Pros and cons of the use of fluoroquinolone antibiotics in patients with kidney disease

Fluoroquinolones are among the most commonly prescribed antibiotics worldwide [1, 2]. In 2020, 4.7 million ciprofloxacin prescriptions and 1.8 million levofloxacin prescriptions were filled in the USA [3]. Between 2016 and 2020, Spain had the highest fluoroquinolone use rates in six European countries, ranging from 2.8 to 8.0 per 1000 persons per month, followed by Belgium, Germany, France and the Netherlands, with rates ranging from 2.0 to 5.7, 1.3 to 2.9, 1.3 to 2.5, and 1.5 to 2.0 per 1000 persons per month, respectively. In contrast, the UK had the lowest incidence rates, ranging from 0.7 to 1.2 per 1000 persons per month. Fluoroquinolones are highly bioavailable and have broad-spectrum antimicrobial activities [1, 2]. These antibiotics are used to treat common bacterial infections, such as urinary tract infections, pneumonia and intra-abdominal infections [1, 2]. In Europe, the most frequent fluoroquinolone indications reported between 2016 and 2020 were respiratory tract infections, urinary tract infections (uncomplicated) and ear infections [3]. The rate of fluoroquinolone resistance has dramatically increased worldwide. In 2021, it was reported that fluoroquinolone resistance in Escherichia coli isolates was high in several European countries. Specifically, 17 out of 45 countries had a resistance rate of 25% or higher. Spain had the highest rate at 27%, followed by Belgium at 19%, the UK at 16%, Germany at 15%, France at 15% and the Netherlands at 13%. The prevalence of E. coli fluoroquinolone resistance in the USA was 22.1%, ranging from 10.5% to 29.7% across US sites. Despite the rising rate of fluoroquinolone resistance observed worldwide, fluoroquinolones remain an effective antibiotic for many patients. A recent meta-analysis of 18 randomized controlled trials, including 4140 participants, showed that fluoroquinolones were more effective than β-lactam plus macrolide combination therapy for treating community-acquired pneumonia in hospitalized adults [4]. Although fluoroquinolones are effective in treating a broad spectrum of bacterial infections, their use has been linked to critical adverse events, including musculoskeletal disorders (e.g. Achilles tendon rupture), nervous system or psychiatric disorders, eye disorders (e.g. retinal detachment), hypoglycemia, Clostridium difficile-associated disease, acute liver injury, QT interval prolongation and aortic aneurysm rupture [2]. European Medicines Agency (EMA), US Food and Drug Administration (FDA) and Health Canada warnings have highlighted these risks associated with fluoroquinolones [2, 5]. In July 2016, the FDA issued an enhanced warning stating that these antibiotics are associated with disabling and potentially irreversible serious adverse reactions, including tendinopathy and tendon rupture, peripheral neuropathy, serious blood sugar and mental health side effects. Health Canada and EMA have also released similar warnings regarding potentially serious adverse reactions to fluoroquinolones. As a result of the potential risks associated with fluoroquinolones, regulatory agencies such as the FDA, EMA and Health Canada have recommended that these antibiotics should only be used for treating more severe bacterial infections when the benefits clearly outweigh the risks. For less severe infections such as acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated urinary tract infections, physicians should consider other treatment options and avoid prescribing fluoroquinolones due to the potential risks outweighing the benefits. In patients with renal impairment, product monographs and prescribing guidelines recommend that fluoroquinolones be administered at a lower dose due to their kidney elimination (Supplementary data, Table S1). However, in practice, many patients with renal impairment receive fluoroquinolones at higher than recommended doses, which can increase their risk of adverse drug events [6]. Safe and effective prescribing of fluoroquinolone antibiotics in patients with renal impairment is a critical concern. To address this issue, we examined the current literature to evaluate the safety and efficacy of fluoroquinolone use in this population. As renal impairment puts these patients at higher risk for adverse drug events, it is crucial to understand the potential benefits and risks associated with fluoroquinolones in this population. We searched Medline and Embase databases from 1946 to 31 August 2023, using relevant keywords and subject headings related to renal impairment, chronic kidney disease, fluoroquinolones, safety or adverse drug reactions, and efficacy or effectiveness. We identified 34 case reports and 4 population-based retrospective cohort studies linking fluoroquinolones to adverse drug events in patients with renal impairment. Out of the 34 patients examined in these case reports (Supplementary data, Table S2), 20 (59%) were male, with 26 (76%) taking an oral dose of fluoroquinolones and 14 (41%) receiving hemodialysis. After experiencing adverse drug events, 24 (71%) discontinued the treatment. The median age [interquartile range (IQR)] was 71 (60–76) years. Ciprofloxacin and levofloxacin were the most frequent fluoroquinolones prescribed, at a median (IQR) daily dose of 1000 (500–1000) mg and 500 (250–500) mg, respectively, despite product monogram and prescribing guidelines recommendations. The most frequent adverse drug events reported were nervous system or psychiatric disorders (24%), renal disorders (18%), hypoglycemia (15%), tendinopathy (12%) and arrhythmia (8%). Using the Naranjo algorithm, we established a probable causal relationship in 30 case reports with a median (IQR) time to adverse events of 3 (2–7) days from fluoroquinolone initiation. Additional information on these case reports is provided in Supplementary data, Table S2. Of the four population-based retrospective cohort studies [7–10], one study was conducted in Ontario, Canada, using linked healthcare data [7], while the other three were conducted in the USA using the US Renal Data System [8–10]. The US Renal Data System is a government-funded national surveillance system that collects information on almost all individuals with kidney failure in the USA [8–10]. In the first population-based study, Muanda et al. [7] evaluated the risk of serious adverse events in a cohort of 11 917 older adults with advanced chronic kidney disease [CKD; defined as an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2] not receiving dialysis who were newly treated with fluoroquinolones (Table 1). The cohort consisted of 7438 (62%) females and 4479 (38%) males, with a median age (IQR) of 83 (77–89) years. The most prescribed fluoroquinolones were ciprofloxacin, levofloxacin and norfloxacin, with median (IQR) daily doses of 500 (500–1000) mg/day, 500 (250–750) mg/day and 800 (400–800) mg/day, respectively. The study found that patients who initiated fluoroquinolones at a higher dose vs a lower dose had a significantly higher risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia or a collagen-associated event within 14 days (weighted risk ratio 1.45; 95% CI 1.01–2.08; weighted risk difference 0.39%; 95% CI 0.01%–0.76%). Altered mental status was the most common adverse event. Population-based retrospective cohort studies linking fluoroquinolones to adverse drug events in patients with renal impairment. We used the Modified Downs and Black checklist to assess the methodological quality of these retrospective cohort studies. We gave a score from 0 to 28, grouped into the following four quality levels: excellent (26 to 28), good (20–25), fair (15–19) and poor (14 or less). CKD, chronic kidney disease; RR, risk ratio; RD, risk difference; HR, hazard ratio. Population-based retrospective cohort studies linking fluoroquinolones to adverse drug events in patients with renal impairment. We used the Modified Downs and Black checklist to assess the methodological quality of these retrospective cohort studies. We gave a score from 0 to 28, grouped into the following four quality levels: excellent (26 to 28), good (20–25), fair (15–19) and poor (14 or less). CKD, chronic kidney disease; RR, risk ratio; RD, risk difference; HR, hazard ratio. In the second population-based study, Assimon et al. [8] compared the risk of sudden cardiac death (SCD) in a cohort of 264 968 patients receiving in-center hemodialysis (Table 1). The study compared patients treated with respiratory fluoroquinolones (levofloxacin or moxifloxacin) versus those treated with amoxicillin (with or without clavulanic acid). The study included 626 322 study antibiotic treatment episodes (264 968 patients), of which 251 726 (40%) were respiratory fluoroquinolone treatment episodes and 374 596 (60%) were amoxicillin-based treatment episodes. The patients had a mean (SD) age of 61 (15) years, and women represented 49% (129 732) of the total patient cohort. The study found that respiratory fluoroquinolones vs amoxicillin-based antibiotic treatment was associated with a higher 5-day risk of SCD among patients receiving in-center hemodialysis (weighted hazard ratio 1.95; 95% CI 1.57–2.41; and weighted risk difference per 100 000 treatment episodes 44.0; 95% CI 31.0–59.2). In the third population-based study, Assimon et al. [9] compared the risk of SCD in a cohort of 245 143 patients who received in-center hemodialysis (Table 1). The study examined patients who initiated different doses of levofloxacin (high or low doses) versus those who initiated azithromycin. The study included 554 557 study antibiotic treatment episodes (245 143 patients), of which 387 382 (70%) were azithromycin treatment episodes and 167 175 (30%) were levofloxacin treatment episodes. Of the 167 175 levofloxacin treatment episodes, 7% were for higher dose levofloxacin (>500 mg/day), and 93% for lower dose (≤500 mg/day) levofloxacin. The study showed that a higher than recommended dose of levofloxacin (>500 mg/day) vs azithromycin treatment was associated with a higher 5-day risk of SCD among patients receiving in-center hemodialysis (weighted hazard ratio 1.78; 95% CI 1.04–3.06). In the fourth population-based study, Pun et al. [10] compared the risk of SCD in a cohort of 79 449 patients receiving in-center hemodialysis (Table 1). The study compared patients treated with respiratory fluoroquinolones (levofloxacin or moxifloxacin) versus those treated with amoxicillin-based antibiotics. The study included 169 735 study antibiotic treatment episodes (79 449 patients), of which 65 959 (39%) were respiratory fluoroquinolone treatment episodes and 103 776 (61%) were amoxicillin-based treatment episodes. The study found that respiratory fluoroquinolones vs amoxicillin-based antibiotic treatment was associated with a higher 14-day risk of SCD among patients receiving in-center hemodialysis (20.3 versus 9.5 events per 100 000 treatment episodes, weighted hazard ratio 1.72; 95% CI 1.30–2.27). The risk of SCD was highest among patients with baseline potassium gradients of ≥3 mEq/L, as compared with those with <3 mEq/L (weighted hazard ratio 2.19; 95% CI 1.37–3.50 vs 1.50; 95% CI 1.06–2.11). However, the difference did not reach statistical significance (P = .71 for multiplicative interaction). Residual confounding may have influenced the study results observed in these four population-based studies. The first study's results may not apply to adults under 66 years of age or those receiving dialysis treatment. Similarly, the results of the three other studies may not apply to patients under 18 years of age or those who are undergoing peritoneal dialysis. We did not find any randomized controlled trials evaluating the efficacy of fluoroquinolones for common indications such as urinary tract infections or respiratory tract infections in patients with CKD. In summary, fluoroquinolone use, more specifically higher than recommended doses, is associated with significant harm in patients with renal impairment (i.e. patients with an eGFR <30 mL/min/1.73 m2 or those receiving dialysis). These findings emphasize the importance of raising awareness among primary care physicians regarding fluoroquinolone dosing recommendations in patients with kidney disease. Taken together, the reviewed evidence has significant clinical implications. Physicians should consider alternative drugs, such as amoxicillin-based antibiotic treatment, for the indication for which they are considering fluoroquinolone following a judicious review of local antimicrobial susceptibility data. If the benefits of fluoroquinolone use are deemed to outweigh the potential risks, fluoroquinolones should be initiated at a dose appropriately reduced for patients’ renal clearance. Patients should be educated on and closely monitored for signs of toxicity early after fluoroquinolone initiation. If a patient is admitted to the hospital with symptoms related to nervous/psychiatric disorders, renal disorders, hypoglycemia, tendinopathy, or arrhythmia, physicians should reconcile the patient's outpatient medications to determine whether fluoroquinolone is a potential cause. Physicians must be educated about these study findings and implement pharmacy strategies to minimize prescribing errors, such as updating computerized medication-order entry warnings [11]. Additionally, regulatory agencies such as the EMA, Health Canada, and the US FDA should also focus on developing new strategies that can further strengthen the existing warning labels and alert prescribers about the potential risk of severe adverse drug events linked to fluoroquinolone, especially among patients with renal impairment. These warning strategies must also be communicated through letters, public health advisories and educational materials to ensure patients know the risks associated with these drugs. Finally, reminding primary care physicians about the importance of accurately adjusting fluoroquinolone doses in patients with kidney disease is crucial. Continuing medical education, disseminating clinical guidelines, and organizing seminars and workshops can increase awareness about fluoroquinolone dosing recommendations for patients with kidney disease. This can lead to improved patient outcomes and better overall healthcare. These labels should also emphasize the need for careful monitoring during fluoroquinolone treatment to ensure early detection of adverse effects. F.T.M. and F.A. conceived and designed the study. F.A. completed the literature search. All authors contributed to the acquisition, analysis or interpretation of data. F.T.M. and F.A. drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors read and approved the submitted manuscript. The authors declare no conflicts of interest.

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