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Karen Rønø Thingholm,1 Frederik Boëtius Hertz,1,2 Anders Løbner-Olesen,3 Niels Frimodt-Møller,1 Karen Leth Nielsen11Department of Clinical Microbiology, Rigshospitalet, Copenhagen 2100, Denmark; 2Department of Clinical Microbiology, Herlev and Gentofte Hospital, Herlev 2730, Denmark; 3Department of Biology, Section for Functional Genomics and Center for Bacterial Stress Response and Persistence, University of Copenhagen, Copenhagen, DenmarkBackground: Extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) causing urinary tract infections often belong to sequence type 131 (ST131), serotype O25, carrying blaCTX-M-15.Aim: The main aim of this study was to examine the conjugational frequencies of E. coli with plasmids carrying blaCTX-M-15 to E. coli isolates from the fecal flora of healthy humans to determine whether ST131 is more likely to uptake or donate ESBL resistance compared to other E. coli clones.Methods: Donors and recipients were all clinical isolates and did not harbor plasmids with identical incompatibility groups (Inc-groups) based on in silico analyses of Inc-groups and restriction/modification systems (R/M-systems). The in vitro conjugation experiments were performed as filter conjugation with verification of transconjugants by random amplified polymorphic DNA (RAPD) PCR and blaCTX-M-15 PCR.Results: The frequencies of conjugation with blaCTX-M-15-carrying plasmids were found to be very rare with detectable conjugation frequencies in the range of 4x10−9–7x10−7 transconjugants/recipient. Recipients of O25/ST131 type yielded significantly lower conjugation frequencies compared to recipients of other O-types (P=0.004). The applied ST131/O25 donors did not yield detectable levels of transconjugants regardless of the applied recipient. Presence of sub-MIC levels of ampicillin increased plasmid transfer frequencies x100 fold (P=0.07).Conclusion: The results indicate that blaCTX-M-15 is rarely transferred by conjugation to E. coli isolates of the intestinal flora, even when the gene is plasmid-borne.Keywords: horizontal gene transfer, antimicrobial resistance, Escherichia coli, molecular typing, ST131, faecal isolates

Filip Jansåker,1,2 Jonas Bredtoft Boel,3 Sara Thønnings,1,2 Frederik Boëtius Hertz,3 Katrine Hartung Hansen,2 Niels Frimodt-Møller,2 Jenny Dahl Knudsen1,21Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre, Denmark; 2Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; 3Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, 2730 Herlev, DenmarkObjectives: 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. Keywords: UTI, ESBL, E. coli, pivmecillinam, nitrofurantoin, cohort

Filip Jansåker,1,2 Niels Frimodt-Møller,3 Thomas L Benfield,2,4 Jenny Dahl Knudsen1,3 1Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 4Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark Purpose: The pharmacokinetic properties of mecillinam (MEC) for urinary tract infections are excellent, and the resistance rate in Enterobacteriaceae is low compared to other recommended antibiotics. The oral prodrug pivmecillinam (P-MEC) has been used successfully as first choice for cystitis in the Nordic countries for many years. Norwegian and Danish guidelines also recommend P-MEC for acute uncomplicated pyelonephritis (AUP) and intravenous (IV) MEC for suspected urosepsis (only in Denmark). Here, we wish to present an updated investigation on the clinical data behind these recommendations together with sparse but more current clinical data.Methods: Prospective clinical trials evaluating MEC as monotherapy or in polytherapy with one other beta-lactam (mostly ampicillin [AMP]) for pyelonephritis or bacteremia were reviewed. Outcomes of primary interest were clinical and bacteriological success and relapse, respectively. Search databases used were PubMed, Cochrane Library, and Embase.Results: Twelve clinical studies (1979–2015) were included in this integrated literature review. Clinical success was seen in 38/51 (75%) patients treated with MEC as monotherapy and in 152/164 (93%) patients treated with MEC and one other beta-lactam. Bacteriological success was seen in 35/47 (74%) and 117/167 (70%) patients treated with MEC alone and with one other beta-lactam, respectively. In complicated infections, bacteriological success was much lower. Clinical relapse rate was not well described. Several uropathogenic bacteremia cases were treated successfully with MEC alone (ie, 10/15 [67%] and 13/15 [87%] for clinical and bacteriological success, respectively) or with one other beta-lactam (ie, 57/65 [88%] and 53/63 [84%] for clinical and bacteriological success, respectively). However, data on bacteremia are very sparse. Adverse reactions were few and mild (73/406 [18%]) and primarily seen when AMP was co-administered (69/73 [95%]). No serious adverse reactions were reported.Conclusion: IV MEC or oral P-MEC for 14 days may be suitable for the treatment of AUP and pediatric pyelonephritis. Randomized controlled trials using a single standardized dose of P-MEC compared to other current recommendations are warranted. Similarly, more evidence is required before MEC should be recommended for bacteremia or sepsis due to Enterobacteriaceae. Keywords: pyelonephritis, mecillinam, review, pivmecillinam, amdinocillin