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Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study

BMJ 2018; 361 doi: (Published 27 June 2018) Cite this as: BMJ 2018;361:k2400
  1. Kimberly G Blumenthal, assistant professor of medicine123,
  2. Na Lu, biostatistician1,
  3. Yuqing Zhang, professor of medicine13,
  4. Yu Li, research assistant12,
  5. Rochelle P Walensky, professor of medicine234,
  6. Hyon K Choi, professor of medicine13
  1. 1Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA 20114, USA
  2. 2Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, MA, USA
  3. 3Harvard Medical School, Boston, MA, USA
  4. 4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  1. Correspondence to: K G Blumenthal kblumenthal1{at} (or @KimberlyBlumen1 on Twitter)
  • Accepted 30 April 2018


Objective To evaluate the relation between penicillin allergy and development of meticillin resistant Staphylococcus aureus (MRSA) and C difficile.

Design Population based matched cohort study.

Setting United Kingdom general practice (1995-2015).

Participants 301 399 adults without previous MRSA or C difficile enrolled in the Health Improvement Network database: 64 141 had a penicillin allergy and 237 258 comparators matched on age, sex, and study entry time.

Main outcome measures The primary outcome was risk of incident MRSA and C difficile. Secondary outcomes were use of β lactam antibiotics and β lactam alternative antibiotics.

Results Among 64 141 adults with penicillin allergy and 237 258 matched comparators, 1365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1688 developed C difficile (442 participants with penicillin allergy and 1246 comparators) during a mean 6.0 years of follow-up. Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26 (1.12 to 1.40). The adjusted incidence rate ratios for antibiotic use among patients with penicillin allergy were 4.15 (95% confidence interval 4.12 to 4.17) for macrolides, 3.89 (3.66 to 4.12) for clindamycin, and 2.10 (2.08 to 2.13) for fluoroquinolones. Increased use of β lactam alternative antibiotics accounted for 55% of the increased risk of MRSA and 35% of the increased risk of C difficile.

Conclusions Documented penicillin allergy was associated with an increased risk of MRSA and C difficile that was mediated by the increased use of β lactam alternative antibiotics. Systematically addressing penicillin allergies may be an important public health strategy to reduce the incidence of MRSA and C difficile among patients with a penicillin allergy label.


  • Contributors: KGB, NL, YZ, RPW, and HKC designed the study. KGB and YL performed the literature review. KGB, NL, YZ, and HKC analyzed the data. KGB, NL, YZ, YL, RPW, and HKC analyzed and interpreted the results. KGB drafted the first report. NL, YZ, YL, RPW, and HKC assisted with interpretation and revision of the report. KGB and RPW obtained funding. KGB and HKC are guarantors of the study. All authors were involved in the review and approval of the manuscript. All authors are independent from funders. All authors had full access of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was supported by the National Institutes of Health (NIH, K01AI125631) and the American Academy of Allergy Asthma and Immunology Foundation. RPW was supported by the Steven and Deborah Gorlin MGH Research Scholars Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by THIN ethics review and deemed exempt by the Partners Human Research Committee.

  • Data sharing: No additional data available.

  • Transparency: The lead author (KGB) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported. No important aspects of the study have been omitted. Any discrepancies from the study as planned have been explained.

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