXAMPLE OF A DRUG SHORTAGE THAT HAS NOT IMPACTED ALL INSTITUTIONS EQUALLY

The number of companies supplying the third-generation , cefotaxime, has dwindled in recent years until only 1 company was supplying cefotaxime by 2016, as reported by the American Society of Health System Pharmacists FIGURE 1 7 Trends in use of cefotaxime and replacement antibiotics (, , , drug shortage Web site. Other cefepime, gentamicin, ) among children hospitalized at 45 Pediatric Hospital Information companies that previously supplied System (PHIS) hospitals, 2014 through 2017. DOT, days of therapy (unpublished data). cefotaxime made a business decision to discontinue production because of an increase in the price of the raw materials. The single-remaining To examine the impact of the by the ongoing cefotaxime shortage, supplier was unable to keep up with cefotaxime shortage on hospitalized which has led to decreased use of children nationwide, we evaluated the demand for cefotaxime, leading to ’ cefotaxime in pediatric hospitals. a national shortage. cefotaxime use, a surrogate for However, when evaluated at drug availability, among children s the institutional level, there was The cefotaxime shortage has hospitals within the Pediatric significant variation in use (and by disproportionately affected infants, Hospital Information System implication, uneven availability) compared with older patients. This is network. The change in cefotaxime of cefotaxime among individual because a comparable cephalosporin, use was quantified for each hospital hospitals. ceftriaxone, that can be used in older between 2014 and 2015 and 2016 children, is generally not used in through quarter 2, 2017. Cefotaxime Variation in supplies of critical infants <2 months of age because use declined by 81%, from 28.8 to medications may be due to of increased risk of kernicterus 5.6 days of therapy per 1000 patient differences in patient populations, and calcium-ceftriaxone vascular days between 2014 and 2017, while drug use patterns, supply chain deposits. Because of limited supply, replacement antibiotic use increased management, existence of the American Academy of Pediatrics (Fig 1). However, the shortage was antimicrobial stewardship programs, recommended in February 2015 not experienced equally among that clinicians use ceftazidime hospitals. There was great variation and restrictions on use of short- in place of cefotaxime in infants in the extent to which cefotaxime use supply drugs. In 2011, the IMS <2 months of age with proven or declined, for all hospitalized children Institute for Healthcare Informatics suspected infections because of and for infants <60 days of age with a reported that some states are impacted more than others by Gram-negative8 bacilli, particularly diagnosis of (Fig 2). meningitis. Use of broad-spectrum CONCLUSIONS AND STRATEGIES TO drug shortages and attributed this therapies in place of cefotaxime may MITIGATE THE IMPACT OF MEDICATION to differences in per capita4 usage select for drug-resistant SHORTAGES of short-supply products. This ’ and have adverse consequences on variability in drug shortage impact patients microbiomes. At each of our seems unjust. More research is institutions, the cefotaxime shortage In the United States, medication needed to identify optimal strategies has led to restricted indications for shortages are common but may for preventing and managing its use and review of alternative not affect all hospitals equally. An shortages of critical medications, regimens. example of inequity is demonstrated which are likely to continue. Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 BANERJEE et al ABBREVIATION

FDA: US Food and Drug Administration REFERENCES 1. Quadri F, Mazer-Amirshahi M, Fox ER, et al. Antibacterial drug shortages from 2001 to 2013: implications for clinical practice [published correction appears in Clin Infect Dis. 2015;61(11):1769]. Clin Infect Dis. 2015;60(12):1737–1742 2. US Food and Drug Administration. A Review of FDA’s Approach to Medical Product Shortages. Washington, DC: US Department of Health and Human Services; 2011 3. Institute for Safe Medical Practices. Medication safety alert. Special issue: Drug shortages: National survey reveals high level of frustration, low level of FIGURE 2 Change in cefotaxime use for infants <60 days with a diagnosis of meningitis, between 2014 and safety. September 23, 2010. Available 2015 and 2016 through second quarter 2017, among 45 Pediatric Hospital Information System (PHIS) at: https://​www.​ismp.​org/​resources/​ hospitals (unpublished data). special-​issue-​drug-​shortages-​national-​ survey-​reveals-​high-​level-​frustration-​low-​ level. Accessed September 21, 2018 4. IMS Institute for Healthcare Informatics. The extent to which medication These include opportunities for Drug Shortages: A Closer Look at shortages have affected outcomes in more judicious antimicrobial use, Products, Suppliers, and Volume children should be better evaluated. wider stewardship efforts, and Volatility. Parsippany, NJ: IMS Institute The shortages of antimicrobial evaluation of replacement drug for Healthcare Informatics; 2011 agents are especially problematic safety in pediatric populations (eg, 5. Gross AE, Johannes RS, Gupta V, Tabak given that fewer antimicrobial ceftriaxone use in young infants). YP, Srinivasan A, Bleasdale SC. The effect agents are FDA approved for use of a piperacillin/tazobactam shortage on There must be interventions to antimicrobial prescribing and Clostridium in neonates, infants, and children, address the problem of critical difficile risk in 88 US medical centers. Clin compared with adults, and finding medication shortages, including Infect Dis. 2017;65(4):613–618 safe, alternative agents during increased awareness of the problem 6. Cook KM, Gillon J, Grisso AG, et al. shortages is therefore challenging. and more advocacy and political Incidence of nephrotoxicity among Antimicrobial stewardship will to increase FDA oversight pediatric patients receiving vancomycin champions frequently manage the of the manufacturing of critical with either piperacillin-tazobactam or rationing of short-supply drugs medications. Manufacturers cefepime: a cohort study [published online and are valuable resources during should be required to disclose ahead of print March 26, 2018]. J Pediatric Infect Dis Soc. doi:10.​ 1093/​ jpids/​ piy030​ medication shortages, even for to the medical community their classes other than antimicrobial manufacturing sites, products, 7. American Society of Health-System agents. Stewards have substantial and volume, and sole-source Pharmacists. Cefotaxime sodium experience in helping to prioritize medications should not be produced injection. Available at: https://www​ .ashp.​ ​ org/​Drug-​Shortages/​Current-​Shortages/​ patients who should receive agents in a single plant. Direct government Drug-​Shortage-​Detail.​aspx?​id=​51. with limited supply, identifying involvement in the manufacturing Accessed July 16, 2018 therapeutic alternatives, developing of critical medications should be clinical guidelines that incorporate explored. Lastly, manufacturers 8. Bradley JS. Alternatives to consider during cefotaxime shortage. AAP News. alternative therapies, and should receive incentives to February 25, 2015. Available at: http://​ communicating with providers about continue making products like www.​aappublications.​org/​content/​ shortages and judicious prescribing. antibiotics, for which there are small early/​2015/​02/​25/​aapnews.​20150225-​1. Additionally, antimicrobial markets, because although these Accessed July 16, 2018 shortages may lead to unintended drugs may not be profitable, they are consequences that have benefits. lifesaving. Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 5, November 2018 3 Antibiotic Shortages in Pediatrics Ritu Banerjee, Cary W. Thurm, Erin R. Fox and Adam L. Hersh Pediatrics 2018;142; DOI: 10.1542/peds.2018-0858 originally published online October 18, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/142/5/e20180858 References This article cites 3 articles, 0 of which you can access for free at: http://pediatrics.aappublications.org/content/142/5/e20180858#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 Antibiotic Shortages in Pediatrics Ritu Banerjee, Cary W. Thurm, Erin R. Fox and Adam L. Hersh Pediatrics 2018;142; DOI: 10.1542/peds.2018-0858 originally published online October 18, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/142/5/e20180858

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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