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Jenny Dahl Knudsen - One of the best experts on this subject based on the ideXlab platform.

  • mutational change of ctx m 15 to ctx m 127 resulting in mecillinam resistant escherichia coli during Pivmecillinam treatment of a patient
    MicrobiologyOpen, 2019
    Co-Authors: Karen Leth Nielsen, Frederik Boetius Hertz, Niels Frimodtmoller, Jenny Dahl Knudsen, Katrine Hartung Hansen, Jesper Bo Nielsen, Kristian Schonning, Filip Jansaker
    Abstract:

    Pivmecillinam (amdinocillin pivoxil) is the recommended first-choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. The frequency of mutation to mecillinam (MEC) resistance is described as high in vitro; however, treatment of UTI has a good clinical response and prevalence of mecillinam resistance in Escherichia coli remains low despite many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of ESBL-producing E. coli following Pivmecillinam treatment. The identified phenotypic differences in the mecillinam resistant isolate compared with the original mecillinam susceptible isolate were a full-length LPS with O-antigen (O25), mecillinam resistance and a lower MIC for ceftazidime. Regarding genotype, the resistant isolate differed with a mutation in blaCTX-M-15 to blaCTX-M-127 , loss of a part of a plasmid and a genomic island, respectively, and insertion of a transposase in wbbL, causing the rough phenotype. The observed mecillinam resistance is expected to be caused by the mutation in blaCTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of Pivmecillinam as first-line treatment for UTI.

  • 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
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Jonas Bredtoft Boel, Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    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 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.

  • Pivmecillinam compared to other antimicrobials for community acquired urinary tract infections with escherichia coli esbl producing or not a retrospective cohort study
    Infection and Drug Resistance, 2019
    Co-Authors: Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Jonas Bredtoft Boel, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    Objectives To compare the therapeutic effect of Pivmecillinam and other common oral antibiotics for community-acquired urinary tract infections (UTIs) caused by Extended Spectrum Beta-Lactamase (ESBL)- or non-ESBL-producing Escherichia coli. Methods Retrospective cohort study from 2010 to mid-2016 with data from the regional Laboratory Database and three national databases on antibiotic prescriptions, hospital admission, and mortality, respectively. Primary care patients (≥18 years) empirically treated for UTI caused by non-ESBL- or ESBL-producing E. coli (non-ESBL and ESBL E. coli) were included. Seven antibiotics, commonly used empirically for UTI, were investigated. Treatment failure measured as the redemption of a new antibiotic prescription or admission to hospital due to UTI. Cox proportional hazard ratios and adjusted risk differences along with 95% confidence intervals were calculated for 14 and 30 days, respectively. Results Thirty-six thousand two hundred and ninety-three (95.7%) and 1624 (4.3%) cases were included in the non-ESBL and ESBL groups, respectively. Male sex, high age, ESBL production, and resistance to empirical therapy were found to independently increase the risk of treatment failure. Compared to Pivmecillinam, ciprofloxacin had significantly lower treatment failure for non-ESBL E. coli, but significantly higher treatment failure in ESBL E. coli. There was no significant difference between nitrofurantoin and Pivmecillinam. Conclusion All antibiotics seem to have a higher risk of treatment failure for UTI caused by ESBL-producing E. coli as compared to non-ESBL-producing E. coli. At present, nitrofurantoin and Pivmecillinam seem to be the most relevant orally available therapies for E. coli UTI. Local resistance data should guide which of the two that should be the contemporary first-line option.

  • Pivmecillinam for uncomplicated lower urinary tract infections caused by staphylococcus saprophyticus cumulative observational data from four recent clinical studies
    Antibiotics, 2019
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

  • in vivo mecillinam resistance in escherichia coli after Pivmecillinam treatment of a urinary tract infection
    MicrobiologyOpen, 2019
    Co-Authors: Karen Leth Nielsen, Frederik Boetius Hertz, Niels Frimodtmoller, Jenny Dahl Knudsen, Katrine Hartung Hansen, Filip Jansaker
    Abstract:

    Pivmecillinam (amdinocillin pivoxil) is the recommended first choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. Yet, in laboratory settings the frequency of mutation to mecillinam resistance has been found to be very high. Treatment of UTI has a good clinical response, but low bacteriological cure rates. Prevalence of mecillinam resistance in Escherichia coli remains low in spite of many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of extended-spectrum β-lactamase producing E. coli following Pivmecillinam treatment. The only identified phenotypic differences in MEC-R compared to the original MEC-S isolate were full-length lipopolysaccharides with O-antigen (O25), mecillinam resistance, and a lower minimum inhibitory concentration for ceftazidime. Whether the serotype change and mutation in fhlA is the cause of the mecillinam resistance is unknown. Further studies are required to elucidate this possible mechanism. We continue to recommend the use of Pivmecillinam as first-line treatment for UTI, yet mecillinam treatment for other foci should be investigated.

Filip Jansaker - One of the best experts on this subject based on the ideXlab platform.

  • mutational change of ctx m 15 to ctx m 127 resulting in mecillinam resistant escherichia coli during Pivmecillinam treatment of a patient
    MicrobiologyOpen, 2019
    Co-Authors: Karen Leth Nielsen, Frederik Boetius Hertz, Niels Frimodtmoller, Jenny Dahl Knudsen, Katrine Hartung Hansen, Jesper Bo Nielsen, Kristian Schonning, Filip Jansaker
    Abstract:

    Pivmecillinam (amdinocillin pivoxil) is the recommended first-choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. The frequency of mutation to mecillinam (MEC) resistance is described as high in vitro; however, treatment of UTI has a good clinical response and prevalence of mecillinam resistance in Escherichia coli remains low despite many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of ESBL-producing E. coli following Pivmecillinam treatment. The identified phenotypic differences in the mecillinam resistant isolate compared with the original mecillinam susceptible isolate were a full-length LPS with O-antigen (O25), mecillinam resistance and a lower MIC for ceftazidime. Regarding genotype, the resistant isolate differed with a mutation in blaCTX-M-15 to blaCTX-M-127 , loss of a part of a plasmid and a genomic island, respectively, and insertion of a transposase in wbbL, causing the rough phenotype. The observed mecillinam resistance is expected to be caused by the mutation in blaCTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of Pivmecillinam as first-line treatment for UTI.

  • 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
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Jonas Bredtoft Boel, Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    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 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.

  • three versus five days of Pivmecillinam for community acquired uncomplicated lower urinary tract infection a randomised double blind placebo controlled superiority trial
    EClinicalMedicine, 2019
    Co-Authors: Filip Jansaker, Frederik Boetius Hertz, Lars Bjerrum, Sara Thonnings, Thomas Kallemose, Jan Vaernet, Thomas Benfield
    Abstract:

    Abstract Background To investigate if a 5-day course Pivmecillinam (amdinocillin pivoxil) 400 mg three times daily is superior to a 3-day course in women with uncomplicated urinary tract infection (UTI). Methods A randomised, double-blind, placebo-controlled trial conducted at nine primary care centres in Denmark. 368 women (18–70 years) with symptoms compatible with UTI were randomised to blinded therapy of 5 days [5d] or 3 days followed by 2 days of placebo [3d] from May 2015 to November 2017. Clinical data were assessed using a validated questionnaire at inclusion (day-0), daily the following 7 days and once again within the 2nd to 6th week after intervention. Bacteriological data were collected prior to intervention and twice between day 7 and 42. Main clinical endpoints were days to symptom resolution within 7 days after inclusion and proportions with clinical success at the end of intervention. Main bacteriological endpoint was proportion of participants with significant reduction of bacteriuria (≥ 102 CFU/mL) in 1st control urine sample. ClinicalTrialsRegister.eu: 2014–001321-32. Findings 180 (5d) and 188 (3d) participants were included in the study (mean age: 35.4 [5d] and 34.9 [3d]). Of these, 125 (70% [5d]) and 122 (66% [3d]) had a positive baseline urine culture. Forty-four participants were lost to follow-up, leaving 161 [5d] and 163 [3d] participants for analysis, respectively. Mean time to symptom resolution was 2.91 (SD 1.46; [5d]) days and 2.94 (SD 1.42; [3d]) days (P = .894). Clinical success at the end of treatment occurred for 117 of 153 (76%) receiving the 5d-course and for 115 of 157 (73%) receiving the 3d course (difference 3.2% [95% CI -7.1% - 13.5%]; P = .601). Bacteriological success was seen in 92 of 104 (88%) participants given the 5d course and in 86 of 99 (87%) given the 3d course (difference 1.6% [95% CI -8.4%-11.6%]; P = .895). Interpretations A 5-day course of Pivmecillinam was not superior to a 3-day course in clinical or bacteriological outcomes for UTI. Primary funding source The Danish Regions [no. 14/217].

  • Pivmecillinam compared to other antimicrobials for community acquired urinary tract infections with escherichia coli esbl producing or not a retrospective cohort study
    Infection and Drug Resistance, 2019
    Co-Authors: Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Jonas Bredtoft Boel, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    Objectives To compare the therapeutic effect of Pivmecillinam and other common oral antibiotics for community-acquired urinary tract infections (UTIs) caused by Extended Spectrum Beta-Lactamase (ESBL)- or non-ESBL-producing Escherichia coli. Methods Retrospective cohort study from 2010 to mid-2016 with data from the regional Laboratory Database and three national databases on antibiotic prescriptions, hospital admission, and mortality, respectively. Primary care patients (≥18 years) empirically treated for UTI caused by non-ESBL- or ESBL-producing E. coli (non-ESBL and ESBL E. coli) were included. Seven antibiotics, commonly used empirically for UTI, were investigated. Treatment failure measured as the redemption of a new antibiotic prescription or admission to hospital due to UTI. Cox proportional hazard ratios and adjusted risk differences along with 95% confidence intervals were calculated for 14 and 30 days, respectively. Results Thirty-six thousand two hundred and ninety-three (95.7%) and 1624 (4.3%) cases were included in the non-ESBL and ESBL groups, respectively. Male sex, high age, ESBL production, and resistance to empirical therapy were found to independently increase the risk of treatment failure. Compared to Pivmecillinam, ciprofloxacin had significantly lower treatment failure for non-ESBL E. coli, but significantly higher treatment failure in ESBL E. coli. There was no significant difference between nitrofurantoin and Pivmecillinam. Conclusion All antibiotics seem to have a higher risk of treatment failure for UTI caused by ESBL-producing E. coli as compared to non-ESBL-producing E. coli. At present, nitrofurantoin and Pivmecillinam seem to be the most relevant orally available therapies for E. coli UTI. Local resistance data should guide which of the two that should be the contemporary first-line option.

  • Pivmecillinam for uncomplicated lower urinary tract infections caused by staphylococcus saprophyticus cumulative observational data from four recent clinical studies
    Antibiotics, 2019
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

Marianne Bollestad - One of the best experts on this subject based on the ideXlab platform.

  • microbial risk factors for treatment failure of Pivmecillinam in community acquired urinary tract infections caused by esbl producing escherichia coli
    Apmis, 2020
    Co-Authors: Heidi Syre, Marianne Bollestad, Nils Grude, Marit Andrea Klokkhammer Hetland, Eva Bernhoff, Gunnar Skov Simonsen, Iren Hoyland Lohr
    Abstract:

    This is the peer reviewed version of the following article: Syre H, Hetland MAK, Bernhoff E, Bollestad M, Grude N, Simonsen GS, Lohr, I.H. Microbial risk factors for treatment failure of Pivmecillinam in community-acquired urinary tract infections caused by ESBL-producing Escherichia coli. APMIS, 2019. which has been published in final form at https://doi.org/10.1111/apm.13013. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

  • Pivmecillinam for uncomplicated lower urinary tract infections caused by staphylococcus saprophyticus cumulative observational data from four recent clinical studies
    Antibiotics, 2019
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

  • Pivmecillinam for Uncomplicated Lower Urinary Tract Infections Caused by Staphylococcus saprophyticus—Cumulative Observational Data from Four Recent Clinical Studies
    MDPI AG, 2019
    Co-Authors: Filip Jansaker, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Niels Frimodt-møller, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18−55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised

  • clinical and bacteriological efficacy of Pivmecillinam treatment for uncomplicated urinary tract infections caused by esbl producing escherichia coli a prospective multicentre observational cohort study
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: Marianne Bollestad, Nils Grude, Sigrid Solhaug, Niclas Raffelsberger, Nina Handal, Hansjohnny Schjelderup Nilsen, Monica Regine Romstad, Andreas Emmert, Yngvar Tveten
    Abstract:

    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.

  • ibuprofen versus Pivmecillinam for uncomplicated urinary tract infection in women a double blind randomized non inferiority trial
    PLOS Medicine, 2018
    Co-Authors: Ingvild Vik, Lars Bjerrum, Marianne Bollestad, Nils Grude, Anders Baerheim, Eivind Damsgaard, Thomas Neumark, Gloria Cordoba, I C Olsen
    Abstract:

    Background Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to Pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. Methods and findings This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18–60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg Pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or Pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the Pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of Pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of Pivmecillinam. After 4 weeks’ follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. Conclusions Ibuprofen was inferior to Pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. Trial registration ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14

Niels Frimodtmoller - One of the best experts on this subject based on the ideXlab platform.

  • mutational change of ctx m 15 to ctx m 127 resulting in mecillinam resistant escherichia coli during Pivmecillinam treatment of a patient
    MicrobiologyOpen, 2019
    Co-Authors: Karen Leth Nielsen, Frederik Boetius Hertz, Niels Frimodtmoller, Jenny Dahl Knudsen, Katrine Hartung Hansen, Jesper Bo Nielsen, Kristian Schonning, Filip Jansaker
    Abstract:

    Pivmecillinam (amdinocillin pivoxil) is the recommended first-choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. The frequency of mutation to mecillinam (MEC) resistance is described as high in vitro; however, treatment of UTI has a good clinical response and prevalence of mecillinam resistance in Escherichia coli remains low despite many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of ESBL-producing E. coli following Pivmecillinam treatment. The identified phenotypic differences in the mecillinam resistant isolate compared with the original mecillinam susceptible isolate were a full-length LPS with O-antigen (O25), mecillinam resistance and a lower MIC for ceftazidime. Regarding genotype, the resistant isolate differed with a mutation in blaCTX-M-15 to blaCTX-M-127 , loss of a part of a plasmid and a genomic island, respectively, and insertion of a transposase in wbbL, causing the rough phenotype. The observed mecillinam resistance is expected to be caused by the mutation in blaCTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of Pivmecillinam as first-line treatment for UTI.

  • 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
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Jonas Bredtoft Boel, Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    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 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.

  • Pivmecillinam compared to other antimicrobials for community acquired urinary tract infections with escherichia coli esbl producing or not a retrospective cohort study
    Infection and Drug Resistance, 2019
    Co-Authors: Filip Jansaker, Frederik Boetius Hertz, Niels Frimodtmoller, Katrine Hartung Hansen, Jonas Bredtoft Boel, Sara Thonnings, Jenny Dahl Knudsen
    Abstract:

    Objectives To compare the therapeutic effect of Pivmecillinam and other common oral antibiotics for community-acquired urinary tract infections (UTIs) caused by Extended Spectrum Beta-Lactamase (ESBL)- or non-ESBL-producing Escherichia coli. Methods Retrospective cohort study from 2010 to mid-2016 with data from the regional Laboratory Database and three national databases on antibiotic prescriptions, hospital admission, and mortality, respectively. Primary care patients (≥18 years) empirically treated for UTI caused by non-ESBL- or ESBL-producing E. coli (non-ESBL and ESBL E. coli) were included. Seven antibiotics, commonly used empirically for UTI, were investigated. Treatment failure measured as the redemption of a new antibiotic prescription or admission to hospital due to UTI. Cox proportional hazard ratios and adjusted risk differences along with 95% confidence intervals were calculated for 14 and 30 days, respectively. Results Thirty-six thousand two hundred and ninety-three (95.7%) and 1624 (4.3%) cases were included in the non-ESBL and ESBL groups, respectively. Male sex, high age, ESBL production, and resistance to empirical therapy were found to independently increase the risk of treatment failure. Compared to Pivmecillinam, ciprofloxacin had significantly lower treatment failure for non-ESBL E. coli, but significantly higher treatment failure in ESBL E. coli. There was no significant difference between nitrofurantoin and Pivmecillinam. Conclusion All antibiotics seem to have a higher risk of treatment failure for UTI caused by ESBL-producing E. coli as compared to non-ESBL-producing E. coli. At present, nitrofurantoin and Pivmecillinam seem to be the most relevant orally available therapies for E. coli UTI. Local resistance data should guide which of the two that should be the contemporary first-line option.

  • Pivmecillinam for uncomplicated lower urinary tract infections caused by staphylococcus saprophyticus cumulative observational data from four recent clinical studies
    Antibiotics, 2019
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

  • in vivo mecillinam resistance in escherichia coli after Pivmecillinam treatment of a urinary tract infection
    MicrobiologyOpen, 2019
    Co-Authors: Karen Leth Nielsen, Frederik Boetius Hertz, Niels Frimodtmoller, Jenny Dahl Knudsen, Katrine Hartung Hansen, Filip Jansaker
    Abstract:

    Pivmecillinam (amdinocillin pivoxil) is the recommended first choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. Yet, in laboratory settings the frequency of mutation to mecillinam resistance has been found to be very high. Treatment of UTI has a good clinical response, but low bacteriological cure rates. Prevalence of mecillinam resistance in Escherichia coli remains low in spite of many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of extended-spectrum β-lactamase producing E. coli following Pivmecillinam treatment. The only identified phenotypic differences in MEC-R compared to the original MEC-S isolate were full-length lipopolysaccharides with O-antigen (O25), mecillinam resistance, and a lower minimum inhibitory concentration for ceftazidime. Whether the serotype change and mutation in fhlA is the cause of the mecillinam resistance is unknown. Further studies are required to elucidate this possible mechanism. We continue to recommend the use of Pivmecillinam as first-line treatment for UTI, yet mecillinam treatment for other foci should be investigated.

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  • three versus five days of Pivmecillinam for community acquired uncomplicated lower urinary tract infection a randomised double blind placebo controlled superiority trial
    EClinicalMedicine, 2019
    Co-Authors: Filip Jansaker, Frederik Boetius Hertz, Lars Bjerrum, Sara Thonnings, Thomas Kallemose, Jan Vaernet, Thomas Benfield
    Abstract:

    Abstract Background To investigate if a 5-day course Pivmecillinam (amdinocillin pivoxil) 400 mg three times daily is superior to a 3-day course in women with uncomplicated urinary tract infection (UTI). Methods A randomised, double-blind, placebo-controlled trial conducted at nine primary care centres in Denmark. 368 women (18–70 years) with symptoms compatible with UTI were randomised to blinded therapy of 5 days [5d] or 3 days followed by 2 days of placebo [3d] from May 2015 to November 2017. Clinical data were assessed using a validated questionnaire at inclusion (day-0), daily the following 7 days and once again within the 2nd to 6th week after intervention. Bacteriological data were collected prior to intervention and twice between day 7 and 42. Main clinical endpoints were days to symptom resolution within 7 days after inclusion and proportions with clinical success at the end of intervention. Main bacteriological endpoint was proportion of participants with significant reduction of bacteriuria (≥ 102 CFU/mL) in 1st control urine sample. ClinicalTrialsRegister.eu: 2014–001321-32. Findings 180 (5d) and 188 (3d) participants were included in the study (mean age: 35.4 [5d] and 34.9 [3d]). Of these, 125 (70% [5d]) and 122 (66% [3d]) had a positive baseline urine culture. Forty-four participants were lost to follow-up, leaving 161 [5d] and 163 [3d] participants for analysis, respectively. Mean time to symptom resolution was 2.91 (SD 1.46; [5d]) days and 2.94 (SD 1.42; [3d]) days (P = .894). Clinical success at the end of treatment occurred for 117 of 153 (76%) receiving the 5d-course and for 115 of 157 (73%) receiving the 3d course (difference 3.2% [95% CI -7.1% - 13.5%]; P = .601). Bacteriological success was seen in 92 of 104 (88%) participants given the 5d course and in 86 of 99 (87%) given the 3d course (difference 1.6% [95% CI -8.4%-11.6%]; P = .895). Interpretations A 5-day course of Pivmecillinam was not superior to a 3-day course in clinical or bacteriological outcomes for UTI. Primary funding source The Danish Regions [no. 14/217].

  • Pivmecillinam for uncomplicated lower urinary tract infections caused by staphylococcus saprophyticus cumulative observational data from four recent clinical studies
    Antibiotics, 2019
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

  • Pivmecillinam for Uncomplicated Lower Urinary Tract Infections Caused by Staphylococcus saprophyticus—Cumulative Observational Data from Four Recent Clinical Studies
    MDPI AG, 2019
    Co-Authors: Filip Jansaker, Lars Bjerrum, Ingvild Vik, Marianne Bollestad, Morten Lindbaek, Niels Frimodt-møller, Jenny Dahl Knudsen
    Abstract:

    Objectives: To investigate Pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where Pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18−55 years) were empirically treated with Pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised

  • ibuprofen versus Pivmecillinam for uncomplicated urinary tract infection in women a double blind randomized non inferiority trial
    PLOS Medicine, 2018
    Co-Authors: Ingvild Vik, Lars Bjerrum, Marianne Bollestad, Nils Grude, Anders Baerheim, Eivind Damsgaard, Thomas Neumark, Gloria Cordoba, I C Olsen
    Abstract:

    Background Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to Pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. Methods and findings This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18–60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg Pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or Pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the Pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of Pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of Pivmecillinam. After 4 weeks’ follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. Conclusions Ibuprofen was inferior to Pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. Trial registration ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14

  • 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
    BMC Infectious Diseases, 2016
    Co-Authors: Filip Jansaker, Niels Frimodtmoller, Lars Bjerrum, Jenny Dahl Knudsen
    Abstract:

    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. 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. 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. EudraCTno.: 2014-001321-32 .