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PubMed2002

A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children.

BACKGROUND: Short-course antibiotic regimens, ranging in duration from a single dose to 3 days, are the current standard of care for the treatment of acute lower urinary tract infections (UTIs) in adult women. Despite multiple small randomized, controlled trials (RCTs) showing no difference in efficacy between short-course (</=3 days) and long-course (7-14 days) therapy in children, concerns about occult pyelonephritis and renal scarring have prompted standard recommendations of 7 to 14 days of antibiotics for UTIs in children. OBJECTIVE: To determine whether long-course antibiotic therapy is more effective than short-course therapy for the treatment of UTIs in children, and to explore potential sources of heterogeneity in the results of existing studies. METHODS: We searched online bibliographic databases (Medline and Cochrane Clinical Trials Registry) for RCTs comparing short- and long-course therapy for the treatment of UTI in children, and examined the references of all retrieved articles. Candidate studies for meta-analysis were restricted to RCTs comparing short-course (</=3 days) and long-course (7-14 days) outpatient therapy for acute UTI in children age 0 to 18 years. We excluded studies that were restricted to children with recurrent UTI or included children with asymptomatic bacteriuria. Sixteen studies met the inclusion criteria. Study quality was evaluated using a 9-item scoring system developed by the investigators. Data on the primary outcomes-treatment failure and reinfection rate-were extracted when available and reanalyzed based on intention to treat whenever possible. To determine whether anatomic level of infection (upper vs lower urinary tract) influenced the results, the meta-analysis was repeated on the subgroup of studies that attempted to restrict their participants to children with lower UTI. To determine whether there was a dose-response effect for the duration of short-course therapy, we performed separate subgroup analyses of studies of single-dose or single-day therapy and studies of 3-day therapy. To explore other potential sources of study result heterogeneity, such as study quality and patient age, we developed a random-effects regression model that included these variables as covariates. RESULTS: The pooled estimate for the relative risk (RR) of treatment failure with short-course antibiotic therapy was 1.94 (95% confidence interval [CI]: 1.19-3.15) and for the RR of reinfection was 0.76 (95% CI: 0.39-1.47). When we excluded the 3 studies that did not attempt to restrict their participants to patients with lower UTI, the pooled RR of treatment failure was 1.74 (95% CI: 1.05-2.88) and of reinfection was 0.69 (95% CI: 0.32-1.52). For the subgroup of studies comparing single-dose or 1-day therapy to long-course therapy, the pooled RR of treatment failure was 2.73 (95% CI: 1.38-5.40) and of reinfection was 0.37 (95% CI: 0.12-1.18). For the subgroup of studies comparing 3-day therapy to long-course therapy, the pooled RR of treatment failure was 1.36 (95% CI: 0.68-2.72) and of reinfection was 0.99 (95% CI: 0.46-2.13). In the meta-regression, neither study quality nor mean participant age was significantly associated with the odds ratio of treatment failure or reinfection, in either the complete set of studies or the subset of studies restricted to patients with lower UTI. CONCLUSIONS: In pooled analyses of published studies comparing long- and short-course antibiotic treatment of UTI in children, long-course therapy was associated with fewer treatment failures without a concomitant increase in reinfections, even when studies including patients with evidence of pyelonephritis were excluded from the analysis. Until there are more accurate methods for distinguishing upper from lower UTI in children, no additional comparative trials are warranted and clinicians should continue to treat children with UTI for 7 to 14 days.

Adolescent↗
PubMed2005

Clinical and demographic factors associated with urinary tract infection in young febrile infants.

OBJECTIVE: Previous research has identified clinical predictors for urinary tract infection (UTI) to guide urine screening in febrile children <24 months of age. These studies have been limited to single centers, and few have focused on young infants who may be most at risk for complications if a UTI is missed. The objective of this study was to identify clinical and demographic factors associated with UTI in febrile infants who are < or =60 days of age using a prospective multicenter cohort. METHODS: We conducted a multicenter, prospective, cross-sectional study during consecutive bronchiolitis seasons. All febrile (> or =38 degrees C) infants who were < or =60 days of age and seen at any of 8 pediatric emergency departments from October through March 1999-2001 were eligible. Clinical appearance was evaluated using the Yale Observation Scale. UTI was defined as growth of a known bacterial pathogen from a catheterized specimen at a level of (1) > or =50000 cfu/mL or (2) > or =10000 cfu/mL in association with a positive dipstick test or urinalysis. We used bivariate tests and multiple logistic regression to identify demographic and clinical factors that were associated with the likelihood of UTI. RESULTS: A total of 1025 (67%) of 1513 eligible patients were enrolled; 9.0% of enrolled infants received a diagnosis of UTI. Uncircumcised male infants had a higher rate of UTI (21.3%) compared with female (5.0%) and circumcised male (2.3%) infants. Infants with maximum recorded temperature of > or =39 degrees C had a higher rate of UTI (16.3%) than other infants (7.2%). After multivariable adjustment, UTI was associated with being uncircumcised (odds ratio: 10.4; bias-corrected 95% confidence interval: 4.7-31.4) and maximum temperature (odds ratio: 2.4 per degrees C; 95% confidence interval: 1.5-3.6). Factors that were reported previously to be associated with risk for UTI in infants and toddlers, such as white race and ill appearance, were not significantly associated with risk for UTI in this cohort of young infants. CONCLUSIONS: Being uncircumcised and height of fever were associated with UTI in febrile infants who were < or =60 days of age. Uncircumcised male infants were at particularly high risk and may warrant a different approach to screening and management.

Circumcision, Male↗
PubMed2004

Role of fluoroquinolones in the treatment of serious bacterial urinary tract infections.

Serious urinary tract infections (UTIs) in adults--defined as acute complicated UTIs or pyelonephritis requiring initial intravenous antimicrobials and/or hospitalisation and nosocomial infections--cause significant morbidity and economic burden. In the US, UTIs are responsible for nearly 7 million outpatient physician office visits, 1 million emergency room visits and over 100 000 hospital admissions annually. Complicated UTIs often affect patients with underlying functional, metabolic or anatomical defects of the urinary tract, whereas most nosocomial UTIs (~80%) are related to short- or long-term catheterisation. Serious UTIs are often difficult to treat because infection involves a diverse array of Gram-negative and Gram-positive bacteria, coupled with increasing antimicrobial resistance in some uropathogens, and a higher rate of recurrent infections. Although Escherichia coli remains a common aetiology (< or =60%), other Enterobacteriaceae, Gram-negative bacilli (e.g. Pseudomonas aeruginosa), and Gram-positive bacteria (e.g. Staphylococcus aureus) are frequently isolated. Patients with long-term catheterisation have UTIs typically caused by organisms that produce biofilms making eradication even more difficult. Overall, aetiology and resistance patterns are not predictable for those with serious UTIs, necessitating confirmation by culture and susceptibility testing.Numerous intravenous and oral antimicrobial treatment options are available and the majority of patients with serious UTIs will need initial intravenous therapy because of the possibility of bacteraemia/sepsis or impaired gastrointestinal absorption. Many experts concur that empirical therapy for the institutionalised or hospitalised patient with a serious UTI should include an intravenous antipseudomonal agent because of an increased risk of urosepsis. While state-of-the-art treatment guidelines are lacking for these infections, targeted therapy should be initiated once susceptibility data are known. The use of targeted therapy--emphasising the "correct antibacterial spectrum" and pharmacodynamic superiority--is likely to provide important benefits (e.g. reduced morbidity and associated costs, reduced emergence of resistance). Agents commonly prescribed include aminoglycosides, beta-lactam/beta-lactamase inhibitor combinations, imipenem, advanced-generation cephalosporins and fluoroquinolones. Fluoroquinolones are often recommended when conventional agents have failed or are less desirable (e.g. toxicity/hypersensitivity concerns), or when resistance is high. Several pivotal clinical trials support the use of fluoroquinolones for serious UTIs with most experience garnered with ciprofloxacin, including a new once-daily extended-release tablet formulation.Treatment of patients with serious UTIs remains challenging. Physicians should choose empirical therapy based on patient demographics/medical history, presumed aetiology and local resistance patterns until more definitive guidelines become available.

Acute Disease↗
PubMed1992

[Clinical efficacy of tosufloxacin on the patients with urinary tract infections].

We evaluated a newly developed quinolone agent, tosurofloxacin (TFLX), for its safety and clinical efficacy on patients with urinary tract infections (UTI). Among 138 cases satisfying the UTI criteria, 75 cases were acute simple UTI and 63 cases were chronic complicated UTI. In principle, a daily dose of 450 mg of TFLX was administered for 3 days and for 5 days for acute simple UTI and for chronic complicated UTI, respectively. Clinical efficacy of TFLX in these cases was evaluated according to the criteria of Japanese UTI committee. Bacteriologically, all 80 strains isolated from acute simple UTI were eradicated following TFLX administration. However, 2 gram positive strains and 1 gram negative strain, appeared following the treatment. In cases of chronic complicated UTI, 29 out of 32 gram positive strains and 29 out of 44 gram negative strains were eradicated. Among the isolated strains, P. aeruginosa and S. marcescens persisted, which suggests that they were less sensitive to TFLX. Overall clinical effectiveness rate of TFLX on acute simple UTI was 100%, while that on chronic complicated UTI was 73%. Adverse drug side effects were minimum, stomach discomfort and constipation was observed in one case each. These findings indicate that TFLX is a useful agent for the treatment of both simple and complicated UTI.

4-Quinolones↗
PubMed2006

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2004) II. Background of patients].

Six hundred six bacterial strains isolated from 490 patients diagnosed as having urinary tract infections (UTIs) in 14 institutions in Japan were collected between August 2004 and July 2005. The frequency of bacteria isolation stratified with patient clinical background was compared. The clinical background investigated included sex, age, type of infections, timing of antibiotics administration, and presence or absence of surgery affecting a decrease in defense against infection. The bacterial strains were stratified with the age and sex of the patients and the types of infections. In males, the number of patients aged less than 60 years was few and the complicated UTIs without indwelling catheter was observed most frequently. In females, the number of patients aged less than 60 years was comparatively more than in males. In all of ages except 0-19 and > or = 80 years, the ratio of the uncomplicated UTIs was high, accounting for 44.1-90.0% of all types of infections. In the present time, the bacteria most frequently isolated were Escherichia coli. Pseudomonas aeruginosa and Enterococcus faecalis also were relatively frequently isolated. E. coli most frequently isolated with the uncomplicated UTIs and P. aeruginosa and E. faecalis most frequently isolated with the complicated UTIs. With respect to the relation of these results to the age of the patients, in the uncomplicated UTIs, the isolation frequency of E. coli was the highest in all age groups except 0-19 years, accounting for 50% or higher. In the complicated UTIs without indwelling catheter, the isolation frequency of E. coli tended to be high in all age groups. In the complicated UTIs with indwelling catheter, P. aeruginosa were more frequently isolated. In comparison of causative bacteria in UTIs between before and after the administration of antibiotics, P. aeruginosa increased after the administration in any types of UTIs. In comparison of causative bacteria in UTIs with or without surgery, E. coli was more frequently isolated in the patients without surgery, while P. aeruginosa and E. faecalis were more frequently isolated in the patients with surgery in any UTIs.

Adult↗
PubMed1984

Canine urinary tract infections: a comparison of in vitro antimicrobial susceptibility test results and response to oral therapy with ampicillin or with trimethoprim-sulfa.

In vitro susceptibility testing correctly predicted the outcome of ampicillin therapy in all 56 urinary tract infections (UTI) caused by coagulase-positive staphylococci (Staphylococcus aureus and S intermedius), in all 26 UTI caused by Proteus mirabilis, in 38 of 44 UTI caused by Escherichia coli, in 29 of 31 UTI caused by Streptococcus spp, in 8 of 10 UTI caused by Klebsiella pneumoniae, and in 16 of 20 UTI caused by other bacterial species. Thus, 173 of 187 (92.5%) isolates responded to ampicillin therapy in a manner predicted by in vitro susceptibility test results. In vitro susceptibility testing correctly predicted the outcome of therapy with trimethoprim-sulfa in 119 of 138 UTI caused by Escherichia coli, in 33 of 45 UTI caused by Klebsiella pneumoniae, in 38 of 43 UTI caused by Proteus mirabilis, in 21 of 25 UTI caused by Streptococcus spp, in 9 of 11 UTI caused by coagulase-positive staphylococci, and in 19 of 21 UTI caused by other bacterial species. Thus, 239 of 283 (84%) isolates responded to trimethoprim-sulfa therapy in a manner predicted by in vitro susceptibility test results.

Ampicillin↗
PubMed2005

A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections.

OBJECTIVE: To investigate the long-term preventive effect of the immunotherapeutic OM-89 versus placebo in uncomplicated recurrent UTI in a large cohort of female patients only. METHODS: Adult female patients could enroll in this multicenter, double-blind study if they had acute UTI at the enrollment visit and positive results of urinalysis (> or =10(3)bacteria/ml). Patients received the immunotherapeutic OM-89 or a matching placebo; 1 capsule per day for 90 days, 3 months without treatment, then the first 10 days in Months 7, 8 and 9 and were followed up during 12 months. Primary efficacy criteria were UTI rates over 12 months, distribution of UTIs and proportion of patients with UTI. RESULTS: A total of 453 patients were treated, 231 in the active group and 222 in the placebo group. Mean rate of post-baseline UTIs was significantly lower in the active group than in the placebo group (0.84 vs. 1.28; p<0.003), corresponding to a 34% reduction of UTIs in patients treated with OM-89. In the active group, 93 patients (40.3%) had 185 post-baseline UTIs, compared to 276 UTIs in 122 patients (55.0%) in the placebo group (p=0.001). The safety profile of OM-89 was good and consistent with that reported in previous studies. CONCLUSIONS: OM-89 significantly reduced the incidence of UTI during the 12 months of the study including 3 months of treatment and three 10-day booster courses. These results confirm that OM-89 is a valuable component of the management of recurrent UTI.

Adult↗
PubMed2001

Long-term antibiotics for preventing recurrent urinary tract infection in children.

BACKGROUND: Acute urinary tract infection (UTI) is common in children. By the age of seven years, 8.4% of girls and 1.7% of boys will have suffered at least one episode. Symptoms are systemic rather than localised in early childhood and consist of fever, lethargy, anorexia, and vomiting. UTI is caused by E. coli in over 80% of cases and treatment consists of a course of antibiotics. Due to the unpleasant acute illness caused by UTI and the risk of pyelonephritis-induced permanent kidney damage, many children are given long-term antibiotics aimed at preventing recurrence. However these medications may cause side effects and promote the development of resistant bacteria. OBJECTIVES: To determine the efficacy and side effects of long-term antibiotics given to prevent recurrent UTI in children. SEARCH STRATEGY: A search of MEDLINE (1966 to Jan 2001), EMBASE (1988 to Jan 2001) and the Cochrane Controlled Trials Register for relevant randomised controlled trials without language restriction; reference lists of review articles; contact with content experts. SELECTION CRITERIA: Randomised comparisons of two or more antibiotics and placebo with one or more antibiotics to prevent recurrent UTI. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed and extracted information. For each trial, information was collected on the methods of the trial, participants, interventions and outcomes. A random-effects model was used to estimate a summary relative risk (RR) and a summary risk difference (RD) for recurrent UTI. Heterogeneity tests and subgroup analyses were carried out based on a priori hypothesis of plausible effect modification. MAIN RESULTS: There were three trials (n = 151) comparing antibiotics with placebo/no treatment. The duration of antibiotic prophylaxis treatment varied among the studies (10 weeks to 12 months). The method of allocation concealment in the three trials was inadequate, unclear and adequate. The overall rate of recurrent UTI in the placebo/no treatment group was 63% (48/76). Compared to placebo/no treatment, antibiotics reduced the risk of recurrent UTI (RR 0.36, 95% CI 0.16 to 0.77; RD -46%, 95% CI -59% to -33%). No side effects were described in any of these three trials. There was one double-blinded trial (n = 120) with unclear allocation concealment that compared two different types of antibiotics to prevent recurrent UTI. Nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a six month period (RR 0.48, 95% CI 0.25 to 0.92; RD -18%, 95% CI -34% to -3%). However, patients receiving nitrofurantoin were more likely to discontinue the antibiotic due to side effects (mainly gastrointestinal) than patients receiving trimethoprim (RR 3.17, 95% CI 1.36 to 7.37; RD 22%, 95% CI 8% to 36%). REVIEWER'S CONCLUSIONS: Most published studies to date have been poorly designed with biases known to overestimate the true treatment effect. Large, properly randomised, double blinded trials are needed to determine the efficacy of long-term antibiotics for the prevention of UTI in susceptible children.

Anti-Infective Agents, Urinary↗
PubMed1995

Inhibition of metastasis of Lewis lung carcinoma by urinary trypsin inhibitor in experimental and spontaneous metastasis models.

A purified human urinary trypsin inhibitor (UTI) and its related synthetic peptides were examined to determine whether they could inhibit production of experimental and spontaneous lung metastases by murine Lewis lung carcinoma (3LL) cells. Three peptides, peptide I, peptide 2 and peptide 3, representing the amino acid sequences within the UTI molecule, were synthesized. UTI and peptide 2 inhibited human leukocyte elastase (HLE). UTI and peptide 3 specifically inhibited human and murine plasmin activity. Peptide I had essentially no inhibitory activity. In an in vivo spontaneous metastasis model, multiple s.c. injections of UTI or peptide 3 for 7 days immediately after s.c. tumor cell inoculation significantly inhibited the formation of lung metastasis in C57BL/6 mice in a dose-dependent manner. UTI reduced lung tumor colonization more effectively than peptide 3. Peptides 1 and 2, however, did not affect the formation of lung metastasis. Inhibition of lung metastasis was not due to direct anti-tumor effects of UTI and peptide 3. In an in vivo experimental metastasis assay, multiple s.c. injections of UTI for 7 days after i.v. tumor cell inoculation inhibited metastatic lung tumor colonization, while peptide 3 did not affect metastasis. Peptides 1 and 2 did not affect the formation of lung metastasis. When examined with an in vitro assay system using a modified Boyden chamber, UTI and peptide 3 suppressed the invasion of tumor cells through Matrigel. UTI and peptide 3 inhibited neither cell proliferation nor the binding of tumor cells to Matrigel and showed no significant suppression of chemotactic migration of tumor cells to fibronectin. Our results suggest that UTI efficiently regulates the mechanism involved in not only the entry into vascular circulation of tumor cells (intravasation, though, at least in part, inhibition of the proteolytic enzyme plasmin) but also the extravasation step of the metastatic process.

Amino Acid Sequence↗
PubMed1997

The role of chondroitin sulfate chains of urinary trypsin inhibitor in inhibition of LPS-induced increase of cytosolic free Ca2+ in HL60 cells and HUVEC cells.

Preincubation of HL60 cells and HUVEC cells with urinary trypsin inhibitor (UTI) inhibited increase of cytosolic free Ca2+ induced by LPS. In contrast, an increase of cytosolic free Ca2+ induced by LPS was not inhibited by deglycosylated UTI, UTI treated with monoclonal antibody of chondroitin sulfate. 45Ca2+ binding showed that UTI binds 45Ca2+ dose-dependently. Scatchard plot analysis showed that UTI has two binding sites for Ca2+, a high affinity binding site (Kd=15 microM) and a low affinity site (Kd=150 microM), and that UTI has more than 70 Ca2+ binding sites per molecule. The Ca2+ binding capacity of deglycosylated UTI and UTI treated with monoclonal antibody of chondroitin sulfate was markedly depressed. Furthermore, UTI forms multi-polymers in the presence of Ca2+ as demonstrated by gel filtration and agarose gel electrophoresis. These results suggest that UTI is a physiological Ca2+ chelator on the cells and that the action is due to chondroitin sulfate chains of UTI.

Binding Sites↗
PubMed2001

Impaired fertility in female mice lacking urinary trypsin inhibitor.

Urinary trypsin inhibitor (UTI) is a serine proteinase inhibitor that is found in blood and urine. To investigate the physiological functions of UTI in vivo, we generated UTI-deficient mice by gene targeting. The mice showed no obvious abnormalities and appeared healthy. However, the females displayed a severe reduction in fertility. Wild-type embryos developed normally when transplanted into UTI-deficient female mice, suggesting that UTI-deficient females have a normal ability to maintain pregnancy. The number of naturally ovulated oocytes from UTI-deficient mice was greatly reduced compared with that from wild-type mice. Histologically, oocytes with disorganized corona radiata were frequently seen in the ovaries of UTI-deficient mice after hormonal stimulation. When ovaries from UTI-deficient mice were transplanted into wild-type mice, pups derived from the transplanted ovaries were obtained, suggesting that the ovary of UTI-deficient mice functions normally if UTI is supplied from the systemic circulation. These results demonstrate that UTI plays an important role in the formation of the stable cumulus-oocyte complex that is essential for oocyte maturation and ovulation.

Animals↗
PubMed2005

Glycosaminoglycans in childhood urinary tract infections.

It has been suggested that urinary glycosaminoglycans (GAGs) form a natural defense mechanism against urinary tract infections (UTIs). This study investigated whether urinary GAGs play a role in pediatric UTIs, and whether urinary GAG level can be used to differentiate upper UTI from lower UTI. Forty-one children with UTIs (33 girls and eight boys; mean age 5.4+/-3.7 years) and 46 age- and sex-matched healthy children (35 girls and 11 boys; mean age 6.6+/-3.9 years) were included in the study. Urinary GAG levels were measured at the onset of acute infection and after a 10-day course of antibiotic treatment. Group GAG findings were compared, and comparisons were also made with the patients divided according to sex and according to UTI type (upper versus lower). The mean urinary GAG level in the patient group at the onset of acute infection (pretreatment) was significantly higher than the mean level in the control group (132.2+/-104.8 mg/g vs 42.2+/-27.1 mg/g creatinine, respectively; P <0.01). In the patient group, the mean urinary GAG level after antimicrobial therapy was significantly lower than the pretreatment level (75.9+/-52.1 mg/g vs 132.2+/-104.8 mg/g creatinine, respectively; P <0.01). However, the mean post-treatment level was still higher than the mean level in the controls ( P <0.05). There was no significant difference in urinary GAG levels when patients were categorized as upper versus lower UTI ( P >0.05). The study results suggest that GAGs play an important role in the pathogenesis of UTIs in children, and that measurement of urinary GAGs may be a valuable noninvasive method for evaluating UTIs in this patient group. However, this assay cannot be used to differentiate upper UTI from lower UTI in children.

Anti-Bacterial Agents↗
PubMed1992

Urinary tract infections in patients with diabetes mellitus.

We have endeavoured to determine whether there is any difference in the bacteriological pattern of UTI and the antibiotic sensitivity patterns of the pathogens concerned between diabetic and non-diabetic patients. Over a period of 1 year, a total of 287 diabetic patients (221 females and 66 males) with community-acquired and nosocomial urinary tract infections were studied. There were 265 patients (228 females and 37 males) without any predisposition to urinary tract infections (UTI) and who served as controls. Although Escherichia coli was the predominant organism in community-acquired UTI in diabetic patients, it was found significantly less than in the non-diabetic population (P less than 0.005). The percentage of Klebsiella species causing community-acquired UTI in diabetic patients was significantly higher than in non-diabetics (P less than 0.005). The antibiotic sensitivity patterns of the organisms in the two groups, however, were not significantly different. The organisms isolated from nosocomial UTI in diabetics showed a significantly greater preponderance of Klebsiella spp. and a significantly lower percentage of E. coli when compared to community-acquired UTI in diabetics (P less than 0.005). Klebsiella spp. in nosocomial UTI of diabetics showed an overall increase in resistance to antibiotics. At least a quarter of the isolates of Klebsiella spp. in nosocomial UTI were resistant to third-generation cephalosporins. Patients with diabetes mellitus appear to have an increased incidence of Klebsiella spp. as the pathogen in both community-acquired and nosocomial UTI. Antibiotic resistance in the organisms isolated from nosocomial UTI is greater than that related to community-acquired UTI in diabetic patients.

Aged↗
PubMed2004

Proinflammatory cytokines up-regulate synthesis and secretion of urinary trypsin inhibitor in human hepatoma HepG2 cells.

Background and Aims: The urinary trypsin inhibitor (UTI), a wide range protein inhibitor synthesized by hepatocytes, is considered to play an important role not only in the protection of organ injury during severe inflammation but also in the inhibition of tumor invasion and metastasis. However, the precise mechanisms underlying control of its synthesis, secretion, and processing remain unclarified. The aim of this study is to determine whether human hepatoma HepG2 cells secrete UTI in free form and whether its synthesis and secretion are regulated by proinflammatory cytokines. Methods: Cultured HepG2 cells were stimulated using different concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The concentration of free UTI in the medium was measured by ELISA and the intracellular UTI precursor was identified by western blotting. UTI mRNA expression was studied by reverse transcription polymerase chain reaction (RT-PCR). Results: HepG2 cells constantly secreted free UTI and this secretion was significantly up-regulated by IL-6, IL-1beta, and TNF-alpha. IL-6, IL-1beta, and TNF-alpha enhanced the synthesis of the intracellular UTI precursor protein, and IL-1beta up-regulated UTI mRNA expression. Conclusions: HepG2 cells constantly secrete free UTI. The proinflammatory cytokines, IL-1beta, IL-6, and TNF-alpha, up-regulate UTI synthesis and secretion by up-regulating UTI mRNA expression.

Journal Article↗
PubMed1996

Failure of pre-natal ultrasonography to prevent urinary infection associated with underlying urological abnormalities.

OBJECTIVES: To analyse the reasons underlying the failure of routine pre-natal ultrasonography to prevent the subsequent development of urinary tract infection (UTI) in children with predisposing urological abnormalities. PATIENTS AND METHODS: This retrospective study comprised 39 children (22 females and 17 males) who had at least one documented UTI, the presence of an anatomical anomaly of the urinary tract recognized as predisposing to UTI and had undergone ultrasonography of the urinary tract undertaken in fetal life as part of routine maternal ante-natal ultrasonography. Four categories of patients were defined: Group A, those with normal findings on pre-natal ultrasonography and no urological abnormality detected; Group B, those with a urological abnormality detected but where there was a subsequent failure of communication among clinicians; Group C, those with a urological abnormality but who received inappropriate or sub-optimal post-natal management and; Group D, those with a urological abnormality but who had a UTI despite appropriate post-natal management. In each case, the most severe documented episode of UTI was categorized as: Grade I, asymptomatic bacteriuria; Grade II, mild/moderate symptomatic UTI and; Grade III, severe symptomatic UTI necessitating hospital admission. RESULTS: Group A comprised 22 (56%), Group B three (9%), Group C two (5%) and Group D 12 children (31%). Of the 22 children in Group A, nine experienced a UTI of sufficient severity to necessitate hospital admission. Of the 12 children in Group D only one required hospital admission. CONCLUSIONS: The failure of pre-natal ultrasonography to identify the underlying predisposing urological abnormality was the most important factor contributing to subsequent UTI in post-natal life. Failure of communication and inappropriate post-natal management were numerically unimportant. In some children, UTI occurred despite pre-natal detection of their underlying anomaly and appropriate post-natal management. However, in this group the UTI was less severe than in those children whose urological anomalies had not been detected by pre-natal ultrasonography.

Child, Preschool↗
PubMed2002

Incidence and risk factors for acquiring nosocomial urinary tract infection in the critically ill.

PURPOSE: A urinary tract infection (UTI) is the most common hospital-acquired infection. However, the epidemiology of intensive care unit (ICU)-acquired UTIs is not well defined. The objective of this study was to describe the incidence, risk factors, and clinical outcomes of ICU-acquired UTIs. MATERIALS AND METHODS: All patients admitted to adult multidisciplinary ICUs in the Calgary Health Region (CHR, population approximately 1 million) during May 1, 1999 to April 30, 2000 were studied using a cohort design. RESULTS: A total of 1,158 admissions to a CHR ICU were 48 hours in duration or more. A total of 111 episodes of ICU-acquired UTI (defined as >10(5) CFU/mL of 1 or 2 organisms >48 hours after ICU admission) occurred in 105 (9%) patients and 5 (0.4%) had ICU-acquired bacteremic/fungemic UTIs for incidences of 11.3 and 0.5 UTIs per 1,000 ICU days, respectively. Significant independent risk factors for developing an ICU-acquired UTI as determined by a logistic regression model were female gender (adjusted odds ratio [OR(adj)], 2.31; 95% confidence interval [CI], 1.48-3.59) and natural logarithmic transformation of ICU length of stay (OR(adj), 3.96; 95% CI, 3.02-5.17). No differences in admitting vital signs, routine blood tests, APACHE II and TISS scores, or overall hospital mortality rate were observed among patients who developed an ICU-acquired UTI as compared with those who did not. The most common UTI etiologies were Enterococcus spp. (24%), Candida albicans (21%), and Escherichia coli (15%). Only 4 (3%) of the organisms were highly antibiotic resistant. CONCLUSIONS: Nosocomial UTIs develop commonly in the critically ill and women and those with an extended ICU stay are at increased risk. Although ICU-acquired UTIs are markers of morbidity, they do not significantly increase mortality.

APACHE↗
PubMed2000

Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways.

Urinary trypsin inhibitor (UTI), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) to evaluate the effect on expression of urokinase-type plasminogen activator (uPA), since the action of uPA has been implicated in matrix degradation and cell motility. Preincubation of the cells with UTI reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. UTI-induced down-regulation of PMA-stimulated uPA expression is irreversible and is independent of a cytotoxic effect. Down-regulation of uPA by UTI is mediated by its binding to the cells. We next asked whether the mechanism of inhibition of uPA expression by UTI was due to interference with the protein kinase C second messenger system. An assay for PKC activity demonstrated that UTI does not directly inhibit the catalytic activity of PKC and that PMA translocation of PKC from cytosol to membrane was inhibited by UTI, indicating that UTI inhibits the activation cascade of PKC. PMA could also activate a signaling pathway involving MEK1/ERK2/c-Jun-dependent uPA expression. When cells were preincubated with UTI, we could detect suppression of phosphorylation of these proteins. Like several types of PKC inhibitor, UTI inhibited PMA-stimulated invasiveness. We conclude that UTI markedly suppresses the cell motility possibly through negative regulation of PKC- and MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes.

Cell Movement↗
PubMed2003

Accuracy of individuals with spinal cord injury at predicting urinary tract infections based on their symptoms.

OBJECTIVE: To determine whether individuals with spinal cord injuries (SCIs) who complain of symptoms of a urinary tract infection (UTI) actually have a UTI. DESIGN: A 9-month prospective case review. PARTICIPANTS: One hundred and forty-seven persons with SCI who presented to an outpatient urology clinic with symptoms they attributed to a UTI. MAIN OUTCOME MEASURES: Presence or absence of a UTI as determined by signs and symptoms of a UTI and a microscopic urine analysis (UA) for white blood cell (WBC) and bacterial colony counts. METHODS: A UTI was defined as new onset of clinical signs and symptoms, significant bacterial colony counts in the urine, and evidence of tissue invasion with elevated WBC count > or = 10/high power field in the urine. Evaluation of each individual included history, physical examination, and UA with a culture and sensitivity. Evaluation for other medical problems was undertaken if history, physical examination, and laboratory results were not consistent with a UTI. RESULTS: Sixty-one percent (90/147) of SCI persons were accurate in predicting the presence of a UTI based on their symptoms; 39% (57/147) were not accurate. In the group of 57 persons who were not accurate in predicting whether they had a UTI, 12 persons had other medical problems including fecal impaction, bowel obstruction, dehydration, heat intolerance, glucosuria, other infectious processes, respiratory problems, and neurologic problems. The remaining 45 had bacteriuria with no pyuria. The type of bladder management did not have an impact on the accuracy of predicting the presence or absence of a UTI (P = 0.03). CONCLUSION: Individuals with SCI were frequently not accurate at predicting whether they had a UTI based on their symptoms.

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