In vitro and in vivo activities of linezolid alone and combined with vancomycin and imipenem against Staphylococcus aureus with reduced susceptibility to glycopeptides

The objective of this study was to evaluate the in vitro and in vivo efficacies of linezolid (35 mg/kg/5 h), vancomycin (60 mg/kg/5 h), imipenem (30 mg/kg/5 h), linezolid+imipenem, linezolid+vancomycin and vancomycin+imipenem against two clinical Staphylococcus aureus isolates with reduced susceptibility to glycopeptides using time–kill curves and the murine peritonitis model. Time–kill curves were performed over 24 h. For the murine peritonitis model, peritonitis was induced by the intraperitoneal inoculation of 108 CFU/ml of each bacterial strain. Four hours later (0 h), the mice were randomly assigned to a control group or to therapeutic groups receiving subcutaneous treatment for 25 h. Bacterial counts in peritoneal fluid, bacteraemia and mortality rates were determined. The time–kill curves showed that the addition of linezolid to imipenem yielded synergistic results after 24 h. The addition of linezolid decreased vancomycin activity. In the animal model, vancomycin and linezolid monotherapies produced comparable bacterial decreases in mice infected with each strain but linezolid achieved higher rates of blood sterilisation. Linezolid tested either in monotherapy or in combination showed similar efficacy against both strains in terms of bacterial killing, number of negative blood cultures and survival. Linezolid and vancomycin were moderately bactericidal and similar in efficacy against glycopeptide-intermediate or -resistant S. aureus. Linezolid combinations, as effective as linezolid tested alone, could be considered as alternative options for the treatment of glycopeptide-intermediate S. aureus (GISA) infections

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19

Actividad in vitro y eficacia de metabolitos del tamoxifeno solos y en combinación con antimicrobianos frente a cepas clínicas de Acinetobacter baumannii y Escherichia coli

Trabajo presentado en el 1er Congreso de la Sociedad Andaluza de Microbiología Clínica y Enfermedades Infecciosas (SAMICEI), celebrado en Málaga (España) del 16 al 18 de noviembre de 2022

Eficacia de N-desmetiltamoxifeno solo y en combinación con colistimetato sódico y tigeciclina, en la neumonía experimental por Escherichia coli y Acinetobacter baumannii

Trabajo presentado en el 1er Congreso de la Sociedad Andaluza de Microbiología Clínica y Enfermedades Infecciosas, celebrado en Málaga (España) del 16 al 18 de noviembre de 2022.Introducción/Objetivos: El reposicionamiento de fármacos, es una alternativa en el desarrollo de nuevos fármacos frente a infecciones por bacilos gramnegativos multirresistentes. El objetivo fue evaluar in vivo la eficacia de Ndesmetiltamoxifeno (N-DTAM), en monoterapia y en combinación con antimicrobianos, en un modelo murino de neumonía experimental por cepas de Escherichia coli y Acinetobacter baumannii

In Vitro Effect of qnrA1, qnrB1, and qnrS1 Genes on Fluoroquinolone Activity against Isogenic Escherichia coli Isolates with Mutations in gyrA and parC ▿

This article provides an analysis of the in vitro effect of qnrA1, qnrB1, and qnrS1 genes, combined with quinolone-resistant Ser83Leu substitutions in GyrA and/or Ser80Arg in ParC, on fluoroquinolone (FQ) resistance in isogenic Escherichia coli strains. The association of Ser83Leu substitution in GyrA, Ser80Arg substitution in ParC, and qnr gene expression increased the MIC of ciprofloxacin to 2 μg/ml. qnr genes present in E. coli that harbored a Ser83Leu substitution in GyrA increased mutant prevention concentration (MPC) values to 8 to 32 μg/ml. qnr gene expression in E. coli may play an important role in selecting for one-step FQ-resistant mutants

Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant staphylococcus aureus

Objectives: The British Thoracic Society, American Thoracic Society and Infectious Diseases Society of America guidelines recommend vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, based on evidence suggesting that a vancomycin AUC 0-24/MIC ratio of 400 predicts clinical success against MRSA pneumonia. The aim of this study was the evaluation of an optimized dose of vancomycin in the treatment of MRSA experimental pneumonia versus linezolid.Methods: In vitro activities of vancomycin and linezolid were tested using time-kill curves. Experimental pneumonia in neutropenic C57BL/6 mice was achieved using two clinical MRSA strains, MR30 and MR33 (vancomycin and linezolid MICs of 1 and 4 mg/L, respectively). In vivo dosages were 30 and 110 mg/kg vancomycin (obtaining an AUC 0-24/MIC ratio lower and higher than 400, respectively), and 30 mg/kg linezolid.Results: Survival rates in controls, and in the groups treated with 120 mg/kg/day vancomycin, 440 mg/kg/day vancomycin and 120 mg/kg/day linezolid were 85.7%, 92.9%, 76.9% and 100%, and 66.7%, 100%, 75% and 100% for MR30 and MR33, respectively. Sterile blood cultures occurred at rates of 21.4%, 64.3%, 100% and 93.8%, and 40%, 66.7%, 100% and 93.3% for MR30 and MR33 strains, respectively. Finally, the respective bacterial lung concentrations (log. 10 cfu/g) were 8.93 ± 0.78, 6.67 ± 3.01, 3.25 ± 1.59 and 2.87 ± 1.86 for MR30, and 8.62 ± 0.72, 5.76 ± 2.43, 3.97 ± 1.52 and 1.59 ± 1.40 for MR33.Conclusions: These results support that a vancomycin AUC. 0-24/MIC ratio >400 is necessary to obtain a high bacterial lung reduction in MRSA pneumonia, comparable to that achieved with linezolid and better than that with the low dose of vancomycin tested. Linezolid was more efficacious than the pharmacodynamically optimized vancomycin dose in the pneumonia caused by the most virulent strain (MR33). © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.This work was supported by research grants (113/03) from the Consejería de Salud of the Junta de Andalucia, and by Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III—co-financed by European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008/0000).Peer Reviewe

Attenuated virulence of a slow-growing pandrug-resistant Acinetobacter baumannii is associated with decreased expression of genes encoding the porins CarO and OprD-like

Part of this study was presented at the 8th International Symposium on the Biology of Acinetobacter, 1–3 September 2010, Rome, Italy.This work has been supported by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III–FEDER, Spanish Network for Research in Infectious Diseases (REIPI C03/14 and REIPI RD06/0008), FIS (PI080209) and by the Junta de Andalucía (288/2008).This work has been supported by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III–FEDER, Spanish Network for Research in Infectious Diseases (REIPI C03/14 and REIPI RD06/0008), FIS (PI080209) and by the Junta de Andalucía (288/2008).Peer Reviewe