Stool donors for fecal microbiota transference (FMT) should be rigorously screened to identify any disorder in health status. The success of our screening protocol to identify eligible donors in the last year and a half was evaluated and compared with the published literature. The target population was medical students who responded to 3 public calls to donate stools. Qualified donors brought stool samples to our lab. Out of the 110 students who responded to the call, 26 were enrolled as study donors and delivered at least one stool sample. The main reason for volunteer exclusion was body mass index (BMI) <18.5kg/m2 or >25kg/m2 (n=11) and for the identification of ESBL Escherichia coli in feces (n=3). Our success rate after the screening protocol was considered high. Understanding the incentives to participate is critical to the success of recruitment strategies as FMT is still a little-known practice for general population.

Systems vaccinology has seldomly been used in therapeutic HIV-1 vaccine research. Our aim was to identify early gene ‘signatures’ that predicted virus load control after analytical therapy interruption (ATI) in participants of a dendritic cell-based HIV-1 vaccine trial (DCV2). mRNA and miRNA were extracted from frozen post-vaccination PBMC samples; gene expression was determined by microarray method. In gene set enrichment analysis, responders showed an up-regulation of 14 gene sets (TNF-alpha/NFkB pathway, inflammatory response, the complement system, Il6 and Il2 JAK-STAT signaling, among others) and a down-regulation of 7 gene sets (such as E2F targets or interferon alpha response). The expression of genes regulated by three (miR-223-3p, miR-1183 and miR-8063) of the 9 differentially expressed miRNAs was significantly down-regulated in responders. The deregulation of certain gene sets related to inflammatory processes seems fundamental for viral control, and certain miRNAs may be important in fine-tuning these processes.

OBJECTIVE:We analyzed the incidence rate of long-term events in patients on antiretroviral therapy (ART) previously exposed to therapy interruption. DESIGN:A single-center cohort study involving participants in ART interruptions (ARTI) clinical trials (n = 10) was conducted. METHODS:Non-AIDS events after ART resumption were analyzed. A control group not exposed to ARTI was randomly selected from the same cohort and a propensity score of belonging to ARTI group was estimated based on age, sex, CD4+ nadir value, time from HIV diagnosis to ARTI, time from HIV diagnosis to starting ART and time of suppressed viral load, and used to adjust effect estimates. RESULTS:One hundred and eighty-one patients were included, 136 in ARTI and 45 in the control arm. Median time of known HIV-1 infection was 21 years and median time from ART resumption to first non-AIDS event was 5.2 years. A significantly higher proportion of patients with ARTI had an event as compared with control group [raw percentages: 43% (n = 53) vs. 23% (n = 10), P = 0.015]. These differences were confirmed when only the non-AIDS events occurring after ART resumption were analyzed [adjusted hazard ratio (aHR) = 2.43, 95% confidence interval (CI) 1.15-5.12]. The logistic model adjusted for the propensity score indicated that patients with an ARTI had a four-fold higher risk of having at least one non-AIDS event (P = 0.002). CONCLUSION:We found a higher risk of having at least one non-AIDS event years after ART resumption in HIV-infected patients exposed to ARTI as compared with controls. These data should be taken into consideration for future functional cure clinical trials.

A functional Human immunodeficiency Virus (HIV) cure has been proposed as an alternative to antiretroviral treatment for life, and therapeutic vaccines represent one of the most promising approaches. The goal of therapeutic vaccination is to augment virus-specific immune responses that have an impact on HIV viral load dynamics. To date, the agreed feature to evaluate the effects of these therapeutic interventions is analytical antiretroviral treatment interruption (ATI), at least until we find a reliable biomarker that can predict viral control. Different host, immunologic, and virologic markers have been proposed as predictors of viral control during ATI after therapeutic interventions. This review describes the relevance of ATI and the different surrogate markers of virological control assessed in HIV therapeutic vaccine clinical trials.

OBJECTIVES:To construct a classifier that predicts the probability of viral control after analytical treatment interruptions (ATI) in HIV research trials. METHODS:Participants of a dendritic cell-based therapeutic vaccine trial (DCV2) constituted the derivation cohort. One of the primary endpoints of DCV2 was the drop of viral load (VL) set point after 12 weeks of ATI (delta VL12). We classified cases as "controllers" (delta VL12 > 1 log10 copies/mL, n = 12) or "noncontrollers" (delta VL12 < 0.5 log10 copies/mL, n = 10) and compared 190 variables (clinical data, lymphocyte subsets, inflammatory markers, viral reservoir, ELISPOT, and lymphoproliferative responses) between the 2 groups. Naive Bayes classifiers were built from combinations of significant variables. The best model was subsequently validated on an independent cohort. RESULTS:Controllers had significantly higher pre-antiretroviral treatment VL [110,250 (IQR 71,968-275,750) vs. 28,600 (IQR 18737-39365) copies/mL, P = 0.003] and significantly lower proportion of some T-lymphocyte subsets than noncontrollers: prevaccination CD4CD45RA+RO+ (1.72% vs. 7.47%, P = 0.036), CD8CD45RA+RO+ (7.92% vs. 15.69%, P = 0.017), CD4+CCR5+ (4.25% vs. 7.40%, P = 0.011), and CD8+CCR5+ (14.53% vs. 27.30%, P = 0.043), and postvaccination CD4+CXCR4+ (12.44% vs. 22.80%, P = 0.021). The classifier based on pre-antiretroviral treatment VL and prevaccine CD8CD45RA+RO+ T cells was the best predictive model (overall accuracy: 91%). In an independent validation cohort of 107 ATI episodes, the model correctly identified nonresponders (negative predictive value = 94%), while it failed to identify responders (positive predictive value = 20%). CONCLUSIONS:Our simple classifier could correctly classify those patients with low probability of control of VL after ATI. These data could be helpful for HIV research trial design.

Clostridioides difficile infection (CDI) is the leading cause of nosocomial infectious diarrhea. Fecal microbiota transplantation (FMT) is a successful treatment for recurrent CDI (rCDI), and in some patients FMT has been associated with the resolution of recurrent urinary tract infections (rUTI). Recent evidence suggests that the origin of most bacterial infections in the urinary tract is the gut. Thus, the possibility of using FMT to displace pathogens commonly involved in rUTIs has major therapeutic implications. We report the case of a 93-year-old female patient with a rCDI and rUTI that underwent FMT and reported a complete clinical resolution of CDI; unexpectedly, no new symptomatic UTI episodes were diagnosed post-FMT. We characterized the gut microbiota of the stool donor and of the patient before and after the procedure. Our patient presented a dysbiosis with clear predominance of Enterobacteriaceae (74%) before FMT, which was significantly reduced to 0.07% after FMT. These findings were maintained for almost a year. We also observed an increase in microbial diversity indices compared with the pre-FMT sample reaching diversity values comparable to the donor stool samples. We reasoned that the disappearance of UTIs in our patient resulted from the reduction of Enterobacteriaceae in the gut microbiota. Our findings support previous evidence suggesting the potential of FMT for rUTI, particularly in cases due to multi-drug resistant pathogens where conventional antibiotic treatment is not an option.

Objectives: To assess risk factors for multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infection in neutropenic patients. Methods: Single-centre retrospective analysis of consecutive bloodstream infection (BSI) episodes (2004-2017, Barcelona). Two multivariate regression models were used at BSI diagnosis and P. aeruginosa detection. Significant predictors were used to establish rules for stratifying patients according to MDR-PA BSI risk. Results: Of 661 Gram-negative BSI episodes, 190 (28.7%) were caused by P. aeruginosa (70 MDR-PA). Independent factors associated with MDR-PA among Gram-negative organisms were haematological malignancy (OR 3.30; 95% CI 1.15-9.50), pulmonary source of infection (OR 7.85; 95% CI 3.32-18.56), nosocomial-acquired BSI (OR 3.52; 95% CI 1.74-7.09), previous antipseudomonal cephalosporin (OR 13.66; 95% CI 6.64-28.10) and piperacillin/tazobactam (OR 2.42; 95% CI 1.04-5.63), and BSI occurring during ceftriaxone (OR 4.27; 95% CI 1.15-15.83). Once P. aeruginosa was identified as the BSI aetiological pathogen, nosocomial acquisition (OR 7.13; 95% CI 2.87-17.67), haematological malignancy (OR 3.44; 95% CI 1.07-10.98), previous antipseudomonal cephalosporin (OR 3.82; 95% CI 1.42-10.22) and quinolones (OR 3.97; 95% CI 1.37-11.48), corticosteroids (OR 2.92; 95% CI 1.15-7.40), and BSI occurring during quinolone (OR 4.88; 95% CI 1.58-15.05) and beta-lactam other than ertapenem (OR 4.51; 95% CI 1.45-14.04) were independently associated with MDR-PA. Per regression coefficients, 1 point was assigned to each parameter, except for nosocomial-acquired BSI (3 points). In the second analysis, a score >3 points identified 60 (86.3%) out of 70 individuals with MDR-PA BSI and discarded 100 (84.2%) out of 120 with non-MDR-PA BSI. Conclusions: A simple score based on demographic and clinical factors allows stratification of individuals with bacteraemia according to their risk of MDR-PA BSI, and may help facilitate the use of rapid MDR-detection tools and improve early antibiotic appropriateness. (C) 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

The appearance and dissemination of antibiotic-resistant bacteria, particularly in specific closed environments such as intensive care units of acute care hospitals, have become a major health concern. The intestinal microbiota has various functions including host protection from overgrowth or colonization by unwanted bacteria. The exposure to antibiotics significantly reduces the bacterial density of intestinal microbiota leaving an ecologic void that can be occupied by potentially pathogenic and/or resistant bacteria frequently present in hospital settings. Consequently, the intestinal microbiota of inpatients acts as a major reservoir and plays a critical role in perpetuating the spread of resistant bacteria. There are novel innovative methods to protect the host microbiota during antibiotic treatment, but they do not offer a solution for already established colonization by resistant microorganisms. Fecal microbiota transfer (FMT) is a promising intervention to achieve this goal; however, controlled trials report lower success rates than initial retrospective studies, especially in case of gram negatives. The aim of the present article is to highlight the importance of the intestinal microbiota in the global spread of multi-drug-resistant (MDR) microorganisms and to review the recent advances to protect the human microbiota from the action of antibiotics as well as a critical discussion about the evidence of decolonization of MDR microorganisms by FMT.

Introduction. Clostridium difficile infections have a high recurrence rate, which can complicate the prognosis of affected patients. It is therefore important to establish an early detection and an appropriate therapeutic strategy. The objective of this manuscript was to gather the opinion of an expert group about the predictive factors of poor progression, as well as when to use fidaxomicin in different groups of high-risk patients. Methods. A scientific committee of three experts in infectious diseases reviewed the most recent literature on the management of C. difficile infections, and the use of fidaxomicin. They developed a questionnaire of 23 items for consensus by 15 specialists in this type of infection using a modified Delphi method. Results. The consensus reached by the panelists was 91.3% in terms of agreement. The most important agreements were: recurrence is a risk criterion per se; fidaxomicin is effective and safe for the treatment of infections caused by C. difficile in critical patients, immunosuppressed patients, or patients with chronic renal failure; fidaxomicin is recommended from the first episode of infection to ensure maximum efficacy in patients with well-contrasted recurrence risk factors. Conclusions. The experts consulted showed a high degree of agreement on topics related to the selection of patients with poorer prognosis, as well as on the use of fidaxomicin in groups of high-risk patients, either in the first line or in situations of recurrence.

BACKGROUND:Analytical treatment interruptions (ATIs) are essential in research on HIV cure. However, the heterogeneity of virological outcome measures used in different trials hinders the interpretation of the efficacy of different strategies. METHODS:We conducted a retrospective analysis of viral load (VL) evolution in 334 ATI episodes in chronic HIV-1-infected patients collected from 11 prospective studies. Quantitative (baseline VL, set point, delta set point, VL, and delta VL at given weeks after ATI, peak VL, delta peak VL, and area under the rebound curve) and temporal parameters (time to rebound [TtR], set point, peak, and certain absolute and relative VL thresholds) were described. Pairwise correlations between parameters were analyzed, and potential confounding factors (sex, age, time of known HIV infection, time on ART, and immunological interventions) were evaluated. RESULTS:The set point was lower than baseline VL (median delta set point, -0.26; P < .001). This difference was >1 log10 copies/mL in 13.9% of the cases. The median TtR was 2 weeks; no patients had an undetectable VL at week 12. The median time to set point was 8 weeks: by week 12, 97.4% of the patients had reached the set point. TtR and baseline VL were correlated with most temporal and quantitative parameters. The variables independently associated with TtR were baseline VL and the use of immunological interventions. CONCLUSIONS:TtR could be an optimal surrogate marker of response in HIV cure strategies. Our results underline the importance of taking into account baseline VL and other confounding factors in the design and interpretation of these studies.

Objectives: The steady progress in resistance of Pseudomonas aeruginosa (PA) has led to difficulties in treating infections due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Ceftazidime/avibactam (CAZ/AVI) has in vitro activity against many of these strains, however clinical experience with CAZ/AVI is limited. This study aimed to evaluate the characteristics and outcomes of eight patients with infections due to MDR- or XDR-PA treated with CAZ/AVI, including four strains resistant to ceftolozane/tazobactam. Methods: This was a retrospective descriptive study of patients admitted to a teaching hospital between January 2016 and May 2017 who received CAZ/AVI as initial or continuation therapy for infection due to MDR- and XDR-PA. Results: The sources of infection were hospital-acquired lower respiratory tract infection in five patients ( 62.5%) and osteomyelitis, meningitis and catheter-related bacteraemia in one patient each. Clinical cure was achieved in 4 patients (50.0%). The 30-dayand 90-day mortality rates were 12.5%and 37.5%, respectively. One patient (12.5%) developed encephalopathy that improved with discontinuation of the drug. Conclusions: CAZ/AVI may be a valuable option for serious infections due to resistant PA. (C) 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Objectives: We aimed to describe the current time-to-positivity (TTP) of blood cultures in individuals with onco-haematological diseases with febrile neutropenia. We assessed the probability of having a multidrug-resistant Gram-negative bacilli (MDR-GNB) bloodstream infection (BSI) 24 h after cultures were taken, to use this information for antibiotic de-escalation strategies. Methods: BSI episodes were prospectively collected (2003-2017). When a patient experienced more than one BSI, only one episode was randomly chosen. Time elapsed from the beginning of incubation to a positive reading was observed; TTP was recorded when the first bottle had a positive result. Results: Of the 850 patient-unique episodes, 323 (38%) occurred in acute leukaemia, 185 (21.8%) in nonHodgkin's lymphoma and 144 (16.9%) in solid neoplasms. Coagulase-negative staphylococci (225; 26.5%), Escherichia coli (207; 26.1%), Pseudomonas aeruginosa (136; 16%), Enterococcus spp. (81; 9.5%) and Klebsiella pneumoniae (67; 7.9%), were the most frequent microorganisms isolated. MDR-GNB were documented in 126 (14.8%) episodes. Median TTP was 12 h (interquartile range 9-16.5 h). Within the first 24 h, 92.1% of blood cultures were positive (783/850). No MDR-GNB was positive over 24 h. Of the 67 (7.9%) episodes with a TTP >= 24 h, 25 (37.3%) occurred in patients who were already receiving active antibiotics against the isolated pathogen. Most common isolations with TTP >= 24 h were coagulase-negative staphylococci, candidaemia and a group of anaerobic GNB. Conclusions: Currently, the vast majority of BSI in individuals with onco-haematological diseases with febrile neutropenia have a TTP <24 h, including all episodes caused by MDR-GNB. Our results support reassessing empiric antibiotic treatment in neutropenic patients at 24 h, to apply antibiotic stewardship de-escalation strategies. (C) 2018 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

We present a method to fit a mixed effects Cox model with interval-censored data. Our proposal is based on a multiple imputation approach that uses the truncated Weibull distribution to replace the interval-censored data by imputed survival times and then uses established mixed effects Cox methods for right-censored data. Interval-censored data were encountered in a database corresponding to a recompilation of retrospective data from eight analytical treatment interruption (ATI) studies in 158 human immunodeficiency virus (HIV) positive combination antiretroviral treatment (cART) suppressed individuals. The main variable of interest is the time to viral rebound, which is defined as the increase of serum viral load (VL) to detectable levels in a patient with previously undetectable VL, as a consequence of the interruption of cART. Another aspect of interest of the analysis is to consider the fact that the data come from different studies based on different grounds and that we have several assessments on the same patient. In order to handle this extra variability, we frame the problem into a mixed effects Cox model that considers a random intercept per subject as well as correlated random intercept and slope for pre-cART VL per study. Our procedure has been implemented in R using two packages: truncdist and coxme, and can be applied to any data set that presents both interval-censored survival times and a grouped data structure that could be treated as a random effect in a regression model. The properties of the parameter estimators obtained with our proposed method are addressed through a simulation study.

BACKGROUND:Ceftazidime-avibactam has in vitro activity against Gram-negative bacilli that produce Class A, C and some D β-lactamases, and has been successfully used in the treatment of infections caused by cephalosporin and carbapenem-resistant Enterobacteriaceae. However, actual experience in the treatment of OXA-48 carbapenemase-producing Enterobacteriaceae (CPE) is limited.OBJECTIVE:To review the characteristics and prognosis of OXA-48 CPE infections treated with ceftazidime-avibactam since introduction of the drug to the current centre during the period October 2014 to December 2016.METHODS:Retrospective assessment of episodes of infection caused by OXA-48 CPE treated with ceftazidime-avibactam, analysing data collected from infection diagnosis until 90 days after the end of treatment.RESULTS:Twenty-four episodes were analysed. Ceftazidime-avibactam was given as the initial definitive treatment in 15 (62.5%) and as salvage therapy in nine (37.5%). Intraabdominal (seven, 29%), urinary (six, 25%) and respiratory (five, 21%) were the most common sources. The 30-day and 90-day mortality rates were 8.3% and 20.8%, respectively. Clinical cure at 30 days was achieved in 62.5% of episodes. Four (16.7%) patients had adverse events, two of them were related to impaired renal function. Among patients who finished the treatment with ceftazidime-avibactam, seven (35%) were diagnosed with infection recurrence within 90 days of the end of treatment.CONCLUSIONS:From experience, ceftazidime-avibactam is an effective drug for treating infections due to OXA-48 CPE. From these results a better safety profile than the current best available therapy could be expected.

OBJECTIVES:To evaluate the influence on mortality of empirical double-active combination antimicrobial therapy (DACT) compared with active monotherapy (AM) in septic shock patients.METHODS:A retrospective study was performed of monomicrobial septic shock patients admitted to a university centre during 2010-15. A propensity score (PS) was calculated using a logistic regression model taking the assigned therapy as the dependent variable, and used as a covariate in multivariate analysis predicting 7, 15 and 30 day mortality and for matching patients who received DACT or AM. Multivariate models comprising the assigned therapy group and the PS were built for specific patient subgroups.RESULTS:Five-hundred and seventy-six patients with monomicrobial septic shock who received active empirical antimicrobial therapy were included. Of these, 340 received AM and 236 DACT. No difference in 7, 15 and 30 day all-cause mortality was found between groups either in the PS-adjusted multivariate logistic regression analysis or in the PS-matched cohorts. However, in patients with neutropenia, DACT was independently associated with a better outcome at 15 (OR 0.29, 95% CI 0.09-0.92) and 30 (OR 0.25, 95% CI 0.08-0.79) days, while in patients with Pseudomonas aeruginosa infection DACT was associated with lower 7 (OR 0.12, 95% CI 0.02-0.7) and 30 day (OR 0.26, 95% CI 0.08-0.92) mortality.CONCLUSIONS:All-cause mortality at 7, 15 and 30 days was similar in patients with monomicrobial septic shock receiving empirical double-active combination therapy and active monotherapy. However, a beneficial influence of empirical double-active combination on mortality in patients with neutropenia and those with P. aeruginosa infection is worthy of further study.

In spite of increased awareness and the efforts taken to optimize Clostridium difficile infection (CDI) management, with the limited number of currently available antibiotics for C. difficile the halt of this increasing epidemic remains out of reach. There are, however, close to 80 alternative treatment methods with controversial anti-clostridial efficacy or in experimental phase today. Indeed, some of these therapies are expected to become acknowledged members of the recommended anti-CDI arsenal within the next few years. None of these alternative treatment methods can respond in itself to all the major challenges of CDI management, which are primary prophylaxis in the susceptible population, clinical cure of severe cases, prevention of recurrences, and forestallment of asymptomatic C. difficile carriage and in-hospital spread. Yet, the greater the variety of treatment choices on hand, the better combination strategies can be developed to reach these goals in the future. The aim of this article is to provide a comprehensive summary of these experimental and currently off-label therapeutic options.

The objective of this study was to evaluate the efficacy and safety of fidaxomicin in the real-life clinical setting. This was a retrospective cohort of patients with Clostridium difficile infection (CDI) treated with fidaxomicin in 20 Spanish hospitals between July 2013 and July 2014. Clinical cure, 30-day recurrence, 30-day mortality, sustained cure, and factors associated with the failure to achieve sustained cure were analyzed. Of the 72 patients in the cohort 41 (56.9 %) had a fatal underlying disease. There were 44 (61.1 %) recurrent episodes and 26 cases (36.1 %) with a history of multiple recurrences. Most episodes were severe (26, 36 %) or severe-complicated (14, 19.4 %). Clinical cure rate was 90.3 %, recurrence rate was 16.7 % and three patients (4.2 %) died during the follow-up period. Sustained cure was achieved in 52 cases (72.2 %). Adverse events were reported in five cases (6.9 %). Factors associated with the lack of sustained cure were cardiovascular comorbidity (OR 11.4; 95 %CI 1.9–67.8), acute kidney failure (OR 7.4; 95 %CI 1.3–43.1), concomitant systemic antibiotic treatment (OR 6.2; 95 %CI 1.1–36.8), and C-reactive protein value at diagnosis (OR 1.2 for each 1 mg/dl increase; 95 %CI 1.03–1.3). Fidaxomicin is an effective and well tolerable treatment for severe CDI and for cases with elevated recurrence risk.

Clostridium difficile infection (CDI) is increasingly recognized as an emerging healthcare problem of elevated importance. Prevention and treatment strategies are constantly evolving along with the apperance of new scientific evidence and novel treatment methods, which is well-reflected in the differences among consecutive international guidelines. In this article, we summarize and compare current guidelines of five international medical societies on CDI management, and discuss some of the controversial and currently unresolved aspects which should be addressed by future research.

OBJECTIVE:We aimed to study the relationship between hyperprolactinemia (HPRL) and sexual dysfunction (SED) in a sample of patients being prescribed a dose-stable antipsychotic medication, and to evaluate sex differences in the prevalence of HPRL and SED and their relationship.METHOD:A cross-sectional study was carried out including patients between 18 and 55 years of age with a psychotic spectrum diagnosis who were attending community mental health services or hospitalized in medium and long stay units. Positive and Negative Syndrome scale, Calgary depression scale for schizophrenia, Personal and Social Performance scale, and Changes in Sexual Functioning questionnaire-short form were administered. Not later than 3 months, a determination of prolactin, follicle-stimulating hormone, luteinizing hormone, estrogen (only in women) and testosterone was performed.RESULTS:A final sample of 101 patients (30 women and 71 men) was recruited. Seventy-two patients (71.3%) showed HPRL. Sexual dysfunction was significantly higher in HPRL patients than in non-HPRL patients (79.17% vs 51.72%) (P = 0.006), and mean prolactin values were significantly higher in case of SED (P = 0.020). No sex differences were found in prevalence of HPRL or SED. Low Personal and Social Performance scale scores and HPRL were factors independently associated with SED, whereas alcohol use was an independent protector factor.CONCLUSIONS:In our study, SED was significantly related to HPRL without showing sex differences. Prevalence of HPRL and SED observed was higher than that in previous studies, which should be taken into consideration because these have been associated with higher morbimortality, and noncompliance and relapse, respectively.