Epidemiological and clinical characteristics of patients with carbapenem-resistant Enterobacterales in a university hospital of Colombia: Enzyme coproductions in rise.

The distribution of carbapenemases in Carbapenem-Resistant Enterobacterales (CRE) has recently undergone a change in our region. According to the Colombian National Institute of Health, there is an increasing prevalence of NDM and NDM-KPC co-producing strains. We carried-out an ambispective cohort study of adult inpatients from Hospital Universitario San Ignacio (2021-2023), infected or colonized with CRE, in which carbapenemases immunochromatographic assay was performed. Out of the 150 patients included in the study, 71.3 % presented with an infection, and carbapenemases were detected in 92.7 % of these cases. Among them, KPC predominated (54 %), while 16.7 % demonstrated enzyme coproductions, mainly KPC-NDM. CRE infected patients had an 18.7 % 30-days mortality, but we could not demonstrate an association between type of carbapenemase and mortality rate (p = 0.82). Logistic regression analysis suggested that ICU admission was independently correlated to fatality (OR 5.08; CI 1.68-16.01). NDM and KPC-NDM presence in CRE poses a public health threat and a therapeutic challenge, with unknown mortality differences according to the carbapenemases pattern. Nevertheless, there was not an association between enzyme type and mortality.

In vitro activity of ceftazidime-avibactam against gram-negative bacteria in patients with bacteremia and skin and soft-tissue infections in Colombia 2019-2021.

OBJECTIVES: Ceftazidime-avibactam (CAZ-AVI) is an option for infections caused by MDR gram-negative bacilli. In this study, we aimed to analyze the in vitro antimicrobial activity of CAZ-AVI and other antimicrobial agents against gram-negative bacilli that were collected in Colombia between 2019 and 2021 from patients with bacteremia and skin and soft-tissue infections (SSTIs). METHODS: A total of 600 Enterobacterales and 259 P. aeruginosa strains were analyzed. The phenotypic resistance of isolates, particularly non-susceptibility to meropenem, multidrug-resistant (MDR) isolates, and difficult-to-treat (DTR) P. aeruginosa, was evaluated according to CLSI breakpoints. RESULTS: Enterobacterales had the most susceptibility to CAZ-AVI (96.5 %) and tigecycline (95 %). Tigecycline and CAZ-AVI were the antimicrobial agents with the most in vitro activity against carbapenem-resistant Enterobacterales (CRE). CAZ-AVI was the antimicrobial treatment with the most activity against P. aeruginosa. CONCLUSIONS: Tigecycline and CAZ-AVI were the antimicrobial agents with the most activity against CRE and MDR Enterobacterales. For P. aeruginosa, CAZ-AVI was the antimicrobial treatment with the most in vitro activity.

In vitro activity of ceftazidime-avibactam against Gram-negative strains in Chile 2015-2021.

OBJECTIVES: Ceftazidime-avibactam (CAZ-AVI) combines ceftazidime and a reversible ß-lactamase inhibitor that has shown activity against multidrug-resistant (MDR) Enterobacterales and P. aeruginosa. Using data from the Antimicrobial Testing Leadership and Surveillance program (ATLAS), this study examined the in vitro antimicrobial activity of CAZ-AVI and other antibiotics against Gram-negative bacteria collected from Chilean hospitals between 2015 and 2021. METHODS: Clinical isolates of Enterobacterales and P. aeruginosa were collected from three medical centres in Chile. Blood, abdominal fluid, urine, soft tissues, and respiratory tract samples were obtained from infected patients. Minimum inhibitory concentrations using the broth microdilution method were determined for susceptibility testing, and the Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for interpreting the results. Extended-spectrum ß-lactamases (ESBL) and carbapenemase genes were also detected through polymerase chain reaction. RESULTS: A total of 2600 Enterobacterales and 836 P. aeruginosa were analysed. CAZ-AVI was the antibiotic with the highest in vitro activity against Enterobacterales (99.72%). The incidence of carbapenem-resistant Enterobacterales (CRE) was 1.5% (n = 39), and the antibiotics with the best in vitro activity were tigecycline (92.31%), CAZ-AVI (88.57%), and amikacin (79.49%). CAZ-AVI was the antibiotic with the best activity against ESBL-producing Enterobacterales (99.34%) and MDR Enterobacterales (99.31%). For KPC-producing Enterobacterales, susceptibility to amikacin was 100%, whereas susceptibility to CAZ-AVI was 91.67%. Regarding MDR and difficult-to-treat resistance P. aeruginosa, 44.83% and 38.99% were susceptible to CAZ-AVI, respectively. CONCLUSION: CAZ-AVI shows excellent in vitro activity against Enterobacterales in general, CRE, ESBL-producing Enterobacterales, and KPC-producing Enterobacterales. CAZ-AVI is also an option against MDR P. aeruginosa.

Conocimientos y prácticas de los médicos cubanos respecto a Enterobacterales resistentes a carbapenémicos / Knowledge and practice on carbapenem-resistant Enterobacterales in medical doctors from a tertiary hospital in Cuba

Introducción: En el contexto de la pandemia de COVID-19, la infección por Enterobacterales resistentes a carbapenémicos productores de carbapenemasas (ERC-PC) se convierte en un problema de salud pública desafiante a nivel mundial. Los médicos desempeñan un papel fundamental en el manejo clínico de las infecciones por patógenos resistentes a carbapenémicos a nivel hospitalario y por ende en el control de estas. Sin embargo, no existen estudios sobre el conocimiento y prácticas de estos sobre ERC-PC en Cuba. Objetivo: Abordar conocimientos y prácticas sobre las infecciones por ERC-PC, su manejo terapéutico, prevención y control en médicos cubanos en un hospital terciario. Métodos: Se realizó un estudio observacional (descriptivo, de corte transversal) y se aplicó un cuestionario específico elaborado a 70 médicos asistenciales. Resultados: Hubo variabilidad en las opiniones sobre las ERC-PC y un conocimiento medio sobre estas en la mayoría de los encuestados. El 58,6 % de los médicos tenía experiencia en el manejo clínico de la infección por ERC-PC. Las brechas de conocimiento encontradas estuvieron asociadas a la escasa experiencia práctica en el manejo de casos. Hubo diferencia estadísticamente significativa en el nivel de conocimientos sobre los ERC-PC en los médicos con experiencia en el manejo de los ERC-PC en comparación con los médicos sin experiencia (p = 0,039). Conclusiones: Es necesario establecer un plan de formación continua en la temática para mejorar el desempeño de los profesionales de la salud en el control de las infecciones por ERC-PC y en el uso optimizado de los antibióticos.

Introduction: In the context of COVID-19 pandemic, carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) infection becomes a global public health threat. Medical doctors play a fundamental role in the clinical management and control of infections caused by carbapenem-resistant pathogens. However, in Cuba there are not previous studies on the knowledge and practice of medical doctors about CR-CRE. Objective: To study the knowledge and practice of Cuban medical doctors in a tertiary hospital about CR-CRE infections, their clinical management, prevention and control. Methods: It was conducted an observational study (descriptive, cross-sectional) and an specific questionnaire to 70 medical doctors was applied. Results: There was variability on the opinions about CP-CRE and average knowledge in the majority of the respondents. 58.6% of the medical doctors had some experience in the clinical management of CP-CRE infections. Knowledge gaps were associated with the limited practical experience in the management of cases. There was statistically significant difference in the level of knowledge about CP-CRE of medical doctors with experience in the management of CP-CRE compared to inexperienced medical doctors (p = 0.039). Conclusions: It is necessary to establish a continuous training plan on this topic to improve the performance of health professionals in the control of CP-CRE infections and in the appropriate use of antibiotics.

Novel Megaplasmid Driving NDM-1-Mediated Carbapenem Resistance in Klebsiella pneumoniae ST1588 in South America.

Carbapenem-resistant Enterobacterales (CRE) is a critical public health problem in South America, where the prevalence of NDM metallo-betalactamases has increased substantially in recent years. In this study, we used whole genome sequencing to characterize a multidrug-resistant (MDR) Klebsiella pneumoniae (UCO-361 strain) clinical isolate from a teaching hospital in Chile. Using long-read (Nanopore) and short-read (Illumina) sequence data, we identified a novel un-typeable megaplasmid (314,976 kb, pNDM-1_UCO-361) carrying the blaNDM-1 carbapenem resistance gene within a Tn3000 transposon. Strikingly, conjugal transfer of pNDM-1_UCO-361 plasmid only occurs at low temperatures with a high frequency of 4.3 × 10-6 transconjugants/receptors at 27 °C. UCO-361 belonged to the ST1588 clone, previously identified in Latin America, and harbored aminoglycoside, extended-spectrum ß-lactamases (ESBLs), carbapenem, and quinolone-resistance determinants. These findings suggest that blaNDM-1-bearing megaplasmids can be adapted to carriage by some K. pneumoniae lineages, whereas its conjugation at low temperatures could contribute to rapid dissemination at the human-environmental interface.

In vitro activity of ceftazidime/avibactam against Gram-negative strains in Colombia 2014-2018.

OBJECTIVES: Ceftazidime/avibactam (CAZ/AVI) has shown in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria, especially Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa. However, in vitro activity of CAZ/AVI against Gram-negative bacteria in Colombian hospitals is still unknown. The study aimed to analyse the in vitro antimicrobial activity of CAZ/AVI against Gram-negative bacteria collected from hospitals in Colombia using the Antimicrobial Testing Leadership and Surveillance (ATLAS) database. METHODS: Enterobacterales and P. aeruginosa samples were obtained from four hospitals in Colombia between 2014 and 2018. Samples of blood, abdominal fluid, urine, soft tissues, and respiratory tract were collected from adult and paediatric patients. The 2020 Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for the interpretation of susceptibility. Meropenem-non-susceptible Enterobacterales and P. aeruginosa isolates were screened for extended-spectrum ß-lactamase (ESBL) production. Isolates that were positive for ESBL activity were examined by PCR for detecting genotypic resistance. RESULTS: A total of 2005 Enterobacterales were isolated; 29.28% were not susceptible to levofloxacin, 29.14% to aztreonam, and 25.19% to cefepime. The CAZ/AVI was the antibiotic with the best susceptibility against carbapenem-resistant Enterobacterales (CRE) (94.64%), non-metallo-ß-lactamase(MBL)-producing Enterobacterales (98.06%), and MDR Enterobacterales (98.36%). For carbapenem-resistant P. aeruginosa, in vitro activity of CAZ/AVI was 59.26%, and 50% for non-MBL-producing P. aeruginosa. CONCLUSION: CAZ/AVI shows excellent in vitro activity against MDR Enterobacterales and CRE. For MDR P. aeruginosa and carbapenem-resistant P. aeruginosa, in vitro activity of CAZ/AVI was lower compared to the activity against Enterobacterales, but CAZ/AVI was the antibiotic with the best activity.

Antimicrobial stewardship programme associated with earlier prescription of in vitro susceptible therapy and lower 14-day mortality in patients with carbapenem-resistant Enterobacterales bacteraemia: a cohort study.

OBJECTIVES: This study analysed the impact of antimicrobial stewardship team (AST) evaluation on time to susceptible in vitro therapy and mortality of patients with carbapenem-resistant Enterobacterales (CRE) bacteraemia. METHODS: We performed a retrospective cohort study (February 2018 to July 2020) to evaluate the impact of AST evaluation, along with other clinical and microbiological variables, on time to appropriate antibiotics, 14-day mortality and in-hospital mortality in patients aged >18 years with CRE bacteraemia. A Cox regression model was used for multivariate analysis. RESULTS: A total of 142 patients were included. The proportion of patients who received appropriate antibiotics in the first 5 days after bacteraemia was 82/92 (89.1%) versus 29/50 (58.0%) evaluated and not evaluated by the AST, respectively (P < 0.01). AST evaluation reduced the median time to appropriate therapy (49.8 h vs. 71.1 h; P = 0.01). AST intervention was independently associated with earlier prescription of appropriate therapy (P = 0.02) when controlled for septic shock (P < 0.01) and CRE isolation in the previous 90 days (P = 0.04). Regarding mortality, 51 patients (35.9%) died within 14 days (25.8% vs. 44.7% with and without AST intervention, respectively; P = 0.02) and 82 patients (57.7%) in hospital (52.2% vs. 68.0% evaluated and not evaluated by the AST, respectively; P = 0.08). AST intervention was independently protective for 14-day mortality (P = 0.03) when controlled for septic shock status (P < 0.01). CONCLUSION: AST guidance improves the quality of antibiotic prescriptions and clinical outcomes in patients with CRE bacteraemia.

Cost-utility analysis of ceftazidime-avibactam versus colistin-meropenem in the treatment of infections due to Carbapenem-resistant Klebsiella pneumoniae in Colombia.

BACKGROUND: Ceftazidime-Avibactam (CAZ-AVI) is a new antimicrobial against carbapenem-resistant Klebsiella pneumoniae. The aim of the study is to examine the cost-effectiveness of CAZ-AVI compared to colistin-meropenem (COL+MEM) in Colombia. METHODS: A decision tree model was developed from health-care system perspective assuming a 30-day time horizon. The clinical course was simulated based on treatment response between 48 and 72 hours, and the duration of the treatment was 7-14 days. Cost inputs were extracted from a published Colombian manual tariffs and official databases, expressed in 2019 dollars (USD). RESULTS: In the base case analysis, CAZ-AVI was associated with reduced mortality, length of hospital stay and fewer add-on antibiotics, resulting in an increase of 1.76 QALYs per patient versus COL+MEM and incremental costs associated in CAZ-AVI were $2,521 higher per patient compared to COL+MEM ($755 versus $3,276). The incremental costs were partially increased due to the lower mortality rate observed with CAZ-AVI. The incremental cost-effectiveness ratio was estimated to be $3,317 per QALY. In the probabilistic sensitivity analysis, with a willingness to pay above $2,438, CAZ-AVI has higher probability of being cost-effective. CONCLUSION: CAZ-AVI demonstrates cost-effectiveness as a treatment for Carbapenem-resistant Klepsiella pneumoniae infections by reducing the number of deaths and increasing QALYs. EXPERT COMMENTARY: Previous studies and surveillance programs from Colombia have reported prevalence of pathogens and the antimicrobial susceptibility of infections caused by multidrug-resistant Gram-negative bacteria. The health authorities have to consider and plan adequate surveillance systems in order to predict the resistance type and in choose the optimal antibiotics when infections occur.

Carbapenem-resistant Klebsiella pneumoniae colonization and infection is associated with lower overall survival in a cohort of haematopoietic stem-cell transplantation patients: mechanism of resistance and virulence by whole-genome sequencing.

Carbapenem-resistant Klebsiella pneumoniae (CRK) infections are a growing concern in immunocompromised patients. The aim of the present study was to evaluate the impact of CRK colonization and infection in overall mortality for haematopoietic stem-cell transplant (HSCT) patients. We also aimed to investigate resistance and virulence profiles of CRK isolates and assess their epidemiological and genetic relatedness. Patients in the HSCT unit were screened for colonization with CRK with weekly rectal swab or stool cultures and placed under contact precautions. We defined CRK colonization as positive culture from a swab or stool sample grown in MacConkey agar with meropenem at 1 µg ml-1. Demographic and clinical data were retrieved from the patients' charts and electronic records. According to resistance mechanisms and pulsed field gel electrophoresis profile, isolates were selected based on whole-genome sequencing (WGS) using MiSeq Illumina. Outcomes were defined as overall mortality (death up to D+100), and infection-related death (within 14 days of infection). We report a retrospective cohort of 569 haematopoietic stem-cell transplant patients with 105 (18.4 %) CRK colonizations and 30 (5.3 %) infections. blaKPC was the most frequent carbapenemase in our cohort with three isolates co-harbouring blaKPC and blaNDM. We found no difference in virulence profiles from the CRK isolates. There were also no significant differences in virulence profiles among colonization and infection isolates regarding genes encoding for type 1 and 3 fimbriae, siderophores, lipopolysaccharide and colibactin. In clonality analysis by PFGE and WGS, isolates were polyclonal and ST340 was the most prevalent. Overall survival at D+100 was 75.4 % in in CRK-colonized (P=0.02) and 35.7 % in infected patients and significantly lower than non-colonized patients (85.8 %; P<0.001). We found a higher overall mortality associated with colonization and infection; KPC was the main resistance mechanism for carbapenems. The polyclonal distribution of isolates and findings of CRK infection in patients not previously colonized suggest the need to reinforce antibiotic stewardship.

Comparative Evaluation of the Modified Carbapenem Inactivation Method for Phenotypic Detection of Guiana Extended-Spectrum ß-Lactamase-Type Carbapenemases in Enterobacterales.

OBJECTIVE: We comparatively evaluated the performance of 3 phenotypic tests for the detection of carbapenemase production. MATERIALS AND METHODS: Carbapenemase production was evaluated using the modified Hodge test (MHT), the modified carbapenemase inhibition method (mCIM), and the Rapidec Carba NP test (RCNP). RESULTS: Among the 170 isolates, 79 were CP-CRE and 91 were non-CP-CRE. The CP-CRE isolates produced GES-5 (n = 66), KPC (n = 4), NDM (n = 7), NDM and OXA-48 (n = 1), and VIM (n = 1). For KPC producers, all 3 methods showed a sensitivity of 75%. The sensitivities of MHT, mCIM, and RCNP were 14.3%, 100%, and 71.4%, respectively, for NDM producers, and 1.5%, 12.1%, and 18.2% for GES-5 producers, respectively. CONCLUSION: The performance of the phenotypic tests varied depending on the type of carbapenemase. For intensive infection control, phenotypic and molecular tests are required for the detection of common and rare types of carbapenemases.

Performance of polymyxin B agar-based tests among carbapenem-resistant Enterobacterales.

Therapeutic options for infections caused by Carbapenem-resistant Enterobacterales (CRE) are restricted and include polymyxins-centred schemes. Evaluation of in vitro susceptibility is difficult and time consuming. Agar-based methodologies are an alternative to broth microdilution (BMD) and we aimed to evaluate the accuracy of those methods among Enterobacterales. A total of 137 non-duplicated CRE were subjected to polymyxin B BMD, agar screening test (Mueller Hinton plates containing 3 µg ml-1 of polymyxin B) and agar dilution (antibiotic serially diluted 0·25-64 µg ml-1 ). CRE of 42·3% were resistant to polymyxin B (MICs range: 0·25->64 µg ml-1 ) and 16·8% presented borderline MICs. Sensitivity, specificity, PPV and NPV were 86·2, 98·7, 98 and 90·7% for screening test and 86·2, 97·5, 96·1 and 90·6% for agar dilution. ME was 0·73 and 1·5% for screening and agar dilution respectively; VME was 5·8% for both techniques. In general, agar-based methods had a good performance. As far as we know, this is the first study to propose an agar screening test using polymyxin B instead of colistin.

Update on the epidemiology of carbapenemases in Latin America and the Caribbean.

INTRODUCTION: Carbapenemases are ß-lactamases able to hydrolyze a wide range of ß-lactam antibiotics, including carbapenems. Carbapenemase production in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp., with and without the co-expression of other ß-lactamases is a serious public health threat. Carbapenemases belong to three main classes according to the Ambler classification: class A, class B, and class D. AREAS COVERED: Carbapenemase-bearing pathogens are endemic in Latin America. In this review, we update the status of carbapenemases in Latin America and the Caribbean. EXPERT OPINION: Understanding the current epidemiology of carbapenemases in Latin America and the Caribbean is of critical importance to improve infection control policies limiting the dissemination of multi-drug-resistant pathogens and in implementing appropriate antimicrobial therapy.

Antibacterial activity of Cinnamomum cassia L. essential oil in a carbapenem- and polymyxin-resistant Klebsiella aerogenes strain

Abstract INTRODUCTION: Essential oils can serve as novel sources of antibiotics for multidrug-resistant bacteria. METHODS: The multidrug-resistance profile of a Klebsiella aerogenes strain was assessed by PCR and sequencing. The antibacterial activity of Cinnamomum cassia essential oil (CCeo) against K. aerogenes was assessed by broth microdilution and time-kill methods. RESULTS: K. aerogenes showed high antibiotic resistance. The genes bla KPC-2, ampC, bla CTX-M-15, bla OXA-1, and bla TEM were present. CCeo exhibited an inhibitory effect with a minimum inhibitory concentration of 17.57 μg/mL. CONCLUSIONS: The antibacterial activity of CCeo makes it a potential candidate for treating carbapenem- and polymyxin-resistant K. aerogenes strains.