Browsing by Subject "Bacteremia"

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    ItemOpen Access
    A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting.
    (BMC Infect Dis, 2014-02-13) Nelson, Charlotte L; Pelak, Kimberly; Podgoreanu, Mihai V; Ahn, Sun Hee; Scott, William K; Allen, Andrew S; Cowell, Lindsay G; Rude, Thomas H; Zhang, Yurong; Tong, Amy; Ruffin, Felicia; Sharma-Kuinkel, Batu K; Fowler, Vance G
    BACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.
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    A prospective study of Escherichia coli bloodstream infection among adolescents and adults in northern Tanzania.
    (Transactions of the Royal Society of Tropical Medicine and Hygiene, 2020-05) Madut, Deng B; Rubach, Matthew P; Kalengo, Nathaniel; Carugati, Manuela; Maze, Michael J; Morrissey, Anne B; Mmbaga, Blandina T; Lwezaula, Bingileki F; Kilonzo, Kajiru G; Maro, Venance P; Crump, John A

    Background

    Characterization of the epidemiology of Escherichia coli bloodstream infection (BSI) in sub-Saharan Africa is lacking. We studied patients with E. coli BSI in northern Tanzania to describe host risk factors for infection and to describe the antimicrobial susceptibility of isolates.

    Methods

    Within 24 h of admission, patients presenting with a fever at two hospitals in Moshi, Tanzania, were screened and enrolled. Cases were patients with at least one blood culture yielding E. coli and controls were those without E. coli isolated from any blood culture. Logistic regression was used to identify host risk factors for E. coli BSI.

    Results

    We analyzed data from 33 cases and 1615 controls enrolled from 2007 through 2018. The median (IQR) age of cases was 47 (34-57) y and 24 (72.7%) were female. E. coli BSI was associated with (adjusted OR [aOR], 95% CI) increasing years of age (1.03, 1.01 to 1.05), female gender (2.20, 1.01 to 4.80), abdominal tenderness (2.24, 1.06 to 4.72) and urinary tract infection as a discharge diagnosis (3.71, 1.61 to 8.52). Of 31 isolates with antimicrobial susceptibility results, the prevalence of resistance was ampicillin 29 (93.6%), ceftriaxone three (9.7%), ciprofloxacin five (16.1%), gentamicin seven (22.6%) and trimethoprim-sulfamethoxazole 31 (100.0%).

    Conclusions

    In Tanzania, host risk factors for E. coli BSI were similar to those reported in high-resource settings and resistance to key antimicrobials was common.
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    A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study.
    (BMC Infect Dis, 2014-05-23) Stryjewski, Martin E; Lentnek, Arnold; O'Riordan, William; Pullman, John; Tambyah, Paul Anantharajah; Miró, Jose M; Fowler, Vance G; Barriere, Steven L; Kitt, Michael M; Corey, G Ralph
    BACKGROUND: Staphylococcus aureus bacteremia is a common infection associated with significant morbidity and mortality. Telavancin is a bactericidal lipoglycopeptide active against Gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). We conducted a randomized, double-blind, Phase 2 trial in patients with uncomplicated S. aureus bacteremia. METHODS: Patients were randomized to either telavancin or standard therapy (vancomycin or anti-staphylococcal penicillin) for 14 days. Continuation criteria were set to avoid complicated S. aureus bacteremia. The primary end point was clinical cure at 84 days. RESULTS: In total, 60 patients were randomized and 58 received ≥1 study medication dose (all-treated), 31 patients fulfilled inclusion/exclusion and continuation criteria (all-treated target [ATT]) (telavancin 15, standard therapy 16), and 17 patients were clinically evaluable (CE) (telavancin 8, standard therapy 9). Mean age (ATT) was 60 years. Intravenous catheters were the most common source of S. aureus bacteremia and ~50% of patients had MRSA. A similar proportion of CE patients were cured in the telavancin (88%) and standard therapy (89%) groups. All patients with MRSA bacteremia were cured and one patient with MSSA bacteremia failed study treatment in each group. Although adverse events (AEs) were more common in the telavancin ATT group (90% vs. 72%), AEs leading to drug discontinuation were similar (7%) in both treatment arms. Potentially clinically significant increases in serum creatinine (≥1.5 mg/dl and at least 50% greater than baseline) were more common in the telavancin group (20% vs. 7%). CONCLUSIONS: This study suggests that telavancin may have utility for treatment of uncomplicated S. aureus bacteremia; additional studies are warranted. (Telavancin for Treatment of Uncomplicated Staphylococcus Aureus Bacteremia (ASSURE); NCT00062647).
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    Antiplatelet Therapy in Staphylococcus aureus Bacteremia: No Time Like the Past?
    (Antimicrobial agents and chemotherapy, 2022-06) Mourad, Ahmad; Holland, Thomas L; Turner, Nicholas A
    In this invited commentary, we reflect on the accompanying study by A. R. Caffrey, H. J. Appaneal, K. L. LaPlante, V. V. Lopes, et al. (Antimicrob Agents Chemother 66:e02117-21, 2022, https://doi.org/10.1128/aac.02117-21), which analyzed the impact of clopidogrel use on clinical outcomes in Staphylococcus aureus bacteremia.
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    Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-06) Eichenberger, Emily M; Ruffin, Felicia; Dagher, Michael; Lerebours, Reginald; Jung, Sin-Ho; Sharma-Kuinkel, Batu; Macintyre, Andrew N; Thaden, Joshua T; Sinclair, Matthew; Hale, Lauren; Kohler, Celia; Palmer, Scott M; Alexander, Barbara D; Fowler, Vance G; Maskarinec, Stacey A
    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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    Bacteremic disseminated tuberculosis in sub-saharan Africa: a prospective cohort study.
    (Clin Infect Dis, 2012-07) Crump, John A; Ramadhani, Habib O; Morrissey, Anne B; Saganda, Wilbrod; Mwako, Mtumwa S; Yang, Lan-Yan; Chow, Shein-Chung; Njau, Boniface N; Mushi, Godfrey S; Maro, Venance P; Reller, L Barth; Bartlett, John A
    BACKGROUND: Disseminated tuberculosis is a major health problem in countries where generalized human immunodeficiency virus (HIV) infection epidemics coincide with high tuberculosis incidence rates; data are limited on patient outcomes beyond the inpatient period. METHODS: We enrolled consecutive eligible febrile inpatients in Moshi, Tanzania, from 10 March 2006 through 28 August 2010; those with Mycobacterium tuberculosis bacteremia were followed up monthly for 12 months. Survival, predictors of bacteremic disseminated tuberculosis, and predictors of death were assessed. Antiretroviral therapy (ART) and tuberculosis treatment were provided. RESULTS: A total of 508 participants were enrolled; 29 (5.7%) had M. tuberculosis isolated by blood culture. The median age of all study participants was 37.4 years (range, 13.6-104.8 years). Cough lasting >1 month (odds ratio [OR], 13.5; P< .001), fever lasting >1 month (OR, 7.8; P = .001), weight loss of >10% (OR, 10.0; P = .001), lymphadenopathy (OR 6.8; P = .002), HIV infection (OR, undefined; P < .001), and lower CD4 cell count and total lymphocyte count were associated with bacteremic disseminated tuberculosis. Fifty percent of participants with M. tuberculosis bacteremia died within 36 days of enrollment. Lower CD4 cell count (OR, 0.88; P = .049) and lower total lymphocyte count (OR, 0.76; P = .050) were associated with death. Magnitude of mycobacteremia tended to be higher among those with lower CD4 cell counts, but did not predict death. CONCLUSIONS: In the era of free ART and access to tuberculosis treatment, almost one half of patients with M. tuberculosis bacteremia may die within a month of hospitalization. Simple clinical assessments can help to identify those with the condition. Advanced immunosuppression predicts death. Efforts should focus on early diagnosis and treatment of HIV infection, tuberculosis, and disseminated disease.
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    Bloodstream Infections and Frequency of Pretreatment Associated With Age and Hospitalization Status in Sub-Saharan Africa.
    (Clin Infect Dis, 2015-11-01) Nichols, Chelsea; Cruz Espinoza, Ligia Maria; von Kalckreuth, Vera; Aaby, Peter; Ahmed El Tayeb, Muna; Ali, Mohammad; Aseffa, Abraham; Bjerregaard-Andersen, Morten; Breiman, Robert F; Cosmas, Leonard; Crump, John A; Dekker, Denise Myriam; Gassama Sow, Amy; Gasmelseed, Nagla; Hertz, Julian T; Im, Justin; Kabore, Leon Parfait; Keddy, Karen H; Konings, Frank; Valborg Løfberg, Sandra; Meyer, Christian G; Montgomery, Joel M; Niang, Aissatou; Njariharinjakamampionona, Andriamampionona; Olack, Beatrice; Pak, Gi Deok; Panzner, Ursula; Park, Jin Kyung; Park, Se Eun; Rabezanahary, Henintsoa; Rakotondrainiarivelo, Jean Philibert; Rakotozandrindrainy, Raphaël; Raminosoa, Tiana Mirana; Rubach, Matthew P; Teferi, Mekonnen; Seo, Hye Jin; Sooka, Arvinda; Soura, Abdramane; Tall, Adama; Toy, Trevor; Yeshitela, Biruk; Clemens, John D; Wierzba, Thomas F; Baker, Stephen; Marks, Florian
    BACKGROUND: The clinical diagnosis of bacterial bloodstream infections (BSIs) in sub-Saharan Africa is routinely confused with malaria due to overlapping symptoms. The Typhoid Surveillance in Africa Program (TSAP) recruited febrile inpatients and outpatients of all ages using identical study procedures and enrollment criteria, thus providing an opportunity to assess disease etiology and pretreatment patterns among children and adults. METHODS: Inpatients and outpatients of all ages with tympanic or axillary temperatures of ≥38.0 or ≥37.5°C, respectively, and inpatients only reporting fever within the previous 72 hours were eligible for recruitment. All recruited patients had one blood sample drawn and cultured for microorganisms. Data from 11 TSAP surveillance sites in nine different countries were used in the analysis. Bivariate analysis was used to compare frequencies of pretreatment and BSIs in febrile children (<15 years old) and adults (≥15 years old) in each country. Pooled Cochran Mantel-Haenszel odds ratios (ORs) were calculated for overall trends. RESULTS: There was no significant difference in the odds of a culture-proven BSI between children and adults among inpatients or outpatients. Among both inpatients and outpatients, children had significantly higher odds of having a contaminated blood culture compared with adults. Using country-pooled data, child outpatients had 66% higher odds of having Salmonella Typhi in their bloodstream than adults (OR, 1.66; 95% confidence interval [CI], 1.01-2.73). Overall, inpatient children had 59% higher odds of pretreatment with analgesics in comparison to inpatient adults (OR, 1.59; 95% CI, 1.28-1.97). CONCLUSIONS: The proportion of patients with culture-proven BSIs in children compared with adults was similar across the TSAP study population; however, outpatient children were more likely to have Salmonella Typhi infections than outpatient adults. This finding points to the importance of including outpatient facilities in surveillance efforts, particularly for the surveillance of typhoid fever. Strategies to reduce contamination among pediatric blood cultures are needed across the continent to prevent the misdiagnosis of BSI cases in children.
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    Bloodstream infections in community hospitals in the 21st century: a multicenter cohort study.
    (PLoS One, 2014) Anderson, Deverick J; Moehring, Rebekah W; Sloane, Richard; Schmader, Kenneth E; Weber, David J; Fowler, Vance G; Smathers, Emily; Sexton, Daniel J
    BACKGROUND: While the majority of healthcare in the US is provided in community hospitals, the epidemiology and treatment of bloodstream infections in this setting is unknown. METHODS AND FINDINGS: We undertook this multicenter, retrospective cohort study to 1) describe the epidemiology of bloodstream infections (BSI) in a network of community hospitals and 2) determine risk factors for inappropriate therapy for bloodstream infections in community hospitals. 1,470 patients were identified as having a BSI in 9 community hospitals in the southeastern US from 2003 through 2006. The majority of BSIs were community-onset, healthcare associated (n = 823, 56%); 432 (29%) patients had community-acquired BSI, and 215 (15%) had hospital-onset, healthcare-associated BSI. BSIs due to multidrug-resistant pathogens occurred in 340 patients (23%). Overall, the three most common pathogens were S. aureus (n = 428, 28%), E. coli (n = 359, 24%), coagulase-negative Staphylococci (n = 148, 10%), though type of infecting organism varied by location of acquisition (e.g., community-acquired). Inappropriate empiric antimicrobial therapy was given to 542 (38%) patients. Proportions of inappropriate therapy varied by hospital (median = 33%, range 21-71%). Multivariate logistic regression identified the following factors independently associated with failure to receive appropriate empiric antimicrobial therapy: hospital where the patient received care (p<0.001), assistance with ≥3 ADLs (p = 0.005), Charlson score (p = 0.05), community-onset, healthcare-associated infection (p = 0.01), and hospital-onset, healthcare-associated infection (p = 0.02). Important interaction was observed between Charlson score and location of acquisition. CONCLUSIONS: Our large, multicenter study provides the most complete picture of BSIs in community hospitals in the US to date. The epidemiology of BSIs in community hospitals has changed: community-onset, healthcare-associated BSI is most common, S. aureus is the most common cause, and 1 of 3 patients with a BSI receives inappropriate empiric antimicrobial therapy. Our data suggest that appropriateness of empiric antimicrobial therapy is an important and needed performance metric for physicians and hospital stewardship programs in community hospitals.
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    Current definitions of central line-associated bloodstream infection: is the emperor wearing clothes?
    (Infect Control Hosp Epidemiol, 2010-12) Sexton, Daniel J; Chen, Luke F; Anderson, Deverick J
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    Cytokine profiles of preterm neonates with fungal and bacterial sepsis.
    (Pediatr Res, 2012-08) Sood, Beena G; Shankaran, Seetha; Schelonka, Robert L; Saha, Shampa; Benjamin, Danny K; Sánchez, Pablo J; Adams-Chapman, Ira; Stoll, Barbara J; Thorsen, Poul; Skogstrand, Kristin; Ehrenkranz, Richard A; Hougaard, David M; Goldberg, Ronald N; Tyson, Jon E; Das, Abhik; Higgins, Rosemary D; Carlo, Waldemar A; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
    BACKGROUND: Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS). METHODS: In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored. RESULTS: Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) (P < 0.05). CONCLUSION: Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.
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    Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial.
    (Trials, 2022-05) Turner, Nicholas A; Zaharoff, Smitha; King, Heather; Evans, Scott; Hamasaki, Toshimitsu; Lodise, Thomas; Ghazaryan, Varduhi; Beresnev, Tatiana; Riccobene, Todd; Patel, Rinal; Doernberg, Sarah B; Rappo, Urania; Fowler, Vance G; Holland, Thomas L; Antibacterial Resistance Leadership Group (ARLG)

    Background

    Staphylococcus aureus bacteremia is a life-threatening infection and leading cause of infective endocarditis, with mortality rates of 15-50%. Treatment typically requires prolonged administration of parenteral therapy, itself associated with high costs and potential catheter-associated complications. Dalbavancin is a lipoglycopeptide with potent activity against Staphylococcus and a long half-life, making it an appealing potential therapy for S. aureus bacteremia without the need for durable central venous access.

    Methods

    DOTS is a phase 2b, multicenter, randomized, assessor-blinded, superiority, active-controlled, parallel-group trial. The trial will enroll 200 adults diagnosed with complicated S. aureus bacteremia, including definite or possible right-sided infective endocarditis, who have been treated with effective antibiotic therapy for at least 72 h (maximum 10 days) and with subsequent clearance of bacteremia prior to randomization to study treatment. Subjects will be randomized 1:1 to complete their antibiotic treatment course with either two doses of dalbavancin on days 1 and 8, or with a total of 4-8 weeks of standard intravenous antibiotic therapy. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for patients randomized to dalbavancin versus standard of care. Key secondary endpoints include quality of life outcomes and pharmacokinetic analyses of dalbavancin.

    Discussion

    The DOTS trial will establish whether dalbavancin is superior to standard parenteral antibiotic therapy for the completion of treatment of complicated S. aureus bacteremia.

    Trial registration

    US National Institutes of Health ClinicalTrials.gov NCT04775953 . Registered on 1 March 2021.
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    De-escalation therapy among bacteraemic patients with community-acquired pneumonia.
    (Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2015-10) Carugati, M; Franzetti, F; Wiemken, T; Kelley, RR; Peyrani, P; Blasi, F; Ramirez, J; Aliberti, S
    There is no evidence supporting the use of de-escalation therapy (DET) among patients with community-acquired pneumonia (CAP). We assessed the outcomes associated with DET among bacteraemic CAP patients. We performed a secondary analysis of the Community-Acquired Pneumonia Organization database, which contains data on 660 bacteraemic patients hospitalized because of CAP in 35 countries (2001-2013). Exclusion criteria were death within 72 h from admission and an inappropriate empirical antibiotic regimen. DET was defined as changing an appropriate empirical broad-spectrum regimen to a narrower-spectrum regimen according to culture results within 7 days from hospital admission. Two study groups were identified: patients whose antibiotic therapy was de-escalated (the DET group), and patients whose antibiotic therapy was not de-escalated (the N-DET group). The primary study outcome was 30-day mortality. Two hundred and sixty-one bacteraemic CAP patients were included. Gram-positive bacteria were responsible for 88.1% of the cases (Streptococcus pneumoniae, 75.9%). Gram-negative bacteria were responsible for for 7.3% of the cases. DET was performed in 165 patients (63.2%). The N-DET group was characterized by a more severe presentation at admission. After adjustment for confounders, DET was not associated with an increased risk of 30-day mortality. DET seems to be safe among bacteraemic patients with CAP. Randomized clinical trials are warranted to further explore these findings.
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    Delays in appropriate antibiotic therapy for gram-negative bloodstream infections: a multicenter, community hospital study.
    (PLoS One, 2013) Moehring, Rebekah W; Sloane, Richard; Chen, Luke F; Smathers, Emily C; Schmader, Kenneth E; Fowler, Vance G; Weber, David J; Sexton, Daniel J; Anderson, Deverick J
    BACKGROUND: Gram-negative bacterial bloodstream infection (BSI) is a serious condition with estimated 30% mortality. Clinical outcomes for patients with severe infections improve when antibiotics are appropriately chosen and given early. The objective of this study was to estimate the association of prior healthcare exposure on time to appropriate antibiotic therapy in patients with gram-negative BSI. METHOD: We performed a multicenter cohort study of adult, hospitalized patients with gram-negative BSI using time to event analysis in nine community hospitals from 2003-2006. Event time was defined as the first administration of an antibiotic with in vitro activity against the infecting organism. Healthcare exposure status was categorized as community-acquired, healthcare-associated, or hospital-acquired. Time to appropriate therapy among groups of patients with differing healthcare exposure status was assessed using Kaplan-Meier analyses and multivariate Cox proportional hazards models. RESULTS: The cohort included 578 patients with gram-negative BSI, including 320 (55%) healthcare-associated, 217 (38%) community-acquired, and 41 (7%) hospital-acquired infections. 529 (92%) patients received an appropriate antibiotic during their hospitalization. Time to appropriate therapy was significantly different among the groups of healthcare exposure status (log-rank p=0.02). Time to first antibiotic administration regardless of drug appropriateness was not different between groups (p=0.3). The unadjusted hazard ratios (HR) (95% confidence interval) were 0.80 (0.65-0.98) for healthcare-associated and 0.72 (0.63-0.82) for hospital-acquired, relative to patients with community-acquired BSI. In multivariable analysis, interaction was found between the main effect and baseline Charlson comorbidity index. When Charlson index was 3, adjusted HRs were 0.66 (0.48-0.92) for healthcare-associated and 0.57 (0.44-0.75) for hospital-acquired, relative to patients with community-acquired infections. CONCLUSIONS: Patients with healthcare-associated or hospital-acquired BSI experienced delays in receipt of appropriate antibiotics for gram-negative BSI compared to patients with community-acquired BSI. This difference was not due to delayed initiation of antibiotic therapy, but due to the inappropriate choice of antibiotic.
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    Detection of Bartonella species in the blood of veterinarians and veterinary technicians: a newly recognized occupational hazard?
    (Vector Borne Zoonotic Dis, 2014-08) Lantos, Paul M; Maggi, Ricardo G; Ferguson, Brandy; Varkey, Jay; Park, Lawrence P; Breitschwerdt, Edward B; Woods, Christopher W
    BACKGROUND: Bartonella species are important emerging pathogens in human and veterinary medicine. In the context of their daily activities, veterinary professionals have frequent animal contact and arthropod exposures. Detection of Bartonella spp. using traditional culture methods has been limited by poor sensitivity, making it difficult to determine the prevalence of infection in this population. We have developed a detection method combining enrichment culture and molecular amplification, which increases testing sensitivity. METHODS: We performed a cross-sectional study to determine the prevalence of detectable Bartonella spp. in the blood of veterinary personnel and nonveterinary control subjects. Bartonella was detected by enrichment blood culture with conventional PCR followed by DNA sequencing. RESULTS were correlated with epidemiological variables and symptoms. RESULTS: We detected DNA from at least one Bartonella species in 32 (28%) of the 114 veterinary subjects. After DNA sequencing, the Bartonella species could be determined for 27 of the 32 infected subjects, including B. henselae in 15 (56%), B. vinsonii subsp. berkhoffii in seven (26%), B. koehlerae in six (22%), and a B. volans-like sequence in one (4%). Seventy percent of Bartonella-positive subjects described headache compared with 40% of uninfected veterinarians (p=0.009). Irritability was also reported more commonly by infected subjects (68% vs. 43%, p=0.04). CONCLUSIONS: Our study supports an emerging body of evidence that cryptic Bartonella bloodstream infection may be more frequent in humans than previously recognized and may induce symptoms. Longitudinal studies are needed to determine the natural course and clinical features of Bartonella infection.
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    Determination of plasma protein binding of dalbavancin.
    (The Journal of antimicrobial chemotherapy, 2022-06) Turner, Nicholas A; Xu, Allan; Zaharoff, Smitha; Holland, Thomas L; Lodise, Thomas P

    Objectives

    Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations.

    Methods

    The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding.

    Results

    Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%.

    Conclusions

    Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.
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    Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis.
    (PLoS Pathog, 2014-06) Yan, Qin; Sharma-Kuinkel, Batu K; Deshmukh, Hitesh; Tsalik, Ephraim L; Cyr, Derek D; Lucas, Joseph; Woods, Christopher W; Scott, William K; Sempowski, Gregory D; Thaden, Joshua T; Rude, Thomas H; Ahn, Sun Hee; Fowler, Vance G
    Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
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    Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.
    (JAMA, 2018-09) Holland, Thomas L; Raad, Issam; Boucher, Helen W; Anderson, Deverick J; Cosgrove, Sara E; Aycock, P Suzanne; Baddley, John W; Chaftari, Anne-Marie; Chow, Shein-Chung; Chu, Vivian H; Carugati, Manuela; Cook, Paul; Corey, G Ralph; Crowley, Anna Lisa; Daly, Jennifer; Gu, Jiezhun; Hachem, Ray; Horton, James; Jenkins, Timothy C; Levine, Donald; Miro, Jose M; Pericas, Juan M; Riska, Paul; Rubin, Zachary; Rupp, Mark E; Schrank, John; Sims, Matthew; Wray, Dannah; Zervos, Marcus; Fowler, Vance G; Staphylococcal Bacteremia Investigators

    Importance

    The appropriate duration of antibiotics for staphylococcal bacteremia is unknown.

    Objective

    To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events.

    Design, setting, and participants

    A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization.

    Interventions

    Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care.

    Main outcomes and measures

    Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia.

    Results

    Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]).

    Conclusions and relevance

    Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.

    Trial registration

    ClinicalTrials.gov Identifier: NCT01191840.
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    Genetic variability in beta-defensins is not associated with susceptibility to Staphylococcus aureus bacteremia.
    (PLoS One, 2012) Fode, Peder; Larsen, Anders Rhod; Feenstra, Bjarke; Jespersgaard, Cathrine; Skov, Robert Leo; Stegger, Marc; Fowler, Vance G; Danish SAB Study Group Consortium; Andersen, Paal Skytt
    INTRODUCTION: Human beta-defensins are key components of human innate immunity to a variety of pathogens, including Staphylococcus aureus. The aim of the present study was to investigate a potential association between gene variations in DEFB1 and DEFB103/DEFB4 and the development of S. aureus bacteremia (SAB) employing a case-control design. METHODS: Cases were unique patients with documented SAB, identified with the National S. aureus Bacteremia Register, a comprehensive dataset of all episodes of community associated-SABs (CA-SAB) occurring in children (≤20 yrs) in Denmark from 1990 to 2006. Controls were age-matched healthy individuals with no history of SAB. DNA obtained from cases and controls using the Danish Newborn Screening Biobank were genotyped for functional polymorphisms of DEFB1 by Sanger sequencing and copy number variation of the DEFB103 and DEFB4 genes using Pyrosequencing-based Paralogue Ratio Test (P-PRT). RESULTS: 193 ethnic Danish SAB cases with 382 age-matched controls were used for this study. S. aureus isolates represented a variety of bacterial (i.e., different spa types) types similar to SAB isolates in general. DEFB1 minor allele frequencies of rs11362 (cases vs. controls 0.47/0.44), rs1800972 (0.21/0.24), and rs1799946 (0.32/0.33) were not significantly different in cases compared with controls. Also, DEFB4/DEFB103 gene copy numbers (means 4.83/4.92) were not significantly different in cases compared with controls. CONCLUSIONS: Using a large, unique cohort of pediatric CA-SAB, we found no significant association between DEFB1 genetic variation or DEFB4/DEFB103 gene copy number and susceptibility for SAB.
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    Invasive Salmonella infections in areas of high and low malaria transmission intensity in Tanzania.
    (Clin Infect Dis, 2014-03) Biggs, Holly M; Lester, Rebecca; Nadjm, Behzad; Mtove, George; Todd, Jim E; Kinabo, Grace D; Philemon, Rune; Amos, Ben; Morrissey, Anne B; Reyburn, Hugh; Crump, John A
    BACKGROUND:  The epidemiology of Salmonella Typhi and invasive nontyphoidal Salmonella (NTS) differs, and prevalence of these pathogens among children in sub-Saharan Africa may vary in relation to malaria transmission intensity. METHODS:  We compared the prevalence of bacteremia among febrile pediatric inpatients aged 2 months to 13 years recruited at sites of high and low malaria endemicity in Tanzania. Enrollment at Teule Hospital, the high malaria transmission site, was from June 2006 through May 2007, and at Kilimanjaro Christian Medical Centre (KCMC), the low malaria transmission site, from September 2007 through August 2008. Automated blood culture, malaria microscopy with Giemsa-stained blood films, and human immunodeficiency virus testing were performed. RESULTS:  At Teule, 3639 children were enrolled compared to 467 at KCMC. Smear-positive malaria was detected in 2195 of 3639 (60.3%) children at Teule and 11 of 460 (2.4%) at KCMC (P < .001). Bacteremia was present in 336 of 3639 (9.2%) children at Teule and 20 of 463 (4.3%) at KCMC (P < .001). NTS was isolated in 162 of 3639 (4.5%) children at Teule and 1 of 463 (0.2%) at KCMC (P < .001). Salmonella Typhi was isolated from 11 (0.3%) children at Teule and 6 (1.3%) at KCMC (P = .008). With NTS excluded, the prevalence of bacteremia at Teule was 5.0% and at KCMC 4.1% (P = .391). CONCLUSIONS:  Where malaria transmission was intense, invasive NTS was common and Salmonella Typhi was uncommon, whereas the inverse was observed at a low malaria transmission site. The relationship between these pathogens, the environment, and the host is a compelling area for further research.
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    Long-term Risk of Serious Infections and Mortality Among Patients Surviving Drug Use-Associated Infective Endocarditis.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2024-07) Figgatt, Mary C; Rosen, David L; Chu, Vivian H; Wu, Li-Tzy; Schranz, Asher J
    Among a statewide cohort of 1874 patients surviving hospitalization for drug use-associated endocarditis during 2017-2020, the 3-year risk of death or future hospitalization was 38% (16% for death before later infection, 14% for recurrent endocarditis, 14% for soft tissue, 9% for bacteremia, 5% for bone/joint, and 4% for spinal infections).