Caracterización y seguimiento de la resistencia a linezolid en staphylococcus epidermidis en la unidad de cuidados intensivos del Hospital Clínico San Carlos tras la descripción del primer brote de staphylococcus aureus linezolid resistente

Linezolid is an oxazolidinone with antimicrobial activity against resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant enterococci, and Streptococcus species. The drug binds to domain V of the 23S ribosomal RNA (rRNA) of the 50S subunit of bacterial ribosomes, thus inhibiting protein synthesis. Three classes of oxazolidinone resistance mechanisms have been previously characterized: mutations in the domain V region of 23S rRNA genes, acquisition of the ribosomal methyltransferase gene cfr, and mutations in the rplD and rplC gene encoding the 50S ribosomal protein L4 and L3 respectively. The first reports of bacteria resistant to linezolid showed the presence of point mutations at the drug target site. The most frequent mutation is G2576T although other mutations have been found in clinical isolates and in vitro indicating that resistance was apparently generated de novo through spontaneous mutations rather than genetic exchange. Resistance develops slowly, because nearly all bacteria possess multiple copies of the 23S rRNA gene (S. aureus strains have 5 or 6 operons encoding 23S rRNA) and it is not transmisible between species. Subsequently, a new mechanism of linezolid resistance was reported in veterinary staphylococcal isolates. The mechanism is nonmutational and involves acquisition of a natural resistance gene, cfr (chloramphenicol-florfenicol resistance). The cfr gene was initially described in a bovine Staphylococcus sciuri isolate. It has been found primarily in plasmids and appears to be capable of horizontal transfer between staphylococci. The cfr gene, encodes methyltransferase, which induces posttranscriptional methylation of 23S rRNA at position A2503, thus affecting the binding of at least four antimicrobial classes of drugs (phenicols, lincosamides, pleuromutilins, and streptogramin A), conferring multidrug-resistant phenotype. In human isolates, the gene was located in the chromosome, unlike the animal isolates, but it was probably part of an integrated plasmid that was potentially capable of excision and mobilization. Therefore, the gene could be transmitted to other pathogenic strains and spread quickly..

Caracterización y seguimiento de la resistencia a linezolid en staphylococcus epidermidis en la unidad de cuidados intensivos del Hospital Clínico San Carlos tras la descripción del primer brote de staphylococcus aureus linezolid resistente

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 25/01/2016Linezolid is an oxazolidinone with antimicrobial activity against resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant enterococci, and Streptococcus species. The drug binds to domain V of the 23S ribosomal RNA (rRNA) of the 50S subunit of bacterial ribosomes, thus inhibiting protein synthesis. Three classes of oxazolidinone resistance mechanisms have been previously characterized: mutations in the domain V region of 23S rRNA genes, acquisition of the ribosomal methyltransferase gene cfr, and mutations in the rplD and rplC gene encoding the 50S ribosomal protein L4 and L3 respectively. The first reports of bacteria resistant to linezolid showed the presence of point mutations at the drug target site. The most frequent mutation is G2576T although other mutations have been found in clinical isolates and in vitro indicating that resistance was apparently generated de novo through spontaneous mutations rather than genetic exchange. Resistance develops slowly, because nearly all bacteria possess multiple copies of the 23S rRNA gene (S. aureus strains have 5 or 6 operons encoding 23S rRNA) and it is not transmisible between species. Subsequently, a new mechanism of linezolid resistance was reported in veterinary staphylococcal isolates. The mechanism is nonmutational and involves acquisition of a natural resistance gene, cfr (chloramphenicol-florfenicol resistance). The cfr gene was initially described in a bovine Staphylococcus sciuri isolate. It has been found primarily in plasmids and appears to be capable of horizontal transfer between staphylococci. The cfr gene, encodes methyltransferase, which induces posttranscriptional methylation of 23S rRNA at position A2503, thus affecting the binding of at least four antimicrobial classes of drugs (phenicols, lincosamides, pleuromutilins, and streptogramin A), conferring multidrug-resistant phenotype. In human isolates, the gene was located in the chromosome, unlike the animal isolates, but it was probably part of an integrated plasmid that was potentially capable of excision and mobilization. Therefore, the gene could be transmitted to other pathogenic strains and spread quickly...Depto. de MedicinaFac. de MedicinaTRUEunpu

Adverse drug reactions to the three doses of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) mRNA-1273 vaccine in a cohort of cancer patients under active treatment of a tertiary hospital in Madrid, Spain [version 2; peer review: 2 approved]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines efficacy and safety have been tested in phase 3 studies in which cancer patients were not included or were underrepresented. Methods: The objective of this study is to evaluate the safety profile of the mRNA-1273 vaccine across cancer patients and its relationship to patients’ demographics. We selected from our records all 18-years or older solid cancer patients under active treatment vaccinated with the complete three-dose schedule mRNA-1273 vaccine whose adverse drug reactions (ADRs)  after each dose were recorded. Medical records were reviewed retrospectively to collect data between April 19, 2021, and December 31, 2021. Patients with documented previous infection by SARS-Cov-2 were excluded. Results: A total of 93 patients met the inclusion criteria. Local ADRs were reported more frequently after the first and second dose than after the third (41.9%, 43% and 31.1% of the patients respectively), while systemic ADRs followed the opposite pattern (16.1%, 34.4% and 52.6% of the patients respectively). We found a statistically significant association between sex and systemic adverse reactions after the third dose, p < 0.001 and between systemic adverse reactions after the second dose and systemic adverse reactions after the third dose, p = 0.001 A significant linear trend, p = 0.012, with a higher Eastern Cooperative Oncology Group (ECOG) score associated with a lower proportion of patients suffering from systemic side effects was found. Women had 5.79 times higher odds to exhibit systemic ADRs after the third dose (p=0.01) compared to males. Increasing age was associated with a decreased likelihood of exhibiting ADRs (p=0.016). Conclusion: The mRNA-1273 vaccine shows a tolerable safety profile. The likelihood of ADRs appears to be associated with gender and age. Its association with ECOG scores is less evident. Further studies are needed to elucidate this data in cancer patients

A Prospective Study of the Serological, Clinical, and Epidemiological Features of a SARS-CoV-2 Positive Pediatric Cohort

Background: SARS-CoV-2 was a global pandemic. Children develop a mild disease and may have a different rate of seroconversion compared to adults. The objective was to determine the number of seronegative patients in a pediatric cohort. We also reviewed the clinical–epidemiological features associated with seroconversion. Methods: A multicenter prospective observational study during September–November 2020, of COVID-19, confirmed by reverse transcription-polymerase chain reaction. Data were obtained 4–8 weeks after diagnosis. Blood samples were collected to investigate the humoral response, using three different serological methods. Results: A total of 111 patients were included (98 symptomatic), 8 were admitted to hospital, none required an Intensive Care Unit visit. Median age: 88 months (IQR: 24–149). Median time between diagnosis and serological test: 37 days (IQR: 34–44). A total of 19 patients were non-seroconverters when using three serological techniques (17.1%; 95% CI: 10.6–25.4); most were aged 2–10 years (35%, p < 0.05). Univariate analysis yielded a lower rate of seroconversion when COVID-19 confirmation was not present amongst household contacts (51.7%; p < 0.05). Conclusions: There was a high proportion of non-seroconverters. This is more commonly encountered in childhood than in adults. Most seronegative patients were in the group aged 2–10 years, and when COVID-19 was not documented in household contacts. Most developed a mild disease. Frequently, children were not the index case within the family

Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu