Regional variation in the potentially inappropriate first-line use of fluoroquinolones in Canada as a key to antibiotic stewardship? A drug utilization review study

Systemic oral fluoroquinolones are commonly prescribed antibiotics [1‐4]. Given their advantageous pharmacokinetic and pharmacodynamics properties, such as high bioavailability and broad-spectrum antimicrobial activity [5], fluoroquinolones are among the most widely prescribed class of antibiotics. Some of this expanded use has been for milder infections, such as uncomplicated urinary tract infection (UTI), acute bacterial sinusitis (ABS), and uncomplicated acute exacerbation of chronic obstructive pulmonary disease (AECOPD), with limited evidence supporting their superiority to other first-line antibiotics [6‐9]. Case reports and observational studies have indicated rare but severe adverse effects associated with fluoroquinolone use including tendon rupture [10], aortic aneurysm [11, 12], retinal detachment [13], and effects on the central and peripheral nervous system [14, 15]. Several safety warnings have been issued by regulatory agencies in the last decade. In 2016, the United States Food and Drug Administration (FDA) advised that the serious side effects of fluoroquinolone antibiotics generally outweigh their benefits in uncomplicated infections where other treatment alternatives are available [16]. In 2017 and 2018, Health Canada and the European Medicines Agency similarly recommended restricting fluoroquinolone use due to their disabling and potentially persistent side effects [17, 18].

Given the rare but potentially harmful adverse effects associated with fluoroquinolone antibiotic use, along with concerns of increasing fluoroquinolone resistance [19, 20], there is a need to ensure that they are prescribed for indications where there is a clear and proven benefit. Antibiotics resistance has important clinical and public health consequences and considerable associated cost impacts [21]. Using administrative health care databases from six Canadian provinces, we aimed to determine the proportion of initial antibiotic dispensations for uncomplicated UTI, ABS, and AECOPD in the outpatient setting across Canada, and to describe variations in the use of systemic oral fluoroquinolones.

In our retrospective cohorts, we observed that systemic oral fluoroquinolones were commonly used in the first-line treatment of uncomplicated UTI and AECOPD in Canada. However, the proportion of fluoroquinolone dispensations varied widely across provinces. Fluoroquinolones were infrequently used in the first-line treatment of ABS. We noted a trend towards decreasing use of fluoroquinolones for uncomplicated UTI and ABS between 2005 and 2015.

We observed potentially inappropriate first-line use of systemic oral fluoroquinolones in the treatment of uncomplicated UTI and AECOPD. Fluoroquinolones, primarily ciprofloxacin, were frequently dispensed in the first-line treatment of uncomplicated UTI. However, the use of fluoroquinolones for this indication tended to decrease in all provinces during the study period, which is consistent with guideline recommendations to restrict fluoroquinolone use to second-line in women with uncomplicated UTI [7, 31]. Respiratory fluoroquinolones, levofloxacin and moxifloxacin, were commonly prescribed for AECOPD events treated with antibiotics although their use is recommended for patients with specific risk factors or treatment failure with first-line antibiotics [32]. The proportion of AECOPD events treated with a fluoroquinolone remained relatively stable over time. A relatively small proportion of ABS events were treated with fluoroquinolones but guidelines suggest that they should be used in second-line only [33, 34]. However, we noted that a substantial proportion of ABS events were treated with antibiotics in our study cohort, although the recommendations suggest limiting their use to patients with severe symptoms or failing to respond to intranasal corticosteroids after 72 h [33]. Additionally, the majority of acute sinusitis cases are of viral etiology, with only 0.5 to 2% progressing to ABS [35]. We observed a trend towards decreasing fluoroquinolone use for this indication. Our findings of fluoroquinolone use for these three infections and overall decline in use of this class of antibiotic have also been previously reported in Canada and in the United States [1, 36‐39].

Differences in provincial formulary criteria and enforcement, local practice, antibiotic resistance rates, and marketing patterns may partly explain the large interprovincial variations observed in the use of fluoroquinolones. As each province and territory has its own publicly funded drug plan, differences in the coverage of drugs are expected. A previous review of provincial drug formulary for antimicrobials has shown that in comparison with other antimicrobials, fluoroquinolones are a class with more restricted benefits [4]. From a review of provincial formularies for fluoroquinolones in 2016, we observed that coverage of fluoroquinolones varies across provinces. Fluoroquinolones were more restricted in Manitoba, while British Columbia was the only province with no restrictions for this class, although levofloxacin was not listed as a benefit. Our results showed that fluoroquinolone dispensations tended to be lower in Nova Scotia and Saskatchewan compared to other provinces. Although Manitoba, Nova Scotia, and Saskatchewan, have a similar restricted benefits for fluoroquinolones, their utilization differs, which may be explained by enforcement and management of formulary restrictions, such as the use of criteria codes on prescription or written forms [4]. In general, prescribing rates are expected to be lower in provinces with a greater number of formulary restrictions [4] and studies have described a reduction in the use of fluoroquinolones following implementation of specific restrictions [40, 41]. We also noted variations in the specific criteria for coverage of ciprofloxacin, levofloxacin, and moxifloxacin across provinces. For example, ciprofloxacin is specifically indicated for the treatment of genitourinary tract infections in Alberta and Ontario which could potentially explain the higher proportion of fluoroquinolone dispensations observed in these provinces for uncomplicated UTI. Local practice patterns could also explain some of these variations in the use of fluoroquinolones. For example, Alberta [42], British Columbia [43], Nova Scotia [44], and Saskatchewan [45] have had educational programs that may have influenced antibiotic prescribing. A recent survey of primary health care providers indicated that fluoroquinolone-prescribing habits were similar for uncomplicated cystitis, uncomplicated pyelonephritis, acute bacterial exacerbation of chronic bronchitis in COPD and ABS across Canada [46]. Other factors such as variations in antibiotic-resistance, adherence to treatment guidelines or marketing patterns, across jurisdictions may also contribute to the interprovincial differences observed in the use of fluoroquinolones. Lastly, an additional explanation is the heterogeneity in the prescription drug data available across the different study sites, i.e. all vs. government reimbursed dispensations. All dispensations (including those for which patient pay out-of-pocket) are captured in Alberta, British Columbia, Manitoba, and Saskatchewan, whereas only provincial government reimbursed dispensations are captured in Nova Scotia and Ontario.

Our study has limitations. Our data is limited to antibiotics dispensed in outpatient pharmacies and thus cannot be generalized to other settings of care. Inter-provincial comparisons in UTI and ABS treatment must take into account the fact that some provinces (such as Nova Scotia and Ontario) only have drug dispensation data available for older adults ≥ 65 years old. Also, not all provinces were represented in our sample and data was not available for all years for the represented provinces. Event definitions are based on outpatient diagnosis codes and do not include clinical characteristics or laboratory values. Although antibiotic exposure was defined as the first antibiotic dispensed within 5 days of the event, we could not be certain the antibiotic was actually prescribed for the indication listed as the diagnosis for the physician visit. While we were able to document provincial formulary prescribing criteria for 2016, these may have varied over the study period and do not consider any supplementary private drug insurance restrictions. We were unable to document all influences on prescribing such as continuing professional development, academic detailing, and antibiotic stewardships programs. Lastly, our findings only provide a descriptive snapshot of fluoroquinolone use in uncomplicated UTI, ABS, and AECOPD in Canada. Utilization data was also used by the FDA during the safety review of fluoroquinolones to guide the policy decision around the 2016 warning. Further studies are needed to evaluate the outcomes of fluoroquinolone therapy compared to first-line antibiotics and assess their need in more complicated situations [47, 48].

In summary, systemic oral fluoroquinolones were commonly used as first-line therapies in Canada, particularly for uncomplicated UTI and AECOPD. However, first-line fluoroquinolone use varied widely across provinces. There was a decline in the proportion of uncomplicated UTI and ABS events treated with fluoroquinolones between 2005 and 2015. Drug formulary criteria and enforcement in addition to prescriber and public education are several key approaches to promoting better antibiotic stewardship and limiting potentially inappropriate first-line use of fluoroquinolones.