Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

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

Steady-State Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Infected Patients with End-Stage Renal Disease Receiving Chronic Dialysis

The steady-state pharmacokinetics of lamivudine were evaluated in 11 subjects with human immunodeficiency virus infection and end-stage renal disease, 9 of whom were receiving hemodialysis and 2 of whom were receiving chronic ambulatory peritoneal dialysis (CAPD). All subjects received 150 mg of lamivudine daily for at least 2 weeks prior to sampling for determination of the pharmacokinetics of lamivudine over a 24-h period on 2 consecutive days. On the first day, subjects received 150 mg of oral lamivudine and underwent dialysis (hemodialysis or CAPD). On the second day, subjects received another 150 mg of oral lamivudine but dialysis was not performed. For the subjects undergoing hemodialysis, the geometric mean predose serum lamivudine concentration was 1.14 μg/ml (95% confidence interval [CI], 0.83 to 1.58 μg/ml), the geometric mean maximum concentration in serum (C(max)) was 3.77 μg/ml (95% CI, 3.01 to 4.71 μg/ml), and the geometric mean area under the serum concentration-time curve from time zero to 24 h (AUC(0-24)) was 49.8 μg · h/ml (95% CI 39.1 to 63.6 μg · h/ml). Hemodialysis removed approximately 28 mg of lamivudine but had no significant effect on C(max) or AUC(0-24). In the absence of hemodialysis, the geometric mean lamivudine terminal elimination half-life was 17.2 h (95% CI, 10.5 to 28.1 h), whereas the geometric mean intradialysis half-life of lamivudine was 5.3 h (95% CI, 3.4 to 8.2 h). The pharmacokinetics of lamivudine in subjects undergoing CAPD were similar to those in subjects undergoing hemodialysis. CAPD removed 24 mg of lamivudine over a 24-h period but had no effect on C(max) or AUC(0-24). Pharmacokinetic modeling suggests that a lamivudine dose of 25 mg daily in hemodialysis subjects would provide serum exposure similar to that provided by a dose of 150 mg twice daily in patients with normal renal function

Can preemptive cytomegalovirus monitoring be as effective as universal prophylaxis when implemented as the standard of care in patients at moderate risk?

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity, mortality, and cost in solid organ transplant recipients. This study was conducted to measure both the clinical efficacy and the pharmacoeconomic impact of implementing, as standard of care, an abbreviated preemptive monitoring strategy compared with universal prophylaxis in a large teaching hospital. METHODS: This prospective observational study included only recipients at moderate risk for CMV infection, specifically recipients who were CMV seropositive before transplant. Recipients transplanted between February 2006 and December 2006 received prophylactic valganciclovir for 90 days after transplant, and those transplanted between January 2007 and December 2007 were enrolled in a preemptive monitoring strategy that included no anti-CMV prophylaxis but instead used serial CMV polymerase chain reactions in weeks 4, 6, 8, 10, 12, 16, 20, and 24 to monitor the development of CMV DNAemia. Costs were analyzed from a societal perspective. RESULTS: A total of 130 patients were included in this study. Baseline and transplant demographics are well matched between groups. CMV syndrome occurred in three patients in each group, and one patient in the preemptive group developed CMV disease. Thirty-seven percent of patients in the preemptive group developed CMV DNAemia, 68% of these patients received antiviral therapy. Personnel and laboratory monitoring costs were significantly higher in the preemptive group, whereas medication cost was significantly higher in the prophylaxis group. CONCLUSIONS: Although outcomes and the overall cost of (1) universal prophylaxis and (2) preemptive monitoring are similar, universal prophylaxis places the cost burden on the patient whereas preemptive monitoring shifts the cost burden to the healthcare system

Phylogenetic analysis of viridans group streptococci causing endocarditis.

International audienceIdentification of viridans group streptococci (VGS) to the species level is difficult because VGS exchange genetic material. We performed multilocus DNA target sequencing to assess phylogenetic concordance of VGS for a well-defined clinical syndrome. The hierarchy of sequence data was often discordant, underscoring the importance of establishing biological relevance for finer phylogenetic distinctions

Clinical characteristics and outcome of infective endocarditis due to Abiotrophia and Granulicatella compared to Viridans group streptococci

Objective : To describe the clinical characteristics and outcome of Abiotrophia and Granulicatella infective endocarditis and compare them with Viridans group streptococci infective endocarditis. Methods : All patients in the International Collaboration on Endocarditis (ICE) - prospective cohort study (PCS) and the ICE-PLUS cohort were included (n=8112). Data from patients with definitive or possible IE due to Abiotrophia species, Granulicatella species and Viridans group streptococci was analyzed. A propensity score (PS) analysis comparing the ABI/GRA-IE and VGS-IE groups according to a 1:2 ratio was performed. Results : Forty-eight (0.64%) cases of ABI/GRA-IE and 1,292 (17.2%) VGS-IE were included in the analysis. The median age of patients with ABI/GRA-IE was lower than VGS-IE (48.1 years vs. 57.9 years; p=0.001). Clinical features and the rate of in-hospital surgery was similar between ABI/GRA-IE and VGS-IE (52.1% vs. 45.4%; p=0.366). Unadjusted in-hospital death was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 8.8%; p=0.003), and cumulative six-month mortality was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 11.9%; p<0.001). After PS analysis, in-hospital mortality was similar in both groups, but six-month mortality was lower in the ABI/GRA IE group (2.1% vs. 10.4%; p=0.029). Conclusions : Patients with ABI/GRA-IE were younger, had similar clinical features and rates of surgery and better prognosis than VGS-IE

Effect of algorithm-based therapy vs usual care on clinical success and serious adverse events in patients with Staphylococcal bacteremia: a randomized clinical trial

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

Genotypic diversity of coagulase-negative staphylococci causing endocarditis: a global perspective

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Comparison between the features of native valve HACEK endocarditis and prosthetic valve HACEK endocarditis^*.

*<p>Values are reported as <i>n/n (%)</i>, unless otherwise noted.</p>†<p>1 year mortality data was available on 33 (70%) subjects with native valve HE and 22(81%) subjects with prosthetic valve HE.</p

HACEK organisms isolated from definite and probable cases of HACEK endocarditis.

a<p>not specified.</p

Important features of HACEK endocarditis compared with all other causes of infective endocarditis in database^*.

*<p>Values are reported as <i>n/n (%)</i>, unless otherwise noted.</p>†<p>Aortic valve- homograft 1, unknown repair 1; mitral valve – repair with prosthesis 1, other 2. TEE = Transesophageal ECHO.</p>‡<p>Specimens that were culture-positive were heart valve (20), joint fluid (2), pacemaker wire (1), urine (1) and other (5) §Myocardial wall 2, chordae 1, intracardiac device 1.</p>**<p>1 year mortality data was available on 57(74%) of HE and 4208(76%) of non-HE subjects.</p