Whole genome sequence analysis of the first reported isolate of Salmonella Agona carrying blaCTX-M-55 gene in Brazil

This study analyzes the genomic findings of the first report of Salmonella isolate carrying the blaCTX-M-55 gene, recovered from a bacteremic patient from Brazil. A bacterial isolate positive for the blaCTX-M-55 gene was submitted to antimicrobial susceptibility testing by disk diffusion and epsilometric test. Whole genome sequencing was performed using Illumina technology. Conjugation assay was performed; plasmid sizes determined by S1-PFGE and plasmid content were investigated by hybrid assembly after MinION long reads sequencing. Isolate 288_18 was identified as sequence type ST13, resistant to ampicillin, cefotaxime, ceftazidime, cefepime, ceftriaxone, and aztreonam. A transferable IncFII plasmid sized approximately 67 kb was found to carry the blaTEM-1 and blaCTX-M-55 in a module consisting of IS26-blaTEM-1B-WbuC-blaCTX-M-55-IS26. In addition, an 117 kb IncI1plasmid was also identified in the 288_18 isolate, but without additional resistance genes. To the best of our knowledge, this is the first report of blaCTX-M-55 in Salmonella isolated from human infection in Brazil. The occurrence of blaCTX-M-55 in the IncFII epidemic plasmid in a relevant clinical human isolate of Salmonella Agona underscores the urgent need for enhanced and effective continuous surveillance for controlling its dissemination.

Resistencia a colistina en aislados de Klebsiella pneumoniae resistente a carbapenémicos en un hospital pediátrico de Corrientes / Colistin resistance in carbapenem-resistant Klebsiella pneumoniae isolates from a pediatric hospital from Corrientes, Argentina

INTRODUCCIÓN: Existe un incremento de las infecciones por Klebsiella pneumoniae resistente a carbapenémicos (KPRC) en la población pediátrica y los datos epidemiológicos son limitados. OBJETIVOS: Conocer la frecuencia de KPRC en pacientes pediátricos, determinar la actividad in vitro de colistina y detectar el gen mcr-1 en dichos aislados. MATERIALES Y MÉTODOS: Se estudiaron 220 aislados de K. pneumoniae en un hospital pediátrico durante los años 2018 y 2019. La susceptibilidad antimicrobiana se determinó por microdilución en caldo según CLSI y EUCAST. Los genes blaKPC, blaNDM, blaIMP, blaVIM, blaOXA-48 y mcr-1 se analizaron mediante reacción de polimerasa en cadena (RPC). RESULTADOS: El 9,5% (n: 21) de los aislados fueron caracterizados como KPRC, donde se observó una resistencia a colistina de 47,6% (10/21) con valores de CIM50 de 2 μg/mL y CIM90 de > 4 μg/mL. En todos los aislados de KPRC se caracterizó el gen blaKPC y no se detectó el gen mcr-1. El perfil de resistencia observado en otros antimicrobianos fue el siguiente: gentamicina 100% (n: 21), ciprofloxacina 100% (n: 21), cotrimoxazol 100% (n: 21) y amikacina 19% (n: 4). Se observó 100% de sensibilidad a tigeciclina y ceftazidima/avibactam. CONCLUSIÓN: Este estudio demuestra un valor significativo de la resistencia a colistina en comparación a ceftazidima/avibactam y tigeciclina.

BACKGROUND: There is an increase of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in the pediatric population and epidemiological data are limited. Aim: To calculate the frequency of CRKP in pediatric patients, to determine the in vitro activity of colistin and to detect the presence of mcr-1 gene in said isolates. METHODS: 220 isolates of K. pneumoniae were studied in a pediatric hospital between January 2018 and December 2019. Antimicrobial susceptibility was determined by microdilution in broth according to guidelines of CLSI and EUCAST. The genes blaKPC, blaNDM, blaIMP, blaVIM, blaOXA-48 and mcr-1 were detected by polymerase chain reaction (PCR). RESULTS: 9.5% (n: 21) of the isolates were characterized as CRKP, where was observed a resistance to colistin of 47.6% (10/21) with values of MIC50 of 2 μg/mL and MIC90 of ≥ 4 μg/mL. In 100% of CRKP strains the blaKPC gene was detected and the mcr-1 gene was not found. The resistance profile to other antimicrobials was as follow: gentamicin 100% (n: 21), trimethoprim/sulfamethoxazole 100% (n: 21), ciprofloxacin 100% (n: 21), amikacin 19% (n: 4). All of the isolates were sensitive to ceftazidime/avibactam and tigecycline. CONCLUSION: This study demonstrates a significant value of resistance to colistin in pediatric patients compared to other last line antimicrobial such as ceftazidime/avibactam and tigecycline.

Caracterização molecular e fenotípica de Klebsiella spp. produtoras de NDM / Molecular and phenotypic characterization of Klebsiella spp. NDM producers

O perfil de resistência, que algumas das espécies do complexo Klebsiella pneumoniae podem expressar, representa uma grande ameaça à saúde humana, particularmente quando resistentes aos carbapenêmicos, que são amplamente utilizados no tratamento de infecções graves em pacientes hospitalizados. O principal mecanismo de resistência aos carbapenêmicos é a produção de carbapenemases, particularmente dos tipos KPC e NDM. Um dos compostos desenvolvidos para o tratamento de infecções causadas por cepas produtoras de KPC é a combinação ceftazidimaavibactam (CAZ-AVI), mas que não tem atividade inibitória sobre metalo-betalactamases, a exemplo das NDMs. Os objetivos deste trabalho foram determinar a frequência das espécies do complexo K. pneumoniae e da coprodução de KPC, avaliar a clonalidade dos isolados, a sensibilidade ao aztreonam-avibactam (ATM-AVI), o desempenho do disco de meropenem (MEM) com inibidores para detecção de coprodução de NDM e KPC e desenvolver um teste de triagem para prever a sensibilidade ao ATM-AVI. Um total de 113 isolados do complexo K. pneumoniae produtoras de NDM ou coprodutoras de NDM e KPC, provenientes da coleção de bactérias do Grupo Fleury, coletadas períodos pré e pós início do uso de CAZ-AVI no Brasil, foram utilizadas neste estudo. A identificação da espécie e a presença dos genes blaNDM e blaKPC foi confirmada por PCR multiplex. A clonalidade dos isolados foi avaliada por eletroforese em campos pulsados (PFGE) após clivagem com XbaI. A produção de carbapenemases foi confirmada utilizando-se o teste Blue Carba. O desempenho dos discos de meropenem e CAZ-AVI contendo um ou mais inibidores de carbapenemases foi comparado com o teste molecular. A pré-difusão combinada foi realizada pré-incubando-se o ágar não inoculado com disco de CAZ-AVI, e a seguir aplicando-se o inóculo bacteriano e um disco de ATM após remover o disco de CAZ-AVI. Após incubação, os halos foram aferidos e correlacionados com a concentração inibitória mínima para ATM-AVI. As CIMs para ATM e ATM-AVI foram determinadas segundo o EUCAST. A identificação das espécies por PCR evidenciou as seguintes frequências: K. pneumoniae 75,2% (n=85); K. quasipneumoniae 16,8% (n=19), e K. variicola 8% (n=9). Uma fração de 12,4% (n=14) dos isolados apresentaram os genes blaNDM e blaKPC e 87,6% (n=99) apenas blaNDM. A análise dos perfis de PFGE de K. pneumoniae evidenciou a presença de cinco grupos clonais predominantes. Isolados do principal grupo clonal Ap (n=15) foram detectados nas cidades de São Paulo e Porto Alegre durante todo o período analisado. O grupo clonal Lp foi detectado nas cidades de São Paulo e Recife em 2019. Os dois principais grupos clonais no período pré-CAZ-AVI continham maior número de isolados do que aqueles no período de uso do CAZ-AVI. Os perfis de PFGE de K. quasipneumoniae evidenciaram quatro grupos clonais predominantes, e presentes apenas no estado de São Paulo, com persistência do grupo clonal Aq desde 2017. Quanto à K. variicola, foram observados dois grupos clonais predominantes Av e Bv, o primeiro presente apenas em São Paulo desde 2018 e o segundo em Porto Alegre apenas em 2019. Calculando-se a diferença entre os diâmetros de halo do disco MEM contendo EDTA e ácido fenilborônico (AFB) e o maior dos halos obtidos para MEM com EDTA ou AFB, observou-se que todos os isolados com coexpressão de KPC e NDM apresentaram diferença ≥ 5 mm. Uma fração de 42,3% dos isolados positivos apenas para blaNDM apresentaram sensibilidade para ATM (CIM ≤ 4 mg/L). Todos os isolados testados apresentaram CIM para ATM-AVI ≤ 1/4 mg/L, sendo a CIM90 0,125/4 mg/l. No teste de pré-difusão combinada, o menor diâmetro de halo obtido foi de 23 mm. A espécie predominante na amostragem foi K. pneumoniae. A disseminação clonal, observada neste estudo, contrasta com a diversidade clonal descrita em outros locais do mundo para produtores de NDM, exceto Grécia e China. Considerando os pontos de corte atuais para ATM, é provável que haja resposta clínica adequada no uso de ATM-AVI no tratamento de infecções causadas por isolados produtores de NDM e coprodutores de KPC e NDM. Utilizando-se o valor de corte de ≤ 5 mm para a diferença entre halos de inibição, de MEM com AFB e EDTA e o segundo maior halo com inibidor, a sensibilidade foi de 100% e a especificidade foi de 96,1,0%. O método de pré-difusão com CAZ-AVI e ATM é um método simples e o diâmetro ≥ 23 mm tem excelente correlação com a CIM para ATM-AVI ≤ 1/4 mg/L

The resistance profile, which some species of the Klebsiella pneumoniae complex may express, represent a great threat to human health, particularly when resistant to carbapenems, which are widely used in the treatment of severe infections in hospitalized patients. The main mechanism of resistance to carbapenems is the production of carbapenemases, particularly KPCs and NDMs. One of the compounds developed for the treatment of infections caused by KPC-producing strains is the combination ceftazidime-avibactam (CAZ-AVI), but which has no inhibitory activity on metallobetalactamases, as is the case for NDMs. The objectives of this work were to determine the frequency of K. pneumoniae complex species and KPC co-production, evaluate the clonality of isolates, the susceptibility to aztreonam-avibactam (ATM-AVI), the performance of meropenem (MEM) disks with inhibitors for detecting NDM co-production and KPC and develop a screening test to predict sensitivity to ATM-AVI. A total of 113 NDM-producing or NDM and KPC co-producing K. pneumoniae complexes, from the Fleury Group's bacteria collection, collected in the pre- and post-starting periods of CAZ-AVI use in Brazil, were used in this study. Species identification and the presence of the blaNDM and blaKPC genes were confirmed by multiplex PCR. The clonality of the isolates was evaluated by pulsed field electrophoresis (PFGE) after cleavage with XbaI. Carbapenemase production was confirmed using the Blue Carba test. The performance of MEM and CAZ-AVI disks containing one or more carbapenemase inhibitors was compared with the molecular test. Combined pre-diffusion was performed by preincubating the uninoculated agar with a CAZ-AVI disk, and then applying the bacterial inoculum and na ATM disk after removal of the CAZ-AVI disk. After incubation, halos were measured and correlated with the minimum inhibitory concentration (MIC) for ATM-AVI. ATM and ATM-AVI MICs were determined according to EUCAST. The identification of species by PCR evidenced the following frequencies: K. pneumoniae 75.2% (n=85); K. quasipneumoniae 16.8% (n=19), and K. variicola 8% (n=9). A fraction of 12.4% (n=14) of the isolates had the blaNDM and blaKPC genes and 87.6% (n=99) had only blaNDM. The analysis of the PFGE profiles of K. pneumoniae evidenced the presence of five predominant clonal groups. Isolates from the main clonal group Ap (n=16) were detected in the cities of São Paulo and Porto Alegre throughout the analyzed period. The clonal group Lp was detected in the cities of São Paulo and Recife 2019. The PFGE profiles of K. quasipneumoniae showed four predominant clonal groups, present only in the state of São Paulo, with persistence of the clonal group Aq since 2017. As for K. variicola, two predominant clonal groups Av and Bv were observed, the first present only in São Paulo since 2018 and the second in Porto Alegre only in 2019. Calculating the difference between the inhibition zone diameters of the MEM disk containing EDTA and phenylboronic acid (AFB) and the largest of the inhibition zone diameters obtained for MEM with EDTA or AFB, it was observed that all isolates with co-expression of KPC and NDM showed a difference 5 ≥mm. A fraction of 42.3% of isolates positive only for blaNDM showed sensitivity to ATM (MIC ≤ 4 mg/L). All tested isolates presented MIC for ATM-AVI ≤ 1/4 mg/L, being the MIC90 0.125/4 mg/l. In the combined pre-diffusion test, the smallest inhibition zone diameter obtained was 23 mm. The predominant species in the sample was K. pneumoniae, but a significant fraction of the other species in the complex was also observed in the sample. The clonal spread observed in this study contrasts with the clonal diversity described elsewhere in the world for NDM-producing isolates, except Greece and China. Considering the current cut-off points for ATM, it is likely that there is an adequate clinical response in the use of ATM-AVI in infections caused by NDM-producing and KPC-NDM co-producing isolates in Brazil. Using the cutoff value of 5 mm for the difference between inhibition zones, of MEM with AFB and EDTA and the second largest zone of MEM with inhibitor, the sensitivity was 100% and the specificity was 96.1%. The pre-diffusion method with CAZ-AVI and ATM is a simple method and the diameter ≥ 23 mm has excellent correlation with the MIC for ATM-AVI ≤ 1/4 mg/L

Impacto da unitarização de ceftazidima + avibactam em um hospital público universitário durante a pandemia de COVID-19 / Impact of ceftazidime + avibactam unitarization in a university public hospital during the COVID-19 pandemic

Introdução: A pandemia de COVID-19 fez aumentar a demanda de medicamentos utilizados em hospitais, como a Ceftazidima + Avibactam. Nesse contexto, a Central de Misturas Intravenosas (CMIV) de um hospital público universitário passou a unitarizar as doses prescritas. O objetivo deste trabalho foi avaliar o impacto da unitarização no consumo deste antibacteriano de alto custo em um hospital público universitário. Métodos: Trata-se de uma análise farmacoeconômica de custos diretos, sobre a utilização de frascos-ampola de Ceftazidima + Avibactam no período de 01/07/2020 a 31/05/2021. Foram unitarizadas todas as doses que correspondiam a uma fração da dose total do frasco-ampola, em Cabine de Segurança Biológica classe II B2. Os frascos-ampola foram utilizados à exaustão, através do compartilhamento e organização dos horários de manipulação. Resultados: O número total de preparos realizados pela CMIV do referido hospital no período foi de 837. O consumo projetado sem a centralização dos preparos seria de 837 (um frasco por dose). Entretanto, o consumo real foi de 437 frascos. A eficiência de unitarização foi de 101%, com economia real de 400 frascos (R$ 244.832,00) para a instituição. Conclusão: A pandemia de COVID-19 sobrecarregou os sistemas de saúde do mundo todo, sendo que a atuação farmacêutica foi fundamental para garantir o acesso aos medicamentos essenciais. A CMIV assumiu a unitarização da Ceftazidima + Avibactam, antibiótico em risco de desabastecimento, gerando um consumo 47,8% menor, contribuindo para o acesso deste medicamento de forma ininterrupta durante os 11 meses avaliados na referida instituição.

Introduction: COVID-19 pandemic has increased the demand for drugs used in hospitals, such as Ceftazidime + Avibactam. In this context, the Central of Intravenous Admixtures (CMIV) of a public university hospital started to unitarize the prescribed doses. The objective of this study was to evaluate the impact of unitarization on the consumption of this high-cost antibacterial in a public university hospital. Methods: This is a pharmacoeconomic analysis of direct costs, on the Ceftazidime + Avibactam vials use, in the period from 07/01/2020 to 05/31/2021. All doses that corresponded to a fraction of the entire vial were unitarized in a Class II B2 Biological Safety Cabin. The vials were used to exhaustion, by sharing them, and organizing the manipulation schedules. Results: The total number of preparations made by the CMIV of that hospital in the period was 837 doses. The projected consumption would be 837 vials (one vial per dose). However, the actual consumption was 437 vials. The unitarization efficiency was of 101%, with real savings of 400 vials (R$ 244,832.00) for the institution. Conclusion: COVID-19 pandemic has overburdened health systems around the world, and pharmaceutical actions have been fundamental to guaranteeing access to essential medicines. CMIV took over the unitarization of Ceftazidime + Avibactam, an antibiotic at risk of shortages, leading to a 47.8% lower consumption, contributing to uninterrupted access to this drug during the 11 months evaluated at that institution.

Pioderma gangrenoso ampollar como forma de presentación de leucemia mieloide agudo: informe de un caso / Acute myeloid leukemia presented in the form of bullous pyoderma gangrenosum: a case report

El pioderma gangrenoso ampollar es una variedad infrecuente de pioderma gangrenoso, que se asocia en el 50-70% de los casos con trastornos oncohematológicos. Se comunica el caso de una paciente de 59 años, que consultó por fiebre y ampollas purpúricas de rápida progresión, con compromiso cutáneo mucoso. Con sospecha de una enfermedad neutrofílica, ampollar, o infección por gérmenes oportunistas, se realizó biopsia de piel para estudio histopatológico, inmunofluorescencia directa y cultivo. Los cultivos y la inmunofluorescencia directa fueron negativos, y la anatomía patológica reveló un denso infiltrado inflamatorio con predominio neutrofílico en dermis. Ante el diagnóstico de pioderma gangrenoso ampollar, se realizó una punción-aspiración de médula ósea cuyo resultado fue compatible con leucemia mieloide aguda. Se instauró tratamiento con corticosteroides sistémicos, a pesar de lo cual la paciente evolucionó desfavorablemente y falleció a los 15 días de su ingreso hospitalario. Este caso ilustra la asociación de esta enfermedad cutánea con trastornos oncohematológicos y el mal pronóstico que esto implica a corto plazo. (AU)

Bullous pyoderma gangrenosum is an infrequent type of pyoderma gangrenosum, associated with onco hematological diseases in 50-70% of cases. We present the case of a 59-year-old patient with fever and mucocutaneous hemorrhagic bullous of rapid progression. A biopsy for histopathology, direct immunofluorescence (DIF) and skin culture was made, considering the possibility of neutrophilic dermatoses, bullous dermatosis or an opportunistic infection. The results of both the culture and the DIF were negative. The histopathological examination of the specimen revealed a dense dermal polymorphic infiltrate composed primarily of neutrophils. Considering bullous pyoderma gangrenosum as a potential diagnosis, a bone-marrow biopsy was performed. This study revealed an acute myeloid leukemia. Although systemic corticosteroid therapy was begun, the patient presented an unfavorable evolution that led to her death 15 days after her admission at the hospital. This case shows the association between bullous pyoderma gangrenosum and onco hematological diseases. In addition, it highlights the poor prognosis related to these diseases in the short term. (AU)

Costo-efectividad de ceftazidima/avibactam versus colistin + meropenem en el tratamiento de infecciones por enterobacterias resistentes a carbapenémicos en Chile / Cost-effectiveness of ceftazidime/avibactam versus colistin + meropenem for treatment of carbapenemic-resistant enterobacteria infections in Chile

INTRODUCCIÓN: Ceftazidima-avibactam (C/A), ha demostrado reducir las tasas de mortalidad y el riesgo de nefrotoxicidad, comparado con colistin, la terapia convencional. OBJETIVO: Estimar la costo-efectividad de C/A versus colistin + meropenem en el tratamiento de infecciones por Enterobacteriaceae resistentes a carbapenémicos (ERC) en Chile. MATERIAL Y MÉTODOS: Se adaptó un modelo económico tipo árbol de decisión. Se utilizó la perspectiva del pagador público, un horizonte de tiempo de 30 días con extrapolación a la expectativa de vida. La información clínica se derivó de un estudio observacional. Los costos de los medicamentos y de atención corresponden a reportes locales. Los resultados se expresan como razón de costo-efectividad incremental (RCEI) por año de vida ganado (AVG) y por año de vida ajustado por calidad (AVAC) en pesos chilenos y en dólares estadounidenses (US$ 1,00 = $792,2218). RESULTADOS: Se obtuvieron 8,65 y 6,48 AVGs y 6,44 y 4,27 AVACs, para C/A y colistin + meropenem, respectivamente. La RCEI estimada de C/A fue $940.488 (US$1.187,2) por AVG y $938.715 (US$1.184,9) por AVAC. DISCUSIÓN: Dada la falta de publicaciones o evidencia, el modelo se basa en un estudio observacional. C/A reduciría la proporción de muertes e incrementaría los AVG y los AVAC, resultando en una alternativa costo-efectiva versus colistin + meropenem para ERC.

BACKGROUND: Ceftazidime-avibactam (C/A), has shown reduction in mortality rates and risk of nephrotoxicity, compared to colistin, conventional therapy. AIM: To estimate the cost-effectiveness of C/A versus colistin + meropenem in the treatment of infections due to carbapenem-resistant Enterobacteriaceae (CRE) in Chile. METHODS: An economic decision tree type model was adapted. The perspective of the public payer was used with a time horizon of 30 days and extrapolation to life expectancy. The clinical information was derived from an observational study. Medication and care costs correspond to local reports. The results are expressed as incremental cost-effectiveness ratio (ICER) per life year gained (LYG) and per quality adjusted life year (QALY) in Chilean pesos and US dollars (US$ 1.00 = $792.2218). RESULTS: 8.65 and 6.48 LYGs and 6.44 and 4.27 QALYs were obtained, for C/A and colistin + meropenem, respectively. The estimated ICER for C/A was $940,488 (US$1,187.2) per AVG and $938,715 (US$1,184.9) per QALY. DISCUSSION: Given the lack of publications or evidence, the model is based on an observational study. C/A would reduce the death rate and increase LYGs and QALYs, resulting in a cost-effective alternative vs. colistin + meropenem for CRE.

Actividad antimicrobiana de ceftolozano-tazobactam y ceftazidima-avibactam contra bacilos gramnegativos clínicamente relevantes aislados en México / Ceftolozane/tazobactam and ceftazidime/avibactam antimicrobial activity against clinically relevant gram-negative bacilli isolated in Mexico

Resumen Introducción: Existe poca información acerca de la efectividad de las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam en cepas clínicamente relevantes aisladas en México. Objetivo: Determinar el perfil antimicrobiano de ambos antibióticos en nuestra comunidad. Método: El presente estudio de investigación fue prospectivo, descriptivo y transversal. Se incluyeron cepas clínicamente relevantes aisladas a partir de cultivos de cepa pura durante el periodo de agosto de 2018 a enero de 2019 en Mexicali, Baja California, México. Resultados: Se analizaron 74 cepas de enterobacterias y 19 cepas de Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftazidima/avibactam fue de 100 % contra enterobacterias y de 72.7 % contra Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftolozano/tazobactam fue de 90.5 % para enterobacterias y de 72.7 % para Pseudomonas aeruginosa. Conclusiones: Las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam ofrecen buena sensibilidad antimicrobiana in vitro, tanto contra enterobacterias productoras de betalactamasas de espectro extendido como contra Pseudomonas aeruginosa. Se requieren más datos para valorar la respuesta clínica en pacientes que reciben esas combinaciones de antibióticos.

Abstract Introduction: There is limited information on the effectiveness of ceftolozane/tazobactam and ceftazidime/avibactam combinations on clinically relevant strains isolated in Mexico. Objective: To determine the antimicrobial profile of both antibiotic combinations in our community. Method: The present research study was prospective, descriptive and cross-sectional. Clinically relevant strains isolated from pure-strain cultures were included during the period from August 2018 to January 2019 in Mexicali, Baja California, Mexico. Results: 74 enterobacteriaceae and 19 Pseudomonas aeruginosa strains were analyzed; the percentage of sensitivity of ceftazidime/avibactam was 100 % for enterobacteriaceae and 72.7 % for Pseudomonas aeruginosa; the percentage of sensitivity of ceftolozane/tazobactam for enterobacteriaceae was 90.5 % and 72.7 % for Pseudomonas aeruginosa. Conclusions: The ceftolozane/tazobactam and ceftazidime/avibactam combinations offer good antimicrobial sensitivity in vitro, both for ESBL-producing enterobacteriaceae and Pseudomonas aeruginosa. More data are required to assess clinical response in patients receiving these antibiotic combinations.

Bacterias Gram negativas resistentes a carbapenemicos en Colombia: un desafío continuo al sistema de salud: [Editorial] / Carbapenem resistant Gram negative bacteria in Colombia: a continuous challenge for the health system: [Editorial]

En Colombia, los Enterobacterales (Escherichia coli, Klebsiella spp y Enterobacter spp) ocupan los primeros lugares en la epidemiología de las infecciones asociadas a la atención en salud (IAAS) y de las adquiridas en comunidad. Estas bacterias pueden desarrollar resistencia a carbapenemicos (Ertapenem, Imipenem, Meropenem y Doripenem) por una combinación de mecanismos que incluye la producción de enzimas hidrolíticas (como las betalactamasas de espectro extendido o BLEEs, las cefalosporinasas AmpC y las carbapenemasas) y las mutaciones en proteínas de la membrana externa. Desde su aparición en 1996, las carbapenemasas han sido las enzimas más temidas. Klebsiella pneumoniae carbapenemase (KPC) Verona integron-mediated metallo- ß-lactamase (VIM), New Delhi metallo-ß-lactamase (NDM), Imipenemase (IMP) y oxacillinase-48-like carbapenemase (OXA-48) han sido las más estudiadas por su diseminación y alta mortalidad. En 2006 se reportó por primera vez la presencia de carbapenemasas en Colombia correspondiente a una KPC-24 . Desde entonces, varios reportes de diversas enzimas han sido publicados por grupos de investigación y por el Instituto Nacional de Salud (INS) en cuyo último informe 66% de los Enterobacterales resistentes a carbapenémicos expresan KPC, 23% expresan NDM y 6% expresan VIM. Llama la atención un 12% de aislamientos sin carbapenemasas detectables.

In Colombia, Enterobacteriaceae (Escherichia coli, Klebsiella spp and Enterobacter spp) occupy the first places in the epidemiology of healthcare-associated infections (HAI) and community-acquired infections. These bacteria can develop resistance to carbapenemics (Ertapenem, Imipenem, Meropenem and Doripenem) by a combination of mechanisms including the production of hydrolytic enzymes (such as extended-spectrum beta-lactamases or BLEEs, AmpC cephalosporinases and carbapenemases) and mutations in outer membrane proteins. Since their emergence in 1996, carbapenemases have been the most feared enzymes. Klebsiella pneumoniae carbapenemase (KPC) Verona integron-mediated metallo- ß-lactamase (VIM), New Delhi metallo-ß-lactamase (NDM), Imipenemase (IMP) and oxacillinase-48-like carbapenemase (OXA-48) have been the most studied because of their dissemination and high mortality. In 2006, the presence of carbapenemases in Colombia corresponding to a KPC-24 was reported for the first time. Since then, several reports of various enzymes have been published by research groups and by the National Institute of Health (INS) in whose last report 66% of carbapenem-resistant Enterobacteriaceae express KPC, 23% express NDM and 6% express VIM. It is noteworthy that 12% of isolates had no detectable carbapenemases.

Nuevos antibióticos en la era de la multiresistencia: revisión sobre ceftolozano/tazobactam y ceftazidima/avibactam / New antibiotics in the multiresistance era: review about ceftolozane/tazobactam and ceftazidime/avibactamISSN 2314-3193. Actualizaciones en sida e infectología. Buenos Aires. noviembre 2020. volumen 28. número 103: 57-71

En los últimos años se han desarrollado nuevos antimicrobianos destinados a combatir infecciones causadas por microorganismos multirresistentes a drogas (MDR), incluyendo combinaciones entre agentes ß-lactámicos (BL) e inhibidores de ß-lactamasas (IBL). En nuestro país se encuentran disponibles dos nuevas combinaciones de BL/IBL: ceftolozano/tazobactam (C/T) y ceftazidima/avibactam (CAZ/AVI). La adición de tazobactam a ceftolozano incrementa la actividad in vitro contra microorganismos productores de BL de espectro extendido (BLEE), por lo que la combinación presenta una potente actividad intrínseca frente a P. aeruginosa. Por su parte, CAZ/AVI conserva las características que definen el perfil de actividad de ceftazidima, por lo que con el agregado de avibactam presenta una potente actividad inhibidora frente a las BLEE y carbapenemasas (KPC, ß-lactamasas de clase C y algunas de clase D). Se presenta a continuación una revisión de la evidencia publicada. A partir de la misma, y considerando la situación actual de tasas crecientes de resistencia antimicrobiana, particularmente en bacilos Gram negativos, se considera que el uso de C/T o CAZ/AVI constituye una excelente alternativa para el manejo de infecciones graves causadas por microorganismos multirresistentes. Sin embargo, su utilización en forma empírica no es recomendable, salvo en situaciones puntuales y estrictamente seleccionadas, y en el contexto un programa de uso racional de antibióticos, bajo el control por parte del equipo de infectología responsable

In recent years, new antimicrobials have been developed to combat infections caused by multidrug-resistant microorganism (MDR), including combinations between ß-lactam agents (BL) and ß-lactamase inhibitors (IBL). Two new combinations of BL / IBL are available in our country: ceftolozano / tazobactam (C / T) and ceftazidime / avibactam (CAZ / AVI). The addition of tazobactam to ceftolozano increases in vitro activity against microorganisms producing extended spectrum BL (ESBL), so the combination has a potent intrinsic activity against P. aeruginosa. For its part, CAZ / AVI retains the characteristics that define the activity profile of ceftazidime, to which with the addition of avibactam it presents a potent inhibitory activity against ESBL and carbapenemases (KPC, ß-lactamases of class C and some of class D). A review of the published evidence is presented below. Based on this, and considering the current situation of increasing rates of antimicrobial resistance, particularly in Gram-negative bacilli, we consider that the use of C/T or CAZ/AVI is an excellent alternative for the management of serious infections caused by multi-resistant microorganisms. However, its use empirically is not recommended, except in specific and strictly selected situations, and in the context of a program for the rational use of antibiotics, under the control of the responsible infectious disease team

Corneal Collagen Cross-linking for Corneal Ulcer from Moraxella Group

PURPOSE: To report a case of corneal collagen cross-linking for corneal ulcer caused by the Moraxella group.CASE SUMMARY: A 77-year-old male had decreased visual acuity for several days in his right eye. The patient showed severe stromal ring infiltrates with a corneal epithelial defect measuring (5.0 × 7.0 mm), a corneal endothelial plaque, and a hypopyon measuring less than 1.0 mm in height in the anterior chamber of the right eye. There was no abnormal finding in the right eye using B-scan ultrasonography. Before starting treatment, a corneal culture was conducted. The culture tests showed the presence of the Moraxella group. Because the patient was diagnosed with a corneal ulcer caused by the Moraxella group, corneal collagen cross-linking (CXL) was performed. The antimicrobial susceptibility test confirmed that this Moraxella group was sensitive to ceftazidime, so the patient was treated with 5% ceftazidime eye drops and 0.5% moxifloxacin eye drops every 2 hours for 9 months after corneal collagen CXL. The uncorrected visual acuity was 0.1 in the right eye, and there was almost no corneal stromal melting on anterior segment optical coherence tomography.CONCLUSIONS: This is the first known case of a corneal ulcer, in the Republic of Korea, caused by the Moraxella group and treated with corneal collagen CXL. Corneal collagen CXL should be considered as a surgical treatment for patients who have an impending corneal perforation due to a corneal ulcer because it is a simple procedure and causes fewer serious complications than other treatments.

Role of Efflux Pump Gene adeIJK to Multidrug Resistance in Acinetobacter baumannii Clinical Isolates / 대한임상미생물학회지

BACKGROUND: The emergence of multidrug-resistant Acinetobacter baumannii as a nosocomial pathogen is one of the major public health problems. The aim of this study was to evaluate the role of an efflux pump gene adeJ for the multidrug resistance of A. baumannii clinical isolates.METHODS: Two groups (MDRAB and SAB) of A. baumannii clinical isolates were studied. The SAB group consisted of strains that did not meet the criteria of MDRAB and were susceptible to more categories of antibiotics than MDRAB. Antimicrobial susceptibility results obtained by VITEKII system were used in data analysis and bacterial group allocation. We performed real-time reverse transcription PCR to determine relative expression of adeJ. We compared relative expression of adeJ in comparison groups by considering two viewpoints: i) MDRAB and SAB groups and ii) susceptible and non-susceptible groups for each antibiotic used in this study.RESULTS: The mean value of relative expression of adeJ of MDRAB and SAB groups was 1.4 and 0.92, respectively, and showed significant difference (P=0.002). The mean values of relative expression of adeJ of susceptible and non-susceptible groups to the antibiotics cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem, tigecycline, piperacillin/tazobactam, ticarcillin/clavulanic acid, trimethoprim/sulfamethoxazole, piperacillin, and gentamicin showed statistically significant differences.CONCLUSION: The overexpression of adeIJK might contribute to the multi-drug resistance in A. baumannii clinical isolates. Further, the overexpression of adeIJK might be one of the factors contributing to the resistance to numerous antibiotics.

Culture-Positive Spontaneous Ascitic Infection in Patients with Acute Decompensated Cirrhosis: Multidrug-Resistant Pathogens and Antibiotic Strategies

Prevalence and Risk Factors for Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae Colonization in Intensive Care Units

Active surveillance culture (ASC) can help detect hidden reservoirs, but the routine use of ASC for extended spectrum β-lactamase-producing Enterobacteriaceae is controversial in an endemic situation. We aimed to determine the prevalence and risk factors of extended spectrum β-lactamase-producing Klebsiella pneumoniae (EBSL-Kpn) colonization among intensive care unit (ICU)-admitted patients. Prospective screening of ESBL-Kpn colonization was performed for ICU-admitted patients within 48 hours for two months. A perirectal swab sample was inoculated on MacConkey agar supplemented with 2 µg/mL ceftazidime. ESBL genotype was determined by PCR-sequencing, and clonal relatedness was evaluated by pulsed-field gel electrophoresis (PFGE). The risk factors of ESBL-Kpn colonization were evaluated. The ESBL-Kpn colonization rate among the 281 patients at ICU admission was 6.4% (18/281), and bla(CTX-M-15) was detected in all isolates. ESBL producers also showed resistance to fluoroquinolone (38.9%, 7/18). All isolates had the same ESBL genotype (bla(CTX-M-15)) and a highly clustered PFGE pattern, suggesting cross-transmission without a documented outbreak. In univariate analysis, the risk factor for ESBL-Kpn colonization over the control was the length of hospital stay (odds ratio=1.062; P=0.019). Routine use of ASC could help control endemic ESBL–Kpn for ICU patients.

Carbapenemase-producing Enterobacteriaceae: A diagnostic, epidemiological and therapeutic challenge / Enterobacteriaceae productoras de carbapenemasas: Un reto diagnóstico, epidemiológico y terapéutico

The global spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a public health problem. Not all CPE are resistant to carbapenems creating a diagnostic and therapeutic challenge. Furthermore, as resistance to carbapenems can also be mediated by other β-lactamases combined with defects in membrane permeability, their detection can be difficult by microbiology laboratories that lack molecular tools, which may limit and often delay the correct antibiotic selection. There is only limited evidence regarding infection control measures to contain the spread of CPE. However, recomendations have been published from the World Health Organization (WHO) and the European Prevention Center and Disease Control (ECDC). Because of the lack of randomized control trials, treatment regimens are mostly based on observational clinical studies. Several of those studies have reported that combination therapy with two or more in vitro-active agents including a carbapenem is superior to monotherapy. On the other hand, a new β-lactamase inhibitor in combination with ceftazidime has shown clinical efficacy Against KPC and some OXA-type producing Enterobacteriaceae

La diseminación global de las Enterobacteriaceae productoras de carbapenemasas (EPC) se ha convertido en un problema de salud pública. No todas las EPC son resistentes a los carbapenémicos, por lo que representan un reto diagnóstico y terapéutico. Adicionalmente, como la resistencia a los carbapenémicos puede ser mediada por otras β-lactamasas en combinación con cambios de la permeabilidad de la membrana plasmática, su detección puede ser difícil en laboratorios de microbiología que no cuentan con técnicas de diagnóstico molecular, lo que puede restringir y frecuentemente retrasar el inicio de la terapia antimicrobiana adecuada. La evidencia respecto a las medidas para la contención de las EPC es escasa. Sin embargo, existen recomendaciones por parte de la Organización Mundial de la Salud y del European Prevention Center and Disease Control (ECDC). Debido a la ausencia de estudios controlados y aleatorizados, los esquemas terapéuticos se basan en estudios clínicos observacionales. Varios de estos estudios han reportado mejores resultados con la terapia combinada de dos o más agentes activos in vitro, incluyendo a los carbapenémicos, en comparación con la monoterapia. Por otra parte, un nuevo inhibidor de β-lactamasas en combinación con ceftazidime, ha mostrado eficacia clínica contra infecciones por Enterobacteriaceae productoras de KPC y algunas carbapenemasas de tipo OXA.

Caracterización molecular y detección de genes blaCTX-M grupos 1 y 9 en Klebsiella pneumoniae resistentes a ceftazidima, en un hospital de San José de Cúcuta, Colombia / Molecular characterization and detection of genes blaCTX-M groups 1 and 9 in Klebsiella pneumoniae resistant to ceftazidime, in a hospital in San José de Cúcuta, Colombia

Resumen Introducción: La expresión de β-lactamasas CTX-M pertenecientes a los grupos 1 y 9 en Klebsiella pneumoniae produce grados altos de resistencia a ceftazidima, y presentan una amplia distribución mundial. Objetivo: Identificar y caracterizar los genes blaCTX-M-Grupo1 y blaCTX-M-Grupo9 en aislados de K. pneumoniae resistentes a ceftazidima en un hospital de San José de Cúcuta, Colombia. Material y Método: Se diseñaron partidores para la identificación de K. pneumoniae y los genes blaCTX-M mediante reacción de polimerasa en cadena (RPC). Posteriormente se realizó el análisis de la relación genética de estos aislados por medio de la RPC basada en secuencias repetitivas (RPC-REP). Resultados: Treinta y ocho por ciento de los 24 aislados identificados por RPC como K. pneumoniae presentaron los genes blaCTX-M-3, blaCTX-M-15 y blaCTX-M-32 (Grupo CTX-M-1) y 42% los genes blaCTX-M14, blaCTX-M-24 y blaCTX-M-27 (Grupo CTX-M-9). El análisis filogenético agrupó los aislados de K. pneumoniae en cuatro clusters, mostrando correlación en los clusters I, II y IV, al comparar los perfiles genéticos con el tipo de muestra y grupo de genes. Discusión: Se encontró una frecuencia similar de los genes blaCTX-M-Grupo1 y blaCTX-M-Grupo 9 en aislados de K. pneumoniae resistentes a ceftazidima. La correlación entre la RPC-REP con los grupos de CTX-M y el tipo de muestra reveló la presencia de tres patrones clonales.

Background: The expression of CTX-M β-lactamases belonging to groups 1 and 9 in Klebsiella pneumoniae produces high levels of resistance to ceftazidime, and they have a wide distribution worldwide. Aim: To identify and characterize the blaCTX-M-Group1 and blaCTX-M-Group9 genes in K. pneumoniae isolates resistant to ceftazidime in a hospital in San José de Cúcuta, Colombia. Material and Methods: Primers were designed for the identification of K. pneumoniae and blaCTX-M genes by PCR. Subsequently, the genetic relationship of these isolates was analyzed by REP-PCR. Results: A 38% of the 24 isolates identified by PCR as K. pneumoniae showed blaCTX-M-3. blaCTX-M-15 y blaCTX-M-32 genes (Group CTX-M-1) and 42% blaCTX-M14. blaCTX-M-24 y blaCTX-M-27 genes (Group CTX-M-9). The phylogenetic analysis grouped the K. pneumoniae isolates into 4 clusters, showing correlation in clusters I, II and IV, when comparing the genetic profiles with the type of sample and group of genes. Discussion: We found a similar frequency of blaCTX-M-Group 1 and blaCTX-M-Group 9 genes in isolates of K. pneumoniae resistant to ceftazidime. The correlation between the REP-PCR with the CTX-M groups and the type of sample revealed the presence of three clonal patterns.

Differences in Antimicrobial Resistance Phenotypes by the Group of CTX-M Extended-Spectrum β-Lactamase / 대한임상미생물학회지

BACKGROUND: Escherichia coli and Klebsiella pneumoniae clinical isolates producing CTX-M extendedspectrum β-lactamases (ESBLs) were assessed for antimicrobial resistance phenotypes varied by group of enzymes. METHODS: A total of 1,338 blood isolates, including 959 E. coli and 379 K. pneumoniae, were studied. All the strains were collected between January and July 2017 from eight general hospitals in South Korea. The species were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Antimicrobial susceptibilities were determined by disk diffusion methods and ESBL phenotypes by double-disk synergy tests using disks containing cefotaxime, ceftazidime, cefepime, aztreonam, and clavulanic acid (CA). The genes for β-lactamases were identified by PCR and sequencing. RESULTS: Of total microbes, 31.6% (303/959) E. coli and 24.0% (91/379) K. pneumoniae were resistant to cefotaxime and 28.1% (269/959) E. coli and 20.1% (76/379) K. pneumoniae were CTX-M-type ESBL producers. Among the detected CTX-M ESBLs, 58.0% (156/269) in E. coli and 86.8% (66/76) in K. pneumoniae belonged to group 1, 46.8% (126/269) in E. coli and 14.5% (11/76) in K. pneumoniae were group 9. Ten E. coli and one K. pneumoniae isolates co-produced both groups of CTX-M ESBL. The group 1 CTX-M producers had a higher level of resistance to cefotaxime, ceftazidime, cefepime, and aztreonam and exhibited stronger synergistic activities when combined with CA compared to group 9. CONCLUSION: ESBL phenotypes differ by CTX-M ESBL group and phenotype testing with drugs including 4th generation cephalosporins and monobactams is critical for screening CTX-M-producers with better sensitivity.

Polymicrobial Keratitis of Pseudomonas aeruginosa, Acinetobacter baumannii, and Ochrobactrum anthropi

PURPOSE: To report polymicrobial keratitis involving Pseudomonas aeruginosa, Acinetobacter baumannii, and Ochrobactrum anthropi. CASE SUMMARY: A 53-year-old female complained of pain and secretion in her right eye, which started 6 weeks before her visit. She applied steroid ointment, which was received from the dermatologist, to her eyelid 7 days prior to her visit but this treatment worsened her symptoms. At the initial visit, the visual acuity of the right eye was light perception, and purulent secretions were observed. Using a slit lamp, severe conjunctival hyperemia, hypopyon, and a ring-shaped central corneal ulcer were observed. The anterior chamber and fundus were not observed due to corneal lesions but ultrasonography showed no intraocular inflammation. Infectious keratitis was suspected and cultured by corneal scraping. During the incubation period, 0.5% moxifloxacin, 2% voriconazole, and 1% cyclopentolate were administered. A total of 400 mg of moxifloxacin and 100 mg of doxycycline were given orally. In the primary culture, Pseudomonas aeruginosa and Acinetobacter baumannii were identified so 5% ceftazidime, which was sensitive for the antibiotic susceptibility results was further instilled. Thereafter, the keratitis improved but the keratitis again worsened while maintaining the topical treatment. A secondary culture was positive for Ochrobactrum anthropi. Treatment with 1.4% gentamicin, which was sensitive for the antibiotic susceptibility test was added and the keratitis improved. A conjunctival flap was performed because of the increased risk of perforation. CONCLUSIONS: We report polymicrobial keratitis involving Pseudomonas aeruginosa, Acinetobacter baumannii, and Ochrobactrum anthropi for the first time in the Republic of Korea.

Musical Hallucination Caused by Ceftazidime in a Woman with a Hearing Impairment

Musical hallucinations remain a poorly understood clinical phenomenon, possibly because these types of hallucination have multiple causes and are rarely the focus of published reports. Here, the case of a 51-year-old female patient with a hearing impairment who developed musical hallucinations during treatment with ceftazidime, a third-generation cephalosporin, is presented. She responded to the discontinuation of ceftazidime and the initiation of low-dose olanzapine treatment. Musical hallucinations associated with ceftazidime are very rare, and the mechanisms underlying its occurrence remain unknown. Further studies will be necessary to determine the pathophysiology of adverse psychiatric reactions associated with ceftazidime.

Antimicrobial Susceptibility of Microorganisms Isolated from Patients with Intraabdominal Infection in Korea: a Multicenter Study

Infectious Keratitis Caused by Shewanella Putrefaciens

PURPOSE: We report a case of infectious keratitis caused by Shewanella putrefaciens in a patient after fishing. CASE SUMMARY: A 75-year-old male with no underlying disease other than hypertension was admitted to our hospital because of decreased visual acuity and congestion in his left eye for 2 weeks. At the first ophthalmic examination, the best-corrected visual acuity (BCVA) of the left eye was counting fingers. Slit lamp examination showed stromal infiltrates with 2.0 × 2.0 mm corneal epithelial defects, endothelial inflammatory plaques and 1 mm height hypopyon with severe inflammation in the anterior chamber. Bacterial culture tests were performed by corneal scraping, which were positive for Shewanella putrefaciens, followed by treatment with moxifloxacin and ceftazidime topical antibiotics. After 2 months of treatment, the BCVA of the left eye improved to 0.4 and the corneal lesion clinically improved with residual mild stromal opacity. CONCLUSIONS: Shewanella putrefaciens should be considered as a causal pathogen of infectious keratitis in patients after fishing. We report a case of infectious keratitis caused by Shewanella putrefaciens, which has never previously been reported in the Republic of Korea.