Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection.

BACKGROUND: Zinc is an essential micronutrient that impacts host-pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker. METHODS: We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations. FINDINGS: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells. INTERPRETATION: Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.

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

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

Validation Protocol of Vitamin D Supplementation in Patients with HIV-Infection.

Hypovitaminosis D and secondary hyperparathyroidism are frequent among HIV-infected patients. As there are no data about the best supplementation therapy both in treatment and in maintenance, we conducted an observational study of 300 HIV-infected patients for whom vitamin D and parathormone (PTH) had been measured in order to validate a protocol of vitamin D supplementation in patients with HIV-infection. Patients with vitamin D deficiency (defined as 25(OH)D < 10 ng/mL), insufficiency (defined as 25(OH)D < 20 ng/mL), or hyperparathyroidism (PTH > 65 pg/mL) were supplemented with cholecalciferol 16.000IU (0.266 mg) weekly (if deficiency) or fortnightly (if insufficiency or high PTH levels). Rates of normalization of 25(OH)D (levels above 20 ng/mL) and PTH levels (<65 pg/mL) were analyzed. Multivariate analysis of factors related to normalization was carried out. With a median follow-up of 2 years, 82.1% of patients with deficiency and 83.9% of cases with insufficiency reached levels above 20 ng/mL. However, only 67.2% of individuals with hyperparathyroidism at baseline reached target levels (<65 pg/mL). Independent factors for not achieving PTH objective were tenofovir (TDF) and protease inhibitors use. In HIV-infected patients with hypovitaminosis, the protocol of cholecalciferol supplementation normalized vitamin D levels regardless of antiretroviral regimen in a high proportion of patients but it was less effective to correct hyperparathyroidism.

An antimicrobial stewardship program reduces antimicrobial therapy duration and hospital stay in surgical wards / Un programa de uso de antimicrobianos reduce la duración de la terapia antimicrobiana y la estancia hospitalaria en salas de cirugía

We report a quasi-experimental study of the implementation of an antimicrobial stewardship program in two surgical wards, with a pre-intervention period with just assessment of prescription and an intervention period with a prospective audit on antibiotic prescription model. There was a significant reduction of length of stay and the total days of antimicrobial administration. There were no differences in mortality between groups. The antimicrobial stewardship program led to the early detection of inappropriate empirical antibiotic treatment and was associated with a significant reduction in length of stay and the total duration of antimicrobial therapy (AU)

Presentamos un estudio cuasi-experimental de la aplicación de un programa de uso de terapia antimicrobiana en dos salas quirúrgicas, con un período de pre-intervención en que se realizó evaluación de la prescripción y un período de intervención con una auditoría prospectiva sobre la prescripción antibiótica siguiendo un modelo de recomendación. Hubo una reducción significativa de la estancia media y del total de días de tratamiento antibiótico. No hubo diferencias en la mortalidad entre los grupos. El programa de uso de terapia antimicrobiana condujo a la detección precoz de tratamiento antibiótico empírico inadecuado y se asoció con una reducción significativa de la estancia media y la duración total de la terapia antimicrobiana (AU)

[Usefulness of PK/PD parameters of antimicrobials in the treatment of complex and extremely-resistant infections]. / Aplicabilidad de los parámetros PK/PD de los antimicrobianos en el tratamiento de infecciones complejas y resistencias extremas.

Complex or difficult to treat infections should benefit from antimicrobial PK/PD data in each specific situation. In the case of multidrug resistant gram negative infections the optimized use of colistin needs the using of PK/PD indexes. Likewise, in infections of inaccessible sources, PK/PD concepts play a key role in choosing the best antimicrobial and dosage. An example would be the potential role of linezolid in CNS infections. Among fungal infections, symptomatic candiduria by fluconazole-resistant strains are a therapeutic challenge. In this context micafungin could be a good alternative, again based on PK/PD concepts.

Future alternatives for the treatment of infections caused by carbapenemase-producing Enterobacteriaceae: what is in the pipeline?

The emergence and spread of carbapenemase-producing Enterobacteriaceae is an important and very concerning problem. There is an urgent need of new antibimicrobials for treating these infections. Currently there are some options in the pipeline. Several new beta-lactamase and carbapenemase inhibitors as avibactam and MK-7655, combined with old or new betalactams are a very interesting option. Some combinations as ceftazidime-avibactam are in the late stages of clinical development and could reach the market in the next years. New aminoglycosides as plazomicin, tetracycline derivates as eravacycline, and several other new molecules as monosulfactams are currently in different stages of development.

Future alternatives for the treatment of infections caused by carbapenemaseproducing Enterobacteriaceae: What is in the pipeline? / Alternativas futuras para el tratamiento de las infecciones causadas por enterobacterias productoras de carbapenemasas: ¿qué hay en proyecto?

The emergence and spread of carbapenemase-producing Enterobacteriaceae is an important and very concerning problem. There is an urgent need of new antibimicrobials for treating these infections. Currently there are some options in the pipeline. Several new beta-lactamase and carbapenemase inhibitors as avibactam and MK-7655, combined with old or new betalactams are a very interesting option. Some combinations as ceftazidime-avibactam are in the late stages of clinical development and could reach the market in the next years. New aminoglycosides as plazomicin, tetracycline derivates as eravacycline, and several other new molecules as monosulfactams are currently in different stages of development (AU)

La aparición y diseminación de enterobacterias productoras de carbapenemasas es un problema importante y muy preocupante. Existe una necesidad urgente de nuevos antimicrobianos para tratar estas infecciones. Actualmente hay varias opciones en desarrollo. Varios inhibidores nuevos de betalactamasas y de carbapenemasas, como el avibactam y el MK-7665, combinados con betalactámicos antiguos y nuevos son una opción interesante. Algunas combinaciones como ceftazidima-avibactam están en las últimas fases del desarrollo clínico y podrían llegar al mercado en los próximos años. Otros compuestos que están en diferentes fases de desarrollo son aminoglucósidos nuevos, como la plazomicina, derivados de las tetraciclinas como la eravacilina, y otras moléculas nuevas como los monosulfactams (AU)

[Shedding light on the use of colistin: still gaps to be filled]. / Luces y sombras en el uso de colistina: falta mucho por conocer.

Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

Tratamiento de las infecciones no complicadas del tracto urinario inferior / Treatment of uncomplicated lower urinary tract infections

El tratamiento antibiótico empírico de las infecciones del tracto urinario inferior debe basarse en los datos clínicos del paciente y en las tasas locales de sensibilidad antibiótica. El aumento de las resistencias de los uropatógenos ha obligado a modificar las recomendaciones para el tratamiento empírico de las infecciones urinarias. Actualmente se desaconseja el uso empírico de cotrimoxazol, ampicilina, cefalosporinas y quinolonas, ambas de primera generación. Las fluoroquinolonas han demostrado ser muy eficaces en estudios comparativos, pero el aumento de resistencias obliga a seleccionar el tipo de paciente que se puede beneficiar de estos antimicrobianos. Las cefalosporinas de segunda y tercera generación mantienen tasas de sensibilidad elevadas, aunque se deben tener en cuenta las mayores tasas de recurrencia asociadas a su utilización y la aparición de enterobacterias productoras de betalactamasas de espectro extendido en la comunidad. La amoxicilina-ácido clavulánico tiene menor eficacia erradicadora que las quinolonas. Fosfomicina-trometamol mantiene tasas de resistencia inferiores al 2% y ha demostrado su eficacia y seguridad con una dosis única. Nitrofurantoína también es activa en la actualidad, aunque precisa una administración de 7 días y no está exenta de toxicidad. Ambos agentes se recomiendan actualmente como opciones alternativas a las fluoroquinolonas en la infección no complicada del tracto urinario inferior

Empirical antibiotic treatment of lower urinary tract infections should be based on the patient's clinical data and on local sensitivity data. Because of the increase in resistance among uropathogens, recommendations on the empirical treatment of urinary tract infections have been modified. Currently, the empirical use of co-trimoxazole, ampicillin, and first-generation cephalosporins and quinolones is not recommended. Fluoroquinolones have been demonstrated to be highly effective in comparative studies but, because of the increase in resistance, the type of patient who can benefit from these antimicrobial agents must be selected. Second- and third-generation cephalosporins still have high sensitivity rates, although the higher recurrence rates associated with their use and the emergence of extended-spectrum beta-lactamase-producing enterobacterial in the community should be taken into account. Amoxicillin-clavulanate is less effective in eradicating infections than quinolones. Fosfomycin-trometamol has resistance rates of below 2% and single-dose therapy has been demonstrated to be safe and effective. Nitrofurantoin is also currently active, although it must be administered for 7 days and can produce toxicity. Both agents are currently recommended as alternative therapeutic options to fluoroquinolones in uncomplicated infections of the lower urinary tract