Does Asymptomatic Bacteriuria Predict Mortality and Does Antimicrobial Treatment Reduce Mortality in Elderly Ambulatory Women?

Asymptomatic bacteriuria, a common problem of the elderly, has been associated with increased mortality in the elderly [1-4], although not all studies have confirmed this finding [5-9]. To reconcile these conflicting results, we did a longitudinal study of urinary tract infection in ambulatory elderly women to evaluate the putative relation between asymptomatic bacteriuria and mortality. We considered resolution of this issue to be important because of the implications for clinical practice. If asymptomatic bacteriuria were shown to be an independent risk factor for mortality and if it could also be shown that eradication of the infection by antimicrobial therapy decreased the risk for death, then screening and antimicrobial treatment of elderly ambulatory women with asymptomatic bacteriuria might be warranted and the cost of identifying and treating such infections might be justified. Conversely, failure to confirm a relation would support the view that programs to screen for bacteriuria would not be justified if their goal was to enhance survival. This report summarizes the findings of our 9-year study to determine whether asymptomatic bacteriuria in elderly ambulatory women is a marker of increased mortality and, if so, whether it is because of an association with other determinants of mortality or because asymptomatic bacteriuria is itself an independent cause, the removal of which might improve longevity. The components of the study were a longitudinal study in elderly ambulatory women to compare mortality in those with and without asymptomatic bacteriuria and a double-blind, controlled clinical trial in which antimicrobial therapy was administered for asymptomatic bacteriuria to assess whether treatment decreases mortality. Methods Participant enrollment and the participating institutions have been described previously [10, 11]. Elderly ambulatory residents of the Philadelphia Geriatric Center and of 21 continuing care retirement communities in the greater Philadelphia metropolitan area who gave informed consent were enrolled in this long-term study of urinary tract infection in the elderly. Enrollment continued throughout the course of the study. Philadelphia Geriatric Center houses about 1000 residents who primarily are Jewish; incomes are higher than the maximum Social Security payment; and congregate living is provided either in an apartment house or in a nursing home. In contrast, the continuing care retirement communities are smaller (bed size range, 108 to 675); incomes are higher; residents are primarily not Jewish; and a higher proportion of residents are fully independent. All female residents were eligible to participate except those with indwelling catheters or those incapable of providing midstream clean-catch urine specimens for culture. Specimens were obtained on enrollment and every 6 months thereafter. The protocol was approved by the appropriate institutional review boards, and informed consent was obtained from the participants or their surrogates. Table 1 shows the study periods and chronology of important study events. Throughout the study, urine cultures were obtained at about 6-month intervals. An observational study to compare mortality of bacteriuric and nonbacteriuric volunteers regardless of treatment status was begun in January 1983 and ended in February 1992. Initially, residents with asymptomatic bacteriuria were identified and followed, but treatment was not given. However, on 10 October 1983, a controlled clinical trial was begun to evaluate whether antimicrobial therapy for asymptomatic bacteriuria decreased mortality; every bacteriuric study participant identified after this date was enrolled in the trial. Mortality among residents who were treated with antimicrobial agents for asymptomatic bacteriuria each time it was present was compared with the mortality of those who received no therapy for their episodes of bacteriuria. At enrollment, participants were assigned to the treatment group or to the control group based on the last digit of an identification number unrelated to the conduct of the study. Urine cultures were read by personnel blinded to the study group assignment. When asymptomatic bacteriuria was identified, participants with even numbers were given antimicrobial therapy according to a defined protocol (see below); those with odd numbers served as controls. From 10 October 1983 to 10 December 1987, controls were given no therapy. Thereafter, on the advice of external consultants, the protocol was changed so that participants not assigned to the active treatment group were given placebo pills in place of no treatment. The placebo pills were identical in appearance to each of the antimicrobial agents used. Thus, after 10 December 1987, volunteers with asymptomatic bacteriuria were given therapy in either the form of antimicrobics or placebo after a new consent was obtained; the volunteers and clinical personnel did not know study group assignments. Table 1. Study Design and Enrollment The methods for collecting first-morning urine and for processing the specimens in our research microbiology laboratory have been previously described [10, 11]. Participants were considered to have asymptomatic bacteriuria on a survey if two urine specimens were culture-positive (105 colony-forming units or more per mL of urine) for the same organism within 2 weeks. From 10 October 1983 through 10 December 1987, residents with asymptomatic bacteriuria who were assigned to receive antimicrobial treatment were given short-course therapy (single dose or 3 days) as follows: trimethoprim, 200 mg in one dose; trimethoprim-sulfamethoxazole, 1 double-strength tablet; cefaclor, 500 mg three times a day for 3 days; amoxicillin, 250 mg three times a day for 3 days; carbenicillin indanyl sodium, four times a day for 3 days; or macrodantin, 100 mg twice a day for 3 days, depending on susceptibility of the infecting organism and history of drug allergy. Participants were considered cured if test-of-cure cultures contained less than 104 colony-forming units/mL of the infecting organism on cultures obtained 5 to 10 days after antimicrobial treatment or placebo or on cultures obtained on the next survey in those receiving no therapy. When positive for the same organism, patients were retreated for 14 days with test-of-cure culture afterward. If the organism differed, reinfection was diagnosed and a single dose or 3-day therapy was used; treatment failures were treated as defined above. Test-of-cure cultures were obtained again after therapy and, if positive for the same organism, participants were treated for 14 days. No treatment was given after failure of a 14-day course or two reinfections after short courses. Controls received no therapy during this period. After 10 December 1987, culture-positive patients were assigned to antimicrobial treatment or placebo. Single-dose therapy was given with trimethoprim, 200 mg, or norfloxacin, 400 mg, depending on the susceptibility of the organism; the same drugs (trimethoprim, 100 mg twice daily, and norfloxacin, 400 mg twice daily) were used for 14 days of therapy in patients failing single-dose therapy. Single-dose therapy was used for reinfection. The placebo pills and regimen given to a placebo recipient matched the regimen administered to the participant in the active treatment group who was treated most recently (for example, if the active treatment participant received short-course trimethoprim followed by 14 days of trimethoprim, the next placebo participant received short-course trimethoprim placebo followed by 14 days of trimethoprim placebo). Symptomatic infections were managed by the participant's personal physician or by physicians associated with the facility in which the patient lived. Reports were received on an annual or semiannual basis from the participating institutions that detailed changes in their census. All deaths were noted, and registry coordinators reviewed available documents to confirm each death. After 1 September 1987, detailed functional and mental status assessments were done when persons were newly enrolled into the study or were seen for an annual follow-up visit using techniques previously described [11, 12]. Self-care activities of daily living were assessed by a modification of the Multilevel Assessment Instrument [13], and mental status was assessed using a modified version of the Kahn and Goldfarb questionnaire [14]. A subjective measure of global health status (scale, 1 to 4) was based on responses to the question: How do you rate your health: excellent (score 1), good, fair, and bad or poor (score 4)? Diagnoses recorded in the person's medical record were extracted and provided a more objective measure of health status; they were coded according to the ICD-9-CM three-digit codes [15]. The Geriatric Depression Scale [16] was used to assess depressive symptoms, and walking ability was assessed on a scale of 1 (specialized help needed) to 3 (help not needed) [11]. Statistical Analysis Observational Study These analyses compared residents with asymptomatic bacteriuria with residents who did not have asymptomatic bacteriuria on any of the urine culture surveys done during the period of their participation. For the purposes of the survival analyses in the observational study, the results of urine cultures were considered a time-dependent covariate. Accordingly, participants were considered in the ever-positive group once asymptomatic bacteriuria was identified, and all subsequent time on study was contributed to the group with positive cultures regardless of urine culture results on subsequent surveys. Persons entering the study with a negative urine culture were considered in the never-positive group until asymptomatic bacteriuria was identified. Thus, a person who entered the study with negative cultures and who later became culture-positive would have contributed person-time to the follow-up of those in the categ