Current status of carbapenem resistance: epidemiology and microbiological aspects

Las infecciones ocasionadas por microorganismos resistentes a carbapenemes (en su mayoria bacterias gram negativas) son, a día de hoy, un problema global de salud pública. La principales razones, por las que estas infecciones suponen una gran amenaza son: su elevada mortalidad, la escasez de terapias antibióticas adecuadas, así como su rápida expansión a nivel mundial. El mecanismo más frecuente por el que se generan tales resistencias, se debe a la producción de unas enzimas que hidrolizan los carbapenemes denominadas carbapenemasas. En esta revisión analizamos los datos epidemiológicos de su expansión y distribucción en el mundo y, sobretodo, en Europa, asi como la clasificación microbiológica de las carbapenemasas y los métodos de los que disponemos actualmente para su detección en laboratorio. Todos estos pasos son clave y tienen gran repercusión en el manejo clínico que de estas infecciones.Nowadays, the infections due to carbapenem-resistant microorganism represent a global public health issue; the microorganisms most frequently involved are the gram-negative bacteria. This infections pose a major threat because of their elevated mortality, the lack of appropiate antibiotics and its rapid spread arround the world. The emergence of carbapenemases, which are a type of enzimes that hydrolize carbapenems, is the resistance mecanism more frequently involved. The aim of this literature review is to analyse the epidemiology arround the world and ,overall, in Europe; as well as the microbiological aspects of the carbapenem restistant bateria: carbapenemases can be classified into different types and are detected by several laboratory methods as well as its detection methods in laboratory. All this are key aspects and have a great impact on the clinical management of these infections

Effect of monotherapy with darunavir/ cobicistat on viral load and semen quality of HIV-1 patients

Many patients previously using darunavir/ritonavir (DRV/r) (800/100mg) have switched to darunavir/cobicistat (DRV/C) (800/150 mg) either as part of triple therapy (ART) or as monotherapy with DRV (mDRV). The latter approach continues to be used in some countries for patients receiving long-term treatment. However, to date, the behaviour of DRV/C in the seminal compartment has not been analysed. This study explores how the combination behaves in monotherapy, with respect to the control of viral load and seminal quality. To this end, we studied 20 patients who were treated with mDRV/C after previous treatment with mDRV/r for at least 24 weeks. A viral load control in seminal plasma similar to that published in the literature was observed after 24 weeks of treatment with mDRV/C (viral load positivity in 20% of patients). Similarly, semen quality was confirmed (70% normozoospermic) in patients treated with this formulation, as has previously been reported for ART and mDRV/r. The DRV levels measured in seminal plasma were above EC50, regardless of whether the seminal viral load was positive or negative. We conclude that this mDRV/C co-formulation behaves like mDRV/r in seminal plasma in terms of viral load control and semen quality

Genetic diversity of HIV in seminal plasma remains higher than in blood after short-term antiretroviral therapy

Objective: To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART). Patients and methods: Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIV env genetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity. Results: Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2-5)) was lower than in the seminal compartment (median 6, (IQR 4-8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1-4.5)) than in blood (median 1 (IQR 1-1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). Conclusion: We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasm

Risk factors for ≥high-grade anal intraepithelial lesions in MSM living with HIV and the response to topical and surgical treatments

The authors are grateful to MercedesA ´ lvarez Romero for coordinating patients and drawing blood samples and to Marina Gutie´rrez and Rodrigo Lo´pez of the Pathology Department for processing samples. The authors are grateful to the participating patients.Background The objective of this study in MSM living with HIV was to determine the incidence of HSIL and ASCC, related factors, and the response to treatment. Patients and methods Data were gathered in 405 consecutive HIV-infected MSM (May 2010-December 2018) at baseline and annually on: sexual behavior, anal cytology, and HPV PCR and/or high-resolution anoscopy results. They could choose mucosectomy with electric scalpel (from May 2010) or self-administration of 5% imiquimod 3 times weekly for 16 weeks (from November 2013). A multivariate logistic regression model was developed for ≥HSIL-related factors using a step-wise approach to select variables, with a significance level of 0.05 for entry and 0.10 for exit, applying the Hosmer-Lemeshow test to assess the goodness of fit. Results The study included 405 patients with a mean age of 36.2 years; 56.7% had bachelor´s degree, and 52.8% were smokers. They had a mean of 1 (IQR 1–7) sexual partner in the previous 12 months, median time since HIV diagnosis of 2 years, and mean CD4 nadir of 367.9 cells/uL; 86.7% were receiving ART, the mean CD4 level was 689.6 cells/uL, mean CD4/CD8 ratio was 0.77, and 85.9% of patients were undetectable. Incidence rates were 30.86/1,000 patient-years for ≥high squamous intraepithelial lesion (HSIL) and 81.22/100,000 for anal squamous cell carcinoma (ASCC). The ≥HSIL incidence significantly decreased from 42.9% (9/21) in 2010 to 4.1% (10/254) in 2018 (p = 0.034). ≥HSIL risk factors were infection with HPV 11 (OR 3.81; 95%CI 1.76–8.24), HPV 16 (OR 2.69, 95%CI 1.22–5.99), HPV 18 (OR 2.73, 95%CI 1.01–7.36), HPV 53 (OR 2.97, 95%CI 1.002–8.79); HPV 61 (OR 11.88, 95%CI 3.67–38.53); HPV 68 (OR 2.44, CI 95% 1.03–5.8); low CD4 nadir (OR1.002; 95%CI 1–1.004) and history of AIDS (OR 2.373, CI 95% 1.009–5.577). Among HSIL-positive patients, the response rate was higher after imiquimod than after surgical excision (96.7% vs 73.3%, p = 0.009) and there were fewer re-treatments (2.7% vs 23.4%, p = 0.02) and adverse events (2.7% vs 100%, p = 0.046); none developed ASCC. Conclusions HSIL screening and treatment programs reduce the incidence of HSIL, which is related to chronic HPV infection and poor immunological status. Self-administration of 5% imiquimod as first-line treatment of HSIL is more effective than surgery in HIV+ MSM

Effect of Monotherapy with Darunavir/Ritonavir on Viral Load in Seminal Fluid, and Quality Parameters of Semen in HIV-1-Positive Patients

Patients with human immunodeficiency virus type 1 (HIV-1) who receive antiretroviral therapy (ART) often achieve increased survival and improved quality of life. In this respect, monotherapy with darunavir/ritonavir (mDRV/r) can be a useful treatment strategy. This prospective study analyses the effect of mDRV/r on sperm quality and viral load in a group of 28 patients who had previously been given conventional ART and who had recorded a viral load 20 copies/ml), and that at V1, after mDRV/r treatment, this figure had fallen to 3%. The quality of seminal fluid was close to normal in 57% of patients at V0 and in 62% at V1. We conclude that, similar to ART, mDRV/r maintains HIV-1 viral load in most patients, and that there is no worsening in seminal fluid quality

ART is key to clearing oncogenic HPV genotypes (HR-HPV) in anal mucosa of HIV-positive MSM

Background: Anal squamous cell carcinoma (ASCC) is one of the most frequent non-AIDS-defining neoplasias in HIV patients, mainly in MSM, and it has been associated with chronic infection with high-risk human papilloma virus (HR-HPV). Our main objective was to determine HR-HPV clearance and acquisition rates and related factors and their relationship with the incidence of HSILs and ASCC in anal mucosa of HIV+ MSM. Patients and methods: The study included consecutive HIV-infected MSM between May 2010 and December 2018. Data were gathered at baseline and annually on their sexual behavior, CD4 and CD8 levels, plasma HIV viral load, and results of anal cytology, HPV PCR, and high-resolution anoscopy. Results: Out of the 405 patients studied, 34.9% of patients cleared oncogenic genotypes (IQR: 37-69) within 49 months, and 42.9% acquired new genotypes within 36 months (IQR:12-60). In multivariate analysis, clearance was only significantly influenced by the duration of antiretroviral therapy (ART) (OR: 1.016, 95% CI 1.003-1.030). The incidence of HSILs was 30.86/1,000 patient-years and that of ASCC was 81.22/100,000 patient-years; these incidences were not influenced by the acquisition (acquired: 14.9% vs. non-acquired: 10.4%; p = 0.238) or clearance (cleared 11.4% vs. non-cleared: 13.2%; p = 0.662) rates of these viruses. Conclusions: The duration of ART appears to positively affect oncogenic genotype clearance in the anal mucosa of HIV+ MSM, although this clearance does not affect the incidence of HSILs or ASCC. The reduction in HSIL+ rate observed in our patients may be attributable to the bundle of measures adopted at our center

Major Histocompatibility Complex Class I Chain-Related (MICA) STR Polymorphisms in COVID-19 Patients

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.Instituto de Salud Carlos III - FEDER funds (European Union) PI 16/00752 B-CTS-410-UGR-20Junta de Andalucia CTS-143 C-0013-201

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

Background: Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. Methodology/principal findings: The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24-48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9-12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). Conclusions/significance: A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9-12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells

Modifications of hepatic fibrosis assessed by transient elastometry in patients with sustained virological response after treatment of hepatitis C in monoinfected (VHC) and coinfected patients(VHC – VIH)

Introducción: Se ha observado que los pacientes infectados por el virus de la hepatitis C (VHC), que ya han desarrollado un grado de fibrosis significativo, son capaces de disminuir ese grado de fibrosis, al alcanzar una respuesta viral sostenida (RVS) tras el tratamiento con interferón pegilado (PEG-IFN) y ribavirina (RBV). Objetivo: Evaluar la modificación de la fibrosis, medida por elastometría transitoria, al erradicar el VHC tanto en pacientes tratados con PEG-IFN y RBV, con Boceprevir/Telaprevir, como con agentes de acción directa (AAD) y determinar la asociación entre la variación de la fibrosis y el grado de fibrosis previo al tratamiento tanto en pacientes monoinfectados (VHC), como en coinfectados (VIH/VHC). Métodos: Estudio observacional prospectivo, en el que se estudiaron 50 pacientes y se evaluó su grado de fibrosis previo y posterior al tratamiento. Resultados: De los 62 pacientes, un 45,2% disminuyeron su fibrosis, con una media de descenso de 9,45kPa y un 45,2% disminuyeron al menos un estadio en la escala Metavir. Se observó una asociación entre un menor grado de fibrosis previo al tratamiento y un mayor descenso de la misma (p<0,001). Sin embargo no se observaron diferencias (p=0,713) entre la monoinfección y la coinfección con VIH; tampoco se detectó asociación significativa, entre los tres tipos de tratamientos y la modificación de la fibrosis (p=0,445). Conclusiones:En nuestro estudio, la consecución de la RVS en los pacientes con hepatitis crónica por VHC facilita la reducción de la fibrosis producida por la enfermedad, tanto en pacientes monoinfectados, como en coinfectados (VIH/VHC), independientemente del tratamiento usado.Introduction: It has been shown that patients infected with hepatitis C virus (HCV), who have already developed a significant degree of fibrosis, are able to reduce that degree of fibrosis by achieving a sustained virological response (SVR) after treatment with Pegylated interferon (PEG-IFN) and ribavirin (RBV). Objective: To evaluate the modification of fibrosis, measured by transient elastometry, after HCV eradication in patients treated with PEG-IFN and RBV, with Boceprevir / Telaprevir, and with direct acting agents (AAD) and to determine the association between the variation in fibrosis and the degree of pre-treatment fibrosis in both monoinfected (HCV) and coinfected (HIV / HCV) patients. Methods: This work is a prospective observational study. 50 patients were studied and their degree of fibrosis before and after treatment was evaluated. Results: 45.2% of patients decreased their fibrosis, with a mean decrease of 9.45kPa and 45.2% decreased at least one stage on the Metavir scale. There was an association between a lower degree of fibrosis before treatment and a greater decrease in fibrosis (p <0.001). However, no differences were observed between monoinfection and HIV coinfection (p = 0.713). No significant association was detected between the three types of treatments and the modification of fibrosis (p = 0.445). Conclusions: In our study, SVR in patients with chronic HCV hepatitis facilitates the reduction of fibrosis produced by the disease, both in monoinfected patients and in coinfected patients (HIV / HCV), regardless of the treatment used