In vitro activity, pharmacodynamic profile and dose optimization of biapenem against NDM and OXA-48-like carbapenemase-producing Klebsiella pneumoniae: A multicentre study in Thailand.

BACKGROUND: Biapenem (BIPM) exhibited a less efficient substrate for various metallo-ß-lactamase (MBL) than other carbapenems. OBJECTIVE: We aimed to evaluate in vitro susceptibility data of BIPM and optimal dose based on Monte Carlo simulation to extend treatment options. METHODS: We collected 192 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients among multicentres in Thailand, from June 2019 to March 2023. BIPM disk diffusion and broth-microdilution testing were performed to obtain minimum inhibitory concentration (MIC). Each BIPM regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes among 192 CRKP isolates were blaOXA-48 (62.3%), blaOXA-48+blaNDM (22.6%) and blaNDM (15.1%). BIPM showed 22.4 and 28.6% susceptible rate when interpreted at clinical breakpoints of 1 and 2 mg/L. The MIC50 and MIC90 of BIPM against CRKP were 8 and 32 mg/L. The BIPM dosing regimens of 300 mg q 6 h infused 6 h and 600 mg q 8 h infused 8 h met the PTA target of %fTime >MIC at 50%, 75% and 100% against isolates MICs of ≤2 mg/L. Based on CFR ≥90%, no BIPM regimens were effective against all the studied CRKP isolates. CONCLUSION: BIPM exhibited a partially susceptible rate among the CRKP isolates in Thailand. The current suggested dose of BIPM with prolonged infusion appears appropriate regimen against CRKP MICs of ≤2 mg/L. However, the empirical use of BIPM for severe CRE infection is not recommended unless the susceptibility has been confirmed.

Rapid Detection of Carbapenemase-producing Enterobacteriaceae From Blood Culture Bottles of Known CPE Carriers: Real-world Experience.

We used a rapid antigen test for the detection of carbapenemases directly from positive blood culture bottles of pediatric hemato-oncologic patients, known carriers of carbapenemase-producing enterobacteriaceae. Resistance mechanism was detected within 15 minutes of observing Gram-negative bacilli from a positive bottle, leading to treatment modification. This simple-to-use, inexpensive assay shortens the interval between empiric to tailored antimicrobial therapy.

The use of multi-pronged screening strategy to understand the epidemiology of carbapenemase-producing Enterobacteriaceae in Hong Kong: transition from epidemic to endemic setting.

A multi-pronged carbapenemase-producing Enterobacteriaceae (CPE) screening strategy was implemented in Hong Kong West healthcare network. Of 199,192 fecal specimens from 77,194 patients screening from 1 July 2011 to 30 June 2019, the incidence of CPE per 1000 patient admission significantly increased from 0.01 (2012) to 1.9 (2018) (p<0.01). With appropriate infection control measures, the incidence of nosocomial CPE per 1000 CPE colonization day decreased from 22.34 (2014) to 10.65 (2018) (p=0.0094). Exposure to wet market for purchasing raw pork (p=0.007), beef (p=0.017), chicken (p=0.026), and vegetable (p=0.034) for >3 times per week significantly associated with community acquisition of CPE. Strategic CPE control measures should be implemented in both the hospital and the community.

Comparison of four low-cost carbapenemase detection tests and a proposal of an algorithm for early detection of carbapenemase-producing Enterobacteriaceae in resource-limited settings.

Rapidly progressing antibiotic resistance is a great challenge in therapy. In particular, the infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are exceedingly difficult to treat. Carbapenemase production is the predominant mechanism of resistance in CRE. Early and accurate identification of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) is extremely important for the treatment and prevention of such infections. In the present study, four phenotypic carbapenemase detection tests were compared and an algorithm was developed for rapid and cost-effective identification of CP-CRE. A total of 117 Enterobacteriaceae (54 CP-CRE, 3 non-CP-CRE, and 60 non-CRE) isolates were tested for carbapenemase production using modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), Carba NP test (CNPt), and CNPt-direct test. The overall sensitivity/specificity values were 90.7%/92.1% for MHT, 100%/100% for mCIM, 75.9%/100% for CNPt, and 83.3%/100% for CNPt-direct. OXA-48-like enzymes were detected with 93.2% sensitivity by MHT and >77.3% sensitivity by two Carba NP tests. MHT could only detect half of the NDM carbapenemase producers. CNPt-direct exhibited enhanced sensitivity compared to CNPt (100% vs 25%) for detection of NDM producers. Considering these findings we propose CNPt-direct as the first test followed by mCIM for rapid detection of CP-CRE. With this algorithm >80% of the CP-CRE could be detected within 24 hours from the time the sample is received and 100% CP-CRE could be detected in day two. In conclusion, mCIM was the most sensitive assay for the identification of CP-CRE. CNPt-direct performed better than CNPt. An algorithm consisting CNPt-direct and mCIM allows rapid and reliable detection of carbapenemase production in resource-limited settings.

Assessment of carbapenem-resistant Enterobacteriaceae-plate formula and quality control procedure.

AIMS: To assess a cost-effective in-house selective plate formula for actively screening carbapenem-resistant Enterobacteriaceae (CRE). METHODOLOGY AND RESULTS: The in-house formula included CHROMagarTM Orientation, meropenem, and ingredients present in the Mac-Conkey formula, such as bile salts and crystal violet (pH 6.9-7.2). American Type Culture Collection strains and 200 clinical strains were used to validate the plate formula. The CRE plates had a sensitivity of 97.4% and a specificity of 98.8% with ATCC andor clinical strains used in the quality control procedure. A point prevalence survey among the 18 inpatients at Viet-Tiep hospital ICU using fecal swabs plated at the in-house agar plate showed a CRE prevalence of 44.4%. CONCLUSION: The in-house plate had high sensitivity and specificity, particularly for Escherichia coli and the KESC group (Klebsiella spp., Enterobacter spp., Serratia marscescens, and Citrobacter spp.), and it may be widely applied as an alternative to other ready-to-use commercial plates. SIGNIFICANCE AND IMPACT OF THE STUDY: The formula developed in the present study may facilitate the early detection and isolation of CRE and decrease transmission, particularly in low- and middle-income countries with a high rate of CRE colonization and limited access to ready-to-use commercial plates.

Surgical site infection by carbapenemase-producing Enterobacteriaceae. A challenge for today's surgeons. / Infección de sitio quirúrgico asociada a enterobacterias productoras de carbapenemasas. Un desafío para el cirujano actual.

INTRODUCTION: Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are dramatically increasing worldwide, with an important impact on surgical patients. Our aim was to assess the clinical profile, outcomes, treatment, mortality and costs of CPE-related surgical site infection (SSI) in patients with abdominal surgery. METHODS: Review of CPE-related SSI in patients with abdominal surgery from January 2013 to December 2018. Patient factors and interventions present previously to the SSI identification were recorded, and a mortality analysis was also performed in patients with abdominal surgery and CPE-related organ/space SSI. RESULTS: Fifty patients were included: superficial incisional SSI 50%, deep incisional SSI 28%, organ/space SSI (or intra-abdominal infection) 70%. Klebsiella pneumoniae OXA-48 was present in 84%, and the most frequent were colorectal surgery (40%) and pancreatic surgery (20%). The antimicrobial susceptibility was: ceftazidime-avibactam 100%, amikacin 91.7%, tigecycline 89.1%, colistin 70.8%, meropenem 62.8%, imipenem 52.1%. An appropriate definitive antimicrobial treatment was administered in 86%, using a combined scheme in 76%. Global 30-day mortality rate for intra-abdominal infection was 20%, and mortality-related factors were: solid tumour (P=.009), solid metastasis (P=.009), septic shock (P=.02), blood transfusions (P=.03). Median global stay was 45 (IQR 26-67) days. Median global cost of hospitalization was €29,946 (IQR 15,405-47,749). CONCLUSIONS: The clinical profile of patients with CPE-related SSI associates several comorbidities, interventions, prolonged stay and elevated costs. Mortality-related factors in intra-abdominal infection are solid tumour, metastasis, septic shock or blood transfusions.

Carbapenem-Resistant Enterobacteriaceae Outbreak in a Medical Ward in Spain: Epidemiology, Control Strategy, and Importance of Environmental Disinfection.

Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) are a growing public health problem. We describe an outbreak by CRE and the measures to control it in a hospitalization unit in Spain. Methods: In June 2015, the system of prevention and control of CRE implemented in the hospital detected an increase in the incidence of patients with CRE in a mixed hospitalization facility (geriatrics, internal medicine, and pneumology), with the appearance of four related patients in 2 weeks, three of them being nosocomial cases. A multidisciplinary group was created and carried out: weekly screenings, general cleaning, four training sessions for personnel, two hand hygiene observation studies and environmental sampling. A higher incidence of new cases was detected in three adjoining rooms, in which environmental decontamination was performed with vaporized hydrogen peroxide. Results: In 5 months, a total of 18 cases were detected, 14 of them were nosocomial. Four different clones of Klebsiella pneumoniae OXA-48 were responsible for 83.3% of the cases. Adherence to hand hygiene increased from 36% to 85% after the training sessions. Seven percent of the environmental samples were positive for CRE in rooms with high incidence, moving to 0% after decontamination with hydrogen peroxide. Three patients died, one of them possibly associated with clinical infection due to CRE. Conclusions: Multidisciplinary information strategies, personnel training, and control of environmental reservoirs are effective to address outbreaks of CRE.

Assessment of the performance of CHROMagar KPC and Xpert Carba-R assay for the detection of carbapenem-resistant bacteria in rectal swabs: First comparative study from Abu Dhabi, United Arab Emirates.

OBJECTIVES: The objective of this study was to evaluate the performance of CHROMagar™ KPC compared with Xpert® Carba-R assay for the detection of carbapenem-resistant bacterial isolates from rectal swabs. METHODS: Rectal swabs were obtained from patients admitted to Cleveland Clinic Abu Dhabi (United Arab Emirates) over a period of 7 months and were screened for carbapenem resistance by either culture on CHROMagar KPC or carbapenemase production using the Xpert Carba-R molecular method. Further testing for carbapenem susceptibility of isolates recovered from CHROMagar KPC was performed using VITEK®2. RESULTS: A total of 1813 rectal swabs were screened, of which 61 (3.4%) were positive for carbapenem resistance by either one or both methods. Both methods were equally efficient in detecting carbapenem resistance in 37/61 swabs (60.7%), mostly positive for Klebsiella pneumoniae (22 isolates), of which 40.9% (9/22) carried blaOXA-48-like and blaNDM. Xpert Carba-R assay detected 12 additional swabs with negative CHROMagar KPC culture and revealed additional carbapenemase-producing organisms carrying blaOXA-48-like and/or blaNDM. CHROMagar KPC recovered organisms in nine swabs not detected by the genotypic method, 44.4% of which were K. pneumoniae. Three swabs yielded false-positive results (carbapenem-susceptible organisms) by both methods. Sensitivity and specificity were, respectively, 75.4% and 99.8% for CHROMagar KPC and 80% and 99.8% for Xpert Carba-R. CONCLUSION: This comparative study of CHROMagar KPC versus Xpert Carba-R in rectal swabs showed a slightly higher sensitivity for the PCR-based method. Whilst CHROMagar KPC provides a less expensive screening method, Xpert Carba-R may be more accurate and faster.

Carbapenemase-producing Enterobacteriaceae - once positive always positive?

PURPOSE OF REVIEW: This review provides an overview of gastrointestinal tract colonization with carbapenemase-producing Enterobacteriaceae (CPE), including risk factors for colonization, determinants for duration of colonization, and whether patients can decolonize, either spontaneously or via targeted interventions. RECENT FINDINGS: CPE colonization is disseminating globally with increasing numbers of carbapenemases being identified in increasing patient cohorts. Numerous risk factors including repeated healthcare contact, patient co-morbidities and international travel have all been linked to increased rates of colonization. Duration of colonization has been investigated in various healthcare settings and ranges many months or even years. Although new methods for expediting decolonization are being investigated, including faecal microbiota transplantation, high quality evidence of impact is lacking. SUMMARY: Current evidence indicates that CPE colonization usually persists throughout the duration of most hospital admissions, although the majority of patients will subsequently spontaneously decolonize. Difficulties remain in determining the point at which patients can be considered decolonized because of the lack acceptable criteria for defining eradication. This has significance implications for infection prevention and control measures during the initial and subsequent hospital admissions. Strategies to reduce the healthcare burden of CPE colonization continue to rely predominantly on preventing acquisition, whereas decolonization efforts remain a focus of research.

Direct ß-Lactam Inactivation Method: a New Low-Cost Assay for Rapid Detection of Carbapenemase- or Extended-Spectrum-ß-Lactamase-Producing Enterobacterales Directly from Positive Blood Culture Bottles.

We validate and evaluate a new phenotypic assay, named the direct ß-lactam inactivation method (dBLIM), for the rapid and simultaneous detection of carbapenemase or extended-spectrum-cephalosporinase activity directly from Enterobacterales (EB)-positive blood cultures (BCs). It originates from the carbapenem inactivation method (CIM), an inexpensive and highly sensitive assay for carbapenemase activity detection. dBLIM cutoff values to detect extended-spectrum ß-lactamase (ESBL) and carbapenemase activities resulted in diameters of ≤12 mm for a 5-µg-cefotaxime disk and for a 10-µg-meropenem disk. dBLIM assessment was determined with both aerobic and anaerobic BC bottles spiked with 422 characterized EB strains, classifiable into the following 4 phenotypic groups: (i) ESBL/AmpC-type ß-lactamase (ACBL)/carbapenemase (CARB)-nonproducing (np-ESBL/ACBL/CARB) EB (n = 116), (ii) ESBL-producing EB (n = 111), (iii) AmpC-ß-lactamase-producing EB (n = 33), and (iv) carbapenemase-producing EB (n = 162). No false-positive results were obtained in any of the np-ESBL/ACBL/CARB EB, ESBL, and AmpC groups, demonstrating an overall assay specificity of 100%. There were no significant discrepancies in dBLIM performance between aerobic and anaerobic BCs across all groups, except with VIM-type carbapenemase-expressing EB. Interestingly, among BCs spiked with blaVIM-harboring EB, the sensitivity rates of the assay in anaerobic and aerobic bottles were 53.6% and 100%, respectively. In contrast, dBLIM performance was deemed excellent for the KPC, OXA-48, and NDM carbapenemase producers regardless of the type of bottle being tested, with a sensitivity rate ranging between 99% and 100%. Concerning the detection of the extended-spectrum cephalosporinases of the ESBL-producing and AmpC types, dBLIM sensitivities was 100% and 84 to 87%, respectively. dBLIM may be a cost-effective and highly robust phenotypic screening method for the reliable detection of carbapenemases or extended-spectrum cephalosporinases directly from BCs on the same day of bottle positivity detection.

Management of carbapenemase-producing Enterobacteriaceae in a low incidence area: A six-year experience in a university hospital.

We conducted a 6-year retrospective analysis of monitoring of carbapenemase-producing Enterobacteriaceae (CPE) in a large hospital in a low CPE incidence area, and we evaluated the "search and isolate" strategy implemented. In total, 40 CPE isolates were collected from 32 patients, and only 1.4% of contact patients screened were CPE carriers.

Survey of screening methods, rates and policies for the detection of carbapenemase-producing Enterobacteriaceae in English hospitals.

Multi-drug-resistant Gram-negative bacteria are of major clinical concern. The increasing prevalence of carbapenemase-producing Enterobacteriaceae (CPE), resistant to all beta-lactams including carbapenems and able to colonize the large intestine, represents a key threat. Rapid, accurate detection of intestinal CPE colonization is critical to minimize transmission, and hence reduce costly, difficult-to-treat CPE infections. There is currently no 'gold standard' CPE detection method. A survey of diagnostic laboratories in England found considerable heterogeneity in diagnostic CPE testing methods and procedures.

Cross sectional study of multiresistant bacteria in Danish emergency departments: prevalence, patterns and risk factors for colonization (AB-RED project).

BACKGROUND: Multiresistant bacteria (MRB) is an increasing problem. Early identification of patients with MRB is mandatory to avoid transmission and to target the antibiotic treatment. The emergency department (ED) is a key player in the early identification of patients who are colonized with MRB. There is currently sparse knowledge of both prevalence and risk factors for colonization with MRSA, ESBL, VRE, CPE and CD in acutely admitted patients in Western European countries including Denmark. To develop evidence-based screening tools for identifying carriers of resistant bacteria among acutely admitted patients, systematic collection of information on risk factors and exposures is required. Since a geographical variation is suspected, it is desirable to include emergency departments across the country. The aim of this project is to provide a comprehensive overview of prevalence and risk factors for MRSA, ESBL, VRE, CPE and CD colonization in patients admitted to Danish ED's. The objectives are to describe the prevalence and demography of resistance, co-infections, to identify risk factors for carrier state and to develop and validate a screening tool for identification of carriers. METHODS: Multicenter descriptive and analytic cross-sectional survey from January-May 2018 of around 10.000 acutely admitted patients > 18 years in 8 EDs for carrier state and risk factors for antibiotic resistant bacteria. Information about the background and possible risk factors for carrier status together with swabs from the nose, throat and rectum is collected and analyzed for MRSA, ESBL, VRE, CPE and CD. The prevalence of the resistant bacteria are calculated at hospital level, regional level and national level and described with relation to residency, sex, age and risk factors. A screening model for identification of carrier stage of resistant bacteria is developed and validated. DISCUSSION: The study will provide the prevalence of colonized patients with resistant bacteria on arrival to the ED and variation in demographic patterns, and will develop a clinical tool to identify certain risk groups. This will enable the clinician to target antibiotic treatments and to reduce the in-hospital spreading of resistant bacteria. This knowledge is important for implementing and evaluating antimicrobial stewardships, screening and infection control strategies. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03352167 (registration date: 20. November 2017).

The Economic Value of the Centers for Disease Control and Prevention Carbapenem-Resistant Enterobacteriaceae Toolkit.

OBJECTIVEWhile previous work showed that the Centers for Disease Control and Prevention toolkit for carbapenem-resistant Enterobacteriaceae (CRE) can reduce spread regionally, these interventions are costly, and decisions makers want to know whether and when economic benefits occur.DESIGNEconomic analysisSETTINGOrange County, CaliforniaMETHODSUsing our Regional Healthcare Ecosystem Analyst (RHEA)-generated agent-based model of all inpatient healthcare facilities, we simulated the implementation of the CRE toolkit (active screening of interfacility transfers) in different ways and estimated their economic impacts under various circumstances.RESULTSCompared to routine control measures, screening generated cost savings by year 1 when hospitals implemented screening after identifying ≤20 CRE cases (saving $2,000-$9,000) and by year 7 if all hospitals implemented in a regional coordinated manner after 1 hospital identified a CRE case (hospital perspective). Cost savings was achieved only if hospitals independently screened after identifying 10 cases (year 1, third-party payer perspective). Cost savings was achieved by year 1 if hospitals independently screened after identifying 1 CRE case and by year 3 if all hospitals coordinated and screened after 1 hospital identified 1 case (societal perspective). After a few years, all strategies cost less and have positive health effects compared to routine control measures; most strategies generate a positive cost-benefit each year.CONCLUSIONSActive screening of interfacility transfers garnered cost savings in year 1 of implementation when hospitals acted independently and by year 3 if all hospitals collectively implemented the toolkit in a coordinated manner. Despite taking longer to manifest, coordinated regional control resulted in greater savings over time.Infect Control Hosp Epidemiol 2018;39:516-524.

Evaluation of the modified carbapenem inactivation method for the detection of carbapenemase-producing Enterobacteriaceae.

Carbapenemase-producing Enterobacteriaceae (CPE) are increasing worldwide. Rapid and accurate detection of CPE is necessary for appropriate antimicrobial treatment and hospital infection control. However, CPE contains some strains that are difficult to detect depending on genotype and MIC value of carbapenem, and a detection method has not been established. The recently reported modified carbapenem inactivation method (mCIM) has been developed in CLSI M100-S27 as a phenotypic technique for detecting carbapenemase activity. In the present study, we examined mCIM as a new CPE detection method using 207 Enterobacteriaceae isolates in comparison with the three existing screening methods of modified Hodge test, Carba NP test and carbapenem inactivation method and evaluated its performance. Consequently, both the sensitivity and specificity of mCIM were 100%, indicating better results than the conventional screening methods. The mCIM is a useful tool for microbiology laboratories due to its simplicity, clear criteria, cost-effectiveness and availability at any laboratory.

Israeli National Policy for Carbapenem-Resistant Enterobacteriaceae Screening, Carrier Isolation and Discontinuation of Isolation.

Since 2006, Israel has been confronting an outbreak of carbapenem-resistant Enterobacteriaceae (CRE), and in 2007 Israel implemented a national strategy to contain spread. The intervention was initially directed toward acute-care hospitals and later expanded to include an established reservoir of carriage in long-term-care hospitals. It included regular reporting of CRE cases to a central registry and daily oversight of management of the outbreak at the institutional level. Microbiological methodologies were standardized in clinical laboratories nationwide. Uniform requirements for carrier screening and isolation were established, and a protocol for discontinuation of carrier status was formulated. In response to the evolving epidemiology of CRE in Israel and the continued need for uniform guidelines for carrier detection and isolation, the Ministry of Health in 2016 issued a regulatory circular updating the requirements for CRE screening, laboratory diagnosis, molecular characterization, and carrier isolation, as well as reporting and discontinuation of isolation in healthcare institutions nationwide. The principal elements of the circular are contained herein. Infect Control Hosp Epidemiol 2018;39:85-89.

A multiplex real-time PCR for the direct, fast, economic and simultaneous detection of the carbapenemase genes blaKPC, blaNDM, blaVIM and blaOXA-48.

A novel multiplex real-time PCR was designed to detect the clinically most important carbapenemase genes, blaKPC, blaVIM, blaNDM and blaOXA-48. The multiplex assay was verified testing genomic DNA of 24 carbapenemase-producing strains. It was validated using a blinded panel of 82 carbapenemase-producing and 50 non-producing isolates by direct colony PCR.