Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study.

OBJECTIVES: To evaluate the importance of treatment duration for therapeutic efficacy of pivmecillinam for community-acquired urinary tract infections (UTIs) caused by Escherichia coli. METHODS: A retrospective cohort study was conducted between 1 January 2010 and 30 September 2016 in adults with community-acquired E. coli bacteriuria, treated empirically with pivmecillinam. Regimens of 3, 5 and 7 days were compared using clinical treatment failure (i.e. redemption of a new antibiotic or hospitalization due to UTI) within 14 and 30 days as outcome. HR and risk difference with 95% CI were estimated for treatment failure. Results were stratified by age (18-50, 51-70, >70 years) and sex. RESULTS: Of the 21864 cases of E. coli UTI that were analysed, 2524 (11.5%) were in men. In 954 cases (4.4%) E. coli produced ESBL and 125 (13.1%) of the cases were in men. The 3 day regimen increased the risk of treatment failure for all groups. The risk differences between the 3 and 5 day regimens were <10% for women, but >10% for men. Comparing the 7 day and 5 day regimens, only women aged >50 years demonstrated an increased risk of treatment failure within 14 days with the 5 day regimen, but not within 30 days. CONCLUSIONS: With the current data, where data on clinical classification of the E. coli UTI were missing, a 5 day treatment with pivmecillinam at 400 mg three times daily seems to be the rational recommendation for lower UTI in men, pregnant women and women >50 years old. A 3 day regimen seems sufficient for non-pregnant women <50 years old.

Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men.

OBJECTIVES: This study aimed to retrospectively assess the clinical outcome with nitrofurantoin and pivmecillinam for lower urinary tract infections (UTI) in men. Patients treated with trimethoprim were also included for comparison. METHODS: All prescriptions of the study antibiotics to adult men in Uppsala County, Sweden, during 2012 were extracted. Data on patient characteristics, therapy, clinical outcome and microbiological results were obtained from the electronic medical records. The relative impact of antibiotic therapy, patient factors and pathogens on clinical outcome was assessed with univariate logistic regression using a 95% confidence interval (CI). RESULTS: 832 prescriptions were identified, and 171 patients treated with nitrofurantoin (n = 69), pivmecillinam (n = 57) and trimethoprim (n = 45) met the inclusion criteria. Treatment failure occurred in one patient treated with nitrofurantoin and in four patients treated with pivmecillinam. New prescriptions of UTI antibiotics and relapse within 3 months after completion of therapy were more frequent with nitrofurantoin (34% and 15%) and pivmecillinam (30% and 17%) than trimethoprim (22 and 7%). However, these differences were not statistically significant and substantial heterogeneity was noted between the treatment groups. Urinary tract catheterization was associated with a higher risk for new antibiotic prescriptions (OR 2.34, 95% CI 1.14-4.80; P = 0.022) and prostate cancer was associated with a higher incidence of relapse (OR 3.01, 95% CI 1.09-8.29; P = 0.042). CONCLUSIONS: The clinical outcome with nitrofurantoin and pivmecillinam was acceptable in comparison with the results of previous studies. These antibiotics are suitable for empirical treatment of lower UTI in men considering their high activity against Escherichia coli and limited impact on the intestinal microbiota.

Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study.

Objectives: To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods: A prospective, multicentre, observational cohort study of women aged ≥16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration: Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results: The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for ≤5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions: Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production.

Optimal dosage and duration of pivmecillinam treatment for uncomplicated lower urinary tract infections: a systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs). METHODS: The MEDLINE, Embase, and Cochrane Library databases were searched. Randomized controlled clinical trials (RCTs) involving adults or children with symptoms suggestive of uncomplicated UTI and that compared different PIV regimes or PIV versus other antibiotics were included. Meta-analyses were conducted to obtain direct and indirect efficacy estimates. PIV regimes were categorized into high total dosage, moderate total dosage, and low total dosage. The risk of bias was evaluated using the Cochrane tool. RESULTS: Twenty-four RCTs were identified. No difference in clinical cure was found for the high vs. moderate (short-term: risk ratio (RR) 1.01, p=0.813; long term: RR 1.09, p=0.174) or high vs. low dosage comparisons (mean difference 0, 95% confidence interval -0.44 to 0.45, p=1). For bacteriological cure, comparisons of high vs. moderate dosage (short term: RR 1.05, p=0.056; long term: RR 1.05, p=0.131) and high vs. low dosage (short term: RR 1.02, p=0.759; long term: RR 1.13, p=0.247) showed a trend in favor of the high dosage treatment. Results for relapse, re-infection, and failure were inconclusive and not statistically significant. Patients treated with high dosages were 40% (p=0.062) and 44% (p=0.293) more likely to report mild to moderate adverse events. CONCLUSIONS: There is insufficient evidence to support the use of an optimal combination of dosage, frequency, and duration of PIV therapy for the treatment of uncomplicated lower UTI. Evidence is limited due to the high risk of bias, poor reporting, and heterogeneous study data.

The efficacy of pivmecillinam: 3 days or 5 days t.i.d against community acquired uncomplicated lower urinary tract infections - a randomized, double-blinded, placebo-controlled clinical trial study protocol.

BACKGROUND: Uncomplicated lower urinary tract infections (LUTI) are very common, and presumably around 200,000 female patients are treated for this annually in Denmark. The current Danish national clinical practice guidelines recommend pivmecillinam as a first-line drug (i.e., 400 mg t.i.d. for 3 days). Pivmecillinam is also one of the first-line drugs recommended in the international guidelines for LUTIs (i.e., 400 mg b.i.d. for 5 days). The international recommended duration is based on evidence saying that a 7-day regimen is better than a 3-day regimen. However, no data says that a 5-day regimen is superior to a 3-day regimen. With this study we aim to identify and to compare the efficacy of pivmecillinam 400 mg t.i.d in a 3-day respectively 5-day regimen, against community acquired uncomplicated LUTI, i.e., in women at the age of 18-70 year old. METHOD/DESIGN: The general practitioner will at consultation give a suitable patient the opportunity to participate in the study. If the patient will give her consent, a double-blinded kit (i.e., the antibiotic with/without placebo, questionnaires and self-urinary samples) will be given to the patient. We aim for 161 evaluable patients in each arm. DISCUSSION: Pivmecillinam is an excellent choice against urinary tract infections and we believe this study will fill in the gaps and strengthen the evidence on the treatment against one of the most common infections in our society. Thus, aiming to provide a more rational and ecological beneficial antimicrobial therapy. TRIAL REGISTRATION: EudraCTno.: 2014-001321-32 .

Best oral empirical treatment for pyelonephritis in children: Do we need to differentiate between age and gender?

BACKGROUND: Pyelonephritis is a common infection in childhood and may cause renal scarring. The aim was to determine an effective oral antibiotic treatment of first time pyelonephritis in children. METHODS: The study is a retrospective analysis of positive urine cultures collected at a Danish paediatric department from 2010-2013. Urine samples from 378 children aged 0-15.9 years, without renal anomalies and treated for first time pyelonephritis, were included. The urine pathogens and antimicrobial susceptibilities were analysed. RESULTS: The most common aetiologic agents found were Escherichia coli (85%), Klebsiella species and other Enterobacteriaecea (9.7%) and Enterococcus species (5.3%). Escherichia coli was significantly more common in girls than in boys (90% vs 74%, p < 0.001) and in children older than 6 months (89% vs 77%, p < 0.001). Children younger than 6 months had a higher prevalence of other Gram-negative rods (16% vs 7%, p < 0.001). These differences may be due to boys representing 63% of patients in the youngest age group compared to 16% of older children (p < 0.001). For all urine isolates, piv-mecillinam and amoxicillin-clavulanate had the lowest resistance rates of 6.9% and 7.2%, respectively, and 6% for both antimicrobials in patients older than 6 months. Uropathogens from boys above 6 months of age were more resistant to piv-mecillinam compared to girls (25% vs 2.4%, p < 0.001). CONCLUSION: This study recommends piv-mecillinam or amoxicillin-clavulanate as empirical treatment of first time pyelonephritis in Danish children from 6 months of age. Age and gender of patients should be taken into consideration when initiating empirical treatment.

Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria.

The continuing spread of resistant Gram-negative bacteria is a therapeutic challenge and prudent use of antimicrobials is therefore essential. Urinary tract infections (UTIs), usually due to Gram-negative bacteria, are among the most common infections seen in the community. Moreover, bacterial strains producing extended-spectrum ß-lactamases (ESBLs) that are resistant not only to cephalosporins and penicillins, but also to fluoroquinolones and trimethoprim, are becoming more prevalent in the community. This means that oral antibiotic options to treat these infections are limited. The discovery of new drugs to tackle these problems has been difficult and slow paced; it is therefore timely to 'rediscover' the current antibiotics we have available in our clinical formulary, to determine how best they can be used. Pivmecillinam is an oral antibiotic with excellent clinical efficacy in the treatment of uncomplicated UTIs. It has been used extensively in Nordic countries with few problems, but, despite this, it is not widely used in other countries. There is emerging in vitro and in vivo evidence of its activity against ESBL-producing organisms and its synergistic potential with ß-lactamase inhibitors. Pivmecillinam is well tolerated with a low side-effect profile. Pivmecillinam also has a minimal effect on the intestinal and vaginal flora of the host; thus, there is a lower rate of selection of resistant bacteria, vaginal candidiasis and, of note, Clostridium difficile.

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 agn43a(CFT073) 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 agn43a(CFT073) or agn43b(CFT073) 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 efficacy of tebipenem pivoxil treatment in children with pneumonia, who had no relief despite having administered oral beta-lactam antibiotics].

We assessed the clinical efficacy of tebipenem pivoxil (TBPM-PI) in 30 children with pneumonia who, despite having received oral administration of beta-lactam antibiotics at the standard dose for at least 3 days, had no relief of symptoms and showed an abnormal shadow on the chest X-ray and elevated serum CRP levels of 3.0 mg/dl or more between December 2009 and November 2010. TBPM-PI was administered at a single dose of 4 mg/kg twice a day for 3 days. The children ranged in age from 8 months to 5 years. The serum CRP level ranged from 3.05 to 12.9 mg/dl. In 28 of the 30 children, either Streptococcus pneumoniae or Haemophilus influenzae or both were detected. Of the 28 children, 7 carried penicillin resistant S. pneumoniae; 9 carried beta-lactamase nonproducing ampicillin resistant H. influenzae; and 3 carried both. In all children, defervescence was observed within 48 hours of the start of TBPM-PI administration, and the severity of coughing/wheezing reduced significantly by the 3rd to 5th day. Thus, TBPM-PI was determined to be effective. Diarrhea or loose stool was observed as an adverse reaction in 4 children (13.3%).

Pivmecillinam versus sulfamethizole for short-term treatment of uncomplicated acute cystitis in general practice: a randomized controlled trial.

OBJECTIVE: To investigate whether short-term treatment with pivmecillinam was more effective than sulfamethizole in patients with acute uncomplicated urinary tract infection (UTI). DESIGN: Randomized controlled trial. SETTING: General practice, Denmark. SUBJECTS: Patients (n = 167) with uncomplicated UTI confirmed by positive urine phase-contrast microscopy. MAIN OUTCOME MEASURES: Drug efficacy based on clinical and bacteriological cure. RESULTS: Urinary symptoms disappeared first in patients treated with pivmecillinam, but after five days there was no significant difference in clinical cure rate between the two antibiotics. At the follow-up visit 7-10 days after initiation of treatment, 95.4% of patients treated with pivmecillinam and 92.6% of patients treated with sulfamethizole had no persistent cystitis symptoms (difference 2.8%, CI -4.5%; 10.0%). Bacteriological cure was observed in 68.8% of patients randomized to pivmecillinam and in 77.9% randomized to sulfamethizole (difference -9.2%, CI -24.7%; 6.3%). Some 26.8% of patients randomized to pivmecillinam experienced a new UTI within 6 months after treatment compared with 18.4% of patients randomized to sulfamethizole (difference 8.4%, CI -4.5%;21.4%). No patients developed septicaemia with urinary pathogens within one year after initial treatment. CONCLUSION: Patients treated with a three-day regime of pivmecillinam experienced faster relief of symptoms compared with patients treated with a three-day regime of sulfamethizole. Five days after initiation of treatment there was no significant difference in clinical and bacteriological cure between the two antibiotic regimes.

Urine bactericidal activity against Escherichia coli isolates exhibiting different resistance phenotypes/genotypes in an in vitro pharmacodynamic model simulating urine concentrations obtained after oral administration of a 400-milligram single dose of cefditoren-pivoxil.

Activity of simulated cefditoren urinary concentrations was determined against seven Escherichia coli isolates. Bactericidal activity was obtained from 4 to 24 h against TEM-1 (penicillinase production/hyperproduction), TEM-34 (IRT-6), and TEM-116 (extended-spectrum beta-lactamase [ESBL]) and from 6 to 8 h against SHV/TEM-116 (ESBL) but never against SHV/TEM-1 (ESBL). Extension of bactericidal activity depended on the resistance genotype/phenotype tested.

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 x 2 x 7 days is recommended as a first-line therapy for LUTIW.

Ecological effects of perorally administered pivmecillinam on the normal vaginal microflora.

The knowledge of the effects of antimicrobial agents on the normal vaginal microflora is limited. The objective of the present study was to study the ecological impact of pivmecillinam on the normal vaginal microflora. In 20 healthy women, the estimated day of ovulation was determined during three subsequent menstrual cycles. Microbiological and clinical examinations were performed on the estimated day of ovulation and on day 3 in all cycles and also on day 7 after ovulation in cycles 1 and 2. Anaerobic and facultative anaerobic gram-positive rods, mainly species of lactobacilli and actinomycetes, dominated the microflora. One woman was colonized on the third day of administration with a resistant Escherichia coli strain, and Candida albicans was detected in one woman on days 3 and 7 in cycle 2. No other major changes in the normal microflora occurred during the study. Administration of pivmecillinam had a minor ecological impact on the normal vaginal microflora.

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.

Hyperammonemic encephalopathy induced by a combination of valproate and pivmecillinam.

We describe the clinical and neurophysiological findings in a case of hyperammonemic encephalopathy. A 72-year-old woman taking valproate (VPA), as monotherapy for her partial epilepsy developed urinary tract infection. She was treated with pivmecillinam 600 mg daily. The following days she deteriorated and became stuporous. At admission her serum ammonia level was increased (113 mmol/l) but the liver function appeared normal. EEG showed bilateral triphasic waves and continuous high-amplitude delta-theta wave. The patient recovered rapidly after discontinuation of VPA and i.v. treatment with cefuroxime for her urinary tract infection. VPA-induced hyperammonemic encephalopathy in adults is a rare phenomenon, especially when VPA is used as monotherapy. It has been suggested that the VPA-induced hyperammonemic encephalopathy is due to reduced serum carnitine concentration. Pivmecillinam, a widely used antibiotic for treatment of urinary tract infections, is also known to decrease the serum carnitine concentration. Our case shows that caution is required when treatment with VPA is combined with pivmecillinam due to the risk of developing hyperammonemic encephalopathy.

[Urinary antimicrobial prophylaxis]. / Antibioprophylaxie urinaire.

Antibiotics are usually used to prevent childhood recurrent urinary tract infections: cystitis or pyelonephritis. The mechanism of action of these antibiotics, although imperfectly known, seems to be double: the antibiotic acts by its bactericidal effect, but also probably for minimal concentrations by reducing adhesion capability of bacteria to the urothelium. The most commonly used molecules are cotrimoxazole, trimethoprime, pivmecillinam, cefaclor and nalidixic acid. However all have not been studied rigorously as for their prophylactic capacity, and in particular very little is known for patients presenting with vesico-ureteral reflux.

Effect of perorally administered pivmecillinam on the normal oropharyngeal, intestinal and skin microflora.

To study the ecological effects of pivmecillinam on the human oropharyngeal, intestinal and skin microflora, 15 healthy volunteers were given pivmecillinam tablets 400 mg twice daily for 7 days. Saliva, stool and skin specimens were taken before (days -3 and 0) and on the 2nd, 4th and 7th days during the administration period and 14 and 21 days after the start of administration. Mecillinam caused no major changes in the aerobic or anaerobic oropharyngeal microflora. In the aerobic intestinal microflora there was a decrease in the numbers of Escherichia coli while no changes occurred in the anaerobic microflora. In the skin microflora there was a transient decrease in the numbers of Propionibacterium spp. underneath the wing of the nose. The major effect of pivmecillinam was seen on E. coli and to some extent on Propionibacterium spp. No further ecological disturbances were noticed in the oropharyngeal, intestinal or skin microflora.

[Repeat antibiotic prescriptions following treatment with sulfonamide or pivmecillinam. A survey of prescriptions among women aged 15-50 years in the county of Nordjylland]. / Indløsning af en ny antibiotikumrecept efter behandling med sulfonamid eller pivmecillinam. En receptundersøgelse blandt 15-50-årige kvinder i Nordjyllands Amt.

INTRODUCTION: A sulphonamide is the antibiotic of first choice for the treatment of uncomplicated urinary tract infections in Denmark. However, this recommendation has been challenged. MATERIAL AND METHODS: The study comprised 9,224 women, aged 15 to 50 years, who were residents in the County of North Jutland, Denmark. During 1997-1998 they had handed in a prescription from a general practitioner for either sulphonamide or pivmecillinam, but no other prescriptions for antibiotics during the preceding six months. Any antibiotic prescription handed in within the ensuing 31-day period was recorded, with the exception of macrolides. The proportion of women with a repeat prescription was a proxy for therapeutic failure. RESULTS: Eight thousand two hundred and sixty-nine women (89.6%) had handed in a prescription for a sulphonamide and 955 (10.4%) a prescription for pivmecillinam. A total of 1,490 women (16.2%) handed in a repeat prescription, i.e. 16.0% (95% confidence limits [CI] 15.2-16.8%) of women treated with sulphonamide and 17.8% (95% CI 15.4-20.4%) of women treated with pivmecillinam. The relative risk of a repeat prescription was 1.11 (95% CI 0.95-1.31) for women with a primary prescription for pivmecillinam, as compared to women with a sulphonamide prescription. Women who had handed in a sulphonamide prescription for less than three defined daily doses had an increased risk of a repeat prescription. DISCUSSION: The proportion of women with a repeat prescription did not differ much between women treated with sulphonamide and those treated with pivmecillinam. Controlled clinical trials should be performed before revision of current Danish recommendations are considered.