Cefiderocol - An effective antimicrobial for MDR infections but a challenge for routine antimicrobial susceptibility testing.

PURPOSE: Cefiderocol is a novel cephalosporin-siderophore conjugate antibiotic that holds promise to thwart infections caused by multi-drug-resistant gram-negative bacilli. Its antibacterial activity against normally susceptible species is not affected by most ß-lactamases, including metallo-ß-lactamases. Due to the siderophore-mediated entry into the cell, the activity of cefiderocol is less affected by porin loss or active efflux resistance than many other ß-lactam antibiotics. The aim of this study was to assess in vitro susceptibility to the cefiderocol of carbapenemase-producing gram-negative bacilli from clinical samples of hospitalized patients. MATERIALS AND METHODS: We analyzed 102 clinical strains of carbapenemase-producing Enterobacterales and non-fermentives from hospital centers in Lódz, Poland. Antimicrobial susceptibility to cefiderocol was tested by the minimum inhibitory concentration test strips and disc diffusion methods. RESULTS: The obtained results turned out to be ambiguous, and the area of technical uncertainty made their interpretation very difficult. CONCLUSIONS: The cost of therapy with this antibiotic, and difficulties in interpreting the drug susceptibility are the limitations to the use of cefiderocol. Intensive work should be carried out to finally standardize an easily accessible and reliable method for the determination of susceptibility to cefiderocol.

Aztreonam Combinations with Avibactam, Relebactam, and Vaborbactam as Treatment for New Delhi Metallo-ß-Lactamase-Producing Enterobacterales Infections-In Vitro Susceptibility Testing.

Antimicrobial resistance is a major global health issue. Metallo-ß-lactamases (MBL), in particular, are problematic because they can inactivate all classes of ß-lactams except aztreonam. Unfortunately, the latter may be simultaneously inactivated by serine ß-lactamases. The most dangerous known MBL is New Delhi Metallo-ß-lactamase (NDM). This study aimed to test the in vitro susceptibility to aztreonam in combination with novel ß-lactamase inhibitors (avibactam, relebactam, and vaborbactam) in clinical strains of Enterobacterales NDM which is resistant to aztreonam. We investigated 21 NDM isolates-including Klebsiella pneumoniae, Escherichia coli, and Citrobacter freundii-which are simultaneously resistant to aztreonam, ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam. MICs for aztreonam combinations with novel inhibitors were determined using the gradient strip superposition method. The most effective combination was aztreonam/avibactam, active in 80.95% strains, while combinations with relebactam and vaborbactam were effective in 61.90% and 47.62%, respectively. In three studied strains, none of the studied inhibitors restored aztreonam susceptibility. Aztreonam/avibactam has the most significant antimicrobial potential for NDM isolates. However, combinations with other inhibitors should not be rejected in advance because we identified strain susceptible only to tested combinations with inhibitors other than avibactam. Standardization committees should, as soon as possible, develop official methodology for antimicrobial susceptibility testing for aztreonam with ß-lactamase inhibitors.

Analysis of Cumulative Antibiogram Reports in Search for Optimal Empirical Urinary Tract Infection Treatment at the Central Teaching Hospital of the Medical University of Lodz, Poland: Results of a 3-Year Surveillance.

Urinary tract infections are among the most common bacterial infections, accounting for about two-fifths of all healthcare-associated infections. Appropriate antimicrobial therapy is crucial, e.g., to avoid prolonged hospitalization and limit antimicrobial resistance spread. This study was performed to analyze the microbiological profiles of urinary tract infections in the Central Teaching Hospital in Lodz, Poland, and develop local empirical therapy guidelines. This study was a 3-year retrospective surveillance of the cumulative antibiograms from urine cultures. The procedures were based on the current EUCAST and CLSI guidelines. In 2020-2022, a total of 4656 urine cultures were performed, of which 1134 were positive. The most common bacterial isolates were Escherichia coli, followed by Klebsiella spp. and Enterococcus spp. High levels of susceptibility (>90%) have been observed for carbapenems, piperacillin/tazobactam, amikacin, and nitrofurantoin. Development of the appropriate empirical antimicrobial is a challenging task with persistently high levels of resistance to commonly used antimicrobials. Eventually, we separated the uncomplicated and complicated urinary tract infections in local guidelines and recommended nitrofurantoin and amikacin, respectively, in empiric therapy. The clinicians should make a decision based on the presented symptoms and then-with the urine culture result-correct or continue the therapy.

Nitrofuran Derivatives Cross-Resistance Evidence-Uropathogenic Escherichia coli Nitrofurantoin and Furazidin In Vitro Susceptibility Testing.

The treatment of urinary tract infections is usually empirical. For example, nitrofuran derivatives, mainly nitrofurantoin (but also furazidin), are used in Eastern Europe. A significant problem is the assessment of the usefulness of furazidin, as there are no standards for susceptibility testing. Additionally, a high percentage of strains resistant to nitrofurantoin should prompt caution when choosing furazidin in therapy. This study aimed to answer the question of whether it is possible to use nitrofurantoin susceptibility for furazidin drug susceptibility analyses and if there is any cross-resistance in the nitrofuran derivatives group. One hundred E. coli clinical isolates, obtained from the Central Teaching Hospital of the Medical University of Lodz, were cultured from positive urine samples. For susceptibility testing, microdilution and disk diffusion methods, following EUCAST guidelines, were used. The results showed that the MICs of furazidin were equal to or lower than those of nitrofurantoin in 89% of the tested strains. The MIC50/90 values for furazidin were two times lower than those for nitrofurantoin. Positive correlations were found between MICs and growth inhibition zones for both antibiotics. Based on the obtained data and previous studies, it was assumed that the transfer of susceptibility testing results from nitrofurantoin to furazidin is acceptable due to cross-resistance in nitrofuran derivatives.

In Vitro Activity of Eravacycline against Carbapenemase-Producing Gram-Negative Bacilli Clinical Isolates in Central Poland.

Eravacycline is a novel antibiotic of the tetracycline class with activity against a broad spectrum of clinically significant bacteria, including multi-drug-resistant organisms. For this reason, it may be an alternative to treating critical infections of this etiology. We aimed to assess the in vitro effectiveness of eravacycline to carbapenemase-producing Gram-negative bacilli clinical isolates identified in hospitals in Lódz, Poland. We analyzed 102 strains producing KPC, MBL, OXA-48, GES, and other carbapenemases. Eravacycline susceptibility was determined following the EUCAST guidelines. The highest susceptibility was found in KPC (73%) and MBL (59%) strains. Our results confirmed in vitro the efficacy of this drug against carbapenem-resistant strains. However, eravacycline has been indicated only for treating complicated intra-abdominal infections, significantly limiting its use. This aspect should be further explored to expand the indications for using eravacycline supported by evidence-based medicine. Eravacycline is one of the drugs that could play a role in reducing the spread of multidrug-resistant microorganisms.

Carbapenem-Resistant Gram-Negative Fermenting and Non-Fermenting Rods Isolated from Hospital Patients in Poland-What Are They Susceptible to?

Gram-negative fermenting and non-fermenting bacteria are important etiological factors of nosocomial and community infections, especially those that produce carbapenemases. Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the most frequently-detected carbapenemase-producing microorganisms. The predominant type of resistance is metallo-ß-lactamase (MBL). These bacteria are predominantly isolated from bronchial alveolar lavage, urine, and blood. Carbapenemase-producing Enterobacterales (CPE) strains are always multi-drug-resistant. This significantly limits the treatment options for this type of infection, extends the time of patient hospitalization, and increases the risk of a more severe and complicated disease course. Preventing the transmission of these microorganisms should be a major public health initiative. New antibiotics and treatment regimens offer hope against these infections.

Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression.

Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06-1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08-1.35) and non-medics (RR = 1.18, 95% CI = 1.07-1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.

Diagnostic value of PPARδ and miRNA-17 expression levels in patients with non-small cell lung cancer.

The PPARδ gene codes protein that belongs to the peroxisome proliferator-activated receptor (PPAR) family engaged in a variety of biological processes, including carcinogenesis. Specific biological and clinical roles of PPARδ in non-small cell lung cancer (NSCLC) is not fully explained. The association of PPARα with miRNA regulators (e.g. miRNA-17) has been documented, suggesting the existence of a functional relationship of all PPARs with epigenetic regulation. The aim of the study was to determine the PPARδ and miR-17 expression profiles in NSCLC and to assess their diagnostic value in lung carcinogenesis. PPARδ and miR-17 expressions was assessed by qPCR in NSCLC tissue samples (n = 26) and corresponding macroscopically unchanged lung tissue samples adjacent to the primary lesions served as control (n = 26). PPARδ and miR-17 expression were significantly lower in NSCLC than in the control (p = 0.0001 and p = 0.0178; respectively). A receiver operating characteristic (ROC) curve analysis demonstrated the diagnostic potential in discriminating NSCLC from the control with an area under the curve (AUC) of 0.914 for PPARδ and 0.692 for miR-17. Significant increase in PPARδ expression in the control for current smokers vs. former smokers (p = 0.0200) and increase in miR-17 expression in control tissue adjacent to adenocarcinoma subtype (p = 0.0422) were observed. Overexpression of miR-17 was observed at an early stage of lung carcinogenesis, which may suggest that it acts as a putative oncomiR. PPARδ and miR-17 may be markers differentiating tumour tissue from surgical margin and miR-17 may have diagnostic role in NSCLC histotypes differentiation.