Antimicrobial use for treatment of healthcare-associated infections and bacterial resistance in a reference neonatal unit

Abstract Objective The use of broad-spectrum antimicrobials, such as third and fourth-generation, are responsible for emergence of multidrug-resistant microorganisms in neonatal units. Furthermore, antimicrobial daily doses are not standardized in neonatology. This study aimed to investigate the association between the use of antimicrobial broad spectrum to bacterial sensitivity profile in a referral unit of neonatal progressive care. Methods This is a cohort study conducted in a referral neonatal progressive care unit from January 2008 to December 2016. The data of all hospitalized neonates was collected daily. The infection criteria used were the standardized national criteria, based on definitions of Center for Diseases Control and Prevention. In this study, the use of antimicrobials was evaluated as antimicrobial-day (ATM-day) and the ratio of multidrug-resistant microorganisms per 1000 ATM-day of broad spectrum was also calculated. The study was approved by the Institutional Review Board of the Universidade Federal de Minas Gerais (ETIC 312/08 e CAAE 58973616.2.0000.5149). Results From 2008 to 2016, 2751 neonates were hospitalized, corresponding to 60,656 patient-days. The ratio of multidrug-resistant microorganisms per 1000 ATM-day of broad spectrum was 1,3 in the first period and 4,3 in the second period (p = 0,005). Conclusion It was observed that use of broad-spectrum antimicrobials, especially those with coverage for Gram-negative bacteria, was associated with an increase of multidrug-resistant bacteria.

Compromiso del sistema nervioso central por Eikenella corrodens: revisión de la literatura médica a propósito de un caso clínico / Commitment of the central nervous system by Eikenella corrodens: literature review about a clinical case

Resumen Se presenta el caso de un paciente de 22 años sin antecedentes mórbidos que desarrolló un absceso cerebral secundario a una endocarditis por Eikenella corrodens. El diagnóstico se estableció mediante la detección por reacción de polimerasa en cadena universal en el líquido de la colección cerebral. La ecocardiografía transesofágica confirmó vegetaciones en la válvula mitral. Requirió la colocación de una derivación ventricular externa por vaciamiento del absceso a ventrículos cerebrales e hidrocefalia secundaria. Recibió 80 días de tratamiento antibacteriano efectivo. Su evolución fue favorable, con resolución completa de la infección verificada con imágenes y ecocardiografía de control. El seguimiento a los siete meses por una disfunción de válvula de drenaje ventrículo-peritoneal no demostró infección.

Abstract We present the case of a 22-year-old patient with no morbid history who developed a brain abscess secondary to endocarditis due to Eikenella corrodens. The diagnosis was established by detecting the microorganism by universal polymerase chain reaction in fluid from the brain collection. Trans-esophageal echocardiogram study confirmed vegetations in the mitral valve. External ventricular shunt placement was required due to emptying of abscess to brain ventricles and secondary hydrocephalus. He received 80 days of effective antibiotic treatment and his evolution was favorable with complete resolution of his infection verified with images and echocardiogram. Follow-up at seven months later due to ventricule-peritoneal drainage valve dysfunction did not confirmed infection.

Active surveillance of carbapenem-resistant Gram-negative healthcare-associated infections in a low-middle-income country city

ABSTRACT Background: Carbapenem-resistance in healthcare-associated infections (HCAIs) is of great concern, and it is urgent to improve surveillance. We aimed to describe and analyze HCAIs trends on Gram-negative antimicrobial susceptibility in a city from a developing country, following the implementation of an active surveillance program. Methods: This is an aggregated study describing data from 24 hospitals with intensive care units, including a trend analysis by Joinpoint regression between January 2012 and December 2017. Results: There were 23,578 pathogens in 39,832 HCAIs, from which 16,225 were Gram-negatives (68.8%). Carbapenem susceptibility was lowest in A. baumannii (15.4-25.9%), K. pneumoniae (51.0-55.9%), and P. aeruginosa (64.9-84.1%) and highest in E. coli (96.5-99.2%). Only K. pneumoniae showed a significant Joinpoint at 95% confidence interval: −10.71% (−18.02; −2.75) from 2012 to 2014, p = 0.02, and 6.54% (−2.00; 15.83) from 2015 to 2017, p = 0.12, which was most influenced by urinary tract infections: −9.98% (−16.02; −3.48) from 2012 to 2014, p = 0.01, and 9.66% (−1.75; 22.39) from 2015 to 2017, p = 0.09. Conclusion: Although we found a significant change toward an improvement in carbapenem susceptibility in K. pneumoniae, resistance is high for most pathogens. These data should encourage health institutions to improve their prevention and control strategies.

Uso racional de antibióticos y tecnología FilmArray para identificación rápida de bacteriemias en unidad de cuidados intensivos pediátrica / Rational use of antibiotics and FilmArray technology for rapid identification of bacteremias in a pediatric intensive care unit

INTRODUCCIÓN: Las infecciones graves son la principal causa de ingreso a cuidados intensivos pediátricos. El panel FilmArray BCID permite identificar rápidamente a microorganismos causantes de bacteriemias. OBJETIVO: evaluar la eficacia de la identificación rápida de microorganismos asociado a un Programa de Uso Racional de Antibióticos (URA) en reducir los tiempos de terapias antibióticas, en un hospital pediátrico. PACIENTES Y MÉTODO: Estudio retrospectivo, que incluyó 100 pacientes, en su primer episo dio de bacteriemia, divididos en 2 grupos de 50 cada uno: Intervención (FilmArray BCID y programa URA) y Controles históricos pareados para la misma especie del microrganismo identificado (microbiología convencional). Las variables evaluadas fueron los tiempos de identificación microbiana, latencia de la terapia dirigida y de desescalar antibióticos. RESULTADOS: Los grupos fueron comparables en características demográficas, foco de infección y etiología de bacteriemia. El tiempo promedio de identificación de microorganismos fue de 23 h (IC 95% 12,4-26,7) en el grupo intervención, y 70,5 h (IC 95% 65,2-78,6) en el control (p < 0,05), mientras que la latencia de inicio de terapia dirigida fue de 27,9 h (IC 95% 22,3-32,8) y 71,9 h (IC 95% 63,2-77,8) respectivamente (p < 0,05). El tiempo de desescalar o suspender antibióticos fue de 6,4 h (IC 95% 2,76-9,49) y 22 h (IC 95% 6,74-35,6) en los grupos mencionados (p > 0,05). CONCLUSIÓN: El panel FilmArray BCID articulado a un programa URA, contribuye a la identificación de los microorganismos causantes de bacteriemias en menor tiempo que los métodos convencionales, siendo una herramienta que optimiza las terapias antibióti cas en niños críticamente enfermos.

INTRODUCTION: Severe infections are the leading cause of admission to pediatric intensive care. The FilmArray BCID panel quickly identifies microorganisms that cause bacteremia. OBJECTIVE: To evaluate if the rapid identification of the microorganisms that cause bacteremia, along with a Rational Use of Antibio tics (RUA) Program, allows optimizing the time of antibiotic therapy in a pediatric hospital. PATIENTS AND METHOD: Retrospective study which included 100 patients presenting their first episode of bacteremia, divided into 2 groups of 50 each. The first one was Intervention (FilmArray BCID and RUA program) and the second one was Historical Controls (conventional automated ID/AST). The variables evaluated were the time required for microbial identification, duration of appropriate therapy, and antibiotic de-escalation. RESULTS: The groups were comparable in terms of demographic characteristics, focus of infection, and etiology of bacteremia. The average time of microorganisms' identification of the control group was 70.5 hours (IC 95% 65.2-78.6) and 23.0 hours (IC 95% 12.4 -26.7) in the intervention one (p < 0.05). The average time of targeted therapy onset was shorter in the intervention group (27.9 h [IC 95% 22.3-32.8]) than that of the control one (71.9 h [IC 95% 63.2-77.8]) (p < 0.05). Finally, the time to de-escalate or discontinue antibiotics in the intervention group and the control one was 6.4 hours (IC 95% 2.76-9.49) hours and 22.0 hours (IC 95% 6.74-35.6 h) respectively (p > 0.05). CONCLUSION: The FilmArray panel along with the RUA Program allows the identification of the microorganisms causing bacteremia faster than conventional methods, which positions it as a tool that optimizes antibiotic therapy of critical patients.

Proposal of a clinical score to stratify the risk of multidrug-resistant gram-negative rods bacteremia in cancer patients

ABSTRACT Introduction: Multidrug-resistant gram-negative rods (MDR GNR) represent a growing threat for patients with cancer. Our objective was to determine the characteristics of and risk factors for MDR GNR bacteremia in patients with cancer and to develop a clinical score to predict MDR GNR bacteremia. Material and Methods: Multicenter prospective study analyzing initial episodes of MDR GNR bacteremia. Risk factors were evaluated using a multiple logistic regression (forward-stepwise selection) analysis including variables with a p < 0.10 in univariate analysis. Results: 394 episodes of GNR bacteremia were included, with 168 (42.6 %) being MDR GNR. Five variables were identified as independent risk factors: recent antibiotic use (OR = 2.8, 95 % CI 1.7-4.6, p = 0.001), recent intensive care unit admission (OR = 2.9, 95 % CI 1.1-7.8, p = 0.027), hospitalization ≥ 7 days prior to the episode of bacteremia (OR = 3.5, 95 % CI 2-6.2, p = 0.005), severe mucositis (OR = 5.3, 95 % CI 1.8-15.6, p = 0.002), and recent or previous colonization/infection with MDR GNR (OR = 2.3, 95 % CI 1.2-4.3, p = 0.028). Using a cut-off value of two points, the score had a sensitivity of 66.07 % (95 % CI 58.4-73.2 %), a specificity of 77.8 % (95 % CI 71.4-82.7 %), a positive predictive value of 68 % (95 % CI 61.9-73.4 %), and a negative predictive value of 75.9 % (95 % CI 71.6-79.7 %). The overall performance of the score was satisfactory (AUROC 0.78; 95 % CI 0.73-0.82). In the cases with one or none of the risk factors identified, the negative likelihood ratio was 0.18 and the post-test probability of having MDR GNR was 11.68 %. Conclusions: With the growing incidence of MDR GNR as etiologic agents of bacteremia in cancer patients, the development of this score could be a potential tool for clinicians.

Microbiologic characteristics and antibiotic resistance rates of diabetic foot infections / Perfil microbiológico e de resistência bacteriana no pé diabético infectado

ABSTRACT Purpose: the purpose of this research was to identify the sociodemographic and microbiological characteristics and antibiotic resistance rates of patients with diabetic foot infections, hospitalized in an emergency reference center. Methods: it was an observational and transversal study. The sociodemographic data were collected by direct interview with the patients. During the surgical procedures, specimens of tissue of the infected foot lesions were biopsied to be cultured, and for bacterial resistance analysis. Results: the sample consisted of 105 patients. The majority of patierns were men, over 50 years of age, married and with low educational level. There was bacterial growth in 95 of the 105 tissue cultures. In each positive culture only one germ was isolated. There was a high prevalence of germs of the Enterobacteriaceae family (51,5%). Gram-negative germs were isolated in 60% of cultures and the most individually isolated germs were the Gram-positive cocci, Staphylococcus aureus (20%) and Enterococcus faecalis (17,9%). Regarding antibiotic resistance rates, a high frequency of Staphylococcus aureus resistant to methicillin (63,0%) and to ciprofloxacin (55,5%) was found; additionally, 43,5% of the Gram-negative isolated germs were resistant to ciprofloxacin. Conclusions: the majority of patients were men, over 50 years of age, married and with low educational level. The most prevalent isolated germs from the infected foot lesions were Gram-negative bacteria, resistant to ciprofloxacin, and the individually most isolated germ was the methicillin resistant Staphylococcus aureus.

RESUMO Objetivo: identificar o perfil sociodemográfico, microbiológico e de resistência bacteriana em pacientes com pé diabético infectado. Métodos: tratou-se de estudo observacional, transversal que avaliou os perfis sóciodemográfico e microbiológico de pacientes portadores de pé diabético infectado internados em Pronto Socorro de referência. Os dados sociodemográficos foram coletados por meio de entrevista. Foram colhidos, durante os procedimentos cirúrgicos, fragmentos de tecidos das lesões podais infectadas para realização de cultura/antibiograma. Resultados: a amostra foi composta por 105 pacientes. O perfil sociodemográfico mais prevalente foi o de pacientes do sexo masculino, acima dos 50 anos, casados e com baixa escolaridade. Das 105 amostras de fragmentos de tecidos colhidos para realização de cultura e antibiograma, 95 foram positivas, com crescimento de um único germe em cada um dos exames. Houve predomínio de germes da família Enterobacteriaceae (51,5%). Germes Gram-negativos foram isolados em 60,0% das culturas e os espécimes mais isolados individualmente foram os cocos Gram-positivos, Staphylococcus aureus (20,0%) e Enterococcus faecalis (17,9%). Considerando-se os perfis de resistência bacteriana, verificou-se alta taxa de Staphylococcus aureus resistente à meticilina (63,0%) e à ciprofloxacino (55,5%); verificou-se, também, que 43,5% dos germes Gram-negativos eram resistentes à ciprofloxacino. Conclusões: o perfil sociodemográfico majoritário, foi o de homens, com mais de 50 anos e com baixa escolaridade. Concluímos que os germes mais prevalentes nas lesões podais dos pacientes diabéticos foram os Gram-negativos, resistentes ao ciprofloxacino e que o germe mais isolado individualmente foi o Staphylococcus aureus resistente à meticilina.

Perfil fenotípico de resistência à colistina e tigeciclina em um hospital público no Brasil / Phenotypical profile of colistin and tigecycline resistance in a public hospital in Brazil / Perfil fenotípico de resistencia a la colistina y tigeciclina en un hospital público de Brasil

Justificativa e objetivos: Infecções Relacionadas à Assistência à Saúde (IRAS) causadas por bacilos Gram negativos multirresistentes (BGN-MDR) são consideradas um problema de saúde pública e um impacto nas taxas de mortalidade nas Unidades de Terapia Intensiva (UTI). O objetivo deste estudo foi verificar o perfil fenotípico de resistência à colistina e à tigeciclina, consideradas como último recurso terapêutico aos BGN-MDR. Métodos: Os dados foram coletados nas fichas de busca ativa do serviço de controle de infecções e prontuários médicos de pacientes internados em duas UTIs de um hospital público de Joinville, entre janeiro de 2016 e junho de 2017. Resultados: Ocorreram 256 IRAS por BGN, acometendo principalmente o gênero masculino (62%), com mediana de idade de 65 anos. Entre os BGN, 37% expressaram MDR; sendo as espécies mais frequentes: Klebsiella pneumoniae e (47%), Acinetobacter baumannii (23%) e Stenotrophomonas maltophilia (11%). A resistência de BGN-MDR à colistina e tigeciclina foi de 5% e de 12%, respectivamente; 5% dos isolados foram resistentes aos dois antibióticos. A taxa de óbito entre os pacientes com IRAS por BGN-MDR resistentes à colistina foi mais alta (60%) que aquelas à tigeciclina (45%). Conclusão: K. pneumoniae e A. baumannii produtores de carbapenemases, resistentes a colistina e tigeciclina prevaleceram entre os BGN-MDR, e estiveram associadas a maioria dos óbitos. Essas observações, junto com o alto uso de carbapenêmicos na terapia empírica, mostra a necessidade do uso racional de antimicrobianos.(AU)

Background and objectives: Healthcare-associated Infections (HAIs) caused by multidrug-resistant Gram-negative bacilli (GNB-MDR) are considered a public health problem and have an impact on mortality rates in Intensive Care Units (ICU). The aim of this study was to verify the phenotypic profile of resistance to colistin and tigecycline, considered as the last antimicrobial choice to treat BGNMDR infections. Methods: Data were collected on the active search records of the infection control service and medical records of patients admitted to two ICUs at a public hospital in Joinville between January 2016 and June 2017. Results: There were 256 HAIs caused by GNB, mainly affecting males (62%), with a median age of 65 years. Among GNBs, 37% expressed MDR; the most frequent species were: Klebsiella pneumoniae (47%), Acinetobacter baumannii (23%) and Stenotrophomonas maltophilia (11%). The resistance of GNB-MDR to colistin and tigecycline was 5% and 12%, respectively; 5% of the isolates were resistant to both antibiotics. The death rate among patients with HAIs caused by colistin-resistant GNB-MDR was higher (60%) than those to tigecycline (45%). Conclusion: Carbapenemase-producing K. pneumoniae and A. baumannii, resistant to colistin and tigecycline, prevailed among GNB-MDRs, and were associated with most deaths. These observations, coupled with the high use of carbapenems in empirical therapy, show the need for rational use of antimicrobials.(AU)

Justificación y objetivos: Las Infección nosocomial (IHs) causadas por bacilos Gram negativos multirresistentes (BGN-MDR) se consideran un problema de salud pública y un impacto en las tasas de mortalidad en las Unidades de Terapia Intensiva (UTI). El objetivo de este estudio fue verificar el perfil fenotípico de resistencia a la colistina ya la tigeciclina, consideradas como último recurso terapéutico a los BGN-MDR. Métodos: Los datos fueron recolectados en las fichas de búsqueda activa del servicio de control de infecciones y prontuarios médicos de pacientes internados en dos UTIs de un hospital público de Joinville, entre enero de 2016 y junio de 2017. Resultados: Ocurrieron 256 IHs por BGN, que afectan principalmente al género masculino (62%), con mediana de edad de 65 años. Entre los BGN, el 37% expresó MDR; siendo las especies más frecuentes: Klebsiella pneumoniae (47%), Acinetobacter baumannii (23%) y Stenotrophomonas maltophilia (11%). La resistencia de BGN-MDR a la colistina y tigeciclina fue del 5% y del 12%, respectivamente; 5% de los aislados fueron resistentes a los dos antibióticos. La tasa de muerte entre los pacientes con IH causadas por los BGN-MDR resistentes la colistina fue más alta (60%) que aquellas a tigeciclina (45%). Conclusión: K. pneumoniae y A. baumannii productoras de carbapenemases, resistentes la colistina y la tigeciclina, fueron más frecuentes entre los BGN-MDR y su asociación estuvo presente en la mayoría de las muertes. Estas observaciones, junto con el alto uso de carbapenems en la terapia empírica, muestran la necesidad de un uso racional de los antimicrobianos.(AU)

Septicemia por Chromobacterium Violaceum en pediatría / Septicemia due to Chromobacterium Violaceum in pediatrics

Chromobacterium violaceum es una bacteria gram negativa anaerobia facultativa, que se encuentra ampliamente distribuida en el agua y el suelo en regiones tropicales y subtropicales, que se asocia con infecciones respiratorias, gastrointestinales, abscesos hepáticos, meningitis, endocarditis, síndrome hemofagocítico y sepsis fulminante. Se presentan 2 casos en niños: el primero es un varón de 8 años con lesiones en piel, fiebre y adenitis inguinal, que ingresó con un cuadro de sepsis severa, síndrome de distrés respiratorio agudo (SDRA) y falleció a las 3 h del ingreso. De los hemocultivos se aisló Chromobacterium violaceum. El segundo caso, es una niña de 12 años con antecedente de fiebre y adenopatía inguinal secundaria a herida cortopunzante en el pie homolateral, que ingresó con un cuadro de sepsis, con desarrollo de abscesos múltiples profundos. De la colección obtenida de piel y partes blandas y de un aspirado traqueal se aisló Chromobacterium violaceum. Recibió tratamiento antibiótico adecuado y posteriormente fue dada de alta. Se realizó una revisión bibliográfica de esta infección en niños y se encontraron 44 casos en todo el mundo. Algunos de éstos, se relacionaron con inmunodeficiencia de base, como la enfermedad granulomatosa crónica. La infección por esta bacteria es rara y se presenta como un cuadro grave que no responde a antibióticos habituales de uso empírico y tiene una alta tasa de mortalidad (AU)

Chromobacterium violaceum is a facultative anaerobic Gramnegative bacillus, widely distributed in water and soil in tropical and subtropical regions and associated with respiratory and gastrointestinal infections, liver abscesses, meningitis, endocarditis, hemophagocytic syndrome, and fulminant sepsis. Here two pediatric cases are presented: The first was an 8-year-old boy with skin lesions, fever, and inguinal adenitis, who was admitted with severe sepsis, acute respiratory distress syndrome (ARDS) and died three hours after. Chromobacterium violaceum was isolated from blood cultures. The second case was a 12-year-old girl with a history of fever and inguinal adenopathy secondary to a wound in the homolateral foot, who was admitted because of sepsis and multiple deep abscesses. From samples collected from the skin and soft tissues as well as tracheal aspirate Chromobacterium violaceum was isolated. Adequate antibiotic treatment was started and the patient was subsequently discharged. In a review of the literature, 44 cases worldwide were identified. Some of these cases were related to underlying immunodeficiency, such as chronic granulomatous disease. Infection with this bacterium is rare and presents with severe manifestations that do not respond to the common empirical antibiotics and are associated with a high mortality rate (AU)

Delftia acidovorans pneumonia with lung cavities formation / Neumonia con formación de cavidades pulmonares causada por Delftia acidovorans

Abstract Case Description: A 52-year-old female patient was admitted to our clinic with complaints of cough, sputum, fever and fatigue. The patient has been receiving immunosuppressive therapy for thrombocytopenic purpura for 5 years. Clinical Finding: Inspiratory crackles were heard on both hemithorax. Oxygen saturation measured with the pulse oximeter was 97%. Chest X-ray showed diffuse reticular opacities that were more prominent in the upper zones of both lungs. WBC counts were 17,600 mm3 and Platelet counts were 29,000 mm3. Thorax CT showed that there were many thin-walled cavities and millimetric nodules accompanied by ground-glass infiltrates in the upper and middle lobes. Gram staining of bronchial fluid, taken by bronchoscopy, revealed Gram-negative bacilli and intense polymorphonuclear leukocytes. The bacteria were defined as Delftia acidovorans by BD Phoenix automated system. Treatment and outcomes: The patient was hospitalized with suspicion of opportunistic pulmonary infections and cavitary lung disease. After the empirical treatment of intravenous piperacillin-tazobactam and oral clarithromycin, her clinical and radiological findings significantly regressed, and she was discharged with outpatient follow-up. Clinical Relevance: This is the first example of cavitary pneumonia due to Delftia acidovorans in an immunocompromised patient. We would like to emphasize that Delftia pneumonia should be considered in the differential diagnosis of pulmonary cavitary involvement in such patients.

Resumen Descripción del caso: Una mujer de 52 años llegó a la clínica con tos, esputo, fiebre y fatiga. El paciente estuvo recibiendo terapia inmunosupresora durante 5 años para el tratamiento de la púrpura trombocitopénica. Hallazgo clínico: se escucharon crepitaciones inspiratorias en ambos hemitórax. La saturación de oxígeno fue del 97%. La radiografía de tórax mostró opacidades reticulares difusas que eran más prominentes en las zonas superiores de ambos pulmones. Los recuentos de leucocitos fueron de 17,600 mm3 y los recuentos de plaquetas fueron de 29,000 mm3. La TC de tórax mostró muchas cavidades de pared delgada y nódulos milimétricos acompañados de infiltrados vitrales en los lóbulos superior y medio. La tinción de Gram del líquido bronquial reveló bacilos gramnegativos y leucocitos polimorfonucleares. Las bacterias fueron identificadas como Delftia acidovorans. Tratamiento y resultados: La paciente fue hospitalizado con una sospecha de infección oportunista pulmonar y enfermedad pulmonar cavitaria. Después del tratamiento empírico de piperacilina-tazobactam intravenosa y claritromicina oral, los síntomas y signos retrocedieron significativamente, y fue dada de alta con seguimiento ambulatorio. Relevancia clínica: este es el primer registro de neumonía cavitaria causado por Delftia acidovorans en una paciente inmunocomprometida. Enfatizamos que la neumonía por Delftia debe considerarse en el diagnóstico diferencial de la afectación de la cavidad pulmonar en tales pacientes.

Clinical and economic impact of generic versus brand name meropenem use in an intensive care unit in Colombia

Abstract Background: Recent studies suggest that sustained use of generic antibiotics may be associated with clinical failure and emergence of antibacterial resistance. The present study was designed to determine the clinical outcome between the use of generic meropenem (GM) and brand-name meropenem (BNM). Additionally, this study evaluated the economic impact of GM and BNM to determine if the former represents a cost-effective alternative to the latter. Methods: Patients treated between January 2011 and May 2014 received GM while patients treated between June 2014 and March 2017 received BNM. Mortality was compared between groups. Total infection cost was defined by the cost of antimicrobial consumption, length of stay, and laboratory and imaging exams until infection resolution. Findings: A total of 168 patients were included; survival rate for the 68 patients treated with GM was 38% compared to 59% in the patients treated with BNM. Multivariate analysis showed that the variables most strongly-associated with mortality were cardiovascular disease (OR 18.18, 95% CI 1.25-262.3, p = 0.033) and treatment with generic meropenem (OR 18.45, 95% CI 1.45-232.32, p = 0.024). On the other hand, total infection cost did not show a significant difference between groups (BNM $10,771 vs. GM $11,343; p = 0.91). Interpretation: The present study suggests that patients treated with GM have a risk of death 18 times higher compared to those treated with BNM. Furthermore, economic analysis shows that GM is not more cost effective than BNM. Summary: More studies measuring clinical outcomes are needed to confirm the clinical equivalence of brand-name versus generic antibiotics, not only for meropenem but also for other molecules.

Infecciones por bacilos Gram-negativos multirresistentes en neonatología / Multidrug resistant Gram-negative infections in neonatology

Introducción. Las infecciones por bacilos Gram-negativos multirresistentes (BGN-MR) constituyen un problema creciente en las unidades de cuidado intensivo neonatal. El objetivo del estudio fue conocer las características epidemiológicas, clínicas, microbiológicas, evolutivas y los factores de riesgo de infección por BGN-MR resistentes a carbapenemes en el Servicio de Neonatología de un hospital de alta complejidad. Población y método. Se realizó un estudio de cohorte retrospectivo en dicho Servicio, donde se incluyeron los pacientes con infección documentada por BGN-MR del 24/4/2013 al 29/4/2015. Resultados. Se incluyeron 21 pacientes. La mediana de edad gestacional y peso de nacimiento fue 35 semanas y 2070 gramos, respectivamente. Dieciocho pacientes (86 %) tuvieron hemocultivos positivos y el aislamiento microbiológico más frecuente fue Acinetobacter baumannii (17 pacientes, 81 %), seguido por Klebsiella pneumoniae productora de carbapenemasa (3 pacientes, 14 %) y Enterobacter cloacae (1 paciente, 5 %). La mediana de edad al momento del diagnóstico fue de 28 días y todos tenían factores de riesgo para la infección, como cirugía, asistencia respiratoria mecánica, nutrición parenteral, catéter central y antibióticos. El tratamiento antibiótico definitivo fue colistina en todos los casos, combinado en el 84 %. Cinco pacientes (24 %) fallecieron por la infección. La prematurez y el peso < 2000 g fueron factores de riesgo estadísticamente significativos asociados a la mortalidad (p = 0,03 y 0,01, respectivamente). Conclusión. Las infecciones por BGN-MR se presentaron en pacientes con factores predisponentes. Acinetobacter baumannii fue el primer agente etiológico. La mortalidad fue elevada y relacionada con prematurez y bajo peso al nacer.

Introduction. Multidrug resistant Gramnegative (MDRGN) infections are an increasing problem in neonatal intensive care units. The objective of this study was to establish the epidemiological, clinical, microbiological, and evolutionary characteristics of carbapenem-resistant MDRGN infections and the risk factors for them at the Division of Neonatology of a tertiary care hospital. Population and method. A retrospective cohort study was done in this Division in patients with a documented MDRGN infection between 4/24/2013 and 4/29/2015. Results. Twenty-one patients were included. Their median gestational age and birth weight were 35 weeks and 2070 g, respectively. Eighteen patients (86 %) had a positive blood culture; the most commonly isolated microorganism was Acinetobacter baumannii (17 patients, 81 %), followed by carbapenemase-producing Klebsiella pneumoniae (3 patients, 14 %) and Enterobacter cloacae (1 patient, 5 %). The median age at diagnosis was 28 days and all patients had risk factors for infection, including surgery, assisted mechanical ventilation, parenteral nutrition, central venous line, and antibiotics. The definite antibiotic therapy included colistin in all cases; in combination, in 84 %. Five patients (24 %) died due to the infection. Prematurity and a birth weight < 2000 g were statistically significant risk factors associated with mortality (p = 0.03 and 0.01, respectively). Conclusion. MDRGN infections were observed in patients with predisposing factors. Acinetobacter baumannii was the main etiologic agent. Mortality was high and related to prematurity and a low birth weight.

Inadequate use of antibiotics and increase in neonatal sepsis caused by resistant bacteria related to health care assistance: a systematic review

ABSTRACT Background Technologies and life support management have enhanced the survival of preterm infants. The immune system of newborns is immature, which contributes to the occurrence of healthcare-associated infections. The overlap of several conditions with neonatal sepsis and the difficulty of diagnosis and laboratory confirmation during this period result in a tendency to over-treat neonatal sepsis. The use of antimicrobial agents is a risk factor for multidrug-resistant bacterial infections. This work aimed to perform a systematic review of the relationship between inadequate use of antimicrobial agents and increase in neonatal sepsis related to healthcare assistance, due to bacterial resistance. Methods Our population, exposition, comparison, outcome and study type was as follows: P: hospitalized neonates with sepsis diagnosis, E: inappropriate use of antimicrobial agents, C: adequate use of antimicrobial agents or no indication of infection, O: resistant bacterial infection, and S: original studies. We performed searches in the PubMed, Scopus, Virtual Health Library (Scielo, LILACS, and MEDLINE), and Embase without limits on time, language, and the references of the articles found. Fourteen studies were included and assessed using the Grading of Recommendations, Assessment, Development, and Evaluation, Newcastle, and the Strengthening the Reporting of Observacional Studies in Epidemiology methodologies. Results All studies found were observational and started with a low-quality evidence level in the Grading of Recommendations, Assessment, Development, and Evaluation. Conclusions Despite their low-quality evidence, the studies demonstrated the association between inadequate use of antimicrobial agents and increase of neonatal resistant bacterial healthcare-associated infections in neonatal units. However, there is significant difficulty in conducting high-quality studies in this population due to ethical issues tied to randomized trials. Therefore, new studies should be encouraged to recommend adequate treatment of newborns without increasing the risk of healthcare-associated infections by multidrug-resistant bacteria.

Nuevas cefalosporinas / New cephalosporins

Resumen La resistencia bacteriana se ha incrementado en América Latina y el mundo, por lo que se requiere investigación y creación de nuevos antimicrobianos capaces de erradicar a los microorganismos resistentes. Se realizó una revisión acerca de nuevas cefalosporinas y sus combinaciones con un inhibidor de β-lactamasas, recopilando información de espectro, farmacocinética, farmacodinamia y estudios clínicos de las indicaciones actuales para ceftarolina, ceftazidima/avibactam y ceftolozano/tazobactam. La primera, con actividad frente a Staphylococcus aureus y Staphylococcus coagulasa negativa sensibles y resistentes a meticilina, y contra Streptococcus pneumoniae resistente a penicilina; por lo tanto, aprobada para uso en neumonía bacteriana adquirida en comunidad e infecciones bacterianas de piel y tejidos blandos. Entre las nuevas combinaciones, ceftazidima, una cefalosporina de tercera generación con actividad anti-pseudomonas, asociada a avibactam, un inhibidor de β-lactamasas, ha demostrado efectividad en el tratamiento de infecciones abdominales e infecciones urinarias complicadas. Por último, la combinación ceftolozano y el conocido tazobactam presenta acción comparable a la combinación de ceftazidima y avibactam por su actividad contra bacilos gramnegativos y, en combinación con metronidazol no presenta inferioridad a meropenem en infecciones intra-abdominales. Se presentan los estudios clínicos y las potenciales indicaciones y escenarios de uso de estas cefalosporinas.

Bacterial resistance has increased in Latin America and the world, making research and creation of new antimicrobials capable of eradicating resistant microorganisms essential. A review of new cephalosporins and their combinations with a beta-lactamase inhibitor was conducted, collecting data on the spectrum, pharmacokinetic and pharmacodynamic profile and clinical studies of the current indications for ceftaroline, and the combinations ceftazidime with avibactam and ceftolozane with tazobactam. The first one has activity against methicillin-resistant Staphylococcus aureus and coagulase negative Staphylococcus (SCoN) and against penicillin-resistant Streptococcus pneumoniae, therefore approved for use in community-acquired pneumonia and acute bacterial skin and skin structure infections. Among the new combinations, ceftazidime, a third generation cephalosporin with antipseudomonal activity, associated with avibactam, a betalactamase inhibitor, has been shown to be effective in the treatment of abdominal infections and complicated urinary infections. Finally, the combination of ceftolozane with tazobactam has comparable action to ceftazidime with avibactam due to its activity against Gram negative rods, and in combination with metronidazole they do not present inferiority to meropenem in intra-abdominal infections. The clinical studies are presented, as well as the potential indications and clinical scenarios for their use of this cephalosporins.

Safety and efficacy of a novel drug elores (ceftriaxone + sulbactam + disodium edetate) in the management of multi-drug resistant bacterial infections in tertiary care centers: a post-marketing surveillance study

Abstract Objective: In India, Elores (CSE-1034: ceftriaxone + sulbactam + disodium edetate) was approved as a broad spectrum antibiotic in year 2011 and is used for management of Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections in tertiary care centers. The objective of this study was to investigate the efficacy of this drug in patients with Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections and identify the incidence of adverse events in real clinical settings. Methods: This Post Marketing Surveillance study was conducted at 17 centers across India and included 2500 patients of all age groups suffering from various bacterial infections and treated with Elores (CSE1034). Information regarding demographic, clinical and microbiological parameters, dosage and treatment duration, efficacy and adverse events (AEs) associated with the treatment were recorded. Results: A total of 2500 patients were included in the study and efficacy was evaluated in 2487 patients. In total, 409 AEs were reported in 211 (8.4%) patients. The major AEs reported were vomiting (3.0%), pain at injection site (2.5%), nausea (2.3%), redness at site (1.96%), thrombophlebitis (1.4%). Of total reported AEs, 40 (5.3%) AEs were reported in pediatric, 310 (20.6%) in adult, and 59 (23.6%) in geriatric group. No AE belonging to grade IV or V was reported in any patient. In terms of efficacy, 1977 (79.4%) patients were cured, 501 (20.1%) patients showed clinical improvement and 5 (0.2%) patients were complete failure. The treatment duration varied from 5 to 7 days in different patients depending on the infection type. Conclusion: In this post-marketing surveillance study, CSE-1034 was found to be an effective and safe option against Pip tazo and meropenem in management of patients with multi-drug resistant (MDR) bacterial infections under routine ward settings.

Anaerobiospirillum succiniciproducens y Desulfovibrio desulfuricans en 2 casos de bacteriemias insidiosas / Anaerobiospirillum succiniciproducens and Desulfovibrio desulfuricans in 2 cases of insidious bacteremia

Se presentan 2 casos de bacteriemias insidiosas por bacilos gram negativos anaerobios curvos, espiralados, móviles e infrecuentes en pacientes atendidos en un hospital de la ciudad de Buenos Aires. Estas bacteriemias, asociadas al aislamiento de Anaerobiospirillum y Desulfovibrio, fueron de origen poco claro y afectaron a pacientes inmunocomprometidos, con patologías simultáneas. Pruebas claves en la identificación del género Anaerobiospirillum fueron el estudio de la micromorfología, su carácter de anaerobio estricto, el resultado negativo en la prueba de catalasa, el patrón de discos de interés taxonómico, la fermentación de glucosa y la producción de β-N-acetilglucosaminidasa. El género Desulfovibrio se diferenció por el perfil presentado en las pruebas con discos, por ser asacarolítico, sin actividad de enzimas glucosídicas, y por producir desulfoviridina y H2S. Se alerta sobre la resistencia o sensibilidad intermedia de Anaerobiospirillum succiniciproducens (especie a la que correspondió el aislado de Anaerobiospirillum) a algunos de los antimicrobianos de primera línea frente a bacilos gram negativos anaerobios, como el metronidazol; fueron activas las combinaciones de aminopenicilinas con inhibidores de β-lactamasas y el imipenem. Desulfovibrio desulfuricans (especie a la que correspondió el aislado de Desulfovibrio) fue productora de β-lactamasas y resistente a las cefalosporinas; en cambio, fueron activos el metronidazol, el imipenem y la levofloxacina. La identificación confiable de estos microorganismos orienta hacia el mejor esquema terapéutico.

Two cases of insidious bacteremia by uncommon curve and spiral-shaped, motile anaerobic gram-negative rods are presented. Both of them were of an unclear origin and occurred in immunosuppressed patients with simultaneous diseases. The key tests for the identification of Anaerobiospirillum were its micromorphology, a strictly anaerobic condition, negative catalase activity, the special-potency disk profile, glucose fermentation, and β-NAG production. Desulfovibrio species was identified by all the above preliminary tests but with a different disk profile, as well as for being asaccharolytic and desulfoviridin and H2S producer. We here alert about the resistance or intermediate susceptibility of Anaerobiospirillum succiniciproducens against antimicrobial agents, such as metronidazole, one of the first-line drugs used for the treatment of anaerobic gram-negative infections. Aminopenicillins with β-lactamase-inhibitor combinations and imipenem were active for this agent. Desulfovibrio desulfuricans was β-lactamase producer and resistant to cephalosporins, while metronidazole, imipenem and levofloxacin were active. A reliable identification of these microorganisms is important for establishing the best therapeutic scheme.

Factores asociados a nefrotoxicidad por polimixina B en un hospital universitario de Neiva, Colombia. 2011-2015 / Risk factors for acute kidney injury in patients treated with polymyxin B experience from 139 cases at a tertiary university hospital in Colombia

Background: The rise of infections caused by multidrug-resistant Gram negative bacilli (MDR-GNB), added to paucity of newer therapy, have led to increase polymyxin B use, despite adverse renal toxicity profile. Aim: To determine the incidence and risk factors associated to acute kidney injury (AKI) and polymyxin B use, in patients with infections caused by MDR-GNB. Methods: A retrospective cohort, with a nested case-control study of adults who received polymyxin B for more than 48 hours at a tertiary university hospital in Colombia (2011-2015) was performed. AKI was defined by AKIN criteria. Results: Of 139 patients included in our study, 102 were male with median age of 49 years (IQR:28-64). Sixty-one patients (44%) developed AKI. Independent risk factors for development of AKI included: total polymyxin B daily dose (OR = 2.19, 95% CI, 1.04-4.64); length of stay at ICU (OR = 1.03, 95% CI, 1.00-1.06); nosocomial infection (OR = 6.43, 95% CI, 2.12, -19.47); and vasopressor use (OR = 5.38, 95% CI, 2.40-12.07). Mortality was higher among AKI-patients (58.6%) compared with non-AKI patients (25.6%) (p = 0.001). Conclusion: In this study, the rate of AKI associated to polymyxin B use was greater than reported in studies from last decade, and associated with increased mortality. AKI associated to polymyxin B use is likely multifactorial and aggravated by the critically ill state of patients suffering nosocomial infections caused by mdr-gnb.

Introducción: El surgimiento de infecciones graves causadas por bacilos gramnegativos multi-resistentes (BGN-MR), sumado a la carencia de nuevas opciones terapéuticas efectivas, ha llevado a retomar el uso de polimixina B, a pesar de su perfil de nefrotoxicidad. Objetivo: Determinar la incidencia y factores relacionados con el desarrollo de nefrotoxicidad asociada al uso de polimixina B, en pacientes adultos con infecciones causadas por BGN-MR. Materiales y Métodos: Estudio observacional, analítico, tipo cohorte histórica, con un análisis de casos y controles anidado, realizado en un hospital universitario de tercer nivel de Colombia entre 2011 y 2015, en pacientes que recibieron polimixina B intravenosa por más de 48 h. Resultados: De 139 pacientes incluidos en el estudio, 61 (44%) desarrollaron falla renal aguda por criterios AKIN. Los factores de riesgo independientes para nefrotoxicidad fueron: dosis diaria de polimixina B (OR 2,19; IC 95% 1,04-4,64), días de estancia en UCI (OR 1,03; IC 95% 1,00-1,06), presencia de infección nosocomial (OR 6,43; IC 95% 2,12-19,47) y requerimiento de fármacos vasopresores (OR 5,38; IC 95%: 2,40-12,07). Conclusión: La tasa de nefrotoxicidad observada en pacientes que recibieron polimixina B es considerable; su origen probablemente multifactorial y agravada por estado crítico de pacientes con infecciones nosocomiales por BGN-MR.

Membrane permeabilization of colistin toward pan-drug resistant Gram-negative isolates

Abstract Pan-drug resistant Gram-negative bacteria, being resistant to most available antibiotics, represent a huge threat to the medical community. Colistin is considered the last therapeutic option for patients in hospital settings. Thus, we were concerned in this study to demonstrate the membrane permeabilizing activity of colistin focusing on investigating its efficiency toward those pan-drug resistant isolates which represent a critical situation. We determined the killing dynamics of colistin against pan-drug resistant isolates. The permeability alteration was confirmed by different techniques as: leakage, electron microscopy and construction of an artificial membrane model; liposomes. Moreover, selectivity of colistin against microbial cells was also elucidated. Colistin was proved to be rapid bactericidal against pan-drug resistant isolates. It interacts with the outer bacterial membrane leading to deformation of its outline, pore formation, leakage of internal contents, cell lysis and finally death. Furthermore, variations in membrane composition of eukaryotic and microbial cells provide a key for colistin selectivity toward bacterial cells. Colistin selectively alters membrane permeability of pan-drug resistant isolates which leads to cell lysis. Colistin was proved to be an efficient last line treatment for pan-drug resistant infections which are hard to treat.

Colistín en la era post-antibiótica / Colistin in the post-antibiotic era

One of the most important features of the post-antibiotic era in the late 20th century is the resurgence of colistin for the treatment of extensively drug resistant gram-negative bacteria (XDR). Colistin is a narrow spectrum anti-biotic, active against microorganisms with clinical significance such as Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Nowadays its toxicity is lower, partly explained by better pharmaceuticals and management of the critically ill patients. However, there has been much confusion regarding the dosage of the drug, its name and labeling, therefore, experts have recommended using a common language about this polymyxin. The lack of PK/PD studies for colistin is perhaps the main weakness of this area of knowledge, even though the before mentioned approach has contributed with new ways to manage and calculate the dose of this antimicrobial. Indeed, the efficiency of colistin in association with a second agent in reducing mortality has not been demonstrated.

El resurgimiento de colistín para el tratamiento de bacilos gramnegativos extensamente resistentes a antimicrobianos a fines del siglo pasado es una de las características más importantes de la era post-antimicrobiana. Su espectro es reducido y cubre microorganismos con importancia clínica como Acinetobacter baumannii, Pseudomonas aeruginosa y Klebsiella pneumoniae. En contraste a lo que se vio en el pasado, la toxicidad descrita en la actualidad es menor, en parte explicado por las mejores preparaciones farmacéuticas y la optimización del manejo del paciente crítico. Mucha confusión se ha generado respecto a la dosificación del fármaco, debido a la distinta denominación, etiquetado y sugerencias de los laboratorios, a pesar de que el compuesto es el mismo. Por lo anterior, el llamado de los expertos es a utilizar un lenguaje común para referirnos a esta polimixina. Los estudios modernos de PK/PD han contribuido con nuevas formas de administrar y calcular las dosis de este antimicrobiano; no obstante, falta mucho por desarrollar en esta área que se posiciona como su gran debilidad. A pesar que la terapia combinada se sustenta sobre una base teórica lógica, no se ha demostrado que la asociación de colistín con un segundo agente logre disminuir la mortalidad.

Pharmacokinetic/pharmacodynamic target attainment of intravenous β-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital

ABSTRACTINTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous β-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital.METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010.RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of β-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii.CONCLUSIONS:These data reinforce the use of prolonged infusions of high-dose β-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.