High-Cost, High-Need Patients: The Impact of Reported Penicillin Allergy

A reported penicillin allergy was common and was associated with suboptimal antibiotic choices and increased healthcare utilization in high-cost, high-need patients.

ABSTRACTObjectives: More than 90% of patients who report a penicillin allergy have the allergy disproved when tested. Unnecessary use of alternative (non—beta-lactam) antibiotics can result in more treatment failures and adverse reactions. We described the prevalence and impact of a reported penicillin allergy in high-cost, high-need (HCHN) patients.

Study Design: Retrospective cohort.

Methods: We identified HCHN patients in a care management program of an urban academic medical center (January 1, 2014, to December 31, 2016). We used multivariable logistic regression models to determine the association between a reported penicillin allergy and antibiotic use. We used multivariable Poisson regression models to determine the association between a reported penicillin allergy, with or without multiple drug intolerance syndrome (MDIS; ≥3 reported drug allergies), and healthcare resource utilization (HRU).

Results: Of 1870 HCHN patients, 383 (20%) reported penicillin allergy, 835 (45%) had MDIS, and 290 (16%) had both. HCHN patients reporting penicillin allergy had an increased odds of beta-lactam alternative antibiotic use (adjusted odds ratio, 3.84; 95% CI, 2.17-6.80). HRU was significantly higher for patients reporting a penicillin allergy alone (adjusted relative risk [aRR], 1.13; 95% CI, 1.03-1.25) and with concurrent MDIS (aRR, 1.20; 95% CI, 1.08-1.34).

Conclusions: HCHN patients had a high burden of reported drug allergy. A reported penicillin allergy conferred a 4-fold increased odds of beta-lactam alternative antibiotic use. Reporting penicillin allergy, with and without MDIS, was associated with significantly more HRU. HCHN care management programs should consider systematic drug allergy evaluations to optimize antibiotic use in these fragile patients.

Am J Manag Care. 2020;26(4):154-161. https://doi.org/10.37765/ajmc.2020.42832

Takeaway Points

  • More than 20% of high-cost, high-need (HCHN) patients reported a penicillin allergy, and 45% had multiple drug intolerance syndrome (MDIS; ≥3 drug allergies).
  • HCHN patients had high prevalence of risk factors for bacterial infections: diabetes (51%), cancer (46%), and systemic corticosteroid exposure (34%).
  • A reported penicillin allergy was associated with an almost 4-fold increased odds of alternative antibiotic exposure, with odds of clindamycin exposure increased more than 8-fold.
  • Reporting a penicillin allergy, with or without MDIS, conferred a 10% to 20% increase in healthcare utilization.
  • HCHN patients may be ideal candidates for systematic drug allergy evaluations, including penicillin allergy testing, to optimize first-line antibiotic treatments.

High-cost, high-need (HCHN) patients comprise 5% of patients nationwide and account for 50% of healthcare spending.1 Although less than 5% of Medicare spending is considered potentially preventable, almost three-quarters of the preventable costs are incurred by this HCHN subset.2 Addressing modifiable risk factors present in HCHN patients may improve clinical outcomes while curbing overall US healthcare spending.1,3

Prominent comorbidities in HCHN patients include conditions associated with increased risk of bacterial infection, such as diabetes, chronic obstructive pulmonary disease, and chronic renal failure.4 Acute bacterial lung and urinary tract infections are among the most common reasons for preventable hospitalizations in HCHN patients2,5,6; the costs of bacterial pneumonia alone comprised almost one-fourth of preventable hospital costs in HCHN patients in 2006, resulting in excess spending of $7.2 billion.7

Beta-lactam antibiotics are first-line treatments for many of these bacterial infections; however, approximately 10% of Americans report a penicillin allergy, limiting treatment choice.8 Patients with infections who report a penicillin allergy are often administered alternatives to beta-lactam antibiotics that can be less effective, resulting in treatment failures9,10; more toxic, resulting in adverse drug reactions9,10; and broader-spectrum, resulting in higher risks of antibiotic resistance.11,12 However, more than 90% of patients reporting a penicillin allergy have their allergy disproved when formally evaluated.8

Active care management that combines chronic disease management and case management improves care and reduces costs in HCHN patients.13-16 Although medication management is a proven feature of successful care management programs for HCHN patients,16,17 programs have generally not previously assessed or addressed drug allergies.18 To assess the potential benefits of proactive drug allergy evaluation in the HCHN population, we described the epidemiology and impact of reported penicillin allergy on antibiotic use and healthcare resource utilization (HRU) in HCHN patients.


Study Design and Population​​​​​​​

This study was conducted at a large Boston-based academic medical center with an active care management program for HCHN patients. HCHN patients received their primary care at 1 of 15 affiliated practice sites. We considered a 36-month study period (January 1, 2014, through December 31, 2016) and included only HCHN patients continuously followed by the active care management program for at least 34 of these months. All data were retrieved exclusively from electronic sources. The study was approved by the Partners Human Research Committee (protocol 2017P000456).


The primary exposure of interest was a reported penicillin allergy, defined as any reported allergy or intolerance to any penicillin antibiotic. After being electronically retrieved, allergy data were manually verified by chart review to determine the first date of penicillin allergy “active” status, the reaction(s) listed, and any allergy status changes that occurred during the study period. Given that antibiotic prescribing might not be affected for patients reporting only a penicillin intolerance, we considered a sensitivity analysis definition of a reported penicillin allergy that excluded patients who had gastrointestinal penicillin intolerance only. We separately considered multiple drug intolerance syndrome (MDIS) as an exposure, defined as a reported allergy or intolerance to 3 or more drugs (1 of which may have been a penicillin) at the time of study entry.19,20


The primary outcome was antibiotic use, defined as antibiotic exposure, regardless of duration, captured by any inpatient antibiotic administration or outpatient antibiotic prescribed in the study period. We considered narrow-spectrum beta-lactam antibiotics as any penicillins, other than antipseudomonal penicillins or penicillin class antibiotic/beta-lactamase inhibitor combinations, and first- or second-generation cephalosporins.11,21,22 Beta-lactam alternative antibiotics included fluoroquinolones, macrolides, vancomycin, clindamycin, sulfonamides, tetracyclines, aminoglycosides, and linezolid.11,21,22

The secondary outcome was HRU, which considered inpatient, emergency, and outpatient visit counts. Inpatient visits excluded residential inpatient stays, and emergency visits excluded those that led to an inpatient visit. Outpatient visits were specified as primary care or specialist visits.

Key Variables

Key variables assessed included patient demographics, insurance, comorbidities, corticosteroid use, other drug allergies, and resistant organisms. Comorbidities considered were cardiovascular disease, diabetes, renal disease, and cancer, defined from established diagnostic codes, when available (eAppendix Table 1 [eAppendix available at ajmc.com]).23-25 Charlson Comorbidity Index (CCI) score was electronically calculated based on diagnostics codes.26,27 Systemic corticosteroid use, a binary variable, was considered yes for any patients with a documented inpatient administration and/or an outpatient prescription for an oral or parenteral steroid. Other reported drug allergies were defined similarly to a reported penicillin allergy (ie, any reported allergy or intolerance). We captured the total number of reported allergies, reported cephalosporin allergies, and reported sulfonamide antibiotic allergies. Colonization or infection with methicillin-resistant Staphylococcus aureus (MRSA) was determined by the presence of a MRSA microbiology culture. Colonization or infection with vancomycin-resistant Enterococcus (VRE) was determined by the presence of a VRE microbiology culture.

Statistical Analysis

Numbers with frequencies and means with SDs were used to describe categorical and continuous variables, respectively. We used simple regression models (ie, models with a single independent variable) to assess bivariate relationships. Multivariable regression models were used to assess the relationship between the exposure(s) and outcomes. Because a patient’s penicillin allergy status can change during the study period (from no reported penicillin allergy to reported penicillin allergy, or vice versa), we used generalized estimating equations to construct regression models to account for the within-patient correlation. Multivariable logistic regression models were used to determine the association of penicillin allergy status with antibiotic use, and multivariable Poisson regression models were used to determine the association between penicillin allergy status and number of healthcare visits per follow-up year.

We considered patient demographics and CCI score as potentially confounding variables warranting inclusion in the final models a priori. All other key variables were individually assessed for confounding. Although we identified other drug allergies as a confounder, this variable was determined to be collinear with the exposure and was not included in the final models. We report odds ratios (ORs) with 95% CIs for antibiotic use outcomes and relative risks (RRs) with 95% CIs for healthcare visits. All P values were 2-sided, with P <.05 considered statistically significant. Statistical analyses were performed in SAS version 9.4 (SAS Institute; Cary, North Carolina).


Cohort Description

Of 1870 patients enrolled in the study, 383 (20%) had a reported penicillin allergy at any time during the study period. There were 835 (45%) patients with MDIS, including 290 patients (16%) with both a reported penicillin allergy and MDIS. The 383 patients reporting penicillin allergy had a total of 513 reactions, commonly rash or dermatitis (n = 179; 35%), unknown (n = 83; 16%), urticaria or hives (n = 75; 15%), gastrointestinal upset (n = 74; 14%), angioedema or swelling (n = 42; 8%), and anaphylaxis (n = 31; 6%) (eAppendix Table 2). There were 40 patients whose only penicillin reaction was gastrointestinal upset. There were 25 patients whose penicillin allergy status changed during the study period: 19 patients had a new penicillin allergy label applied and 6 patients had their penicillin allergy label resolved (4 [67%] of which were resolved by allergy testing). Therefore, the final cohort consisted of 1895 penicillin allergy observations in 1870 unique patients, with a total of 5599 person-years of follow-up time for analysis.

Age, race, and body mass index did not differ by penicillin allergy status (Table 1). Patients reporting a penicillin allergy were more often female (73% vs 56%; P <.001). The most common insurance was an accountable care organization external risk (89%), with fewer patients part of a commercial external risk-based contract (11%). Active smoking was uncommon (8%), and former smokers comprised 38% of patients.

CCI scores were high, on average (mean [SD] = 4.74 [3.30]), but also not differential by penicillin allergy status. Patients had cardiovascular disease (61%), diabetes (51%), renal disease (45%), and cancer (46%), not differential by reported penicillin allergy status. Systemic corticosteroid use was present in 34% overall, with no difference by penicillin allergy status.

Only 14% of patients had no reported drug allergies overall. One or 2 drug allergies were present in 42% of patients overall, 3 or 4 drug allergies were present in 21% of patients, and 5 or more drug allergies were present in 24% of patients. Compared with patients not reporting penicillin allergy, patients with a reported penicillin allergy more frequently had more total reported drug allergies (P <.001). Reported cephalosporin and sulfonamide antibiotic allergies were present in 3% and 16% of patients overall, more frequently in patients reporting penicillin allergy (cephalosporin: 6% vs 2%; P <.001; sulfonamide antibiotic: 26% vs 13%; P <.001). MRSA and VRE colonization and/or infection were overall low at baseline (4%), without a difference by penicillin allergy status.

Primary Outcome: Antibiotic Use

Antibiotics in HCHN patients included fluoroquinolones (n = 912), first-generation cephalosporins (n = 576), macrolides (n = 529), vancomycin (n = 431), third-generation cephalosporins (n = 380), sulfonamides (n = 360), tetracyclines (n = 334), and clindamycin (n = 184) (Table 2). HCHN patients used beta-lactam alternative antibiotics more frequently than narrow-spectrum beta-lactam antibiotics overall.

The use of narrow-spectrum beta-lactam antibiotics was lower in patients reporting a penicillin allergy (17% vs 47%; P <.001) (Table 2). In the multivariable adjusted regression model, patients reporting penicillin allergy had lower odds of narrow-spectrum beta-lactam antibiotic use (adjusted OR, 0.20; 95% CI, 0.15-0.26) compared with those reporting no penicillin allergy (Figure [A]). This association strengthened in the sensitivity analysis that excluded patients with gastrointestinal penicillin intolerance only (adjusted OR, 0.11; 95% CI, 0.08-0.16) (data not shown).

Alternative antibiotic use was higher in patients reporting a penicillin allergy (80% vs 71%; P <.001) (Table 2). Specific alternative antibiotics used more in patients reporting a penicillin allergy were fluoroquinolones (53% vs 47%; P = .026), clindamycin (28% vs 5%; P <.001), and tetracyclines (25% vs 16%; P <.001). In the multivariable regression model, patients reporting penicillin allergy had an increased odds of beta-lactam alternative antibiotic use (adjusted OR, 3.84; 95% CI, 2.17-6.80) (Figure [B]), with clindamycin use having the greatest OR (adjusted OR, 8.40; 95% CI, 5.99-11.79) compared with those reporting no penicillin allergy. This association between reported penicillin allergy and beta-lactam alternative antibiotic use strengthened in the sensitivity analysis that excluded patients with gastrointestinal penicillin intolerance only (adjusted OR, 5.64; 95% CI, 2.78-11.44).

Secondary Outcome: HRU

Total number of visits per follow-up year were higher for patients reporting a penicillin allergy (3.03 vs 0.70; P <.001) and for those who also had MDIS (2.05 vs 0.44; P <.001) (Table 3). Inpatient visits per follow-up year were comparable between patients with and without a reported penicillin allergy, but emergency, primary care, and specialist outpatient visits were more frequent for patients reporting a penicillin allergy (Table 3). All visit types were more frequent in patients reporting MDIS (Table 3).

In the multivariable adjusted analysis, numbers of healthcare visits were significantly greater for patients with a reported penicillin allergy compared with those not reporting a penicillin allergy (RR, 1.13; 95% CI, 1.03-1.25) (Table 4). The RR demonstrating increased visits was nearly identical when excluding patients with gastrointestinal penicillin intolerance only. Patients with reported penicillin allergy and concurrent MDIS had a higher incidence of HRU (RR, 1.20; 95% CI, 1.08-1.34) (Table 4) compared with those without penicillin allergy and MDIS.


We performed a retrospective cohort study of HCHN patients and identified that more than 1 in 5 of these patients had a reported penicillin allergy and almost half had MDIS. Patients had risk factors for bacterial infections, but MRSA and VRE were infrequent, suggesting that narrow-spectrum beta-lactams would be potentially useful treatments in this population. HCHN patients had high antibiotic use overall; HCHN patients with a reported penicillin allergy were about 7-fold less likely to be exposed to narrow-spectrum beta-lactams and more than 3-fold more likely to be exposed to beta-lactam alternative antibiotics. HCHN patients with penicillin allergy alone had 13% more healthcare visits; there were 20% more healthcare visits if there was concurrent MDIS.

The HCHN patients had a markedly high prevalence of reported penicillin allergy (20%). Although the prevalence of reported penicillin allergy varies among adult populations, it is often reported to range from 6% to 10%.19,28,29 Penicillin allergy reporting increases with increasing age, and our HCHN cohort was composed of older adults (mean age, 77 years).30 Hospitalized patients and patients with cancer have even higher reported penicillin allergy prevalence rates (up to 15%).31-34 MDIS was identified in almost half (45%) of HCHN patients, but previous studies indicated that general patient populations rarely have MDIS (from 2% to 6%).19,20

Penicillin allergy testing removes false penicillin allergy labels in more than 90% of patients who carry a historical penicillin allergy diagnosis.8 Testing includes a detailed allergy history and often procedures such as penicillin skin testing and/or drug administration under medical observation (ie, a drug challenge). Although penicillin allergy evaluation is broadly encouraged by organizations such as the CDC and the National Quality Forum, currently less than 1% of Americans with a documented penicillin allergy report having been tested.35-37 Drug allergy testing for other antibiotics is available in some US allergy practices and can be used to disprove prior drug allergies and clarify true drug reactions in patients with MDIS. Antibiotic allergy evaluations in one Australian center disproved 85% of all reported antibiotic allergies.21 Although fewer antibiotic allergies may be disproved in an HCHN population, it is quite likely that many antibiotic allergies will be found untrue, which would improve antibiotic prescribing and minimize risks of treatment failure and adverse effects.

The HCHN patients had high prevalence of risk factors for bacterial infections that included diabetes (51%), cancer (46%), and systemic corticosteroid exposure (34%). Additionally, almost half of the patients (46%) were current or former smokers, a strong risk factor for bacterial pneumonia that was the single most common reason for preventable hospitalization in HCHN patients.2,5,6 Increasing the use of narrow-spectrum beta-lactam antibiotics in HCHN patients may not only serve to improve their clinical outcomes but may also reduce HRU and decrease healthcare costs. Although this has not been assessed specifically to date, one study demonstrated that patients reporting a penicillin allergy who received penicillin allergy evaluations had lower antibiotic costs in the year after their allergy testing compared with the year before their allergy testing.38

The resistant organisms MRSA and VRE were surprisingly uncommon in HCHN patients (4%). This low level of colonization with resistant organisms suggests that, when infected, HCHN patients may have infections treatable with narrow-spectrum beta-lactams. As such, reclaiming the use of narrow-spectrum beta-lactams in HCHN patients previously labeled as penicillin-allergic would be helpful. Findings of prior studies identified that patients reporting penicillin allergy had an increased prevalence of MRSA and VRE39 and an increased incidence of new MRSA, with more than half of the increased MRSA risk attributable to beta-lactam alternative antibiotic prescribing.11 Addressing reported penicillin allergies, therefore, is also a useful antibiotic stewardship tool for fighting antimicrobial resistance.8

A reported penicillin allergy in HCHN patients was associated with a 7-fold lower use of narrow-spectrum beta-lactams and a more than 3-fold increased use of alternative antibiotics. These associations magnified to 9-fold less likely to receive a narrow-spectrum beta-lactam and 6-fold more likely to receive beta-lactam alternatives when excluding patients with gastrointestinal penicillin intolerance in a sensitivity analysis. A prior population-based outpatient cohort study found that patients reporting penicillin allergy had approximately 4-fold increased risks of macrolide and clindamycin exposure and 2-fold increased fluoroquinolone exposure.11 Although we found that all beta-lactam alternative antibiotics were used more frequently in HCHN patients in this study, the largest difference by reported penicillin allergy status was clindamycin use, where a more than 8-fold increased odds of use was identified in patients reporting a penicillin allergy. Clindamycin is considered one of the most common causative antibiotics for Clostridioides difficile infection (CDI).40 Findings of prior studies support that CDI incidence is greater for patients with a reported penicillin allergy and that some of the observed increased CDI risk is directly attributable to macrolide, clindamycin, and fluoroquinolone prescribing.11 As such, if routine penicillin allergy evaluations could improve antibiotic prescribing, CDI cases might be averted. Recently, patients with penicillin allergy histories who were penicillin tested were subsequently exposed to less clindamycin and macrolides than matched patients who were not penicillin tested.41

Although all patients were high utilizers, reporting a penicillin allergy, both alone and with concurrent MDIS, conferred a 10% to 20% significant increase in HRU. The observed utilization differences were driven by increased emergency and outpatient visits. Given that narrow-spectrum beta-lactams are first-line therapies for many infections,8 utilization might be reduced after removal of the penicillin allergy label. Indeed, one prior matched cohort study determined that patients with penicillin allergy histories who received penicillin allergy evaluations had fewer outpatient visits (P <.001), emergency visits (P = .29), and hospital days (P <.001) per coverage year during follow-up compared with matched controls with penicillin allergy histories who did not receive the penicillin allergy evaluation.41


This study used a retrospective design. Although we reduced misclassification through manual review of the primary exposure (penicillin allergy) and studied outcomes derived from electronically captured antibiotic and HRU data, misclassification could still exist. Because drug dosage and duration details were not consistently available, we studied antibiotic and corticosteroid use, regardless of dose and duration. However, drug use did include both inpatient and outpatient use through administration and prescription data. We assessed total healthcare system visits as our measure of HRU and did not consider inpatient length of stay nor procedures and tests performed. We assessed many potential confounders in our analysis but could not consider all possible confounders; other illnesses and/or social factors (eg, living situation) might affect antibiotic choice or healthcare visits. However, because these factors would not be related to the exposure of penicillin allergy, their inclusion into our models would be unlikely to yield different results. Our findings come from 1 sample of HCHN patients enrolled in the care management program of a single large academic medical center in the Boston area; such patients may not be representative of other HCHN patients in the United States.


This large, retrospective cohort analysis demonstrates that there is a high burden of drug allergy in HCHN patients and substantial room for improvement in the antibiotic choices made for HCHN patients reporting a penicillin allergy. Systematic efforts focused on penicillin and drug allergy management in HCHN patients may benefit both the patients and the healthcare systems tasked with supporting the care of these complex patients in a cost-conscious manner.


The authors thank Tyler Harkness, BS, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, for his research assistance.Author Affiliations: Division of Rheumatology, Allergy, and Immunology (KGB, XF, CMM) and Division of Infectious Diseases (RPW), Department of Medicine, Massachusetts General Hospital, Boston, MA; The Medical Practice Evaluation Center, The Mongan Institute, Massachusetts General Hospital (KGB, FMS, CMM, RPW), Boston, MA; Harvard Medical School (KGB, NMO, FMS, RPW), Boston, MA; Division of General Academic Pediatrics, Massachusetts General Hospital for Children (NMO), Boston, MA; Integrated Care Management Program, Massachusetts General Hospital (NMO, JMM), Boston, MA.

Source of Funding: Dr Blumenthal receives career development support from NIH K01AI125631; the American Academy of Allergy, Asthma & Immunology (AAAAI) Foundation; and the Massachusetts General Hospital (MGH) Claflin Distinguished Scholar Award. Dr Walensky was supported by the Steven and Deborah Gorlin MGH Research Scholars Award. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health, the AAAAI Foundation, or MGH.

Author Disclosures: Dr Blumenthal reports a clinical decision support tool used institutionally for beta-lactam allergy at Partners HealthCare System. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (KGB, RPW); acquisition of data (KGB, NMO, JMM); analysis and interpretation of data (KGB, NMO, XF, FMS, CMM, RPW); drafting of the manuscript (KGB); critical revision of the manuscript for important intellectual content (KGB, NMO, FMS, RPW); statistical analysis (XF, FMS, CMM); provision of patients or study materials (KGB, NMO, JMM); obtaining funding (KGB); administrative, technical, or logistic support (XF, CMM, JMM); and supervision (KGB, RPW).

Address Correspondence to: Kimberly G. Blumenthal, MD, MSc, Division of Rheumatology, Allergy, and Immunology, The Medical Practice Evaluation Center, The Mongan Institute, Massachusetts General Hospital, 100 Cambridge St, 16th Floor, Boston, MA 02114. Email: kblumenthal@mgh.harvard.edu.REFERENCES

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