Carbapenem-resistant Enterobacteriaceae Research Articles

Probiotic-Loaded Bacterial Cellulose as an Alternative to Combat Carbapenem-Resistant Bacterial Infections

Background: Carbapenems are one of the mainstays of treatment for antibiotic-resistant bacteria (ARB). This has made the rise of carbapenem-resistant bacteria a threat to global health. In fact, the World Health Organization (WHO) has identified carbapenem-resistant bacteria as critical pathogens, and the development of novel antibacterials capable of combating infections caused by these bacteria is a priority. Objective: With the aim of finding new alternatives to fight against ARB and especially against carbapenem-resistant bacteria, we have developed a series of living materials formed by incorporating the probiotics Lactobacillus plantarum (Lp), Lactobacillus fermentum (Lf), and a mixture of both (L. plantarum+L. fermentum) into bacterial cellulose (BC). Results: These probiotic-loaded bacterial celluloses inhibited the proliferation of three ARB, including two carbapenem-resistant enterobacteria (CRE), identified as Klebsiella pneumoniae and Enterobacter cloacae, and a carbapenem-resistant Pseudomonas aeruginosa. Interestingly, while the probiotics L. plantarum, L. fermentum, and the mixture of both were found to be inactive against these ARB, they became active once incorporated into BC. Conclusions: The increase in activity is due to the known effect that cells increase their activity once incorporated into a suitable matrix, forming a living material. For the same reasons, the probiotics in the living materials BC–L. plantarum, BC–L. fermentum, and BC–L. plantarum+L. fermentum showed increased stability, allowing them to be stored with bacterial activity for long periods of time (two months).

Characterization of novel sequence type 12531 and O8:H7 serotype carbapenem-resistant Escherichia coli with strong swimming and intestinal epithelial cell barrier migration abilities.

Carbapenem-resistant Enterobacteriaceae have become widely prevalent globally because of antibiotic misuse and the spread of drug-resistant plasmids, where carbapenem-resistant Escherichia coli (CREC) is one of the most common and prevalent pathogens. Furthermore, E. coli has been identified as a member of normal gut flora and does not cause disease under normal circumstances. However, certain strains of E. coli, due to the expression of virulence genes, can cause severe intestinal and extra-intestinal infections. Therefore, clinically, drug resistance and pathogenic E. coli strains are significantly challenging to treat. In this study, a novel CREC strain DC8855 was isolated from the ascites of a patient with intestinal perforation, identified as a novel sequence type 12531 (ST12531) and an unreported serotype O8:H7. It was revealed that the resistance of ST12531 CREC was predominantly conferred by an IncFII(K) plasmid carrying blaNDM-4. Furthermore, phylogenetic analysis indicated that this is the first discovery of such plasmids in China and the first identification in E. coli. Moreover, regarding virulence, the swimming assays, qRT-PCR, and in vitro intestinal barrier model indicated that DC8855 had significantly higher motility, flagella gene expression, and intestinal epithelial cell barrier migration ability than the other sequence types CREC strains (ST167 and ST410). In conclusion, this study identified novel CREC which was multidrug resistant as well as enteropathogenic and therefore requires continuous monitoring.

In Vitro Synergistic Activity of Ceftazidime-Avibactam and Aztreonam against New Delhi Metallo-β-Lactamase-Producing Clinical Enterobacterales Isolates

Background: Carbapenemase-producing-Enterobacterales (CPE) infections are on the rise and associated with increased morbidity and mortality, due to a limited number of therapeutic options. The goal of this study was to assess the synergistic activity of ceftazidime-avibactam (CZA) and aztreonam (ATM) combination against phenotypically and genetically characterized blaMBL-producing Enterobacterales.Methods: In this study, forty (n=40) non-repeat, CPE clinical isolates, including: n=35 Klebsiella pneumoniae, n=2 each of Escherichia coli and Klebsiella oxytoca, and n=1 Enterobacter cloacae isolates were identified and susceptibilities were assessed using the Vitek-II compact (bioMérieux, Inc., France) and Microscan Walkaway (Beckman Coulter) systems. Genotypic analysis of clinically relevant carbapenemases was performed by using Xpert-Carba-R assay on GeneXpert (Cepheid, USA). The minimum inhibitory concentrations (MICs) and synergy testing of CZA and ATM, were tested by the Etest fixed ratio method (bioMérieux, Inc., France). The fractional inhibitory concentration index (FICI) was calculated for each antibiotic.Results: Our results showed that 97.5% of blaMBL-producing Enterobacterales isolates were susceptible to an in-vitro CZA + ATM combination regimen. The fractional inhibitory concentration index (FICI) ranged from 0.001 to 1.001. Among the tested CPE isolates, Synergy was observed in 36/40 (90%), an additive effect was observed in 5% (n=2)’ while two (5%) isolates showed indifference. There was no antagonism observed in our study.Conclusion: Our study exhibited a potent activity of CZA and ATM combination synergy against clinical CPE metallo- β-lactamase producers. More extensive studies involving a variety of Gram-negative pathogens with different resistance mechanisms are required to determine the efficacy of this combination regimen.Keywords: Synergy; Aztreonam; Ceftazidime-Avibactam; Carbapenem-Resistant Enterobacterales; Etest

Ceftazidime-Avibactam Versus Polymyxin-Based Combination Therapies: A Study on 30-Day Mortality in Carbapenem-Resistant Enterobacterales Bloodstream Infections in an OXA-48-Endemic Region.

Background: Ceftazidime-avibactam (CAZ-AVI) is recommended as first-line treatment for Oxacillinase-48 (OXA-48) β-Lactamase-producing carbapenem-resistant Enterobacterales (CRE) infections, while polymyxin-based combination therapies (PBCTs) are used as a last resort when CAZ-AVI is unavailable. Research comparing the effectiveness of CAZ-AVI and PBCT in CRE blood stream infections (CRE-BSIs) is limited, mostly focusing on Klebsiella pneumoniae carbapenemase (KPC)-producing isolates. In Turkey, OXA-48 is endemic and OXA-48-Like is common. Therefore, our study aimed to compare the impact of these treatments on 30-day mortality in patients with CRE-BSIs in endemic regions. Methods: Retrospective data from January 2019 to May 2023 were collected from four tertiary healthcare centers in Istanbul. Demographic, clinical, and outcome data of ICU patients treated with CAZ-AVI monotherapy or PBCT for CRE-BSIs were analyzed. The effect on 30-day survival was evaluated using Cox regression analysis post propensity score matching (PSM). Results: Out of 151 patients, 44.4% (n: 67) received CAZ-AVI and 55.6% (n: 84) received PBCT. All-cause mortality rates were 20% (n: 13) with CAZ-AVI and 36.9% (n: 31) with PBCT. Cox regression analysis post PSM indicated CAZ-AVI monotherapy significantly reduced the mortality risk compared to PBCT (HR: 0.16, 95%CI: 0.07-0.37, p < 0.001), while age increased the risk (HR: 1.02 per year, 95% CI 1.0-1.04, p: 0.01). Conclusions: In OXA-48-predominant areas, CAZ-AVI demonstrated significantly lower mortality in patients with CRE-BSIs compared to PBCT. The results were attributed to the pharmacokinetic and pharmacodynamic disadvantages of polymyxins compared to CAZ-AVI, and the impact of age-related physical conditions. Therefore, CAZ-AVI should be the preferred treatment for CRE-BSIs in OXA-48-endemic regions.

Evaluation of blaOXA-48-like point mutation carbapenemase-producing Enterobacterales in Prapokklao Hospital, Thailand.

In this study, we aimed to investigate genetic variation and CPE among blaOXA-48-like carrying isolates recovered from Prapokklao Hospital, Chanthaburi Province, Thailand, during 2016-2017. A total of 122 carbapenem-resistant Enterobacterales (CRE) were recovered from clinical samples in Prapokklao Hospital. All CRE samples were confirmed by standard biochemical tests and minimum inhibitory concentration (MIC) test strips (E-test). The carbapenemase production was determined using the modified Hodge test (MHT), the modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM). Three single mutations (E168Q, S171A, and R214S) were characterized in this study. This mutation might reflect the hydrolysis of the modified β-lactam spectrum, especially carbapenem, by OXA-48-like. Our report provides evidence of the blaOXA-48-like point mutation and carbapenemase-producing phenotype of CRE detected in this healthcare setting. Effective control measures and active surveillance of drug resistance in nosocomial pathogens are crucial for controlling diseases associated with difficult-to-treat bacteria.

Decolonization strategies for ESBL-producing or carbapenem-resistant Enterobacterales carriage: a systematic review and meta-analysis

The prevalence of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) and carbapenem-resistant Enterobacterales (CRE) has become a global public health problem. ESBL-E/CRE colonization can increase the risk of infection in patients and lead to poor disease prognosis. We conducted a systematic review and meta-analysis to evaluate current decolonization strategies regarding ESBL-E/CRE and their efficacy. A literature search was conducted until August 2023 on the five databases to review decolonization strategies associated with ESBL-E/CRE. A meta-analysis was conducted using RevMan 5.4 to compare differences in the decolonization strategy with placebo controls. The primary outcome was decolonization rates, with secondary outcomes of attributable death and adverse events. Quality of identified studies was determined using the Newcastle–Ottawa scale and cochrane risk assessment tool. Random and fixed effects meta-analyses were performed to calculate pooled value. A total of 25 studies were included. In five randomized controlled trial (RCT) studies, the decolonization effect of selective digestive decontamination(SDD) on ESBL-E/CRE at the end of treatment was significantly better in the experimental group than the controls [risk radio (RR): 3.30; 95% CI 1.78–6.14]. In three n-RCT studies, the decolonization effect in the experimental group was still better than the controls one month after SDD therapy [odds ratio (OR): 4.01; 95% CI 1.88–8.56]. The combined decolonization rates reported by six single-arm trial studies of SDD therapy ranged from 53.8 to 68.0%. Additionally, TSA analysis confirmed the effectiveness of SDD therapy. In studies on Faecal microbiota transplantation (FMT) therapy, the decolonization effect of the experimental group was significantly better than the controls 1 month after treatment (OR: 2.57; 95% CI 1.07–6.16). In studies without a control group and with varying follow-up times, the decolonization rates varied widely but indicated the effectiveness trend of FMT therapy (61.3–81.2%). Currently, research on the decolonization effect of probiotic therapy on ESBL-E/CRE is insufficient, and only a systematic review was conducted. SDD and FMT strategies have short-term benefits for ESBL-E/CRE decolonization, but long-term effects are unclear. The effect of probiotic therapy on ESBL-E/CRE decolonization is an interesting topic that still requires further investigation.

Insights into the Rising Threat of Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa Epidemic Infections in Eastern Europe: A Systematic Literature Review.

Antimicrobial resistance is a major global public health challenge, particularly with the rise of carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA). This study aimed to describe the characteristics of CRE and CRPA infections in Eastern Europe, focusing on Bulgaria, Croatia, Czechia, Greece, Hungary, Poland, Romania, Serbia, Slovakia, and Slovenia. Following MOOSE and PRISMA guidelines, a systematic literature review of articles published between 1 November 2017 and 1 November 2023 was conducted using the MEDLINE, Embase, Web of Science, CDSR, DARE, and CENTRAL databases. The search strategy used a combination of free text and subject headings to gather pertinent literature regarding the incidence and treatment patterns of CRE and CRPA infections. A total of 104 studies focusing on infections in both children and adults were included in this review. This review revealed a significant prevalence of carbapenem-resistant Gram-negative isolates and underscored the effectiveness of imipenem/relebactam and ceftazidime/avibactam (CAZ/AVI) against Klebsiella pneumoniae carbapenemase-producing Enterobacterales and of ceftolozane/tazobactam, imipenem/relebactam and ceftazidime/avibactam against non-metallo-β-lactamase-producing CRPA strains. This study highlights the urgent need for comprehensive measures to combat the escalating threat of CRE and CRPA infections in Eastern European countries. At the same time, it shows the activity of the standard of care and new antimicrobials against carbapenem-resistant Gram-negative pathogens in Eastern Europe. Clinical real-world data on the treatment of carbapenem-resistant infections in Eastern Europe are needed.

Transmission of carbapenem-resistant enterobacterales producing NDM-5 during the broiler breeding process in China

This study conducted a four-month monitoring of carbapenem resistance in a broiler breeding farm in China. A total of 185 carbapenem-resistant bacterial isolates were obtained from 2298 cloacal swabs from broiler breeders and their offspring within a production cycle. The detection rate of carbapenem-resistant isolates was higher during the brooding period. Whole-genome sequencing (WGS) was performed on 133 isolates based on sampling stages, including 113 carbapenem-resistant Enterobacterales (CRE) isolates and 20 Stenotrophomonas pavanii isolates, which have intrinsic resistance to carbapenems. A total of 69 antibiotic resistance genes (ARGs), including blaNDM-1, mcr-1, and blaNDM-5, were identified among the sequenced CRE isolates. Notably, blaNDM-5 (92.0 %, 104/113) was the primary contributor to carbapenem resistance. CRE isolates from the same breeding stage exhibited close genomic relationships, and the blaNDM-5 genes were observed in similar genetic backgrounds, indicating the transmission of CRE strains and blaNDM-5 during the broiler breeding process. No CRE was isolated from 0 d broiler offspring, suggesting that broiler breeders were not the direct source of CRE in their offspring. Tracing the feeding process revealed that brooder and rearing houses were likely key factors in the cross-transmission of CRE between broiler breeders and their offspring. CRE pose a significant threat to public health and food safety. China is one of the world's leading poultry producing and consuming countries. This study provided insights into the epidemiological trends and key transmission nodes of carbapenem resistance and CRE within the broiler breeding process, which could help the control of antibiotic resistance and bacterial infections in the broiler industry.

Comparison of two commercial broth microdilution panels for multidrug-resistant Gram-negative bacteria: Thermo Scientific™ Sensititre DKMGN vs. Beckman Coulter MicroScan NMDRM1.

Antimicrobial susceptibility testing (AST) using broth microdilution (BMD) is usually the reference method to obtain accurate minimum inhibitory concentrations and optimally manage infections with resistant organisms. Several commercial dry BMD are available for AST in clinical laboratories. Two commercial BMD panels for testing of multidrug-resistant Gram-negative bacteria were compared: the Thermo Scientific™ Sensititre DKMGN and the Beckman Coulter NMDRM1, for 17 antimicrobial agents. A total of 207 isolates were tested: three ATCC strains and one NCTC strain, six quality control strains from the Belgian National Antimicrobial Committee, and 197 clinical isolates, including carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2023 breakpoints version 13.1 were used to assign susceptibility categories. Overall, the categorical agreement (CA) and essential agreement (EA) were both above 90%, but several useful antibiotics for the treatment of multi-resistant organisms showed CA and EA under 90%, that is, meropenem, imipenem, and colistin for Enterobacterales and meropenem and colistin for P. aeruginosa. For Enterobacterales, the NMDRM1 panel showed a significantly higher resistance rate for meropenem, imipenem, amikacin, and colistin. For carbapenems, the minimal inhibitory concentrations (MICs) were underestimated by the DKMGN panel, as already pointed out by a warning on the EUCAST website. To better assess carbapenem susceptibility in carbapenem-resistant organisms, the DKMGN panel now requires the use of a higher inoculum in the insert kit. However, for a given isolate whose susceptibility to carbapenems is not known, there is a risk of underestimating the MIC values. Our results show that colistin testing remains a challenge, highlighting the urgent need for the development of more accurate commercial methods. The use of a single commercial method cannot guarantee good precision in the determination of the MIC value for colistin.

Safety Assessment and Evaluation of Probiotic Potential of Lactobacillus bulgaricus IDCC 3601 for Human Use

Lactic acid bacteria (LAB) are probiotic microorganisms widely used for their health benefits in the food industry. However, recent concerns regarding their safety have highlighted the need for comprehensive safety assessments. In this study, we aimed to evaluate the safety of L. bulgaricus IDCC 3601, isolated from homemade plain yogurt, via genomic, phenotypic, and toxicity-based analyses. L. bulgaricus IDCC 3601 possessed a single circular chromosome of 1,865,001 bp, with a GC content of 49.72%, and 1910 predicted coding sequences. No virulence or antibiotic resistance genes were detected. Although L. bulgaricus IDCC 3601 exhibited antibiotic resistance to gentamicin and kanamycin, this resistance is an intrinsic feature of this species. L. bulgaricus IDCC 3601 did not produce biogenic amines and did not exhibit hemolytic activity. Phenotypic analysis of enzyme activity and carbohydrate fermentation profiles revealed the metabolic features of L. bulgaricus IDCC 3601. Moreover, no deaths or abnormalities were observed in single-dose oral toxicity tests, suggesting that L. bulgaricus IDCC 3601 has no adverse effect on human health. Finally, L. bulgaricus IDCC 3601 inhibited the growth of potential carbapenem-resistant Enterobacteriaceae. Therefore, our results suggest that L. bulgaricus IDCC 3601 is a safe probiotic strain for human consumption.

Risk of invasive MDRO infection in MDRO-colonized patients.

In this study, we aim to estimate the risk of developing clinical multidrug-resistant organism (MDRO) infection with carbapenem-resistant Enterobacterales (CRE), methicillin-resistant Staphylococcus aureus (MRSA), or vancomycin-resistant enterococci (VRE) in colonized patients compared with non-colonized admitted to high-risk areas with a main focus on CRE colonization/infection. Retrospective cohort study conducted at a tertiary care facility. This study included patients enrolled in active surveillance testing (AST) for CRE, MRSA, or VRE during the year 2021. Development of relevant invasive infection within 365 days of the AST result was collected as the primary outcome. The association between MDRO colonization and infection was calculated using the risk ratio. The prevalence of CRE organisms and carbapenemase genes is presented. A total of 19,134 ASTs were included in the analysis (4,919 CRE AST, 8,303 MRSA AST, and 5,912 VRE AST). Patient demographics were similar between colonized and non-colonized groups. Colonization was associated with an increased risk of infection in the 3 cohorts (CRE, MRSA, and VRE), with risk ratios reported as 4.6, 8.2, and 22, respectively. Most patients (88%) develop CRE infection with the same colonizing carbapenemase gene. Oxa-48/NDM Klebsiella pneumoniae was the most common organism detected in CRE infection. The study demonstrated that colonization with CRE, MRSA, or VRE is a risk factor for developing infections caused by the respective bacteria. The high percentage of match between carbapenemase genes detected in colonization and infection indicates that screening results might be used to inform infection management and treatment.

MALDI-TOF MS profiling to predict resistance or biofilm production in gram-positive ESKAPE pathogens from healthcare-associated infections

Antimicrobial resistance and biofilm production in healthcare-associated infections is a health issue worldwide. This study aimed to identify potential biomarker peaks for resistance or biofilm production in ESKAPE pathogens using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Antimicrobial susceptibility and biofilm production were assessed on selected isolates. Biomarker peaks were identified using MALDI Biotyper and ClinProTools software. Among resistant strains, 90.0 % were carbapenem-resistant Acinetobacter baumannii (CRAB), 39.0 % were methicillin-resistant Staphylococcus aureus (MRSA), 17.98 % were multidrug-resistant (MDR) Pseudomonas aeruginosa, 21.6 % were vancomycinresistant Enterococcus (VRE), and 2.55 % were carbapenem-resistant Enterobacterales (CRE). Biofilm production was 40.0 % in VRE and 45.8 % in MRSA. Although no potential biomarker peaks for biofilm production were detected, several potential biomarker peaks for drug resistance in VRE (n=5), MRSA (n=4), and MDR P. aeruginosa (n=4) were detected, suggesting avenues for the development of rapid diagnostic tools.

In vitro activity of ceftazidime-avibactam and meropenem-vaborbactam against carbapenem-resistant Enterobacterales in Egyptian Hospitals: A challenge for clinical practice

In vitro activity of ceftazidime-avibactam and meropenem-vaborbactam against carbapenem-resistant Enterobacterales in Egyptian Hospitals: A challenge for clinical practice

Colistin Insusceptibility in Carbapenem-Resistant Enterobacteriaceae Isolates From a Tertiary Referral Centre.

Background Antimicrobial resistance has developed significant importance as a worldwide health concern more so in the 21st century. This is more specifically observed among the Enterobacteriaceae family, the major group of Gram-negative bacteria. Resistance to carbapenems and colistin antimicrobials from the reserve group, in critical infection treatment poses a substantial therapeutic challenge. This study aims to detect resistance to both carbapenems and colistin in Enterobacteriaceae isolates, emphasizing the importance of monitoring. Materials and methods A laboratory-based study investigated 82 Carbapenem-Resistant Enterobacteriaceae (CRE) isolates from hospitalized patients at Krishna Hospital & Medical Research Centre, Karad, India, for two years (November 2021-November 2023). The Kirby-Bauer disc diffusion method was used to determine the antimicrobial susceptibility following Clinical Laboratory Standards Institute 2022 recommendations. To validate Carbapenem-Resistant Enterobacteriaceae isolates, the Modified Carbapenem Inactivation Method (mCIM) was used, and Colistin resistance was ascertained using Broth Microdilution Susceptibility Testing (BMD). Results Among 309 Enterobacteriaceae isolates, 82 (26.5%) exhibited carbapenem resistance, with 75 confirmed by Modified Carbapenem Inactivation Method (mCIM) testing. For patients in the age group 51-60 years (20%), with men being the most prevalent, the predominance of CRE isolates was from the Intensive Care Unit (44%), mostly from urine samples (34.6%). The most dominant CRE was Klebsiella pneumoniae (62.7%), followed by Escherichia coli (32%). Colistin resistance was found in 14 (18.7%) of CRE isolates, with the highest minimum inhibitory concentration (MIC) at 4 µg/mL (n=10) and 16 µg/mL (n=4). Colistin-resistant isolates (n=10) were sensitive to amikacin (71.4%) and resistant to many antibiotics. Conclusion The extreme rise of colistin-resistant cases among CRE in healthcare settings is a solemn alarm. Among the most effective treatments, aminoglycosides amikacin and netilmicin show the greatest sensitivity against these colistin-resistant CRE infections. The findings stress the difficulties in treating such infections and the dire need for solid antimicrobial stewardship and novel therapeutic strategies.

Antimicrobial Stewardship: A Game Changer in the Fight against Carbapenem-Resistant Enterobacteriaceae (CRE) among Children with Cancer

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) is an emerging threat among pediatric cancer patients, with a high mortality rate. A previous study in our center reported that 254 patients with CRE BSI were diagnosed from (2013-2018) with mortality from CRE BSI being 30%. Previous colonization was reported in 35% of those patients. Time to start adequate antibiotics is an independent prognostic factor for patients with CRE BSI, (48%) of patients started active treatment after 48h from culture and associated with higher mortality when compared to patients who started treatment earlier. Our recommendations include antimicrobial stewardship for early detection through routine screening and timely adequate therapy that may impact the outcome for such high-risk patient groups. Methods This prospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSI) at a children’s cancer hospital in Egypt (2020–2022) with adopting antimicrobial stewardship program goals by (1) applying routine screening by rectal swab for high-risk patients and starting active treatment for patients colonized by CRE. (2) Introduction of PCR-based method (Cepheid XpertCarba-R assay) is developed for detecting carbapenemase genes with the availability of results within one hour which can allow for rapid time to start active treatment in less than 48h. Results One hundred and fifty pediatric cancer patients with CRE BSI were identified; 83% had hematological malignancies, and 17% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (47%). The main clinical features for acquiring CRE-BSI were prolonged neutropenia &amp;gt; 7 days (62%), previous Carbapenem exposure (82%), Quinilone prophylaxis (44%), central venous catheter use (40%), previous colonization with a resistant pathogen (35%) and ICU admission within 90 days (18%). E. coli was the most common isolated pathogen (65%), followed by Klebsiella pneumoniae (31%). Documented site of infection was reported with pneumonia in (32%), typhlitis in 15% skin soft tissue infection (57%), CNS infection (18%), and urinary tract infection in (10%). Time to start active antibiotics in less than 48h was reported in 89% with clinical cure reported in 71% and microbiological clearance was reported in in less than 7 days in 70% of patients. The need for ICU admission as sepsis related to CRE was reported in 29/150 (19%). The Gentopyic profile for CRE in our study reported that class B (69%) with NDM reported in 98/150 (65%) and VIM 6/150 (4%) was the most common carbanamases followed by Oxa-48 in 89/150(59%) of patients while KPC enzyme reported only in 6/150(4%). Day 30 mortality was reported in 23/150(15%). Upon multivariate analysis, patients with Klebsiella pneumoniae BSI, NDM genotype carbapenemases, CRE with aminoglycosides resistance or associated with pneumonia, and CRE patients who developed septic shock with the need for ICU admission were predictors of poor outcome. Conclusion CRE-BSI is a major threat among pediatric cancer patients in limited-resource countries and is considered a barrier against better outcomes. Antimicrobial stewardship through routine screening for colonization detection and Rapid diagnosis by using gene expert with rapid time to start adequate active antibiotics treatment is associated with improvement of outcome and decreasing mortality. Table 1: Comparison between retrospective study and prospective study (after adopting antimicrobial stewardship goals)

A Surveillance Study of Culturable and Antimicrobial-Resistant Bacteria in Two Urban WWTPs in Northern Spain.

Wastewater treatment plants (WWTPs) are hotspots for the spread of antimicrobial resistance into the environment. This study aimed to estimate the proportion of clinically relevant antimicrobial-resistant bacteria in two Spanish urban WWTPs, located in the region of La Rioja (Spain); Methods: Ninety-four samples (48 water/46 sludge) were collected and streaked on ten different selective media, in order to recover the culturable bacterial diversity with relevant resistance phenotypes: Extended-Spectrum β-Lactamase-producing Escherichia coli/Klebsiella pneumoniae (ESBL-Ec/Kp), Carbapenem-resistant Enterobacteriaceae (CR-E), Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-resistant Enterococcus faecium/faecalis (VR-E. faecium/faecalis). Isolates were identified by MALDI-TOF and were tested for antimicrobial susceptibility using the disk diffusion method. The confirmation of ESBL production was performed by the double-disk test; Results: A total of 914 isolates were recovered (31 genera and 90 species). Isolates with clinically relevant resistance phenotypes such as ESBL-Ec/Kp and CR-E were recovered in the effluent (0.4 × 100-4.8 × 101 CFU/mL) and organic amendment samples (1.0-101-6.0 × 102 CFU/mL), which are discharged to surface waters/agricultural fields. We reported the presence of VR-E. faecium in non-treated sludge and in the digested sludge samples (1.3 × 101-1 × 103 CFU/mL). MRSA was also recovered, but only in low abundance in the effluent (0.2 × 101 CFU/mL); Conclusions: This study highlights the need for improved wastewater technologies and stricter regulations on the use of amendment sludge in agriculture. In addition, regular monitoring and surveillance of WWTPs are critical for early detection and the mitigation of risks associated with the spread of antimicrobial resistance.

In vitro activity assessment of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp., including β-lactam nonsusceptible molecularly characterized isolates, collected from 2020 to 2021 in the United States and European hospitals.

This study reports the activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. isolates collected from the United States and Europe, including Israel and Turkey, from 2020 to 2021. Among Enterobacterales, 2.8% were carbapenem nonsusceptible (CNSE); cefiderocol inhibited 96.6%/85.1% [Clinical Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints] of these isolates. Imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam displayed susceptibilities lower than cefiderocol against CNSE isolates (67.4-84.6% susceptible, CLSI). Cefiderocol was the only agent active against CNSE isolates carrying metallo-β-lactamase (MBL) carbapenemase or multiple carbapenemase genes (84.6%-92.3% susceptible, CLSI). Approximately 18% of carbapenem-susceptible Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis carried extended-spectrum-β-lactamases and/or plasmid-borne AmpC-encoding genes; cefiderocol inhibited 99.8%-100.0% (CLSI) of these genotypic groups. Multi-drug resistance (MDR) phenotypes were observed in 16.9% and 52.5% of P. aeruginosa and A. baumannii-calcoaceticus isolates, respectively. Carbapenemase genes were rare (4.9%) among cephalosporin and/or carbapenem nonsusceptible P. aeruginosa, compared to 87.6% carriage in A. baumannii-calcoaceticus, respectively. Against the MDR and carbapenemase-carrying P. aeruginosa and A. baumannii-calcoaceticus subsets, cefiderocol was active against 98.6%/98.7% and 97.1%/97.4% (CLSI), respectively. Only 69 isolates (0.3%) across all species groups were identified as cefiderocol nonsusceptible per CLSI criteria (>4 mg/L). Cefiderocol was the most active agent in vitro against Enterobacterales, P. aeruginosa, and Acinetobacter spp., with uniform activity against all phenotypic- and genotypic-resistant subsets. Coupled with the low incidence of nonsusceptibility observed across species groups, these results demonstrate cefiderocol as an important option for treating infections caused by pathogens with diverse mechanisms of resistance in US and European hospitals.IMPORTANCEThe worldwide spread of multi-drug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales and Acinetobacter spp. poses a serious challenge in healthcare settings as infections caused by these organisms are commonly refractory to many frontline therapeutic agents. Multiple global health organizations highlighted these pathogens as critical priorities for new antibiotic development, thus necessitating continued surveillance of the activities of currently available antimicrobial agents and circulating mechanisms of resistance. To meet this need, this study phenotypically and genotypically characterized priority Gram-negative pathogens collected from patients in US and European hospitals to examine the activity of cefiderocol and other currently available treatment options, including carbapenems and β-lactam-β-lactamase inhibitor combinations. The results presented here provide a detailed perspective to healthcare practitioners of cefiderocol's broad applicability, manifested in high activity and low nonsusceptibility rates, across phenotypic and genotypic organism groups relative to other agents and further support its use against the most intransigent infections.

High prevalence of colonization with extended-spectrum β-lactamase-producing and multidrug-resistant Enterobacterales in the community in Addis Ababa Ethiopia: risk factors, carbapenem resistance, and molecular characterization

BackgroundGlobally, extended-spectrum beta-lactamase-producing and carbapenem-resistant Enterobacterales are major causes of hospital-acquired infections and there are increasing concerns about their role in community-acquired infections.ObjectiveWe aimed to investigate the prevalence of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE) and Carbapenemase-producing-Carbapenemresistant-Enterobacterales (CP-CRE) and associated factors in community settings in Gulele sub city, Addis Ababa, Ethiopia.MethodsA cross-sectional study was conducted among 261 healthy individuals. Stool samples were collected and processed using standard microbiological methods. Antimicrobial susceptibility and phenotypic ESBL and carbapenemase tests were performed. Antibiotic resistance genes were detected by Polymerase Chain Reaction (PCR).ResultsThe colonization rate of ESBL-PE and CP-CRE were 31.4% (82/261, 95% CI: 25.91–37.48) and 0.8% (2/261, 95% CI: 0.13–3.1), respectively by phenotypic method. Molecular detection of genes for ESBL-PE was 27.9% (73/261, 95% CI:22.7–33.9), and for CP-CRE was 0.8% (2/261, 95% CI: 0.13–3.1). The most prevalent genes were blaTEM [76.7% (56/73)] and blaCTX-M [45.2% (33/73)]. Previous antibiotic use (AOR:2.04, 95%CI: 1.35–4.41, P:0.041) and age between 42 and 53 years old (AOR:3.00, 95%CI:1.12–7.48, P:0.019) were significantly associated with ESBL-PE colonization.ConclusionIntestinal colonization by ESBL-PE harboring the associated antibiotic resistance genes was substantially high but with low CP-CRE. Continued surveillance of community-level carriage of antimicrobial resistance Enterobacterales is warranted.

Economic Burden of Community-Acquired Antibiotic-Resistant Urinary Tract Infections: Systematic Review and Meta-Analysis.

Antibiotic resistance (ABR) poses a major burden to global health and economic systems. ABR in community-acquired urinary tract infections (CA-UTIs) has become increasingly prevalent. Accurate estimates of ABR's clinical and economic burden are needed to support medical resource prioritization and cost-effectiveness evaluations of urinary tract infection (UTI) interventions. This study aims to systematically synthesize the evidence on the economic costs associated with ABR in CA-UTIs, using published studies comparing the costs of antibiotic-susceptible and antibiotic-resistant cases. We searched the PubMed, Ovid MEDLINE and Embase, Cochrane Review Library, and Scopus databases. Studies published in English from January 1, 2008, to January 31, 2023, reporting the economic costs of ABR in CA-UTI of any microbe were included. Independent screening of titles/abstracts and full texts was performed based on prespecified criteria. A quality assessment was performed using the Integrated Quality Criteria for Review of Multiple Study Designs (ICROMS) tool. Data in UTI diagnosis criteria, patient characteristics, perspectives, resource costs, and patient and health economic outcomes, including mortality, hospital length of stay (LOS), and costs, were extracted and analyzed. Monetary costs were converted into 2023 US dollars. This review included 15 studies with a total of 57,251 CA-UTI cases. All studies were from high- or upper-middle-income countries. A total of 14 (93%) studies took a health system perspective, 13 (87%) focused on hospitalized patients, and 14 (93%) reported UTI pathogens. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the most prevalent organisms. A total of 12 (80%) studies reported mortality, of which, 7 reported increased mortality in the ABR group. Random effects meta-analyses estimated an odds ratio of 1.50 (95% CI 1.29-1.74) in the ABR CA-UTI cases. All 13 hospital-based studies reported LOS, of which, 11 reported significantly higher LOS in the ABR group. The meta-analysis of the reported median LOS estimated a pooled excess LOS ranging from 1.50 days (95% CI 0.71-4.00) to 2.00 days (95% CI 0.85-3.15). The meta-analysis of the reported mean LOS estimated a pooled excess LOS of 2.45 days (95% CI 0.51-4.39). A total of 8 (53%) studies reported costs in monetary terms-none discounted the costs. All 8 studies reported higher medical costs spent treating patients with ABR CA-UTI in hospitals. The highest excess cost was observed in UTIs caused by carbapenem-resistant Enterobacterales. No meta-analysis was performed for monetary costs due to heterogeneity. ABR was attributed to increased mortality, hospital LOS, and economic costs among patients with CA-UTI. The findings of this review highlighted the scarcity of research in this area, particularly in patient morbidity and chronic sequelae and costs incurred in community health care. Future research calls for a cost-of-illness analysis of infections, standardizing therapy-pathogen combination comparators, medical resources, productivity loss, intangible costs to be captured, and data from community sectors and low-resource settings and countries.

Genomic epidemiology of carbapenem-resistant Enterobacterales at a New York City hospital over a 10-year period reveals complex plasmid-clone dynamics and evidence for frequent horizontal transfer of bla KPC.

Transmission of carbapenem-resistant Enterobacterales (CRE) in hospitals has been shown to occur through complex, multifarious networks driven by both clonal spread and horizontal transfer mediated by plasmids and other mobile genetic elements. We performed nanopore long-read sequencing on CRE isolates from a large urban hospital system to determine the overall contribution of plasmids to CRE transmission and identify specific plasmids implicated in the spread of bla KPC (the Klebsiella pneumoniae carbapenemase [KPC] gene). Six hundred and five CRE isolates collected between 2009 and 2018 first underwent Illumina sequencing for genome-wide genotyping; 435 bla KPC-positive isolates were then successfully nanopore sequenced to generate hybrid assemblies including circularized bla KPC-harboring plasmids. Phylogenetic analysis and Mash clustering were used to define putative clonal and plasmid transmission clusters, respectively. Overall, CRE isolates belonged to 96 multilocus sequence types (STs) encoding bla KPC on 447 plasmids which formed 54 plasmid clusters. We found evidence for clonal transmission in 66% of CRE isolates, over half of which belonged to four clades comprising K. pneumoniae ST258. Plasmid-mediated acquisition of bla KPC occurred in 23%-27% of isolates. While most plasmid clusters were small, several plasmids were identified in multiple different species and STs, including a highly promiscuous IncN plasmid and an IncF plasmid putatively spreading bla KPC from ST258 to other clones. Overall, this points to both the continued dominance of K. pneumoniae ST258 and the dissemination of bla KPC across clones and species by diverse plasmid backbones. These findings support integrating long-read sequencing into genomic surveillance approaches to detect the hitherto silent spread of carbapenem resistance driven by mobile plasmids.