Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections.

In recent years, the worldwide spread of the so-called high-risk clones of multidrug-resistant or extensively drug-resistant (MDR/XDR) Pseudomonas aeruginosa has become a public health threat. This article reviews their mechanisms of resistance, epidemiology, and clinical impact and current and upcoming therapeutic options. In vitro and in vivo treatment studies and pharmacokinetic and pharmacodynamic (PK/PD) models are discussed. Polymyxins are reviewed as an important therapeutic option, outlining dosage, pharmacokinetics and pharmacodynamics, and their clinical efficacy against MDR/XDR P. aeruginosa infections. Their narrow therapeutic window and potential for combination therapy are also discussed. Other "old" antimicrobials, such as certain ß-lactams, aminoglycosides, and fosfomycin, are reviewed here. New antipseudomonals, as well as those in the pipeline, are also reviewed. Ceftolozane-tazobactam has clinical activity against a significant percentage of MDR/XDR P. aeruginosa strains, and its microbiological and clinical data, as well as recommendations for improving its use against these bacteria, are described, as are those for ceftazidime-avibactam, which has better activity against MDR/XDR P. aeruginosa, especially strains with certain specific mechanisms of resistance. A section is devoted to reviewing upcoming active drugs such as imipenem-relebactam, cefepime-zidebactam, cefiderocol, and murepavadin. Finally, other therapeutic strategies, such as use of vaccines, antibodies, bacteriocins, anti-quorum sensing, and bacteriophages, are described as future options.

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2⁻2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Impact of colistin plasma levels on the clinical outcome of patients with infections caused by extremely drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Colistin has a narrow therapeutic window with nephrotoxicity being the major dose-limiting adverse effect. Currently, the optimal doses and therapeutic plasma levels are unknown. METHODS: Prospective observational cohort study, including patients infected by colistin-susceptible P. aeruginosa treated with intravenous colistimethate sodium (CMS). Clinical data and colistin plasma levels at steady-state (Css) were recorded. The primary and secondary end points were clinical cure and 30-day all-cause mortality. RESULTS: Ninety-one patients were included. Clinical cure was observed in 72 (79%) patients. The mean (SD) Css was 1.49 (1.4) mg/L and 2.42 (1.5) mg/L (p = 0.01) in patients who achieved clinical cure and those who not, respectively. Independent risk factors for clinical failure were male sex (OR 5.88; 95% CI 1.09-31.63), APACHE II score (OR 1.15; 95% CI 1.03-1.27) and nephrotoxicity at the EOT (OR 9.13; 95% CI 95% 2.06-40.5). The 30-day mortality rate was 30.8%. Risk factors for 30-day mortality included the APACHE II score (OR 1.98; 95% CI 1-1.20), the McCabe score (OR 2.49; 95% CI 1.14-5.43) and the presence of nephrotoxicity at the end of treatment (EOT) (OR 3.8; 95% CI 1.26-11.47). CONCLUSION: In this series of patients with infections caused by XDR P. aeruginosa infections, Css is not observed to be related to clinical outcome.

Characterization and rapid control of a vancomycin-resistant Enterococcus faecium (VREF) outbreak in a renal transplant unit in Spain: The environment matters.

OBJECTIVE: To describe a clonal outbreak due to vancomycin-resistant Enterococcus faecium (VREF) in the nephrology and renal transplant unit of a tertiary teaching hospital in Barcelona, Spain, and to highlight how active patient and environment surveillance cultures, as well as prompt and directed intervention strategies, mainly environmental, helped to successfully bring it under control. PATIENTS AND METHODS: A study was conducted on patients admitted to the nephrology ward with any culture positive for VREF over a 6-month period (August 2012-January 2013). Based on the identification of a clonal link between the isolates, weekly rectal screening using swabs was implemented for all patients, as well as environmental cultures and cleaning of medical equipment and the ward. VREF isolates were identified by MicroScan and confirmed by Etest. Bacterial identification was confirmed by MALDI-TOF MS. The presence of van genes, and esp and hyl virulence genes was determined using PCR. The clonal relationship between the isolates was studied first with DiversiLab (bioMérieux), and then by PFGE-Smal and MLST. A two-tier sequence of infection control measures was implemented. RESULTS: During the study period, VREF was isolated from 13 patients. All cases were colonized with no criteria for infection. VREF isolates were also extensively recovered from the environment and medical equipment. Isolates carried the vanA gene, and were multidrug-resistant, including high-level resistance (MIC >16mg/L) to vancomycin and teicoplanin. Molecular analysis showed that all VREF isolates belonged to sequence type 17 (ST17) carrying hyl virulence genes. After implementing infection control measures in a two-tier sequence, and reinforcing particularly environmental and medical equipment cleaning, no further cases were detected in the follow-up year. CONCLUSION: A clonal outbreak of VREF-ST17 involving only colonization is reported. The prompt implementation of aggressive infection control measures in patients and the environment was effective in controlling the outbreak and avoided the potential emergence of infection among patients.

Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology.

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum ß-lactamases and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. Clinically relevant questions were selected and the literature was reviewed for each of them. The information from the selected articles was extracted and recommendations were provided and graded according to the strength of the recommendations and quality of the evidence. The document was opened to comments from the members from the Spanish Society of Infectious Diseases and Clinical Microbiology, which were considered for inclusion in the final version. Evidence-based recommendations are provided for the use of microbiological techniques for the detection of extended-spectrum ß-lactamases and carbapenemases in Enterobacteriaceae, and for antibiotic therapy for invasive/severe infections caused by these organisms. The absence of randomised controlled trials is noteworthy; thus, recommendations are mainly based on observational studies (that have important methodological limitations), pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Executive summary of the diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum ß-lactamases (ESBL) and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. After the selection of clinically relevant questions, this document provides evidence-based recommendations for the use of microbiological techniques for the detection of ESBL- and carbapenemase-producing Enterobacteriaceae, and for antibiotic therapy for invasive infections caused by these organisms. The absence of randomized-controlled trials is noteworthy, thus recommendations are mainly based on observational studies, that have important methodological limitations, pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection.

INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO2/FiO2 ratio, whereas haplotype 1A(1) was associated with a higher PaO2/FiO2 ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics.

Pseudomonas stutzeri bloodstream infection is a prevailing community-onset disease with important mortality rates: results from a retrospective observational study in Australia.

BACKGROUND: The recognition of Pseudomonas stutzeri as a cause of infections in humans has been increasing. However, only case reports and small series of P. stutzeri bloodstream infections have been published. Epidemiological data on these infections are extremely scarce. Our objective was to describe the incidence, epidemiology, antimicrobial resistance rates, and outcomes of P. stutzeri bloodstream infections in a large population-based cohort in Australia. METHODS: Retrospective, laboratory-based surveillance study conducted in Queensland, Australia (population ≈ 5 million) during 2000-2019. Clinical information was obtained from public hospital admissions and vital statistics databases. RESULTS: In total, 228 episodes of P. stutzeri bloodstream infections were identified. Increased incidence was observed in the later years, especially in older men, and was higher during the rainy months of the year and in the warmest and more humid regions of the state. The majority of bloodstream infections were community-onset with 120 (52.6%) community-associated and 59 (25.9%) ambulatory healthcare-associated episodes. Only 49 cases (21.5%) were nosocomial. The most common foci of infection were skin and soft tissue, lower respiratory tract, and intra-abdominal. No isolate showed antimicrobial resistance. Thirty-one patients (13.6%) died. The mortality rate in patients with a respiratory infectious source was higher (21%). CONCLUSIONS: P. stutzeri bloodstream infection was predominantly a community-onset condition including ambulatory healthcare related cases, with increasing incidence, especially in older males. No antimicrobial resistance was observed. Mortality was high in patients with respiratory infectious source. This new observational data have implications when considering the epidemiology of these infections and for patient management.

Globally expanding carbapenemase finally appears in Spain: nosocomial outbreak of acinetobacter baumannii producing plasmid-encoded OXA-23 in Barcelona, Spain.

Resistance of Acinetobacter baumannii clinical isolates to carbapenems is on the rise worldwide mainly in association with the production of OXA-23. Until recently, however, OXA-23 was absent in Spain. In this work, we report the molecular characterization of a hospital outbreak of OXA-23-producing A. baumannii in Barcelona caused by a multidrug-resistant (MDR) clone belonging to international clone IC-II/sequence type ST85 between October 2010 and May 2011. blaOXA-23 was carried in a plasmid of 90 kb and located within the composite transposon Tn2006.

Colistin for the treatment of urinary tract infections caused by extremely drug-resistant Pseudomonas aeruginosa: Dose is critical.

OBJECTIVES: Optimal dosage regimens of colistin for the treatment of urinary tract infections (UTI) are unknown. Colistimethate sodium (CMS), the inactive prodrug of colistin, is mainly excreted in urine and converts to colistin after filtration by glomeruli, suggesting that concentrations of colistin in urine could be much higher than in plasma. Therefore, there is a need to optimize dosage regimens of intravenous CMS for UTI. The aim of this study was to examine the relationship between AUC/MIC of formed colistin and clinical outcomes in patients with UTI caused by extremely drug resistant (XDR) Pseudomonas aeruginosa. METHODS: This prospective, observational cohort study involved patients with UTI caused by XDR P. aeruginosa. Clinical cure, bacteriological clearance and acute kidney injury (AKI) were analyzed. Steady-state colistin plasma concentrations (Css) were measured using HPLC. Based on the PK/PD of colistin in neutropenic mouse thigh infection models with P. aeruginosa, the optimal AUC/MIC should be ≥60 mg·h/L. According to the pharmacokinetics (PK) in critically-ill patients, the Css target of formed colistin in plasma was 2.5 mg/L. RESULTS: Thirty-three patients were included (24 lower UTI and 9 pyelonephritis). The MIC50 and MIC90 values for colistin were 0.5 and 2 mg/L respectively. Nineteen patients (57.6%) received colistin monotherapy (84.2% lower UTI and 15.8% pyelonephritis). Of these, clinical cure was achieved in 89.5% of cases. Among patients with clinical cure and monotherapy, only 5 (29.4%) attained an optimal plasma AUC/MIC and only 1 (5.9%) the therapeutic level of formed colistin (2.5 mg/L). However, 10 (58.8%) patients showed colistin plasma concentrations above the MIC of the isolated P. aeruginosa. Microbiological eradication was achieved in 76.9% of patients. AKI at the end of treatment was present in 29.4% of patients. CONCLUSIONS: The currently recommended dosage regimens of CMS showed high efficacy for the treatment of lower complicated UTI caused by XDR P. aeruginosa in non-critically ill patients and in the case of low MIC values, but also a considerable nephrotoxicity rate. Our data suggest that the use of lower CMS doses for lower UTI should be investigated in future studies to minimize the unnecessary nephrotoxicity.

Global cardiovascular risk in patients with HIV infection: concordance and differences in estimates according to three risk equations (Framingham, SCORE, and PROCAM).

To compare cardiovascular risk stratification according to Framingham, PROCAM (Prospective Cardiovascular Münster), and SCORE (Systematic Coronary Risk Evaluation) equations in patients with HIV infection, a cross-sectional study of a well-characterized cohort of 760 HIV-infected adults managed at the outpatient Infectious Disease Unit in 2003 was conducted. Cardiovascular risk score was examined and patients were classified as having low, moderate, or high risk using Framingham and PROCAM (<10%, 10%-20%, and <20%, respectively) and SCORE (<3%, 3%-4%, and >/=5%, respectively) equations. The prevalence of patients with low, moderate and high cardiovascular risk was 76.6%, 15.1%, and 8.3% by the Framingham, respectively, 90.1%, 4.9%, and 5% by the PROCAM, respectively, and 88.6%, 3%, and 8.4% by SCORE, respectively. Concordance between these three risk functions was significant, but globally moderate (Framingham and PROCAM, kappa 0.36, p < 0.0001; Framingham and SCORE, kappa 0.32, p < 0.0001; PROCAM and SCORE, kappa 0.46, p < 0.0001). The Framingham equation categorized a higher proportion of HIV-infected male patients with moderate cardiovascular risk and a lower proportion of those with low risk (p < 0.0001) compared with PROCAM and SCORE. The present study showed a high prevalence of HIV-infected patients at low cardiovascular risk regardless of the assessed coronary risk system used. However, compared with PROCAM and SCORE, Framingham risk equation in HIV-infected patients identified a higher number of male patients with moderate cardiovascular risk.

Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors.

OBJECTIVE: To assess the prevalence in HIV-infected patients of the metabolic syndrome as defined by the National Cholesterol Education Program, i.e., three or more of the following components: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting glucose. RESEARCH DESIGN AND METHODS: In this cross-sectional study, 710 HIV-infected patients managed at the outpatient clinic of a tertiary hospital during 2003 completed the study protocol consisting of a medical examination and laboratory analysis after a 12-h overnight fast. RESULTS: Metabolic syndrome prevalence was 17% and increased from 5.1% among HIV-infected patients under age 30 years to 27.0% for those aged 50-59 years. Age (per 10-year increment) (odds ratio [OR] 1.41 [95% CI 1.12-1.77]), BMI (1.27 [1.19-1.36]), past and present protease inhibitor exposure (2.96 [1.03-3.55] and 4.18 [1.4-12.5], respectively) were independently associated with the metabolic syndrome on logistic regression analysis. Furthermore, only stavudine (d4T) (1.74 [1.01-2.98]) and lopinavir/ritonavir (2.46 [1.28-4.71]) were associated with the metabolic syndrome after adjustment for age and BMI. CONCLUSIONS: The prevalence of metabolic syndrome among these HIV-infected patients is similar to that previously reported in uninfected individuals. Of specific concern is the association of protease inhibitor exposure with the metabolic syndrome and, more specifically, with exposure to stavudine and lopinavir/ritonavir when individual antiretroviral drugs were analyzed.

The Framingham function overestimates the risk of ischemic heart disease in HIV-infected patients from Barcelona.

BACKGROUND: Cardiovascular risk (CVR) assessment helps to identify patients at high CVR. The Framingham CVR score (FRS) is the most widely used methods but may overestimate risk in regions with low incidence of cardiovascular disease. The objective was to compare the 10-year performance of the original and the adapted REGICOR - Framingham CVR functions in HIV-infected individuals. METHODS: We carried out a longitudinal study of HIV-infected patients with CVR evaluation in a hospital in Barcelona between 2003 and 2013. STATISTICS: Risk probability was calculated using the FRAMINGHAM function and REGICOR adaptation to the Spanish population, and individuals were categorized in three groups (low, 0 < 5%; moderate, 5-10%; and high, >10%). For each risk group, the number of events over 10 years was calculated using the Kaplan-Meier method, and the expected number of events was calculated by multiplying the frequency of participants in the group by the mean of the probabilities from the risk function. We used the X(2) goodness-of-fit test to assess agreement between observed and expected. RESULTS: Six hundred and forty-one patients were followed up for a median of 10.2 years, and 20 ischemic heart events (IHE) were observed. The mean (95% CI) number of IHEs per 1000 person-years was 3.7 (2.06-5.27). The estimates from the Framingham and REGICOR functions were 40 and 14 IHEs, respectively. The estimate from the original Framingham function differed significantly from the observed incidence (p < 0.001), whereas that from the REGICOR-adapted function did not (p = 0.15). In terms of the number of cardiovascular events (38 events observed), the REGICOR function significantly underestimated risk (p = 0.01), whereas the estimate from the Framingham function was similar to observed (p:0.93). CONCLUSIONS: The FRS significantly overestimates risk of IHE events in our HIV-infected patients, while the REGICOR function is a better predictor of these events. In terms of cardiovascular events, the REGICOR function significantly underestimates risk, whereas the FRS is a better estimator. We recommend using CVR scales and adjusting them to the origin of the population being studied.

Validation of a colistin plasma concentration breakpoint as a predictor of nephrotoxicity in patients treated with colistin methanesulfonate.

Nephrotoxicity limits the effective use of colistin for the treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections. We previously defined a steady-state colistin plasma concentration (Css) of 2.42 mg/L that predicted nephrotoxicity at end of treatment (EOT). The objective of this study was to validate this breakpoint in a prospective cohort. This was a multicentre, prospective, observational study conducted at three hospitals with a cohort of patients treated for MDR-GNB infection with colistin methanesulfonate from September 2011 until January 2015. Nephrotoxicity was evaluated at Day 7 and at EOT using the RIFLE criteria. Css values were measured and analysed using HPLC. Taking the previously defined breakpoint for colistin concentration as a criterion, patients were divided into two groups (Css, ≤2.42 mg/L vs. >2.42 mg/L). Sixty-four patients were included. Seven patients (10.9%) had a Css > 2.42 mg/L and were compared with the remaining patients. Bivariate analysis showed that patients with a Css > 2.42 mg/L were older and had a significantly higher incidence of nephrotoxicity at Day 7 and EOT. Although not statistically significant, nephrotoxicity occurred earlier in these patients (6.2 days vs. 9.2 days in patients with lower Css; P = 0.091). Multivariate analysis of nephrotoxicity showed that Css > 2.42 mg/L was the only predictive factor. Nephrotoxicity was more frequent and occurred earlier in patients with colistin plasma concentrations higher than the previously defined breakpoint (2.42 mg/L). Colistin therapeutic drug monitoring should be routinely considered to avoid reaching this toxicity threshold and potential clinical consequences.

Hypertension in HIV-infected patients: prevalence and related factors.

BACKGROUND: Little is known about hypertension in the HIV-infected population. This study aimed to assess the prevalence of hypertension and related factors in HIV-infected patients. METHODS: In this prospective cross-sectional study, 710 HIV-infected patients (626 on combination antiretroviral therapy and 84 naive) managed at the outpatient clinic of a tertiary hospital during 2003 and 802 controls completed the study protocol consisting of medical examination and a 6-month follow-up period including three control visits. RESULTS: Hypertension prevalence was 13.1% in HIV-infected patients and 13.5% in the control group. Age (per 10-year increment) (odds ratio [OR]: 1.92; 95% confidence interval [CI]: 1.48-2.48), body mass index (OR: 1.18; 95% CI: 1.10-1.27), and lipoaccumulation pattern of fat redistribution (OR: 2.26; 95% CI: 1.20-4.24) were independently and significantly associated with the presence of hypertension in HIV-infected patients at logistic regression analysis. CONCLUSIONS: The present results suggest no meaningful difference in prevalence of hypertension between subjects with and without HIV infection. Thus, the influence of combination antiretroviral therapy appears to have little impact on the prevalence of hypertension.

Clinical experience with the use of daptomycin in a tertiary care teaching hospital in Barcelona, Spain.

AIM: We reviewed the clinical use of daptomycin in daily practice. MATERIALS & METHODS: Efficacy and safety were assessed in 175 consecutive patients given daptomycin for at least 72 h. RESULTS: Daptomycin was given as rescue treatment in 50.9% of cases. Bloodstream infection (34.8%) and skin/soft-tissue infection (19.4%) were the most frequent. In 62.3% of patients, the dose of ≤ 6 mg/kg/day was administered. Staphylococcus spp. were isolated in 52.6% of cases (MRSA in 9.5%, CoNS in 34.3%) and Enterococcus spp. in 8.7%. Clinical success was 75% and microbiological eradication 48.6%. Two patients discontinued daptomycin due to hemolytic anemia of unlikely and possible relationship with daptomycin, respectively. CONCLUSION: Daptomycin was effective and well tolerated in patients with severe Gram-positive infections.

Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Microbial translocation has been associated with an increase in immune activation and inflammation in HIV infection despite effective highly active antiretroviral therapy. It has been shown that some probiotics have a beneficial effect by reducing intestinal permeability and, consequently, microbial translocation. OBJECTIVES: To assess changes in microbial translocation and inflammation after treatment with probiotics (Saccharomyces boulardii) in HIV-1-infected patients with virologic suppression. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 44 nonconsecutive HIV-1-infected patients with viral load of <20 copies per milliliter for at least 2 years. Patients were randomized to oral supplementation with probiotics or placebo during 12 weeks. Markers of microbial translocation (lipopolysaccharide-binding protein [LBP] and soluble CD14), inflammation (interleukin 6 [IL-6], tumor necrosis factor alpha, interferon gamma, high-sensitivity C-reactive protein), and immunological and clinical data were determined before and after the intervention and 3 months after treatment discontinuation. Quantitative variables were compared using the Mann-Whitney U test, and categorical variables were compared using the Fisher exact test. RESULTS: After 12 weeks of treatment, differences between the probiotic arm and the placebo arm were observed in LBP values (-0.30 vs +0.70 pg/mL) and IL-6 (-0.60 vs +0.78 pg/mL). These differences were also noted at 3 months after treatment withdrawal. Qualitative analysis was performed, defining a variable as "decreased" or "increased" from baseline LBP. A significant decrease of LBP at 12 weeks of treatment was observed (57.9% patients in the probiotic group vs 6.2% in the placebo group, P = 0.002). CONCLUSIONS: Treatment with S. boulardii decreases microbial translocation (LBP) and inflammation parameters (IL-6) in HIV-1-infected patients with long-term virologic suppression.

Impact of an antimicrobial stewardship program on urinary tract infections caused by extended-spectrum Beta-lactamase-producing Escherichia coli / Impacto de un programa de optimización de antimicrobianos en infecciones urinarias por Escherichia coli productor de Beta-lactamasas de espectro extendido

Objective. To analyze the clinical and economic impact of an antimicrobial stewardship program (ASP) targeting urinary tract infections (UTI) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli. Methods. An observational retrospective study that included adults with a diagnosis of UTI caused by ESBL-producing E. coli admitted to a tertiary care hospital in Barcelona, Spain, between January 2014 and December 2015. The impact of the ASP was analyzed in terms of clinical and economic outcomes. Results. A total of 222 patients met the inclusion criteria and an intervention was made by the ASP team in 104 cases (47%). ASP intervention was an independent variable related to clinical cure (p = 0.008). Other variables influencing clinical outcomes were the McCabe Jackson score (p = 0.005) and outpatient status (p < 0.001). The ASP interventions in this study had no economic impact. Conclusion. Antimicrobial stewardship has a positive clinical impact on UTIs caused by ESBL-producing E. coli. Further prospective studies are needed to assess the economic impact of ASPs on UTI caused by ESBL-producing E. col

Objetivo. Analizar el impacto clínico y económico de un Programa de Optimización de Antimicrobianos (PROA) en las infecciones del tracto urinario (ITU) causadas por Escherichia coli productor de β-lactamasas de espectro extendido (BLEE). Métodos. Estudio observacional retrospectivo que incluye adultos con ITU por E. coli BLEE diagnosticados en un hospital terciario en Barcelona, España, entre enero de 2014 y diciembre de 2015. El impacto del PROA se analizó en términos de evolución clínica y consumo de recursos sanitarios. Resultados. Se incluyeron un total de 222 pacientes, de los cuales se realizó algún tipo de intervención por parte del equipo de PROA en 104 casos (47%). La intervención del PROA resultó ser una variable independiente relacionada con la curación clínica (p = 0,008). Otras variables relacionadas con la evolución clínica fueron la clasificación de McCabe Jackson (p = 0,005) y el manejo ambulatorio (p < 0,001). Las intervenciones del PROA no demostraron tener un impacto económico en este estudio. Conclusión. Las intervenciones de los PROA tienen un impacto positivo en la evolución clínica de los pacientes con ITU por E. coli productor de BLEE. Se necesitan más estudios prospectivos para determinar el impacto económico de los PROA en las ITU por E. coli productor de BLEE

Community-onset healthcare-related urinary tract infections: comparison with community and hospital-acquired urinary tract infections.

OBJECTIVES: To analyze the characteristics of infection, adequacy of empirical treatment and outcome of patients with community-onset healthcare-associated (HCA) urinary tract infections (UTI) and compare them with hospital (HA) and community-acquired (CA) UTI. METHODS: Prospective observational cohort study performed at a university 600-bed hospital between July 2009 and February 2010. Patients with UTI requiring hospital admission were included. Epidemiological, clinical and outcome data were recorded. RESULTS: 251 patients were included. Patients with community-onset HCA UTI were older, had more co-morbidities and had received previous antimicrobial treatment more frequently than CA UTI (p = 0.02, p = 0.01 and p < 0.01). ESBL-Escherichia coli and Pseudomonas aeruginosa infections were more frequent in HCA than in CA UTI (p = 0.03 and p < 0.01). Inadequate empirical treatment was not significantly different between community-onset HCA and CA. Factors related to mortality were P. aeruginosa infection (OR 6.51; 95%CI: 1.01-41.73), diabetes mellitus (OR 22.66; 95%CI: 3.61-142.21), solid neoplasia (OR 22.48; 95%CI: 3.38-149.49) and age (OR 1.15; 95%CI 1.03-1.28). CONCLUSIONS: Epidemiological, clinical and microbiological features suggest that community-onset HCA UTI is different from CA and similar to HA UTI. However, in our series inadequate empirical antimicrobial therapy and mortality were not significantly higher in community-onset HCA than in CA UTI.

Characterization and rapid control of a vancomycin-resistant Enterococcus faecium (VREF) outbreak in a renal transplant unit in Spain: The environment matters / Caracterización y control rápido de un brote de Enterococcus faecium resistente a vancomicina en una unidad de trasplantados renales en España: el ambiente importa

OBJECTIVE: To describe a clonal outbreak due to vancomycin-resistant Enterococcus faecium (VREF) in the nephrology and renal transplant unit of a tertiary teaching hospital in Barcelona, Spain, and to highlight how active patient and environment surveillance cultures, as well as prompt and directed intervention strategies, mainly environmental, helped to successfully bring it under control. PATIENTS AND METHODS: A study was conducted on patients admitted to the nephrology ward with any culture positive for VREF over a 6-month period (August 2012-January 2013). Based on the identification of a clonal link between the isolates, weekly rectal screening using swabs was implemented for all patients, as well as environmental cultures and cleaning of medical equipment and the ward. VREF isolates were identified by MicroScan and confirmed by Etest. Bacterial identification was confirmed by MALDI-TOF MS. The presence of van genes, and esp and hyl virulence genes was determined using PCR. The clonal relationship between the isolates was studied first with DiversiLab (bioMérieux), and then by PFGE-Smal and MLST. A two-tier sequence of infection control measures was implemented. RESULTS: During the study period, VREF was isolated from 13 patients. All cases were colonized with no criteria for infection. VREF isolates were also extensively recovered from the environment and medical equipment. Isolates carried the vanA gene, and were multidrug-resistant, including high-level resistance (MIC >16mg/L) to vancomycin and teicoplanin. Molecular analysis showed that all VREF isolates belonged to sequence type 17 (ST17) carrying hyl virulence genes. After implementing infection control measures in a two-tier sequence, and reinforcing particularly environmental and medical equipment cleaning, no further cases were detected in the follow-up year. CONCLUSION: A clonal outbreak of VREF-ST17 involving only colonization is reported. The prompt implementation of aggressive infection control measures in patients and the environment was effective in controlling the outbreak and avoided the potential emergence of infection among patients

OBJETIVO: Describir un brote clonal de Enterococcus faecium resistente a vancomicina (VREF) en la unidad de trasplante renal de un hospital universitario en Barcelona (España) y destacar que los controles ambientales, así como las estrategias de intervención dirigidas y tempranas, principalmente ambientales, fueron suficientes para controlar el brote. PACIENTES Y MÉTODOS: Se estudiaron todos los pacientes ingresados en la unidad de nefrología con un cultivo positivo para VREF en un periodo de 6 meses (Agosto de 2012 a Enero de 2013). Basados en la identificación de una relación clonal entre las cepas, se implementaron frotis rectales de cribado para todos los pacientes, así como frotis ambientales y limpieza de todo el material médico y de la unidad. Se identificaron las cepas de VREF por MicroScan y se confirmaron con Etest. La identificación bacteriana se confirmó con MALDI-TOF MS. La presencia de genes van, y de genes de virulencia esp y hyl, se investigó por PCR. La relación clonal entre las cepas se estudió con DiversiLab (bioMérieux), y después con PFGE-Smal y MLST. RESULTADOS: Durante el periodo estudiado, se aislaron cepas de VREF de 13 pacientes. Todos fueron casos de colonización sin casos de infección. Se aislaron numerosas cepas del ambiente y del equipo médico. Las cepas presentaban el gen VanA y eran multirresistentes. El análisis molecular mostró que todas las cepas pertenecían a la secuencia tipo17 (ST17), portando genes de virulencia hyl. Tras la implementación de medidas de control de infección de 2 niveles, e incrementando sobretodo la limpieza del ambiente y del equipo médico, no se detectaron nuevos casos en el año posterior. CONCLUSIÓN: Se informa de un brote clonal de VREF-ST17. La pronta implementación de medidas agresivas de control de infección en pacientes y en el ambiente fue efectiva para el control del brote