Costos médicos directos de las infecciones del tracto urinario por bacilos Gram negativos resistentes a betalactámicos en un hospital de alta complejidad de Medellín, Colombia / Direct medical costs of urinary tract infections by Gram-negative bacilli resistant to beta-lactams in a tertiary care hospital in Medellín, Colombia

Resumen Introducción. Las infecciones del tracto urinario son muy frecuentes en el ámbito hospitalario. Debido a la aparición de la resistencia antimicrobiana, la complejidad de los procesos de atención ha aumentado y, con ello, la demanda de recursos. Objetivo. Describir y comparar el exceso de los costos médicos directos de las infecciones del tracto urinario por Klebsiella pneumoniae, Enterobacter cloacae y Pseudomonas aeruginosa resistentes a betalactámicos. Materiales y métodos. Se llevó a cabo un estudio de cohorte en una institución de tercer nivel de Medellín, Colombia, entre octubre del 2014 y septiembre del 2015. Se incluyeron los pacientes con infección urinaria, unos por bacterias sensibles a los antibióticos betalactámicos, y otros por bacterias resistentes a las cefalosporinas de tercera y cuarta generación y a los antibióticos carbapenémicos. Los costos se analizaron desde la perspectiva del sistema de salud. La información clínico-epidemiológica se obtuvo de las historias clínicas y los costos se calcularon utilizando los manuales tarifarios estándar. El exceso de costos se estimó mediante análisis multivariados. Resultados. Se incluyeron 141 pacientes con infección urinaria: 55 (39 %) por bacterias sensibles a los betalactámicos, 54 (38,3 %) por bacterias resistentes a las cefalosporinas y 32 (22,7 %) por bacterias resistentes a los carbapenémicos. El exceso de costos totales ajustado de los 86 pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas y a los carbapenémicos, fue de USD$ 193 (IC95% -347 a 734) y USD$ 633 (IC95% -50 a 1.316), respectivamente comparados con el grupo de 55 pacientes por bacterias sensibles a los betalactámicos. Las diferencias se presentaron principalmente en el uso de antibióticos de amplio espectro, como el meropenem, la colistina y la fosfomicina. Conclusión. Los resultados evidenciaron un incremento sustancial de los costos médicos directos de los pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas o a los carbapenémicos. Esta situación genera especial preocupación en los países endémicos como Colombia, donde la alta frecuencia de infecciones del tracto urinario y de resistencia a los betalactámicos puede causar un mayor impacto económico en el sector de la salud.

Abstract Introduction: Urinary tract infections are very frequent in the hospital environment and given the emergence of antimicrobial resistance, they have made care processes more complex and have placed additional pressure on available healthcare resources. Objective: To describe and compare excess direct medical costs of urinary tract infections due to Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa resistant to beta-lactams. Materials and methods: A cohort study was conducted in a third level hospital in Medellín, Colombia, from October, 2014, to September, 2015. It included patients with urinary tract infections caused by beta-lactam-susceptible bacteria, third and fourth generation cephalosporin-resistant, as well as carbapenem-resistant. Costs were analyzed from the perspective of the health system. Clinical-epidemiological information was obtained from medical records and the costs were calculated using standard tariff manuals. Excess costs were estimated with multivariate analyses. Results: We included 141 patients: 55 (39%) were sensitive to beta-lactams, 54 (38.3%) were resistant to cephalosporins and 32 (22.7%) to carbapenems. The excess total adjusted costs of patients with urinary tract infections due to cephalosporin- and carbapenem-resistant bacteria were US$ 193 (95% confidence interval (CI): US$ -347-734) and US$ 633 (95% CI: US$ -50-1316), respectively, compared to the group of patients with beta-lactam sensitive urinary tract infections. The differences were mainly found in the use of broad-spectrum antibiotics such as meropenem, colistin, and fosfomycin. Conclusion: Our results show a substantial increase in the direct medical costs of patients with urinary tract infections caused by beta-lactam-resistant Gram-negative bacilli (cephalosporins and carbapenems). This situation is of particular concern in endemic countries such as Colombia, where the high frequencies of urinary tract infections and the resistance to beta-lactam antibiotics can generate a greater economic impact on the health sector.

Multidrug resistance and risk factors associated with community-acquired urinary tract infections caused by Escherichia coli in Venezuela / Multirresistencia a medicamentos y factores de riesgo asociados con infecciones urinarias por Escherichia coli adquiridas en la comunidad, Venezuela

Abstract Introduction: The treatment of urinary tract infections has become more challenging due to the increasing frequency of multidrug-resistant Escherichia coli in human populations. Objective: To characterize multidrug-resistant E. coli isolates causing community-acquired urinary tract infections in Cumaná, Venezuela, and associate possible risk factors for infection by extended-spectrum beta-lactamases (ESBL)-producing isolates. Materials and methods: We included all the patients with urinary tract infections attending the urology outpatient consultation and emergency unit in the Hospital de Cumaná, Estado Sucre, Venezuela, from January through June, 2014. blaTEM, blaSHV and blaCTX-M genes detection was carried out by PCR. Results: We found a high prevalence of multidrug-resistant E. coli (25.2%) with 20.4% of the isolates producing ESBL. The ESBL-producing isolates showed a high frequency (66.7%) of simultaneous resistance to trimethoprim-sulphamethoxazole, fluoroquinolones and aminoglycosides compared to non-producing isolates (2.4%). Of the resistant isolates, 65.4% carried the blaTEM gene, 34.6% the blaCTX-M and 23.1% the blaSHV. The blaCTX-M genes detected belonged to the CTX-M-1 and CTX-M-2 groups. Plasmid transfer was demonstrated by in vitro conjugation in 17 of the 26 ESBL-producing isolates. All three genes detected were transferred to the transconjugants. Age over 60 years, complicated urinary tract infections and previous use of a catheter predisposed patients to infection by ESBL-producing E. coli. Conclusions: The high frequency of multidrug-resistant ESBL-producing isolates should alert the regional health authorities to take measures to reduce the risk of outbreaks caused by these types of bacteria in the community.

Resumen Introducción. El tratamiento de las infecciones urinarias constituye un reto creciente por el aumento de Escherichia coli proveniente de la comunidad multirresistente a los medicamentos. Objetivo. Caracterizar aislamientos de E. coli multirresistente causantes de infecciones urinarias adquiridas en la comunidad en Cumaná, Venezuela, y detectar los posibles riesgos de infección por aislamientos productores de betalactamasas de espectro extendido (BLEE). Materiales y métodos. Se incluyeron todos los pacientes atendidos en la consulta externa de urología y en urgencias del Hospital de Cumaná entre enero y junio de 2014 y que evidenciaban infecciones urinarias. La detección de los genes blaTEM, blaSHV y blaCTX-M se hizo mediante la reacción en cadena de la polimerasa (PCR). Resultados. Se encontró una alta prevalencia de E. coli multirresistente a los medicamentos (25,2 %), con 20,4 % de aislamientos productores de BLEE y una gran frecuencia de resistencia simultánea a trimetoprim-sulfametoxazol, fluoroquinolonas y aminoglucósidos (66,7 %) comparados con los no productores (2,4 %). En el 65,4 % de los aislamientos resistentes, se encontró el gen blaTEM; en 34,6 %, el blaCTX-M, y en 23,1 %, el blaSHV. Los genes blaCTX-M detectados pertenecían a los grupos CTX-M-1 y CTX-M-2. Se demostró la transferencia in vitro de plásmidos por conjugación en 17 de los 26 aislamientos productores de BLEE. Los tres tipos de genes detectados se transfirieron a los transconjugantes. La edad mayor de 60 años, las infecciones urinarias con complicaciones y el uso previo de catéter, predispusieron a la infección por cepas de E. coli productoras de BLEE. Conclusiones. La gran frecuencia de aislamientos multirresistentes productores de BLEE debería alertar a las autoridades sanitarias para tomar medidas que reduzcan el riesgo de epidemias causadas por este tipo de bacterias en la comunidad.

Carbapenem-resistant Pseudomonas aeruginosa: association with virulence genes and biofilm formation

Abstract Pseudomonas aeruginosa is an opportunistic pathogen that causes frequently nosocomial infections, currently becoming more difficult to treat due to the various resistance mechanisms and different virulence factors. The purpose of this study was to determine the risk factors independently associated with the development of bacteremia by carbapenem-resistant P. aeruginosa, the frequency of virulence genes in metallo-β-lactamases producers and to evaluate their ability to produce biofilm. We conducted a case–control study in the Uberlândia Federal University – Hospital Clinic, Brazil. Polymerase Chain Reaction was performed for metallo-β-lactamases and virulence genes. Adhesion and biofilm assays were done by quantitative tests. Among the 157 strains analyzed, 73.9% were multidrug-resistant, 43.9% were resistant to carbapenems, 16.1% were phenotypically positive for metallo-β-lactamases, and of these, 10.7% were positive for blaSPM gene and 5.3% positive for blaVIM. The multivariable analysis showed that mechanical ventilation, enteral/nasogastric tubes, primary bacteremia with unknown focus, and inappropriate therapy were independent risk factors associated with bacteremia. All tested strains were characterized as strongly biofilm producers. A higher mortality was found among patients with bacteremia by carbapenem-resistant P. aeruginosa strains, associated independently with extrinsic risk factors, however it was not evident the association with the presence of virulence and metallo-β-lactamases genes.

Factores de riesgo asociados al aislamiento de Escherichia coli o Klebsiella pneumoniae productoras de betalactamasas de espectro extendido en un hospital de cuarto nivel en Colombia / Risk factors associated with the isolation of extended spectrum betalactamases producing Escherichia coli or Klebsiella pneumoniae in a tertiary care hospital in Colombia

Introducción. Las betalactamasas de espectro extendido (BLEE) son un fenómeno de resistencia emergente de particular incidencia en América Latina. En Colombia existe poca información sobre los factores de riesgo asociados con su adquisición. Objetivo. Determinar los factores de riesgo que están asociados a la infección o colonización por Escherichia coli o Klebsiella pneumoniae productoras de BLEE en pacientes mayores de 18 años. Materiales y métodos. Se llevó a cabo un estudio de casos y controles con relación 1:1 en pacientes con aislamientos de E. coli o K. pneumoniae productoras de BLEE en cualquier tipo de muestra durante el periodo de enero de 2009 a noviembre de 2011 en el Hospital Universitario de San José. Resultados. Se estudiaron 110 casos y 110 controles; 62,7 % correspondió a E. coli y 37,3 %, a K. pneumoniae . Como factores de riesgo independiente en el análisis multivariado se encontraron la insuficiencia renal crónica (OR=2,99; IC 95%, 1,10-8,11; p=0,031), la cirugía urológica (OR=4,78; IC 95%, 1,35-16,87; p=0,015), el antecedente de uso de antibióticos en los tres meses anteriores (OR=2,24; IC 95%, 1,09-4,60; p=0,028), el origen hospitalario de la infección (OR=2,92; IC 95%, 1,39-6,13; p=0,004) y la hospitalización previa (OR=1,59; IC 95%, 1,03-2,46; p=0,036). Conclusión. Anticiparse al patrón de resistencia del microorganismo que infecta a un paciente con base en los factores de riesgo asociados permitiría la elección de un tratamiento antibiótico empírico apropiado, con el fin de lograr la disminución de la morbimortalidad de los pacientes.

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The minimal inhibitory concentration for sulbactam was not associated with the outcome of infections caused by carbapenem-resistant Acinetobacter sp. treated with ampicillin/sulbactam

OBJECTIVE: The objective of this study was to evaluate whether the outcomes of carbapenem-resistant Acinetobacter infections treated with ampicillin/sulbactam were associated with the in vitro susceptibility profiles. METHODS: Twenty-two infections were treated with ampicillin/sulbactam. The median treatment duration was 14 days (range: 3-19 days), and the median daily dose was 9 g (range: 1.5-12 g). The median time between Acinetobacter isolation and treatment was 4 days (range: 0-11 days). RESULTS: The sulbactam minimal inhibitory concentration (MIC) ranged from 2.0 to 32.0 mg/L, and the MIC was not associated with patient outcome, as 4 of 5 (80%) patients with a resistant infection (MIC≥16), 5 of 10 (50%) patients with intermediate isolates (MIC of 8) and only 1 of 7 (14%) patients with susceptible isolates (MIC ≤4) survived hospitalization. CONCLUSION: These findings highlight the need to improve the correlation between in vitro susceptibility tests and clinical outcome. .

Colonization pressure as a risk factor for colonization by multiresistant Acinetobacter spp and carbapenem-resistant Pseudomonas aeruginosa in an intensive care unit

OBJECTIVE: To determine factors associated with colonization by carbapenem-resistant Pseudomonas aeruginosa and multiresistant Acinetobacter spp. METHODS: Surveillance cultures were collected from patients admitted to the intensive care unit at admission, on the third day after admission and weekly until discharge. The outcome was colonization by these pathogens. Two interventions were implemented: education and the introduction of alcohol rubs. Compliance with hand hygiene, colonization pressure, colonization at admission and risk factors for colonization were evaluated. RESULTS: The probability of becoming colonized increased during the study. The incidence density of colonization by carbapenem-resistant P. aeruginosa and multiresistant Acinetobacter spp. and colonization pressure were different between periods, increasing gradually throughout the study. The increase in colonization pressure was due to patients already colonized at admission. The APACHE II score, colonization pressure in the week before the outcome and male gender were independent risk factors for colonization. Every 1% increase in colonization pressure led to a 2% increase in the risk of being colonized. CONCLUSION: Colonization pressure is a risk factor for carbapenem-resistant P. aeruginosa and multiresistant Acinetobacter spp. colonization. When this pressure reaches critical levels, efforts primarily aimed at hand hygiene may not be sufficient to prevent transmission. .

Risk factors for pan-resistant Pseudomonas aeruginosa bacteremia and the adequacy of antibiotic therapy

INTRODUCTION: The aim of this study was to determine risk factors for acquiring carbapenemresistant Pseudomonas aeruginosa bacteremia (CR-PA) and factors associated with in-hospital mortality. METHODS: Seventy-seven cases of bacteremia caused by P. aeruginosa were evaluated in a hospital with high incidence of CR-PA. Clinical and laboratorial factors, and previous use of antibiotics were also evaluated. In one analysis, CR-PA and carbapenem-susceptible P. aeruginosa (CS-PA) bacteremia were compared. A second analysis compared patients who died with survivors. RESULTS: Among 77 P. aeruginosa bacteremia, 29 were caused by CR-PA. Admission to the intensive care unit, higher number of total leukocytes, and previous use of carbapenem were statistically associated with CR-PA. In the multivariate analysis, only previous use of carbapenem (including ertapenem) turned out to be a risk factor for CR-PA (p = 0.014). The 30-day mortality of patients with P. aeruginosa bloodstream infection was 44.8% for CS-PA and 54.2% for patients with CR-PA (p = 0.288). Chronic renal failure, admission to the intensive care unit, mechanical ventilation, and central venous catheter were risk factors for mortality. Incorrect treatment increased mortality of patients with bacteremia caused by CS-PA, but not for CR-SA. The odd ratio of mortality associated with incorrect therapy in patients with CS-PA was 3.30 (1.01-10.82; p = 0.043). The mortality of patients with bacteremia caused by CR-PA was unexpectedly similar regardless of antimicrobial treatment adequacy. CONCLUSION: Appropriate treatment for CS-PA bacteremia initiated within the first 24 hours was associated with lower mortality, but this cannot be extrapolated for CR-PA.

Expressão de fatores de virulência, mecanismos de resistência aos agentes antimicrobianos e análise molecular da resistência aos beta-lactâmicos de enterobactérias isoladas de bolsas periodontais / Expression of virulence factors, mechanisms of resistance to antimicrobial agents and molecular analysis of beta-lactam resistance to Enterobacteriaceae isolated from periodontal pockets

Em estudo anterior, as espécies de enterobactérias apresentando perfis variados de resistência aos antimicrobianos foram detectadas em 20% dos sítios com lesões periodontais de pacientes sadios do ponto de vista sistêmico. Tais cepas microbianas foram submetidas a investigações com o intuito de determinar à expressão de enzimas hidrolíticas para substratos diversos, a multirresistência aos agentes antimicrobianos e os mecanismos de resistência aos antimicrobianos da classe dos B lactâmicos. A maioria das amostras expressou atividade de gelatinase (65%), caseinase (30%) e elastase (10%). Lipase, lecitinase e DNase foram observadas apenas para Serratia marcescens. A multirresistência (considerado como a resistência a pelo menos dois agentes antimicrobianos de famílias diferentes) foi observada em 56% das amostras isoladas. A maioria das cepas foi resistente à ampicilina (93,75%) e amoxicilina/ácido clavulânico (81,25%). Investigações sobre a resistência aos antibióticos B-lactâmicos mostraram que três amostras resistentes à cefalosporinas de 2ª geração, apresentaram perfis plasmidiais de diferentes pesos moleculares. A expressão fenotípica de B-lacatamases, foi detectada nas cepas de Enterobacter cloacae (PcOM46 e PcOM5) e S. marcescens (PcOM63). No entanto, na análise molecular, não foi possível confirmar a expressão fenotípica de diferentes B-lactamases, com exceção do E. cloacae PcOM46, que apresentou amplificação para AmpC e blatem. Embora sensível à maioria dos antibióticos B-lactâmicos (exceção feita à ampicilina e amoxicilina/ácido clavulânico), amostra de S. marcescens PcOM68 apresentou amplificação para o gene blashv. Os experimentos de conjugação não detectaram a transferência de plasmídios para uma cepa de Escherichia coli K12 sensível aos B-lactâmicos, o mesmo ocorreu nos procedimentos de transformação por eletroporação e por CaCI2, sugerindo uma resistência dependente de genes cromossomiais. A expressão de diferentes atividades enzimáticas...

In a previous study, the enterobacterial species were detected in 20% of systemically healthy patients presenting periodontal lesions, with diferent profiles of antimicrobial resistance. These microbial strains were investigated in view to determine the expression of hydrolytic enzymes for diverse substrates, multiresistance to antimicrobial agents, and the mechanisms of resistance to beta-lactam antibiotics. The enzymes related to bacterial virulence were detected phenotypically in 90% isolates. The proteolytic activity displayed by the isolates against gelatin, casein and elastin was detected in 65%, 30% and 10%, respectively. Lipase, lecithinase, and DNase were observed only for Serratia marcescens strains. Multi-resistant phenotypes (considered as the resistance to at least two antimicrobial agents from different families) were observed for 56% enterobacterial isolates. Most of the strains were resistant to ampicillin (93.75%) and amoxicillin/clavulanic acid (81.25%). Investigations concerned to the resistance to beta-lactam antibiotics demonstrated that three bacterial strains resistant to penicilins and 2nd generation cephalosporins, had detectable plasmids. The extended resistance to B-lactams was detected phenotypically for E. cloacae (PcOM46 and PcOM5) and S. marcescens (PcOM63) strains. However, the molecular detection of extended spectrum beta-lactamase failed to confirm the phenotypic expression of different B-lactamases, with exception to the E. cloacae PcOM46 isolate, which presented amplification for both ampC and blatem. Although sensitive to most of the B-lactam antibiotics (exception made to ampicilin and ampicilin/clavulanate), the strain S. marcescens PcOM68 was shown to amplify the blashv gene. Plasmid transference by both conjugation and transformation procedures failed to detect the resistance by a B-lactam-sensitive strain (E. coli K12), suggesting a chromosomal dependent resistance. The expression of varied enzymatic activities...

Betalactámicos con inhibidores de betalactamasas: Amoxicilina-sulbactam / Betalactam antibiotics combined with bectalactamases inhibitors: Amoxicillin-sulbactam

La producción de betalactamasas constituye uno de los principales mecanismos de resistencia bacteriana a los antibióticos betalactámicos. La utilización de inhibidores de betalactamasas en combinación con antibióticos betalactámicos permite la inactivación de determinadas betalactamasas producidas por gérmenes Gram positivos, Gram negativos, anaerobios, y aun por micobacterias. Los inhibidores de betalactamasas representan una alternativa terapéutica mejorada respecto del resto de los betalactámicos al asegurar, en la mayoría de los casos, un mayor espectro antimicrobiano comparado con el de sus análogos. La actividad enzimática de las betalactamasas está dirigida específicamente a la hidrólisis del anillo betalactámico, con producción de un compuesto sin actividad antibacteriana. De acuerdo con su posición genómica dentro de los microorganismos, las betalactamasas pueden ser cromosómicas o plasmídicas. Actualmente existen tres inhibidores de betalactamasas localmente disponibles: ácido clavulánico, sulbactam y tazobactam. De ellos, sólo el sulbactam posee actividad antimicrobiana intrínseca sobre las proteínas ligadoras de penicilina. La experiencia clínica acumulada durante más de 20 años confirma que las combinaciones de betalactámicos-inhibidores de betalactamasas son efectivas en el tratamiento empírico inicial de infecciones respiratorias, intraabdominales, urinarias y ginecológicas, incluidas las de origen polimicrobiano. En el caso particular de amoxicilina-sulbactam, la evidencia citada indica que esta combinación es efectiva para el tratamiento de absceso periamigdalino, otitis media, sinusitis, neumonía extrahospitalaria, exacerbación aguda de enfermedad pulmonar obstructiva crónica (EPOC), infección del tracto urinario e infecciones ginecoobstétricas. Por su espectro y propiedades farmacológicas, la combinación amoxicilina-sulbactam constituye una excelente opción también para el tratamiento de infecciones de piel y partes blandas e infecciones intraabdominales.

Betalactamases production is one of the main bacterial resistance mechanisms to betalactam antibiotics. The use of bectalactamases inhibitors combined with betalactam antibiotics allows the inactivation of certain betalactamases produced by Gram positive, Gram negative and anaerobic organisms, and even by mycobacteria. Betalactamases inhibitors are an improved therapeutic alternative compared with the other betalactam since, in most cases, they cover a wider antimicrobial spectrum than their analogues. Betalactamases enzimatic activity is specifically directed to the betalactam ring hydrolisis, producing a compound without antibacterial activity. According to their genomic position within microorganisms, betalactamases can be either chromosomic or plasmidic. Currently there are three betalactamases inhibitors locally available: clavulanic acid, sulbactam and tazobactam. Of them, only sulbactam has an intrinsic antimicrobial activity against penicillin binding proteins. The clinical experience from over 20 years confirms that the combination of betalactam antibiotics is effective in the empirical initial treatment of respiratory, intraabdominal, urinary tract and gynecologic infections, including those of polymicrobial origin. In the specific case of amoxicillin-sulbactam, experiences have shown the effectiveness of the combination in the treatment of peritonsillar abscess, otitis media, sinusitis, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonar disease (COPD), urinary tract infection and obstetric/ gynecologic infections. The spectrum and pharmacologic properties of this combination makes it also an excellent option for the treatment of skin/soft tissue and intraabdominal infections.

Risk factors for infection by extended-spectrum beta-lactamase producing Klebsiella pneumoniae in a tertiary hospital in Salvador, Brazil

Nosocomial infection caused by extended-spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-Kp) have been frequently reported worldwide. We have no information on such problems in Bahia, Brazil. OBJECTIVES: Evaluate the risk factors for nosocomial infections caused by ESBL-Kp, in a tertiary hospital, in Bahia, Brazil. MATERIAL AND METHODS: We evaluated all reported cases of nosocomial infections caused by ESBL-Kp in a private, tertiary hospital, in Salvador, Brazil, from 2000 through 2004. We compared patients with a diagnosis of ESBL-Kp (cases) and patients infected by non-ESBL producing K. pneumoniae (controls). Mean age, underlying disease, and frequency of invasive procedures were compared between the two groups. History of previous use of antibiotics was also analyzed. RESULTS: Based on multivariate analysis, previous use of antibiotics, diagnosis of malignant diseases, and diabetes mellitus were independent risk factors for acquisition of ESBL-Kp infection. No correlation was found for age, use of corticosteroids, diagnosis of chronic renal failure or AIDS, and infection by ESBL-Kp. CONCLUSION: Our findings suggest that the use of antibiotics or underlying disease that increases the chance of antibiotic are the main risk factors for ESBL-Kp infections. Programs focusing on rational use of antibiotics are mandatory for prevention and control of such infections.