Caracterização fenotípica e molecular de isolados de Salmonella spp. e Escherichia coli Patogênica Extraintestinal resistentes às polimixinas / Phenotypic and molecular characterization of Salmonella spp. and extraintestinal pathogenic Escherichia coli resistant to polymyxins

A resistência antimicrobiana está se tornando um grande desafio para saúde pública devido ao aumento da resistência aos beta-lactâmicos em geral. Os isolados de Salmonella spp. e Escherichia coli são os mais frequentes agentes causadores de doenças de transmissão hídrica e alimentar, mas também podem causar doenças invasivas graves, principalmente em imunodeprimidos, idosos e crianças. Ambos os patógenos vêm apresentando perfis de resistência as principais classes de antibióticos, nestes casos é necessária a busca de uma nova opção terapêutica, como por exemplo, as polimixinas. Em 2015, surgiu o primeiro relato da resistência às polimixinas mediado pelo gene mcr (mobile colistin resistance), que se disseminou por diversos continentes e ocasionou uma grande preocupação global em saúde pública. O objetivo deste trabalho foi identificar e caracterizar os mecanismos que medeiam à resistência à polimixinas em cepas de Salmonella spp. e E. coli Patogênica extraintestinal (ExPEC). Foi realizado a triagem pelo teste da gota e teste da CIM frente a colistina e polimixina B no total de 1026 isolados de Salmonella enterica e 159 isolados de ExPEC. Nos isolados resistentes foi verificado a presença de mutações nos genes (pmrA/B, phoP/Q) associados à resistência às polimixinas, e através da PCR foi feita a identificação dos genes de resistência plasmidial (mcr). Das 124 cepas de Salmonella resistentes a colistina e polimixina B, apenas um isolado foi positivo para o gene mcr-1, e este gene foi detectado em um plasmídeo do grupo IncX4. A cepa 2018.466 foi caracterizada como S. Choleraesuis proveniente de sangue de origem humana. Foram identificados 44 isolados de Salmonella spp. apresentando mutações em pmrA e pmrB. Dos 56 isolados de ExPEC resistentes a colistina, 21 isolados apresentaram o gene mcr-1. Este gene foi detectado em plasmídeos do grupo IncX4 (n=17) e em plasmídeos do grupo IncF (n=4). Cinco isolados de E.coli não apresentaram mutações nos genes estudados,sendo que três eram positivos para o gene mcr-1, enquanto as demais cepas apresentaram mutações em pmrA/B e phoP/Q. A tipagem pela PFGE foi realizada nos isolados de E.coli positivos para o gene mcr-1, com o objetivo de verificar a diversidade genética encontrada entre elas. Foram identificados 18 perfis genéticos, sem um clone principal...(AU)

Antimicrobial resistance is becoming a major public health challenge due to increasing resistance to beta-lactams in general. Salmonella spp. and Escherichia coli are the most frequent causative agents of diseases transmitted by water and food, but they can also cause serious invasive diseases, especially in immunosuppressed individuals, the elderly and children. Both pathogens have shown resistance profiles to the main classes of antibiotics, in these cases it is necessary to search for a new therapeutic option, such as polymyxins. In 2015, the first report of resistance to polymyxins mediated by the mcr gene (mobile colistin resistance) appeared, which spread across several continents and caused a major global concern in public health. The objective of this work was to identify and characterize the mechanisms that mediate resistance to polymyxins in strains of Salmonella spp. and extraintestinal pathogenic E. coli (ExPEC). Screening by drop test and MIC test against colistin and polymyxin B was performed on a total of 1026 Salmonella enterica isolates and 159 ExPEC isolates. In the resistant isolates, the presence of mutations in the genes (pmrA/B, phoP/Q) associated with resistance to polymyxins was verified, and through PCR the plasmid resistance genes (mcr) were identified. Of the 124 Salmonella strains resistant to colistin and polymyxin B, only one isolate was positive for the mcr-1 gene, and this gene was detected in a plasmid from the IncX4 group. Strain 2018.466 was characterized as S. Choleraesuis from blood of human origin. Forty-four Salmonella spp. showing mutations in pmrA and pmrB. Of the 56 colistin-resistant ExPEC isolates, 21 isolates harbored the mcr-1 gene. This gene was detected in plasmids from the IncX4 group (n=17) and in plasmids from the IncF group (n=4). Five E.coli isolates did not show mutations in the genes studied, three of which were positive for the mcr-1 gene, while the other strains showed mutations in pmrA/B and phoP/Q. Typing by PFGE was performed on E.coli isolates positive for the mcr-1 gene, with the objective of verifying the genetic diversity found among them. Eighteen genetic profiles were identified, without a main clone...(AU)

Pathogenic characterization of Klebsiella pneumoniae resistant to carbapenems and polymyxin / 中华预防医学杂志

Objective: Analysis and investigation of pathogenic characteristics of polymyxin-and carbapenem-resistant Klebsiella pneumoniae (PR-CRKP). Methods: A total of 23 PR-CRKP strains isolated from clinical specimens from the General Hospital of Southern Theater Command from March 2019 to July 2021 were retrospectively collected, Whole-genome sequencing was performed on 23 PR-CRKP strains, resistance genes were identified by comparison of the CARD and the ResFinder database, high-resolution typing of PR-CRKP strains was analyzed by core genomic multilocus sequencing (cgMLST) and single nucleotide polymorphism (SNP); polymyxin resistance genes were determined by PCR and sequencing. Results: All PR-CRKP strains were KPC-2 producing ST11 types. cgMLST results showed that the evolutionary distance between the PR-CRKP strains and Klebsiella pneumoniae in mainland China was 66.44 on average, which is more closely related than foreign strains; the 23 PR-CRKP strains were divided into 3 main subclusters based on SNP phylogenetic trees, with some aggregation among Clade 2-1 in the isolation department and date. The two-component negative regulatory gene mgrB has seven mutation types including point mutations, different insertion fragments and different insertion positions. Conclusion: The close affinity of PR-CRKP strains indicate the possibility of nosocomial clonal transmission and the need to strengthen surveillance of PR-CRKP strains to prevent epidemic transmission of PR-CRKP.

Infección de piel y tejidos blandos por Burkholderia stabilis en un niño con quemaduras graves / Skin and soft tissue infection due to Burkholderia stabilis in a severely burned child

Resumen Las heridas por quemadura representan un grave problema, sobre todo en la población pediátrica, dada la severidad de su presentación y la morbimortalidad asociada. La infección es la complicación más frecuente y grave en el paciente quemado. Las bacterias que conforman el complejo Burkholderia cepacia (CBc) son capaces de causar enfermedades en plantas, humanos y animales. En el hombre pueden establecer infecciones crónicas y frecuentemente graves, por lo general en pacientes con fibrosis quística y en inmunocomprometidos. El CBc está compuesto por al menos 22 especies filogenéticamente muy relacionadas. El objetivo de esta publicación fue describir el primer caso de una infección de piel y partes blandas por Burkholderia stabilis, una especie poco frecuente, en un niño con grandes quemaduras en la Argentina. Las especies del CBc son intrínsecamente resistentes a la mayoría de los antimicrobianos disponibles clínicamente, como aminoglucósidos, quinolonas, polimixinas y β-lactámicos. Esto representa un serio problema en el momento de tratar las infecciones por las escasas opciones terapéuticas.

Abstract Burn wounds represent a serious problem, especially in the pediatric population, given the severity of their presentation and the associated morbidity and mortality. Infection is the most frequent and serious complication in the burned patient. Burkholderia cepacia (CBc) complex bacteria are capable of causing disease in plants, humans, and animals. In human beings they can establish chronic and frequently serious infections, generally in patients with cystic fibrosis and in immunocompromised patients. The CBc is composed of 22 phylogenetically closely related species. The objective of this publication was to describe the first report of a skin and soft tissue infection by Burkholderia stabilis, a rare species, in a child with extensive burns in Argentina. CBc species are inherently resistant to most clinically available antimicrobials, such as aminoglycosides, quinolones, polymyxins, and β-lactams. This represents a serious problem when treating infections, due to the limited therapeutic options.

Resumo As feridas por queimadura representam um grave problema, principalmente na população pediátrica, devido à gravidade de sua apresentação e morbimortalidade associada. A infecção é a complicação mais frequente e grave do paciente queimado. As bactérias que compõem o complexo Burkholderia cepacia (CBc) são capazes de causar doenças em plantas, humanos e animais. No homem, podem estabelecer infecções crônicas e freqüentemente graves, geralmente em pacientes com fibrose cística e imunocomprometidos. O CBc é composto, no mínimo, por 22 espécies filogeneticamente muito relacionadas. O objetivo desta publicação é descrever o primeiro caso de uma infecção de pele e tecidos moles por Burkholderia stabilis, uma espécie rara, em uma criança com queimaduras extensas na Argentina. As espécies do CBc são inerentemente resistentes à maioria dos antimicrobianos disponíveis clinicamente, como aminoglicosídeos, quinolonas, polimixinas e β-lactâmicos. Isso representa um problema sério na hora de tratar as infecções devido às opções terapêuticas limitadas.

Combination of polymyxin B and Aquilaria malaccensis extract enhanced the killing and inhibited the growth of Acinetobacter baumannii and Klebsiella pneumoniae

Aims@#Polymyxins are an important last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Nonetheless, the emergence of polymyxin-resistance and the limiting of polymyxin monotherapy urgently demands its optimisation. Aquilaria malaccensis (Agarwood) has been widely used as traditional medicine. Many parts of the plant including leaves exhibit a considerable in vitro antibacterial activity against microbial pathogens. Exploiting A. malaccensis in combination with polymyxins provides a novel strategy in fighting antimicrobial resistance. The objective of this study was to evaluate the combination effects of A. malaccensis extract with polymyxins against Acinetobacter baumannii and Klebsiella pneumoniae.@*Methodology and results@#In vitro time-kill studies and GC-MS analysis were performed to evaluate the bacterial killing of polymyxin B and extract combination and analyse chemical compounds of the extract, respectively. The combination of polymyxin B (1 mg/L) and A. malaccensis extract (32 mg/mL and 64 mg/mL) treatments exhibited enhanced bacterial killing compared to polymyxin B alone at 4 h and 24 h. Combination treatments also inhibited the bacterial growth of both A. baumannii and K. pneumoniae observed throughout the 24 h. More than sixty compounds including phytol, 9,12-octadecadienal, fatty acid, alkanes and terpenoids were putatively identified as the compounds that likely contributed to the antibacterial activity.@*Conclusion, significance and impact of study@#This study was the first to report the potential application of A. malaccensis extract in combination with polymyxin B in treatment against A. baumannii and K. pneumoniae and can be further investigated and optimized for the treatment of bacterial infectious diseases.

Resistência aos antimicrobianos e diversidade genética de variantes fenotípicas de Pseudomonas aeruginosa não sensíveis aos carbapenêmicos recuperadas de pacientes com fibrose cística com infecção pulmonar crônica: uma análise temporal / Antimicrobial resistance and genetic diversity of phenotypic variants of carbapenem non susceptible Pseudomonas aeruginosa recovered from patients with cystic fibrosis with chronic lung infection: a temporal analysis

Pseudomonas aeruginosa, bactéria ubíqua e versátil, pode se comportar como um patógeno oportunista, com ampla capacidade adaptativa, por múltiplos fatores de virulência e resistência. Como agente patogênico nas infecções pulmonares em pacientes com fibrose cística (FC), é motivo de prognóstico ruim, aumento de hospitalizações e altas taxas de morbimortalidade, sendo quase impossível a sua erradicação, ao evoluírem para a cronicidade. Globalmente, é notável o aumento nos índices de amostras não sensíveis aos carbapenêmicos e a múltiplos antimicrobianos, essenciais à terapêutica. Assim, avaliamos temporalmente a susceptibilidade aos antimicrobianos e a presença de amostras hipermutáveis (HPM) em P. aeruginosa de diferentes morfotipos, não sensíveis aos carbapenêmicos (PANSC), obtidas de pacientes FC com infecção pulmonar crônica, acompanhados em dois centros de referência no Rio de Janeiro. De 2007 a 2016, a análise retrospectiva, através dos resultados obtidos no teste de disco-difusão (TDD), permitiu selecionar amostras de PANSC incluídas neste trabalho. Usando os resultados obtidos no TDD, foi definida a susceptibilidade a outros antimicrobianos, bem como os fenótipos de resistência, multi-(MDR), extensivo-(XDR) e pandroga resistentes (PDR). Adicionalmente, determinou-se a concentração inibitória mínima (CIM) para imipenem (IPM), meropenem (MEM), doripenem (DOR) e polimixina (POL). Através de teste fenotípico, foi calculada a frequência de mutação espontânea e as amostras hipermutáveis foram caracterizadas. O sequenciamento de genoma total (SGT) foi realizado em seis amostras de diferentes morfotipos, incluindo uma variante fenotípica rara, a small colony variant (SCV). Essas amostras foram recuperadas em dois episódios de exacerbação do paciente. Foram investigadas a clonalidade, resistência a antimicrobianos e virulência. Das 143 amostras, de 18 pacientes (9 pediátricos e 9 adultos), os resultados do TDD apontaram taxas de não susceptibilidade superiores a 44% para gentamicina, amicacina, tobramicina e ciprofloxacina, e maiores de 30 % para POL. Pela determinação da CIM, quase a totalidade (96%) das amostras foram não sensíveis a IMP, seguidos de 56% para MEM e 44% para DOR. Analisando-se a distribuição dos valores da CIM50 e CIM90 nos dois grupos de pacientes, os valores para IMP foram maiores entre as amostras dos pacientes pediátricos, equivalendo a 32 µg/mL e 64 µg/mL, respectivamente. Cerca de 25%, 37% e 6% eram MDR, XDR e PDR, respectivamente. Aproximadamente 12% eram HPM, e mais da metade destas foram XDR. Após o SGT, as seis amostras, recuperadas do caso clínico foram classificadas em um novo sequence type (ST2744), com a presença de genes de resistência adquiridos blaPAO, blaOXA-50, aph(3')-Iib, fosA, catB7 e crpP, apresentando mutações em genes codificadores de porinas e bombas de efluxo. Entretanto, não foram observados marcadores genéticos clássicos exclusivos para os fenótipos SCV e HPM. Este é o primeiro relato de P. aeruginosa SCV na FC, no Brasil. A vigilância epidemiológica de P. aeruginosa é crucial para a conduta terapêutica, bem como para o sucesso da resposta do paciente e erradicação da infecção pulmonar, justificando o uso de técnicas fenotípicas e moleculares na detecção dos mecanismos de resistência e virulência desse microrganismo na FC.

Pseudomonas aeruginosa, a ubiquitous and versatile bacterium, can behave as an opportunistic pathogen, with strong adaptive capacity, due to multiple virulence and resistance factors. As a pulmonary infection pathogen in patients with cystic fibrosis (CF), it is related with poor prognosis, increased hospitalizations and high rates of morbidity and mortality, and the eradication is almost impossible, especially after chronicity. The increase rates of isolates non-susceptible to carbapenem and multiple antimicrobials, essentials to therapy, have been observed worldwide. Therefore, we assessed the antimicrobial susceptibility and the presence of hypermutability (HPM) in non-susceptible to carbapenem P. aeruginosa (PANSC) isolates from different morphotypes, obtained from CF patients with chronic pulmonary infection, followed at two reference centers in Rio de Janeiro. Using the results obtained by disk-diffusion test (DDT) between 2007 to 2016, we select 143 PANSC and susceptibility to other antimicrobials was defined, as well as the resistance phenotypes, multi- (MDR), extensive- (XDR) and pandrug resistant (PDR). Additionally, the minimum inhibitory concentration (MIC) for imipenem (IPM), meropenem (MEM), doripenem (DOR) and polymyxin (POL) was determined. Hypermutable isolates were characterized by determination of mutation frequency. Whole genome sequencing (WGS) was performed in six morphotypes isolates, including the small colony variant (SCV), a rare variant phenotype. These isolates were recovered in two exacerbation episodes. Clonality, antimicrobial resistance and virulence were investigated. Of the total (143 isolates) isolated from 18 patients (9 pediatric and 9 adults), non-susceptibility rates above than 44% for gentamicin, amikacin, tobramycin and ciprofloxacin, and more than 30% for POL were observed. Almost all (96%) of the isolates were non-susceptible to IPM by MIC determination, followed by 56% for MEM and 44% for DOR. MIC50 (32 µg/mL) and MIC90 (64 µg/mL) rates for IPM were higher among pediatric patient isolates and 25%, 37% and 6% were MDR, XDR and PDR, respectively. 12% of all isolates were classified as HPM and more than half were categorized as XDR. Using WGS, the six isolates recovered from the clinical case, were identified as a new sequence type (ST2744). Acquired resistance genes blaPAO, blaOXA-50, aph (3')-Iib, fosA, catB7 and crpP and mutations in encoding genes for porins and efflux pumps, was annotated. None exclusive classic genetic markers related to SCV and HPM phenotypes were not observed. This is the first Brazilian report of P. aeruginosa SCV in CF. Our results highlight the importance of epidemiological surveillance in P. aeruginosa. The application of phenotypic and molecular techniques to investigate resistance and virulence mechanisms, can contribute to therapeutic success in CF.

Rational use of Polymyxins against multi-drug resistant Gram-Negative bacteria

@#The current strategy in treating multi-drug resistant gram-negative bacterial (MDR-GNB) infections is salvage therapy by using polymyxins. However, the beginning emergence of polymyxin resistance should enforce strict antimicrobial stewardship programs to preserve polymyxin efficacy. Knowledge of structural characteristics, pharmacodynamic, and pharmacokinetic profiles of polymyxins, as well as consideration of efficacy, safety, suitability, and cost, will help in the choice of the appropriate polymyxin for therapy. Polymyxin B is the recommended polymyxin for systemic use, while colistin is recommended for lower urinary tract infections, intraventricular, and intrathecal use. Either polymyxin can be used for hospital-acquired and ventilator-associated pneumonia. Combination therapy over monotherapy remains to be advantageous due to synergism and decreased resistance development. The choice of the second drug to be used should be based on full susceptibility, or if unavailable, a drug with the least minimum inhibitory concentration relative to the breakpoint set by the Clinical and Laboratory Standards Institute. Using the mnemonic ESCAPE can also guide physicians in their polymyxin prescription process: (1) Checking if the pathogen is Extensively resistant or multi-drug resistant; (2) checking the patient’s clinical status if compatible with Significant infection; (3) using Combination therapy; (4) ensuring Adequate dosing; (5) Proper preparation and administration of drug; and (6) keeping an Eye for response and adverse effects.

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.

Non-clonal occurrence of pmrB mutations associated with polymyxin resistance in carbapenem-resistant Klebsiella pneumoniae in Brazil

BACKGROUND Polymyxins are currently used as a "last-line" treatment for multidrug-resistant Gram-negative infections. OBJECTIVES To identify the major mechanisms of resistance to polymyxin and compare the genetic similarity between multi-drug resistant Klebsiella pneumoniae strains recovered from inpatients of public hospitals in the Mid-West of Brazil. METHODS 97 carbapenems non-susceptible K. pneumoniae were studied. β-lactamases (bla OXA-48, bla KPC, bla NDM, bla CTX-M, bla SHV, bla TEM, bla IMP, bla VIM) and mcr-1 to mcr-5 genes were investigated by polymerase chain reaction (PCR). Mutations in chromosomal genes (pmrA, pmrB, phoP, phoQ, and mgrB) were screened by PCR and DNA sequencing. Clonal relatedness was established by using pulsed-field gel electrophoresis and multilocus sequence typing. FINDINGS K. pneumoniae isolates harbored bla KPC (93.3%), bla SHV (86.6%), bla TEM (80.0%), bla CTX-M (60%) genes. Of 15 K. pneumoniae resistant to polymyxin B the authors identified deleterious mutations in pmrB gene, mainly in T157P. None K. pneumoniae presented mcr gene variants. Genetic polymorphism analyses revealed 12 different pulsotypes. MAIN CONCLUSIONS Deleterious mutations in pmrB gene is the main chromosomal target for induction of polymyxin resistance in carbapenem-resistant K. pneumoniae in public hospitals in the Mid-West of Brazil.

Resistencia plasmídica a colistin por el gen mcr-1 en Enterobacteriaceae en Paraguay / Plasmid-Mediated Colistin Resistance Gene mcr-1 in Enterobacteriaceae in Paraguay

La resistencia a las polimixinas mediada por plásmidos (gen mcr-1) representa una amenaza para la salud pública, puesto que colistina es utilizada en la práctica médica como una de las últimas alternativas para el tratamiento de gérmenes multiresistentes. Este estudio describe la circulaciónde cepas de Enterobacterias que portan este gen de resistencia, aisladas de pacientes hospitalizados, así como también de la comunidad. Los hallazgos de la Red de Vigilancia de la Resistencia a los Antimicrobianos-Paraguay fueron de casi el 5 % (4,7) en cepas remitidas con criterio de sospecha, siendo las especies involucradas Escherichiacoli, Klebsiella pneumoniae y Salmonella Schwarzengrund. Además, por métodos moleculares se confirmaron en todas ellas la portación de otros genes de resistencia (KPC, CTX-M, Qnr B, Qnr S, aac (6`)-Ib-cr) asociados al mcr-1. Palabras claves: Enterobacterias, resistencia, colistina, mcr-1.

Resistance to polymyxins mediated by plasmids (mcr-1 gene) represents a threat to public health, since colistin is used in medical practice, as one of the last alternatives, for the treatment of multi-resistant germs. This study describes the circulation of strains of Enterobacteria that carry this resistance gene, isolated from hospitalized patients, as well as from the community. The findings of the Red de Vigilancia de la Resistencia a los Antimicrobianos­Paraguay were almost 5% (4.7) in strains submitted with suspicion criteria; the species involved being Escherichia coli, Klebsiella pneumoniae and Salmonella Schwarzengrund. In addition, molecular methods confirmed in all of them the carrying of other resistance genes (KPC, CTX-M, Qnr B, Qnr S, aac (6`)-Ib-cr) associated with mcr-1. Key words: Enterobacteria, resistance, colistin, mcr-1.

Lesão renal aguda associada ao uso de polimixinas em pacientes críticos / Acute kidney injury associated with the use of polymyxins in critically ill patients

Introdução: A Lesão renal aguda (LRA) é uma síndrome de alta incidência (23,2%) e mortalidade (23,0%), que acomete principalmente pacientes críticos, internados em unidades de terapia intensiva (UTI). A sepse é a principal causa de LRA (40,0%). A infecção por microrganismos multirresistentes exige o uso de agentes antimicrobianos potencialmente nefrotóxicos, como as polimixinas (Pmxs). Dentre elas, destaca-se a Pmx B e a colistina (Pmx E) utilizadas no controle de infecções por bacilos gram negativos (BGN). Objetivos: avaliar a incidência de LRA associada ao uso de Pmxs e identificar os fatores de risco para desenvolvimento de LRA associada ao uso de Pmxs. Métodos: Trata-se de um estudo transversal, retrospectivo, de abordagem quantitativa. A amostra foi composta por 1009 pacientes internados em UTI, provenientes de um banco de dados universal (BDU) organizado no período de abril a dezembro de 2012. Resultados: Foram incluídos 936 pacientes. A incidência geral de LRA na amostra foi de 43,1%, enquanto que para pacientes que receberam Pmxs foi de 87,0%. O principal fator de risco para LRA geral foi a pré existência de Doença Renal Crônica. Dentre os pacientes com LRA e que fizeram uso de Pmxs, a maioria era do sexo masculino (69,2%); 54,4±15,7 anos, internação do tipo clínica e com o maior tempo de internação em UTI, as características clínicas mais prevalentes foram o estado de choque (81,5%), a hipertensão arterial sistêmica (35,3%), o Diabetes Mellitus (20,0%) e a sepse (23,0%). Esse grupo apresentou maiores índices de gravidade SAPS II e LODS e o choque se confirmou como fator de risco nesse grupo. Conclusões: As Pmxs confirmaram-se como medicamento nefrotóxico em pacientes críticos (87%), tendo o choque como fator de risco.

Introduction: Acute kidney injury (AKI) is a syndrome of high incidence (23.2%) and mortality (23.0%), which affects mainly critically ill patients admitted to intensive care units (ICUs). Sepsis is the main cause of AKI (40.0%). Infection with multiresistant microorganisms requires the use of potentially nephrotoxic antimicrobial agents, such as polymyxins (Pmxs). Among them, Pmx B and colistin (Pmx E) are used to control gram-negative bacilli (GNB) infections. Objectives: to evaluate the incidence of AKI associated with the use of Pmxs and to identify the risk factors for the development of AKI associated with the use of Pmxs. Methods: It´s a cross-sectional, retrospective, quantitative approach The sample consisted of 1009 patients hospitalized in ICUs from a universal database (BDU) organized from April to December 2012. Results: A total of 936 patients were included. The overall incidence of AKI in the sample was 43.1%, whereas for patients receiving Pmxs it was 87.0%. The main risk factor for overall AKI was the pre-existence of Chronic Kidney Disease. Among the patients with AKI who used Pmxs, the majority were male (69.2%); 54.4 ± 15.7 years, hospitalization of the clinical type and with the longer ICU stay. The most prevalent clinical characteristics in the AKI and Pmx groups were shock state (81.5%), systemic arterial hypertension (35.3%), Diabetes Mellitus (20.0%) and sepsis (23.0% ). This group presented highest SAPS II and LODS severity indexes and the shock was confirmed as a risk factor. Conclusions: Pmxs were confirmed as nephrotoxic drugs in critical patients (87%), with shock as a risk factor.

The Infinity War: How to Cope with Carbapenem-resistant Enterobacteriaceae

Carbapenem-resistant Enterobacteriaceae (CRE) are now spread worldwide. In Korea, the number of CRE isolation is rapidly increasing, and impending endemicity is a concern. To cope well with CRE, thorough infection control, such as active surveillance, early detection, strict contact precaution, cleaning the environment, and antibiotic stewardship is very important. Therapeutic options include polymyxin, tigecycline, fosfomycin or the combination of them with carbapenem, which is currently the mainstay of treatment. In addition, various combination regimens with new carbapenemase inhibitors such as avibactam, vaborbactam, or relebactam, and other classes of antimicrobials such as plazomicin and siderophore cephalosporin are in the process of evaluation.

Antimicrobial resistance in Enterobacteriaceae in Brazil: focus on ß-lactams and polymyxins

ABSTRACT During the last 30 years there has been a dissemination of plasmid-mediated β-lactamases in Enterobacteriaceae in Brazil. Extended spectrum β-lactamases (ESBL) are widely disseminated in the hospital setting and are detected in a lower frequency in the community setting. Cefotaximases are the most frequently detected ESBL type and Klebsiella pneumoniae is the predominant species among ESBL producers. Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae became widely disseminated in Brazil during the last decade and KPC production is currently the most frequent resistance mechanism (96.2%) in carbapenem resistant K. pneumoniae. To date KPC-2 is the only variant reported in Brazil. Polymyxin B resistance in KPC-2-producing K. pneumoniae has come to an alarming rate of 27.1% in 2015 in São Paulo, the largest city in Brazil. New Delhi metallo-β-lactamase was detected in Brazil in 2013, has been reported in different Brazilian states but are not widely disseminated. Antimicrobial resistance in Enterobacteriaceae in Brazil is a very serious problem that needs urgent actions which includes both more strict adherence to infection control measures and more judicious use of antimicrobials.

Use of Polymyxin B Hemoperfusion in a Patient with Septic Shock and Septic Cardiomyopathy Who Was Placed on Extracorporeal Membrane Oxygen Support / 대한중환자의학회지

Although shock in sepsis is usually managed successfully by conventional medical treatment, a subset of cases do not respond and may require salvage therapies such as veno-arterial extracorporeal membrane oxygenation (VA ECMO) support as well as an attempt to remove endotoxins. However, there are limited reports of attempts to remove endotoxins in patients with septic shock on VA ECMO support. We recently experienced a case of septic shock with severe myocardial injury whose hemodynamic improvement was unsatisfactory despite extracorporeal membrane oxygenation (ECMO) support. Since the cause of sepsis was acute pyelonephritis and blood cultures grew gram-negative bacilli, we additionally applied polymyxin B direct hemoperfusion (PMX-DHP) to the ECMO circuit and were able to successfully taper off vasopressors and wean off ECMO support. To the best of our knowledge, this is the first adult case in which PMX-DHP in addition to ECMO support was successfully utilized in a patient with septic shock. This case indicates that additional PMX-DHP therapy may be beneficial and technically feasible in patients with septic shock with severe myocardial injury refractory to ECMO support.

Use of Polymyxin B Hemoperfusion in a Patient with Septic Shock and Septic Cardiomyopathy Who Was Placed on Extracorporeal Membrane Oxygen Support / 대한구급학회지

Although shock in sepsis is usually managed successfully by conventional medical treatment, a subset of cases do not respond and may require salvage therapies such as veno-arterial extracorporeal membrane oxygenation (VA ECMO) support as well as an attempt to remove endotoxins. However, there are limited reports of attempts to remove endotoxins in patients with septic shock on VA ECMO support. We recently experienced a case of septic shock with severe myocardial injury whose hemodynamic improvement was unsatisfactory despite extracorporeal membrane oxygenation (ECMO) support. Since the cause of sepsis was acute pyelonephritis and blood cultures grew gram-negative bacilli, we additionally applied polymyxin B direct hemoperfusion (PMX-DHP) to the ECMO circuit and were able to successfully taper off vasopressors and wean off ECMO support. To the best of our knowledge, this is the first adult case in which PMX-DHP in addition to ECMO support was successfully utilized in a patient with septic shock. This case indicates that additional PMX-DHP therapy may be beneficial and technically feasible in patients with septic shock with severe myocardial injury refractory to ECMO support.

Induction and nosocomial dissemination of carbapenem and polymyxin-resistant Klebsiella pneumoniae

Polymyxins are antimicrobial agents capable of controlling carbapenemase-producing Klebsiella pneumoniae infection.

Efficacy of polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis

In recent years, carbapenem-resistant Enterobacteriaceae has become endemic in many countries. Because of limited treatment options, the abandoned "old antibiotics", polymyxins, have been reintroduced to the clinic. To evaluate the clinical efficacy of polymyxins in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae, we systemically searched the PubMed, Embase, and Cochrane Library databases and analyzed the available evidence. The Preferred Reporting Items for Systematic reviews and Meta-Analysis statement were followed, and the I2 method was used for heterogeneity. Nineteen controlled and six single-arm cohort studies comprising 1086 patients met the inclusion criteria. For controlled studies, no significant difference was noted for overall mortality (OR, 0.79; 95% CI, 0.58-1.08; p = 0.15), clinical response rate (OR, 1.24; 95% CI, 0.61-2.54; p = 0.55), or microbiolog- ical response rate (OR, 0.59; 95% CI, 0.26-1.36; p = 0.22) between polymyxin-treated groups and the control groups. Subgroup analyses showed that 28-day or 30-day mortality was lower in patients who received polymyxin combination therapy than in those who received monotherapy (OR, 0.36; 95% CI, 0.19-0.68; p < 0.01) and the control groups (OR, 0.49; 95% CI, 0.31-0.75; p < 0.01). The results of the six single-arm studies were in accordance with the findings of controlled studies. One controlled and two single-arm studies that evaluated the occurrence of nephrotoxicity reported a pooled incidence rate of 19.2%. Our results suggest that polymyxins may be as efficacious as other antimicrobial therapies for the treatment of carbapenem-resistant Enterobacteriaceae infection. Compared to polymyxin monotherapy, combination regimens may achieve lower 28-day or 30-day mortality. Future large-volume, well-designed randomized control trials are required to determine the role of polymyxins in treating carbapenem-resistant Enterobacteriaceae infections.

Polymyxin B Hemoperfusion in Pneumonic Septic Shock Caused by Gram-Negative Bacteria / 대한중환자의학회지

Severe sepsis and septic shock are the main causes of death in critically ill patients. Early detection and appropriate treatment according to guidelines are crucial for achieving favorable outcomes. Endotoxin is considered to be a main element in the pathogenic induction of gram-negative bacterial sepsis. Polymyxin B hemoperfusion can remove endotoxin and is reported to improve clinical outcomes in patients with intra-abdominal septic shock, but its clinical efficacy for pneumonic septic shock remains unclear. Here, we report a case of a 51-year-old man with pneumonic septic shock caused by Pseudomonas aeruginosa, who recovered through polymyxin B hemoperfusion.

Polymyxin B Hemoperfusion in Pneumonic Septic Shock Caused by Gram-Negative Bacteria / 대한구급학회지

Severe sepsis and septic shock are the main causes of death in critically ill patients. Early detection and appropriate treatment according to guidelines are crucial for achieving favorable outcomes. Endotoxin is considered to be a main element in the pathogenic induction of gram-negative bacterial sepsis. Polymyxin B hemoperfusion can remove endotoxin and is reported to improve clinical outcomes in patients with intra-abdominal septic shock, but its clinical efficacy for pneumonic septic shock remains unclear. Here, we report a case of a 51-year-old man with pneumonic septic shock caused by Pseudomonas aeruginosa, who recovered through polymyxin B hemoperfusion.

Mecanismos de resistência antimicrobiana em pseudomonasaeruginosa / Mechanisms responsible for antimicrobial resistance in pseudomonas aeruginosa

Pseudomonas aeruginosa é uma bactéria de grande importância para indivíduos imunocomprometidos. No Brasil, ela é um dos principais agentes em infecções hospitalares e pode provocar diversos tipos de processos clínicos. Atualmente, um dos maiores desafios em infecções provocadas por P. aeruginosa é a resistência apresentada diante de inúmeros antimicrobianos. Além da resistência intrínseca de P.aeruginosa, essa bactéria facilmente desenvolve mecanismos de resistência adicionais, através de mutações e da aquisição de elementos genéticos móveis, por exemplo. Dessa forma, P. aeruginosa é considerada um patógeno multirresistente, o que limita as alternativas terapêuticas capazes de combatê-lo. Portanto, compreender osmecanismos que levam a essa resistência é de extrema importância para enfrentar as infecções por P. aeruginosa.

Pseudomonas aeruginosa is a bacterium of great importance forimmunocompromised individuals. In Brazil, it is one of the leadingcauses of hospital infections and can cause many types of infections.Currently, one of the biggest challenges in infections caused by P.aeruginosa is the resistance presented against numerousantimicrobials. In addition to the intrinsic resistance of P. aeruginosa,inherent in the species, this bacterium easily acquire additionalmechanisms of resistance via mutation and acquisition of mobilegenetic elements, for example. Accordingly, P. aeruginosa isconsidered a multidrug-resistant pathogen, which limits thetherapeutic alternatives able to fight it. Therefore, understanding themechanisms that lead to this resistance is of utmost importance totackle infections by P. aeruginosa.