Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Sinovitis por Mycobacterium heckeshornense en paciente con artritis reumatoide en tratamiento con infliximab / Synovitis due to Mycobacterium heckeshornense in a patient with rheumatoid arthritis and treatment with infliximab

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Buruli ulcers in a Spanish aid worker after a stay in Peru.

Buruli ulcer (BU) is a chronic and destructive infection of the skin and soft tissues caused by Mycobacterium ulcerans. Recently, population flows have triggered the appearance of several sporadic cases of BU in non-endemic countries. This represents a significant diagnostic challenge for clinicians and microbiologists. We describe the first case of BU imported to Spain. The patient was a Spanish woman who had stayed 5 months in the jungle of Peru.

In vitro infection with Mycobacterium tuberculosis induces a distinct immunological pattern in blood from healthy relatives of tuberculosis patients.

Part of the susceptibility to tuberculosis has a genetic basis, which is clear in primary immunodeficiencies, but is less evident in apparently immunocompetent subjects. Immune responses were analysed in blood samples from tuberculosis patients and their healthy first-degree relatives who were infected in vitro with mycobacteria (either Mycobacterium tuberculosis or M. bovis BCG). The antimicrobial activity against M. tuberculosis in blood from relatives was significantly lower than that observed in healthy controls. Tuberculosis patients exhibited a higher number of neutrophils, and monocyte phagocytosis was inhibited in both relatives and tuberculosis patients. A remarkable finding was that the production of reactive oxygen species by infected neutrophils was higher in relatives than in healthy controls. A higher production of TNFα in infected blood from relatives was also observed. These results may indicate that relatives display a stronger inflammatory response and that their immune response to M. tuberculosis is different from those of unrelated controls. First-degree relatives may represent a highly informative group for the analysis of tuberculosis susceptibility.

Immunological response to Mycobacterium tuberculosis infection in blood from type 2 diabetes patients.

The convergence of tuberculosis and diabetes represents a co-epidemic that threatens progress against tuberculosis. We have investigated type 2 diabetes as a risk factor for tuberculosis susceptibility, and have used as experimental model whole blood infected in vitro with Mycobacterium tuberculosis. Blood samples from diabetic patients were found to have a higher absolute neutrophil count that non-diabetic controls, but their immune functionality seemed impaired because they displayed a lower capacity to phagocytose M. tuberculosis, a finding that had been previously reported only for monocytes. In contrast, an increased production of TNFα was detected in infected blood from diabetic patients. Despite the altered phagocytic capacity showed by cells from these patients, the antimicrobial activity measured in both whole blood and monocyte derived macrophages was similar to that of controls. This unexpected result prompts further improvements in the whole blood model to analyze the immune response of diabetes patients to tuberculosis.

Plasma contributes to the antimicrobial activity of whole blood against Mycobacterium tuberculosis.

The whole blood model for infection has proven useful to analyze the immunological response to Mycobacterium tuberculosis, because it exerts a significant antimicrobial activity. Although this activity has been generally assumed to be cellular, we have found that the leukocyte fraction of blood from healthy volunteers did not kill the bacilli. We have discovered that plasma was responsible for a large proportion, but not all, of the antimicrobial activity. Furthermore, infected monocytes controlled the mycobacterial multiplication when cultivated in the presence of plasma. Intriguingly, serum from the same donors did not share this activity, although it was able to eliminate the non-pathogenic Mycobacterium gordonae To identify the remaining components that participate in the antimycobacterial activity we fractionated blood in leukocytes, plasma, erythrocytes and platelets, and analyzed the bactericidal power of each fraction and their combinations using a factorial design. We found that erythrocytes, but not platelets, participated and showed by flow cytometry that mycobacteria physically associated with erythrocytes. We propose that in exposed healthy individuals that show 'early clearance' of the mycobacteria, the innate response is predominantly humoral, probably through the effect of antimicrobial peptides and proteins.

Colección intraabdominal en paciente con infección por virus de la inmunodeficiencia humana / Abdominal collection in a patient with Human Inmunodeficieny Virus infection

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Microarray analysis of Mycobacterium tuberculosis-infected monocytes reveals IL26 as a new candidate gene for tuberculosis susceptibility.

Differences in the activity of monocytes/macrophages, important target cells of Mycobacterium tuberculosis, might influence tuberculosis progression. With the purpose of identifying candidate genes for tuberculosis susceptibility we infected monocytes from both healthy elderly individuals (a tuberculosis susceptibility group) and elderly tuberculosis patients with M. tuberculosis, and performed a microarray experiment. We detected 78 differentially expressed transcripts and confirmed these results by quantitative PCR of selected genes. We found that monocytes from tuberculosis patients showed similar expression patterns for these genes, regardless of whether they were obtained from younger or older patients. Only one of the detected genes corresponded to a cytokine: IL26, a member of the interleukin-10 (IL-10) cytokine family which we found to be down-regulated in infected monocytes from tuberculosis patients. Non-infected monocytes secreted IL-26 constitutively but they reacted strongly to M. tuberculosis infection by decreasing IL-26 production. Furthermore, IL-26 serum concentrations appeared to be lower in the tuberculosis patients. When whole blood was infected, IL-26 inhibited the observed pathogen-killing capability. Although lymphocytes expressed IL26R, the receptor mRNA was not detected in either monocytes or neutrophils, suggesting that the inhibition of anti-mycobacterial activity may be mediated by lymphocytes. Additionally, IL-2 concentrations in infected blood were lower in the presence of IL-26. The negative influence of IL-26 on the anti-mycobacterial activity and its constitutive presence in both serum and monocyte supernatants prompt us to propose IL26 as a candidate gene for tuberculosis susceptibility.

Aproximación a la incidencia real de tuberculosis en el Área de Salud de León: aplicación del método captura-recaptura para comparar 2 fuentes de información / Estimate of the real incidence of tuberculosis in the Leon Health Area: Application of the capture-recapture method to compare two information sources

Introducción: La incidencia real de la tuberculosis podría ser mayor que la recogida en registros tanto nacionales como internacionales. Se estima una infradeclaración que varía entre un 7 y un 27% según los estudios. Objetivo Analizar la tasa de incidencia de tuberculosis en el Área de Salud de León comparando 2 fuentes de información: consumo de tuberculostáticos (asociación isoniacida-rifampicina) y registro del Sistema de Información de Vigilancia Epidemiológica de Castilla y León (SIVE).Método Estudio descriptivo retrospectivo en un área de salud de 351.086 habitantes durante los años 2008 y 2009. Fueron recogidas 2 fuentes de información: consumo de tuberculostáticos y registro SIVE. Se calcularon las tasas de incidencia para cada fuente y posteriormente se aplicó el método captura-recaptura. Se analizaron las características epidemiológicas como datos demográficos, clínicos, diagnósticos, tratamiento y seguimiento. Resultados La incidencia obtenida para 2008 según el SIVE fue de 18,80 × 100.000 habitantes y según el registro de farmacia de 26,77. En 2009, según el SIVE, fue de 18,23 × 100.000 habitantes y según farmacia 22,50. Cuando se aplicó el método captura-recaptura, la incidencia anual para 2008 fue de 44,14 × 100.000 (IC 95%: 37,88-50,41) y para 2009 de 34,17 (IC 95%: 30,19-38,17). En cada uno de los años estudiados el número de casos obtenidos en el registro de farmacia fue mayor que en el SIVE. Conclusiones Los datos del SIVE sobre la incidencia de tuberculosis en el Área de Salud de León infraestiman la tasa de incidencia real. La fuente de información que supone el registro de consumo de tuberculostáticos de la comunidad está infrautilizada. El método de captura-recaptura constituye una buena alternativa para medir incidencias y exhaustividad de los sistemas de vigilancia (AU)

Introduction: The actual incidence of tuberculosis is probably higher than that previously published in national and international records. Under-reporting is estimated to fluctuate between 7% and 27%,according to studies. Objective: To estimate the incidence rate of tuberculosis in the area of León for 2008 and 2009 using the capture-recapture method in order to compare two sources of information: prescribed tuberculostatic drugs (combination of rifampicin-isoniazid) and the regional epidemiological surveillance system register (SIVE).Method: Retrospective descriptive study in an area of 351,086 inhabitants of tuberculosis cases using assources: (i), information on prescribed tuberculostatic drugs, and (ii), the SIVE register. We calculated incidence rates for each source by the capture-recapture method. We analyzed epidemiological and demographic data, symptoms, diagnosis, treatment and follow-up. Results: The incidence based on the SIVE data for 2008 was 18.80/100,000 inhabitants and according to the pharmacy register, the rate was 26.77. The estimated value for 2009 based on the SIVE data was 18.23/100,000 inhabitants, and according to the pharmacy register, it was 22.50. After applying the capture-recapture method, the annual incidence for 2008 was 44.14/100,000 (95% CI; 37.88-50.41) and for 2009, it was 34.17/100,000 (95% CI; 30.19-38.17). In the study of all these years we have found that the number of cases were higher in the pharmacy register than the SIVE one. Conclusions: The SIVE data on the incidence of tuberculosis in our study area underestimates the actual incidence rate. The source of information that involves case record of tuberculosis in the community is under-used. The capture-recapture method is a good alternative to measure the incidence of tuberculosis, and to check the surveillance systems (AU)

[Estimate of the real incidence of tuberculosis in the Leon Health Area: application of the capture-recapture method to compare two information sources]. / Aproximación a la incidencia real de tuberculosis en el Área de Salud de León: aplicación del método captura-recaptura para comparar 2 fuentes de información.

INTRODUCTION: The actual incidence of tuberculosis is probably higher than that previously published in national and international records. Under-reporting is estimated to fluctuate between 7% and 27%, according to studies. OBJECTIVE: To estimate the incidence rate of tuberculosis in the area of León for 2008 and 2009 using the capture-recapture method in order to compare two sources of information: prescribed tuberculostatic drugs (combination of rifampicin-isoniazid) and the regional epidemiological surveillance system register (SIVE). METHOD: Retrospective descriptive study in an area of 351,086 inhabitants of tuberculosis cases using as sources: (i), information on prescribed tuberculostatic drugs, and (ii), the SIVE register. We calculated incidence rates for each source by the capture-recapture method. We analyzed epidemiological and demographic data, symptoms, diagnosis, treatment and follow-up. RESULTS: The incidence based on the SIVE data for 2008 was 18.80/100,000 inhabitants and according to the pharmacy register, the rate was 26.77. The estimated value for 2009 based on the SIVE data was 18.23/100,000 inhabitants, and according to the pharmacy register, it was 22.50. After applying the capture-recapture method, the annual incidence for 2008 was 44.14/100,000 (95% CI; 37.88-50.41) and for 2009, it was 34.17/100,000 (95% CI; 30.19-38.17). In the study of all these years we have found that the number of cases were higher in the pharmacy register than the SIVE one. CONCLUSIONS: The SIVE data on the incidence of tuberculosis in our study area underestimates the actual incidence rate. The source of information that involves case record of tuberculosis in the community is under-used. The capture-recapture method is a good alternative to measure the incidence of tuberculosis, and to check the surveillance systems.

Macrophages from elders are more permissive to intracellular multiplication of Mycobacterium tuberculosis.

The elderly account for a disproportionate share of all tuberculosis cases, and the population ageing may not fully explain this phenomenon. We have performed in vitro infection experiments to investigate whether there is an immunological basis for the apparent susceptibility of elders to tuberculosis. In our infection model, Mycobacterium tuberculosis induces a higher production of interleukin (IL)-6 and reactive oxygen species in macrophages from elders than from younger adults. This response did not prevent, however, an increased multiplication of M. tuberculosis in macrophages from elders as compared with the growth observed within cells from adults. By performing a factorial experiment, we have found that IFN-γ, but not IL-1ß, IL-6 or TNF-α, stimulate the macrophages to restrict the multiplication of the bacterium in macrophages from elders. Although monocytes from elders seem to be in a higher level of activation, we present evidences that protein tyrosine phosphorylation response induced by M. tuberculosis is stronger in monocytes from adults than from elders. Using a protein array that detects 71 tyrosine phosphorylated kinases, we identified Pyk2 as the only kinase that displayed a difference of intensity larger than 50 % in adults than in elders. Furthermore, monocytes from elders that were incubated in the presence of tyrosine kinase inhibitors (genistein and PP2) allowed a higher level of bacterial multiplication. These observations may help to explain the susceptibility of elders to tuberculosis. An unexpected result was that both genistein and its negative control, daidzein, abundant soy isoflavones, promoted intracellular mycobacterial growth.

Non-chemotactic influence of CXCL7 on human phagocytes. Modulation of antimicrobial activity against L. pneumophila.

We have investigated the role of CXCL7 in the immune response of human phagocytes against the intracellular bacteria Mycobacterium tuberculosis and Legionella pneumophila. We have observed that polymorphonuclear neutrophil (PMN) chemotaxis induced by the supernatants of infected monocyte derived macrophages (MDM) may be attributed to CXCL8 rather than CXCL7, although both chemokines are present in large quantities. We have also found that CXCL7 is present not only in the supernatants of MDM, but also in the supernatants of PMN of some, but not all, individuals. Western blot analysis revealed that, in both MDM and PMN supernatants appeared two bands with molecular weights consistent with the platelet basic protein (PBP) and the neutrophil activating protein-2 (NAP-2) sizes. Regarding the influence on infected cells, recombinant NAP-2 enhanced the antimicrobial activity of IFNγ activated MDM against L. pneumophila, but not against M. tuberculosis. In addition, U937 cells transfected with a NAP-2 construct inhibited the intracellular multiplication of L. pneumophila, supporting its role in the modulation of the antimicrobial activity. Finally, U937 cells transfected with the NAP-2 construct showed an adherence that was dramatically enhanced when the substrate was fibronectin. We conclude that human phagocytes produce CXCL7 variants that may have a significant influence on the immune response against bacterial pathogens.