Impact of sulfonamide allergy label on clinical outcomes of acute cystitis: a retrospective matched cohort study.

Impact of sulfonamide allergy label on clinical outcomes of acute cystitis: a retrospective matched cohort study - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Intern Med J . 2025 Apr 8;55(6):993–1000. doi: 10.1111/imj.70057 Impact of sulfonamide allergy label on clinical outcomes of acute cystitis: a retrospective matched cohort study Ray Moussa 1 , Tyler Miluski 1 , Gisoo Ghaffari 1 , Taha Al‐Shaikhly 1, ✉ Author information Article notes Copyright and License information 1 Section of Allergy, Asthma and Immunology, Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA * Correspondence , Taha Al‐Shaikhly, Section of Allergy, Asthma and Immunology, Department of Medicine, Penn State College of Medicine, 500 University Drive, PO Box 850, Hershey, PA 17033, USA. Email: talshaikhly@pennstatehealth.psu.edu ✉ Corresponding author. Received 2024 Sep 6; Accepted 2025 Mar 16; Issue date 2025 Jun. © 2025 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. PMC Copyright notice PMCID: PMC12155082  NIHMSID: NIHMS2069553 PMID: 40197657 Abstract Background Cystitis is a common infection in an otherwise healthy individual. Sulfonamide antibiotics are first‐line treatment options. Sulfonamide allergy label (SAL) is the second most common antibiotic allergy label in electronic health records, yet its impact on clinical outcomes in patients with cystitis is not well‐characterised. Aims The aim of this study is to characterise the impact of SAL on clinical outcomes of acute cystitis. Methods In this retrospective matched cohort study utilising the TriNetX US Collaborative Network (Cambridge, MA, USA), adult patients with cystitis were categorised based on their SAL status. The 28‐day risks of acute pyelonephritis and Clostridium difficile infection and the risk of recurrent or relapsed cystitis (defined as cystitis 15–28 days post‐indexed cystitis) were contrasted. Antibiotic prescription practices within 14 days of the index cystitis were also compared. Results When comparing 19 767 patients with cystitis and SAL to an equal number of matched controls, more patients with SAL had acute pyelonephritis (RR 1.27; 95% CI 1.08–1.48; P = 0.003; corrected P = 0.027) within 28 days of index. More patients with SAL developed recurrent/relapsed cystitis 15–28 days post‐indexed cystitis (RR 1.19; 95% CI 1.08–1.31; P = 0.001; corrected P = 0.009) as compared to controls. SAL altered antibiotic prescription practices with under‐utilisation of trimethoprim and sulfamethoxazole and increased utilisation of alternative antibiotics, including fluoroquinolones and nitrofurantoin, which was associated with an increased risk of Clostridium difficile infection. Conclusions SAL alters antibiotic prescription practices and is associated with a slightly increased risk of poor outcomes in adult patients with cystitis. Keywords: sulfonamide allergy label, sulfa allergy, acute cystitis, de‐labelling, antibiotic allergy Abbreviations CPT Current Procedural Terminology HCO healthcare organisation ICD‐10‐CM International Code of Diseases Tenth Revision Clinical Modification LNC Logical Observation Identifiers Names and Codes PSM propensity score matching SAL sulfonamide allergy label TMP‐SMX trimethoprim‐sulfamethoxazole Introduction Urinary tract infections (UTIs) are one of the most frequently diagnosed infections in an otherwise healthy adult. 1 In the United States, UTIs accounted for ~1.6 million emergency department (ED) visits in 2022 according to the National Hospital Ambulatory Medical Care Survey, thereby contributing to substantial healthcare costs. 2 , 3 , 4 Joint clinical practice guidelines for the treatment of acute uncomplicated cystitis by the Infectious Disease Society of America and the European Society for Microbiology and Infectious Diseases highlight trimethoprim‐sulfamethoxazole (TMP‐SMX) as a first‐line therapeutic option for the treatment of uncomplicated cystitis. 5 However, approximately 3%–8% of patients carry a sulfonamide or sulfa allergy label (SAL), making it the second most common allergy label in electronic health records, second to the penicillin allergy label, 6 and the SAL is often used to describe an allergy to sulfonamide antimicrobials. 7 Although most adverse reactions to sulfonamide antimicrobials consist of self‐reported gastrointestinal upset and benign cutaneous reactions, many individuals labelled as having a sulfa allergy may tolerate sulfonamide antibiotics after proper evaluation. 8 Nonetheless, having a SAL could still impact antibiotic selection and potentially affect clinical outcomes, as has been noted with other antibiotic allergies. 9 , 10 , 11 For example, the presence of a penicillin allergy label has been consistently demonstrated to influence the choice of antibiotic treatment and is linked to both personal and public health‐adverse clinical outcomes including longer hospital stays, increased risk of surgical site infection, and higher healthcare costs. 12 , 13 , 14 The impact of a SAL, the second most common allergy label in electronic health records, on antibiotic prescription practices and clinical outcomes has not been well characterised. In our previous study, we noted altered antibiotic prescription practices related to the presence of SAL; however, SAL did not influence morbidity or mortality in patients with Pneumocystis jirovecii pneumonia. 15 Herein, we leveraged the TriNetX US collaborative Network (Cambridge, MA, USA), a multicentre US database, to investigate the impact of having a SAL on clinical outcomes of acute cystitis in adults. We hypothesise that SAL would be associated with poor clinical outcomes in adult patients with acute cystitis. Methods Data source The data used in this study were captured on 14 June 2024, from the TriNetX US Collaborative Network (Cambridge, MA, USA), which provides access to electronic medical records (diagnoses, procedures, medications, laboratory values and genomic information) from approximately 110 million patients from 64 healthcare organisations (HCOs) across the United States. TriNetX complies with the Health Insurance Portability and Accountability Act (HIPAA), the US federal law that protects the privacy and security of healthcare data and any additional data privacy regulations applicable to the contributing HCO. The data within the TriNetX platform are deidentified as per the deidentification standard defined in Section 164.514(a) of the HIPAA Privacy Rule and displayed in aggregate form. The process by which the data are deidentified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule (this formal determination by a qualified expert was refreshed in December 2020). Because this study used only deidentified patient records and the study did not involve intervention or interaction with human subjects, no institutional review board approval was sought. Study design and definition of study cohorts We conducted a retrospective matched‐cohort study. Using a compilation of the International Code of Diseases Tenth Revision Clinical Modification (ICD‐10‐CM), we identified two cohorts of adult patients (age ≥ 18 years) with an acute cystitis diagnosis (ICD‐10‐CM N30.0) indexed between 1 January 2016 and 1 January 2022, with and without SAL. SAL was defined based on the presence or absence of an ICD‐10‐CM of allergy status to sulfonamides, Z88.2 on or before the indexed cystitis. TriNetX uses the general equivalence mappings plus custom algorithms to convert ICD‐9 to ICD‐10. Meeting the foregoing criteria defined the index event. Matching variables The two study cohorts were matched using 1:1 propensity score matching (PSM). TriNetX generates a propensity score for each patient and uses a ‘greedy nearest‐neighbour matching’ with a calliper of 0.1 pooled standard deviations (SDs) to identify matched subsets. We matched the cohorts for demographics (age, sex, race and ethnicity) and a multitude of comorbidities that might influence cystitis severity and clinical outcomes. These comorbidities were captured by ICD‐10‐CM, the Current Procedural Terminology (CPT), or RxNorm codes on or within 1 year before the index event (indexed cystitis) and included chronic kidney disease, Stage 3; chronic kidney disease, stage 4; chronic kidney disease, stage 5; end‐stage renal disease; diabetes mellitus; chronic obstructive pulmonary disease; emphysema; fibrosis and cirrhosis of liver; nicotine dependence; alcohol‐related disorders; heart failure; ischaemic heart disease; neuromuscular dysfunction of bladder; benign prostatic hyperplasia; calculus in bladder; hemiplegia and hemiparesis; cerebral infarction; extended spectrum beta lactamase (ESBL) resistance; Alzheimer's disease; vascular dementia; other peripheral vascular diseases; malignant neoplasms of lymphoid, haemopoietic and related tissue; human immunodeficiency virus disease; cystocele; malignant neoplasm of bladder; malignant neoplasm of prostate; indwelling catheter; body mass index (BMI) 40+; BMI 30–39; tobacco use; bone marrow transplant; and allergy status to penicillin (Table 1 ). Table 1. Baseline characteristics of study cohorts before and after propensity score matching Code Baseline characteristics Before matching After matching SAL ( n = 19 770) Control ( n = 874 074) P d SAL ( n = 19 767) Control ( n = 19 767) P d AI Age at index 62.6 (16.8) 52.2 (20) <0.001 0.56 62.6 (16.8) 62.9 (16.7) 0.032 0.02 F Female 16 336 (82.6) 698 174 (79.9) <0.001 0.07 16 333 (82.6) 16 188 (81.9) 0.056 0.02 M Male 2070 (10.5) 138 800 (15.9) <0.001 0.16 2070 (10.5) 2184 (11) 0.064 0.02 2054‐5 Black or African American 1700 (8.6) 127 926 (14.6) <0.001 0.19 1700 (8.6) 1717 (8.7) 0.761 <0.01 UN Unknown Gender 1364 (6.9) 37 100 (4.2) <0.001 0.12 1364 (6.9) 1395 (7.1) 0.541 0.01 2135‐2 Hispanic or Latino 830 (4.2) 91 321 (10.4) <0.001 0.24 830 (4.2) 848 (4.3) 0.653 <0.01 2028‐9 Asian 325 (1.6) 24 587 (2.8) <0.001 0.08 325 (1.6) 340 (1.7) 0.557 0.01 E08–E13 Diabetes mellitus 7334 (37.1) 166 374 (19) <0.001 0.41 7331 (37.1) 7528 (38.1) 0.041 0.02 I20–I25 Ischemic heart diseases 5633 (28.5) 90 830 (10.4) <0.001 0.47 5630 (28.5) 5873 (29.7) 0.007 0.03 Z88.0 Allergy status to penicillin 4471 (22.6) 15 014 (1.7) <0.001 0.67 4468 (22.6) 4395 (22.2) 0.379 0.01 I50 Heart failure 3899 (19.7) 56 978 (6.5) <0.001 0.40 3897 (19.7) 3931 (19.9) 0.668 <0.01 F17 Nicotine dependence 3604 (18.2) 86 550 (9.9) <0.001 0.24 3603 (18.2) 3889 (19.7) <0.001 0.04 J44 Other chronic obstructive pulmonary disease 3589 (18.2) 50 308 (5.8) <0.001 0.39 3587 (18.1) 3550 (18) 0.629 <0.01 Z68.3 BMI 30–39, adult 3390 (17.1) 51 555 (5.9) <0.001 0.36 3388 (17.1) 3428 (17.3) 0.594 0.01 N18.3 CKD, Stage 3 (moderate) 2708 (13.7) 45 983 (5.3) <0.001 0.29 2705 (13.7) 2680 (13.6) 0.714 <0.01 Z72.0 Tobacco use 2280 (11.5) 44 019 (5) <0.001 0.24 2279 (11.5) 2357 (11.9) 0.223 0.01 Z68.4 BMI 40 or greater, adult 2013 (10.2) 29 932 (3.4) <0.001 0.27 2010 (10.2) 2022 (10.2) 0.842 <0.01 I73 Other peripheral vascular diseases 1988 (10.1) 29 326 (3.4) <0.001 0.27 1986 (10) 1977 (10) 0.880 <0.01 I63 Cerebral infarction 1890 (9.6) 33 549 (3.8) <0.001 0.23 1889 (9.6) 1882 (9.5) 0.905 <0.01 F10 Alcohol related disorders 1375 (7) 26 058 (3) <0.001 0.18 1375 (7) 1453 (7.4) 0.128 0.02 N31 Neuromuscular dysfunction of bladder, not elsewhere classified 1060 (5.4) 15 840 (1.8) <0.001 0.19 1058 (5.4) 1028 (5.2) 0.500 0.01 N40 Benign prostatic hyperplasia 946 (4.8) 41 747 (4.8) 0.954 <0.01 946 (4.8) 1073 (5.4) 0.004 0.03 J43 Emphysema 879 (4.4) 15 217 (1.7) <0.001 0.16 879 (4.4) 841 (4.3) 0.349 0.01 N18.4 Chronic kidney disease, stage 4 (severe) 858 (4.3) 12 853 (1.5) <0.001 0.17 856 (4.3) 813 (4.1) 0.282 0.01 N18.6 End stage renal disease 849 (4.3) 24 220 (2.8) <0.001 0.08 849 (4.3) 894 (4.5) 0.270 0.01 K74 Fibrosis and cirrhosis of liver 689 (3.5) 12 170 (1.4) <0.001 0.14 689 (3.5) 686 (3.5) 0.934 <0.01 C81–C96 Malignant neoplasms of lymphoid, haemopoietic and related tissue 540 (2.7) 10 365 (1.2) <0.001 0.11 540 (2.7) 534 (2.7) 0.853 <0.01 N81.1 Cystocele 453 (2.3) 9120 (1) <0.001 0.10 453 (2.3) 443 (2.2) 0.735 <0.01 G30 Alzheimer's disease 447 (2.3) 9263 (1.1) <0.001 0.09 447 (2.3) 426 (2.2) 0.472 0.01 G81 Hemiplegia and hemiparesis 439 (2.2) 8447 (1) <0.001 0.10 439 (2.2) 450 (2.3) 0.709 <0.01 Z16.12 ESBL resistance 387 (2) 3620 (0.4) <0.001 0.14 386 (2) 337 (1.7) 0.066 0.02 C67 Malignant neoplasm of bladder 301 (1.5) 9246 (1.1) <0.001 0.04 301 (1.5) 304 (1.5) 0.902 <0.01 B20 HIV disease 287 (1.5) 7783 (0.9) <0.001 0.05 286 (1.4) 301 (1.5) 0.533 0.01 C61 Malignant neoplasm of prostate 265 (1.3) 11 438 (1.3) 0.697 <0.01 265 (1.3) 277 (1.4) 0.604 0.01 N18.5 CKD, stage 5 260 (1.3) 4231 (0.5) <0.001 0.09 260 (1.3) 256 (1.3) 0.859 <0.01 F01 Vascular dementia 260 (1.3) 5314 (0.6) <0.001 0.07 260 (1.3) 267 (1.4) 0.759 <0.01 N21.0 Calculus in bladder 168 (0.8) 3461 (0.4) <0.001 0.06 168 (0.8) 165 (0.8) 0.869 <0.01 Z94.81 Bone marrow transplant status 50 (0.3) 592 (0.1) <0.001 0.05 50 (0.3) 32 (0.2) 0.047 0.02 A4338 Indwelling catheter; Foley type, two‐way latex with coating 68 (0.3) 770 (0.1) <0.001 0.06 68 (0.3) 46 (0.2) 0.039 0.02 A4344 Indwelling catheter, Foley type, two‐way, all silicone, each 18 (0.1) 276 (0) <0.001 0.02 18 (0.1) 19 (0.1) 0.869 <0.01 Open in a new tab Values are expressed as mean (standard deviation) for continuous variables and number (%) for categorical variables. SMD of <0.1 denotes adequate balance. CKD, chronic kidney disease; ESBL, extended spectrum beta‐lactamase; HIV, human immunodeficiency virus; SAL, sulfonamide allergy label; SMD, standardised mean difference. Study outcomes Study outcomes were identified based on a combination of TriNetX‐specific terms, ICD‐10‐CM, ICD‐10–procedure coding system (PCS), Logical Observation Identifiers Names and Codes (LNC) and RxNorm codes. The study outcomes included (1) risk of progression to pyelonephritis, which was defined by the appearance of the ICD‐10‐CM code for pyelonephritis (N10) and was assessed within 28 days of index cystitis; (2) recurrent or relapsed cystitis, which was defined by the ICD‐10‐CM code for cystitis (N30.0) 14–28 days post‐indexed cystitis, (3) Clostridium difficile infection within 28 days following the indexed cystitis and defined by either the ICD‐10‐CM code for Enterocolitis due to Clostridium difficile or a positive laboratory test for C. difficile and (4) antibiotic prescription patterns of trimethoprim, sulfamethoxazole, beta‐lactams (cephalosporin or penicillin that are commonly used for treating cystitis), nitrofurantoin, fosfomycin or fluoroquinolones, which were captured within 14 days of the indexed event using RxNorm codes. TriNetX obfuscates counts 1–10, which are presented as 10, and therefore, composite outcomes were chosen, when possible, to account for anticipated rare outcomes. The codes used to identify the different studies are listed in Table 2 . Table 2. Terms used to define the different study outcomes Study outcome Codes used Definition Acute pyelonephritis ICD‐10‐CM: N1 Acute pyelonephritis Recurrent or relapsed cystitis ICD‐10‐CM: N30.0 Acute cystitis C. difficile colitis LNC: 34712‐0 Clostridioides difficile (presence) in stool (result: positive) LNC: 57901‐1 Clostridioides difficile glutamate dehydrogenase (presence) in stool (result: positive) LNC: 20761‐3 Clostridioides difficile (presence) in stool by agglutination (result) LNC: 54067‐4 Clostridioides difficile toxin genes (presence) in stool by NAA with probe detection (result: positive) LNC: 61367‐9 Clostridioides difficile DNA (presence) in specimen by NAA with probe detection (result: positive) LNC: 34468‐9 Clostridioides difficile toxin A + B (presence) in stool by immunoassay (result: positive) LNC: 34713‐8 Clostridioides difficile toxin A + B (presence) in stool (result: positive) LNC: 10895‐1 Clostridioides difficile toxin B (presence) in stool (result: positive) LNC: 83087‐7 Clostridioides difficile glutamate dehydrogenase (presence) in stool by immunoassay (result: positive) LNC: 79177‐2 Clostridioides difficile glutamate dehydrogenase and toxins A + B (presence) in stool by rapid immunoassay (result: positive) LNC: 74822‐8 Clostridioides difficile toxin B tcdB gene (presence) in stool by NAA with probe detection (result: positive) LNC: 87755‐5 Clostridioides difficile BI‐NAP1‐027 strain DNA (presence) in stool by NAA with probe detection (result: positive) LNC: 6362‐8 Clostridioides difficile toxin A + B (presence) in stool by cytotoxin tissue culture assay (result: positive) LNC: 82197‐5 Clostridioides difficile toxin A + B tcdA + tcdB genes (presence) in stool by NAA with non‐probe detection (result: positive) LNC: 80685‐1 Clostridioides difficile toxin A + B tcdA + tcdB genes (presence) in stool by NAA with probe detection (result: positive) LNC: 562‐9 Clostridioides difficile (presence) in stool by organism specific culture (result: positive) LNC: 563‐7 Clostridioides difficile (presence) in specimen by organism specific culture (result: positive) ICD‐10‐CM: A04.7 Enterocolitis due to Clostridium difficile Nitrofurantoin RxNorm:745 Nitrofurantoin Fosfomycin RxNorm: 4550 Fosfomycin Beta lactams RxNorm: 20489 Cefpodoxime RxNorm: 25037 Cefdinir RxNorm: 2231 Cephalexin RxNorm: 2177 Cefadroxil RxNorm: 723 Amoxicillin Trimethoprim RxNorm: 10829 Trimethoprim Fluoroquinolones RxNorm: 2551 Ciprofloxacin RxNorm: 7623 Ofloxacin RxNorm: 82122 Levofloxacin Sulfamethoxazole RxNorm: 10180 Sulfamethoxazole Open in a new tab ICD‐10‐CM, International Code of Diseases Tenth Revision Clinical Modification; LNC, Logical Observation Identifiers Names and Codes; NAA, nucleic acid amplification. Statistical analysis Statistical analyses were conducted utilising the live TriNetX web platform. We described continuous variables as mean and standard deviation (SD) and categorical variables as the number ( n ) and percentage of the total (%). TriNetX employed the χ 2 test and t test for comparing baseline characteristics in categorical and continuous data, respectively. In the assessment of outcomes, relative risks (RR) and 95% confidence intervals (CI) were employed to determine the magnitude and direction of any interaction. The Z ‐test was utilised to evaluate the significance of differences in proportions between study groups. As a sensitivity analysis, we conducted Kaplan–Meier curve survival analysis to account for patients who might have exited the cohort before the end of the observation period. The TriNetX platform estimates the survival probability (i.e. the probability of not developing a particular study outcome), and we therefore calculated the reverse estimate (per 1000 patients) as 1 Kaplan–Meier estimate, and significance was assessed using the log rank test. The Cox proportional hazard regression was conducted to estimate the hazard ratio (HR) and 95% CIs were used in order to characterise the magnitude and direction of the association between the presence of SAL and clinical outcomes. While all study outcomes were a priori hypothesised, correction for multiple comparisons using the Bonferroni method was further applied, by multiplying the uncorrected P ‐values by 9, which corresponds to the number of the study outcomes (both corrected and uncorrected P ‐values are presented). 16 A significance level of P < 0.05 was adopted to determine statistical significance. Results Patients with SAL had a slightly higher risk of progressing to acute pyelonephritis and C. difficile infection We identified 19 770 patients with acute cystitis with SAL and 874 074 patients with acute cystitis without a preceding SAL. After PSM, 19767 patients remained in each cohort, and both cohorts were well adjusted for baseline comorbidities and demographics with a standardised mean difference of less than 1 across all variables (Table 1 ). Within 28 days following the indexed cystitis, 343 (1.7%) patients with SAL were diagnosed with pyelonephritis, which was significantly higher when compared to 271 (1.4%) controls (RR 1.27; 95% CI 1.08–1.48; P = 0.003; corrected P = 0.027) (Fig. 1 ). Within 28 days following the indexed cystitis, more patients with SAL were diagnosed with C. difficile infection (348 (1.8%) vs 250 (1.3%) controls; RR 1.39; 95% CI 1.19–1.64; P < 0.001). Within 15–28 days following the indexed cystitis diagnosis, 830 (4.2%) SAL patients experienced recurrent or relapsed cystitis as compared with 699 (3.5%) patients without SAL (RR 1.19; 95% CI 1.08–1.31; P = 0.001; corrected P = 0.009) (Fig. 1 ). Although we have controlled for a multitude of comorbidities, using the TriNetX‐specific term ‘deceased’, we noted that fewer patients with SAL died during the 28‐day observation period following the indexed cystitis than patients without SAL (275 (1.4%) vs 393 (2%); RR 0.70; 95% CI 0.60–0.82; P < 0.001). Therefore, we conducted additional Kaplan–Meier survival analyses to account for patients who exited the cohort before the end of the 28‐day observation period. We noted similar results with a higher probability for developing recurrent/relapsed cystitis 15–28 days post‐indexed cystitis, having acute pyelonephritis, or C. difficile infection within 28 days of indexed cystitis (Table 3 and Fig. S1 ). Figure 1. Open in a new tab Sulfa allergy label (SAL) was associated with increased risk of medical complications among patients with cystitis. There was an increased risk of progression to pyelonephritis and C. difficile infection within 28 days of indexed cystitis. More patients had recurrent cystitis 15–28 days post‐indexed cystitis. Shown are the percentages of patients with study outcome (left) along with the respective relative risk (RR) and 95% confidence interval (CI) (right). Results shown are after propensity score matching for baseline demographics and comorbidities. Table 3. Survival analysis Outcome Estimated probability (per 1000 patients) HR 95% CI P † SAL Controls Pyelonephritis 17.6 13.9 1.26 (1.08–1.48) 0.036 Recurrent/relapsed cystitis 44 37.6 1.18 (1.06–1.30) 0.018 C. difficile infection 17.9 12.9 1.39 (1.18–1.64) <0.001 Open in a new tab † Significance was assessed using the log rank test. The P ‐values are corrected for multiple comparisons using the Bonferroni method. Results shown are after propensity score matching. CI, confidence interval; HR, hazard ratio; SAL, sulfa allergy label. Sulfa allergy label and antibiotic prescription patterns We also explored antibiotic prescription patterns within 14 days following the indexed cystitis. We noted altered prescription practices based on the presence or absence of SAL (Fig. 2 ). As compared to controls, fewer patients with cystitis were treated with trimethoprim (RR 0.21; 95% CI 0.19–0.23; P < 0.001) or sulfamethoxazole (RR 0.19; 95% CI 0.18–0.21; P < 0.001). Relatively more patients received alternative antibiotics including nitrofurantoin (RR 1.10; 95% CI 1.06–1.14; P < 0.001), fosfomycin (RR 1.92; 95% CI 1.64–2.26; P < 0.001), a cephalosporin or a penicillin (RR 1.27; 95% CI 1.22–1.31; P < 0.001) or fluoroquinolones (RR 1.20; 95% CI 1.16–1.24; P < 0.001). Figure 2. Open in a new tab SAL altered antibiotic prescription practices. There was under‐utilisation of trimethoprim or sulfamethoxazole and over‐utilisation of alternative agents used to treat urinary tract infection. Results shown are after propensity score matching for baseline demographics and comorbidities. Discussion This is the first matched‐cohort study to explore the impact of a SAL on clinical outcomes of adult patients with cystitis. It underscores the adverse health consequences of the SAL, including progressing to have pyelonephritis and developing recurrent/relapsed cystitis in adult patients with acute cystitis. Additionally, we were able to appreciate altered antibiotic prescription patterns in association with an increased probability of C. difficile infection within 28 days of indexed cystitis. Although the risk difference across these outcomes was small, these findings support the precedent that a SAL could be associated with detriment to an individual's health and might support de‐labelling efforts, especially in low‐risk individuals. Previous studies largely demonstrated a negative impact of having a penicillin allergy label on various clinical outcomes. 9 , 17 This included an increased risk of renal abscess formation and acute kidney injury among adult patients with pyelonephritis and an increased risk of respiratory failure, intensive care unit admission and mortality rates among patients with pneumonia compared with patients without a penicillin allergy label. 9 , 17 Limited studies have, however, explored the impact of SAL on clinical outcomes. SAL does not appear to negatively affect the outcomes of Pneumocystis jirovecii pneumonia. 15 In this study, we demonstrated an association between SAL and having acute pyelonephritis, recurrent/relapsed cystitis and C. difficile infection among patients with cystitis and SAL. The overall risk of progression to pyelonephritis among patients with cystitis is generally low, around 1%, and therefore the small risk difference related to the presence of SAL observed in our study could remain important. 18 Recurrent cystitis is common among patients with uncomplicated cystitis, and herein, we noticed that early recurrence was more common within 15–28 days of indexed cystitis in association with SAL. The increased risk of these complications needs further exploration but could be secondary to the altered antibiotic prescription practices we observed in patients with SAL. The presence of a penicillin allergy label alters antibiotic prescription patterns, with a higher likelihood of using restricted or broad‐spectrum antibiotic classes including vancomycin, higher generation cephalosporins, clindamycin, carbapenems or quinolones. 9 , 17 In this study, we focused on antibiotic classes commonly used for the treatment of cystitis, and we similarly identified a discernible change in antibiotic prescription patterns among cystitis patients related to the presence of SAL. More specifically, we found increased use of antibiotics like fluoroquinolones, beta‐lactams, nitrofurantoin and fosfomycin in sulfa allergy‐labelled individuals with cystitis. Both fluoroquinolones and beta‐lactams that were over‐utilised in the SAL group have been associated with C. difficile infection. 19 Furthermore, the use of nitrofurantoin has been linked to a higher risk of community‐acquired C. difficile infection. 19 While penicillin allergy‐labelled patients and sulfa allergy‐labelled patients differ in their respective treatment limitations, we noticed a similar increased risk of C. difficile infection. 20 Penicillin allergy label has been linked to increased mortality. In this study, we observed a lower risk of death among the SAL as compared to controls after controlling for a multitude of comorbidities. While the reason behind such an observation would require further investigation, we draw similarities to previous observations from studies examining the association between penicillin allergy label and mortality. In one study evaluating the impact of registered penicillin allergy label on clinical outcomes of hospitalised patients, Sousa‐Pinto and colleagues noted lower mortality among patients with registered penicillin allergy label compared to controls, despite those patients having a higher comorbidity index. 21 Another study which assessed the impact of penicillin allergy label on patients hospitalised in the Dutch University Medical Center found no significant mortality difference attributed to the label. Current practice guidelines recommend a proactive evaluation to de‐label patients with a penicillin allergy label. 22 Whether such a strategy could be applied to patients with SAL remains unknown. Considering that patients might have been mislabelled as having sulfonamide allergy because of non‐immune‐mediated side effects as opposed to a true allergic reaction and that most of those with immune‐mediated allergic reactions are benign cutaneous reactions, 8 evaluation for de‐labelling could represent a valuable opportunity to improve care outcomes and supplement antibiotic stewardship efforts. Using a clinical decision tool such as the SULF‐FAST could assist in identifying these low‐risk patients with SAL who could benefit from direct oral challenge. 23 , 24 While SALs might serve an important role in patient care, an attentive examination of their impact on health outcomes is crucial. 25 The use of a large database to examine this important subject is a strength of this study. The retrospective design poses a limitation to this study, as is inherent in this type of design. The reliance on ICD‐10 codes in defining study subjects and outcomes could have limited specificity and is further subjected to reporting bias. Additionally, while we have controlled for a multitude of demographics and comorbidities in our analysis, ICD‐10 codes cannot distinguish between complicated and uncomplicated cystitis, and there is always a potential for missed confounders. The observed differences in study outcomes were small, and therefore findings should be interpreted with caution. Conclusions Through a retrospective analysis of a multicentre US database, we showed a potential association between SAL and increased risk of negative outcomes among adult patients with cystitis. Prospective studies are needed to corroborate our findings and further examine the impact of sulfonamide allergy de‐labelling on clinical outcomes. Considering our findings, evaluation and de‐labelling of sulfa allergy‐labelled adults with low risk for reaction can be explored to contribute toward antibiotic stewardship efforts and provide an opportunity to optimise treatment of patients with cystitis. Supporting information Figure S1. Kaplan–Meier analysis for the different study outcomes. The estimated probabilities for developing acute pyelonephritis (A), C. difficile infection (B) and recurrent or relapsed cystitis (C) are presented per 1000 patients. Results shown are after propensity score matching for baseline demographics and comorbidities. P ‐values are corrected for multiple comparisons. IMJ-55-993-s001.docx (242.9KB, docx) Funding: The project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 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