Sven Ferry

The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study.

This prospective, multicentre, randomized, double-blind and placebo controlled study was performed to describe the natural course of uncomplicated lower urinary tract infection (UTI). A total of 1143 women 18 y and above, consulting at 18 primary health care centres in northern Sweden for symptoms suggestive of UTI were included. The symptoms urgency, dysuria, suprapubic pain and loin pain were registered, and urine cultures performed at inclusion and follow-up visits 8–10 d and 5–7 weeks later. Associations between all symptoms and bacteriuria or bacterial counts were unpredictable. Eradication of symptoms and bacteriuria and combinations of them were studied in 288 patients placebo treated for 7 d, of whom 39% dropped out after the first follow-up visit. The spontaneous cure rate of symptoms was 28% after the first week, and 37% had neither symptoms nor bacteriuria after 5–7 weeks. Considering the high dropout rate after the first follow-up visit, the spontaneous cure rate of symptoms and bacteriuria was calculated to 24% at the end of study. We conclude that patient near-laboratory tests are required to establish the diagnosis of lower UTI, and the guidelines for diagnosis of UTI need to be revised.

Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: The LUTIW project

Objective. To analyse associations between symptoms and bacteriuria in uncomplicated lower urinary tract infection in women (LUTIW) and to evaluate outcome of therapy with three different regimens of pivmecillinam or placebo. Design. Prospective, multicentre, randomized, double-blind, and placebo-controlled therapy study. Symptoms registered at inclusion, during therapy and at follow-up visits after 8–10 and 35–49 days. Significant bacteriuria defined according to current European guidelines. Setting. A total of 18 primary healthcare centres in northern Sweden. Subjects. Women aged 18 years and above with symptoms of urgency, dysuria, supra pubic or loin pain. Main outcome measures. Symptoms and bacteriuria at inclusion and course of symptoms, bacteriuria, and their combinations during and post-therapy. Results. At inclusion, no associations or significant differences were found between symptom scores and bacteriuria, bacterial counts, or species. The 884 patients (77%) with significant bacteriuria were followed up. All pivmecillinam therapies were superior to placebo (p < 0.001). From day six until first follow-up, the mean values of all symptoms were higher and the bacteriological cure was lower at first follow-up in the three days (84%) compared with the seven days regimens (93–94%, p < 0.001). At final follow-up clinical cure was similar in all pivmecillinam regimens (65–72%) as was bacteriological cure (83–89%). Pivmecillinam had few low to mild adverse reactions, comparable to placebo. Conclusions. Symptoms are not conclusive for diagnosis of LUTIW. Pivmecillinam therapies are superior to placebo and seven days regimens are more efficient than three days. Pivmecillinam 200 mg×2×7 days is recommended as a first-line therapy for LUTIW.

Pulsed-Field Gel Electrophoresis Typing of Escherichia coli Strains from Samples Collected before and after Pivmecillinam or Placebo Treatment of Uncomplicated Community-Acquired Urinary Tract Infection in Women

ABSTRACT The primary infecting Escherichia coli strains from 156 women with community-acquired uncomplicated urinary tract infection (UTI) randomized to pivmecillinam or placebo and the E. coli strains causing UTI at two follow-up visits were typed using pulsed-field gel electrophoresis (PFGE). In the pivmecillinam treatment group PFGE showed that among patients having a negative urine culture at the first follow-up 77% (46/60) had a relapse with the primary infecting E. coli strain and 23% (14/60) had reinfection with a new E. coli strain at the second follow-up. Among patients having E. coli at the first follow-up PFGE showed that 80% (32/40) had persistence with the primary infecting E. coli strain, 15% (6/40) had reinfection with a new E. coli strain, and 5% (2/40) had different E. coli strains at the two follow-up visits (one had reinfection followed by relapse, and the other had persistence followed by reinfection). In the placebo group the majority had E. coli at the first follow-up. PFGE showed that among these patients 96% (50/52) had persistence with the primary infecting E. coli strain and 4% (2/50) had different E. coli strains at the two follow-up visits (both had persistence followed by reinfection). The finding that the majority of UTIs at follow-up are caused by the primary infecting E. coli strain supports the theory of a vaginal and rectal reservoir but could also support the recent discovery that E. coli strains are able to persist in the bladder epithelium despite appropriate antibiotic treatment, constituting a reservoir for recurrent UTI.

Characteristics of Escherichia coli causing persistence or relapse of urinary tract infections: phylogenetic groups, virulence factors and biofilm formation.

Recurrent urinary tract infections (RUTIs) pose a major problem but little is known about characteristics of Escherichia coli associated with RUTI. This study includes E. coli from 155 women with community-acquired lower urinary tract infections (UTIs) randomized to one of three dosing regiments of pivmecillinam and aimed to identify associations between the presence of 29 virulence factor genes (VFGs), phylogenetic groups and biofilm formation and the course of infection during follow-up visits at 8-10 and 35-49 days post-inclusion, respectively. E. coli causing persistence or relapse were more often of phylogenetic group B2 and had a significantly higher aggregate VFG score than E. coli that were not detectable at follow-up. Specifically, these E. coli causing persistence or relapse were characterized by a higher prevalence of hemolysis and 12 VFGs (sfa/focDE, papAH, agn43, chuA, fyuA, iroN, kpsM II, kpsM II K2, cnf1, hlyD, malX and usp). KpsM II K2 and agn43aCFT073 were independently associated with persistence or relapse. No specific combination of presence/absence of VFGs could serve as a marker to predict RUTI. Stratifying for VFGs, seven days of pivmecillinam treatment reduced the prevalence of persistence or relapse of UTI compared with three days. In vitro biofilm formation was not higher among E. coli causing persistence or relapse. The presence of agn43aCFT073 or agn43bCFT073 was associated with biofilm forming capacity. In conclusion, our results show potential targets for prevention and treatment of persistence/relapse of UTI and potential markers for selecting treatment lengths and warrant studies of these and new VFGs.

Clinical and Bacteriological Effects of Therapy of Urinary Tract Infection in Primary Health Care: Relation to in vitro Sensitivity Testing

17 primary health care (PHC) centres participated in a 1-month evaluation of a county urinary tract infection (UTI) management program. A total of 302 patients contributing 355 episodes, dominated by female (93%), lower symptomatic (75%) and Escherichia coli (74%) episodes were studied. In therapeutic failure gram-negative bacteria other than E. coli showed an increased prevalence whereas Staphylococcus saprophyticus was not found. The general pattern of drug resistance was little influenced by UTI history and the mean pretherapy prevalence of resistance to the 7 antibacterial agents studied was low (7%). Drug resistance was increased in failure (mean 24%) also for agents not used for therapy (sulphonamides and nitrofurantoin) but not in early or repeated recurrence. UTI symptoms were eradicated in only two-thirds of bacteriologically cured episodes but in one-third of the failures at the posttreatment control. On average, therapy resulted in 8% bacteriological failure and 12% early recurrence. The bacteriological cure rate was the same irrespective of whether the infecting bacteria were classified as sensitive or resistant in vitro to the drug given. Thus, sensitivity testing of isolates is rarely needed in sporadic or recurrent UTI in PHC but may be relevant in failure. In order to be of prognostic value in uncomplicated UTI high-level breakpoints focusing more on peak urinary drug concentrations need to be studied.

Molecular Epidemiology of Staphylococcus saprophyticus Isolated from Women with Uncomplicated Community-Acquired Urinary Tract Infection

ABSTRACT Staphylococcus saprophyticus is a common cause of urinary tract infections (UTIs) in women. Little is known about the molecular epidemiology of S. saprophyticus UTIs. In the current study, we compared 76 isolates of S. saprophyticus prospectively isolated from women with uncomplicated UTI participating in a randomized placebo-controlled treatment trial performed in northern Sweden from 1995 to 1997 with 50 strains obtained in 2006 from five different locations in northern Europe with pulsed-field gel electrophoresis (PFGE). The aim was to elucidate the molecular epidemiology of this uropathogenic species and to investigate whether specific clones are associated with UTI in women. A total of 47 different PFGE profiles were detected among the 126 analyzed isolates. Ten clusters consisting of 5 to 12 isolates each showing PFGE DNA similarity of >85% were identified. Several clusters of genetically highly related isolates were detected in the original trial as well as among isolates obtained during 2006 from different locations. In the original trial, clonal persistence was found among 16 of 21 (76%) patients examined in the placebo group at follow-up 8 to 10 days after inclusion, indicating a low spontaneous short-time bacteriological cure rate. We conclude that multiple clones of S. saprophyticus were causing lower UTIs in women. The result suggests that some human-pathogenic clones of S. saprophyticus are spread over large geographical distances and that such clones may persist over long periods of time.

Urinary Tract Infection in Primary Health Care in Northern Sweden: I. Epidemiology

During a 12-month study at the primary health care (PHC) centre in Vännäs (population 8,000) 632 encounters by 265 individuals because of suspected urinary tract infection (UTI) or control after treatment resulted in 279 episodes of bacteriuria in 185 patients. Nine per cent of the episodes concerned patients with indwelling catheter or incontinence requiring other aids. Symptoms of lower and higher UTI were recorded in 56 and 12%, respectively, whereas one third of the episodes were associated with vague or no symptoms and discovered mainly at planned treatment controls. The annual incidence of bacteriuria recorded increased from 0.5% in the first decade of life to more than 10% in the age group 90-100 years. Male UTI comprised 13% of the episodes, increased after middle age and contributed 40% at greater than or equal to 80 years of age. The risk of recurrence (on average 50% during the year studied) was relatively independent of sex and age. No seasonal variation of UTI was observed except for a peak in late summer due to Staphylococcus saprophyticus confined to females aged 15-64 years and causing 28% of the episodes in August. Although UTI in PHC appears to be similar globally it represents a far more complex patient group than indicated by the UTI drug trials frequently published.

Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women

Pivmecillinam (PIV) is a first‐line antimicrobial for treatment of lower urinary tract infection in women (LUTIW). Mecillinam, the active substance of PIV, is bactericidal mainly against gram‐negative uropathogens, whereas gram‐positive species are considered intrinsically resistant. However, successful treatment of LUTIW caused by Staphylococcus saprophyticus has been reported, but more rarely for other gram‐positive species. The aim of this study was to compare clinical and bacteriological outcome of PIV vs placebo treatment among uropathogens with special focus on mecillinam‐resistant isolates. We analysed data from a prospective, multicentre, placebo‐controlled, primary health care, therapy study performed in Sweden in 1995–1998 that included 1143 women with symptoms suggestive of LUTIW. Urine cultures were collected and symptoms registered at inclusion and at follow‐up visits. Overall, the efficacy of PIV was superior to that of placebo. Clinical and bacteriological outcomes of PIV treatment were similar for S. saprophyticus, Escherichia coli as for most other uropathogens irrespective of their susceptibility to mecillinam. However, the occurrence of enterococci increased nearly fivefold shortly post PIV treatment, although with mild symptoms and a high spontaneous eradication. As susceptibility to mecillinam in vitro did not predict bacteriological and clinical outcome of PIV treatment, we suggest that the present breakpoints for mecillinam should be revised.

Waiting Room Time in the Assessment of an Appointment System in Primary Care

Excessive time spent waiting in health care facilities is a nuisance to patients as well as to physicians who then have to see these dissatisfied patients. Most efforts to enhance surgery efficiency have been to optimize physician working hours and patient waiting time has been a minor concern, in particular in countries with a shortage of physicians. At the Vännäs Primary Health Care Centre in northern Sweden, efforts were made to reduce waiting time by making changes in office routines and by introducing a new appointment system. All visits to physicians during two four-week periods (March 1977 and March 1979) were analyzed, with the changes being introduced in the interim. The total time spent waiting by patients, and the patient waiting time in relation to the time scheduled were reduced. A slight increase in physician idle time was also noted. The measures taken to reduce waiting time were effective and contributed to the fulfillment of a postulated aim.

Uricult® and Sensicult® Dipslides for Diagnosis of Bacteriuria and Prediction of Drug Resistance in Primary Health Care

Uricult dipslide as an indicator of bacteriuria yielded acceptable results in primary health care (PHC), and readings by local staffs were similar to those by laboratory technicians. Sensicult dipslide detected somewhat fewer bacteriurias and predicted bacterial drug sensitivity better than resistance (predictive values 93% and 50%, respectively). The mean risk of bacterial drug resistance against seven common urinary tract infection (UTI) antibiotics in PHC was 17%. The use of Sensicult for targeting UTI therapy resulted in an average risk of 7% for prescribing drugs to which the organism was resistant. The corresponding risk with Uricult for classification of UTI bacteria by Gram grouping, lactose and catalase reactions, and local guidelines for therapy of different bacterial groups, was also 7%. The latter method is simple, offers qualitative, and thus prognostic information, but can be further improved.