Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales: a prospective multicentre study.

OBJECTIVES: Treatment options for urinary tract infections (UTIs) caused by ESBL-producing Enterobacterales are limited. Moreover, evidence to support therapeutic decisions is lacking. This study assessed current treatment strategies and patient and pathogen characteristics in relation to clinical and microbiological outcomes. METHODS: Patients with UTI caused by ESBL-producing Enterobacterales were prospectively recruited by investigators at 15 infectious disease hospital departments. Data were collected on patient characteristics, treatments, clinical and microbiological cure 10-14 days after the end of treatment, and relapse within 3 months. Bacterial isolates were subjected to MIC determination and WGS. RESULTS: In total, 235 patients (107 febrile UTI, 128 lower UTI) caused by Escherichia coli (n = 223) and Klebsiella spp. (n = 12) were included. Clinical and microbiological cure rates were 83% and 64% in febrile UTI, and 79% and 65% in lower UTI. Great variability in treatments was observed, especially in oral therapy for febrile UTI. No difference was seen in clinical outcomes with piperacillin/tazobactam (n = 28) compared with carbapenems (n = 41). Pivmecillinam was frequently used in lower UTI (n = 62), and was also associated with high clinical cure rates when used as initial therapy (10/10) or follow-up (7/8) for febrile UTI. Recurrent infection, diabetes mellitus and urogenital disease were associated (P < 0.05) with clinical failure and relapse. In E. coli, ST131 was significantly associated with relapse, and haemolysin with microbiological failure or relapse. CONCLUSIONS: Antibiotic treatments were highly variable. Patient and pathogen factors were identified as potential determinants of disease presentation and outcomes and may prove useful to guide individualized treatment and follow-up.

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.

Synergistic and bactericidal activities of mecillinam, amoxicillin and clavulanic acid combinations against extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli in 24-h time-kill experiments.

This study aimed to evaluate the potential synergistic and bactericidal effects of mecillinam in combination with amoxicillin and clavulanic acid against extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli. Eight clinical E. coli isolates with varying susceptibility to mecillinam [minimum inhibitory concentrations (MICs) of 0.125 mg/L to >256 mg/L] and high-level resistance to amoxicillin (MICs > 256 mg/L) were used. Whole-genome sequencing was performed to determine the presence of ß-lactamase genes and mutations in the cysB gene. The activities of single drugs and the combinations of two or three drugs were tested in 24-h time-kill experiments. Population analysis was performed for two strains before and after experiments. Only one strain had a mutation in the cysB gene resulting in an amino acid substitution. With the two-drug combinations, initial killing was observed both with mecillinam and amoxicillin when combined with clavulanic acid. Synergy was observed with mecillinam and clavulanic acid against one strain and with amoxicillin and clavulanic acid against three strains. However, following significant re-growth, a bactericidal effect was found only with amoxicillin and clavulanic acid against two strains. Pre-existing subpopulations with elevated mecillinam MICs were detected before experiments and were selected with mecillinam alone or in two-drug combinations. In contrast, the three-drug combination showed enhanced activity with synergy against six strains, a bactericidal effect against all eight strains, and suppression of resistance during 24-h antibiotic exposure. This combination may be of clinical interest in the treatment of urinary tract infections caused by ESBL-producing E. coli.