Biomedical subjects
Publications and source records attributed to Thomas M Hooton.
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Nearly 50% of women experience at least one urinary tract infection (UTI) in their lifetime. Studies with mice have revealed that uropathogenic Escherichia coli (UPEC) isolates invade superficial umbrella cells that line the bladder, allowing them to find a safe haven and subvert clearance by innate host responses. Rapid intracellular replication results in the formation of distinctive intracellular bacterial communities (IBCs). In this study, we evaluated whether UPEC strains cultured from the urine of women and classified as causing acute cystitis, recurrent cystitis, asymptomatic bacteriuria, or pyelonephritis could progress through the IBC cascade in a well-characterized mouse model of cystitis. Of 18 UPEC isolates collected from women, 15 formed IBCs. Variations in the size, number, and kinetics of IBC formation were observed with strains isolated from women with different clinical syndromes. Two of the three isolates that did not form IBCs when inoculated alone were able to do so when coinoculated with an isolate that was capable of generating IBCs. The mixed infections dramatically altered the behavior of the coinfecting bacteria relative to their behavior in a single infection. The study also showed that mice with five different genetic backgrounds can support IBC formation. Although UPEC isolates differ genetically in their virulence factors, the majority of UPEC isolates from different types of UTI proceed through the IBC pathway, confirming the generality of IBCs in UTI pathogenesis in mice.
A common dilemma in clinical medicine is whether to treat asymptomatic patients who present with bacteria in their urine. There are few scenarios in which antibiotic treatment of asymptomatic bacteruria has been shown to improve patient outcomes. Because of increasing antimicrobial resistance, it is important not to treat patients with asymptomatic bacteriuria unless there is evidence of potential benefit. Women who are pregnant should be screened for asymptomatic bacteriuria in the first trimester and treated, if positive. Treating asymptomatic bacteriuria in patients with diabetes, older persons, patients with or without indwelling catheters, or patients with spinal cord injuries has not been found to improve outcomes.
Escherichia coli is a model laboratory bacterium, a species that is widely distributed in the environment, as well as a mutualist and pathogen in its human hosts. As such, E. coli represents an attractive organism to study how environment impacts microbial genome structure and function. Uropathogenic E. coli (UPEC) must adapt to life in several microbial communities in the human body, and has a complex life cycle in the bladder when it causes acute or recurrent urinary tract infection (UTI). Several studies designed to identify virulence factors have focused on genes that are uniquely represented in UPEC strains, whereas the role of genes that are common to all E. coli has received much less attention. Here we describe the complete 5,065,741-bp genome sequence of a UPEC strain recovered from a patient with an acute bladder infection and compare it with six other finished E. coli genome sequences. We searched 3,470 ortholog sets for genes that are under positive selection only in UPEC strains. Our maximum likelihood-based analysis yielded 29 genes involved in various aspects of cell surface structure, DNA metabolism, nutrient acquisition, and UTI. These results were validated by resequencing a subset of the 29 genes in a panel of 50 urinary, periurethral, and rectal E. coli isolates from patients with UTI. These studies outline a computational approach that may be broadly applicable for studying strain-specific adaptation and pathogenesis in other bacteria.
OBJECTIVE: To investigate genital tract sources of HIV-1, we conducted extensive genitourinary sampling of 23 seropositive men without urethritis who shed HIV in their seminal plasma. DESIGN: Semen was collected, then samples were obtained for HIV RNA in blood plasma, urethral fluid, pre-prostate massage fluid/urine (PMF/U) and post-PMF/U, and expressed prostatic secretions. Systematic transrectal ultrasound-guided prostate biopsies obtained from multiple prostate areas were evaluated for HIV RNA and DNA. RESULTS: Seminal HIV RNA levels correlated with HIV RNA levels in urethral fluid and post-PMF/U and with prostate biopsies HIV DNA, but not with expressed prostatic secretions HIV RNA. However, only the HIV RNA level in post-PMF/U independently predicted that in semen (2.77-fold change in semen for each 10-fold change in post-PMF/U; 95% confidence interval, 1.0-7.7) accounting for one third of the seminal HIV RNA level variation, irrespective of adjustment for antiretroviral therapy. CONCLUSIONS: These data indicate that distal genitourinary sources other than the prostate appear to be the major source of seminal HIV in men without clinical urethritis or prostatitis. Because the HIV RNA level in blood plasma is not reliable as an independent clinical predictor of virus levels in seminal plasma, these findings also extend the concept that the male genital tract is a distinct virological compartment from blood.
OBJECTIVES: Given increasing rates of co-trimoxazole resistance among uropathogens causing acute uncomplicated cystitis, fluoroquinolones, nitrofurantoin and fosfomycin are often considered as alternative empirical therapy. The choice between these drugs should depend in part on whether they are associated with the isolation of drug-resistant microbial flora. We conducted a randomized treatment trial to assess the effects of ciprofloxacin, nitrofurantoin and fosfomycin on the rectal microbial flora of women with acute uncomplicated cystitis, including isolation of fluoroquinolone-resistant strains. METHODS: Pre-menopausal women presenting with acute uncomplicated cystitis were randomized to treatment with 3 days of ciprofloxacin, 7 days of nitrofurantoin, or a single dose of fosfomycin. Women were followed for 1 month for evaluation of clinical and microbiological responses as well as for isolation of resistant rectal E. coli. RESULTS: Sixty-two women (25 ciprofloxacin, 17 nitrofurantoin, 20 fosfomycin) were enrolled and eligible for analysis. All three regimens were well tolerated and resulted in >90% clinical and bacteriological cure. The prevalence of rectal E. coli was markedly decreased by ciprofloxacin and fosfomycin, but not by nitrofurantoin. One woman treated with ciprofloxacin had emergence of two ciprofloxacin-resistant rectal E. coli strains within 10 days of completing therapy. No emergence of resistance was observed in the other two treatment groups. CONCLUSIONS: This study demonstrates that fluoroquinolone-resistant E. coli remain infrequent in the rectal flora of women with uncomplicated cystitis in Seattle. However, a 3 day course of a fluoroquinolone for treatment of uncomplicated cystitis was followed by isolation of fluoroquinolone-resistant rectal E. coli in one patient.
CONTEXT: The high prevalence of resistance to trimethoprim-sulfamethoxazole and other antimicrobials among Escherichia coli causing acute cystitis in women has led to increased use of alternative antibiotics. One such antibiotic, amoxicillin-clavulanate, has not been well studied. OBJECTIVE: To compare the efficacy of a 3-day regimen of amoxicillin-clavulanate to that of a 3-day regimen of ciprofloxacin in the treatment of acute cystitis in women. The primary study hypothesis was that the amoxicillin-clavulanate and ciprofloxacin treatment groups would differ in clinical cure. DESIGN, SETTING, AND PATIENTS: Randomized, single-blind treatment trial of 370 women, aged 18 to 45 years, with symptoms of acute uncomplicated cystitis and a urine culture with at least 10(2) colony-forming units of uropathogens per milliliter from a university student health center or a health maintenance organization. INTERVENTIONS: Women were randomly assigned to receive amoxicillin-clavulanate (500 mg/125 mg twice daily) or ciprofloxacin (250 mg twice daily) for 3 days and were followed up for 4 months. MAIN OUTCOME MEASURES: The main outcome measure was clinical cure. Secondary study outcomes of interest were microbiological cure and vaginal E coli colonization at the 2-week follow-up visit. RESULTS: Clinical cure was observed in 93 (58%) of 160 women treated with amoxicillin-clavulanate compared with 124 (77%) of 162 women treated with ciprofloxacin (P<.001). Amoxicillin-clavulanate was not as effective as ciprofloxacin even among women infected with strains susceptible to amoxicillin-clavulanate (65 [60%] of 109 women in the amoxicillin-clavulanate group vs 114 [77%] of 149 women in the ciprofloxacin group; P = .004). The difference in clinical cure rates occurred almost entirely within the first 2 weeks after therapy. Microbiological cure at 2 weeks was observed in 118 (76%) of 156 women treated with amoxicillin-clavulanate compared with 153 (95%) of 161 women treated with ciprofloxacin (P<.001). At this visit, 45% of women in the amoxicillin-clavulanate group compared with 10% in the ciprofloxacin group had vaginal colonization with E coli (P<.001). CONCLUSIONS: A 3-day regimen of amoxicillin-clavulanate is not as effective as ciprofloxacin for the treatment of acute uncomplicated cystitis, even in women infected with susceptible strains. This difference may be due to the inferior ability of amoxicillin-clavulanate to eradicate vaginal E coli, facilitating early reinfection.
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BACKGROUND: Although most cases of acute pyelonephritis occur in otherwise healthy women, data on risk factors for this condition are lacking. OBJECTIVE: To evaluate infection characteristics, incidence, and risk factors associated with acute pyelonephritis in a sample of women. DESIGN: Population-based case-control study. SETTING: Group Health Cooperative, a prepaid health plan in Washington. PARTICIPANTS: 788 nonpregnant women, 18 to 49 years of age. Case-patients (n = 242) were women with pyelonephritis who were identified from computerized databases. Controls were 546 similar-age women with no pyelonephritis diagnosis in the previous 5 years who were randomly selected from enrollment databases. Response rates for case-patients and controls were 73% and 64%, respectively. MEASUREMENTS: Characteristics of infection and potential risk factors for pyelonephritis, ascertained through computer-assisted telephone interview and computerized databases. RESULTS: 7% of case-patients were hospitalized. Escherichia coli was the infecting pathogen in 85% of cases. In multivariable models, factors associated with pyelonephritis risk were frequency of sexual intercourse in the previous 30 days (odds ratio, 5.6 [95% CI, 2.8 to 11.0] for > or =3 times per week), recent urinary tract infection (UTI) (odds ratio, 4.4 [CI, 2.8 to 7.1]), diabetes (odds ratio, 4.1 [CI, 1.6 to 10.9]), recent incontinence (odds ratio, 3.9 [CI. 2.6 to 5.9]), new sexual partner in the previous year (odds ratio, 2.2 [CI, 1.4 to 3.6]), recent spermicide use (odds ratio, 1.7 [CI, 1.1 to 2.8]), and UTI history in the participant's mother (odds ratio, 1.6 [CI, 1.1 to 2.5]). Risk factors for selected subgroups (patients < or = 30 years of age, patients > 30 years of age, patients with no UTI history, and inpatients) were also evaluated. LIMITATIONS: Potential recall bias, reliance on automated case definition criteria, and limited data on diabetes and incontinence variables. CONCLUSIONS: Few nonpregnant, community-dwelling women younger than 50 years of age with pyelonephritis are hospitalized. As with cystitis in reproductive-age women, sexual behaviors and patient and family history of UTI are associated with increased pyelonephritis risk. Diabetes and incontinence also seem to independently increase the risk for pyelonephritis.
Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05). During ciprofloxacin treatment, only procainamide and NAPA renal clearances decreased significantly.
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BACKGROUND: No safe and convenient regimen has proved to be effective for the management of recurrent vulvovaginal candidiasis. METHODS: After inducing clinical remission with open-label fluconazole given in three 150-mg doses at 72-hour intervals, we randomly assigned 387 women with recurrent vulvovaginal candidiasis to receive treatment with fluconazole (150 mg) or placebo weekly for six months, followed by six months of observation without therapy. The primary outcome measure was the proportion of women in clinical remission at the end of the first six-month period. Secondary efficacy measures were the clinical outcome at 12 months, vaginal mycologic status, and time to recurrence on the basis of Kaplan-Meier analysis. RESULTS: Weekly treatment with fluconazole was effective in preventing symptomatic vulvovaginal candidiasis. The proportions of women who remained disease-free at 6, 9, and 12 months in the fluconazole group were 90.8 percent, 73.2 percent, and 42.9 percent, as compared with 35.9 percent, 27.8 percent, and 21.9 percent, respectively, in the placebo group (P< 0.001). The median time to clinical recurrence in the fluconazole group was 10.2 months, as compared with 4.0 months in the placebo group (P<0.001). There was no evidence of fluconazole resistance in isolates of Candida albicans or of superinfection with C. glabrata. Fluconazole was discontinued in one patient because of headache. CONCLUSIONS: Long-term weekly treatment with fluconazole can reduce the rate of recurrence of symptomatic vulvovaginal candidiasis. However, a long-term cure remains difficult to achieve.
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BACKGROUND: Sulfamethoxazole hydroxylamine formation, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)-infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection. METHODS: HIV-1-infected subjects (CD4 + count >/=200 cells/mm 3 ) were enrolled in a 2-part (A and B), open-label drug interaction study (Adult AIDS Clinical Trial Group [AACTG] 283). In part A (n = 9), subjects received cotrimoxazole (1 tablet of 800 mg sulfamethoxazole/160 mg trimethoprim daily) alone for 2 weeks and then, in a randomly assigned order, cotrimoxazole plus either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 12) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. RESULTS: In part A, fluconazole decreased the area under the plasma concentration-time curve (AUC), percent of dose excreted in 24-hour urine, and formation clearance (CL f ) of the hydroxylamine by 37%, 53%, and 61%, respectively (paired t test, P < .05). Rifabutin increased the AUC, percent excreted, and CL f of the hydroxylamine by 55%, 45%, and 53%, respectively ( P < .05). Fluconazole plus rifabutin decreased the AUC, percent excreted, and CL f of the hydroxylamine by 21%, 37%, and 46%, respectively ( P < .05). In part B the fluconazole data were similar to those of part A. Overall, clarithromycin had no effect on hydroxylamine production. CONCLUSIONS: If the exposure (AUC) to sulfamethoxazole hydroxylamine is predictive of sulfamethoxazole toxicity, then rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole will decrease the rates of adverse reactions to sulfamethoxazole in HIV-infected subjects.
BACKGROUND: Dapsone hydroxylamine formation is thought to be the cause of the high rates of adverse reactions to dapsone in human immunodeficiency virus (HIV)-infected individuals. Therefore we studied the effect of the commonly coadministered drugs fluconazole, clarithromycin, and rifabutin on hydroxylamine formation in individuals with HIV infection. METHODS: HIV-infected subjects (CD4 + > or =200 cells/mm 3 ) were enrolled in a 2-part (A or B) open-label drug interaction study. In part A, subjects (n = 12) received dapsone (100-mg tablet once daily) alone for 2 weeks and then, in a randomly assigned order, received dapsone and either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 11) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. On the last study day of each 2-week period, plasma and urine were collected over ascorbic acid for 24 hours. RESULTS: In part A, fluconazole decreased the area under the plasma concentration-time curve, percent of dose excreted in 24-hour urine, and formation clearance of the hydroxylamine by 49%, 53%, and 55% (n = 12, P < .05), respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on hydroxylamine area under the plasma concentration-time curve or percent excreted in 24-hour urine but increased formation clearance of the hydroxylamine by 92% (n = 12, P < .05). Dapsone clearance was increased by rifabutin or rifabutin plus fluconazole (67% and 38%, respectively) (n = 12, P < .05) but was unaffected by fluconazole or clarithromycin. In part B, hydroxylamine production was unaffected by clarithromycin but was affected by fluconazole in a manner identical to that in part A. CONCLUSIONS: On the basis of these data and with the assumption that the exposure to the hydroxylamine is a determinant of dapsone toxicity, we predict that coadministration of fluconazole should decrease the rate of adverse reactions to dapsone in persons with HIV infection but that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary in light of the increase in dapsone clearance.
Urinary tract infections in young, healthy women frequently recur, despite their traditional classification as acute infections. Conventional wisdom dictates that uropathogens causing recurrent infections in such individuals come from the fecal or vaginal flora, in the same manner as the initial infection. However, recent studies of uropathogenic Escherichia coli have found that it can carry out a complex developmental program within the superficial epithelial cells of the mouse bladder, forming intracellular bacterial communities with many biofilm-like properties. These intracellular biofilms allow the bacteria to outlast a strong host immune response to establish a dormant reservoir of pathogens inside the bladder cells. Re-emergence of bacteria from this reservoir might be the source of recurrent infection.
We conducted a prospective study of an electronic clinical reminder system in an academic medical center-based human immunodeficiency virus (HIV) specialty clinic. Published performance indicators were used to examine adherence to HIV practice guidelines before and after its implementation for 1204 patients. More than 90% of patients received CD4 cell count and HIV type 1 (HIV-1) RNA level monitoring every 3-6 months during both time periods, and approximately 80% of patients with a CD4 cell count nadir of <350 cells/mm(3) received highly active antiretroviral therapy. Patients were significantly more likely to receive prophylaxis against Mycobacterium avium complex (hazard ratio, 3.84; 95% confidence interval [CI], 1.58-9.31; P=.003), to undergo annual cervical carcinoma screening (OR, 2.09; 95% CI, 1.04-4.16; P=.04), and to undergo serological screening for Toxoplasma gondii (odds ratio [OR], 1.86; 95% CI, 1.05-3.27; P=.03) and syphilis infection (OR, 3.71; 95% CI, 2.37-5.81; P<.0001). HIV clinical reminders delivered at the time that HIV care is provided were associated with more timely initiation of recommended practices.