Risk of collagen-related disorders and neurological events among patients with uncomplicated urinary tract infection following short treatment with fluoroquinolones: a cohort study

Abstract

Studies of fluoroquinolone (FQ) safety across indications show increased collagen/neurological adverse event (AE) risk, yet patients still receive FQs for uncomplicated urinary tract infections (uUTIs). This retrospective, cohort study investigated the risk of collagen/neurological AEs of special interest (AESIs) with short-term FQ use versus standard-of-care antibiotics (trimethoprim-sulfamethoxazole [SXT], nitrofurantoin [NTF]) among female outpatients with uUTIs. This study was conducted between December 2009 and 2019 using Optum's de-identified Clinformatics Data Mart Database. Adjusted absolute risks were calculated for composite/collagen/neurological AESIs (Kaplan-Meier cumulative hazards, after applying stabilized inverse probability of treatment weighting [sIPTW]). Adjusted hazard ratios were generated (sIPTW Cox proportional hazard modeling). Overall, 954,777 patients were included: FQ (n = 386,537 [40.5%]); SXT (n = 237,120 [24.8%]); NTF (n = 314,585 [32.9%]). Adjusted absolute risk range for collagen/neurological AESIs was <1%-4.5%. The hazard (95% CI) of tendon rupture was 25% higher with FQ versus SXT (1.25 [1.00-1.57]; P = 0.0497). Patients receiving FQ had lower hazard of neurological (0.95 [0.93-0.97]; P < 0.0001), central nervous system (0.85 [0.80-0.89]; P < 0.0001), and peripheral nervous system (0.96 [0.93-0.98]; P = 0.0016) AESIs versus NTF. Following a short treatment duration, FQs were associated with increased risk of tendon rupture versus SXT and reduced risk (adjusted hazard ratios) of neurological AESI versus NTF. Individual patient risk and consequences for known uncommon, yet serious, AEs need to inform appropriate antibiotic choice in treating uUTIs. Patient profile, efficacy, microbiome impact, safety, and surveillance should inform antibiotic selection for uUTI management, in accordance with guidelines.

Keywords: adverse events of special interest; antibiotics; collagen events; fluoroquinolones; neurological events; risk; standard-of-care; uncomplicated urinary tract infection.

Fig 1

Study design. AESIs, adverse events of special interest; uUTI, uncomplicated urinary tract infection.

Fig 2

Patient attrition diagram. AMC, amoxicillin clavulanate; FQ, fluoroquinolone; HIV, human immunodeficiency virus; IV, intravenous; NTF, nitrofurantoin; SXT, trimethoprim/sulfamethoxazole; uUTI, uncomplicated urinary tract infection; UTI, urinary tract infection.

Fig 3

Crude and adjusted absolute risks over time by index antibiotic treatment: (A and B) collagen AESIs (aggregate), (C and D) tendon rupture, and (E and F) neurological AESIs (aggregate). AESI, adverse event of special interest; FQ, fluoroquinolone; NTF, nitrofurantoin; sIPTW, inverse probability of treatment weighting; SXT, trimethoprim/sulfamethoxazole.

Fig 4

Forest plot of crude and adjusted absolute risks of (A) collagen and (B) neurological AESIs. Collagen AESIs comprised tendon rupture, aortic aneurysm with or without dissection, retinal detachment, uveitis, and a composite category for all collagen AESIs. Neurological AESIs comprised CNS AESIs (seizures/convulsions, intracranial hypertension, psychosis/delirium, and altered mental status/encephalopathy), PNS AESIs (muscle weakness, paresthesia/sensory disturbance [tingling, numbness, burning pain, and allodynia], gait dysfunction, and peripheral neuropathy), and a composite category for all CNS and PNS AESIs. AESIs, adverse events of special interest; CNS, central nervous system; FQ, fluoroquinolone; NTF, nitrofurantoin; PNS, peripheral nervous system; sIPTW, inverse probability of treatment weighting; SXT, trimethoprim/sulfamethoxazole.

Fig 5

Forest plot of crude and adjusted hazard ratios for (A) collagen and (B) neurological AESIs. Collagen and neurological AEs are aggregate. Reference HR = 1. HRs are adjusted for age, race/ethnicity, region, year of new uUTI, uUTI recurrence, prior antimicrobial exposure, prior hospitalization, prior physician visits, prior UTI, comorbidities, and comedications. AESIs, adverse events of special interest; CI, confidence interval; FQ, fluoroquinolone; HR, hazard ratio; NTF, nitrofurantoin; PNS, peripheral nervous system; sIPTW, inverse probability of treatment weighting; SXT, trimethoprim/sulfamethoxazole.