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41 emner vises.
Infection, 10.06.2021
Tilføjet 12.06.2021
Abstract
Purpose
Fluid management is challenging in malaria patients given the risks associated with intravascular fluid depletion and iatrogenic fluid overload leading to pulmonary oedema. Given the limitations of the physical examination in guiding fluid therapy, we evaluated point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) and lungs as a novel tool to assess volume status and detect early oedema in malaria patients.
Methods
To assess the correlation between IVC and lung ultrasound (LUS) indices and clinical signs of hypovolaemia and pulmonary oedema, respectively, concurrent clinical and sonographic examinations were performed in an observational study of 48 malaria patients and 62 healthy participants across age groups in Gabon.
Results
IVC collapsibility index (CI) ≥ 50% on enrolment reflecting intravascular fluid depletion was associated with an increased number of clinical signs of hypovolaemia in severe and uncomplicated malaria. With exception of dry mucous membranes, IVC-CI correlated with most clinical signs of hypovolaemia, most notably sunken eyes (r = 0.35, p = 0.0001) and prolonged capillary refill (r = 0.35, p = 0.001). IVC-to-aorta ratio ≤ 0.8 was not associated with any clinical signs of hypovolaemia on enrolment. Among malaria patients, a B-pattern on enrolment reflecting interstitial fluid was associated with dyspnoea (p = 0.0003), crepitations and SpO2 ≤ 94% (both p < 0.0001), but not tachypnoea (p = 0.069). Severe malaria patients had increased IVC-CI (p < 0.0001) and more B-patterns (p = 0.004) on enrolment relative to uncomplicated malaria and controls.
Conclusion
In malaria patients, POCUS of the IVC and lungs may improve the assessment of volume status and detect early oedema, which could help to manage fluids in these patients.
Læs mere Tjek på PubMedInfection, 10.06.2021
Tilføjet 12.06.2021
Abstract
Background
Comprehensive nationwide data on prevalence and distribution of intestinal parasites (IPIs) among pregnant women are lacking. Therefore, the aim of this study was to provide pooled prevalence estimate, prevalence in different regions and species-specific IPIs among pregnant women in Ethiopia.
Methods
The search was carried out in Medline via PubMed, Scopus, Science Direct, Web of Science and Google Scholar on published and unpublished data between 2008 and Sep 2020 for studies describing rate of IPIs among pregnant women in Ethiopian. A random-effects model and forest plots to estimate pooled effect size and effect of each study with their confidence interval (CI) were used to provide a visual summary of the data. We conducted meta-regression to understand the source of heterogeneity and pooled the prevalence using ‘metaprop’ command using STATA software version 14.
Results
A total of 3149 of the 9803 pregnant women were infected with one or more species of IPIs resulted in an overall prevalence of 29% (95% CI 22–37%). The prevalence estimate varied among studies with considerable heterogeneity (χ2 = 2069.19, p < 0.001 I2 = 98.84). The prevalence of IPIs was 36% (95% CI 22–50%) in Oromia region, 29% (95% CI 10–47%) in Amhara region, 24% (95% CI 17–32%) in southern nation, nationality and people region, 24% (95% CI 22–27%) in Tigray region and 24% (95% CI 20–29%) in Addis Ababa city. Hookworms with pooled prevalence estimate of 10% (95% CI 8–13%) followed by Ascaris lumbricoides 10% (95% CI 7–13%), and Entamoeba histolytica/dispar 6% (95% CI 4–8%) were the three common species of IPIs identified in this group of population.
Conclusion
The prevalence of IPIs among pregnant women is relatively high in comparison to other general population. Hookworms and Ascaris lumbricoides were the most dominant species of intestinal helminths, whereas Entamoeba histolytica/dispar was the dominant intestinal protozoa among pregnant women in Ethiopia.
Læs mere Tjek på PubMedInfection, 6.06.2021
Tilføjet 12.06.2021
Abstract
Purpose
Few data are currently available on persistent symptoms and late organ damage in patients who have suffered from COVID-19. This prospective study aimed to evaluate the results of a follow-up program for patients discharged from a nonintensive COVID-19 ward.
Methods
3–6 months after hospital discharge, 59 of 105 COVID-19 patients (31 males, aged 68.2 ± 12.8 years) were recruited in the study. Forty-six patients were excluded because of nontraceability, refusal, or inability to provide informed consent. The follow-up consisted of anamnesis (including a structured questionnaire), physical examination, blood tests, ECG, lower limb compression venous ultrasound (US), thoracic US, and spirometry with diffusion lung capacity for carbon monoxide (DLCO).
Results
22% of patients reported no residual symptoms, 28.8% 1 or 2 symptoms and 49.2% 3 or more symptoms. The most frequently symptoms were fatigue, exertional dyspnea, insomnia, and anxiety. Among the inflammatory and coagulation parameters, only the median value of fibrinogen was slightly above normal. A deep vein thrombosis was detected in 1 patient (1.7%). Thoracic US detected mild pulmonary changes in 15 patients (25.4%), 10 of which reported exertional dyspnea. DLCO was mildly or moderately reduced in 19 patients (37.2%), 13 of which complained of exertional dyspnea.
Conclusion
These results highlight that a substantial percentage of COVID-19 patients (77.8%) continue to complain of symptoms 3–6 months after hospital discharge. Exertional dyspnea was significantly associated with the persistence of lung US abnormalities and diffusing capacity alterations. Extended follow-up is required to assess the long-term evolution of postacute sequelae of COVID-19.
Læs mere Tjek på PubMedInfection, 5.06.2021
Tilføjet 12.06.2021
Abstract
Purpose
Limited mechanical ventilators (MV) during the Coronavirus disease (COVID-19) pandemic have led to the use of non-invasive ventilation (NIV) in hypoxemic patients, which has not been studied well. We aimed to assess the association of NIV versus MV with mortality and morbidity during respiratory intervention among hypoxemic patients admitted with COVID-19.
Methods
We performed a retrospective multi-center cohort study across 5 hospitals during March–April 2020. Outcomes included mortality, severe COVID-19-related symptoms, time to discharge, and final oxygen saturation (SpO2) at the conclusion of the respiratory intervention. Multivariable regression of outcomes was conducted in all hypoxemic participants, 4 subgroups, and propensity-matched analysis.
Results
Of 2381 participants with laboratory-confirmed SARS-CoV-2, 688 were included in the study who were hypoxemic upon initiation of respiratory intervention. During the study period, 299 participants died (43%), 163 were admitted to the ICU (24%), and 121 experienced severe COVID-19-related symptoms (18%). Participants on MV had increased mortality than those on NIV (128/154 [83%] versus 171/534 [32%], OR = 30, 95% CI 16–60) with a mean survival of 6 versus 15 days, respectively. The MV group experienced more severe COVID-19-related symptoms [55/154 (36%) versus 66/534 (12%), OR = 4.3, 95% CI 2.7–6.8], longer time to discharge (mean 17 versus 7.1 days), and lower final SpO2 (92 versus 94%). Across all subgroups and propensity-matched analysis, MV was associated with a greater OR of death than NIV.
Conclusions
NIV was associated with lower respiratory intervention mortality and morbidity than MV. However, findings may be liable to unmeasured confounding and further study from randomized controlled trials is needed to definitively determine the role of NIV in hypoxemic patients with COVID-19.
Læs mere Tjek på PubMedInfection, 5.06.2021
Tilføjet 12.06.2021
Abstract
Purpose
To evaluate the impact of a multidisciplinary the “Endocarditis Team” (ET) on the course and outcome of infective endocarditis (IE) patients.
Methods
A retrospective before–after study, including hospitalized patients with definite IE, managed before (01.2013–12.2015) and after (01.2016–07.2019) the introduction of an ET. The primary outcomes were defined as 30-day and 1-year mortality and the secondary as conservative vs. invasive strategy, the interval from clinical suspicion of IE to the performance of echocardiography, utilization of multimodality evaluation, time to an invasive procedure, and the duration of hospitalization.
Results
Study population included 92 pre-ET and 128 post-ET implementation patients. Baseline characteristics were similar. During the post-ET period compared with pre-ET, we found higher rates of abscesses and extra-cardiac emboli (27.8% vs. 16.3%, p = 0.048); and a higher invasive procedures rate, including lead extraction (15.6% vs. 6.5%, p = 0.035) and noncardiac surgeries (14.8% vs. 6.5%, p = 0.05). Patients managed during the post-ET period had reduced short (8.5% vs. 17.4%, p = 0.048) and long-term mortality (Log-rank = 0.001). In multivariate analysis of risk factors for long-term mortality, period (pre- or post-ET) was not found to be significantly associated with the mortality.
Conclusion
Establishment of an ET was associated with faster and more intensive evaluation of patients with IE. During the period of an ET activity, mortality rates were reduced compared with the previous period.
Læs mere Tjek på PubMedInfection, 5.06.2021
Tilføjet 12.06.2021
Abstract
Background
Increasing use of cardiovascular implantable electronic devices (CIED), as permanent pacemakers (PPM), implantable cardioverter defibrillators (ICD), or cardiac resynchronization therapy (CRT), is associated with the emergence of CIED-related infective endocarditis (CIED-IE). We aimed to characterize CIED-IE profile, temporal trends, and prognostic factors.
Methods
CIED-IE diagnosed at Rennes University Hospital during years 1992–2017 were identified through computerized database, and included if they presented all of the following: (1) clinical signs of infection; (2) microbiological documentation through blood and/or CIED lead cultures; (3) lead or valve vegetation, or definite IE according to Duke criteria. Data were retrospectively extracted from medical charts. The cohort was categorized in three periods: 1992–1999, 2000–2008, and 2009–2017.
Results
We included 199 patients (51 women, 148 men, median age 73 years [interquartile range, 64–79]), with CIED-IE: 158 PPMs (79%), 24 ICD (12%), and 17 CRT (9%). Main pathogens were coagulase-negative staphylococci (CoNS: n = 86, 43%), Staphylococcus aureus (n = 60, 30%), and other Gram-positive cocci (n = 28, 14%). Temporal trends were remarkable for the decline in CoNS (P = 0.002), and the emergence of S. aureus as the primary cause of CIED-IE (24/63 in 2009–2017, 38%). Factors independently associated with one-year mortality were chronic obstructive pulmonary disease (COPD: hazard ratio 3.84 [1.03–6.02], P = 0.03), left-sided endocarditis (HR 2.25 [1.09–4.65], P = 0.03), pathogens other than CoNS (HR 3.16 [1.19–8.39], P = 0.02), and CIED removal/reimplantation (HR 0.41 [0.20–0.83], P = 0.01).
Conclusions
S. aureus has emerged as the primary cause of CIED-IE. Left-sided endocarditis, COPD, pathogens other than CoNS, and no CIED removal/reimplantation are independent risk factors for one-year mortality.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Infection, 1.06.2021
Tilføjet 12.06.2021
Abstract
A 58-year-old woman was diagnosed with severe endometriosis and had multiple gastrointestinal tract complications for many years. Candida auris and C. parapsilosis were isolated from the bloodstream. Identification of C. auris was confirmed by amplification and sequencing of the internal transcriber spacer and the D1/D2 domain of the large rRNA gene subunit. Antifungal susceptibility was tested in both isolates using the Clinical Laboratory Standards Institute protocol M27-A3/S4. The patient evolved favorably with systemic antifungal therapy consisting of caspofungin and liposomal amphotericin B.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Abstract
Severe 2019 novel coronavirus infectious disease (COVID-19) with pneumonia is associated with high rates of admission to the intensive care unit (ICU). Bacterial coinfection has been reported to be rare. We aimed at describing the rate of bacterial coinfection in critically ill adult patients with severe COVID-19 pneumonia. All the patients with laboratory-confirmed severe COVID-19 pneumonia admitted to the ICU of Tenon University-teaching hospital, from February 22 to May 7th, 2020 were included. Respiratory tract specimens were obtained within the first 48 h of ICU admission. During the study period, 101 patients were referred to the ICU for COVID-19 with severe pneumonia. Most patients (n = 83; 82.2%) were intubated and mechanically ventilated on ICU admission. Overall, 20 (19.8%) respiratory tract specimens obtained within the first 48 h. Staphylococcus aureus was the main pathogen identified, accounting for almost half of the early-onset bacterial etiologies. We found a high prevalence of early-onset bacterial coinfection during severe COVID-19 pneumonia, with a high proportion of S. aureus. Our data support the current WHO guidelines for the management of severe COVID-19 patients, in whom antibiotic therapy directed to respiratory pathogens is recommended.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Abstract
Case presentation
We report the first confirmed case of the novel coronavirus disease (COVID-19) in a lactating patient in Chizhou, Anhui Province, China. The lactating patient presented with intermittent fever for 16 days and cough for 10 days. Given her travel history to the epidemic area and the chest CT scan results, the patient was immediately admitted to the isolation ward of the Infectious Disease Department and breastfeeding was discontinued. Pharyngeal swab specimens tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) in nucleic acid testing. During hospitalization, she also experienced bilateral breast tenderness. After active treatment, the patient ultimately achieved remission and was discharged from the hospital.
Discussion and conclusions
SARS-CoV-2 is transmitted mainly through respiratory droplets and patient contact, rendering the general population to a high risk of infection. The management of mother–child interactions and breastfeeding in women with COVID-19 is a difficult problem. The purpose of this case report is to help clinicians by improving the understanding of COVID-19, particularly in lactating patients.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Infection, 1.06.2021
Tilføjet 12.06.2021
Abstract
To determine the most relevant pathogens for CAP in Germany, patients with radiologically confirmed pulmonary infiltrates and at least one clinical sign of lung infection were prospectively recruited within the CAPNETZ cohort from 2004 until 2016. In 990 out of 4.672 patients (21%) receiving complete diagnostics the most prominent change of pathogens was a decrease of S. pneumoniae (58% in 2004 to 37.5% in 2016; p ≤ 0.001, ρ = − 0.148) and an increase of H. influenzae (12.2% to 20.8%; p = 0.001, ρ = 0.104).
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Abstract
Purpose
The establishment of candidate genetic determinants associated with tuberculosis (TB) is a challenge, considering the divergent frequencies among populations. The objective of this study was to evaluate the association between MIF − 794 CATT 5−8 polymorphism and susceptibility to TB.
Methods
Case–control study. Patients > 18 years, with pulmonary TB were included. The control group consisted of blood donors and household contacts, not relatives, healthy and > 18 years. MIF − 794 CATT 5−8 were genotyped using sequencing of PCR and capillary electrophoresis.
Results
126 patients and 119 controls were included. The genotype 5/5 was more frequent among cases (15.1%) than in controls (5.9%) (p = 0.019). Cases had more frequently the allele 5 (29.4%) as compared with controls (19.3%) (p = 0.010). Prevalence of 7/X + 8/X genotypes was not different between cases and controls (p = 0.821). There was no difference between patients with alleles 7 and 8 and those with alleles 5 and 6 (p = 0.608).
Conclusions
The genotype 5/5 and the allele 5 of MIF − 794 CATT 5−8 were more frequent among TB patients than in controls.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Abstract
The high cost of fidaxomicin has restricted its use despite the benefit of a lower Clostridioides difficile infection (CDI) recurrence rate at 4 weeks of follow-up. This short follow-up represents the main limitation of pivotal clinical trials of fidaxomicin, and some recent studies question its benefits over vancomycin. Moreover, the main risk factors of recurrence after treatment with fidaxomicin remain unknown. We designed a multicentre retrospective cohort study among four Spanish hospitals to assess the efficacy of fidaxomicin in real life and to investigate risk factors of fidaxomicin failure at weeks 8 and 12. Two-hundred forty-four patients were included. Fidaxomicin was used in 96 patients (39.3%) for a first episode of CDI, in 95 patients (38.9%) for a second episode, and in 53 patients (21.7%) for a third or subsequent episode. Patients treated with fidaxomicin in a first episode were younger (59.9 years vs 73.5 years), but they had more severe episodes (52.1% vs. 32.4%). The recurrence rates for patients treated in the first episode were 6.5% and 9.7% at weeks 8 and 12, respectively. Recurrence rates increased for patients treated at second or ulterior episodes (16.3% and 26.4% at week 8, respectively). Age greater than or equal to 85 years and having had a previous episode of CDI were identified as recurrence risk factors at weeks 8 and 12. We conclude that the outcomes with fidaxomicin in real life are at least as good as those observed in clinical trials despite a more demanding evaluation. Be it 85 years of age or older, and the use after a first episode appears to be independent factors of CDI recurrence after treatment with fidaxomicin.
Læs mere Tjek på PubMedInfection, 1.06.2021
Tilføjet 12.06.2021
Abstract
Background
SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered.
Case presentation
We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery.
Discussion
We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19.
Læs mere Tjek på PubMedMichael D. L. Johnson, Usir S. Younis, Sanjay V. Menghani, Kenneth J. Addison, Michael Whalen, Aprile L. Pilon, Anne E. Cress, Francesca Polverino, Casey E. Romanoski, Monica Kraft, Fernando D. Martinez, Stefano Guerra, Julie G. Ledford
American Journal of Respiratory and Critical Care Medicine , 4.06.2021
Tilføjet 12.06.2021
American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue 11, Page 1410-1418, June 1, 2021.
Læs mere Tjek på PubMedEmerging Infectious Diseases, 10.05.2021
Tilføjet 11.05.2021
Emerging Infectious Diseases, 10.05.2021
Tilføjet 11.05.2021
Cook, L. C.
Infection and Immunity, 10.05.2021
Tilføjet 11.05.2021
M-type 28 Streptococcus pyogenes (Group A Strep, GAS) strains are highly associated with life-threatening puerperal infections. Genome sequencing has revealed a large mobile genetic element, RD2, present in most M28 GAS isolates but not found widely in other serotypes. Previous studies have linked RD2 to the ability of M28 GAS to colonize the vaginal tract. A new study by Roshika and colleagues use gain-of-function mutants in three different GAS serotypes to help determine why RD2 appears to have a serotype preference and what that could mean for GAS mucosal colonization and pathogenesis.
Læs mere Tjek på PubMedDongari-Bagtzoglou, A.
Infection and Immunity, 10.05.2021
Tilføjet 11.05.2021
This work combines a clinical investigation with a mouse model of fungal infection to study the role of bacterial microbiota in fungal invasion. The investigators identified a dysbiosis in the oropharyngeal mucosa that was associated with a high risk for invasive infection in hematologic oncology patients. This study builds on our current understanding that the pathogenesis of fungal infections has to be studied in the context of a specific host background and a site-specific bacterial microbiota.
Læs mere Tjek på PubMedSonawane, V. V., Ruth, M. M., Pennings, L. J., Svensson, E. M., Wertheim, H. F. L., Hoefsloot, W., Van Ingen, J.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Objective: For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence based combination therapy we assessed the in vitro activity of six drugs - clarithromycin (CLR), rifampicin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CFZ), and minocycline (MIN) alone and in combinations against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy.
Methods: The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed time-kill kinetic assays (TKA) of all single drugs and clinically relevant two, three, four and five drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence.
Results: Adding a second drug yielded an average increase of the effect size (E) of 18.7 ± 32.9% log10 cfu/mL*day, though antagonism was seen in some combinations. Adding a third drug showed a lower increase in effect size (+12.2 ± 11.5%). The rifampicin-clofazimine-clarithromycin (E=102 log10 cfu/mL*day), rifampicin-amikacin-clarithromycin (E=101 log10 cfu/mL*day) and amikacin-minocycline-ethambutol (E=97.8 log10 cfu/mL*day) regimens proved more active than the recommended rifampicin-ethambutol-clarithromycin regimen (E=89.1 log10 cfu/mL*day). The addition of a fourth drug had little impact on effect size (+4.54 ± 3.08%).
Conclusions: In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be rifampicin-amikacin-macrolide or rifampicin-clofazimine-macrolide.
Læs mere Tjek på PubMedNguyen, N. T. Q., Gras, E., Tran, N. D., Nguyen, N. N. Y., Lam, H. H., Weiss, W. J., Doan, T. N. M., Diep, B. A.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia is needed for testing new drug candidates in a manner mimicking how they will be used clinically. We have developed a new model in which rabbits were ventilated with low-tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal β-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection when compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.
Læs mere Tjek på PubMedMok, S., Roycroft, E., Flanagan, P. R., Montgomery, L., Borroni, E., Rogers, T. R., Fitzgibbon, M. M.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Pyrazinamide (PZA) is one of the first-line agents used for the treatment of tuberculosis. However, current phenotypic PZA susceptibility testing in the BACTEC MGIT 960 system is unreliable and false resistance is well documented. Rapid identification of resistance-associated mutations can confirm the phenotypic result. This study aimed to investigate the use of genotypic methods in combination with phenotypic susceptibility testing for confirmation of PZA resistant M. tuberculosis isolates. Sanger sequencing and/or whole genome sequencing were performed to detect mutations in pncA, rpsA, panD and clpC1. Isolates were screened for heteroresistance, and PZA susceptibility testing was performed in the BACTEC MGIT 960 system using a reduced inoculum to investigate false resistance.
Overall, 40 phenotypically PZA resistant isolates were identified. Of these, PZA resistance was confirmed in 22/40 (55%) isolates by detecting mutations in pncA, rpsA and panD genes. 16/40 (40%) isolates were found to be susceptible using the reduced inoculum method (i.e. false resistance). No mutations were detected in two PZA resistant isolates. False resistance was observed in isolates with MICs close to the critical concentration. In particular, EAI strains (lineage 1) appeared to have an elevated MIC that is close to the critical concentration. While this study illustrates the complexity and challenges associated with PZA susceptibility testing of M. tuberculosis, we conclude that a combination of genotypic and phenotypic drug susceptibility testing methods is required for accurate detection of PZA resistance.
Læs mere Tjek på PubMedWelte, R., Oberacher, H., Gasperetti, T., Pfisterer, H., Griesmacher, A., Santner, T., Lass-Flörl, C., Hörtnagl, C., Leitner-Rupprich, S., Aigner, M., Lorenz, I., Schmid, S., Edlinger, M., Eller, P., Dankl, D., Joannidis, M., Bellmann, R.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG) and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida (C.) albicans and C. glabrata at concentrations of 0.03 to 16.00 μg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations, because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG, had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata. Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication.
Læs mere Tjek på PubMedFredericks, L. R., Lee, M. D., Eckert, H. R., Li, S., Shipley, M. A., Roslund, C. R., Boikov, D. A., Kizer, E. A., Sobel, J. D., Rowley, P. A.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Compared to other species of Candida yeasts, the growth of Candida glabrata was inhibited by many different strains of Saccharomyces killer yeasts. The ionophoric K1 and K2 killer toxins were broadly inhibitory to all clinical isolates of C. glabrata from patients with recurrent vulvovaginal candidiasis, despite high levels of resistance to clinically relevant antifungal therapeutics.
Læs mere Tjek på PubMedCheung, C. H. P., Alorabi, M., Hamilton, F., Takebayashi, Y., Mounsey, O., Heesom, K. J., Williams, P. B., Williams, O. M., Albur, M., MacGowan, A. P., Avison, M. B.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Meropenem is a clinically important antibacterial reserved for treatment of multi-resistant infections. In meropenem-resistant bacteria of the family Enterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolysing meropenem with almost identical kinetics. We show that blaNDM-1 consistently confers meropenem resistance in wild-type Enterobacterales, but blaIMP-1 does not. The reason is higher blaNDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of blaNDM-1 positive Enterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded blaNDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost but, consequently, the isolates were not meropenem resistant. However, we identified aKlebsiella pneumoniae isolate from this same clinical case carrying the same blaNDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation, reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.
Læs mere Tjek på PubMedKazmierczak, K. M., Karlowsky, J. A., de Jonge, B. L. M., Stone, G. G., Sahm, D. F.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
To estimate the incidence of carbapenem-resistant Enterobacterales (CRE), a global collection of 81,781 surveillance isolates of Enterobacterales collected from patients in 39 countries in five geographic regions from 2012 to 2017 was studied. Overall, 3.3% of isolates were meropenem-nonsusceptible (MIC ≥2 μg/ml), ranging from 1.4% (North America) to 5.3% (Latin America) of isolates by region. Klebsiella pneumoniae accounted for the largest number of meropenem-nonsusceptible isolates (76.7%). The majority of meropenem-nonsusceptible Enterobacterales carried KPC-type carbapenemases (47.4%), metallo-β-lactamases (MBLs; 20.6%) or OXA-48-like β-lactamases (19.0%). Forty-three carbapenemase sequence variants (8 KPC-type, 4 GES-type, 7 OXA-48-like, 5 NDM-type, 7 IMP-type, and 12 VIM-type) were detected, with KPC-2, KPC-3, OXA-48, NDM-1, IMP-4, and VIM-1 identified as the most common variants of each carbapenemase type. The resistance mechanisms responsible for meropenem-nonsusceptibility varied by region. A total of 67.3% of all carbapenemase-positive isolates identified carried at least one additional plasmid-mediated or intrinsic chromosomally encoded extended-spectrum β-lactamase, AmpC β-lactamase, or carbapenemase. The overall percentage of meropenem-nonsusceptible Enterobacterales increased from 2.7% in 2012-2014 to 3.8% in 2015-2017. This increase could be attributed to the increasing proportion of carbapenemase-positive isolates that was observed, most notably among isolates carrying NDM-type MBLs in Asia/South Pacific, Europe and Latin America, OXA-48-like carbapenemases in Europe, Middle East/Africa and Asia/South Pacific, VIM-type MBLs in Europe, and KPC-type carbapenemases in Latin America. Ongoing CRE surveillance combined with a global antimicrobial stewardship strategy, sensitive clinical laboratory detection methods, and adherence to infection control practices will be needed to interrupt the spread of CRE.
Læs mere Tjek på PubMedCameron, A., Mangat, R., Taffner, S., Wang, J., Dumyati, G., Stanton, R. A., Daniels, J. B., Campbell, D., Lutgring, J. D., Pecora, N. D.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Infections caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are a significant cause of morbidity and healthcare costs. Globally, the prevailing clonal type is ST131 in association with the blaCTX-M-15 β-lactamase gene. However, other ESBLs such as blaCTX-M-14 and blaCTX-M-27 can also be prevalent in some regions. We identified ST38 ESBL-producing E. coli from different regions in the US which carry blaCTX-M-27 embedded on two distinct plasmid types, suggesting the potential emergence of new ESBL lineages.
Læs mere Tjek på PubMedHeidrich, D., Pagani, D. M., Koehler, A., de Oliveira Alves, K., Scroferneker, M. L.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Chromoblastomycosis (CBM) is a chronic subcutaneous infection caused by genera of melanized fungi: Fonsecaea, Cladophialophora, Phialophora, Exophiala and Rhinocladiella. Melanin is a virulence factor known to influence antifungal susceptibility. A specific inhibitor of melanin biosynthesis is tricyclazole. The aim of this study was to evaluate the effect of melanin inhibition on antifungal susceptibility of chromoblastomycosis agents and describe the susceptibility profile of some unusual CBM agents. Seventy-six clinical isolates, representing 13 species of the five main CBM agents genera, were studied. The antifungal susceptibility was performed according to the M38-A2 protocol of CLSI. In the melanin inhibition test, 16 mg/L of tricyclazole was added to the medium used in the inoculum preparation and the susceptibility assay. CBM agents were less susceptible to amphotericin B in comparison with azoles and terbinafine. The unusual species showed similar susceptibilities profiles to those of other species of the same genera. With tricyclazole exposition, MICs of terbinafine, posaconazole and itraconazole for Fonsecaea spp. significantly decreased (p<0,05). For Phialophora spp., this reduction was significative for posaconazole and itraconazole. For the other genera, there was a reduction in MICs of terbinafine and itraconazole, however, the statistical tests were not significant. Melanin inhibition can increase the antifungal susceptibility of most CBM agents to itraconazole and terbinafine, the main used drugs in the disease treatment. This increased susceptibility may open up new possibilities for therapy in refractory cases of CBM and/or caused by resistant fungal strains. Further studies are needed to confirm the same results in vivo.
Læs mere Tjek på PubMedRuelens, P., de Visser, J. A. G. M.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Antibiotic-resistance trajectories with different final resistance may critically depend on the first mutation due to epistatic interactions. Here, we study the effect of mutation bias and concentration-dependent fitness effects of two clinically important mutations in TEM-1 β-lactamase initiating alternative trajectories to cefotaxime resistance. We show that mutation R164S, conferring relatively low resistance, is competitively superior over larger-effect mutation G238S at low cefotaxime concentrations, highlighting a critical influence of antibiotic concentration on long-term resistance evolution.
Læs mere Tjek på PubMedWu, X., Li, N., Wang, G., Liu, W., Yu, J., Cao, G., Wang, J., Chen, Y., Ma, J., Wu, J., Yang, H., Mao, X., He, J., Yu, Y., Qiu, C., Li, N., Yao, S., Feng, H., Yan, J., Zhang, W., Zhang, J.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479 or LY-CoV016), in healthy adults. This paper involves a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or a placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.)
Læs mere Tjek på PubMedSchencking, I., Schäfer, E. M., Scanlan, J. H. W., Wenzel, B. M., Emmerich, R. E., Steinmetzer, T., Diederich, W. E., Schlitzer, M., Hartmann, R. K.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
RNase P is an essential enzyme responsible for tRNA 5'-end maturation. In most bacteria, the enzyme is a ribonucleoprotein consisting of a catalytic RNA subunit and a small protein cofactor termed RnpA. Several studies reported small molecule inhibitors directed against bacterial RNase P that were identified by high-throughput screenings. Using the bacterial RNase P enzymes from Thermotoga maritima, Bacillus subtilis and Staphylococcus aureus as model systems, we found that such compounds, including RNPA2000 and derivatives, iriginol hexaacetate and purpurin, induce the formation of insoluble aggregates of RnpA rather than acting as specific inhibitors. In the case of RNPA2000, aggregation was induced by Mg2+ ions. These findings were deduced from solubility analyses by microscopy and HPLC, RnpA-inhibitor co-pulldown experiments, detergent addition and RnpA titrations in enzyme activity assays. Finally, we used a B. subtilis RNase P depletion strain, whose lethal phenotype could be rescued by a protein-only RNase P of plant origin, for inhibition zone analyses on agar plates. These cell-based experiments argued against RNase P-specific inhibition of bacterial growth by RNPA2000. We were also unable to confirm the previously reported non-specific RNase activity of S. aureus RnpA itself. Our results indicate that high-throughput screenings searching for bacterial RNase P inhibitors are prone to the identification of "false positives" that are also termed Pan-assay interference compound s (PAINS).
Læs mere Tjek på PubMedDarlow, C. A., Docobo-Perez, F., Farrington, N., Johnson, A., McEntee, L., Unsworth, J., Jimenez-Valverde, A., Gastine, S., Dona, R. K., de Costa, R. M. A., Ellis, S., Franceschi, F., Standing, J. F., Sharland, M., Neely, M., Piddock, L., Das, S., Hope, W.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Antimicrobial resistance (particularly by extended spectrum β-lactamase and aminoglycoside modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, causing significant mortality. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis; ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance.
The combination was studied in a 16 arm dose ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented emergence of resistance compared to monotherapy of either antibiotic. Modelling of the experimental quantitative outputs and data from checkerboard assays, indicated synergy.
We further assessed the combination regimen at clinically relevant doses in HFIM with nine Enterobacterales strains with high fosfomycin/amikacin MICs and demonstrated successful kill to sterilisation in 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales - MICF * MICA < 256 (where MICF and MICA are MICs for fosfomycin and amikacin). Monte Carlo simulations predict that a standard fosfomycin/amikacin neonatal regimen will achieve a >99% probability of pharmacodynamic success for strains with MICs below this threshold.
We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empiric treatment of neonatal sepsis and is suitable for further clinical assessment in a randomised controlled trial.
Læs mere Tjek på PubMedSingh, K. V., Murray, B. E.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
In a mouse urinary tract infection model, omadacycline (OMC) was comparable to gentamicin and better than ciprofloxacin (CIP) against a tetracycline (TET) susceptible, CIP-R Escherichia coli strain. Gentamicin showed better efficacy than OMC against a TET-R, CIP-R E. coli strain and OMC again showed better efficacy than CIP against this strain. OMC may warrant further study as a potential option for UTI treatment against CIP-R E. coli strains.
Læs mere Tjek på PubMedLebreton, F., Corey, B. W., McElheny, C. L., Iovleva, A., Preston, L., Margulieux, K. R., Cybulski, R. J., McGann, P., Doi, Y., Bennett, J. W.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
KPC-82 is a KPC-2 variant, identified in a carbapenem non-susceptible Citrobacter koseri that confers high-level resistance to ceftazidime-avibactam. Genomic analysis revealed that blaKPC-82 is carried by a chromosomally integrated Tn4401 transposon (disrupting porin gene phoE) and evolved by a 6-nucleotide tandem-repeat duplication causing a two-amino-acid insertion (Ser-Asp) within the Ala267-Ser275 loop. Similar to related KPC variants, KPC-82 showed decreased carbapenemase activity when expressed in a heterologous background and remained susceptible to carbapenem/β-lactamase inhibitor combinations.
Læs mere Tjek på PubMedWasserman, S., Davis, A., Stek, C., Chirehwa, M., Botha, S., Daroowala, R., Bremer, M., Maxebengula, M., Koekemoer, S., Goliath, R., Jackson, A., Crede, T., Naude, J., Szymanski, P., Vallie, Y., Moosa, M. S., Wiesner, L., Black, J., Meintjes, G., Maartens, G., Wilkinson, R. J.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Background
Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.
Materials and methods
We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).
Results
Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg·h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing.
Conclusions
Plasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.
Læs mere Tjek på PubMedMcGuire, R. J., Yu, S. C., Payne, P. R. O., Lai, A. M., Vazquez-Guillamet, M. C., Kollef, M. H., Michelson, A. P.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Infection caused by carbapenem resistant (CR) organisms is a rising problem in the United States. While the risk factors for antibiotic resistance are well known, there remains a large need for the early identification of antibiotic resistant infections. Using machine learning (ML), we sought to develop a prediction model for carbapenem resistance. All patients >18 years of age admitted to a tertiary-care academic medical center between Jan 1, 2012 and Oct 10, 2017 with ≥1 bacterial culture were eligible for inclusion. All demographic, medication, vital sign, procedure, laboratory, and culture/sensitivity data was extracted from the electronic health record. Organisms were considered CR if a single isolate was reported as intermediate or resistant. CR and non-CR patients were temporally matched to maintain positive/negative case ratio. Extreme gradient boosting was used for model development. In total, 68,472 patients met inclusion criteria with 1,088 CR patients identified. Sixty-seven features were used for predictive modeling. The most important features were number of prior antibiotic days, recent central venous catheter placement, and inpatient surgery. After model training, the area under the receiver operating characteristic curve was 0.846. The sensitivity of the model was 30%, with a positive predictive value (PPV) of 30% and a negative predictive value of 99%. Using readily available clinical data, we were able to create a ML model capable of predicting CR infections at the time of culture collection with a high PPV.
Læs mere Tjek på PubMedKong, X., Tang, C., Singh, A., Ahmed, S. A., Al-Hatmi, A. M. S., Chowdhary, A., Nenoff, P., Gräser, Y., Hainsworth, S., Zhan, P., Meis, J. F., Verweij, P. E., Liu, W., de Hoog, G. S.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Background: During the past decade, a prolonged and serious outbreak of dermatophytosis due to a terbinafine-resistant novel species in the Trichophyton mentagrophytes/T. interdigitale complex is ongoing in India, and it spreads to several European countries.
Objective: To investigate the molecular background of the squalene epoxidase (SQLE) gene in order to understand the risk of emergence and spread of multi-resistance in dermatophytes.
Methods: Antifungal susceptibility for fluconazole, griseofulvin, itraconazole, ketoconazole, miconazole, naftifine, sertaconazole, and terbinafine was tested in 135 isolates from India, China, Australia, Germany and The Netherlands. Based on the latest taxonomic insights, strains were identified as three species: T. mentagrophytes s. str. (n=35), T. indotineae (n=64 representing the Indian clone) and T. interdigitale s. str. (n=36).
Results: High minimum inhibitory concentrations (MICs) of terbinafine (>16 mg/L) were found in 34 (53%) T. indotineae isolates. These isolates showed an amino acid substitution in the 397th position of the SQLE gene. Elevated MICs of terbinafine (0.5 mg/L) were noted in 2 (3%) T. indotineae isolates; these isolates lead to Phe415Val and Leu393Ser of the SQLE gene. Stability of the effect of the mutations was proven by serial transfer on drug-free medium. Substitutions of Lys276Asn and Leu419Phe were found in susceptible T. mentagrophytes strains. The double mutant Phe377Leu/Ala448Thr showed higher MIC values for triazoles.
Conclusions: High MICs of terbinafine are as yet limited to T. indotineae, and are unlikely to be distributed through the T. mentagrophytes species complex by genetic exchange.
Læs mere Tjek på PubMedAlbasanz-Puig, A., Gudiol, C., Puerta-Alcalde, P., Ayaz, C. M., Machado, M., Herrera, F., Martin-Davila, P., Laporte-Amargos, J., Cardozo, C., Akova, M., Alvarez-Uria, A., Torres, D., Fortun, J., Garcia-Vidal, C., Munoz, P., Bergas, A., Pomares, H., Mercadal, S., Dura-Miralles, X., Garcia-Lerma, E., Pallares, N., Carratala, J.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Objective: To test the hypothesis that the addition of an aminoglycoside to a ß-lactam antibiotic could provide better outcomes than ß-lactam monotherapy for the initial empirical treatment of hematological neutropenic patients with subsequently documented Gram-negative bacilli (GNB) bloodstream infection (BSI).
Methods: Multinational, retrospective, cohort study of GNB BSI episodes in hematological neutropenic patients in six centers (2010–2017). Combination therapy (ß-lactam plus aminoglycoside) was compared to ß-lactam monotherapy. The primary endpoint was the case-fatality rate assessed at 7 and 30-days from BSI onset. Secondary endpoints were nephrotoxicity and persistent BSI. Propensity score (PS) matching was performed.
Results: Among 542 GNB BSI episodes, 304 (56%) were initially treated with combination therapy, with cefepime plus amikacin being most common (158/304, 52%). Overall, Escherichia coli (273/304, 50.4%) was the main etiological agent, followed by Pseudomonas aeruginosa, which predominated in the combination group [76/304 (25%) vs. 28/238 (11.8%); p<0.001]. Multidrug resistance rates were similar between groups [83/294 (28.2%) vs. 63/233 (27%); p=0.95]. In the multivariate analysis combination therapy was associated with lower 7-day case-fatality rate (OR 0.37, 95%CI 0.14-0.91;p=0.035) with a tendency towards lower mortality at 30 days (OR 0.56, 95%CI 0.29–1.08;p=0.084). After PS-matching, these differences remained for the 7-day case-fatality rate (OR 0.33, 95%CI 0.13–0.82;p=0.017). In addition, aminoglycoside use was not significantly associated with renal function impairment (OR 1.12, 95%CI 0.26–4.87;p=0.9).
Conclusions: The addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered.
Læs mere Tjek på PubMedJohansen, M. D., Shalini, , Kumar, S., Raynaud, C., Quan, D. H., Britton, W. J., Hansbro, P. M., Kumar, V., Kremer, L.
Antimicrobial Agents And Chemotherapy, 10.05.2021
Tilføjet 11.05.2021
Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report herein, the design, synthesis and anti-mycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis with minimal inhibitory concentrations in the range of 0.195-0.39 μg/mL and exerted a more potent bactericidal effect than the standard anti-tubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 μg/mL) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants and biochemical analysis allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising anti-tubercular molecules for further evaluation in pre-clinical settings.
Læs mere Tjek på PubMedThorey K. Jonsdottir, Mikha Gabriela, Brendan S. Crabb, Tania F. de Koning-Ward, Paul R. Gilson
Trends in Parasitology, 10.05.2021
Tilføjet 11.05.2021
To survive inside red blood cells (RBCs), malaria parasites export many proteins to alter their host cell™s physiological properties. Although most proteins of this exportome are involved in immune avoidance or in the trafficking of exported proteins to the host membrane, about 20% are essential for parasite survival in culture but little is known about their biological functions. Here, we have combined information from large-scale genetic screens and targeted gene-disruption studies to tabulate all currently known Plasmodium falciparum exported proteins according to their likelihood of being essential.
Læs mere Tjek på PubMed