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

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

Chemical genetic approaches for the discovery of bacterial cell wall inhibitors

“…96 Mecillinam is the active form of the prodrug pivmecillinam and is used to treat lower urinary tract infections. 97 Apart from PBP2, MreB is the most studied protein, and several attempts have been made to search for drugs targeting this protein. However, despite many efforts, no clinically significant drug has been discovered to target the protein due to toxicity issues, while some are still in the initial discovery phase.…”

Pivmecillinam with Amoxicillin/Clavulanic acid as step down oral therapy in febrile Urinary Tract Infections caused by ESBL-producing Enterobacterales (PACUTI)

“…Treating febrile UTI (e.g., pyelonephritis) with pivmecillinam is still controversial due to a lack of evidence from RCTs but is practiced in many institutions in Sweden, Denmark and Norway [ 15 ]. A recent prospective observational study from Norway supported the use of pivmecillinam as step-down therapy for pyelonephritis with E. coli bacteraemia [ 16 ] while a retrospective study of pivmecillinam in EPE-causing pyelonephritis showed high rates of clinical failure [ 17 ]. We believe that these observational studies may reflect a true association, i.e.…”

Prevalence of antibiotic-resistant gram-negative bacteria among patients with urinary tract infection at a facility in Ado Ekiti, Ekiti-State, Nigeria

“…The common antibiotics that are used for the treatment and management of UTIs include the fluoroquinolones, third generation cephalosporins and other types of beta lactams (Bader et al, 2020). Other novel antibiotics such as pivmecillinam and mecillinam have been used for treatment of UTIs in different setting (Hansen et al, 2022;Jensen et al, 2022). The heavy dependence on the use of antibiotics for the treatment and management of UTI has raised concerns due the emergence of antibiotic resistant bacteria (Haindongo et al, 2022).…”