Delia Scholes

A prospective study of risk factors for symptomatic urinary tract infection in young women.

BACKGROUND Although acute urinary tract infections are common in young women, the associated risk factors have not been defined prospectively. METHODS We recruited sexually active young women who were starting a new method of contraception at a university health center or a health maintenance organization (HMO) and monitored them for six months for symptomatic urinary tract infections. Daily diaries and serial interviews were used to collect data on potential risk factors. RESULTS Among 796 women, the incidence of urinary tract infections per person-year was 0.7 in the university cohort (mean age, 23 years; n = 348) and 0.5 in the HMO cohort (mean age, 29; n = 448). In both cohorts, there were strong dose-response relations between the risk of infection and both recent use of a diaphragm with spermicide (respective relative risks for one, three, and five days of use in the past week, 1.42, 2.83, and 5.68 in the university cohort, P<0.001; and 1.29, 2.14, and 3.54 in the HMO cohort, P=0.04) and recent sexual intercourse (respective relative risks for one, three, and five days with intercourse in the past week, 1.37, 2.56, and 4.81 in the university cohort, P<0.001; and 1.24, 1.91, and 2.96 in the HMO cohort, P=0.002). The risk of acute infection was also associated with a history of recurrent infection (relative risk, 5.58 in the university group and 2.10 in the HMO group) but not with cervical-cap use, ABO-blood-group nonsecretor phenotype, or delayed postcoital voiding. CONCLUSIONS Among sexually active young women the incidence of symptomatic urinary tract infection is high, and the risk is strongly and independently associated with recent sexual intercourse, recent use of a diaphragm with spermicide, and a history of recurrent urinary tract infections.

Risk Factors for Recurrent Urinary Tract Infection in Young Women

To define host factors associated with an increased risk of recurrent urinary tract infection (RUTI), a case-control study was conducted in 2 populations: university women and health maintenance organization enrollees. Case patients were 229 women 18-30 years old with RUTIs; control subjects were 253 randomly selected women with no RUTI history. In a multivariate model, independent risk factors for RUTI included recent 1-month intercourse frequency (odds ratio [OR], 5.8; 95% confidence interval [CI], 3.1-10.6 for 4-8 episodes), 12-month spermicide use (OR, 1.8; 95% CI, 1.1-2.9), and new sex partner during the past year (OR, 1.9; 95% CI, 1.2-3.2). Two newly identified risk factors were age at first urinary tract infection (UTI) </=15 years (OR, 3.9; 95% CI, 1.9-8.0) and UTI history in the mother (OR, 2.3; 95% CI, 1.5-3.7). Blood group and secretor phenotype were not associated with RUTI. In young women, risk factors for sporadic UTI are also risk factors for recurrence. Two predictors suggest that genetic/long-term environmental exposures also predispose to RUTI.

A Prospective Study of Asymptomatic Bacteriuria in Sexually Active Young Women

BACKGROUND Asymptomatic bacteriuria is common in young women, but little is known about its pathogenesis, natural history, risk factors, and temporal association with symptomatic urinary tract infection. METHODS We prospectively evaluated 796 sexually active, nonpregnant women from 18 through 40 years of age over a period of six months for the occurrence of asymptomatic bacteriuria (defined as at least 10(5) colony-forming units of urinary tract pathogens per milliliter). The women were patients at either a university student health center or a health maintenance organization. Periodic urine cultures were taken, daily diaries were kept, and regularly scheduled interviews were performed. Escherichia coli strains were tested for hemolysin, the papG genotype, and the ribosomal RNA type. RESULTS The prevalence of asymptomatic bacteriuria (the proportion of urine cultures with bacteriuria in asymptomatic women) was 5 percent (95 percent confidence interval, 4 percent to 6 percent) among women in the university group and 6 percent (95 percent confidence interval, 5 percent to 8 percent) among women in the health-maintenance-organization group. Persistent asymptomatic bacteriuria with the same E. coli strain was rare. Symptomatic urinary tract infection developed within one week after 8 percent of occasions on which a culture showed asymptomatic bacteriuria, as compared with 1 percent of occasions when asymptomatic bacteriuria was not found (P<0.001). Asymptomatic bacteriuria was associated with the same risk factors as for symptomatic urinary tract infection, particularly the use of a diaphragm plus spermicide and sexual intercourse. CONCLUSIONS Asymptomatic bacteriuria in young women is common but rarely persists. It is a strong predictor of subsequent symptomatic urinary tract infection.

The Epidemic of Extended-Spectrum-β-Lactamase-Producing Escherichia coli ST131 Is Driven by a Single Highly Pathogenic Subclone, H30-Rx

ABSTRACT The Escherichia coli sequence type 131 (ST131) clone is notorious for extraintestinal infections, fluoroquinolone resistance, and extended-spectrum beta-lactamase (ESBL) production, attributable to a CTX-M-15-encoding mobile element. Here, we applied pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing to reconstruct the evolutionary history of the ST131 clone. PFGE-based cluster analyses suggested that both fluoroquinolone resistance and ESBL production had been acquired by multiple ST131 sublineages through independent genetic events. In contrast, the more robust whole-genome-sequence-based phylogenomic analysis revealed that fluoroquinolone resistance was confined almost entirely to a single, rapidly expanding ST131 subclone, designated H30-R. Strikingly, 91% of the CTX-M-15-producing isolates also belonged to a single, well-defined clade nested within H30-R, which was named H30-Rx due to its more extensive resistance. Despite its tight clonal relationship with H30Rx, the CTX-M-15 mobile element was inserted variably in plasmid and chromosomal locations within the H30-Rx genome. Screening of a large collection of recent clinical E. coli isolates both confirmed the global clonal expansion of H30-Rx and revealed its disproportionate association with sepsis (relative risk, 7.5; P < 0.001). Together, these results suggest that the high prevalence of CTX-M-15 production among ST131 isolates is due primarily to the expansion of a single, highly virulent subclone, H30-Rx. IMPORTANCE We applied an advanced genomic approach to study the recent evolutionary history of one of the most important Escherichia coli strains in circulation today. This strain, called sequence type 131 (ST131), causes multidrug-resistant bladder, kidney, and bloodstream infections around the world. The rising prevalence of antibiotic resistance in E. coli is making these infections more difficult to treat and is leading to increased mortality. Past studies suggested that many different ST131 strains gained resistance to extended-spectrum cephalosporins independently. In contrast, our research indicates that most extended-spectrum-cephalosporin-resistant ST131 strains belong to a single highly pathogenic subclone, called H30-Rx. The clonal nature of H30-Rx may provide opportunities for vaccine or transmission prevention-based control strategies, which could gain importance as H30-Rx and other extraintestinal pathogenic E. coli subclones become resistant to our best antibiotics. We applied an advanced genomic approach to study the recent evolutionary history of one of the most important Escherichia coli strains in circulation today. This strain, called sequence type 131 (ST131), causes multidrug-resistant bladder, kidney, and bloodstream infections around the world. The rising prevalence of antibiotic resistance in E. coli is making these infections more difficult to treat and is leading to increased mortality. Past studies suggested that many different ST131 strains gained resistance to extended-spectrum cephalosporins independently. In contrast, our research indicates that most extended-spectrum-cephalosporin-resistant ST131 strains belong to a single highly pathogenic subclone, called H30-Rx. The clonal nature of H30-Rx may provide opportunities for vaccine or transmission prevention-based control strategies, which could gain importance as H30-Rx and other extraintestinal pathogenic E. coli subclones become resistant to our best antibiotics.

Abrupt Emergence of a Single Dominant Multidrug-Resistant Strain of Escherichia coli

BACKGROUND Fluoroquinolone-resistant Escherichia coli are increasingly prevalent. Their clonal origins--potentially critical for control efforts--remain undefined. METHODS Antimicrobial resistance profiles and fine clonal structure were determined for 236 diverse-source historical (1967-2009) E. coli isolates representing sequence type ST131 and 853 recent (2010-2011) consecutive E. coli isolates from 5 clinical laboratories in Seattle, Washington, and Minneapolis, Minnesota. Clonal structure was resolved based on fimH sequence (fimbrial adhesin gene: H subclone assignments), multilocus sequence typing, gyrA and parC sequence (fluoroquinolone resistance-determining loci), and pulsed-field gel electrophoresis. RESULTS Of the recent fluoroquinolone-resistant clinical isolates, 52% represented a single ST131 subclonal lineage, H30, which expanded abruptly after 2000. This subclone had a unique and conserved gyrA/parC allele combination, supporting its tight clonality. Unlike other ST131 subclones, H30 was significantly associated with fluoroquinolone resistance and was the most prevalent subclone among current E. coli clinical isolates, overall (10.4%) and within every resistance category (11%-52%). CONCLUSIONS Most current fluoroquinolone-resistant E. coli clinical isolates, and the largest share of multidrug-resistant isolates, represent a highly clonal subgroup that likely originated from a single rapidly expanded and disseminated ST131 strain. Focused attention to this strain will be required to control the fluoroquinolone and multidrug-resistant E. coli epidemic.

Risk factors associated with acute pyelonephritis in healthy women.

Context Little information is available about risk factors for pyelonephritis among healthy, community-dwelling women. Contribution In a population-based casecontrol study of women with pyelonephritis 18 to 49 years of age, intercourse history variables, including frequency, new sexual partners, and spermicide use, were strongly associated with pyelonephritis. Personal and family histories of urinary tract infection, presence of diabetes, and stress incontinence were also associated with pylonephritis on multivariable analysis. Escherichia coli was the predominant infecting organism. Implications Risk factors for pyelonephritis were similar to those for acute and recurrent cystitis and asymptomatic bacteriuria, supporting the concept that pyelonephritis is usually caused by the ascent of organisms from the bladder. The Editors Acute pyelonephritis, a potentially severe infection of the upper urinary tract, is estimated to account for more than 250000 office consultations with physicians and nearly 200000 hospital admissions annually in the United States (1, 2). The vast majority of these infections occur in women, and most of these women are treated in ambulatory care settings (3). While numerous studies have evaluated factors predisposing to acute cystitis, most studies of pyelonephritis have been treatment studies or descriptive studies that focused on hospitalized patients (3-6). To date, pyelonephritis in community-dwelling, healthy adults has not been extensively investigated, and, to our knowledge, risk factors have not been evaluated. We thus undertook a population-based, casecontrol study to increase our understanding of the epidemiology of acute pyelonephritis in adult women 18 to 49 years of age. Specifically, we evaluated whether the risk factors that predispose women to acute cystitis also predispose them to pyelonephritis and whether additional exposures are associated with upper urinary tract infection. The estimated incidence of infection and, among case-patients, the infecting organisms and their antimicrobial susceptibility profiles were also of interest. Methods Study Setting and Participants We performed our study at Group Health Cooperative, Seattle, Washington, a mixed-model health maintenance organization. During study recruitment (April 2000 to October 2001), approximately 87000 of 475000 enrollees in Group Health Cooperative were women between 18 and 49 years of age (our target population). Group Health Cooperatives Human Subjects Committee reviewed and approved all study procedures. We selected potential cases of pyelonephritis by using the health plans computerized enrollment, ambulatory care, inpatient, and laboratory databases. Each month we selected all women 18 to 49 years of age who had received a diagnosis of acute pyelonephritis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], codes 590.1 [acute pyelonephritis, without lesion of renal medullary necrosis], 590.11 [acute pyelonephritis, with lesion of renal medullary necrosis], or 590.8 [pyelonephritis, unspecified]) and who had a positive urine culture (103 colonies of a urinary pathogen, as previously defined [7]). Because laboratory data were not available for some inpatients who were treated in affiliate hospitals, we also selected any additional inpatients with acute pyelonephritis as their primary reason for hospitalization. We reviewed 58 randomly chosen medical records of cases selected in this manner and found that 57 (98%) patients had a diagnosis of pyelonephritis, defined as a diagnosis of pyelonephritis recorded in the chart, at least 1 symptom or sign of pyelonephritis (fever, chills, severe back or flank pain, nausea or vomiting, or costovertebral angle tenderness), and antibiotic treatment consistent with pyelonephritis. Most reviewed patients also had other symptoms of urinary tract infection (UTI). We selected potential controls concurrently each month by sampling randomly from age-eligible women in Group Health Cooperative enrollment files; controls were frequency-matched to the case-patients by 5-year age groups. We sent potential participants a letter that described the study and invited them to participate in a telephone interview. Interviewers began calling 1 week thereafter. During telephone screening, we excluded women who were pregnant within 12 months of the reference date (the diagnosis date for case-patients and the midpoint of the sampling month for controls), who had ever received kidney dialysis, who had had problems with their bladder or kidneys that required surgery (such as urogenic bladder or reflux) or kidney stones that did not pass or were not removed before the reference date, or who were nonambulatory at the reference date. We excluded potential control participants who reported a diagnosis of pyelonephritis within 5 years of the reference date. We identified 386 potential case-patients during recruitment, 54 (14%) of whom were not eligible. Of the remaining 332 women, 242 (73%) agreed to participate and were interviewed, 46 (14%) declined to participate, and 44 (13%) could not be contacted. Of the 242 case-patients, 18 (7.4%) were hospitalized. We randomly selected 960 similar-age women from the enrollment database as potential controls, 109 (11%) of whom were ineligible. Of the 851 women remaining, 546 (64%) were interviewed, 163 (19%) declined, and 142 (17%) could not be contacted. Data Collection After providing oral consent, participants received a 15- to 25-minute structured interview that was conducted by using computer-assisted telephone interviewing software (Raosoft, Inc., Seattle, Washington), which allowed all responses to be entered directly into a computer database. We programmed item wording, skip patterns, and range checks into the instrument to minimize errors and standardize administration. We pretested the instrument for length, flow, and comprehension. After training in the study instrument (interviewers were already experienced in epidemiologic interviewing), the project manager monitored interviewers for accuracy and completeness during initial fielding by an audit telephone line and continued periodic monitoring throughout the study. The interview included items on demographic characteristics, sexual behavior, contraceptive practices, genitourinary infection history, history of other medical conditions, and other behaviors (contraceptive practices, personal and family genitourinary infection history, history of other health conditions, and other health habits). We also asked case-patients about signs and symptoms close to their index pyelonephritis episode and collected data on infecting organism and antimicrobial susceptibility from Group Health Cooperative automated laboratory files. Statistical Analysis We characterized the study group on selected variables of interest by casecontrol status, further characterizing the case group by symptoms and infecting organisms. We assessed data on potential risk factors of interest for their univariate association with the study outcome, pyelonephritis, by calculating odds ratios and 95% CIs. We developed multivariable logistic regression models to identify independent risk factors for pyelonephritis from univariately associated exposures and to evaluate their relative contributions. We considered variables for the models by incorporating exposures that were important in earlier studies of cystitis in this or similar populations and, in addition, considered other variables that seemed to be associated with pyelonephritis in our data set. When several variables were highly correlated, principally sexual activity and UTI history variables, we selected 1 variable for inclusion in the model. Substitution of other related variables into the final model did not substantially alter the results. We also examined how the risk factors in the final model for the entire study group performed in selected subgroups of interest: 2 age subgroups (age 30 years and age > 30 years), women who reported no previous UTI history, and inpatients. Because we selected this study group from a defined population, an estimated incidence of pyelonephritis may be derived with some assumptions. We determined the numerator (the estimated number of case-patients) by applying the proportion of women eligible among the contacted and screened case-patients (242 of 296 participants [81.8%]) to the remaining potential case-patients (participants who declined or could not be contacted [n= 90]), which yielded an estimated total number of 316 case-patients over the 19-month sampling interval. To estimate the denominator (the number of at-risk enrollees), we identified the total number of age-eligible women enrolled at the midpoint of recruitment (n= 86738) and applied the proportion of women eligible among participating controls (546 of 655 participants [83.4%]) to this estimate, which yielded an estimated 72306 women who were eligible and at risk for pyelonephritis. We expressed the estimated rate (number of cases/at-risk women) as an annual incidence rate. Role of the Funding Source The National Institute of Diabetes and Digestive and Kidney Diseases provided financial support for this study. The agency had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Study Sample Characteristics Case-patients and controls were similar with respect to age and ethnicity (Table 1). Case-patients were likely to be less educated, to report an annual household income less than

Injectable hormone contraception and Bone density: Results from a prospective study

40000, to have a history of UTI, and to report being in fair or poor health. Case-patients who were hospitalized (n= 18) were similar in age to the larger case-patient group but were less likely to be white (61% vs. 80%, respectively) (data not shown). The estimated annual incidence of pyelonephritis was 27.6 cases per 10000 persons: (316/72306)/19 months 12 months 10000 = 27.6 cases per

Population-Based Epidemiologic Analysis of Acute Pyelonephritis

Background Depot medroxyprogesterone acetate (DMPA) injectable contraception may decrease bone density and increase the risk for osteoporosis in later life. Prospective data are scarce, especially of the effects of DMPA discontinuation on bone. Methods Between 1994 and 1999, we conducted a population-based prospective cohort study among women enrollees of a Washington State health maintenance organization. We enrolled 457 nonpregnant women, ages 18–39 years (183 DMPA users and 274 non-users). Bone density was measured by dual-energy x-ray absorptiometry every 6 months for 3 years. Results Bone density decreased notably among DMPA-exposed women at the spine (adjusted mean bone density was −0.0053 gm/cm2 for DMPA users compared with +0.0023 gm/cm2 for non-users for each 6-month interval) and total hip (−0.0060 compared with −0.0002 gm/cm2). This represents an annualized mean rate of change at the spine of −0.87% compared with +0.40% and, at the hip, −1.12% compared with −0.05%. Discontinuers of this method (N = 110) showed sizable increases in bone density over comparison women (for each 6-month interval, adjusted mean spine bone density was +0.0067 gm/cm2 compared with +0.0023 gm/cm2, respectively; adjusted mean hip bone density was +0.0035 compared with −0.0002 gm/cm2). Estimated annualized mean rates of change were +1.41% compared with +1.03% at the spine and +0.40% compared with −0.05% at the hip. After 30 months, mean bone density for discontinuers was similar to that of non-users. Conclusions In this study, DMPA use was strongly associated with bone density loss. Substantial postdiscontinuation recovery of bone provides evidence that the effects may be largely reversible.

Bone mineral density in women using depot medroxyprogesterone acetate for contraception

BACKGROUND Acute pyelonephritis is a potentially severe disease for which there are few population-based studies. We performed a population-based analysis of trends in the incidence, microbial etiology, antimicrobial resistance, and antimicrobial therapy of outpatient and inpatient pyelonephritis. METHODS A total of 4887 enrollees of Group Health Cooperative, based in Seattle, Washington, who received an International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis of acute pyelonephritis from 1997 through 2001 were identified using computerized records. Diagnoses were linked to urine culture and antibiotic prescription data. Case patients (n=3236) included subjects who had received an inpatient or culture-confirmed outpatient diagnosis of acute pyelonephritis. RESULTS Among the female population, annual rates of outpatient and inpatient pyelonephritis were 12-13 cases per 10,000 population and 3-4 cases per 10,000 population, respectively; among the male population, the rates were 2-3 cases per 10,000 population and 1-2 cases per 10,000 population, respectively. Rates were relatively stable from year to year. Incidence was highest among young women, followed by infants and the elderly population. The ratio of outpatient to inpatient cases was highest among young women (ranging from 5 : 1 to 6 : 1). Escherichia coli caused 80% of cases of acute pyelonephritis in women and 70% of cases in men and was less dominant in older age groups. Among E. coli strains, the rate of ciprofloxacin resistance increased from 0.2% of isolates to 1.5% of isolates (P=.03), and the rate of trimethoprim-sulfamethoxazole resistance decreased from 25% of isolates to 13% of isolates (P<.01) from 1997 to 2001. Among outpatient cases, the rate of fluoroquinolone use increased from 35% to 61%, whereas the rate of trimethoprim-sulfamethoxazole use decreased from 53% to 32% over the 5-year period (P<.01). CONCLUSIONS This comprehensive, population-based analysis adds to our limited knowledge of the epidemiology of acute pyelonephritis, especially among outpatients, in whom the majority of cases now occur.

Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women.

OBJECTIVE To evaluate the possible effects of depot medroxyprogesterone acetate injectable contraception on bone mineral density in reproductive-age women. METHODS We conducted a population-based cross-sectional comparison of bone mineral density levels in women using depot medroxyprogesterone acetate contraception and in women of similar age not using this method. The study recruited 457 nonpregnant women aged 18-39 years who were enrollees of a Washington state health maintenance organization. One hundred eighty-three women were receiving injections and 274 were not. Bone mineral density at several anatomic sites (spine, femoral neck, greater trochanter, and whole body) was measured using dual-energy x-ray absorptiometry. Data on other factors potentially related to bone density were collected through questionnaire and examination. RESULTS Overall, age-adjusted mean bone density levels were lower for users of this method than for nonusers at all anatomic sites: The mean difference was 2.5% for the spine (P = .03) and 2.2% for the femoral neck (P = .12). Exposure to depot medroxyprogesterone acetate continued to be significantly (P < .01) associated with decreased bone density at the femoral neck, spine, and trochanter after multivariate adjustment for other risk factors related to bone density. Age-specific comparisons indicated that the major differences in bone density between users and nonusers occurred in the youngest age group (women 18-21 years); the mean femoral neck bone density was 10.5% lower (P < .01) for the exposed women, and differences were consistent (P < .01) across all anatomic sites. We also noted a significant dose-response relation between longer use of depot medroxyprogesterone acetate and decreased bone density levels in this age group (P < .01 for all sites). CONCLUSION These results provide evidence that contraception with depot medroxyprogesterone acetate, particularly long-term use, may adversely affect bone mineral density levels in young women aged 18-21 years. The implications for future bone health need further study.