Publications by authors named "Vance G Fowler"

288 Publications

Bacterial genotype and clinical outcomes in solid organ transplant recipients with Staphylococcus aureus Bacteremia.

Transpl Infect Dis 2021 Sep 9. Epub 2021 Sep 9.

Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America.

Introduction: Outcomes from Staphylococcus aureus bacteremia (SAB) in solid organ transplant (SOT) recipients are poorly understood.

Methods: This is a prospective cohort study comparing the bacterial genotype and clinical outcomes of SAB among SOT and non-transplant (non-SOT) recipients from 2005 to 2019. Each subject's initial S. aureus bloodstream isolate was genotyped using spa typing and assigned to a clonal complex.

Results: A total of 103 SOT and 1783 non-SOT recipients with SAB were included. Bacterial genotype did not differ significantly between SOT and non-SOT recipients (P=0.4673), including the proportion of SAB caused by USA300 (13.2% vs 16.0%, p=0.2680). Transplant status was not significantly associated with 90-day mortality (18.4% vs 29.5%, aOR 0.74, 95% CI: 0.44, 1.25), but was associated with increased risk for septic shock (50.0% vs 21.8%, aOR 2.31, 95% CI: 1.48, 3.61) and acute respiratory distress syndrome (21.4% vs 13.7%, aOR 2.03, 95%CI: 1.22, 3.37), and a significantly lower risk of metastatic complications (33.0% vs 45.5%, aOR 0.49, 95% CI: 0.32, 0.76). No association was found between bacterial genotype and 90-day mortality (P=0.6222) or septic shock (P=0.5080) in SOT recipients with SAB.

Conclusions: SOT recipients with SAB do not experience greater mortality than non-SOT recipients. The genotype of S. aureus bloodstream isolates in SOT recipients is similar to that of non-SOT recipients, and does not appear to be an important determinant of outcome in SOT recipients with SAB. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/tid.13730DOI Listing
September 2021

Microbial Cell-Free DNA Identifies Etiology of Bloodstream Infections, Persists Longer Than Conventional Blood Cultures, and its Duration of Detection is Associated with Metastatic Infection in Patients with Staphylococcus aureus and Gram-Negative Bacteremia.

Clin Infect Dis 2021 Aug 30. Epub 2021 Aug 30.

Karius, Inc., Redwood City, California, USA.

Background: Microbial cell-free DNA (mcfDNA) sequencing of plasma can identify presence of a pathogen in a host. This study evaluated the duration of pathogen detection by mcfDNA sequencing vs. conventional blood culture in patients with bacteremia.

Methods: Blood samples from patients with culture-confirmed bloodstream infection were collected within 24 hours of the index positive blood culture and 48 to 72 hours thereafter. mcfDNA was extracted from plasma and next-generation sequencing (NGS) applied. Reads were aligned against a curated pathogen database. Statistical significance was defined with Bonferroni adjustment for multiple comparisons (p < 0.0033).

Results: A total of 175 patients with Staphylococcus aureus bacteremia (SAB; n=66), Gram-negative bacteremia (GNB; n=74), or non-infected controls (n=35) were enrolled. The overall sensitivity of mcfDNA sequencing compared to index blood culture was 89.3% (125/140) and the specificity was 74.3%. Among patients with bacteremia, pathogen specific mcfDNA remained detectable for significantly longer than conventional blood cultures (median 15 days vs. 2 days; p<0.0001). Each additional day of mcfDNA detection significantly increased the odds of metastatic infection (Odds Ratio [OR]: 2.89; 95% Confidence Interval [CI]: 1.53-5.46; p=0.0011).

Conclusions: Pathogen mcfDNA identified the bacterial etiology of bloodstream infection for a significantly longer interval than conventional cultures, and its duration of detection was associated with increased risk for metastatic infection. mcfDNA could play a role in the diagnosis of partially treated endovascular infections.
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http://dx.doi.org/10.1093/cid/ciab742DOI Listing
August 2021

Staphylococcus aureus Bacteremia Among Patients Receiving Maintenance Hemodialysis: Trends in Clinical Characteristics and Outcomes.

Am J Kidney Dis 2021 Jul 22. Epub 2021 Jul 22.

Department of Medicine, Duke University Medical Center, Durham, North Carolina; Infectious Diseases, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina;. Electronic address:

Rationale & Objective: Staphylococcus aureus (S. aureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes following SAB in this population over a 21-year period.

Study Design: Prospective cohort study.

Setting & Participants: 453 hospitalized, non-neutropenic, adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015.

Exposures: Clinical characteristics and bacterial genotype.

Outcomes: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic infection complications.

Analytical Approach: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression.

Results: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% per year, 95% confidence interval [CI] 0.36, 0.46), persistent bacteremia (0.86% per year, 95% CI 0.14, 1.55), metastatic infection complications (0.84% per year, 95% CI 0.11, 1.56), and infection with the virulent S. aureus clone USA300 (1.47% per year, 95% CI 0.33, 2.52). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% per year, 95% CI -2.05, -0.56) or arteriovenous (AV) graft (-1.08% per year, 95% CI -1.54, -0.56), but more likely to be a non-vascular access source (1.89% per year, 95% CI 1.29, 2.43). Patients with a non-vascular access suspected source of infection were more likely to die as a result of their S. aureus infection (Odds Ratio [OR] =3.20, 95% CI 1.36, 7.55). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR=2.96, CI 1.12, 7.83) but did not explain the observed increases in SAB-attributable mortality (OR=0.83, CI 0.19, 3.61) or metastatic complications (OR=1.34, CI 0.53, 3.41).

Limitations: Single-center, inpatient cohort.

Conclusions: The clinical and molecular epidemiology of SAB in HD-dependent patients has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.
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http://dx.doi.org/10.1053/j.ajkd.2021.06.018DOI Listing
July 2021

Infective endocarditis and solid organ transplantation: Only worse outcomes during initial transplantation hospitalization.

Am Heart J 2021 Jun 20;240:63-72. Epub 2021 Jun 20.

Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Duke University Medical Center, Durham, North Carolina; Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, MD.

Background: The epidemiology, and outcome of infective endocarditis (IE) among solid organ transplant (SOT) recipients is unknown.

Methods: We used data from the 2013-2018 Nationwide Readmissions Database (NRD). IE- and SOT-associated hospitalizations were identified using diagnosis and procedure codes. Outcomes included inpatient mortality, length of stay, and inpatient costs. Adjusted analyses were performed using weighted regression models.

Results: A total of 99,052 IE-associated hospitalizations, corresponding to a weighted national estimate of 193,164, were included for analysis. Of these, 794 (weighted n = 1,574) were associated with transplant history (SOT-IE). Mortality was not significantly different between SOT-IE and non-SOT-IE (17.2% vs. 15.8%, adjusted relative risk [aRR]: 0.86, 95% confidence interval [CI] [0.71, 1.03]), and fewer SOT-IE patients underwent valve repair or replacement than non-SOT-IE (12.5% vs. 16.2%, aRR 0.82, 95% CI [0.71, 0.95]). We then compared outcomes of patients diagnosed with IE during their index transplant hospitalization (index-SOT-IE) to patients without IE during their transplant hospitalization (index-SOT). Index-SOT-IE occurred most frequently among heart transplant recipients (45.1%), and was associated with greater mortality (27.1% vs. 2.3%, aRR 6.07, 95% CI [3.32, 11.11]).

Conclusion: Dual diagnosis of SOT and IE was associated with worse outcomes among SOT recipients during index hospitalization, but not overall among patients with IE.
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http://dx.doi.org/10.1016/j.ahj.2021.06.007DOI Listing
June 2021

Maternal and fetal outcomes associated with infective endocarditis in pregnancy.

Clin Infect Dis 2021 Jun 10. Epub 2021 Jun 10.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.

Introduction: Infective endocarditis (IE) is a rare but serious infection complicating pregnancy. Little is known about IE management and outcomes in this population.

Methods: The National Readmissions Database was used to obtain data between October 2015 and October 2018. Billing codes identified admissions for IE in female patients of reproductive age. Demographic characteristics, comorbidities, and outcomes were compared between a) patients with maternity-associated and non-maternity associated IE, and b) obstetric patients who delivered with and without IE. Weighted regressions were used to examine outcomes in adjusted models.

Results: We identified 12,602 reproductive-aged female patients with a diagnosis of IE, of which 382 (weighted national estimate: 748) were maternity-associated. Of these cases, 117 (weighted national estimate: 217) occurred during a delivery admission. Compared to patients with non-maternity-associated IE, maternity-associated infection was associated with younger age (mean 29.0 vs. 36.6 years, P < 0.001), Medicaid coverage (72.5% vs. 47.2%, P < 0.001), and drug use (76.2% vs. 59.8%, P < 0.001). Mortality was comparable (8.1% vs. 10.6%, aRR = 1.03, 95% CI 0.71-1.48). Compared to patients delivering without IE, IE complicating delivery was associated with worse maternal and fetal outcomes, including maternal mortality (17.2% vs. <0.01%, aRR = 323.32, 95% CI 127.74-818.37) and preterm birth (55.7% vs. 10.1%, aRR = 3.61, 95% CI 2.58-5.08).

Conclusion: Maternity-associated IE does not appear to confer additional risk for adverse outcome over non-maternity-associated infection. Patients delivering with IE have worse maternal and fetal outcomes than those whose deliveries are not complicated by IE.
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http://dx.doi.org/10.1093/cid/ciab533DOI Listing
June 2021

Macrophage-Produced Peroxynitrite Induces Antibiotic Tolerance and Supersedes Intrinsic Mechanisms of Persister Formation.

Infect Immun 2021 Sep 7;89(10):e0028621. Epub 2021 Jun 7.

Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic-tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia, and recent work has identified a role for oxidative burst in the formation of antibiotic-tolerant S. aureus. We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host and suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.
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http://dx.doi.org/10.1128/IAI.00286-21DOI Listing
September 2021

Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.

Crit Care Med 2021 Oct;49(10):1651-1663

Durham Veterans Affairs Health Care System, Durham, NC.

Objectives: Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test.

Design: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.

Setting: Four U.S. emergency departments.

Patients: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.

Interventions: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.

Measurements And Main Results: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.

Conclusions: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.
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http://dx.doi.org/10.1097/CCM.0000000000005085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448917PMC
October 2021

Impact of immunosuppressive agents on clinical manifestations and outcome of Staphylococcus aureus bloodstream infection - A propensity score matched analysis in two large, prospectively evaluated cohorts.

Clin Infect Dis 2021 Apr 29. Epub 2021 Apr 29.

Division of Infectious Diseases, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection. The impact of immunosuppressive agents on the outcome of patients with SAB is incompletely understood.

Methods: Data from two large prospective, international, multicenter cohort studies (INSTINCT and ISAC) between 2006 and 2015 were analyzed. Patients receiving immunosuppressive agents were identified and a 1:1 propensity score (PS) matched analysis was performed to adjust for baseline characteristics of patients. Overall survival and time to SAB-related late complications (SAB relapse, infective endocarditis, osteomyelitis, or other deep-seated manifestations) were analyzed by Cox regression and competing risk analyses, respectively. This approach was then repeated for specific immunosuppressive agents (corticosteroids [CSMT] and immunosuppressive agents other than steroids [IMOTS]).

Results: Of 3,188 analyzed patients, 309 were receiving immunosuppressive treatment according to our definitions and were matched to 309 non-immunosuppressed patients. After PS matching, baseline characteristics were well balanced. In the Cox regression analysis, we observed no significant difference in survival between the two groups (death during follow-up: 105/309 (33.9 %) immunosuppressed patients vs. 94/309 (30.4 %) non-immunosuppressed, hazard ratio 1.20 (95% CI 0.84-1.71). Competing risk analysis showed a cause-specific hazard ratio (CSHR) of 1.81 (95% CI 0.85-3.87) for SAB-related late-complications in patients receiving immunosuppressive agents. CSHR was higher in patients taking IMOTS (3.69; 95% CI 1.41-9.68).

Conclusions: Immunosuppressive agents were not associated with an overall higher mortality. The risk for SAB-related late complications in patients receiving specific immunosuppressive agents such as IMOTs warrants further investigations.
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http://dx.doi.org/10.1093/cid/ciab385DOI Listing
April 2021

Infective Endocarditis in Patients on Chronic Hemodialysis.

J Am Coll Cardiol 2021 Apr;77(13):1629-1640

Infectious Diseases Service, Hospital Clínic-August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain. Electronic address:

Background: Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD).

Objectives: This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients.

Methods: Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression.

Results: A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001).

Conclusions: HD-IE is a health care-associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non-HD-IE patients, whereas cardiac surgery is less frequently performed.
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http://dx.doi.org/10.1016/j.jacc.2021.02.014DOI Listing
April 2021

Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;

Persistent methicillin-resistant (MRSA) bacteremia is life threatening and occurs in up to 30% of MRSA bacteremia cases despite appropriate antimicrobial therapy. Isolates of MRSA that cause antibiotic-persistent methicillin-resistant bacteremia (APMB) typically have in vitro antibiotic susceptibilities equivalent to those causing antibiotic-resolving methicillin-resistant bacteremia (ARMB). Thus, persistence reflects host-pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in APMB remain unclear. We compared DNA methylomes in circulating immune cells from patients experiencing APMB vs. ARMB. Overall, methylation signatures diverged in the distinct patient cohorts. Differentially methylated sites intensified proximate to transcription factor binding sites, primarily in enhancer regions. In APMB patients, significant hypomethylation was observed in binding sites for CCAAT enhancer binding protein-β (C/EBPβ) and signal transducer/activator of transcription 1 (STAT1). In contrast, hypomethylation in ARMB patients localized to glucocorticoid receptor and histone acetyltransferase p300 binding sites. These distinct methylation signatures were enriched in neutrophils and achieved a mean area under the curve of 0.85 when used to predict APMB using a classification model. These findings validated by targeted bisulfite sequencing (TBS-seq) differentiate epigenotypes in patients experiencing APMB vs. ARMB and suggest a risk stratification strategy for antibiotic persistence in patients treated for MRSA bacteremia.
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http://dx.doi.org/10.1073/pnas.2000663118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958259PMC
March 2021

Antibacterial Resistance Leadership Group 2.0: Back to Business.

Clin Infect Dis 2021 08;73(4):730-739

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

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 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 1 or more of the research priority areas of ARLG 2.0.
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http://dx.doi.org/10.1093/cid/ciab141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366825PMC
August 2021

A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus.

J Clin Microbiol 2021 03 19;59(4). Epub 2021 Mar 19.

Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia

The cefazolin inoculum effect (CzIE) has been associated with therapeutic failures and mortality in invasive methicillin-susceptible (MSSA) infections. A diagnostic test to detect the CzIE is not currently available. We developed a rapid (∼3 h) CzIE colorimetric test to detect staphylococcal-β-lactamase (BlaZ) activity in supernatants after ampicillin induction. The test was validated using 689 bloodstream MSSA isolates recovered from Latin America and the United States. The cefazolin MIC determination at a high inoculum (10 CFU/ml) was used as a reference standard (cutoff ≥16 μg/ml). All isolates underwent genome sequencing. A total of 257 (37.3%) of MSSA isolates exhibited the CzIE by the reference standard method. The overall sensitivity and specificity of the colorimetric test was 82.5% and 88.9%, respectively. Sensitivity in MSSA isolates harboring type A BlaZ (the most efficient enzyme against cefazolin) was 92.7% with a specificity of 87.8%. The performance of the test was lower against type B and C enzymes (sensitivities of 53.3% and 72.3%, respectively). When the reference value was set to ≥32 μg/ml, the sensitivity for isolates carrying type A enzymes was 98.2%. Specificity was 100% for MSSA lacking The overall negative predictive value ranged from 81.4% to 95.6% in Latin American countries using published prevalence rates of the CzIE. MSSA isolates from the United States were genetically diverse, with no distinguishing genomic differences from Latin American MSSA, distributed among 18 sequence types. A novel test can readily identify most MSSA isolates exhibiting the CzIE, particularly those carrying type A BlaZ. In contrast to the MIC determination using high inoculum, the rapid test is inexpensive, feasible, and easy to perform. After minor validation steps, it could be incorporated into the routine clinical laboratory workflow.
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http://dx.doi.org/10.1128/JCM.01938-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092731PMC
March 2021

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.

Am J Transplant 2021 06 20;21(6):2113-2122. Epub 2020 Nov 20.

Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, USA.

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).
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http://dx.doi.org/10.1111/ajt.16388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085168PMC
June 2021

COVID-19-Lessons Learned and Questions Remaining.

Clin Infect Dis 2021 06;72(12):2225-2240

Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA.

In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.
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http://dx.doi.org/10.1093/cid/ciaa1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797746PMC
June 2021

Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study.

Lancet Infect Dis 2020 12 4;20(12):1409-1417. Epub 2020 Aug 4.

Service of Infectious Diseases, Hospital Clínic of Barcelona, Barcelona, Spain. Electronic address:

Background: Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia.

Methods: We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1.

Findings: Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51-75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2-4 days, 43% (30 of 69) with 5-7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51-2·46; p<0·0001).

Interpretation: We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(20)30447-3DOI Listing
December 2020

Temporal encoding of bacterial identity and traits in growth dynamics.

Proc Natl Acad Sci U S A 2020 08 3;117(33):20202-20210. Epub 2020 Aug 3.

Department of Biomedical Engineering, Duke University, Durham, NC 27708;

In biology, it is often critical to determine the identity of an organism and phenotypic traits of interest. Whole-genome sequencing can be useful for this but has limited power for trait prediction. However, we can take advantage of the inherent information content of phenotypes to bypass these limitations. We demonstrate, in clinical and environmental bacterial isolates, that growth dynamics in standardized conditions can differentiate between genotypes, even among strains from the same species. We find that for pairs of isolates, there is little correlation between genetic distance, according to phylogenetic analysis, and phenotypic distance, as determined by growth dynamics. This absence of correlation underscores the challenge in using genomics to infer phenotypes and vice versa. Bypassing this complexity, we show that growth dynamics alone can robustly predict antibiotic responses. These findings are a foundation for a method to identify traits not easily traced to a genetic mechanism.
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http://dx.doi.org/10.1073/pnas.2008807117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443910PMC
August 2020

Complement levels in patients with bloodstream infection due to Staphylococcus aureus or Gram-negative bacteria.

Eur J Clin Microbiol Infect Dis 2020 Nov 4;39(11):2121-2131. Epub 2020 Jul 4.

Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA.

The complement system is a vital component of the innate immune system, though its role in bacteremia is poorly understood. We present complement levels in Staphylococcus aureus bacteremia (SAB) and Gram-negative bacteremia (GNB) and describe observed associations of complement levels with clinical outcomes. Complement and cytokine levels were measured in serum samples from 20 hospitalized patients with SAB, 20 hospitalized patients with GNB, 10 non-infected hospitalized patients, and 10 community controls. C5a levels were significantly higher in patients with SAB as compared to patients with GNB. Low C4 and C3 levels were associated with septic shock and 30-day mortality in patients with GNB, and elevated C3 was associated with a desirable outcome defined as absence of (1) septic shock, (2) acute renal failure, and (3) death within 30 days of bacteremia. Low levels of C9 were associated with septic shock in patients with GNB but not SAB. Elevated IL-10 was associated with increased 30-day mortality in patients with SAB. Complement profiles differ in patients with SAB and those with GNB. Measurement of IL-10 in patients with SAB and of C4, C3, and C9 in patients with GNB may help to identify those at higher risk for poor outcomes.
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http://dx.doi.org/10.1007/s10096-020-03955-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334117PMC
November 2020

PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the ICU.

Chest 2020 12 29;158(6):2370-2380. Epub 2020 Jun 29.

Duke University, Durham, NC; Duke Clinical Research Institute, Durham, NC.

Background: Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials.

Research Question: What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia?

Study Design And Methods: Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission.

Results: Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days.

Interpretation: Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.
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http://dx.doi.org/10.1016/j.chest.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722207PMC
December 2020

The Diversity of Lipopolysaccharide (O) and Capsular Polysaccharide (K) Antigens of Invasive in a Multi-Country Collection.

Front Microbiol 2020 12;11:1249. Epub 2020 Jun 12.

Department of Clinical Microbiology and Microbiology, National Institute for Biomedical Research, University Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo.

is a common cause of sepsis and is particularly associated with healthcare-associated infections. New strategies are needed to prevent or treat infections due to the emergence of multi-drug resistant . The goal of this study was to determine the diversity and distribution of O (lipopolysaccharide) and K (capsular polysaccharide) antigens on a large (>500) global collection of strains isolated from blood to inform vaccine development efforts. A total of 645 isolates were collected from the blood of patients in 13 countries during 2005-2017. Antibiotic susceptibility was determined using the Kirby-Bauer disk diffusion method. O antigen types including the presence of modified O galactan types were determined by PCR. K types were determined by multiplex PCR and capsular typing. Sequence types of isolates were determined by multilocus sequence typing (MLST) targeting seven housekeeping genes. Among 591 isolates tested for antimicrobial resistance, we observed that 19.3% of isolates were non-susceptible to carbapenems and 62.1% of isolates were multidrug resistant (from as low as 16% in Sweden to 94% in Pakistan). Among 645 isolates, four serotypes, O1, O2, O3, and O5, accounted for 90.1% of strains. Serotype O1 was associated with multidrug resistance. Fifty percent of 199 tested O1 and O2 strains were -positive, indicating the presence of the modified polysaccharide subunit D-galactan III. The most common K type was K2 by both multiplex PCR and capsular typing. Of 39 strains tested by MLST, 36 strains were assigned to 26 known sequence types of which ST14, ST25, and ST258 were the most common. Given the limited number of O antigen types, diverse K antigen types and the high multidrug resistance, we believe that an O antigen-based vaccine would offer an excellent prophylactic strategy to prevent invasive infection.
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http://dx.doi.org/10.3389/fmicb.2020.01249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303279PMC
June 2020

Risk Factors for Recurrent Staphylococcus aureus Bacteremia.

Clin Infect Dis 2021 06;72(11):1891-1899

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Background: To understand the clinical, bacterial, and host characteristics associated with recurrent Staphylococcus aureus bacteremia (R-SAB), patients with R-SAB were compared to contemporaneous patients with a single episode of SAB (S-SAB).

Methods: All SAB isolates underwent spa genotyping. All isolates from R-SAB patients underwent pulsed-field gel electrophoresis (PFGE). PFGE-indistinguishable pairs from 40 patients underwent whole genome sequencing (WGS). Acute phase plasma from R-SAB and S-SAB patients was matched 1:1 for age, race, sex, and bacterial genotype, and underwent cytokine quantification using 25-analyte multiplex bead array.

Results: R-SAB occurred in 69 (9.1%) of the 756 study patients. Of the 69 patients, 30 experienced relapse (43.5%) and 39 reinfection (56.5%). Age, race, hemodialysis dependence, presence of foreign body, methicillin-resistant Staphyloccus aureus, and persistent bacteremia were individually associated with likelihood of recurrence. Multivariate risk modeling revealed that black hemodialysis patients were nearly 2 times more likely (odds ratio [OR] = 9.652 [95% confidence interval [CI], 5.402-17.418]) than white hemodialysis patients (OR = 4.53 [95% CI, 1.696-10.879]) to experience R-SAB. WGS confirmed PFGE interpretations in all cases. Median RANTES (regulated on activation, normal T cell expressed and secreted) levels in acute phase plasma from the initial episode of SAB were higher in R-SAB than in matched S-SAB controls (P = .0053, false discovery rate < 0.10).

Conclusion: This study identified several risk factors for R-SAB. The largest risk for R-SAB is among black hemodialysis patients. Higher RANTES levels in R-SAB compared to matched controls warrants further study.
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http://dx.doi.org/10.1093/cid/ciaa801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315037PMC
June 2021

Lead Extraction for Cardiovascular Implantable Electronic Device Infection in Patients With Left Ventricular Assist Devices.

JACC Clin Electrophysiol 2020 06 29;6(6):672-680. Epub 2020 Apr 29.

Division of Electrophysiology, Duke University Medical Center, Durham, North Carolina, USA. Electronic address:

Objectives: The goal of this study was to assess the utility of transvenous lead extraction for cardiovascular implantable electronic device (CIED) infection in patients with a left ventricular assist device (LVAD).

Background: The use of transvenous lead extraction for the management CIED infection in patients with a durable LVAD has not been well described.

Methods: Clinical and outcomes data were collected retrospectively among patients who underwent lead extraction for CIED infection after LVAD implantation at Duke University Hospital.

Results: Overall, 27 patients (n = 6 HVAD; n = 15 HeartMate II; n = 6 Heartmate III) underwent lead extraction for infection. Median (interquartile range) time from LVAD implantation to infection was 6.1 (2.5 to 14.9) months. Indications included endocarditis (n = 16), bacteremia (n = 9), and pocket infection (n = 2). Common pathogens were Staphylococcus aureus (n = 10), coagulase-negative staphylococci (n = 7), and Enterococcus faecalis (n = 3). Sixty-eight leads were removed, with a median lead implant time of 5.7 (3.6 to 9.2) years. Laser sheaths were used in all procedures, with a median laser time of 35.0 s (17.5 to 85.5s). Mechanical cutting tools were required in 11 (40.7%) and femoral snaring in 4 (14.8%). Complete procedural success was achieved in 25 (93.6%) patients and clinical success in 27 (100%). No procedural failures or major adverse events occurred. Twenty-one patients (77.8%) were alive without persistent endovascular infection 1 year after lead extraction. Most were treated with oral suppressive antibiotics after extraction (n = 23 [82.5%]). Persistent infection after extraction occurred in 4 patients and was associated with 50% 1-year mortality.

Conclusions: Transvenous lead extraction for LVAD-associated CIED infection can be performed safely with low rates of persistent infection and 1-year mortality.
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http://dx.doi.org/10.1016/j.jacep.2020.02.006DOI Listing
June 2020

A Narrative Review of Early Oral Stepdown Therapy for the Treatment of Uncomplicated Bacteremia: Yay or Nay?

Open Forum Infect Dis 2020 Jun 5;7(6):ofaa151. Epub 2020 May 5.

Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Historically, intravenous (IV) antibiotics have been the cornerstone of treatment for uncomplicated bacteremia (SAB). However, IV antibiotics are expensive, increase the rates of hospital readmission, and can be associated with catheter-related complications. As a result, the potential role of oral antibiotics in the treatment of uncomplicated SAB has become a subject of interest. This narrative review article aims to summarize key arguments for and against the use of oral antibiotics to complete treatment of uncomplicated SAB and evaluates the available evidence for specific oral regimens. We conclude that evidence suggests that oral step-down therapy can be an alternative for select patients who meet the criteria for uncomplicated SAB and will comply with medical treatment and outpatient follow-up. Of the currently studied regimens discussed in this article, linezolid has the most support, followed by fluoroquinolone plus rifampin.
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http://dx.doi.org/10.1093/ofid/ofaa151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270708PMC
June 2020

Case Report: Successful Rescue Therapy of Extensively Drug-Resistant Osteomyelitis With Cefiderocol.

Open Forum Infect Dis 2020 May 5;7(5):ofaa150. Epub 2020 May 5.

Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina, USA.

Cefiderocol is a novel catechol siderophore cephalosporin antibiotic developed to treat resistant gram-negative infections. We describe its successful use as rescue therapy, combined with surgical debridement, to treat a patient with osteomyelitis due to extensively drug-resistant Bacterial whole-genome sequencing identified the strain and antibiotic resistance determinants.
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http://dx.doi.org/10.1093/ofid/ofaa150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252278PMC
May 2020

Newly Named Klebsiella aerogenes (formerly Enterobacter aerogenes) Is Associated with Poor Clinical Outcomes Relative to Other Species in Patients with Bloodstream Infection.

J Clin Microbiol 2020 08 24;58(9). Epub 2020 Aug 24.

Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina, USA.

was recently renamed This study aimed to identify differences in clinical characteristics, outcomes, and bacterial genetics among patients with versus species bloodstream infections (BSI). We prospectively enrolled patients with or complex () BSI from 2002 to 2015. We performed whole-genome sequencing (WGS) and pan-genome analysis on all bacteria. Overall, 150 patients with (46/150 [31%]) or (104/150 [69%]) BSI were enrolled. The two groups had similar baseline characteristics. Neither total in-hospital mortality (13/46 [28%] versus 22/104 [21%];  = 0.3) nor attributable in-hospital mortality (9/46 [20%] versus 13/104 [12%];  = 0.3) differed between patients with versus BSI, respectively. However, poor clinical outcome (death before discharge, recurrent BSI, and/or BSI complication) was higher for than BSI (32/46 [70%] versus 42/104 [40%];  = 0.001). In a multivariable regression model, BSI, relative to BSI, was predictive of poor clinical outcome (odds ratio 3.3; 95% confidence interval 1.4 to 8.1;  = 0.008). Pan-genome analysis revealed 983 genes in 323 genomic islands unique to isolates, including putative virulence genes involved in iron acquisition ( = 67), fimbriae/pili/flagella production ( = 117), and metal homeostasis ( = 34). Antibiotic resistance was largely found in lineage 1, which had a higher rate of multidrug resistant phenotype (23/54 [43%]) relative to all other bacterial isolates (23/96 [24%];  = 0.03). BSI was associated with poor clinical outcomes relative to BSI. Putative virulence factors in may account for these differences.
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http://dx.doi.org/10.1128/JCM.00582-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448666PMC
August 2020

Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model.

J Antimicrob Chemother 2020 09;75(9):2622-2632

Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA.

Background: MBL-producing strains of Enterobacteriaceae are a major public health concern. We sought to define optimal combination regimens of ceftazidime/avibactam with aztreonam in a hollow-fibre infection model (HFIM) of MBL-producing strains of Escherichia coli and Klebsiella pneumoniae.

Methods: E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied in the HFIM using simulated human dosing regimens of ceftazidime/avibactam and aztreonam. Experiments were designed to evaluate the effect of staggered versus simultaneous administration, infusion duration and aztreonam daily dose (6 g/day versus 8 g/day) on bacterial killing and resistance suppression. Prospective validation experiments for the most active combination regimens were performed in triplicate to ensure reproducibility.

Results: Staggered administration of the combination (ceftazidime/avibactam followed by aztreonam) was found to be inferior to simultaneous administration. Longer infusion durations (2 h and continuous infusion) also resulted in enhanced bacterial killing relative to 30 min infusions. The rate of killing was more pronounced with 8 g/day versus 6 g/day aztreonam combination regimens for both tested strains. In the prospective validation experiments, ceftazidime/avibactam with aztreonam dosed every 8 and 6 h, respectively (ceftazidime/avibactam 2/0.5 g every 8 h + aztreonam 2 g every 6 h), or ceftazidime/avibactam with aztreonam as continuous infusions resulted in maximal bacterial killing and resistance suppression over 7 days.

Conclusions: Simultaneous administration of aztreonam 8 g/day given as a continuous or 2 h infusion with ceftazidime/avibactam resulted in complete bacterial eradication and resistance suppression. Further study of this combination is needed with additional MBL-producing Gram-negative pathogens. The safety of this double β-lactam strategy also warrants further study in Phase 1 clinical trials.
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http://dx.doi.org/10.1093/jac/dkaa197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444334PMC
September 2020

Patients' Experiences With Staphylococcus aureus and Gram-negative Bacterial Bloodstream Infections: A Qualitative Descriptive Study and Concept Elicitation Phase To Inform Measurement of Patient-reported Quality of Life.

Clin Infect Dis 2021 07;73(2):237-247

Duke University, Department of Medicine, Durham North Carolina, USA.

Background: Although Staphylococcus aureus and gram-negative bacterial bloodstream infections (SAB/GNB) cause substantial morbidity, little is known regarding patient perceptions' of their impact on quality of life (QOL). Guidance for assessing QOL and disease-specific measures are lacking. We conducted a descriptive qualitative study to gain an in-depth understanding of patients' experiences with SAB/GNB and concept elicitation phase to inform a patient-reported QOL outcome measure.

Methods: We conducted prospective one-time, in-depth, semi-structured, individual, qualitative telephone interviews 6- 8 weeks following bloodstream infection with either SAB or GNB. Patients were enrolled in an institutional registry (tertiary academic medical center) for SAB or GNB. Interviews were audio-recorded, transcribed, and coded. Directed content analysis identified a priori and emergent themes. Theme matrix techniques were used to facilitate analysis and presentation.

Results: Interviews were completed with 30 patients with SAB and 31 patients with GNB. Most patients were at or near the end of intravenous antibiotic treatment when interviewed. We identified 3 primary high-level concepts: impact on QOL domains, time as a critical index, and sources of variability across patients. Across both types of bloodstream infection, the QOL domains most impacted were physical and functional, which was particularly evident among patients with SAB.

Conclusions: SAB/GNB impact QOL among survivors. In particular, SAB had major impacts on multiple QOL domains. A combination of existing, generic measures that are purposefully selected and disease-specific items, if necessary, could best capture these impacts. Engaging patients as stakeholders and obtaining their feedback is crucial to conducting patient-centered clinical trials and providing patient-centered care.
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http://dx.doi.org/10.1093/cid/ciaa611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282311PMC
July 2021

Consensus on Language for Advance Informed Consent in Health Care-Associated Pneumonia Clinical Trials Using a Delphi Process.

JAMA Netw Open 2020 05 1;3(5):e205435. Epub 2020 May 1.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

Importance: Information to be included in advance informed consent forms for health care-associated pneumonia treatment trials remains to be determined.

Objective: To identify and determine how to describe information to be included in an advance informed consent form for an early-enrollment noninferiority hospital-acquired and/or ventilator-associated bacterial pneumonia (HABP/VABP) clinical trial.

Design, Setting, And Participants: A Delphi consensus process with stakeholders in HABP/VABP clinical trials was conducted using qualitative semistructured telephone interviews from June to August 2016, followed by 2 online surveys, the first from April to May 2017, and the second from September to October 2017. All stakeholders who participated in the interview were invited to participate in the first survey. Stakeholders who participated in the first survey were invited to participate in the second survey. Stakeholders were patients at risk of pneumonia, caregivers, representatives of institutional review boards, investigators, and study coordinators.

Main Outcomes And Measures: Description and consensus of information to be included in advance informed consent forms for early enrollment in noninferiority HABP/VABP clinical trials.

Results: Suggestions from 52 stakeholders about what key informed consent concepts to include and how to explain them were used to create 3 categories to be included in an advance consent form: (1) reassurances on patient health and treatment, (2) rationale for advance consent and early enrollment, and (3) an explanation of noninferiority. At the end of the Delphi process, at least 80% consensus was reached among the 40 stakeholders who participated in the second online survey on each of the statements to include in the proposed consent text. Throughout the process, however, describing and reaching consensus on statements about noninferiority was more problematic than the other categories.

Conclusions And Relevance: The stakeholders endorsed consent language to be used in combination with a strategy for enrolling patients at highest risk for pneumonia before infection onset. Data-driven consent language may help potential participants make informed decisions about their involvement in clinical research and improve enrollment rates, which are necessary to evaluate new treatments and improve patient care. The proposed consent language may be adapted for other trials using an early enrollment strategy and for noninferiority trials.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.5435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244987PMC
May 2020

Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis.

J Clin Invest 2020 07;130(7):3750-3760

ContraFect Corporation, Yonkers, New York, USA.

BACKGROUNDNovel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics.METHODSIn this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14.RESULTSClinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference = -21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone.CONCLUSIONThis study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs.TRIAL REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.
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http://dx.doi.org/10.1172/JCI136577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324170PMC
July 2020

Analytical Evaluation of the Abbott RealTime CT/NG Assay for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae in Rectal and Pharyngeal Swabs.

J Mol Diagn 2020 06 2;22(6):811-816. Epub 2020 Apr 2.

Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California. Electronic address:

Chlamydia trachomatis and Neisseria gonorrhoeae infections in the rectum and pharynx are important extragenital reservoirs of infection. Few assays approved by the US Food and Drug Administration are commercially available to diagnose pharyngeal or rectal infections. The current study reports on the analytical performance of the Abbott RealTime CT/NG assay, including the limit of detection, inclusivity, and analytical specificity for C. trachomatis and N. gonorrhoeae in rectal and pharyngeal specimens. The limit of detection was performed using known concentrations of organisms, elementary bodies per milliliter (EB/mL) for C. trachomatis and colony-forming units per milliliter (CFU/mL) for N. gonorrhoeae, in clinical rectal and pharyngeal swab matrices. Inclusivity was performed against 12 serovars of C. trachomatis and seven strains of N. gonorrhoeae. The analytical specificity was performed using 28 different bacteria and viruses. The limit of detection for C. trachomatis was 2.56 EB/mL in pharyngeal specimens and 12.8 EB/mL in rectal specimens. The limit of detection for N. gonorrhoeae was 0.0256 CFU/mL for both pharyngeal and rectal specimens. The inclusivity and analytical specificity were 100% for both rectal and pharyngeal specimens. These analytical performance data demonstrate that the Abbott CT/NG RealTime assay is an accurate, sensitive, and specific assay in rectal and pharyngeal specimens, supporting the potential of the assay for detection of rectal and pharyngeal C. trachomatis and N. gonorrhoeae infections.
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http://dx.doi.org/10.1016/j.jmoldx.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295135PMC
June 2020

Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study.

Lancet Infect Dis 2020 06 6;20(6):731-741. Epub 2020 Mar 6.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA.

Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227.

Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died.

Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(19)30755-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473597PMC
June 2020
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