Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study.

Introduction: Novel last resort beta-lactam antibiotics are now available for management of infections due to New-Delhi Metallo-Beta-Lactamase (NDM) producing Enterobacterales and non-fermenters with Difficult-to-Treat Resistance. However, data regarding the use of imipenem-cilastatin-relebactam (IMI-REL), cefiderocol (CFD) and ceftazidime-avibactam plus aztreonam (CAZ-AVI-ATM) are scarce in real-life settings. This study aimed to describe the use of last resort beta-lactam antibiotics, the microbiology and the outcome, in patients hospitalized in a tertiary hospital. Methods: We conducted a monocentric observational cohort study from 2020/01/01, to 2022/08/31. We screened all patients admitted to Nimes University Hospital who have received ≥ 1 dose of last resort beta-lactam antibiotics during the study period, using the Pharmacy database. We included patients treated with IMI-REL, CFD and CAZ-AVI-ATM. The primary endpoint was the infection-free survival rate. We also calculated rates of microbiological and clinical cure, recurrent infection, death and adverse events. Results: Twenty-seven patients were included in the study and 30 treatment courses were analyzed: CFD (N=24; 80%), CAZ-AVI-ATM (N=3; 10%) and IMI-REL (N=3; 10%). Antibiotics were used in 21 males (70%) and 9 females (30%) with a median age at 65-year-old [50-73.5] and a median Charlson index at 1 [0-2]. Almost all the patients had ≥ 1 risk factor for carbapenem resistant bacteria, a half of them was hospitalized for severe COVID-19, and most of antibiotic courses (N=26; 87%) were associated with ICU admission. In the study population, the probability of infection-free survival at day-90 after last resort beta-lactam therapy initiation was 48.4% CI95% [33.2-70.5]. Clinical failure rate was at 30%, microbiological failure rate at 33% and mortality rate at 23%. Adverse events were documented in 5 antibiotic courses (17%). In details, P. aeruginosa were mainly treated with CFD and IMI-REL, S. maltophilia with CFD and CAZ-AVI-ATM, A. baumannii with CFD, and NDM producing-K. pneumoniae with CAZ-AVI-ATM and CFD. After a treatment course with CFD, CAZ-AVI-ATM and IMI-REL, the probability of infection-free survival was 48% CI95% [10.4-73.5], 33.3% CI95% [6.7-100], 66.7% CI95% [30-100], respectively. Discussion/conclusion: Use of last resort beta-lactam antimicrobials in real-life settings was a safe and efficient therapeutic option for severe infections related to Gram-negative bacteria with Difficult-to-Treat Resistance.

A Multicenter, Randomized, Placebo-Controlled Study Evaluating the Efficacy of a Combination of Propolis and Cranberry (Vaccinium macrocarpon) (DUAB®) in Preventing Low Urinary Tract Infection Recurrence in Women Complaining of Recurrent Cystitis.

OBJECTIVES: The purpose of the study was to compare the efficacy of a product containing cranberry and propolis (DUAB) to placebo for reducing frequency of cystitis in women with recurrent acute cystitis. METHOD: A multicenter, placebo-controlled, randomized study of women aged >18 years with at least 4 episodes of cystitis in the previous 12 months was performed. The number of cystitis episodes over a 6-month follow-up was the primary end point. RESULTS: Forty-two women were included in the cranberry + propolis group, and 43 women were in the placebo group. The mean age was 53 ± 18 years, with 6.2 ± 3.6 cystitis episodes in the previous year, with no differences between the 2 groups. The mean number of infections was lower in the propolis + cranberry group (respectively, 2.3 ± 1.8 vs. 3.1 ± 1.8). The total number of cystitis episodes in the first 3 months was lower in the propolis + cranberry group (0.7 ± 1.1 vs. 1.3 ± 1.1, p = 0.0257) after adjusting for water consumption. The mean time to onset of the first urinary tract infection (UTI) was also significantly longer in the propolis + cranberry group (69.9 ± 45.8 days vs. 43.3 ± 45.9, p = 0.0258). Tolerance to the treatments was good and comparable in both groups. CONCLUSIONS: We demonstrate for the first time that cranberry and propolis supplementation significantly reduces the incidence of UTIs during the first 3 months and delays the onset of an episode of cystitis.

Propolis potentiates the effect of cranberry (Vaccinium macrocarpon) in reducing the motility and the biofilm formation of uropathogenic Escherichia coli.

One strategy to prevent urinary tract infections is the use of natural products such as cranberry (Vaccinium macrocarpon) and propolis. The objective of this study was to evaluate the impact of these products alone and combined on the motility and biofilm formation of a collection of representative uropathogenic Escherichia coli (UPEC). Motility was evaluated by the swarming and swimming capacity of the isolates in presence/absence of cranberry ± propolis. Early and late biofilm formation was observed with the Biofilm Ring test (BioFilm Control) and the crystal violet method. Cranberry alone was seen to have a variable effect on motility and biofilm formation unrelated to bacterial characteristics, but a reduced motility and biofilm formation was observed for all the isolates in the presence of cranberry + propolis. These results suggest that cranberry alone doesn't work on all the E. coli strains and propolis potentiates the effect of cranberry on UPEC, representing a new strategy to prevent recurrent urinary tract infections.

Propolis potentiates the effect of cranberry (Vaccinium macrocarpon) against the virulence of uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC), the most prevalent bacteria isolated in urinary tract infections (UTI), is now frequently resistant to antibiotics used to treat this pathology. The antibacterial properties of cranberry and propolis could reduce the frequency of UTIs and thus the use of antibiotics, helping in the fight against the emergence of antibiotic resistance. Transcriptomic profiles of a clinical UPEC strain exposed to cranberry proanthocyanidins alone (190 µg/mL), propolis alone (102.4 µg/mL) and a combination of both were determined. Cranberry alone, but more so cranberry + propolis combined, modified the expression of genes involved in different essential pathways: down-expression of genes involved in adhesion, motility, and biofilm formation, and up-regulation of genes involved in iron metabolism and stress response. Phenotypic assays confirmed the decrease of motility (swarming and swimming) and biofilm formation (early formation and formed biofilm). This study showed for the first time that propolis potentiated the effect of cranberry proanthocyanidins on adhesion, motility, biofilm formation, iron metabolism and stress response of UPEC. Cranberry + propolis treatment could represent an interesting new strategy to prevent recurrent UTI.

Aminoglycosides use in patients over 75 years old.

OBJECTIVE: to describe aminoglycoside use and nephrotoxicity in patients older than 75 years. DESIGN: retrospective multicenter study. SETTING: hospital department, rehabilitation, long-term care center. POPULATION: patients ≥75 years old treated by aminoglycosides. RESULTS: 184 patients, mean age: 84.4 years (range: 75-101). One hundred and twenty-seven patients received other nephrotoxic drug(s). Gentamicin (70%) and amikacin (30%) were used and the once-daily dosing was preferred (92%). Average treatment period was 2.75 (1-10) days for amikacin and 4.4 (1-30) for gentamicin with average dosage 13.5 and 3.5 mg/kg/day, respectively. The monitoring of maximal plasmatic concentration (Cmax) was done in 37 patients, 9 of them had probabilistic treatment. Only one had a Cmax fulfilling the objective of French recommendations (gentamicin >30 mg/l, amikacin >60 mg/l). When infection was documented, the objective of Cmax >10 × minimal inhibitory concentration of the strain was reached for 27%. Minimal plasmatic concentration was checked in 38% of cases, with adequate value (gentamicin <0.5 mg/l, amikacin <2.5 mg/l) for 37%. At the end of aminoglycoside course, 40 patients increased their serum creatinine >25% of the baseline value. In multivariate analysis, this was associated with treatment length ≥3 days and concomitant use of nephrotoxic drugs. CONCLUSION: aminoglycosides dosing used in elderly patients probably need therapeutic drug monitoring and dose adjustment. Aminoglycosides are used to treat severe infections. One of the most important side effects is nephrotoxicity in oldest patients. To minimise nephrotoxicity, short treatments are necessary and avoiding others nephrotoxic drugs could be relevant.