Emergence of Fluoroquinolone Resistance in Outpatient Urinary Escherichia coli Isolates
Article Outline
Abstract
Background
Because of high rates of trimethoprim-sulfamethoxazole resistance in Escherichia coli, Denver Health switched to levofloxacin as the initial therapy for urinary tract infections (UTIs) in 1999. We evaluated the effects of that switch 6 years later.
Methods
Levofloxacin prescriptions per 1000 outpatient visits and levofloxacin resistance in outpatient E. coli were evaluated over time. E. coli isolated in 2005 were further characterized by specimen source and antimicrobial susceptibilities. Risk factors for levofloxacin-resistant E. coli UTI among nonpregnant adult outpatients were evaluated in a case-control study.
Results
Between 1998 and 2005, levofloxacin use increased from 3.1 to 12.7 prescriptions per 1000 visits (P
<.01) and resistance in outpatients increased from 1% to 9% (P<.01). Although prescriptions for sulfonamide antibiotics decreased by half during the same period, E. coli resistance to trimethoprim-sulfamethoxazole increased from 26.1% to 29.6%. Levofloxacin-resistant E. coli were more likely resistant to other antibiotics than levofloxacin-susceptible isolates (90% vs 43%, P<.0001). Risk factors for levofloxacin-resistant E. coli UTI were hospitalization (odds ratio for each week of hospitalization, 2.0; 95% confidence interval, 1.0-3.9) and use of levofloxacin (odds ratio, 5.6; 95% confidence interval, 2.1-27.5) within the previous year.
Conclusion
Fluoroquinolone prescriptions increased markedly after an institutional policy change for empiric treatment of UTI, and a rapid increase in fluoroquinolone resistance among outpatient E. coli followed. Risk factors for infection with resistant E. coli were recent hospitalization and levofloxacin use. Risk factors should be considered before initiating empiric treatment with a fluoroquinolone.
Keywords: Bacterial, Drug resistance, Escherichia coli, Fluoroquinolones, Risk factors, Urinary tract infection
Urinary tract infections (UTIs) are one of the most common reasons for antibiotic therapy among adults, with more than 8 million physician visits per year.1 The management of UTIs is complicated by increasing rates of resistance in Escherichia coli, the most common cause of this infection, to common oral antibiotics. Our health care system noted steadily increasing rates of resistance to trimethoprim-sulfamethoxazole among urinary tract isolates.2 In 1999, when the rate of resistance to trimethoprim-sulfamethoxazole among urinary isolates from outpatients reached 24%, we advised clinicians in our system to switch from trimethoprim-sulfamethoxazole to levofloxacin for initial treatment of UTI. That decision reflected an attempt to balance the risks of inadequate treatment of UTIs with the risks of more broad use of fluoroquinolone antibiotics. The switch to a fluoroquinolone also was consistent with national guidelines for management of UTIs, which recommended switching from trimethoprim-sulfamethoxazole if community rates of resistance exceeded 20%.3
Less than a decade after this change, we noted an appreciable increase in resistance to levofloxacin among E. coli isolates from outpatients, originating almost exclusively from urinary isolates. The goals of this study were to examine the relationships between levofloxacin use and the emergence of fluoroquinolone-resistant E. coli to identify risk factors for fluoroquinolone resistance and to consider responses to the emergence of fluoroquinolone resistance in an adult outpatient population.
Materials and Methods
Study Setting
Denver Health is a comprehensive, urban public health care system composed of a 400-bed teaching hospital with 23,000 admissions per year, emergency department and Level 1 trauma center, urgent care center, 8 community health centers, 11 school-based clinics, subspecialty clinics, and a public health department.4 Community Health Services at Denver Health manages more than 400,000 outpatient visits and serves one third of Denver's population each year. A single electronic medical record system is shared by all facilities. A large proportion of patients who access Denver Health rely on this system as their sole source of care.
Levofloxacin Prescribing Trends
Because of previous data demonstrating the completeness of the Denver Health pharmacy database for assessing prescription patterns for outpatient infections,5 we were able to use our institutional pharmacy database to accurately assess changes in antibiotic use among outpatients between January of 1998 and December of 2005. Prescriptions were classified according to antimicrobial drug class and expressed as the number of prescriptions per 1000 clinic visits. Within the fluoroquinolones class, levofloxacin prescriptions also were specifically documented.
Descriptive Epidemiology
We used the laboratory database to identify all outpatients from April of 1999 to December of 2005 who had E. coli isolated from clinically relevant specimens, including urine, cerebrospinal fluid, fluid, respiratory tract, tissue specimens, blood, and “other” clinical specimen at any outpatient setting. During this time period, bacterial cultures were obtained at the discretion of the health care provider as part of the patient's medical care. Routine urine cultures were not advocated for diagnosing acute cystitis during this time period. Among the E. coli isolates identified, E. coli reported as resistant (minimal inhibitory concentration [MIC]≥4 μg/mL) to levofloxacin were expressed as a percentage of total E. coli versus time.
A more detailed analysis was performed on the isolates obtained in the 2005 study period. Susceptibilities to common antibiotics used to treat UTIs (ampicillin, trimethoprim-sulfamethoxazole, cefazolin, gentamicin, amoxicillin-clavulanate, ceftriaxone, and nitrofurantoin) were recorded for all urine cultures growing more than 100,000 colonies per milliliter of E. coli for levofloxacin susceptible and levofloxacin-resistant isolates.
Microbiology
All microbiologic testing was performed in a central laboratory at Denver Health Medical Center. Urine specimens were plated using 1:1000 loop for quantification and incubated overnight. Susceptibility testing for urinary tract isolates was routinely performed if there were more than 100,000 colonies per milliliter and only 1 or 2 bacterial species isolated. Cultures with 3 or more bacterial species were considered contaminated. Suspected pathogens (including E. coli) were identified using a gram-negative urine combination panel (Dade International Inc, West Sacramento, Calif). Susceptibility to antimicrobials at breakpoint MIC was determined by microdilution broth testing (MicroScan; Dade International Inc, Deerfield, Ill) according to the method recommended by the Clinical and Laboratory Standards Institute.6, 7 E. coli was considered resistant to levofloxacin at MIC≥4 μg/mL; to ampicillin at MIC≥16 μg/mL; to amoxicillin-clavulanate at MIC≥16/8 μg/mL; to ceftriaxone at MIC≥16 μg/mL; to cefazolin at MIC≥16 μg/mL; to nitrofurantoin at MIC≥64 μg/mL; to gentamicin at MIC≥8 μg/mL; and to trimethoprim-sulfamethoxazole at MIC≥4/76 μg/mL.
Case-Control Study
We performed a retrospective case-control study on a subset of patients with urine cultures positive for E. coli during 2005. All adult, nonpregnant patients ages 18 to 89 years who presented to Denver Health and Hospital outpatient clinics (including emergency and urgent care clinics) during 2005 with symptoms of cystitis and who had a urine culture growing more than 100,000 colonies per milliliter of E. coli were eligible for study inclusion. Subjects with an isolate resistant to levofloxacin were identified as cases. A control group with levofloxacin susceptible isolates was matched to the cases by sex, clinic site, and age (±5 years) in a 2:1 ratio. Some individuals had E. coli isolated from more than 1 culture; only the first isolate was included in the study.
Medical record review was performed using an abstraction form to document possible risk factors for levofloxacin resistance in the previous 12 months before the urine culture. These risk factors included the number of clinically diagnosed UTIs, weeks of previous antibiotic use, previous levofloxacin use, weeks of previous hospitalization, use of urinary catheters, residence in a long-term care facility, and history of specific chronic illnesses or surgical procedure. Chronic illnesses were determined via chart abstraction of physician-documented medical history and included diabetes mellitus, renal disease, congestive heart failure, pulmonary disease, autoimmune disease, immunosuppressive therapy, liver disease, and malignancy (excluding skin). Catheter use was grouped into urinary indwelling (chronic and non-chronic), suprapubic, and intermittent. Surgical procedures were classified as urologic, gynecologic, colorectal, upper gastrointestinal/biliary, orthopedic/podiatry, cardiothoracic, ear/nose/throat, neurosurgical, dermatologic/cosmetic, or vascular. Ethnicity was self-reported by each patient during clinic registration.
Statistical Analysis
Univariate analyses were run to describe the distribution, central tendency, and variability. Bivariate and multivariate conditional logistic regression analyses were performed to compare the cases and controls. Any risk factor with a borderline significant P value (P<.10) from the bivariate analysis was a candidate for inclusion in the multivariate model. All analyses were processed in SAS version 9.1 (SAS Institute Inc, Cary, NC).
Human Subjects
The study was approved by the Colorado Multiple Institutional Review Board.
Results
Outpatient fluoroquinolone prescriptions increased from 3.8 prescriptions per 1000 outpatient visits in 1998 to 12.8 prescriptions per 1000 outpatient visits in 2005. Levofloxacin specifically increased from 3.1 to 12.7 prescriptions per 1000 outpatient visits during the same time period (P<.01). Although prescribing of other classes remained stable, prescriptions of sulfonamide antibiotics decreased from 24.0 prescriptions per 1000 outpatient visits in 1998 to 11.7 prescriptions per 1000 outpatient visits in 2005. The changes in prescribing of these 2 classes of antimicrobials first became evident in 1999 and correlated in time when institutional guidelines for initial empiric therapy for UTIs switched from trimethoprim-sulfamethoxazole to levofloxacin.
By the end of 2005, 9.4% of all E. coli isolated in the outpatient setting was found to be resistant to levofloxacin, compared with 1% in 1999 (P<.01), and parallels the observed increase in fluoroquinolone prescribing described above (Figure 1). In contrast, although prescriptions for sulfonamide antibiotics had decreased by 49% during the same time period, resistance of E. coli to trimethoprim-sulfamethoxazole remained stable to slightly increased, from 26.1% in 1999 to 29.6% by the end of 2005 (Figure 2).
Figure 1.
Levofloxacin use and outpatient Escherichia coli resistance to levofloxacin versus time.
Figure 2.
Trimethoprim-sulfamethoxazole use and outpatient E. coli resistance to trimethoprim-sulfamethoxazole versus time.
Among the 81 levofloxacin-resistant isolates identified from outpatients who had specimens submitted for microbiology in 2005, all but one originated from a urinary source—76 (93.8%) were isolated directly from urine and 5 (6.2%) were isolated from blood. Four of the 5 blood isolates were duplicate cultures from patients who also had positive urine cultures within 24 hours of the blood culture and with a phenotypically similar levofloxacin-resistant E. coli. The other levofloxacin-resistant isolate was from an undetermined source.
The case-control study population consisted of 123 adult, nonpregnant outpatients, ages 18 to 89 years. Forty-one unique patients who had levofloxacin-resistant UTI during 2005 met the criteria for inclusion as a case and were matched to 82 control patients. The study sample consisted of 102 female patients (82.9%) and 21 male patients (17.1%). The cases and controls were matched by age within 5 years and did not significantly differ (55.9 vs 55.4 years; odds ratio [OR], 1.05; 95% confidence interval [CI], 0.96-1.15). The racial distribution for cases was non-Hispanic white (27%), black (7%), Hispanic (66%), and Asian (0%), whereas the racial distribution for controls was non-Hispanic white (32%), black (15%), Hispanic (51%), and Asian (2%). These differences were not significant (P>.3 for all comparisons).
Risk factors with a borderline significant P value (P<.10) from the bivariate analysis included diabetes, congestive heart failure, any catheter use, any levofloxacin use, or any surgical procedure. In addition, the number of previous clinically diagnosed UTIs, the number of previous weeks of antibiotics, and the number of previous weeks of hospitalization also had significant relationships with levofloxacin nonsusceptible UTI (Table 1). These risk factors were considered for inclusion in the multivariate conditional logistic regression model (Table 2). Because weeks of previous antibiotic use and previous levofloxacin use were highly collinear, only previous levofloxacin (the more strongly associated in bivariate analysis) use was included in the multivariate analysis. Previous surgical procedures were dropped from the model because these also were clearly collinear with hospitalizations. With these changes, the variables that could enter the multivariate analysis were any levofloxacin use, diabetes, congestive heart failure, any catheter use, number of previous UTIs, and weeks of previous hospitalization. Only weeks of previous hospitalization (OR for each week of hospitalization, 2.0; 95% CI, 1.0-3.9, P=.4)) and use of levofloxacin (OR, 5.6; 95% CI, 2.1-27.5) within the previous year were significantly associated with a levofloxacin-resistant isolate E. coli infection.
Table 1. Bivariate Analysis of Risk Factors for Fluoroquinolone-Resistant Escherichia coli Urinary Tract Infection
| Risk Factor | Levofloxacin Resistant (n=41) | Levofloxacin Sensitive (n=82) | OR (95% CI) | P Value |
|---|---|---|---|---|
| Chronic Illnesses⁎ | ||||
| Diabetes | 21(51.2) | 26(31.7) | 2.6(1.1-6.2) | .03 |
| CHF | 5(12.2) | 2(2.4) | 4.6(0.88-23.8) | .07 |
| COPD or asthma | 4(9.8) | 7(8.5) | 1.2(0.30-4.6) | .81 |
| Autoimmune disease | 0(0.0) | 4(4.9) | — | .99 |
| Malignancy | 1(2.4) | 3(3.7) | 1.0(0.09-11.0) | 1.00 |
| Chronic liver disease | 3(7.3) | 1(1.2) | 6.0(0.62-57.7) | .12 |
| Immunosuppression therapy | 6(14.6) | 6(7.3) | 6.6(0.72-60.9) | .10 |
| Renal disease, hemodialysis independent | 2(4.9) | 1(1.2) | 3.2(0.29-36.6) | .34 |
| Renal disease, hemodialysis dependent | 0(0.0) | 1(1.2) | — | .99 |
| Levofloxacin used | 22(53.7) | 15(18.3) | 8.7(2.5-29.8) | <.001 |
| Residence in long-term care facility | 3(7.3) | 1(1.2) | 6.0(0.62-57.7) | .12 |
| Catheter used | 6(14.6) | 2(2.4) | 6.0(1.2-29.7) | .03 |
| Surgical procedure | 13(31.7) | 12(14.6) | 2.8(1.1-6.8) | .03 |
| Prior UTIs, median (IQR) | 1(0-2) | 0(0) | 3.0(1.4-6.4) | .004 |
| Previous weeks of antibiotic use, median (IQR) | 1(0-3) | 0(0-1) | 1.8(1.3-2.4) | <.001 |
| Previous weeks of hospitalization, median (IQR) | 0(0-1.5) | 0(0) | 2.0(1.2-3.5) | .01 |
⁎Data are given as number (percentage) of patients unless otherwise indicated. |
Table 2. Multivariate Conditional Logistic Regression of Risk Factors for Fluoroquinolone-Resistant Escherichia coli Urinary Tract Infection
| Risk Factor | Unadjusted OR | Adjusted OR (95% CI) | P Value |
|---|---|---|---|
| Diabetes | 2.6 | — | — |
| Congestive heart failure | 4.6 | — | — |
| Catheter used | 6.0 | — | — |
| No. of previous UTIs | 3.0 | — | — |
| Levofloxacin use | 8.7 | 7.6(2.1-27.5) | .002 |
| Previous weeks of hospitalization | 2.0 | 2.0(1.0-3.9) | .04 |
All but 2 of the 81 levofloxacin-resistant E. coli isolates were fully resistant at an MIC greater than 4. Two strains with intermediate resistance were identified with an MIC of 4 μg/mL. These levofloxacin-resistant isolates were more often resistant to other antibiotics used to treat UTIs than were levofloxacin-susceptible isolates (90% [37/41] vs 43% [36/81], P<.0001). In addition to levofloxacin, 32 of 41 isolates (78.0%) were resistant to 2 or more additional antimicrobial classes. Antibiotics retaining activity against outpatient levofloxacin-resistant E. coli urinary isolates included nitrofurantoin (95.1%), ceftriaxone (95.1%), amoxicillin-clavulanate (90.2%), gentamicin (75.6%), and cefazolin (73.2%). Only a minority of levofloxacin-resistant E. coli retained susceptibility to trimethoprim-sulfamethoxazole (34.1%) and ampicillin (22.0%) (Figure 3).
Figure 3.
Rates of susceptibility to other antimicrobial agents among levofloxacin-resistant and susceptible E. coli causing UTI, 2005.
Discussion
We examined the consequences of a system-wide change in the initial management of outpatient UTIs. The suggested change in management (from trimethoprim-sulfamethoxazole to levofloxacin) was implemented rapidly by clinicians, as shown by prompt changes in the use of these 2 classes of antibiotics. Unfortunately, this change was followed by the emergence of resistance among urinary E. coli isolates. Although antibiotic use predictably leads to resistance, we did not anticipate the pace of the emergence of resistance; in just 6 years levofloxacin resistance increased more than 5-fold. In addition, our study shows that emergence of resistance to levofloxacin among E. coli isolated in our outpatient setting has occurred almost exclusively from urinary tract sources and that levofloxacin-resistant E. coli were more likely to be resistant to other classes of antibiotics considered for treatment of UTIs.
Rapid emergence of resistance may have been fueled by the increase in the rate of levofloxacin prescribing, because risk factors for infection with a levofloxacin-resistant isolate in our adult nonpregnant outpatients included levofloxacin use and hospitalization within the preceding 12 months. It is unfortunate that the widespread, escalating use of fluoroquinolones also is a phenomenon reported by others. Even contrary to guidelines that recommend them in only select situations, the use of fluoroquinolone antibiotics for treating UTIs has been observed in nearly all settings.8, 9 Quinolone antibiotics now have surpassed sulfa antibiotics in recent years as the most commonly prescribed therapy for outpatient UTIs in women.10
Thus, it is not surprising that resistance among E. coli to fluoroquinolones also has been an increasing problem in other reports, and resistance among urinary isolates is posing treatment dilemmas. A North American survey of antimicrobial susceptibility to commonly used agents for UTIs among outpatient E. coli urinary isolates from April of 2003 to June of 2004 reported levofloxacin resistance to be 5.1%, with higher rates of resistance to all antimicrobials in US medical centers compared with Canadian centers (P<.05).11 Another study of uncomplicated UTI in older women in Israel found that crude resistance rates to ofloxacin reached 19.9% (95% CI, 13.2-26.5) among women aged 56 to 75 years.12 The phenomenon of increasing fluoroquinolone-resistant E. coli UTI also is well documented in the long-term care setting.13
Previous exposure to a quinolone class has been identified as a significant risk factor for fluoroquinolone resistance in community-acquired UTIs.14, 15, 16 Other reported risk factors have included older age,14, 16 recurrent UTI,15 underlying chronic disease,15 urinary tract abnormalities, and urinary catheterization.16 Although self-reported hospital admission within 1 year has been found to predict acquisition of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci,17 previous reports have not cited hospitalization as a risk factor for fluoroquinolone-resistant E. coli UTI in outpatients; however, others have documented the increasing rates of E. coli resistance in the inpatient setting.18 It is plausible that potential for patient-to-patient spread could provide an explanation for our findings. Fluoroquinolone resistance in hospitalized patients was reported to be more common in men than in women,19 but this risk factor along with sex and clinic site would have been impossible to determine in our series, because we matched for these variables.
In our study, urinary E. coli isolates resistant to levofloxacin also were more frequently resistant to other antimicrobials, compared with levofloxacin susceptible E. coli. Similar findings by others have reported that development of fluoroquinolone resistance in E. coli is associated with mutations that lead to increased multidrug efflux, presumably through activation of expression of the AcrAB multidrug efflux pump.20 In another report, detection of strains of E. coli producing extended-spectrum beta-lactamase enzymes was twice as common in patients who received ciprofloxacin than those who did not (15% vs 7.4%).14 It is possible that exposure to any class of antibiotic may be important, because any exposure may induce or select for bacteria carrying resistance genes to multiple classes of antibiotics.21 Indeed, in our study, previous antibiotic exposure seemed significant on the bivariate analysis, but only previous levofloxacin (the more strongly associated in bivariate analysis) use could be included in the multivariate analysis. Another striking finding in our study is the increase in rates of resistance to trimethoprim-sulfamethoxazole among E. coli isolates despite a 50% decrease in the use of sulfonamide antimicrobial agents in our health care system. The mechanisms above (multidrug resistance plasmids or multidrug efflux pumps) could explain this complete lack of reversion of resistance despite a decrease in selective pressure.
The strengths of the current study include our ability to combine data from multiple community health center sites resulting in a wide range of ages and considerable racial and ethnic diversity. Our study also has several limitations. First, we used overall antibiotic prescription patterns to judge the effect of a change in pattern of antibiotic treatment for UTIs. The temporal relationship between the policy change and the marked increase in levofloxacin use and corresponding decrease in trimethoprim-sulfamethoxazole use argues that the change was due to treatment of UTIs. Second, we did not prospectively sample patients with symptoms of a UTI to ensure that rates of resistance were not inflated by a bias to obtain cultures from patients with clinical risk factors for infection with a levofloxacin-resistant isolate. This made evaluation of uncomplicated UTI separate from complicated cases impossible, and there may be major differences in the frequency of fluoroquinolone resistance in uncomplicated UTI. However, in a previous study of trimethoprim-sulfamethoxazole resistance at Denver Health, the rate of resistance did not differ among prospectively sampled patients, compared with a retrospectively studied population.2 Third, our case-control study used the information available in the medical chart, and therefore we could not assess putative risk factors that are not reliably included in medical records, such as recent travel outside the country. Finally, we did not evaluate pregnant women and children; our interest was in those patient groups who would currently be offered treatment with fluoroquinolones as first-line therapy: nonpregnant adult outpatients.
Despite these important limitations, the implications of these findings for clinical use are significant. The rapidity of the emergence of fluoroquinolone resistance in E. coli suggests that further system-wide use would make the class unreliable for initial treatment of UTIs within a relatively short time. Loss of fluoroquinolone susceptibility in E. coli also would adversely affect the treatment of other infections caused by this organism. We interpret these findings as making a strong case for changing the initial treatment of outpatient UTIs. However, there are limited options for doing so. The continued high and increasing prevalence of trimethoprim-sulfamethoxazole resistance in isolates from our population precludes recycling that drug class. To date, published guidelines have not addressed treatment recommendations in this increasingly common setting.
In light of these data and the increasing trends of resistance noted, Denver Health and Hospital has decided to switch to nitrofurantoin as a way of providing predictably active initial treatment of adult outpatients with uncomplicated UTI, while avoiding further selection pressure from a key antibiotic class, the fluoroquinolones (Figure 4). Even in patients without risk factors for resistance, we believe nitrofurantoin is a more responsible choice for uncomplicated UTI: It has a single indication for acute cystitis, narrow tissue distribution with negligible serum concentration, narrow spectrum of activity, bactericidal activity against E. coli in urine at therapeutic doses, and limited contact with bacteria outside the urinary tract,22 which portends less potential for development of antimicrobial resistance. In addition, development of resistance to this unique class should not carry over to other classes of antimicrobials commonly used to treat more serious infection. However, the limitations of nitrofurantoin should be acknowledged. A longer course of treatment is required for cystitis (at least 5 days, rather than 3 days).23, 24, 25 In addition, nitrofurantoin should not be used empirically for acute complicated cystitis because the spectrum of uropathogens causing complicated cystitis is broader than that causing uncomplicated cystitis,26 nor should it be used for pyelonephritis because it does not achieve reliable tissue levels.22 In such cases, cause and susceptibility profile should be determined through cultures, and the presence of the risk factors identified in our study should be considered before initiating empiric treatment with a fluoroquinolone.
Figure 4.
Modified Denver Health and Hospital Guidelines for the management of UTI in nonpregnant adults.
Conclusions
A switch to a fluoroquinolone, levofloxacin, for the initial management of outpatient UTIs was followed by the rapid emergence of resistance in E. coli, the most common cause of UTIs. A corresponding decrease in trimethoprim-sulfamethoxazole use was not associated with an increase in susceptibility to that drug; resistance actually trended toward increase. Previous levofloxacin use and weeks of hospitalization in the previous 12 months were identified as risk factors for levofloxacin resistance. These factors suggest a need to change the initial management of UTIs. Future studies should focus on efforts to curtail the increase of antibiotic resistance rates and to evaluate alternative empiric antimicrobial regimens for treating UTIs.
Acknowledgments
We are grateful to the Denver Health and Hospital microbiology laboratory for assistance in compiling the microbiology data, particularly Mark Tarletsky, MT, for laboratory information technology expertise; to Deborah Anderson, PharmD, for sharing expertise on the problem of antimicrobial resistance in UTIs; and to the Adult Urgent Care Clinic and Emergency Department staff for practical insights on treatment and management issues of UTI in the outpatient setting.
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- Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women (Infectious Diseases Society of America (IDSA)). Clin Infect Dis. 1999;29:745–758
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Financial Disclosures: none.
PII: S0002-9343(08)00606-2
doi:10.1016/j.amjmed.2008.04.039
© 2008 Elsevier Inc. All rights reserved.
