The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study

Bjørn Åsheim Hansen, Nils Grude, Morten Lindbæk, Tore Stenstad, Bjørn Åsheim Hansen, Nils Grude, Morten Lindbæk, Tore Stenstad

Abstract

Background: The role of oral beta-lactam antibiotics in treating febrile urinary tract infections (UTI) is not yet definite. Today, fluoroquinolones together with trimethoprim-sulfamethoxazole (TMP-MTX) are considered standard of care and often the only available evidence-based oral treatment for febrile UTI. This study clarifies the efficacy and safety of pivmecillinam (PIV) used as step-down therapy for bacteremic urinary tract infection (UTI).

Methods: A single-arm, uncontrolled treatment trial was conducted in the period September 2017-March 2020. Candidates for inclusion were men and women suffering from E. coli bacteremia due to UTI and were consecutively included in a Norwegian hospital. Exclusion criteria were among others: other ongoing bacterial infection, septic shock, pyonephrosis/abscess and pregnancy. After 3 days of parenteral antibiotic, the treatment was converted to the study drug; oral PIV 400 mg QID for 1 week. Primary endpoint was a combination of three elements; afebrility, no need for retreatment and improvement in self-reported health status. Test Of Cure (TOC) was 1 week post-treatment. Secondary endpoints included among others microbiological efficacy and CRP value < 30 mg/L.

Results: Of 476 screened subjects, 53 patients were included. Median age was 67 years, 28 (56%) were women. 50 patients were evaluated for per-protocol analysis. 44 of 50 patients (88%) (95% CI [75.7-95.5]) reached the primary endpoint on TOC. 14 of 48 patients (29.2%) had significant growth (> 103 CFU/mL) of E.coli on TOC. CRP-level was strongly associated to treatment outcome, (OR 0.006 [95% CI 0.00-0.11], p < 0.001).

Conclusions: This trial documents that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics, is a suitable treatment option in patients suffering from bacteremic UTI due to E. coli. Randomised clinical trials studying the efficacy of PIV vs standard of care of febrile UTI are warranted. Trial registration The trial was registered at ClinicalTrials.gov under the identifier: NCT03282006 13/09/2017 and approved by The Regional Committees for Medical Research Ethics South East Norway (2015/2384/REK sør-øst) and the Norwegian Medicines Agency (SLV; reference No 16/06018-09; EudraCT No 2016-000984-18) before initiation.

Keywords: Beta-lactam; Hospitalised; Mecillinam; Oral treatment; PROM; Pivmecillinam; Pyelonephritis; Urosepsis.

Conflict of interest statement

All authors have completed the ICMJE uniform disclosure form and report no conflicts of interest relevant to this article.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Patient course from admission to study completion
Fig. 2
Fig. 2
Trial algorithm

References

    1. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–e120. doi: 10.1093/cid/ciq257.
    1. EAU Guidelines on Urological Infections. 2018. . Accessed Oct 2020.
    1. EMA. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. 2019. . Accessed Sept 2020.
    1. Adriaenssens NC, Versporten S, Muller A, Minalu A, Faes G, Vankerckhoven C, Aerts V, Hens M, Molenberghs N, Goossens G. European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe (1997–2009) J Antimicrob Chemother. 2011;66(Suppl 6):vi47–56. doi: 10.1093/jac/dkr457.
    1. NORM/NORM-VET 2019. Usage of antimicrobial agents and occurrence of antimicrobial resistance in Norway. Tromsø/Oslo 2019. . Accessed Aug 2020.
    1. The electronic medicines compendium (emc). Co-Trimoxazole 80 mg/400 mg Tablets—SmPC 2020. . Accessed Nov 2020.
    1. Lund F, Tybring L. 6-amidinopenicillanic acids–a new group of antibiotics. Nat New Biol. 1972;236(66):135–137. doi: 10.1038/newbio236135a0.
    1. Dewar S, Reed LC, Koerner RJ. Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria. J Antimicrob Chemother. 2014;69(2):303–308. doi: 10.1093/jac/dkt368.
    1. Demos CH, Green E. Review of clinical experience with amdinocillin monotherapy and comparative studies. Am J Med. 1983;75(2a):72–81. doi: 10.1016/0002-9343(83)90098-0.
    1. SmPC - Pivmecillinamhydroklorid 200 mg resp. 400 mg Norwegian Medicines Agency 2019. . Accessed June 2020.
    1. Ostri P, Frimodt-Møller C. Concentrations of mecillinam and ampicillin determined in serum and renal tissue: a single-dose pharmacokinetic study in patients undergoing nephrectomy. Curr Med Res Opin. 1986;10(2):117–121. doi: 10.1185/03007998609110428.
    1. Nicolle LE. Pivmecillinam in the treatment of urinary tract infections. J Antimicrob Chemother. 2000;46(Suppl 1):35–39. doi: 10.1093/jac/46.suppl_1.35.
    1. Pinart M, Kranz J, Jensen K, Proctor T, Naber K, Kunath F, et al. Optimal dosage and duration of pivmecillinam treatment for uncomplicated lower urinary tract infections: a systematic review and meta-analysis. Int J Infect Dis. 2017;58:96–109. doi: 10.1016/j.ijid.2017.03.012.
    1. Swedres-Svarm 2019. Sales of antibiotics and occurrence of resistance in Sweden. Solna/Uppsala. 2019. . Accessed Aug 2020.
    1. DANMAP 2019—Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. 2019. . Accessed Aug 2020.
    1. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. 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. Scand J Prim Health Care. 2007;25(1):49–57. doi: 10.1080/02813430601183074.
    1. Jonsson M, Englund G, Nörgård K. Norfloxacin vs. pivmecillinam in the treatment of uncomplicated lower urinary tract infections in hospitalized elderly patients. Scand J Infect Dis. 1990;22(3):339–344. doi: 10.3109/00365549009027057.
    1. Bjerrum L, Gahrn-Hansen B, Grinsted P. Pivmecillinam versus sulfamethizole for short-term treatment of uncomplicated acute cystitis in general practice: a randomized controlled trial. Scand J Prim Health Care. 2009;27(1):6–11. doi: 10.1080/02813430802535312.
    1. Jansaker F, Frimodt-Moller N, Benfield TL, Knudsen JD. Mecillinam for the treatment of acute pyelonephritis and bacteremia caused by Enterobacteriaceae: a literature review. Infect Drug Resist. 2018;11:761–771. doi: 10.2147/IDR.S163280.
    1. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. 2020. . Accessed Nov 2020
    1. Charlson ME, Pompei P, Ales KL, Ronald MacKenzie C. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. doi: 10.1016/0021-9681(87)90171-8.
    1. Wittrup-Jensen KU LJ, Gudex C, Brooks R, Pedersen KM. Estimating Danish EQ-5D tariffs using TTO and VAS. Proceedings of the 18th plenary meeting of the EuroQol Group. IHE, The Swedish Institute for Health Economics. 2002.
    1. Norwegian Directorate of Health. Antibiotika i sykehus 2018. . Accessed Jan 2019.
    1. Cronberg S, Banke S, Bergman B, Boman H, Eilard T, Elbel E, et al. Fewer bacterial relapses after oral treatment with norfloxacin than with ceftibuten in acute pyelonephritis initially treated with intravenous cefuroxime. Scand J Infect Dis. 2001;33(5):339–343. doi: 10.1080/003655401750173922.
    1. Stamm WE, McKevitt M, Counts GW. Acute renal infection in women: treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks. A randomized trial. Ann Intern Med. 1987;106(3):341–345. doi: 10.7326/0003-4819-106-3-341.
    1. Sandberg T, Englund G, Lincoln K, Nilsson LG. Randomised double-blind study of norfloxacin and cefadroxil in the treatment of acute pyelonephritis. Eur J Clin Microbiol Infect Dis. 1990;9(5):317–323. doi: 10.1007/BF01973737.
    1. Punjabi C, Tien V, Meng L, Deresinski S, Holubar M. Oral fluoroquinolone or trimethoprim-sulfamethoxazole vs. ß-lactams as step-down therapy for enterobacteriaceae bacteremia: systematic review and meta-analysis. Open Forum Infect Dis. 2019;6(10):ofz364. doi: 10.1093/ofid/ofz364.
    1. Bollestad M, Grude N, Solhaug S, Raffelsberger N, Handal N, Nilsen HS, et al. Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study. J Antimicrob Chemother. 2018;73(9):2503–2509. doi: 10.1093/jac/dky230.
    1. Frimodt-Møller N. Correlation between pharmacokinetic/pharmacodynamic parameters and efficacy for antibiotics in the treatment of urinary tract infection. Int J Antimicrob Agents. 2002;19(6):546–553. doi: 10.1016/S0924-8579(02)00105-X.
    1. Sutton JD, Stevens VW, Chang NN, Khader K, Timbrook TT, Spivak ES. Oral β-lactam antibiotics vs fluoroquinolones or trimethoprim-sulfamethoxazole for definitive treatment of enterobacterales bacteremia from a urine source. JAMA Netw Open. 2020;3(10):e2020166. doi: 10.1001/jamanetworkopen.2020.20166.

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