Carbapenem-resistant Enterobacterales Infections Research Articles

Phenotypic detection of carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa by mCIM and eCIM and their ceftazidime-avibactam with aztreonam synergy profile in a tertiary care hospital in Eastern India

Background: Worldwide, the emergence of carbapenem-resistant enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global concern to public health as they are responsible for several serious infections that lead to elevated treatment expenses, prolonged hospitalization, and a higher mortality rate. Aims and Objectives: To detect Carbapenem resistance in Enterobacterales and Pseudomonas aeruginosa by phenotypic methods such as mCIM and eCIM. To determine synergism between Ceftazidime-Avibactum and Aztreonum in metallobetalactamase producing isolates. Materials and Methods: Total 217 isolates including enterobacterales and Pseudomonas aeruginosa from patient’s samples such as urine, pus, blood, wound swab, sputum, and ET tube were processed as per standard protocol during the study period from July 2023 to January 2024 at Calcutta National Medical College, Kolkata. Results: Resistance to carbapenem was observed in 110/217 (50.69%) isolates. Phenotypically, 99/110 (90%) produced metallo-β-lactamase and 11/110 (10%) produced serine carbapenemase by mCIM with eCIM test. MBLs producing organisms were most commonly isolated from blood culture samples. On an average, 76% of the MBL producing isolates shows positive synergy result to the combination of CZA+AT by disk elution method. Conclusion: eCIM and mCIM test was performed for identification of carbapenemase producing CRE and CRPA, which causes serious infection in patients with no definitive treatment. The combination of CZA-AT is a potential treatment option to manage CRE and CRPA-associated infections.

Efficacy of ceftazidime/avibactam and plazomicin on carbapenem-resistant Klebsiella pneumoniae and Escherichia coli.

Carbapenem-resistant Enterobacterales (CRE) have become a major public health problem worldwide. The aim of this study was to investigate efficacy of ceftazidime/avibactam and plazomicin on carbapenem-resistant Klebsiella pneumoniae and Escherichia coli isolates. Susceptibility of imipenem, meropenem, ertapenem, ceftazidime/avibactam and plazomicin was investigated by broth-microdilution method. Major carbapenemases NDM, VIM, IMP, KPC, OXA-48 as well as other β-lactamases namely, TEM, SHV, OXA-1-like, CTX-M, ACC, FOX, MOX, DHA, CIT, EBC, VEB, GES, PER were investigated by PCR. A total of 120 carbapenem-resistant isolates (60 E. coli and 60 K. pneumoniae) were included in this study and blaOXA-48-like was found in 78.33%, blaNDM in 26.66%, blaKPC in 7.5%, blaIMP in 5.83%, and blaVIM in 5%. Among 94 isolates with the blaOXA-48-like gene, 22.3% were resistant to ceftazidime/avibactam and 51.1% were resistant to plazomicin. Of 32 isolates with blaNDM, 31 (96.9%) were resistant to ceftazidime/avibactam and 30 (93.75%) were resistant to plazomicin, and both antibiotics had limited effects against blaNDM carriers (P < 0.001). Of the 12 isolates with blaNDM+OXA-48 combination, 11 (91.7%) were resistant to ceftazidime/avibactam and plazomicin. The effect of both antibiotics was significantly lower in strains with blaNDM+OXA-48 combination (P < 0.005).The most common carbapenemase genes in this study were blaOXA-48-like and blaNDM. Ceftazidime/avibactam demonstrated a good efficacy among OXA-48 producing K. pneumoniae and E. coli, however, plazomicin had a significantly lower antibacterial effect in our study. Both antimicrobial agents should be considered as an option by evaluating combined susceptibility results and gene patterns obtained by regional and global molecular data in the treatment of CRE infections.

The impact of colistin-based regimens on mortality compared to other antimicrobials in patients with carbapenem-resistant Enterobacterales bacteremia in South African hospitals: a cross-sectional study

BackgroundTreatment of carbapenem-resistant Enterobacterales (CRE) infections in low-resource settings is challenging particularly due to limited treatment options. Colistin is the mainstay drug for treatment; however, nephrotoxicity and neurotoxicity make this drug less desirable. Thus, mortality may be higher among patients treated with alternative antimicrobials that are potentially less efficacious than colistin. We assessed mortality in patients with CRE bacteremia treated with colistin-based therapy compared to colistin-sparing therapy.MethodsWe conducted a cross-sectional study using secondary data from a South African national laboratory-based CRE bacteremia surveillance system from January 2015 to December 2020. Patients hospitalized at surveillance sentinel sites with CRE isolated from blood cultures were included. Multivariable logistic regression modeling, with multiple imputations to account for missing data, was conducted to determine the association between in-hospital mortality and colistin-based therapy versus colistin-sparing therapy.ResultsWe included 1 607 case-patients with a median age of 29 years (interquartile range [IQR], 0–52 years) and 53% (857/1 607) male. Klebsiella pneumoniae caused most of the infections (82%, n=1 247), and the most common carbapenemase genes detected were blaOXA-48-like (61%, n=551), and blaNDM (37%, n=333). The overall in-hospital mortality was 31% (504/1 607). Patients treated with colistin-based combination therapy had a lower case fatality ratio (29% [152/521]) compared to those treated with colistin-sparing therapy 32% [352/1 086]) (p=0.18). In our imputed model, compared to colistin-sparing therapy, colistin-based therapy was associated with similar odds of mortality (adjusted odds ratio [aOR] 1.02; 95% confidence interval [CI] 0.78-1.33, p=0.873).ConclusionIn our resource-limited setting, the mortality risk in patients treated with colistin-based therapy was comparable to that of patients treated with colistin-sparing therapy. Given the challenges with colistin treatment and the increasing resistance to alternative agents, further investigations into the benefit of newer antimicrobials for managing CRE infections are needed.

The importance of meropenem resistance, rather than imipenem resistance, in defining carbapenem-resistant Enterobacterales for public health surveillance: an analysis of national population-based surveillance

BackgroundIn Japan, carbapenem-resistant Enterobacterales (CRE) infections were incorporated into the National Epidemiological Surveillance of Infectious Diseases (NESID) in 2014, necessitating mandatory reporting of all CRE infections cases. Subsequently, pathogen surveillance was initiated in 2017, which involved the collection and analysis of CRE isolates from reported cases to assess carbapenemase gene possession. In this surveillance, CRE is defined as (i) minimum inhibitory concentration (MIC) of meropenem ≥2 mg/L (MEPM criteria) or (ii) MIC of imipenem ≥2 mg/L and MIC of cefmetazole ≥64 mg/L (IPM criteria). This study examined whether the current definition of CRE surveillance captures cases with a clinical and public health burden.MethodsCRE isolates from reported cases were collected from the public health laboratories of local governments, which are responsible for pathogen surveillance. Antimicrobial susceptibility tests were conducted on these isolates to assess compliance with the NESID CRE definition. The NESID data between April 2017 and March 2018 were obtained and analyzed using antimicrobial susceptibility test results.ResultsIn total, 1681 CRE cases were identified during the study period, and pathogen surveillance data were available for 740 (44.0%) cases. Klebsiella aerogenes and Enterobacter cloacae complex were the dominant species, followed by Klebsiella pneumoniae and Escherichia coli. The rate of carbapenemase gene positivity was 26.5% (196/740), and 93.4% (183/196) of these isolates were of the IMP type. Meanwhile, 315 isolates were subjected to antimicrobial susceptibility testing. Among them, 169 (53.7%) fulfilled only the IPM criteria (IPM criteria-only group) which were susceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-only group and MEPM criteria group significantly differed in terms of carbapenemase gene positivity (0% vs. 67.8%), multidrug resistance rates (1.2% vs. 65.8%), and mortality rates (1.8% vs 6.9%).ConclusionThe identification of CRE cases based solely on imipenem resistance has had a limited impact on clinical management. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public health burden. This emphasis will enable the efficient allocation of limited health and public health resources and preservation of newly developed antimicrobials.

Association of Diabetes Mellitus With Increased Mortality in Carbapenem-Resistant Enterobacterales Infections.

Introduction Carbapenem-resistant Enterobacterales (CRE) infections have high mortality. We aimed to examine the diabetes mellitus (DM) association with CRE mortality. Methodology Our study is a retrospective cohort study including patients who were admitted to the medical wards in the main district hospital (New Jahra Hospital, Kuwait) between January 1, 2022, and January 1, 2023, and diagnosed with CRE infections during hospitalization. The patients were divided into diabetic and non-diabetic groups. Clinical and laboratory data were collected. The presence of carbapenemase genes was detected. The primary outcome was 30-day hospital mortality. We assessed the effect of glycemic control on the outcomes. Results We included 47 patients in the diabetic group and 39 patients in the non-diabetic group. Females represented 54.7% of patients, and the median age was 73 and 55 years in the two groups, respectively. Klebsiella pneumonia (86%) and Escherichia coli (12.8%) were the most frequently isolated CRE. Carbapenemase genes were detected in all patients: NDM-1 in 67.4%, OXA-48 in 18.6%, and both genes coexisted in 14%. The 30-day hospital mortality was significantly higher in the diabetic group compared to the non-diabetic group (48.9% vs. 28.2%, P = 0.041). Among the diabetic patients, there was no significant difference between survivors and non-survivors regarding median glucose or glycated hemoglobin (HbA1c) levels (P = 0.465 and 0.932, respectively). Moreover, levels of glucose (odds ratio (OR) 0.928, confidence interval (CI) 0.763-1.13, P = 0.457) and HbA1c (OR 0.89, CI 0.63-1.26, P = 0.507) were not risk factors for increased mortality among diabetic patients. Conclusion We demonstrated the association between DM and increased CRE mortality regardless of the level of glycemic control. This study demonstrates the interaction between communicable and non-communicable diseases.

O01 Epidemiology and clinical characteristics of patients with carbapenem-resistant Enterobacterales infections: experience from a large tertiary care centre in a developing country

Abstract Background Carbapenem-resistant (CR) Enterobacterales (CREs) are a significant source of healthcare-associated infections. These bacteria are difficult to treat and have a high mortality rate due to high rates of antibiotic resistance. These pathogens are also linked to major outbreaks in healthcare institutions, especially those with limited resources in infection prevention and control. Objectives To describe the epidemiology and clinical characteristics of patients with carbapenem-resistant Enterobacteriaceae in a referral hospital in a developing country. Methods This was a retrospective cross-sectional study that included 218 patients admitted to An-Najah National University Hospital between 1 January 2021, and 31 May 2022. The target population was all patients with CRE infection or colonization in the hospital setting. Results Of the 218 patients, 135 had CR Klebsiella pneumoniae (61.9%) and 83 had CR Escherichia coli (38.1%). Of these, 135 were male (61.9%) and 83 were female (38.1%), with a median age of 51 years (IQR 24–64). Malignancy was a common comorbidity in 36.7% of the patients. Approximately 18.3% of CRE patients were obtained from patients upon admission to the emergency department, the largest percentage among departments. Most CRE pathogens were isolated from rectal swabs, accounting for 61.3%. Among the 218 patients, colistin was the most widely used antimicrobial agent (13.3%). CR E. coli showed resistance to amikacin in 23.8% of the pathogens tested and 85.7% for trimethoprim/sulfamethoxazole compared with CR K. pneumoniae, for which the resistance to trimethoprim/sulfamethoxazole was 74.1%, while for amikacin it was 64.2%. Regarding meropenem MIC, 85.7% of CR E. coli were greater than 16 mg/L compared with 84% of CR K. pneumoniae isolates. Conclusions This study found that CREs are frequently reported in this tertiary care setting, implying the presence of selective pressure and transmission associated with healthcare setting. The antibiotics tested showed a variety of resistance rates, with CR K. pneumoniae being more prevalent than CR E. coli and exhibiting an extremely high resistance pattern to the available therapeutic options.

Rapid characterization of carbapenem-resistant Enterobacterales by multiplex lateral flow assay and detection of ceftazidime-avibactam-aztreonam synergy

PurposeThe choice of antibiotics for treatment of Carbapenem-Resistant Enterobacterales (CRE) is increasing becoming limited due to co-expression of Metallo-beta-lactamases (MBL) along with other carbapenemases in these isolates. The study aimed to investigate the occurrence of CRE and to determine the in-vitro synergy and clinical outcomes of Ceftazidime-Avibactam and Aztreonam combination in CRE infections in adult Intensive Care Units (ICUs). Methods79 CRE isolates recovered from adult ICUs during January to March 2023 were tested by O.K.N.V.I. RESIST-5, a lateral flow multiplex assay for rapid detection of OXA-48-like, NDM, IMP, VIM, and KPC carbapenemases. Ceftazidime-Avibactam MIC was determined by microbroth dilution method and in vitro synergy between Ceftazidime-Avibactam and Aztreonam was assessed by Modified E-test/disc diffusion method for these isolates. ResultsThe study revealed 7.5 % occurrence of CRE in our hospital, with high occurrence of NDM (n = 42, 53.1 %) and OXA-48-like (n = 63, 79.7 %) carbapenemase. Production of more than one type of carbapenemases was found in 44 isolates. A total of 57 isolates (72 %) had Ceftazidime-Avibactam resistance and 44 of them displayed Ceftazidime-Avibactam and Aztreonam in-vitro synergy. Successful clinical outcome was observed in two patients who received Ceftazidime-Avibactam and Aztreonam combination therapy for 7 days or more. ConclusionsDespite the preponderance of Ceftazidime-Avibactam resistant CRE expressing NDM and OXA-48-like carbapenemase in our hospital, 77.2 % of them displayed in-vitro synergy of Ceftazidime-Avibactam with Aztreonam. It emphasizes the potential therapeutic utility of this combination in CRE strains showing coproduction of MBL and serine carbapenemases. Greater therapeutic potential of Ceftazidime-Avibactam and Aztreonam combination was observed with extended duration of therapy. However, further clinical evidence is needed to establish the efficacy of this combination and consider other factors that influence treatment outcomes.

1706. Risk factors for infections caused by extended spectrum beta lactamase (ESBL) producing and Carbapenem-resistant Enterobacterales (CRE) in pediatric critical care settings: A case control study

Abstract Background Infections due to Gram negative resistant bacterial pathogens are a major concern in intensive care units. The purpose of this study is to determine the risk factors for developing ESBL-producing and CRE infections in pediatric patients in critical care settings (PICU and NICU). Methods A retrospective case control study of infections due to ESBL-producing and CRE during a 5-year period (2016-2021) at Children’s Hospital of Michigan, Detroit. All patients had positive cultures during their PICU/NICU stay. Control cases were matched for age, infection site and year of infection but their cultures grew Enterobacterales that were non-ESBL or carbapenemase producers. Results A total of 58 patients with ESBL/Carbapenemase-producing Enterobacterales (cases) and 59 control patients were included. Majority of organisms were E. coli and Klebsiella species recovered from respiratory tract. There was no difference in both groups in regards to age, gender, race or length of hospital stay (p &amp;gt;0.3). There was no difference in prior hospital admission, PICU or NICU stay during the previous 6 months, indwelling devices, comorbid conditions, or surgery in the last 6 months (p &amp;gt;0.3). However, the presence of gastrostomy tube was more frequent in the cases group (29.3%) than the control group (15.3%) (p=0.078). Risk factors by univariate analysis included history of antibiotic use in last 6 months (93% in cases vs 73% in controls; p=0.006), cephalosporins use &amp;gt; 14 days (67% vs 31.2%; p=0.006),Trimethoprim/Sulfamethoxazole treatment duration &amp;gt; 14 days (11.1% vs 0%; p=0.012), carbapenem treatment duration &amp;gt; 14 days (14% vs 1.9%; p=0.027), and vancomycin use &amp;gt; 14 days (43.6% vs 21.6%; p=0.053). However, multivariate logistic regression analysis showed that antibiotic usage in the last 6 months was the single best predictor for cases with odds ratio of 5.02-fold (95% CI 1.56-16.13) (p=0.007). Conclusion Prior broad spectrum antibiotic usage was significantly associated with acquisition of ESBL and carbapenemase producing Enterobacterales. The study further underscores the need for optimizing antimicrobial stewardship practices to limit unnecessary and prolonged use of antibiotics to prevent the emergence of resistant pathogens. Disclosures All Authors: No reported disclosures

A critical role of outer membrane vesicles in antibiotic resistance in carbapenem-resistant Klebsiella pneumoniae

BackgroundThis study aimed to illustrate the status of carbapenem-resistant Enterobacterales (CRE) infections in a Chinese tertiary hospital and to investigate the role of outer membrane vesicles (OMVs) in antibiotic resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP).MethodsThe data of CRE infections was collected from laboratory records, and the CRE isolates from two distinct periods (2015/07 to 2017/07 and 2020/04 to 2021/04) were enrolled to detect the carbapenemase genes by polymerase chain reaction (PCR). Multilocus sequence typing (MLST) was used to analyze the molecular characterization of CRKP. The conjugation assay was performed to verify the transmission of the antibiotic resistance plasmid. The OMVs of CRKP were isolated with a method combining an electrophoretic technique with a 300 kDa cut-off dialysis bag. The protein components in CRKP OMVs were analyzed by liquid chromatography tandem-mass spectrometry (LC–MS/MS), and the meropenem-hydrolyzing bioactivity of KPC in CRKP OMVs was determined with different treatments in vitro.ResultsA total of 178 CRE isolates, including 100 isolates from 2015/07 to 2017/07 and 78 isolates from 2020/04 to 2021/04, were collected for the detection of carbapenemase genes. We found that the carbapenemase gene blaKPC was the most prevalent, followed by blaNDM. By MLST, we found that sequence type (ST) 11 CRKP (96.1%) was the leading type during 2015/07 to 2017/07 and that the ST15 CRKP increased to 46.2% in the late period of 2020/04 to 2021/04. The diameters of Klebsiella pneumoniae OMVs ranged from 100 to 200 nm, and by proteomics analysis the most proteins from OMVs belonged to the “enzyme” group. The KPC enzyme was found in the OMVs from CRKP, and the OMVs could protect inside KPC from proteinase K digestion. Moreover, the KPC enzymes within OMVs, which could be released after Triton X-100 treatment, could hydrolyze meropenem.ConclusionsCRE has increasingly caused infections in hospitals, and blaKPC-positive CRKP infections have constituted a major proportion of infections in the past decade. The OMVs play a critical role in antibiotic resistance in CRKP.

Carbapenem-Resistant Enterobacterales Infections and Their Association with Rectal Colonization

Objectives: Carbapenem-resistant Enterobacterales (CRE) infections have limited treatment options, and these infections are associated with high mortality rates. Asymptomatic carriers colonized with CRE contribute to the spread of CRE in hospitals. It was aimed to determine the frequency of CRE isolates detected in our center, carbapenemase ratios in these strains, carbapenemase genes, antibiotic resistance profiles, rectal CRE colonization rates and to evaluate various clinical features of CRE infections.&#x0D; Methods: Enterobacterales species isolated from various specimens and Enterobacterales species isolated from rectal swab specimens sent for colonization screening were examined. Patients with CRE colonization in rectal swab samples were examined for the development of CRE infection at a later time. CRE isolates were examined for carbapenemase production and the presence of carbapenemase gene.&#x0D; Results: 12,721 Enterobacterales (10,161 E. coli and 2395 K. pneumoniae, 165 Citrobacter) isolates were examined. Carbapenem resistance was detected in 10.3% of these strains. CRE was detected in 4.7% of 15695 rectal swab samples evaluated for colonization. In 23.4% of the patients with CRE colonization, CRE growth was detected in other samples besides the rectal swab in the later period. It was observed that CRE infections developed on average 21 days after colonization.&#x0D; Conclusion: CRE infections have started to emerge as a factor not only in hospitalized patients but also in community-acquired infections. Our study also showed that CRE colonization could be a significant risk factor for the development of infection. Therefore, early screening detection to detect colonization can help prevent or limit CRE infections with appropriate isolation methods.

Detection of carbapenemase production in gram negative bacilli in medical and surgical intensive care unit patients in a tertiary care hospital

Background: Carbapenem-resistant Enterobacterales (CRE) are an urgent global public health problem. CRE infections are associated with high mortality and have limited available effective treatment. Carbapenemase enzymes are encoded by genes on mobile genetic elements, such as plasmids, which are highly transmissible between organisms and increase the potential spread of resistance. The study aim was to detect carbapenemase production in Gram negative bacilli by phenotypic (CarbaNP and mCIM only or in conjunction with eCIM) and genotypic (Xpert Carba-R) methods. Material and methods: The various clinical samples were processed as per standard recommended procedures. Identification and antibiotic susceptibility test were done by using GN cards and AST N280 &amp; AST N281 cards of Vitek 2 Compact (bioMérieux) respectively. Phenotypic (CarbaNP and mCIM only or in conjunction with eCIM) and genotypic (Xpert Carba-R) methods were used for detection of carbapenemases. Result: 144 carbapenem-resistant Gram-negative bacilli isolated from various ICUs includes Klebsiella pneumoniae 52.7% (76/144) followed by Escherichia coli 18.05% (26/144) and 15.9% (23/144) Acinetobacter baumannii. Phenotypic test (CarbaNP and mCIM and or in conjunction with eCIM) showed sensitivity of 90%, 100% and 93.75% respectively. Genotypic test of 40 isolates showed predominant expression of NDM in 82.5% (33/40) isolates followed by OXA-48 in 40% (16/40). Conclusion: The study showed mCIM as the most useful diagnostic test with less economic burden to the patients. There is an urgent need for more sensitive, rapid, highly precise and accurate genotypic test which is less expensive and less labor-intensive. Keywords: carbapenem resistant; Enterobacterales; mCIM; eCIM; Xpert Carba-R

Epidemiology and clinical characteristics of patients with carbapenem-resistant enterobacterales infections: experience from a large tertiary care center in a developing country

BackgroundCarbapenem-resistant Enterobacterales (CREs) are a significant source of healthcare-associated infections. These bacteria are difficult to treat and have a high mortality rate due to high rates of antibiotic resistance. These pathogens are also linked to major outbreaks in healthcare institutions especially those with limited resources in infection prevention and control (IPC). Therefore, our study aimed to describe the epidemiology and clinical characteristics of patients with carbapenem-resistant Enterobacteriaceae in a referral hospital in a developing country.MethodsThis was a retrospective cross-sectional study that included 218 patients admitted to An-Najah National University Hospital between January 1, 2021, and May 31, 2022. The target population was all patients with CRE infection or colonization in the hospital setting.ResultsOf the 218 patients, 135 had CR-Klebsiella pneumoniae (61.9%), and 83 had CR-Escherichia coli (38.1%). Of these, 135 were male (61.9%) and 83 were female (38.1%), with a median age of 51 years (interquartile range 24–64). Malignancy was a common comorbidity in 36.7% of the patients. Approximately 18.3% of CRE patients were obtained from patients upon admission to the emergency department, the largest percentage among departments. Most CRE pathogens were isolated from rectal swabs, accounting for 61.3%. Among the 218 patients, colistin was the most widely used antimicrobial agent (13.3%). CR- E. coli showed resistance to amikacin in 23.8% of the pathogens tested and 85.7% for trimethoprim/sulfamethoxazole compared to CR- K. pneumonia, for which the resistance to trimethoprim/sulfamethoxazole was 74.1%, while for amikacin it was 64.2%. Regarding meropenem minimum inhibitory concentration, 85.7% of CR- E. coli were greater than 16 µg/mL compared to 84% of CR- K. pneumonia isolates.ConclusionThis study found that CRE is frequently reported in this tertiary care setting, implying the presence of selective pressure and transmission associated with healthcare setting. The antibiotics tested showed a variety of resistance rates, with CR-K. pneumoniae being more prevalent than CR-E. coli, and exhibiting an extremely high resistance pattern to the available therapeutic options.

An observational study on carbapenem-resistant Enterobacterales (CRE) colonisation and subsequent risk of infection in an adult intensive care unit (ICU) at a tertiary care hospital in India

Carbapenem-resistant Enterobacterales (CRE) are a global health problem with a growing prevalence. India has a high prevalence of CRE. CRE infections are difficult to treat, and are associated with significant morbidity and mortality. Colonisation is generally a prerequisite for infection and the prevention of CRE colonisation is key to the prevention of CRE infection. To determine the prevalence of CRE colonisation and subsequent infections in an adult intensive care unit (ICU) in India. We conducted a prospective observational study in which perirectal swabs were obtained along with relevant clinical details of consenting adult patients upon ICU admission between January 2019 and August 2020. Rectal screening was performed using MacConkey agar plates with ertapenem disks and further identification was performed using conventional microbiological techniques. Ertapenem minimum inhibitory concentration (MIC) was determined using an epsillometer (E) test. The modified carbapenem inactivation (mCIM) test and EDTA carbapenem inactivation test (eCIM) were performed to confirm carbapenem resistance using the Clinical Laboratory Standards Institute (CLSI) 2020 guidelines. 192 ICU patients were screened for CRE. 37 patients were found to be colonised with CRE. Klebsiella pneumoniae (N=25; 67.6%) was the most frequent CRE isolate, followed by Escherichia coli (N=11; 29.7%) and one Enterobacter species (N=1; 2.7%). 89.2% (33/37) patients developed CRE infection. Pneumonia was the most common CRE infection identified in 12/33 (36.4%) patients.during the hospital stay. The median duration of hospital stay was longer (17 days) for CRE colonised compared to CRE non-colonised patients (9 days) (P<0.001). Death occurred in 27 % (N=10/37) of CRE-colonised patients during the hospital admission. CRE colonisation is associated with high risk of subsequent CRE infection and longer ICU and hospital admission.

High Prevalence of Carbapenem-Resistant Enterobacterales Colonization Among Intensive Care Unit Patients in a Tertiary Hospital, China.

Intestinal colonization with carbapenem-resistant Enterobacterales (CRE) has been shown as a significant risk factor for subsequent CRE infections, especially in intensive care units (ICUs). The aim of this study was to determine the prevalence of intestinal CRE colonization among ICU patients in a Chinese tertiary hospital. Fecal sample screenings for CRE were performed on ICU patients weekly. Antibiotic-susceptibility profile of CRE strains was determined using the Vitek-2 analysis system and broth microdilution method. The carbapenemases of all isolates were determined by phenotypes and genotypes. Clonal relatedness was analyzed by pulsed-field gel electrophoresis (PFGE). Whole-genome sequencing was used to identify the multilocus sequence type (ST), plasmid replicons, and insertion sequences (ISs) of isolates. The overall colonization rate of CRE was 40.4% (82/203). A total of 84 CRE strains were detected, mostly with Klebsiella pneumoniae (92.9%). Antibiotic susceptibility testing profile revealed that 84 CRE strains were resistant to most antibiotics except for tigecycline and colistin. The carbapenemase-encoding genes including blaKPC-2, blaNDM-1, and blaIMP-4 were detected, and blaKPC-2 was the predominant genotype (90.8%). A total of 9 STs were identified among 84 CRE strains, and ST11 was the most common type (83.3%). A variety of mobile genetic elements, including plasmids and ISs, were detected via online tool prediction. PFGE analysis of the 78 K. pneumoniae strains showed 8 different pulsotypes, and pulsotype A was highly prevalent. This study found that the prevalence of CRE colonization was alarmingly high in the ICU, and that effective infection control measures are urgently needed to prevent the dissemination of CRE.

In Vitro Susceptibility to Ceftazidime-Avibactam and Comparator Antimicrobial Agents of Carbapenem-Resistant Enterobacterales Isolates.

The emergence of carbapenem-resistant Enterobacterales (CRE) has been recognized as a significant concern globally. Ceftazidime/avibactam (CZA) is a novel β-lactam/β-lactamase inhibitor that has demonstrated activity against isolates producing class A, C, and D β-lactamases. Here-in, we evaluated the in vitro activity of CZA and comparator antimicrobial agents against 858 CRE isolates, arising from the Southeast Asian region, collected from a large tertiary hospital in Singapore. These CRE isolates mainly comprised Klebsiella pneumoniae (50.5%), Escherichia coli (29.4%), and Enterobacter cloacae complex (17.1%). Susceptibility rates to levofloxacin, imipenem, meropenem, doripenem, aztreonam, piperacillin/tazobactam, cefepime, tigecycline, and polymyxin B were low. CZA was the most active β-lactam agent against 68.9% of the studied isolates, while amikacin was the most active agent among all comparator antibiotics (80% susceptibility). More than half of the studied isolates (51.4%) identified were Klebsiella pneumoniae carbapenemase (KPC)-2 producers, 25.9% were New Delhi metallo-β-lactamase (NDM) producers, and Oxacillinase (OXA)-48-like producers made up 10.7%. CZA was the most active β-lactam agent against KPC-2, OXA-48-like, and Imipenemase (IMI) producers (99.3% susceptible; MIC50/90: ≤1/2 mg/L). CZA had excellent activity against the non-carbapenemase-producing CRE (91.4% susceptible; MIC50/90: ≤1/8 mg/L). Expectedly, CZA had no activity against the metallo-β-lactamases (MBL)-producing CRE (NDM- and Imipenemase MBL (IMP) producers; 27.2% isolates), and the carbapenemase co-producing CRE (NDM + KPC, NDM + OXA-48-like, NDM + IMP; 3.0% isolates). CZA is a promising addition to our limited armamentarium against CRE infections, given the reasonably high susceptibility rates against these CRE isolates. Careful stewardship and rational dosing regimens are required to preserve CZA's utility against CRE infections.

Containment of carbapenem-resistant Enterobacterales colonisations and infections: Results from an integrated infection control intervention in a large hospital trust of northern Italy

We describe the results of an infection control intervention, implemented in 4 tertiary hospitals in Romagna, Italy, aiming at containing the spread of carbapenem-resistant Enterobacterales (CRE). The intervention consisted of rectal screening in patients at risk for CRE; pre-emptive contact precaution waiting for screening results; timely notification of CRE identification and concomitant computerized alert; contact precaution for confirmed CRE-positive patients. We performed an interrupted time series analysis to compare the incidence of CRE bacteraemia, of other CRE infections, and CRE-positive rectal swabs in the pre and postintervention period (January 2015-July 2017 and August 2017-June 2020, respectively). 4,332 CRE isolates were collected. Klebsiella pneumoniae was the most represented pathogen (n=3,716, 85%); KPC production was the most common resistance mechanism (n=3,896, 90%). The incidence rate of CRE bacteraemia significantly decreased from 0.554 to 0.447 episodes per 10.000 patient days in the early postintervention period (P=.001). The incidence rate of other CRE infections significantly decreased from 2.09 to 1.49 isolations per 10.000 patient days in the early postintervention period (P=.021). The monthly number of rectal swabs doubled in the postintervention period and there was a significant reduction trend of CRE-positive swabs, sustained over time (P<.001). The infection control intervention was successful in containing the spread of CRE infections and colonisations.

In vitro activity of aztreonam–avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019–2021

This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019–2021) clinical isolates of Enterobacterales from 27 countries in Latin America, Eurasia, Africa/Middle East, and Asia with a focus on the investigational combination aztreonam–avibactam against metallo-β-lactamase (MBL) isolates. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution methodology. Minimum inhibitory concentrations (MICs) were interpreted using the CLSI (2022) breakpoints for all agents except aztreonam–avibactam (provisional pharmacokinetic/pharmacodynamic susceptible breakpoint, ≤ 8 mg/L) and tigecycline (US-FDA). Molecular testing for β-lactamase genes was performed on isolates with meropenem MICs ≥ 2 mg/L, ceftazidime–avibactam MICs ≥ 16 mg/L, and/or aztreonam–avibactam MICs ≥ 16 mg/L, and 50% of isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs ≥ 2 mg/L. Aztreonam–avibactam inhibited 99.8% of all Enterobacterales at ≤ 8 mg/L (MIC90, 0.25 mg/L) and maintained activity against phenotypically resistant subsets of multidrug-resistant (MDR) (99.5% susceptible), extensively drug-resistant (XDR) (98.7%), and carbapenem-resistant Enterobacterales (CRE) (99.1%) isolates. At ≤ 8 mg/L, aztreonam–avibactam inhibited 100%, 99.6%, 99.6%, and 98.8% of KPC-, OXA-48-like-, ESBL-, and MBL-carrying isolates, respectively. MBL-positive isolates were most prevalent in India (20.5%), Guatemala (13.8%), and Jordan (13.2%). No differences in the activity of aztreonam–avibactam were observed across the global regions evaluated. At a concentration of ≤ 8 mg/L, aztreonam–avibactam inhibited almost all Enterobacterales collected from developing countries, including MBL-producing isolates. The widespread dissemination of MBLs among Enterobacterales highlights the unmet need for new agents such as aztreonam–avibactam for the treatment of CRE infections.

Epidemiology of carbapenem-resistant and extended-spectrum beta-lactamase-producing Enterobacterales in US children, 2016–2020

Background: The Centers for Disease Control and Prevention’s Emerging Infections Program conducts active laboratory- and population-based surveillance for carbapenem-resistant Enterobacterales (CRE) and extended spectrum beta-lactamase-producing Enterobacterales (ESBL-E). To better understand the U.S. epidemiology of these organisms among children, we determined the incidence of pediatric CRE and ESBL-E cases and described their clinical characteristics. Methods: Surveillance was conducted among children &lt;18 years of age for CRE from 2016–2020 in 10 sites, and for ESBL-E from 2019–2020 in 6 sites. Among catchment-area residents, an incident CRE case was defined as the first isolation of Escherichia coli, Enterobacter cloacae complex, Klebsiella aerogenes, K. oxytoca, or K. pneumoniae in a 30-day period resistant to ≥1 carbapenem from a normally sterile site or urine. An incident ESBL-E case was defined as the first isolation of E. coli, K. pneumoniae, or K. oxytoca in a 30-day period resistant to any third-generation cephalosporin and non-resistant to all carbapenems from a normally sterile site or urine. Case records were reviewed. Results: Among 159 CRE cases, 131 (82.9%) were isolated from urine and 19 (12.0%) from blood; median age was 5 years (IQR 1–10) and 94 (59.1%) were female. Combined CRE incidence rate per 100,000 population by year ranged from 0.47 to 0.87. Among 207 ESBL-E cases, 160 (94.7%) were isolated from urine and 6 (3.6%) from blood; median age was 6 years (IQR 2–15) and 165 (79.7%) were female. Annual ESBL incidence rate per 100,000 population was 26.5 in 2019 and 19.63 in 2020. Incidence rates of CRE and ESBL-E were &gt;2-fold higher in infants (children &lt;1 year) than other age groups. Among those with data available, CRE cases were more likely than ESBL-E cases to have underlying conditions (99/158 [62.7%] versus 59/169 [34.9%], P&lt;0.0001), prior healthcare exposures (74/158 [46.8%] versus 38/169 [22.5%], P&lt;0.0001), and be hospitalized for any reason around time of their culture collection (75/158 [47.5%] versus 38/169 [22.5%], P&lt;0.0001); median duration of admission was 18 days [IQR 3–103] for CRE versus 10 days [IQR 4–43] for ESBL-E. Urinary tract infection was the most frequent infection for CRE (89/158 [56.3%]) and ESBL-E (125/169 [74.0%]) cases. Conclusion: CRE infections occurred less frequently than ESBL-infections in U.S. children but were more often associated with healthcare risk factors and hospitalization. Infants had highest incidence of CRE and ESBL-E. Continued surveillance, infection prevention and control efforts, and antibiotic stewardship outside and within pediatric care are neededDisclosure: None

Comparative Activities of Novel Therapeutic Agents against Molecularly Characterized Clinical Carbapenem-Resistant Enterobacterales Isolates.

Limited treatment options exist for the treatment of carbapenem-resistant Enterobacterales (CRE) bacteria. Fortunately, there are several recently approved antibiotics indicated for CRE infections. Here, we examine the in vitro activity of various novel agents (eravacycline, plazomicin, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) and comparators (tigecycline, amikacin, levofloxacin, fosfomycin, polymyxin B) against 365 well-characterized CRE clinical isolates with various genotypes. Nonduplicate isolates collected from the largest public health hospital in Singapore between 2007 and 2020 were subjected to antimicrobial susceptibility testing (broth microdilution or antibiotic gradient test strips). Susceptibilities were defined using Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration (FDA) interpretative criteria. Sequence types and resistance mechanisms were characterized using short-read whole-genome sequencing. Overall, tigecycline and plazomicin exhibited the highest susceptibility rates (89.6% and 80.8%, respectively). However, the tigecycline susceptibility breakpoint utilized here may be outdated in view of prevailing pharmacokinetic-pharmacodynamic (PK/PD) data. Susceptibility varied by carbapenemase genotype; the β-lactam/β-lactamase inhibitor combinations were equally active (92.3 to 99.2% susceptible) against KPC producers, but only ceftazidime-avibactam retained high susceptibility (98.7%) against OXA-48-like producers. Against metallo-β-lactamase producers, only plazomicin exhibited moderate activity (77.0% susceptible). Aminoglycoside activity was also influenced by carbapenemase genotypes. This work provides an insight into the comparative activity and presumptive utility of novel agents in this geographic region. IMPORTANCE This study determined the susceptibilities of carbapenem-resistant Enterobacterales isolates to various novel antimicrobial agents (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, eravacycline, and plazomicin). Whole-genome sequencing was performed for all strains. Our study findings provide insights into the comparative activities of novel agents in this geographic region. Plazomicin and ceftazidime-avibactam exhibited the lowest nonsusceptibility rates and may be considered promising agents in the management of carbapenem-resistant Enterobacterales infections. We note also that antibiotic activity is influenced by genotypes and that understanding the geographic region's molecular epidemiology could aid in the definition of the presumptive utility of novel agents and contribute to antibiotic decision-making.

Impact of a real-time diagnostic and antimicrobial stewardship workflow on time to appropriate therapy for infections caused by multidrug-resistant Gram-negative organisms

IntroductionMultidrug-resistant (MDR) Gram-negative organisms cause life-threatening infections, and the incidence is rising globally. Timely therapy for these infections has a direct impact on patient survival. This study aimed to determine the impact of a multidisciplinary diagnostic and antimicrobial stewardship (AMS) workflow on time to appropriate therapy (TAP) for these infections using novel beta-lactam/beta-lactamase inhibitors. MethodsThis was a retrospective quasi-experimental study of adult patients with carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas (MDR PsA) infections at a 1500 bed university hospital. Included patients who received ≥ 72 hours of ceftazidime-avibactam (CZA) or ceftolozane-tazobactam (C/T) from December 2017 to December 2019. During the pre-intervention period (December 2017 to December 2018), additional susceptibilities (including CZA and C/T) were performed only upon providers’ request. In 2019, reflex algorithms were implemented for faster identification and testing of all CRE/MDR PsA isolates. Results were communicated in real-time to the AMS team to tailor therapy. ResultsA total of 99 patients were included, with no between-group differences at baseline. The median age was 60 years and 56 (56.7%) were in intensive care at the time of culture collection. Identified organisms included 71 (71.7%) MDR PsA and 26 CRE, of which 18 were carbapenemase producers (Klebsiella-producing carbapenemase = 12, New Delhi metallo-β-lactamase = 4, Verona integron-encoded metallo-β-lactamase = 2). The most common infections were pneumonia (49.5%) and bacteraemia (30.3%). A decrease was found in median TAP (103 [IQR 76.0–156.0] vs. 75 [IQR 56–100] hours; P < 0.001). Median time from culture collection to final susceptibility results was shorter in the post-intervention group (123 vs. 93 hours; P < 0.001). ConclusionThis study identified improvement in TAP in MDR PsA and CRE infections with implementation of a reflex microbiology workflow and multidisciplinary antimicrobial stewardship initiatives.