Letters

that legalization of recreational marijuana is associated with in- Association Between Penicillin creased traffic fatality rates. Applying these results to national driv- Documentation and Antibiotic Use ing statistics, nationwide legalization would be associated with Approximately half of hospitalized patients receive antibiot- 6800 (95% CI, 4200-9700) excess roadway deaths each year. De- ics, and more than 10% of these patients have a penicillin spite certain methodological differences, we found an increase allergy documented in the medical record.1 Hospitalized similar to that reported by Aydelotte et al.4 They reported an in- patients with ongoing crease of 1.8 fatal crashes (equivalent to 2.0 fatalities) per BVMT. who report an We concur with their opinion that changes may not be detected Supplemental content allergy to penicillin have an immediately after legalization but only after a longer time period increased risk of adverse or after commercial sales begin. CME Quiz at drug events, including Clos- We chose a control group consisting of all states with nei- jamacmelookup.com tridioides difficile , ther legal recreational nor medical marijuana to isolate the ef- when not treated with a fects of marijuana. We did not require that control states have β-lactam antibiotic.2 Allergy assessment with or without baseline attributes similar to the experimental states because diagnostic testing disproves more than 90% of documented the difference-in-difference technique removes biases in com- penicillin .1 parisons between experimental and control groups that re- sult from permanent differences between those groups. Our Table. Multivariable Assessment of the Association of Documented conclusions, nonetheless, are limited by adjusting for only 3 Penicillin Allergies With Inpatient Antibiotic Use state-specific factors that may have changed during the study a period. It is possible that another confounder, rather than mari- Odds ratio (95% CI) juana legalization and commercialization, caused the ob- Partially adjusted Fully adjusted Antibiotic modelb modelc served increase in roadway deaths. β-lactam alternativesd 2.04 (1.82-2.27) 1.94 (1.74-2.17) Vancomycin 1.21 (1.07-1.36) 1.14 (1.01,1.29) Russell S. Kamer, MD Fluoroquinolones 1.93 (1.64-2.26) 1.91 (1.61-2.25) Stephen Warshafsky, MD Gordon C. Kamer Macrolides 0.94 (0.78-1.12) 0.94 (0.78-1.12) Sulfonamides 1.14 (0.90-1.45) 1.16 (0.91-1.48) Tetracyclines 1.41 (1.07-1.85) 1.37 (1.03-1.83) Author Affiliations: Department of Medicine, New York Medical College, Valhalla, New York (R. S. Kamer, Warshafsky); Harvard College, Harvard Clindamycin 5.78 (4.39-7.61) 5.34 (3.99-7.13) University, Cambridge, Massachusetts (G. C. Kamer). Aminoglycosides 1.74 (1.34-2.25) 1.53 (1.16-2.02) Corresponding Author: Russell S. Kamer, MD, Department of Medicine, New Linezolid 2.30 (1.45-3.63) 2.18 (1.37-3.48) York Medical College, 15 N Broadway, White Plains, NY 10601 (drkamer@ e drkamer.com). Narrow-spectrum β-lactams 0.33 (0.29-0.38) 0.35 (0.31-0.40) f g g Accepted for Publication: April 13, 2020. Penicillins 0.17 (0.12-0.25) 0.17 (0.12-0.25) Published Online: June 22, 2020. doi:10.1001/jamainternmed.2020.1769 Cephalosporins Author Contributions: Dr R Kamer had full access to all of the data in the study First generation 0.44 (0.37-0.52) 0.47 (0.40-0.55) and takes responsibility for the integrity of the data and the accuracy of the data Second generation 1.30 (0.79-2.12) 1.34 (0.82-2.18) analysis. Concept and design: R. Kamer, Warshafsky. Other β-lactams Acquisition, analysis, or interpretation of data: All authors. Cephalosporins Drafting of the manuscript: All authors. Third generation 0.87 (0.75-1.02) 0.92 (0.78-1.08) Critical revision of the manuscript for important intellectual content: R. Kamer, Warshafsky. Fourth generation 1.44 (1.20-1.72) 1.47 (1.23-1.76) Statistical analysis: All authors. Carbapenems 1.83 (1.48-2.26) 1.72 (1.38-2.14) Supervision: Warshafsky, G. Kamer. Aztreonam or 22.49 (14.39-35.15) 18.44 (11.13-30.55) Conflict of Interest Disclosures: None reported. monobactams 1. Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem. 2013; a Documented penicillin allergy compared with no documented penicillin 59(3):478-492. doi:10.1373/clinchem.2012.194381 allergy. 2. Aydelotte JD, Brown LH, Luftman KM, et al. Crash fatality rates after b Adjusted for age, sex, race/ethnicity, length of hospitalization, inpatient recreational marijuana legalization in Washington and Colorado. Am J Public Health. location within the hospital, and number of infections. 2017;107(8):1329-1331. doi:10.2105/AJPH.2017.303848 c Adjusted for age, sex, race/ethnicity, length of hospitalization, number of 3. Hansen B, Miller K, Weber C. Early evidence on recreational marijuana staffed beds, hospital geographic location, diabetes, cephalosporin allergy, legalization and traffic fatalities. Econ Inq. 2018. doi:10.3386/w24417 inpatient location within the hospital, and number of infections. 4. Lane TJ, Hall W. Traffic fatalities within US states that have legalized d Includes vancomycin, fluoroquinolones, macrolides, sulfonamides, recreational cannabis sales and their neighbours. Addiction. 2019;114(5):847-856. tetracyclines, clindamycin, aminoglycosides, and linezolid. doi:10.1111/add.14536 e Includes all penicillins except antipseudomonal penicillins and first- 5. Aydelotte JD, Mardock AL, Mancheski CA, et al. Fatal crashes in the 5 years and second-generation cephalosporins. after recreational marijuana legalization in Colorado and Washington. Accid Anal f Other than antipseudomonal penicillins. Prev. 2019;132:105284. doi:10.1016/j.aap.2019.105284 g Similar when considering amoxicillin-clavulanic acid, ampicillin-sulbactam, 6. National Highway Traffic Safety Administration. Fatality Analysis Reporting and piperacillin-tazobactam together: adjusted odds ratio, 0.18 (95% CI, System (FARS) encyclopedia. Accessed November 22, 2019. https://www-fars. 0.14-0.22). nhtsa.dot.gov/States/StatesFatalitiesFatalityRates.aspx Published 2019.

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Figure. Association of Documented Penicillin Allergies With Inpatient Antibiotic Use Among US Inpatients

A β-Lactam alternative antibiotic use

Lesser odds Greater odds of β-lactam of β-lactam alternative alternative Infection aOR (95% CI) antibiotic use antibiotic use All 1.94 (1.74-2.17) Pneumonia 1.48 (1.13-1.95) Skin and soft tissue 1.38 (1.08-1.75) Urinary tract 2.07 (1.51-2.85) Prophylaxis for surgical procedure 7.31 (5.01-10.69)

0 2 4 6 8 10 12 aOR (95% CI)

B Narrow-spectrum β-lactam antibiotic use Lesser odds Greater odds of narrow- of narrow- spectrum spectrum β-lactam β-lactam Infection aOR (95% CI) antibiotic use antibiotic use All 0.35 (0.31-0.40) Pneumonia 0.31 (0.19-0.50) Adjusted odds ratios (aORs) are Skin and soft tissue 0.53 (0.39-0.71) adjusted for age, sex, race/ethnicity, length of hospitalization, number of Urinary tract 0.26 (0.13-0.54) staffed beds, hospital geographic Prophylaxis for surgical procedure 0.11 (0.07-0.15) location, diabetes, cephalosporin 0 0.2 0.4 0.6 0.8 1.0 1.2 allergy, inpatient location within the aOR (95% CI) hospital, and number of specific infections treated.

The inpatient prevalence and effects of documented peni- tients (16%) had a penicillin allergy documented in the medi- cillin allergies has been exclusively investigated in single hos- cal record. Most penicillin reactions (946 of 2112 [45%]) were pitals or health care systems. We used a large cross-sectional cutaneous. Patient characteristics by penicillin allergy status database of inpatients receiving antibiotics to assess the preva- were similar. lence and association of documented penicillin allergy with Compared with patients without a documented penicil- inpatient antibiotic use in the US. lin allergy, patients with a documented penicillin allergy had higher β-lactam alternative antibiotic use (1114 of 1741 Methods | This cohort study used cross-sectional inpatient data [64%] vs 4438 of 9251 [48%]) and lower narrow-spectrum collected through Acute Care Hospital Groups within Vizient β-lactam antibiotic use (227 of 1741 [13%] vs 2811 of 9251 Inc, Irving, Texas, from September 2018, through January 2019 [30%]). (eMethods in the Supplement). Data analysis was performed In the fully adjusted model (Table), patients with a docu- from January 2019, through January 2020. The study was re- mented penicillin allergy had increased odds of β-lactam al- viewed by the Partners Human Research Committee, Boston, ternative antibiotic use (aOR, 1.94; 95% CI, 1.74-2.17), with es- Massachusetts, and was determined to be exempt because it pecially high odds of clindamycin use (aOR, 5.34; 95% CI, 3.99- was categorized as nonhuman research. 7.13). Patients with a documented penicillin allergy had lower The exposure was an allergy to any penicillin antibiotic odds of narrow-spectrum β-lactam antibiotic use (aOR, 0.35; documented in the medical record. The outcomes were anti- 95% CI, 0.31-0.40). biotic use overall and for specified indications, considering in- The association between a documented penicillin dividual antibiotic classes and 2 antibiotic groupings: (1) β-lac- allergy and β-lactam alternative antibiotic use was stronger tam alternative antibiotics and (2) narrow-spectrum β-lactam among patients receiving antibiotics for urinary tract infec- antibiotics. tion (aOR, 2.07; 95% CI, 1.51-2.85) and as prophylaxis We examined the association of documented penicillin for surgical procedures (aOR, 7.31; 95% CI, 5.01-10.69]) allergy with antibiotic use overall and for specified indica- (Figure, A). The association between a documented penicil- tions, such as pneumonia, skin and soft-tissue infection, lin allergy and narrow-spectrum β-lactam antibiotic use urinary tract infection, and prophylaxis for surgical proce- was stronger among patients receiving antibiotics for dures. We used generalized estimating equations models to pneumonia (aOR, 0.31; 95% CI, 0.19-0.50), urinary tract account for clustering by hospital with logit link in SAS, ver- infection (aOR, 0.26; 95% CI, 0.13-0.54), and as prophylaxis sion 9.4 (SAS Institute Inc). We report adjusted odds ratios for surgical procedures (aOR, 0.11; 95% CI, 0.07-0.15]) (aORs) with 95% CIs. (Figure, B).

Results | Of 10 992 inpatients (5567 [51%] male; mean [SD] age, Discussion | In this cross-sectional study of 10 992 inpatients 57.0 [21.5] years) receiving antibiotics at 106 hospitals, 1741 pa- receiving antibiotics from 106 US hospitals, 16% of

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patients with a documented penicillin allergy had almost Corresponding Author: Kimberly G. Blumenthal, MD, MSc, Division of 2-fold higher odds of receiving a β-lactam alternative antibi- Rheumatology, Allergy and , The Mongan Institute, Massachusetts General Hospital, 100 Cambridge St, 16th Floor, Boston, MA 02114 (kblumenthal otic. We reported the largest increased odds of a specific @mgh.harvard.edu). β-lactam alternative for clindamycin, an antibiotic associ- Published Online: June 29, 2020. doi:10.1001/jamainternmed.2020.2227 ated with C difficile infection risk, for which use was more Author Contributions: Dr Blumenthal had full access to all of the data in the than 5-fold more likely. We identified more than 7-fold study and takes responsibility for the integrity of the data and the accuracy of increased odds of alternative antibiotic use for inpatients the data analysis. with a documented penicillin allergy receiving antibiotics as Concept and design: All authors. prophylaxis for a surgical procedure, a narrow-spectrum Acquisition, analysis, or interpretation of data: Blumenthal, Kuper, Schulz, Postelnick, Lee, Walensky. β-lactam antibiotic indication for reducing infection risk at Drafting of the manuscript: Blumenthal, Lee. the surgical site.1,3 Patients with a penicillin allergy docu- Critical revision of the manuscript for important intellectual content: Blumenthal, mented in their medical record also had more than 18-fold Kuper, Schulz, Bhowmick, Postelnick, Walensky. Statistical analysis: Blumenthal, Lee. increased odds of aztreonam use. Obtained funding: Blumenthal. When considering that a small number of the inpatients Administrative, technical, or material support: Blumenthal, Kuper, Schulz, reporting penicillin allergy would have been truly allergic to Walensky. penicillin, at least 90% of these antibiotic substitutions Supervision: Schulz, Bhowmick, Walensky. were likely unnecessary.1,4 Although penicillin allergy Conflict of Interest Disclosures: Dr Blumenthal reported intellectual property for a clinical decision support tool used institutionally for β-lactam allergy evaluations are recommended as part of inpatient antibiotic assessment at Partners HealthCare System, which is licensed to Persistent 5 stewardship, most hospitals do not have access to penicil- Systems. Dr Kuper reported being an employee of Vizient Inc at the time of the lin allergy assessment.6 However, allergy history alone study. Dr Lee reported receiving grants from Lynntech outside the submitted is associated with a high negative predictive value work. No other disclosures were reported. (96.5%; 95% CI, 94.1%-97.8%) for excluding true penicillin Funding/Support: Dr Blumenthal was supported by a career development 4 grant (K01AI125631) from the National Institutes of Health; the American allergy. Academy of Allergy, Asthma, and Immunology Foundation; and the Although our study data came from a large sample of hos- Massachusetts General Hospital Claflin Distinguished Scholar Award. Dr pitals, these data may not be nationally representative. Cross- Walensky was supported by the Steven and Deborah Gorlin Massachusetts sectional data did not permit determination of cumulative an- General Hospital Research Scholars Award. tibiotic use metrics. Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and The 16% of inpatients with a penicillin allergy docu- interpretation of the data; preparation, review, or approval of the manuscript; mented on their medical record were treated more com- and decision to submit the manuscript for publication. monly with alternatives that may be inferior and/or associ- Disclaimer: The content is solely the responsibility of the authors and does not ated with more adverse drug events. Hospitals may target necessarily represent the official views of the National Institutes of Health; the patients prescribed clindamycin or patients with planned sur- American Academy of Allergy, Asthma, and Immunology Foundation; or Massachusetts General Hospital. gical procedures for inpatient penicillin allergy interven- Additional Contributions: Christian M. Mancini, BS, Xioqing Fu, MS, and Yuqing tions. Zhang, DSc (Massachusetts General Hospital, Boston), provided data analytic support. Vizient Inc, Irving, Texas, facilitated this study through their hospital network, including the assistance of Arati Kurani, PharmD, Jade Vitug, PharmD, Larry Huang, PharmD, Alyzeh Haider, MHA, and Sam Hohmann, PhD. Christie Kimberly G. Blumenthal, MD, MSc Bertram, PharmD (Northwestern Memorial Hospital, Chicago, Illinois), provided Kristi Kuper, PharmD administrative study support to the hospitals during data acquisition. None of these individuals was compensated for their assistance. Lucas T. Schulz, PharmD 1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of Tanaya Bhowmick, MD penicillin allergy: a review. JAMA. 2019;321(2):188-199. doi:10.1001/jama. Michael Postelnick, RPh 2018.19283 Francesca Lee, MD 2. MacFadden DR, LaDelfa A, Leen J, et al. Impact of reported β-lactam allergy Rochelle P. Walensky, MD, MPH on inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. 2016;63(7):904-910. doi:10.1093/cid/ciw462 3. Bratzler DW, Dellinger EP, Olsen KM, et al; American Society of Author Affiliations: Division of Rheumatology, Allergy, and Immunology, Health-System Pharmacists; Infectious Disease Society of America; Surgical Department of Medicine, Massachusetts General Hospital, Boston Infection Society; Society for Healthcare Epidemiology of America. Clinical (Blumenthal); The Mongan Institute, Massachusetts General Hospital, Boston practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. (Blumenthal, Walensky); Department of Medicine, Harvard Medical School, 2013;70(3):195-283. doi:10.2146/ajhp120568 Boston, Massachusetts (Blumenthal, Walensky); Vizient Inc, Irving, Texas (Kuper); Department of Pharmacy, University of Wisconsin Health, Madison 4. Trubiano JA, Vogrin S, Chua KYL, et al. Development and validation of a (Schulz); Division of Allergy, Immunology, and Infectious Diseases, Department penicillin allergy clinical decision rule. JAMA Intern Med. 2020;180(5):1-9. of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, doi:10.1001/jamainternmed.2020.0403 New Jersey (Bhowmick); Department of Pharmacy, Northwestern Memorial 5. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary: implementing Hospital, Chicago, Illinois (Postelnick); Division of Infectious Diseases, an antibiotic stewardship program: guidelines by the Infectious Diseases Department of Pathology and Internal Medicine, The University of Texas Society of America and the Society for Healthcare Epidemiology of America. Clin Southwestern Medical Center, Dallas (Lee); Division of Infectious Diseases, Infect Dis. 2016;62(10):1197-1202. doi:10.1093/cid/ciw217 Department of Medicine, Massachusetts General Hospital, 6. Mancini CM, Fu X, Zhang Y, et al. Penicillin allergy evaluation access: Boston (Walensky). a national survey. Clin Infect Dis. Published online May 18, 2020. doi:10.1093/ Accepted for Publication: April 27, 2020. cid/ciaa567

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