Penicillin Allergy and Association with Ciprofloxacin Coverage in Community-Onset Urinary Tract Infection

INTRODUCTION

The prevalence of patients with a documented penicillin allergy is greater than 10% in many healthcare settings in the United States.^1,2 Though up to 90% of these patients may safely tolerate penicillin, the presence of an allergy label is associated with increased use of broad-spectrum antimicrobials including fluoroquinolones, glycopeptides, and carbapenems.^2–4 In the treatment of urinary tract infections (UTIs), recent fluoroquinolone use is a demonstrated risk factor for ciprofloxacin-resistance among Escherichia coli UTIs.⁵ As part of a study aimed at developing predictive models for empiric antibiotic prescribing, we investigated the relationship between a documented penicillin-class allergy and ciprofloxacin-resistant, community-onset UTIs in adult hospitalized patients. Our analysis is inclusive of all urinary pathogens.

METHODS

Using electronic health record (EHR) data from a 1300-bed teaching hospital, we established a retrospective cohort of adult patients admitted to an inpatient unit from 11/1/2011–6/30/16 with a UTI diagnosis and a positive urine culture in the first 48 hours. Only the first encounter during the study period was included. We defined the exposure as presence of a penicillin-class allergy label (e.g. penicillin, amoxicillin, piperacillin) documented in the EHR and defined the outcome as a UTI not covered by ciprofloxacin. We included all urinary pathogens for infections where multiple pathogens were present. For UTIs with un-reported ciprofloxacin susceptibilities, subject matter experts inferred susceptibility according to previously reported methods.⁶

We used modified Poisson regression with stabilized inverse probability weights (IPW) to estimate the adjusted relative risk of resistance.^7,8 Inverse probability weighting adjusted for potential measured confounders including: sex, age, Elixhauser score, number of inpatient and emergency department admissions in the past year, and indicator variables for transfer from a nursing home and presence of a cephalosporin or carbapenem allergy label. We adjusted for cephalosporin and carbapenem allergy to isolate the effect of a penicillin-class allergy label. Stabilized IPW were estimated via boosted logistic regression, and covariate balance between exposure groups after weighting was evaluated by standardized differences between exposure groups via the twang package (version 1.5) in R.⁸ Analyses were conducted in Stata, (Release 15. College Station, TX: StataCorp LLC) and R (version 3.4.2).

Additionally, we examined the potential mediation effect of recent fluoroquinolone use in the relationship between a penicillin-class allergy label and lack of ciprofloxacin coverage. We estimated the total, direct, and indirect effects of prior fluoroquinolone use, adjusted by IPW, through the mediation package (version 4.4.6) in R.⁹ This study was approved by the Institutional Review Board of the Office of Responsible Research Practices at The Ohio State University.

RESULTS

Among 6,361 patients admitted with community-onset UTI, 1,252 (19.7%) had a penicillin-class allergy label documented in the EHR. A total of 7,431 isolates representing 75 organisms were included in the analysis. The most prevalent organisms were Escherichia coli (n=2,797), Enterococcus faecalis (n=1,281), Klebsiella pneumoniae (n=876), Pseudomonas aeruginosa (n=391), and Enterococcus faecium (n=292), accounting for 75.9% of isolates. Prior to IPW, exposure groups were notably imbalanced on sex, age, and cephalosporin allergy. After IPW, all standardized differences between exposure groups were <10%. Patients with a penicillin-class allergy label were 1.13 times more likely to have a ciprofloxacin-resistant UTI (707 of 1,252 (56.5%)) compared to those without a penicillin-class allergy label (2,601 of 5,109 (50.9%)) (aRR: 1.13, 95% CI: 1.06, 1.19). Mediation analysis revealed that 24% of the total effect of a penicillin-class allergy label on ciprofloxacin-resistant UTI was explained by fluoroquinolone use in the past 90 days (as documented in our EHR at least 24 hours prior to culture) (95% CI: 0.08, 0.49) (Figure 1).

Figure 1.

Directed acyclic graph of the proposed association between penicillin-class allergy label and ciprofloxacin-resistant urinary tract infection (UTI), including partial mediation by recent fluoroquinolone use. Potential confounding variables accounted for in our analysis also presented: demographics (sex and age), healthcare exposure (nursing home transfer, emergency department admissions, inpatient admissions), and medical history (Elixhauser score, cephalosporin allergy, carbapenem allergy).

A major assumption in development of susceptibilities for this cohort was that enterococci were not covered by ciprofloxacin if susceptibilities were not reported. However, since enterococci may be susceptible to ciprofloxacin, we re-evaluated our models assuming enterococci with missing susceptibilities were susceptible to ciprofloxacin (21% of encounters affected); Overall inference in the association of interest and mediation effect by fluoroquinolone use in this sensitivity analysis did not substantially change (aRR: 1.20, 95% CI: 1.09, 1.31; average proportion mediated: 17%, 95% CI: 0.06, 0.37).

DISCUSSION

Among patients presenting with a UTI, those with a penicillin-class allergy label may have a slightly increased risk of not being covered by ciprofloxacin. Recent fluoroquinolone use partially contributes to this effect, suggesting additional mechanisms behind this association. Since we were limited to evaluating antibiotic exposures that occurred within our healthcare system, the proportion of the total effect mediated by fluoroquinolone use may be higher than 24% if similar patterns of recent fluoroquinolone use by allergy status occurred outside of our health system. Additional mediators could include recent exposure to other antimicrobial classes which were not evaluated in this study.

Targeting areas of antibiotic overuse is key to combating resistance and improving patient outcomes through appropriate antibiotic prescribing. With respect to penicillin-class allergy labels, antimicrobial stewardship initiatives have focused on allergy confirmation through skin testing and oral challenge.¹⁰ In many cases, patients with a documented but unconfirmed penicillin-class allergy can be de-labeled following appropriate testing.¹⁰ Our finding that nearly 20% of patients in this cohort had a documented penicillin-class allergy highlights the potential for more accurate classification and labeling of allergies to support antimicrobial stewardship. We show that a penicillin-class allergy is a modest risk factor for ciprofloxacin resistance, which may be due in part to increased use of fluoroquinolones. This finding suggests that one possible solution to fluoroquinolone overuse would be to reassess the veracity of penicillin allergy labels at the point of care.