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Hospital and Community Fluoroquinolone Use and Resistance in Staphylococcus aureus and Escherichia coli in 17 US Hospitals

  1. Conan MacDougall1,
  2. J. Patrick Powell1,
  3. Christopher K. Johnson3,
  4. Michael B. Edmond2, and
  5. Ronald E. Polk1,2
  1. 1School of Pharmacy, Department of Pharmacy, Richmond, Virginia
  2. 2School of Medicine, Department of Internal Medicine, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia
  3. 3College of Pharmacy, Department of Pharmacy Practice, Idaho State University, Boise
  1. Reprints or correspondence: Dr. Ronald E. Polk, 410 N. 12th St., Rm. 454, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298 (repolk{at}vcu.edu).
 
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Abstract

Background. Fluoroquinolones are widely prescribed in hospitals and the community. Previous studies have shown associations between fluoroquinolone use and isolation of fluoroquinolone-resistant Eshcerichia coli and methicillin-resistant Staphylococcus aureus (MRSA). We performed an ecologic-level study to determine whether variability in hospital percentages of fluoroquinolone-resistant E. coli and MRSA were associated with fluoroquinolone use in hospitals and their surrounding communities.

Methods. We measured fluoroquinolone use in 17 US hospitals and their surrounding communities in the year 2000. Data on fluoroquinolone use in hospitals was electronically extracted from billing data. Data on fluoroquinolone use in communities was obtained from IMS health data for all prescriptions filled in pharmacies within a 16-km radius of each hospital. We used hospital antibiograms to determine the percentage of isolates that were fluoroquinolone-resistant E. coli and MRSA, and we performed linear regression to determine the relationship between percentage of resistant isolates and fluoroquinolone use in hospitals and their surrounding communities.

Results. There was a significant association between total fluoroquinolone use within hospitals and percentage of S. aureus isolates that were MRSA (r = 0.77; P = .0003) and between total fluoroquinolone use in the community and percentage of E. coli isolates that were fluoroquinolone-resistant E. coli (r = 0.68; P = .003). Population density within the 16-km radius also correlated with MRSA percentage (r = 0.57; P = .015) and fluoroquinolone-resistant E. coli percentage (r = 0.85; P = .002), but associations between total fluoroquinolone use and resistance remained significant after adjustment for population density.

Conclusions. In this ecologic analysis, we found associations between fluoroquinolone use in hospitals and methicillin resistance in S. aureus and between fluoroquinolone use in communities and fluoroquinolone resistance in E. coli in hospitals. Antimicrobial use in hospitals and communities may have different relative importance with regard to resistance in different pathogens encountered in hospitals.

The fluoroquinolone class of antimicrobials is characterized by proven clinical efficacy for a number of infections, excellent oral bioavailability, and an acceptable safety profile [1]. These characteristics have resulted in their widespread use in the community and in hospitals [2]. Fluoroquinolone use in hospitals has been linked to the emergence of resistance in Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli [3]. Community antimicrobial use is also believed to be an important contributor to rates of resistance in hospitals, but there is little available data to support this hypothesis [4]. We have recently reported significant associations between resistance to fluoroquinolones in strains of P. aeruginosa in hospitals and use of fluoroquinolones both within those hospitals and in their surrounding communities [5]. The objective of the current study was to determine whether similar relationships exist between fluoroquinolone use and methicillin-resistant S. aureus (MRSA) or fluoroquinolone-resistant E. coli. We analyzed fluoroquinolone use in 17 US hospitals and their surrounding communities in the year 2000 and correlated this data with hospital-resistance data.

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Methods

Details of the participating hospitals in the Surveillance and Control of Pathogens of Epidemiologic Importance–MediMedia Information Technologies Antimicrobial Surveillance Network and the methods used to obtain and analyze data in hospitals and surrounding communities have been previously described [5]. In brief, data on patient-level fluoroquinolone use was extracted from claims data from 17 general medical/surgical hospitals for the year 2000. Total grams of each fluoroquinolone were aggregated at the hospital level and converted to defined daily doses (DDD) per 1000 patient-days for each hospital, as recommended by the World Health Organization [6]. The DDDs used were as follows: levofloxacin, 500 mg; moxifloxacin, 400 mg; gatifloxacin, 400 mg; and ciprofloxacin, 1000 mg (because we did not distinguish between the proportion of intravenous versus oral ciprofloxacin used, we used the oral DDD for ciprofloxacin of 1000 mg).

The dosage and number of prescriptions for each fluoroquinolone dispensed from retail pharmacies in all US zip codes during 2000 were obtained from IMS Health through its Xponent database. Fluoroquinolone use in a 16-km radius surrounding each hospital was determined by summing the total grams dispensed in each zip code within that radius. The population in the corresponding zip codes was determined from year 2000 census data. Density of fluoroquinolone use is expressed as DDDs per 1000 inhabitant-days. Demographic data for the hospitals in the year 2000 was obtained from the MediMedia Information Technologies database and the American Hospital Directory (http://www.ahd.com). Members of the Council of Teaching Hospitals and Health Systems were designated as teaching hospitals.

Percentages of pathogens with resistance to the studied antimicrobials for year 2000 were abstracted from antibiograms provided by participating hospitals. To be included in the analysis, antibiograms must have reported the number of isolates and percentage of resistant isolates for organisms from all clinical sites (e.g., blood or urine) and all hospital units (including intensive care units). Results from specimens submitted from an outpatient facility (e.g., clinics), when reported separately, were excluded. Ciprofloxacin or levofloxacin susceptibility was used to determine the percentage of fluoroquinolone-resistant E. coli; 15 hospitals tested ciprofloxacin, and 2 tested levofloxacin. Of 12 hospitals that reported the fluoroquinolone susceptibility of S. aureus, 10 tested ciprofloxacin, and 2 tested levofloxacin. Oxacillin or nafcillin susceptibility was used to determine the percentage of S. aureus that were MRSA. Least-squares linear regression was used to examine the univariate relationship between predictor variables, including hospital demographic data, hospital fluoroquinolone use, community fluoroquinolone use, and the dependent variable (percentage of isolates with resistance) for the studied pathogens. Variables with nonnormal distributions were log-transformed. Multivariate regression was used to determine the independent effect of fluoroquinolone use in the hospital and in the community on resistance. Data analysis was performed with JMP software, version 5.1 (SAS Institute). A P value of <.05 was considered to be statistically significant, and all tests of significance were 2-tailed. Because of the exploratory nature of this analysis, P values were not adjusted for multiple testing.

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Results

Characteristics of study hospitals. Demographic characteristics of the participating hospitals were as follows: mean number of admissions (±SD), 15,954 ± 8539; mean number of patient-days (±SD), 80,737 ± 56,921; mean case-mix index (±SD), 1.49 ± 0.19; mean number of staffed beds (±SD), 319 ± 161; mean number of intensive care unit beds (±SD), 23 ± 17; mean number of inpatient surgeries per 1000 admissions (±SD), 310 ± 102; and mean population within a 16-km radius of each hospital (±SD), 520,799 ± 589,269. Six hospitals were teaching hospitals. Nine hospitals were located in the east, 4 in the south, and 2 each in the west and midwest of the United States. There was a significant correlation between log-transformed population density and use of levofloxacin in the community (r = 0.85; P < .0001), but there was no correlation between log-transformed population density and ciprofloxacin use or use of all fluoroquinolones. Population density was also significantly correlated to the percentage of MRSA (r = 0.57; P = .0148) and fluoroquinolone-resistant E. coli (r = 0.85; P = .002). There were no statistically significant relationships between any other demographic characteristics and fluoroquinolone use, fluoroquinolone-resistant E. coli, or MRSA.

Hospital fluoroquinolone use. Mean total fluoroquinolone use in hospitals (±SD) was 131 ± 49 DDD per 1000 patient-days (figure 1). Levofloxacin was the most commonly used fluoroquinolone, representing a mean percentage (±SD) of total use of 58% ± 35%. Levofloxacin represented >90% of fluoroquinolone use at 6 hospitals; in 1 hospital, levofloxacin use represented <5% of fluoroquinolone use. Ciprofloxacin use represented a mean percentage (±SD) of 38% ± 33% of total fluoroquinolone use.

Figure 1
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Figure 1

Total fluoroquinolone use in the hospital (FQ Hosp) and community (FQ Comm), percentage of Staphylococcus aureus isolates that are methicillin resistant (MRSA), and percentage of Escherichia coli isolates that are fluoroquinolone resistant (FQ-R Ecoli) at the 17 study hospitals. Fluoroquinolone use is expressed in defined daily doses per 1000 patient-days for hospital use and defined daily doses per 1000 inhabitant-days for community use.

Community fluoroquinolone use. The mean of total fluoroquinolone use (±SD) within a 16-km radius of each hospital was 2.82 ± 0.7 DDD per 1000 inhabitant-days (figure 1). Ciprofloxacin was used most often (representing 54% of all use), followed by levofloxacin (36%), gatifloxacin (6%), and moxifloxacin (3%). Total fluoroquinolone use in the community was not correlated with hospital use of fluoroquinolones (r = 0.33; P = .19). However, community use of levofloxacin was correlated with hospital use of levofloxacin (r = 0.69; P = .002), as were community and hospital use of ciprofloxacin (r = 0.5; P = .04).

Resistance in hospital antibiograms. The median number of isolates tested was 616 for S. aureus (range, 93–2769 isolates), and it was 1492 (range, 212–8594 isolates) for E. coli. The mean percentage (±SD) of S. aureus isolates that were MRSA was 40% ± 15% (figure 1) Among all S. aureus isolates obtained from 12 hospitals, the mean percentage of isolates with fluoroquinolone resistance (±SD) was 38% ± 17%. Fluoroquinolone and methicillin resistance in these S. aureus isolates were highly correlated (r = 0.92; P < .0001). The median percentage of fluoroquinolone-resistant E. coli isolates was 4%, with an interquartile range of 2%–6.5% (figure 1). One hospital reported that 22% of E. coli isolates were resistant to levofloxacin.

Relationship between hospital use of fluoroquinolones and resistance. There was a significant relationship between total fluoroquinolone use in hospitals and the percentage of S. aureus isolates that were MRSA (r = 0.77; P = .0003) (figure 2). There was also a statistically significant relationship between the percentage of S. aureus isolates that were MRSA and levofloxacin use (r = 0.74; P = .0007). Associations between the percentage of S. aureus isolates that were MRSA and ciprofloxacin use were not statistically significant (r = 0.24; P = .32).

Figure 2
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Figure 2

Resistance rates in study pathogens at individual hospitals, expressed as the percentage of isolates with drug resistance, versus hospital fluoroquinolone use, expressed in defined daily doses (DDD) per 1000 patient-days, for methicillin-resistant Staphylococcus aureus (MRSA) (r = 0.77; P = .0003) and fluoroquinolone-resistant Escherichia coli (FQ-R E. coli) (r = 0.41; P = .12).

When all hospitals were included, there was not a significant relationship between total hospital fluoroquinolone use and resistance in E. coli (r = 0.41; P = .12) (figure 2). There was no significant relationship between fluoroquinolone-resistant E. coli and use of levofloxacin or ciprofloxacin in the hospital.

Relationship between community use of fluoroquinolones and resistance rates. Total fluoroquinolone use within a 16-km radius was not associated with the prevalence of MRSA in the hospital (r = 0.35; P = .18) (figure 3). In contrast, community use of levofloxacin was associated with the percentage of MRSA in the hospital (r = 0.72; P = .0011). Ciprofloxacin use did not correlate to the prevalence of MRSA in the hospital, even though ciprofloxacin was used in the community more often than was levofloxacin.

Figure 3
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Figure 3

Resistance rates in study pathogens at individual hospitals, expressed as the percentage of isolates with drug resistance, versus community fluoroquinolone use, expressed in defined daily doses (DDD) per 1000 inhabitant-days for methicillin-resistant Staphylococcus aureus (MRSA) (r = 0.35; P = .18) and fluoroquinolone-resistant Escherichia coli (FQ-R E. coli) (r = 0.68; P = .003).

For fluoroquinolone-resistant E. coli, total community fluoroquinolone use correlated with resistance (r = 0.68; P = .003) across all hospitals (figure 3). Levofloxacin use was also significantly related to resistance (r = 0.73; P = .001), whereas ciprofloxacin use was not.

Multivariate analysis. After adjusting for the effect of population density, total hospital fluoroquinolone use remained a statistically significant predictor of hospital MRSA (P = .0028). When total community fluoroquinolone use and population density were combined in multivariate regression versus fluoroquinolone-resistant E. coli, both were statistically significant predictors after adjustment (P = .045 for total fluoroquinolone use; P = .048 for population density).

Because of the high degree of correlation between population density, levofloxacin use in the hospital, and levofloxacin use in the community, multivariate regression was used to determine whether any of these variables were statistically independent predictors of resistance. After adjustment for the other variables, levofloxacin use in the community was no longer a significant predictor of the percentage of S. aureus that were MRSA (P = .07), nor was hospital levofloxacin use (P = .27) or population density (P = .93). For E. coli, none of the contributions of community levofloxacin use (P = .15), hospital levofloxacin use (P = .57), and population density (P = .53) were independently statistically significant.

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Discussion

This multihospital, observational, ecologic study reports an association between volume of use of fluoroquinolones in individual hospitals and percentages of S. aureus that are MRSA. We also observed a significant correlation between fluoroquinolone use in the surrounding community and resistance to fluoroquinolones among E. coli in hospitals. Population density in the surrounding community was related to resistance in both pathogens. Among individual fluoroquinolones, levofloxacin use appeared to be the strongest predictor of resistance, although this relationship was confounded by greater use of levofloxacin in areas with the greatest population density.

Although the spread of MRSA has primarily been thought of as an infection-control problem, studies suggest that antimicrobial use—and fluoroquinolone use, in particular—plays a significant role [7]. Fluoroquinolones have been strongly associated with MRSA acquisition in case-control studies [8–10] and in ecologic-level investigations [11]. Aside from simple selection pressure as a mechanism to explain the relationship between quinolone use and MRSA [10], in vitro studies have demonstrated that fluoroquinolones have unique effects on the expression of resistance determinants [12] and fibronectin-binding proteins [13] in MRSA. We found an association between hospital use of all fluoroquinolones and the percentage of S. aureus isolates that were methicillin resistant. We could not definitively demonstrate that this occurred solely through selection of fluoroquinolone-resistant MRSA, because we did not have information as to what percentage of MRSA were fluoroquinolone resistant. In antimicrobial surveillance studies, the vast majority of MRSA reported in hospitals have been fluoroquinolone resistant [14]. Also, there was a high degree of correlation between percentages of methicillin and fluoroquinolone resistance among all S. aureus isolates in our hospitals, suggesting that most MRSA were also fluoroquinolone resistant. Thus, greater levels of MRSA in hospitals using larger quantities of fluoroquinolones could be explained, at least partially, by selection of fluoroquinolone-resistant MRSA.

Fluoroquinolone resistance in E. coli is emerging as a significant problem both in hospitals and among outpatients [15–17]. Case-control studies have identified previous fluoroquinolone use as a risk factor for resistance in E. coli, both in the hospital [18, 19] and among community-acquired isolates [20, 21]. In our study, use of fluoroquinolones in the surrounding community had a stronger association with resistance in E. coli isolated in the hospital than did in-hospital use of fluoroquinolones. Greater exposure to fluoroquinolones in the community may increase gastrointestinal colonization with fluoroquinolone-resistant E. coli among the general population. The resultant effect would be a large reservoir of resistant organisms in the community that are detected when patients present to the hospital. Use of fluoroquinolones in the community may be more influential than their use in the hospital, because a greater percentage of E. coli isolates may be of community (rather than of hospital) origin. Although our study could not address the origin of these isolates, a previous study by Eom et al. [22] found that 73% of quinolone-resistant E. coli isolates in their university hospital originated in the community.

There was a significant relationship between population density within a 16-km radius of our study hospitals and the percentage of resistant S. aureus and E. coli reported in hospital antibiograms. Hospitals in dense urban areas may have a greater burden of seriously ill patients who are more likely to develop infections with resistant organisms. However, we did not find that case-mix index (a marker for overall severity of illness for hospitalized patients) was significantly associated with resistance in the study organisms. Another possibility is that population density influences the circulation of antimicrobial resistance in the community through a higher rate of cross-transmission among people living in close proximity. Bruinsma et al. [23] studied carriage of antibiotic-resistant E. coli and enterococci in stool samples from volunteers in 3 different cities. They found that correlations between community antimicrobial use and levels of resistance were stronger when population density was accounted for. We found that both population density and total fluoroquinolone use in the community were independent predictors of the burden of fluoroquinolone resistance in E. coli in hospitals. These findings suggest that the factors that are considered important in the spread of antimicrobial resistance in hospitalized patients (i.e., antimicrobial use and cross-transmission) may apply, as well, to the community setting.

When we investigated the effects of use of individual fluoroquinolones on resistance, we observed that resistance in both MRSA and E. coli was more closely linked to levofloxacin use than to the use of other fluoroquinolones. Of interest, the volumes of use of levofloxacin and ciprofloxacin in the surrounding communities were correlated to the use of those drugs in the hospital (e.g., when hospitals used more levofloxacin, pharmacies in the surrounding communities were more likely to dispense levofloxacin). One explanation for this phenomenon would be that formulary decisions made in the hospital may affect community prescribing; physicians that use a particular fluoroquinolone in their hospitalized patients may preferentially prescribe that drug to outpatients. Also, patients who are discharged from a hospital will likely be prescribed the hospital formulary drug, which will be reflected in community prescribing data. We also observed that community levofloxacin use was correlated to population density; areas with the greatest population tended to use more levofloxacin. It is unclear whether this represents a general trend or is unique to our sample.

The associations between population density and levofloxacin use in the community and hospital made it difficult to determine the independent effect of levofloxacin use. When controlling for population size and levofloxacin use in the hospital, a trend towards a higher percentage of MRSA in hospitals with the highest use of levofloxacin in the surrounding community remained. Although true community-associated MRSA clones are largely susceptible to fluoroquinolones [24], most MRSA infections that are associated with community onset occur in patients with health care–associated risk factors [25–28]. These organisms are often resistant to fluoroquinolone [29]. It is possible that high levels of fluoroquinolone use in the community may further amplify the prevalence of resistant strains outside of the hospital and lead to an increased MRSA burden in the hospital, resulting from the admission of infected or colonized patients. However, levofloxacin's greater in vitro potency against gram-positive organisms suggests that it would be less likely than ciprofloxacin (which has marginal activity against S. aureus) to select for resistance. Gilbert et al. [30] performed serial passage studies on S. aureus (including both methicillin-susceptible and methicillin-resistant isolates) and E. coli with levofloxacin and ciprofloxacin. They found that emergence of resistance in E. coli occurred significantly more rapidly with levofloxacin than with ciprofloxacin. However, their study also demonstrated that levofloxacin was less likely to select for resistance in S. aureus than was ciprofloxacin, which was consistent with levofloxacin's greater in vitro potency. Of interest, Bhavnani et al. [31] found that levofloxacin use was more strongly correlated to fluoroquinolone resistance in Streptococcus pneumoniae than was ciprofloxacin use (as measured by MICs) in an ecologic, multicenter study. As in the current study, fluoroquinolone use was measured in the geographic area surrounding each hospital from which the isolates were obtained, and ciprofloxacin was used more frequently than was levofloxacin. Thus, despite levofloxacin's greater in vitro activity against gram-positive organisms, epidemiologic data suggest a stronger association with resistance in these pathogens than with those treated with ciprofloxacin. These differences in the effects of individual fluoroquinolones on resistance should be further investigated.

Ecologic investigations such as this study have a number of limitations. A key limitation of this study is the inability to distinguish what percentage of the isolates that constitute the antibiograms of the participating hospitals originated in the community, as opposed to those representing hospital-acquired organisms. A priori criteria for assigning origin on the basis of time of submission of the isolate to the clinical microbiology laboratory—for example, defining nosocomial isolates as those submitted >48 h after admission—are a possible solution; however, we did not have access to this level of detailed microbiology data. Thus, the resistant isolates in our study represent both community-acquired and nosocomial isolates. It is possible that the risk factors for resistance that we identified—hospital fluoroquinolone use, community fluoroquinolone use, and population density—may have differential effects, depending on whether community-acquired or nosocomial infections are the outcome variable. A second limitation is our inability to control for differences between hospitals in their methods of reporting of duplicate isolates, which can affect reported resistance [32]. Standardization of methods to report antibiograms has been advocated by the NCCLS, but adherence is poor [33]. Another limitation includes differences in infection-control measures between hospitals, and this is a likely source of variability in the burden of resistant organisms. Our measures of antimicrobial use reflected quantity of drug dispensed, not actually consumed; measurement of consumption is difficult in a hospital environment and practically impossible in the community. Finally, the associations between antimicrobial use and resistance found in ecological studies such as ours may differ from those observed at an individual patient level, although this is of greater concern when there is a lack of an association [34].

The results of this ecologic study suggest that resistance among selected pathogens isolated in hospitals may be linked to antimicrobial use within the hospital and within the surrounding community. The design of interventions to reduce resistance among particular pathogens in the hospital should consider community antimicrobial use as well as hospital use to obtain the maximum impact.

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Acknowledgments

We thank Jim Letcavage and Annie Mahoney, for providing antimicrobial use data; Dr. Gordon Archer, for his valuable suggestions; Carol Baum (Aventis Pharmaceuticals), for providing IMS Health data; and the hospital pharmacists, infection-control practitioners, microbiologists, and physicians who participated in the Surveillance and Control of Pathogens of Epidemiologic Importance–MediMedia Information Technologies Antimicrobial Surveillance Network.

Financial support. Bayer Merck provides fellowship support to C.M.

Potential conflicts of interest. R.E.P. has received grant support from and is a member of the speaker's bureau and a consultant for Merck and Bayer. All other authors: no conflicts.

  • Received December 27, 2004.
  • Accepted April 6, 2005.
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  1. Clin Infect Dis. (2005) 41 (4): 435-440. doi: 10.1086/432056
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