Unnecessary use of fluoroquinolone antibiotics in hospitalized patients

Fluoroquinolones are among the most commonly prescribed antibiotics in outpatient and inpatient settings in the United States [1]. Increases in the use of fluoroquinolones in recent years have coincided with steady increases in the incidence of fluoroquinolone-resistance among gram-negative bacilli in intensive care units [2]. In addition, fluoroquinolone exposure has been associated with colonization and infection with other healthcare-associated pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile [3–5]. Reducing the use of fluoroquinolones may be an effective strategy to limit the dissemination of these pathogens [6, 7]. For example, a restriction program that resulted in a 66% reduction in use of fluoroquinolones was associated with control of an outbreak of C. difficile infection (CDI) associated with fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strains [7].

Several studies have demonstrated that fluoroquinolones are often used inappropriately [8–12]. Lautenbach et al. [8] found that 81% of fluoroquinolone prescriptions in two academic emergency departments were inappropriate based on institutional guidelines. In a French teaching hospital, Mean et al. [9] found that 51% of fluoroquinolone regimens were innappropriate based on local prescription guidelines. In a tertiary care hospital in Cleveland, we found that 30% of all days of antimicrobial therapy were unnecessary, with ciprofloxacin being the agent most often prescribed unnecessarily [11]. Other small studies have reported frequent misuse of ciprofloxacin and levofloxacin in U.S. hospitals [11, 12]. In order to develop effective stewardship interventions, there is a need for additional data on current patterns of inappropriate fluoroquinolone prescribing among hospitalized patients. Therefore, we performed a prospective study to determine the frequency of, reasons for, and adverse effects of unnecessary fluoroquinolone use in a tertiary care medical center. We hypothesized that longer than necessary treatment durations would account for a significant proportion of unnecessary fluoroquinolone use.

Two hundred twenty-six study subjects received 227 fluoroquinolone regimens during the study period (1 patient was prescribed 2 fluoroquinolone regimens). Figure 1 summarizes the findings regarding the necessity of fluoroquinolone regimens. Of the 227 fluoroquinolone regimens, 70 (31%) were deemed unnecessary. These unnecessary regimens resulted in 391 days of fluoroquinolone therapy, which accounted for 22% of the total days of fluoroquinolone therapy. Analysis of the 157 necessary fluoroquinolone regimens revealed that an additional 299 days of therapy were unnecessary. Overall, 690 of the 1773 (39%) days of fluoroquinolone therapy were deemed unnecessary and 120 of the 226 (53%) study patients received at least one day of unnecessary fluoroquinolone therapy.

Urinary syndromes, including asymptomatic bacteriuria, urinary tract infection, and pyelonephritis, accounted for 51% of the unnecessary fluoroquinolone regimens. In addition, urinary syndromes accounted for 36 of the 299 (12%) days of unnecessary therapy that were prescribed as part of necessary regimens. In total, urinary syndromes accounted for 210 of the 690 (30%) unnecessary days of fluoroquinolone therapy.

For necessary fluoroquinolone regimens, we also assessed whether equally effective alternative agents could have been used for therapy. Of 157 necessary regimens, 87 (55%) could have been replaced with an alternative agent; these regimens accounted for 648 of 1773 (37%) total days of fluoroquinolone therapy. The most common indications for which alternative agents could have been used were gastrointestinal infections (22 regimens, 184 days of therapy), pulmonary infections (21 regimens, 159 days of therapy), and urinary tract infections (21 regimens, 132 days of therapy).

During the study period, 11,304 total days of antibiotic therapy were administered to inpatients. Fluoroquinolones accounted for 1,959 of the total days of antibiotic therapy (17%). Ciprofloxacin was the most commonly used fluoroquinolone (1,627 days of therapy); moxifloxacin accounted for the remaining 332 days of therapy. Assuming that fluoroquinolone therapy during the study period was representative of usage patterns throughout the year, the estimated total cost of all of fluoroquinolones administered in 2009 was $205,051 ($127,877 for ciprofloxacin and $77,174 for moxifloxacin). Based on actual pharmacy acquisition charges, the total costs of all fluoroquionolones administered in 2009 was $22,281 ($11,144 for ciprofloxacin and $11,137 for moxifloxacin). If a stewardship program had been effective in eliminating the 31% of fluoroquinolone therapy that was considered unnecessary, the estimated cost savings for the hospital based only on pharmacy expenditures during the year of the study would have been ~$63,566 based on average wholesale prices or $6,907 in actual pharmacy acquisition costs.

We found that 31% of fluoroquinolone regimens prescribed in our institution during the study period were unnecessary. These unnecessary regimens accounted for 22% of all days of fluoroquinolone therapy (391 of 1,773 total days of therapy). The most common reason for unnecessary fluoroquinolone regimens was administration of antimicrobials for non-infectious or non-bacterial syndromes. These findings are consistent with previous studies that evaluated appropriateness of fluoroquinolone therapy regimens [8–11]. For example, Lautenbach et al. [8] found that there was no evidence of infection in 33% of the fluoroquinolone prescriptions that were deemed inappropriate in two emergency departments.

A new observation from our study is that nearly half of all unnecessary days of fluoroquinolone therapy (299 of 690 unnecessary days of therapy) occurred when only part of a treatment regimen was unnecessary. The most common reason for part of a regimen being unnecessary was administration of fluoroquinolones for longer than necessary durations, either because treatment duration was longer than is recommended in current guidelines or because therapy was not discontinued when there was no evidence of infection. These results suggest that interventions to reduce overuse of fluoroquinolones should include efforts to ensure that the duration of therapy is appropriate. Such measures may be clinically important because increased duration of fluoroquinolone therapy has been associated with increased risk of CDI [16]. Efforts to reduce the length of antimicrobial regimens have been advocated as a safe and palatable means to limit overuse of antibiotics [17].

Urinary syndromes were the most common reason for unnecessary fluoroquinolone therapy (30% of all unnecessary days of therapy). Treatment of asymptomatic bacteriuria accounted for 51% of all unnecessary fluoroquinolone regimens, and was particularly common in elderly patients. It is likely that we underestimated the actual number of cases of asymptomatic bacteriuria because documentation of urinary symptoms in the medical record was sometimes lacking and we required documentation that urinary symptoms were not present to classify a case as asymptomatic bacteriuria. Current guidelines for management of asymptomatic bacteriuria recommend treatment only for pregnant women or individuals undergoing invasive urologic procedures [18]. This recommendation is based on randomized trials that have demonstrated that treatment of asymptomatic bacteriuria is not beneficial in other patient populations [18–22]. A recent survey in our hospital demonstrated that most physicians were unaware of the guidelines for management of asymptomatic bacteriuria (authors' unpublished data). To address the overuse of fluoroquinolones in our facility, we have initiated an intervention that focuses primarily on improving adherence to current guidelines for management of asymptomatic bacteriuria and other urinary syndromes. The intervention includes education, audit and feedback regarding appropriateness of therapy, and automated electronic reminders regarding appropriate choice and duration of therapy.

In addition to the evaluation of the necessity of fluoroquinolone therapy, we assessed whether equally effective alternative agents could have been used for therapy. Of the necessary fluoroquinolone regimens, we found that 55% could have been replaced with an alternative agent; these regimens accounted for 37% of the total days of fluoroquinolone therapy. Therefore, our findings suggest that a stewardship program that includes both elimination of unnecessary therapy and formulary substitution when effective alternatives are available could eliminate up to 75% of days of fluoroquinolone therapy without adversely affecting care of patients.

Our study has some limitations. First, the study was conducted in a single tertiary care institution. Additional studies are needed in other tertiary care hospitals and in community hospitals. Second, categorization of therapy as necessary or unnecessary was based on review of medical records, and therefore it is possible that some regimens were misclassified due to inadequate documentation of the indications for treatment. However, as noted previously, the reviewers did not classify therapy as unnecessary in cases where inadequate documentation was available. Third, we examined fluoroquinolone use during a single 6-week period in the springtime. It is possible that fluoroquinolone use may be greater during the winter respiratory virus season. Fourth, we did not include a comparison of the appropriateness of prescribing for physicians at different levels of training. Finally, for regimens in which fluoroquinolones were administered in combination with other agents, it is not possible to determine whether adverse effects were attributable to the fluoroquinolones or to the other agents.

Fluoroquinolones accounted for 17% of all days of antibiotic therapy in our institution, and 39% of all days of fluoroquinolone therapy were unnecessary. The most common reasons for unnecessary therapy were administration of antimicrobials for non-infectious or non-bacterial syndromes and administration of antimicrobials for longer than recommended durations. These results suggest that interventions that focus on improving adherence with current guidelines for antimicrobial use and for duration of therapy could significantly reduce overuse of fluoroquinolones.