Publications by authors named "Yohei Doi"

298 Publications

Functional and Structural Characterization of Acquired Pan-Aminoglycoside Resistance 16S rRNA Methyltransferase NpmB1.

Antimicrob Agents Chemother 2021 Jul 26:AAC0100921. Epub 2021 Jul 26.

Department of Microbiology, Fujita Health University School of Medicine.

Post-translational methylation of the A site of 16S rRNA at position A1408 leads to pan-aminoglycoside resistance encompassing both 4,5- and 4,6-disubstituted 2-deoxystreptamine (DOS) aminoglycosides. To date, NpmA is the only acquired enzyme with such function. Here, we present function and structure of NpmB1 whose sequence was identified in genomes registered from the United Kingdom. NpmB1 possesses 40% amino acid identity with NpmA1 and confers resistance to all clinically relevant aminoglycosides including 4,5-DOS agents. Phylogenetic analysis of NpmB1 and NpmB2, its single amino acid variant, revealed that the encoding gene was likely acquired by from a soil bacterium. The structure of NpmB1 suggests that it requires a structural change of the β6/7 linker in order to bind to 16S rRNA. These findings establish NpmB1 and NpmB2 as the second group of acquired pan-aminoglycoside resistance 16S rRNA methyltransferases.
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http://dx.doi.org/10.1128/AAC.01009-21DOI Listing
July 2021

Association of Time-Updated Anion Gap With Risk of Kidney Failure in Advanced CKD: A Cohort Study.

Am J Kidney Dis 2021 Jul 16. Epub 2021 Jul 16.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

Rationale And Objective: High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD.

Study Design: Retrospective cohort study.

Setting And Participants: 1,168 patients with CKD stages G3b-G5 who had available data on anion gap.

Exposure: High time-updated anion gap defined as values ≥9.2 (top 25th percentile).

Outcomes: KFRT and death.

Analytical Approach: Marginal structural models (MSM) were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding.

Results: The mean baseline eGFR of the study participants was 28 mL/min/1.73m. Over a median follow-up of 3.1 years, 317 patients progressed to KFRT (7.5/100 patient-years) and 146 died (3.5/100 patient-years). In the MSM, a high anion gap was associated with a higher rate of KFRT (hazard ratio [HR], 3.04; 95% confidence interval [CI], 1.94-4.75; P<0.001). This association was stronger in patients with baseline eGFR of <30 mL/min/1.73m (P for interaction=0.05). High anion gap was also associated with a higher mortality rate (HR, 5.56; 95% CI, 2.95-10.5; P<0.001). Sensitivity analyses with different definitions of high anion gap showed similar results.

Limitations: Observational study design; selection bias due clinical indications for measuring anion gap.

Conclusion: Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.022DOI Listing
July 2021

Mean corpuscular hemoglobin concentration: an anemia parameter predicting cardiovascular disease in incident dialysis patients.

J Nephrol 2021 Jul 2. Epub 2021 Jul 2.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Background: Hemoglobin levels usually decline before dialysis initiation. The influence of overhydration on anemia progression and iron sequestration is poorly documented. Furthermore, clinical implications of anemia at dialysis initiation remain to be elucidated.

Methods: This multicenter retrospective cohort study enrolled incident dialysis patients. The patients were stratified by tertiles of overhydration rate (OH-R) defined by (BW - DW)/DW*100 (BW: body weight just before dialysis initiation, DW: dry weight). Time courses (6 months before, to 1 month after, dialysis initiation) of hemoglobin, C-reactive protein (CRP), and iron sequestration index (ISI) were examined using mixed effects models. We used Cox models to identify anemia parameters predicting subsequent cardiovascular disease (CVD).

Results: Among the 905 enrolled patients, hemoglobin levels gradually decreased before dialysis initiation and rapidly increased thereafter. An inverse V-shaped time course was observed for CRP and ISI with an increase during dialysis initiation. Patients with a higher OH-R showed lower hemoglobin levels along with higher CRP and ISI levels before dialysis initiation. Mean corpuscular hemoglobin concentration (MCHC) was more stable before dialysis initiation than were mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Low MCHC (< 32 g/dL) was independently associated with the incidence of nonatherosclerotic CVD. Patients with low MCHC tended to have increased left ventricular wall thickness and left atrial diameter.

Conclusions: Progression of anemia before dialysis among overhydrated patients may mainly occur through hemodilution and iron sequestration partly induced by inflammation. Low MCHC reflects left atrial overload and left ventricular hypertrophy and hence may predict nonatherosclerotic CVD.
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http://dx.doi.org/10.1007/s40620-021-01107-wDOI Listing
July 2021

Impact of Renal Impairment on Intensive Blood-Pressure-Lowering Therapy and Outcomes in Intracerebral Hemorrhage: Results From ATACH-2.

Neurology 2021 Jul 1. Epub 2021 Jul 1.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan

Background And Objectives: The clinical impact of renal impairment on intracerebral hemorrhage (ICH) is unknown. This study sought to exploratory assess whether the estimated glomerular filtration rate (eGFR) affects clinical outcomes or modifies the efficacy of intensive systolic blood pressure (BP) control (target, 110-139 mmHg) against the standard (target, 140-179 mmHg) among patients with ICH.

Methods: We conducted post-hoc analyses of ATACH-2, a randomized, two-group, open-label trial. The baseline eGFR of each eligible patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The outcome of interest was death or disability at 90 days. Multivariate logistic regression models were used for analysis.

Results: Among the 1000 patients randomized, 974 were analyzed. The median baseline eGFR was 88 (interquartile range: 68, 99) ml/min/1.73 m; 451 (46.3%), 363 (37.3%) and 160 (16.4%) patients had baseline eGFR values of ≥90, 60-89, and <60 ml/min/1.73 m, respectively. Compared with normal eGFR (≥90 ml/min/1.73 m), higher odds of death or disability were noted among those with eGFR values of <60 ml/min/1.73 m (adjusted odds ratio (OR) 2.02, 95% confidence interval (CI) 1.25-3.26) but not among those with eGFR values of 60-89 ml/min/1.73 m (OR 1.01, 95% CI 0.70-1.46). The odds of death or disability were significantly higher in the intensive arm among patients with decreased eGFR; the ORs were 0.89 (95% CI 0.55-1.44), 1.13 (0.68-1.89), and 3.60 (1.47-8.80) in patients with eGFR values of ≥90, 60-89, and <60 ml/min/1.73 m, respectively (p for interaction = 0.02).

Discussion: Decreased eGFR is associated with unfavorable outcomes following ICH. The statistically significant interaction between the eGFR group and treatment assignment raised safety concerns for the intensive BP-lowering therapy among patients with renal impairment.

Trial Registration Information: Clinicaltrials.gov (NCT01176565), first submitted on August 6, 2010. The first patient enrolled on May 2011.

Classification Of Evidence: This study provides Class II evidence that in spontaneous ICH, decreased eGFR identifies patients at risk of death or disability following intensive blood pressure control.
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http://dx.doi.org/10.1212/WNL.0000000000012442DOI Listing
July 2021

Virological and genomic analysis of SARS-CoV-2 from a favipiravir clinical trial cohort.

J Infect Chemother 2021 Sep 12;27(9):1350-1356. Epub 2021 Jun 12.

Department of Virology and Parasitology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Introduction: Several clinical studies have reported the efficacy of favipiravir in reducing viral load and shortening the duration of symptoms. However, the viability of SARS-CoV-2 in the context of favipiravir therapy and the potential for resistance development is unclear.

Methods: We sequenced SARS-CoV-2 in nasopharyngeal specimens collected from patients who participated in a randomized clinical trial of favipiravir at hospitals across Japan between March and May 2020. Paired genomes were sequenced from those who remained RT-PCR-positive 5-8 days into favipiravir therapy. Daily nasopharyngeal specimens from 69 patients who were RT-PCR-positive at randomization were examined for a cytopathic effect (CPE).

Results: Some strains early in the trial belonged to clade 19 B, whereas the majority belonged to clade 20 B. The median time from the disease onset to negative CPE was 9 days. CPE was strongly correlated with the time from disease onset, viral load, age, and male sex. Among 23 patients for whom paired genomes were available, all except one had identical genomes. Two mutations were observed in one patient who received favipiravir, neither in the RdRp gene.

Conclusions: The SARS-CoV-2 genome distribution in this clinical trial conducted in Japan reflected the early influx of strains from China followed by replacement by strains from Europe. CPE was significantly associated with age, male sex, and viral loads but not with favipiravir therapy. There was no evidence of resistance development during favipiravir therapy.
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http://dx.doi.org/10.1016/j.jiac.2021.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196299PMC
September 2021

Duration of carbapenemase-producing Enterobacteriales carriage among ICU patients in Miami, FL: A retrospective cohort study.

Am J Infect Control 2021 Jun 17. Epub 2021 Jun 17.

Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL.

Background: Current recommendations by the Centers for Disease Control and Prevention suggest placing patients with carbapenem-producing Enterobacteriales (CPE) in contact precautions, but there is no consensus on the appropriate duration of precautions.

Aim: We aimed to evaluate predictors for prolonged CPE carriage and median clearance time.

Methods: Patients with first isolated CPE identified from 2012-2016 were followed for clearance of CPE using at least two rectal or tracheal aspirate surveillance cultures and clinical cultures during intensive-care-unit admission. Predictors associated with prolonged CPE carriage were assessed using Cox proportional-hazards.

Results: Out of 75 eligible patients, 25 (33%) cleared their CPE-carrier status; median time to clearance was 80 days (Range, 16-457). Patients who were immunocompromised, had mechanical ventilation exposure, or exposure to carbapenems had 66%, 66%, and 86% (HR, 0.34, 0.34, and 0.14, respectively [P-value <.05]) lower probability of clearing compared to those immunocompetent of without such exposures. Patients with CPE isolated from more than one body site had a 5.3 times higher probability of clearing their CPE-carrier status (P-value <.001).

Conclusions: Patients immunocompromised, with mechanical ventilation exposure, or exposure to carbapenems had higher risk for prolonged CPE carriage. Infection prevention programs should consider these predictors as part of their assessment of discontinuing contact precautions among CPE carriers to prevent horizontal transmission and outbreaks within healthcare facilities.
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http://dx.doi.org/10.1016/j.ajic.2021.06.006DOI Listing
June 2021

Rapid diagnostic testing for antimicrobial stewardship: Utility in Asia Pacific.

Infect Control Hosp Epidemiol 2021 Jul 15;42(7):864-868. Epub 2021 Jun 15.

Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Rapid diagnostic testing (RDT) can provide prompt, accurate identification of infectious organisms and be a key component of antimicrobial stewardship (AMS) programs. However, their use is less widespread in Asia Pacific than western countries. Cost can be prohibitive, particularly in less resource-replete settings. A selective approach is required, possibly focusing on the initiation of antimicrobials, for differentiating bacterial versus viral infections and identifying locally relevant tropical diseases. Across Asia Pacific, more data are needed on RDT use within AMS, focusing on the impact on antimicrobial usage, patient morbidity and mortality, and cost effectiveness. Moreover, in the absence of formal guidelines, regional consensus statements to guide clinical practice are warranted. These will provide a regionally relevant definition for RDT; greater consensus on its role in managing infections; advice on implementation and overcoming barriers; and guidance on optimizing human resource capacity. By addressing these issues, the outcomes of AMS programs should improve.
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http://dx.doi.org/10.1017/ice.2021.149DOI Listing
July 2021

Shedding of Viable Virus in Asymptomatic SARS-CoV-2 Carriers.

mSphere 2021 05 19;6(3). Epub 2021 May 19.

Department of Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Information regarding the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in asymptomatic carriers is scarce. In order to determine the duration of infectivity and its correlation with reverse transcription-PCR (RT-PCR) results and time since initial positive PCR test in this population, we evaluated SARS-CoV-2 cell infectivity in nasopharyngeal samples longitudinally obtained from asymptomatic carriers who disembarked from a cruise ship during a COVID-19 outbreak. Of 166 nasopharyngeal samples collected from 39 asymptomatic carriers every 48 h until two consecutive negative PCR test results were obtained, SARS-CoV-2 was successfully isolated from 9 PCR-positive samples which were obtained from 7 persons (18%; 7/39). Viable viruses were isolated predominantly within 7 days after the initial positive PCR test, except for one person who shed viable virus until day 15. The median crossing point (Cp) value of RT-PCR of culture-positive samples was 24.6 (interquartile range [IQR], 20.4 to 25.8; range, 17.9 to 30.3), and Cp values were significantly associated with isolation of viable virus (odds ratio, 0.496; 95% confidence interval [CI], 0.329 to 0.747; value, 0.001), which was consistent with existing data for symptomatic patients. Genome sequence analysis of SARS-CoV-2 samples consecutively obtained from a person who shed viable virus for 15 days identified the emergence of two novel single nucleotide variants (C8626T transition and C18452T transition) in the sample collected on day 15, with the latter corresponding to an amino acid substitution in nonstructural protein 14. The impact of these mutations on prolonged viable-virus shedding is unclear. These findings underscore the potential role of asymptomatic carriers in transmission. A growing number of studies suggest the potential role of asymptomatic SARS-CoV-2 carriers as a major driver of the COVID-19 pandemic; however, virological assessment of asymptomatic infection has largely been limited to reverse transcription-PCR (RT-PCR), which can be persistently positive without necessarily indicating the presence of viable virus (e.g., replication-competent virus). Here, we evaluated the infectivity of asymptomatic SARS-CoV-2 carriers by detecting SARS-CoV-2-induced cytopathic effects on Vero cells using longitudinally obtained nasopharyngeal samples from asymptomatic carriers. We show that asymptomatic carriers can shed viable virus until 7 days after the initial positive PCR test, with one outlier shedding until day 15. The crossing point (Cp) value of RT-PCR was the leading predictive factor for virus viability. These findings provide additional insights into the role of asymptomatic carriers as a source of transmission and highlight the importance of universal source control measures, along with isolation policy for asymptomatic carriers.
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http://dx.doi.org/10.1128/mSphere.00019-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265619PMC
May 2021

Cyclosporine A Treatment of Proteinuria in a New Case of MAFB-Associated Glomerulopathy without Extrarenal Involvement: A Case Report.

Nephron 2021 11;145(4):445-450. Epub 2021 May 11.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The MAFB gene encodes an important basic leucine zipper transcription factor that functions in glomerular podocytes, macrophages, and osteoclasts. Recently, MAFB was identified as the gene that was responsible for causing nephropathy with focal segmental glomerulosclerosis (FSGS) with multicentric carpotarsal osteolysis (MCTO) or Duane retraction syndrome (DRS). Here, we describe a patient with nephropathy associated with FSGS who exhibited a novel stop-gain variant in the MAFB gene (NM_005461:c.590C>A (p.Ser197Ter)). The patient's father exhibited proteinuria with FSGS with possible DRS, whereas the patient exhibited nephropathy with FSGS and nearly normal eye movement and hearing function, as well as intact bone structure in the extremities. Conventional oral steroids or immunosuppressive drugs have not demonstrated effectiveness for patients with nephropathy who exhibit pathogenic variants in MAFB, except for a patient with nephropathy with FSGS and MCTO who experienced attenuated proteinuria within the subnephrotic range in response to cyclosporine A (CyA) treatment for at least 4 years. Thus, we attempted administration of CyA in our patient. Unexpectedly, the patient demonstrated good and rapid responses to CyA, including a partial reduction in proteinuria from approximately 2.0 g/g Cr to proteinuria within the subnephrotic range (0.27 g/g Cr) after 13 months of observation. Our findings suggest that CyA may be a suitable treatment option for patients with nephropathy with FSGS who exhibit pathogenic MAFB variants.
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http://dx.doi.org/10.1159/000516248DOI Listing
May 2021

Characterization of KPC-82, a KPC-2 Variant Conferring Resistance to Ceftazidime-Avibactam in a Carbapenem-Nonsusceptible Clinical Isolate of Citrobacter koseri.

Antimicrob Agents Chemother 2021 06 17;65(7):e0015021. Epub 2021 Jun 17.

Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

KPC-82 is a KPC-2 variant identified in a carbapenem-nonsusceptible Citrobacter koseri that confers high-level resistance to ceftazidime-avibactam. Genomic analysis revealed that is carried by a chromosomally integrated Tn transposon (disrupting porin gene ) and evolved by a 6-nucleotide tandem repeat duplication causing a two-amino-acid insertion (Ser-Asp) within the Ala-Ser 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.
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http://dx.doi.org/10.1128/AAC.00150-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218621PMC
June 2021

Comparative Analysis of Antigen-Specific Anti-SARS-CoV-2 Antibody Isotypes in COVID-19 Patients.

J Immunol 2021 05 3;206(10):2393-2401. Epub 2021 May 3.

Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan.

Serological tests for detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Abs in blood are expected to identify individuals who have acquired immunity against SARS-CoV-2 and indication of seroprevalence of SARS-CoV-2 infection. Many serological tests have been developed to detect Abs against SARS-CoV-2. However, these tests have considerable variations in their specificity and sensitivity, and whether they can predict levels of neutralizing activity is yet to be determined. This study aimed to investigate the kinetics and neutralizing activity of various Ag-specific Ab isotypes against SARS-CoV-2 in serum of coronavirus disease 2019 (COVID-19) patients confirmed via PCR test. We developed IgG, IgM, and IgA measurement assays for each Ag, including receptor-binding domain (RBD) of spike (S) protein, S1 domain, full-length S protein, S trimer, and nucleocapsid (N) domain, based on ELISA. The assays of the S protein for all isotypes showed high specificity, whereas the assays for all isotypes against N protein showed lower specificity. The sensitivity of all Ag-specific Ab isotypes depended on the timing of the serum collection and all of them, except for IgM against N protein, reached more than 90% at 15-21 d postsymptom onset. The best correlation with virus-neutralizing activity was found for IgG against RBD, and levels of IgG against RBD in sera from four patients with severe COVID-19 increased concordantly with neutralizing activity. Our results provide valuable information regarding the selection of serological test for seroprevalence and vaccine evaluation studies.
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http://dx.doi.org/10.4049/jimmunol.2001369DOI Listing
May 2021

Elastase Activity From Pseudomonas aeruginosa Respiratory Isolates and ICU Mortality.

Chest 2021 Apr 17. Epub 2021 Apr 17.

Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. Electronic address:

Background: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.

Research Question: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?

Methods: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality were calculated using logistic regression. For subgroup analysis, the two patterns of early (<72h) and late sample (>72h) collections from index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer.

Results: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95%CI]. 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity is a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer.

Interpretation: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo.
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http://dx.doi.org/10.1016/j.chest.2021.04.015DOI Listing
April 2021

Diagnostic accuracy of LAMP versus PCR over the course of SARS-CoV-2 infection.

Int J Infect Dis 2021 Jun 20;107:195-200. Epub 2021 Apr 20.

Department of Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Objective: Reverse transcription loop-mediated isothermal amplification (RT-LAMP) has been validated to diagnose several viral infections. However, its diagnostic accuracy in detecting SARS-CoV-2 in real-life clinical settings remains unclear. This study aimed to determine the diagnostic sensitivity and specificity of RT-LAMP compared to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) over the disease course of COVID-19.

Methods: A total of 124 nasopharyngeal swab samples obtained from 24 COVID-19 patients were tested by RT-LAMP and RT-qPCR. Sensitivities and specificities of RT-LAMP compared with RT-qPCR were analyzed as a function of time from onset.

Results: Up to the 9th day after onset, the RT-LAMP had a positivity of 92.8%, and the sensitivity and specificity compared with RT-qPCR was 100%. However, after the 10th day after onset, the positivity of RT-LAMP decreased to less than 25%, and the concordance of positivity between the two methods was below 60%. The limit of detection of RT-LAMP was 6.7 copies/reaction.

Conclusions: Until the 9th day after the onset of symptoms, RT-LAMP had the same diagnostic accuracy as RT-qPCR. These findings suggest that RT-LAMP can be used as a diagnostic tool for COVID-19 as an alternative to RT-qPCR in the acute symptomatic phase of COVID-19.
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http://dx.doi.org/10.1016/j.ijid.2021.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056478PMC
June 2021

Outcomes of Adjunctive Therapy with Intravenous Cefoperazone-Sulbactam for Ventilator-Associated Pneumonia Due to Carbapenem-Resistant .

Infect Drug Resist 2021 29;14:1255-1264. Epub 2021 Mar 29.

Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand.

Introduction: The efficacy of adjunctive therapy with cefoperazone-sulbactam (CEP-SUL) for ventilator-associated pneumonia (VAP) due to carbapenem-resistant (CRAB) is unclear.

Methods: We retrospectively analyzed the therapeutic effect of adding CEP-SUL to standard regimens for VAP due to CRAB. Patients with VAP due to CRAB strains that were susceptible to CEP-SUL were enrolled into the study. The patients were divided into two groups: those who receive cefoperazone-sulbactam (CEP-SUL), and those who did not receive cefoperazone-sulbactam (CEP-SUL). Mortality rates and resource utilization of these two groups were compared. Factors associated with mortality were explored.

Results: Eighty patients were enrolled into the study, 52 CEP-SUL and 28 CEP-SUL. The baseline characteristics of the two groups were comparable, except for median Acute Physiology and Chronic Health Evaluation (APACHE) II score which was significantly higher for CEP-SUL. Thirty-day, and in-hospital mortality rates for CEP-SUL were significantly lower than CEP-SUL with values of 35%, 39% and 61%, 68%, for CEP-SUL and CEP-SUL, respectively. The survival rate for CEP-SUL was significantly higher compared with CEP-SUL ( < 0.001). The number of hospital days, ventilator days since diagnosis of VAP and hospital costs were lower for CEP-SUL.

Conclusion: Overall results suggested that patients with VAP due to CRAB strains who received adjunctive therapy with CEP-SUL had lower mortality rates and resource utilization compared with CEP-SUL.
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http://dx.doi.org/10.2147/IDR.S305819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018428PMC
March 2021

Institutional outbreak involving multiple clades of IMP-producing Enterobacter cloacae complex sequence type 78 at a cancer center in Tokyo, Japan.

BMC Infect Dis 2021 Mar 22;21(1):289. Epub 2021 Mar 22.

Department of Infectious Diseases, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: Information about the clinical and microbiological characteristics of IMP-producing Enterobacterales has been limited. Here, we describe an institutional outbreak of IMP-producing Enterobacter cloacae complex (ECC) involving multiple clades of ECC sequence type (ST) 78 strains.

Methods: Antimicrobial susceptibility testing, whole-genome sequencing, and conjugation experiments of 18 IMP-producing ECC strains isolated during four-year study period were performed. Species and subspecies were determined by average nucleotide identity analysis and clonal relatedness of the isolates was analyzed with multilocus sequence typing and core-genome single nucleotide polymorphism (SNP) analysis. Relevant clinical information was extracted from medical records.

Results: Fourteen of 18 IMP-producing ECC isolates were determined as Enterobacter hormaechei ST78. Sixteen isolates, including 13 isolates belonging to ST78, carried bla in In316-like class 1 integron and also carried IncHI2 plasmids. Conjugation experiments were successful for 12 isolates carrying bla on IncHI2 plasmids and for an isolate carrying bla on an IncL/M plasmid. Although isolation of ST78 strains was clustered in a 14-months period suggesting nosocomial transmission, these strains were subdivided into three clades by SNP analysis: clade A (n = 10), clade B (n = 1), clade C (n = 3). A part of clonal relatedness was unexpected by the epidemiological information at the time of isolation of the strains. Most of the IMP-producing ECC strains were susceptible to non-β-lactam antibiotics and had relatively low minimum inhibitory concentrations to carbapenems (≤4 μg/mL). Five of six infections caused by IMP-producing ECC were treated successfully.

Conclusions: Whole-genome sequencing analysis revealed the outbreak was caused by three different clades of ST78 strains, where patients had favorable treatment outcome of the infections compared with that caused by Enterobacterales producing other carbapenemases, possibly due to their non-multidrug-resistant phenotype.
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http://dx.doi.org/10.1186/s12879-021-05952-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983292PMC
March 2021

Molecular characterization of clinical carbapenem-resistant Enterobacterales from Qatar.

Eur J Clin Microbiol Infect Dis 2021 Aug 22;40(8):1779-1785. Epub 2021 Feb 22.

Division of Infectious Diseases, Department of Medicine, Hamad Medical Corporation, Doha, Qatar.

One hundred forty-nine carbapenem-resistant Enterobacterales from clinical samples obtained between April 2014 and November 2017 were subjected to whole genome sequencing and multi-locus sequence typing. Klebsiella pneumoniae (81, 54.4%) and Escherichia coli (38, 25.5%) were the most common species. Genes encoding metallo-β-lactamases were detected in 68 (45.8%) isolates, and OXA-48-like enzymes in 60 (40.3%). bla (45; 30.2%) and bla (29; 19.5%) were the most frequent. KPC-encoding genes were identified in 5 (3.6%) isolates. Most common sequence types were E. coli ST410 (8; 21.1%) and ST38 (7; 18.4%), and K. pneumoniae ST147 (13; 16%) and ST231 (7; 8.6%).
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http://dx.doi.org/10.1007/s10096-021-04185-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295067PMC
August 2021

Antibacterial Resistance Leadership Group 2.0 - Back to Business.

Clin Infect Dis 2021 Feb 15. Epub 2021 Feb 15.

Duke Clinical Research Institute, Durham, North Carolina, USA.

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another seven-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has three overarching research priorities: (1) infections caused by antibiotic resistant (AR) Gram-negative bacteria; (2) infections caused by AR Gram-positive bacteria, and (3) diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers three mentoring opportunities: the ARLG Fellowship, Early Stage Investigator Seed Grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses one or more of the research priority areas of ARLG 2.0.
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http://dx.doi.org/10.1093/cid/ciab141DOI Listing
February 2021

The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study.

Am J Transplant 2021 Feb 10. Epub 2021 Feb 10.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m (95% CI; -0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m (95% CI, -0.02 to 3.7) in the placebo group, with no significant between-group difference (-0.7 mL/min/1.73 m [95% CI; -3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m (P <0.05, between-group difference; -4.3 mL/min/1.73 m [95% CI; -7.3 to -1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs. Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN000020597 (please refer to the links below). UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023776.
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http://dx.doi.org/10.1111/ajt.16530DOI Listing
February 2021

Lung Pathology of Mutually Exclusive Co-infection with SARS-CoV-2 and Streptococcus pneumoniae.

Emerg Infect Dis 2021 03 14;27(3):919-923. Epub 2021 Jan 14.

Postmortem lung pathology of a patient in Japan with severe acute respiratory syndrome coronavirus 2 infection showed diffuse alveolar damage as well as bronchopneumonia caused by Streptococcus pneumoniae infection. The distribution of each pathogen and the accompanying histopathology suggested the infections progressed in a mutually exclusive manner within the lung, resulting in fatal respiratory failure.
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http://dx.doi.org/10.3201/eid2703.204024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920656PMC
March 2021

Electrocardiogram findings at the initiation of hemodialysis and types of subsequent cardiovascular events.

Hypertens Res 2021 May 4;44(5):571-580. Epub 2021 Jan 4.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The prognostic value of electrocardiograms (ECGs) has been reported in predialysis patients but not in incident hemodialysis patients with overhydration and electrolyte disturbances, both of which potentially affect ECG results. We performed a retrospective multicenter cohort study involving incident hemodialysis patients and examined whether ECG parameters immediately before hemodialysis initiation can predict subsequent cardiovascular disease (CVD) using Cox proportional hazards models. We explored potential effect modifications by several electrolytes on the predictive power of ECG abnormalities. Among the 618 enrolled patients, 16%, 10%, 46%, and 22% showed a PR interval ≥ 200 ms, QRS interval ≥120 ms, QTc interval ≥ 450/460 ms (male/female), and left ventricular hypertrophy (LVH) by voltage criteria, respectively. Over a median 3-year follow-up, 19% and 16% of the patients developed atherosclerotic and nonatherosclerotic CVD, respectively. The Cox regression model results revealed that the sum of the number of abnormalities in PR, QRS, and QT intervals was a significant risk factor for nonatherosclerotic CVD (hazard ratios (HRs) [95% confidence interval (CI)]: 1.58 [1.24-2.01] per number of abnormalities). The predictive value of LVH for atherosclerotic CVD was attenuated over time. At up to 36 months, although the proportional hazards assumption was met, LVH was significantly associated with atherosclerotic CVD (HR [95% CI]: 1.89 [1.15-3.11]). The adjusted HR was particularly high (HR [95% CI]: 4.02 [1.68-9.60]) among patients who were in the lowest tertile of serum magnesium levels (P for interaction = 0.04). PR, QRS, and QT prolongation additively predicted nonatherosclerotic CVD, while LVH predicted atherosclerotic CVD in the short term.
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http://dx.doi.org/10.1038/s41440-020-00592-zDOI Listing
May 2021

Genomic patterns and characterizations of chromosomally-encoded mcr-1 in Escherichia coli populations.

Gut Pathog 2020 Nov 28;12(1):55. Epub 2020 Nov 28.

Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.

The emergence and transmission of the mobile colistin resistance gene (mcr-1) threatened the extensive use of polymyxin antimicrobials. Accumulated evidence showed that the banning of colistin additive in livestock feed efficiently reduce mcr-1 prevalence, not only in animals but also in humans and environments. However, our previous study has revealed that a small proportion of Escherichia coli could continually carry chromosomally-encoded mcr-1. The chromosomally-encoded events, indicated the existence of stabilized heritage of mcr-1 and revealed a potential threat in the antimicrobial stewardship interventions, are yet to be investigated. In this study, we systematically investigated the genetic basis of chromosomally-encoded mcr-1 in prevalence and potential mechanisms of lineage, plasmid, insertion sequence, and phage. Our results demonstrated that the emergence of chromosomally-encoded mcr-1 could originate from multiple mechanisms, but mainly derived through the recombination of ISApl1/Tn6330. We reported a specific transmission mechanism, which is a phage-like region without lysogenic components, could associate with the emergence and stabilization of chromosomally-encoded mcr-1. These results highlighted the potential origin and risks of chromosomally-encoded mcr-1, which could be a heritable repository and thrive again when confronted with new selective pressures. To the best of our knowledge, this is the first study to systematically reveal the genomic basis of chromosomally-encoded mcr-1, and report a specific transmission pattern involved in phage-like region. Overall, we demonstrate the origin mechanisms and risks of chromosomally-encoded mcr-1. It highlights the need of public attention on chromosome-encoded mcr-1 to prevent from its reemergence.
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http://dx.doi.org/10.1186/s13099-020-00393-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700713PMC
November 2020

Extensively drug-resistant IMP-16-producing Pseudomonas monteilii isolated from cerebrospinal fluid.

Infect Genet Evol 2021 01 30;87:104658. Epub 2020 Nov 30.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. Electronic address:

IMP-1-producing Pseudomonas aeruginosa was first reported in Japan and since then, bacteria with this metallo-β-lactamase have been detected worldwide. Pseudomonas monteilii (part of P. putida group) were considered an environmental pathogen with low virulence potential; however, multidrug-resistant and carbapenem-resistant P. monteilii have emerged. The present study reports the draft sequence of an extensively drug-resistant IMP-16-producing P. monteilii 597/14 isolated from cerebrospinal fluid in 2014. The sequencing data revealed bla as a gene cassette on class 1 integron, In1738 characterized in this study. Furthermore, the resistome of Pm597/14 consisted of 7 resistance genes (aadA1b, strA, strB, aacA4, bla, bla, sul1) and diverse virulence determinants involved in the adherence, LPS, antiphagocytosis, iron uptake and mercuric resistance. Although different virulence determinants were found in this study, using Galleria mellonella infection model, Pm597/14 did not kill any larvae between 7 days post-infection. P. monteilii isolates have been reported from clinical and environmental sources, carrying different MBL genes showing its potential role as their reservoir.
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http://dx.doi.org/10.1016/j.meegid.2020.104658DOI Listing
January 2021

Risk factors for the development of infections associated with carbapenemase-producing among previously colonized patients: A retrospective cohort study.

Infect Control Hosp Epidemiol 2021 Jun 20;42(6):763-766. Epub 2020 Nov 20.

Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, Florida.

Not all patients who acquire carbapenemase-producing Enterobacteriaceae (CPE) develop infections by these organisms; many remain only colonized. Of 54 CPE-colonized patients, 16 (30%) developed CPE infections. We identified indwelling urinary catheter exposure, exposure to intravenous colistin, and overseas transfer as variables associated with CPE infection development among colonized patients.
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http://dx.doi.org/10.1017/ice.2020.1270DOI Listing
June 2021

KPC-3-Producing Serratia marcescens Outbreak between Acute and Long-Term Care Facilities, Florida, USA.

Emerg Infect Dis 2020 11;26(11):2746-2750

We describe an outbreak caused by Serratia marcescens carrying bla that was sourced to a long-term care facility in Florida, USA. Whole-genome sequencing and plasmid profiling showed involvement of 3 clonal lineages of S. marcescens and 2 bla-carrying plasmids. Determining the resistance mechanism is critical for timely implementation of infection control measures.
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http://dx.doi.org/10.3201/eid2611.202203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588513PMC
November 2020

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

Lancet Infect Dis 2021 02 12;21(2):226-240. Epub 2020 Oct 12.

Shionogi, Osaka, Japan. Electronic address:

Background: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Funding: Shionogi.
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http://dx.doi.org/10.1016/S1473-3099(20)30796-9DOI Listing
February 2021

Aminoglycoside Resistance: Updates with a Focus on Acquired 16S Ribosomal RNA Methyltransferases.

Infect Dis Clin North Am 2020 12 30;34(4):887-902. Epub 2020 Sep 30.

Department of Bacteriology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan; Department of Medical Technology, Shubun University, Japan.

The clinical usefulness of aminoglycosides has been revisited as an effective choice against β-lactam-resistant and fluoroquinolone-resistant gram-negative bacterial infections. Plazomicin, a next-generation aminoglycoside, was introduced for the treatment of complicated urinary tract infections and acute pyelonephritis. In contrast, bacteria have resisted aminoglycosides, including plazomicin, by producing 16S ribosomal RNA (rRNA) methyltransferases (MTases) that confer high-level and broad-range aminoglycoside resistance. Aminoglycoside-resistant 16S rRNA MTase-producing gram-negative pathogens are widespread in various settings and are becoming a grave concern. This article provides up-to-date information with a focus on aminoglycoside-resistant 16S rRNA MTases.
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http://dx.doi.org/10.1016/j.idc.2020.06.002DOI Listing
December 2020

Reliability of serological tests for COVID-19: comparison of three immunochromatography test kits for SARS-CoV-2 antibodies.

Heliyon 2020 Sep 10;6(9):e04929. Epub 2020 Sep 10.

Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Background: Several immunochromatographic serological test kits have been developed to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, but their relative performance and potential clinical utility is unclear.

Methods: Three commercially available serological test kits were evaluated using 99 serum samples collected from 29 patients diagnosed with coronavirus disease 2019 (COVID-19) and 100 serum samples collected from 100 healthy volunteers in 2017 as negative controls.

Results: The specificity of the IgM and IgG antibodies showed comparable results among the three immunochromatographic serological test kits. The specificity for IgM antibody was 98.0%, 98.0%, and 97.0%, and the specificity for IgG antibody was identical among the three kits (99.0%). The IgM antibody-positive rates of the three test kits for samples taken at the early stage of the disease (0-4 days after onset) were consistent with all three kits (18.2%); however, the IgM antibody-positive rates thereafter showed considerable differences among the kits, making it difficult to interpret the kinetics of IgM response against SARS-CoV-2. The IgG antibody-positive rates for samples taken after 13 days of onset were 100.0%, 97.6%, and 97.6%, respectively.

Conclusion: There were large differences among the results of the three test kits. Only few cases showed positive results for IgM, suggesting that at least 2 of these kits used in this study were unsuitable for diagnosis of COVID-19. The IgG antibody was positive in almost all samples after 13 days of onset, suggesting that it may be useful for determining infections in the recent past.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495099PMC
September 2020

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Center for Clinical Trial and Research Support, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).
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http://dx.doi.org/10.1128/AAC.01897-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674035PMC
November 2020

Evolution of CTX-M-215, a Novel Narrow-Spectrum β-Lactamase in an Escherichia coli Clinical Isolate Conferring Resistance to Mecillinam.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China

Here, we report a novel narrow-spectrum β-lactamase CTX-M-215 identified in an clinical isolate in China and conferring high-level resistance to mecillinam but not to cefotaxime. CTX-M-215 differed from CTX-M-125, a CTX-M extended-spectrum β-lactamase (ESBL), by an N132D substitution, which decreased hydrolytic activities toward penicillins and cephalosporins except for mecillinam. High similarity was observed between CTX-M-215- and CTX-M-125-bearing plasmids, carried by different isolates in the same patient, indicating evolution of CTX-M-215 from CTX-M-125.
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http://dx.doi.org/10.1128/AAC.00562-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577136PMC
October 2020
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