Predictors of mortality and clinical characteristics among carbapenem-resistant or carbapenemase-producing Enterobacteriaceae bloodstream infections in Spanish children.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging problem in the paediatric population worldwide with high mortality rates in bloodstream infection (BSI). OBJECTIVES: To evaluate predictors of 30 day mortality in CRE BSI in a paediatric cohort. METHODS: A retrospective observational single-centre study (December 2005-August 2018) was conducted. Cases of CRE BSI in children 0 to 16 years were included. Microbiological identification (MALDI Biotyper) and antimicrobial susceptibility testing (Vitek2® and MicroScan panel NBC44) according to EUCAST breakpoints were performed. PCR OXVIKP® was used to confirm carbapenemase genes (OXA-48, VIM, KPC, NDM). Demographic characteristics, underlying diseases, source of bacteraemia, antimicrobial therapy and outcomes were collected from medical records. Survival analysis to establish predictors of 30 day mortality was performed. RESULTS: Thirty-eight cases were included; 76.3% were hospital-acquired infections and 23.7% related to healthcare. All patients had at least one underlying comorbidity and 52.6% were recipients of an organ transplant. VIM carbapenemase was the predominant mechanism (92.1%). Previous CRE colonization or infection rate was 52.6%. Intestinal tract (26.3%) and vascular catheter (21.1%) were the most common sources of infection. Crude mortality within 30 days was 18.4% (7/38); directly related 30 day mortality was 10.5%. Conditions associated with an increment in 30 day mortality were intensive care admission and inadequate empirical therapy (P < 0.05). Combination-antibiotic targeted treatment and a low meropenem MIC were not related to improved survival. CONCLUSIONS: CRE BSI mortality rate is high. The most important factor related to 30 day survival in our CRE BSI cohort in children was empirical treatment that included at least one active antibiotic.

Prevalence and distribution of hepatitis C virus genotypes in Spain during the 2000-2015 period (the GEHEP 005 study).

We report the largest study on the prevalence and distribution of HCV genotypes in Spain (2000-2015), and we relate them with clinical, epidemiological and virological factors. Patients from 29 hospitals in 10 autonomous communities (Andalusia, Aragon, Castilla-Leon, Catalonia, Galicia, Canary Islands, Madrid Community, Valencian Community, Murcia Region and Basque Country) have been studied. Annual distribution of HCV genotypes and subtypes, as well as gender, age, transmission route, HIV and/or HBV coinfection, and treatment details were recorded. We included 48595 chronically HCV-infected patients with the following characteristics: median age 51 years (IQR, 44-58), 67.9% male, 19.1% HIV-coinfected, 23.5% HBV-coinfected. Parenteral transmission route was the most frequent (58.7%). Genotype distribution was 66.9% GT1 (24.9% subtype 1a and 37.9% subtype 1b), 2.8% GT2, 17.3% GT3, 11.4% GT4 and 0.1% GT5 and 0.02% GT6. LiPA was the most widely HCV genotyping test used (52.4%). HCV subtype 1a and genotypes 3 and 4 were closely associated with male gender, parenteral route of infection and HIV and HBV coinfection; in contrast, subtype 1b and genotype 2 were associated with female gender, nonparenteral route and mono-infection. Age was related to genotype distribution, and different patterns of distribution and biodiversity index were observed between different geographical areas. Finally, we describe how treatment and changes in transmission routes may have affected HCV genotype prevalence and distribution patterns. We present the most recent data on molecular epidemiology of hepatitis C virus in Spain. This study confirms that genotype distributions vary with age, sex, HIV and HBV coinfection and within geographical areas and epidemiological groups.

Increasing isolation of rapidly growing mycobacteria in a low-incidence setting of environmental mycobacteria, 1994-2015.

To determine trends in incidence and clinical relevance of rapidly growing mycobacteria (RGM) in a low-prevalence region of non-tuberculous mycobacteria. We retrospectively identified all patients with RGM-positive cultures between January 1994 and December 2015. Trends in incidence, clinical significance, and outcomes were assessed. One hundred and forty patients had RGM-positive cultures (116 respiratory and 24 extra-respiratory sources). The incidence of RGM isolates increased steadily from 2003 (0.34 per 100,000) to 2015 (1.73 per 100,000), with an average annual increase of 8.3%. Thirty-two patients (22.9%) had clinical disease, which trended to cluster in the second half of the study period. A positive acid-fast bacilli smear (odds ratio [OR] 97.7, 95 % CI 13.8-689.4), the presence of extra-respiratory isolates (OR 19.4, 95 % CI 5.2-72.7), and female gender (OR 5.9, 95 % CI 1.9-19.1) were independently associated with clinical disease. Cure rates were 73.3 and 87.5% for pulmonary and extra-pulmonary disease respectively. Although the burden of disease remains low, the presence of RGM isolates is increasing in our geographical setting. Whether this rise will be sustained over time and will coincide with an increase in clinical disease, or whether it is merely a cycle in the poorly understood epidemiological behaviour of environmental mycobacteria, will be seen in the near future.

Delignification and enhanced gas release from soil containing lignocellulose by treatment with bacterial lignin degraders.

AIMS: The aim of the study was to isolate bacterial lignin-degrading bacteria from municipal solid waste (MSW) soil, and to investigate whether they could be used to delignify lignocellulose-containing soil, and enhance methane release. METHODS AND RESULTS: A set of 20 bacterial lignin degraders, including 11 new isolates from MSW soil, were tested for delignification and phenol release in soil containing 1% pine lignocellulose. A group of seven strains were then tested for enhancement of gas release from soil containing 1% lignocellulose in small-scale column tests. Using an aerobic pretreatment, aerobic strains such as Pseudomonas putida showed enhanced gas release from the treated sample, but four bacterial isolates showed 5-10-fold enhancement in gas release in an in situ experiment under microanaerobic conditions: Agrobacterium sp., Lysinibacillus sphaericus, Comamonas testosteroni and Enterobacter sp. CONCLUSIONS: The results show that facultative anaerobic bacterial lignin degraders found in landfill soil can be used for in situ delignification and enhanced gas release in soil containing lignocellulose. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrates the feasibility of using an in situ bacterial treatment to enhance gas release and resource recovery from landfill soil containing lignocellulosic waste.

Chemoselective and stereoselective lithium carbenoid mediated cyclopropanation of acyclic allylic alcohols.

The reaction of geraniol with different lithium carbenoids generated from n-BuLi and the corresponding dihaloalkane has been evaluated. The reaction occurs in a chemo and stereoselective manner, which is consistent with a directing effect from the oxygen of the allylic moiety. Furthermore, a set of polyenes containing allylic hydroxyl or ether groups were chemoselectively and stereoselectively converted into the corresponding gem-dimethylcyclopropanes in one single step in moderate to good yields mediated by a lithium carbenoid generated in situ by the reaction of n-BuLi and 2,2-dibromopropane.

Titanium carbenoid-mediated cyclopropanation of allylic alcohols: selectivity and mechanism.

A new method for the chemo- and stereoselective conversion of allylic alcohols into the corresponding cyclopropane derivatives has been developed. The cyclopropanation reaction was carried out with an unprecedented titanium carbenoid generated in situ from Nugent's reagent, manganese and methylene diiodide. The reaction involving the participation of an allylic hydroxyl group, proceeded with conservation of the alkene geometry and in a high diastereomeric excess. The scope, limitations and mechanism of this metal-catalysed reaction are discussed.

The synthesis of 3-hydroxy-2,4,8-trimethyldec-8-enolides and an approach to 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide.

The synthesis of several derivatives of 3-hydroxy-2,4,8-trimethyldec-8-enolide and attempts at the synthesis of 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (1), a structure which has been assigned to a metabolite of the phytopathogenic fungus, Botrytis cinerea, gave products whose spectroscopic data had significant differences from those reported for the natural product 1. The rare 11-membered lactone rings were constructed by ring-closing metathesis reactions. The increase in conformational restrictions imposed by the substituents has a high influence on the stereochemistry of the ring-closing metathesis reaction and gives rise to a decrease in the yield for the synthesis of 11-membered lactones. The predominant alkene which was obtained was the (Z)-isomer. The observed spectroscopic differences between the synthesized lactones and the natural product and the spectroscopic data of its acetylated derivative 26a allowed us to revise the structure 1 to that of the γ-butyrolactone 26.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus.

AIMS: Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. METHODS: Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. RESULTS: In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. CONCLUSIONS: Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.

Exploring mutasynthesis to increase structural diversity in the synthesis of highly oxygenated polyketide lactones.

The enantioselective synthesis of (2R,3R,4E,8E)-3-hydroxy-2,4,8-trimethyldeca-4,8-dienolide (5) by ring-closing metathesis is described. This compound is an analogue of 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (4) which is a rare 11-membered lactone produced by the fungus, Botrytis cinerea. Mutasynthetic studies with compound 5 using two mutants of B. cinerea led to the isolation of four new highly oxygenated 11-membered lactones (11-14) in which compound 5 has been stereoselectively epoxidized and hydroxylated at sites that were not easily accessible by classical synthetic chemistry.

Molecular characterization of enteroviruses associated with neurological infections in Spain, 2008.

In order to investigate the etiology of viral neurological infections in Spain, a national study was performed in 2008. The results obtained have been published. Enteroviruses were the most frequent cause of the aseptic meningitis and infant febrile syndromes. The present report supplements the previous study with the genotyping of the detected enteroviruses. Typing was by amplification of partial VP1 region and sequencing in 70 (53%) of the 132 available cerebrospinal fluid samples positive for enteroviruses. Twelve different genotypes within the B species were identified. Echovirus 4 was predominant (24%), followed by echovirus 30 (19%), echovirus 9 (17%), and echovirus 6 (14%). In summary, a co-circulation of several enterovirus types associated with meningitis in children under 15 years old was observed. Although infrequently detected, echovirus 4 was the predominant genotype identified due to an aseptic meningitis outbreak which occurred in the Canary Islands in 2008.

Viral infections of the central nervous system in Spain: a prospective study.

The aim of the study was to determine the incidence of viruses causing aseptic meningitis, meningoencephalitis, and encephalitis in Spain. This was a prospective study, in collaboration with 17 Spanish hospitals, including 581 cases (CSF from all and sera from 280): meningitis (340), meningoencephalitis (91), encephalitis (76), febrile syndrome (7), other neurological disorders (32), and 35 cases without clinical information. CSF were assayed by PCR for enterovirus (EV), herpesvirus (herpes simplex [HSV], varicella-zoster [VZV], cytomegalovirus [CMV], Epstein-Barr [EBV], and human herpes virus-6 [HHV-6]), mumps (MV), Toscana virus (TOSV), adenovirus (HAdV), lymphocytic choriomeningitis virus (LCMV), West Nile virus (WNV), and rabies. Serology was undertaken when methodology was available. Amongst meningitis cases, 57.1% were characterized; EV was the most frequent (76.8%), followed by VZV (10.3%) and HSV (3.1%; HSV-1: 1.6%; HSV-2: 1.0%, HSV non-typed: 0.5%). Cases due to CMV, EBV, HHV-6, MV, TOSV, HAdV, and LCMV were also detected. For meningoencephalitis, 40.7% of cases were diagnosed, HSV-1 (43.2%) and VZV (27.0%) being the most frequent agents, while cases associated with HSV-2, EV, CMV, MV, and LCMV were also detected. For encephalitis, 27.6% of cases were caused by HSV-1 (71.4%), VZV (19.1%), or EV (9.5%). Other positive neurological syndromes included cerebellitis (EV and HAdV), seizures (HSV), demyelinating disease (HSV-1 and HHV-6), myelopathy (VZV), and polyradiculoneuritis (HSV). No rabies or WNV cases were identified. EVs are the most frequent cause of meningitis, as is HSV for meningoencephalitis and encephalitis. A significant number of cases (42.9% meningitis, 59.3% meningoencephalitis, 72.4% encephalitis) still have no etiological diagnosis.

[Congenital cytomegalovirus infection, is more prevalent in our country in newborns exposed to HIV?] / La infección congénita por citomegalovirus, ¿es más prevalente en nuestro medio en neonatos expuestos al VIH?

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) has been considered more prevalent among HIV-exposed children during pregnancy. Spanish national guidelines recommend the cCMV screening in these newborns. Nowadays, pregnant women have a better control of HIV infection compared to previous decades. We aim to analyze the prevalence and associated risk factors to cCMV in these children. METHODS: A retrospective cross-sectorial study was performed. All newborns exposed to HIV were assisted in a third-level hospital (2014-2020). Epidemiological and clinical data of the mother and newborn were recorded. Shell vial urine culture and/or CRP were performed along the two first weeks of life for the neonatal screening of cCMV. RESULTS: Overall 69 newborns were enrolled. A high proportion (82.4%) of the mothers had been diagnosed with HIV before getting pregnant. All women received ART during the pregnancy. Median T-CD4 lymphocytes before delivery was 641/mm3 (IQR: 480-865) and the viral load was undetectable in 83.6%. Serological test for CMV along the first trimester of pregnancy was performed in 73.5% (positive IgG in 96%). There were no congenital cases of HIV neither cCMV (CI 95%:0-5.3%). CONCLUSIONS: The cCMV prevalence in newborns exposed to HIV was 0%, lower than reported before, probably related to a better and earlier ART during pregnancy, leading to a better immunological status.

Intestinal giardiasis in children: Five years' experience in a reference unit.

BACKGROUND: Giardiasis is highly prevalent in children and is often mildly symptomatic. First-line treatment is metronidazole, but treatment failure is not uncommon. We describe a paediatric series, to identify risk factors for treatment failure and to analyse the safety and effectiveness of other treatment strategies. METHODS: Retrospective observational study, including children diagnosed with giardiasis from 2014 to 2019. Diagnosis was based on direct visualisation by microscopy after concentration using an alcohol-based fixative, antigen detection and/or DNA detection by polymerase chain reaction in stool. Treatment failure was considered when GI was detected 4 weeks after treatment. RESULTS: A total of 120 patients were included, 71.6% internationally adopted, median age 4.2 (2.3-7.3) years. Only 50% presented with symptoms, mainly diarrhoea (35%) and abdominal pain (14.1%); co-parasitism was frequent (45%). First-line treatment failure after a standard dose of metronidazole was 20%, lowering to 8.3% when a higher dose was administered (p < 0.001). Quinacrine was administered in 10 patients, with 100% effectiveness. Children <2 years were at higher risk of treatment failure (OR 3.49; 95% CI 1.06-11.53; p = 0.040). CONCLUSIONS: In children with giardiasis, treatment failure is frequent, especially before 2 years of age. Quinacrine can be considered as a second-line treatment. After treatment, eradication should be confirmed.

Effect of parathyroidectomy for primary hyperparathyroidism on bone mineral density in postmenopausal women.

BACKGROUND: The bone mineral density (BMD) response to parathyroidectomy is heterogeneous and difficult to predict. Available data come from mixed populations of men and women, of different age and degrees of disease severity, and preoperative BMD loss. METHODS: This was a longitudinal, prospective cohort study of 103 postmenopausal women with osteopenia or osteoporosis at the femoral neck site, successfully operated on for primary hyper parathyroidism. BMD and metabolic variables were recorded before and 1 year after parathyroidectomy. RESULTS: After surgery, there was a 1.3 per cent increase in the median BMD at the femoral neck site (0.615 versus 0.623 g/cm(2); P = 0.001). Overall, positive responses were also observed at total hip (0.4 per cent) and lumbar spine (2.3 per cent) sites. Analysing the individual responses, however, only 45 (46 per cent) of 97 patients showed a significant (at least 3.7 per cent) increase in BMD at the femoral neck site compared with the preoperative value and 52 had a decreased (15) or unchanged (37) femoral neck BMD. Patients who gained BMD were younger, had more severe hyperparathyroidism and better renal function. CONCLUSION: Almost half of the postmenopausal women with hyperparathyroidism and low BMD have a significant remineralization response 1 year after parathyroidectomy. Differential mineralization responses of BMD after surgery appear to be related to severity of primary hyperparathyroidism, age and renal function.

Tuberculosis in a Spanish cohort of children living with HIV: the CHOTIS study (Childhood HIV & TB study).

BACKGROUND: Tuberculosis (TB) is the leading opportunistic infection in children with human immunodeficiency virus (HIV), but is uncommon in low prevalence regions. We aim to describe the changing epidemiology and clinical presentation of TB-HIV co-infection in a cohort of HIV-infected children in Spain.METHODS: Children diagnosed with TB between 1995 and 2016 in the paediatric HIV cohort were identified. The incidence and clinical presentation were compared in three periods: 1995-1999 (P1, before initiation of combined antiretroviral therapy, cART), 2000-2009 (P2, increase in immigration), and 2010-2016 (P3, decrease in immigration).RESULTS: We included 29 TB cases among 1183 children aged <18 years (2.4%, 243/100 000 person-years). The proportion was stable in P1 and P2 (1.3%), but decreased in P3 (0.8%). The median age at TB diagnosis was 6.4 years (IQR 4-10.6); most children in P3 were aged >10 years (20% vs. 23.1% vs. 83.3%, P = 0.01). TB was diagnosed at HIV presentation in 11/29 children (37.9%). Foreign-born children accounted for respectively 0%, 8% and 67% of the total number of children in each period (P ≤ 0.0001). One third had extrapulmonary TB; four children died (13.8%).CONCLUSION: In our cohort, the incidence of TB-HIV co-infection decreased with decline in immigration. In regions with adequate cART coverage and low TB transmission, paediatric TB-HIV coinfection is uncommon, but associated with significant morbidity. Strategies for TB surveillance, diagnosis and treatment in this vulnerable population should be reinforced.

[Recommendations of the Spanish Society for Pediatric Infectious Diseases (SEIP) on the management of drug-resistant tuberculosis]. / Documento de consenso de la Sociedad Española de Infectología Pediátrica sobre la tuberculosis resistente a fármacos.

Drug resistant tuberculosis (TB-R), and in particular, multidrug resistant tuberculosis (MDR-TB) is a global public health problem, as well as a problem in our country. Cases of TB-R and MDR-TB have increased mainly in HIV, immigrant and socially disadvantaged populations, but a notable increase in the general population has also been observed. This aspect reinforces the need for a systematic study of sensitivity of all the isolates in a reference laboratory to optimally guide the treatment. Children are especially vulnerable to this severe disease due to the limited knowledge of second line anti-tuberculous drugs, in terms of their pharmacokinetic data, optimal doses, or their long term toxicity, all this eventually resulting in the compassionate use of drugs. Another aspect which further complicates the management of R-TB in children is the limited yield of cultures, which frequently leads to clinician designing drug combinations according to the sensitivity of the initial strain. The epidemiological pattern in our country has currently changed. There is a reported increase in isoniazid-resistant strains; therefore, a four drugs regime is mandatory for the initial period in children, until reliable sensitivity results are available. Treatment should be directly observed or at least supervised by paediatricians. The management of latent infections or exposure to a resistant TB case also requires an accurate, strict and prolonged supervision by expert paediatricians. Authorities and health care professionals who deal with TB should be prepared to face this new phenomenon with appropriate measures. The knowledge of second line drugs for children, as well as mechanisms to ensure the therapeutic adherence and long term control of disease, are essential.

[HIV-1 genetic variability in non Spaniard infected children]. / Identificación de las diferentes variantes geneticas del VIH-1 en niños de procedencia no española.

INTRODUCTION: The prevalence of HIV-1 non-B subtypes (HIV-NBS) is increasing in Europe, because of emigration from countries where genetic variants are endemic. Although HIV-NBS could have a different clinical evolution and could respond differently to antiretrovirals (AR) than B-subtypes, these variant's response remain undocumented. AIMS: To identify HIV-1 genetic variants and to determine clinical evolution in a non-Spaniard children infected with HIV-1. PATIENTS AND METHOD: Children with HIV-1 infection from endemic countries were tested for HIV-1 subtypes between 1-1-1988 and 31-12-2006. Twelve children less than 18 years old and born abroad were selected. RESULTS: HIV-NBS were isolated in 5 children (42%): CRF2_AG recombinant in 3 cases (Equatorial Guinea), Subtype C in one (Equatorial Guinea) and CRF13_cpx in last one (India). DISCUSSION: Because of the increasing frequency of patients with HIV-NBS and their unknown long-term evolution, all children from endemic countries should be tested for HIV subtypes. We believe new studies with more patients during longer times could reveal differences in these patient's clinical, immunological and virological evolution.

[Filarial infestation in patients emanating from endemic area. 14 cases series presentation]. / Filariosis en pacientes procedentes de área endémica. Presentación de una serie de 14 casos.

INTRODUCTION: The migration causes the emergence of new diseases in our environment. One of them is the filariosis which, due to the biologic cycle peculiarity, it's weird its appearance in pediatrics. This studio accomplishes a review of all the filariosis cases diagnosed the last years in an Unit specialized in Tropical Pediatrics Diseases. MATERIAL AND METHODS: Retrospective analysis comprising 14 patients than were diagnosed with filariosis from 1995 to 2007 in the Pediatrics Unit of Carlos III Hospital (Madrid). They have been analyzed several variables to cope with clinic-epidemiological, therapeutics and evolutional characteristics. RESULTS: All patients in the study came from Equatorial Guinea, their ages were between 3 and 15 years old. The isolated species were: 6 cases with O. volvulus, 8 with M. perstans and 2 with Loa-loa. The pruritus was the main symptom in the 71% of the cases. The eosinophilia was detected in the 78% of the patients, and the Loa-loa was the specie with higher figures. The 85% of the patients showed co-parasitation, being the intestinal the most frequent. The diagnostics was established by epidermic biopsy, microfilaremia detection, direct visualization and serology. The utilized drugs were: Mebendazole for the cases with M. perstans and Ivermectin or Dietylcarbamazine for the rest of the species. One child showed mixed filariosis. The cure was successful in the 8 cases that could be followed up. CONCLUSIONS: We consider essential to execute a filariosis screening to every patient emanating from endemic area, especially to those with eosinophilia. The diagnostic in the childhood, even though it's difficult, it allows the prevention of the disease development, serious complications as blindness and break the parasite life cycle.

Virological Failure in HIV to Triple Therapy With Dolutegravir-Based Firstline Treatment: Rare but Possible.

We describe a case of virological failure during initial treatment with tenofovir disoproxil fumarate/emtricitabine/dolutegravir twice daily, with concomitant rifampin treatment of staphylococcal infection, selection of R263K + E157Q, and low plasma dolutegravir levels. Using rifampin together with dolutegravir may require closer follow-up, and, if possible, plasma dolutegravir levels should be monitored.